Clinical trial NCT00408005
Conditions: T Acute Lymphoblastic Leukemia T Lymphoblastic Lymphoma
Sponsor: National Cancer Institute (NCI)
Start date: 2007-01-30; Completion date: 2025-03-31
Enrollment: 1895 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase III trial is studying different combination chemotherapy regimens and their side effects and comparing how well they work in treating young patients with newly diagnosed T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. It is not yet known which combination chemotherapy regimen is more effective in treating T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma. After a common induction therapy, patients were risk assigned and eligible for one or both post-induction randomizations: Escalating dose Methotrexate versus High Dose Methotrexate in Interim Maintenance therapy, No Nelarabine versus Nelarabine in Consolidation therapy. T-ALL patients are risk assigned as Low Risk, Intermediate Risk or High Risk. Low Risk patients are not eligible for the Nelarabine randomization, Patients with CNS disease at diagnosis were assgined to receive High Dose Methotrexate, patients who failed induction therapy were assigned to receive Nelarabine and High Dose Methotrexate. T-LLy patients were all assigned to escalating dose Methotrexate and were risk assigned as Standard Risk, High Risk and induction failures. Standard risk patients did not receive nelarabine, High risk T-LLy patients were randomized to No Nelarabine versus Nelarabine, and Induction failures were assigned to receive Nelarabine.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine, through randomization, the relative safety and efficacy of the addition of nelarabine (Compound 506U78) to augmented Berlin-Frankfurt-Münster (BFM) therapy (Regimen C, Children's Cancer Group \[CCG\]-1961).

II. To determine the relative safety and efficacy of high dose methotrexate (5 g/m\^2) with leucovorin (leucovorin calcium) rescue compared to escalating methotrexate without leucovorin rescue plus pegaspargase (Capizzi I) delivered during interim maintenance.

III. To gain preliminary data on the use of nelarabine in patients with high risk T-cell lymphoblastic lymphoma and its effect on long-term survival.

SECONDARY OBJECTIVES:

I. To determine the relative safety and efficacy of withholding radiation in patients with low risk T-cell acute lymphoblastic leukemia (T-ALL), while treating Intermediate and high risk patients with 1200 cGy of prophylactic cranial radiation.

OUTLINE: This is a randomized, controlled, factorial-group, multicenter study.

GROUP 0 (INDUCTION THERAPY): All patients (T-ALL and T-LLy) receive cytarabine intrathecally (IT) on day 1; vincristine sulfate intravenously (IV) on days 1, 8, 15, and 22; prednisone IV or orally (PO) twice daily (BID) on days 1-28; pegaspargase intramuscularly (IM) (may give IV over 1 to 2 hours) on day 4, 5, or 6; duanorubicin IV on days 1, 8, 15 and 22; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease).

GROUP I ARM I COMBINATION CHEMOTHERAPY (CONSOLIDATION CHEMOTHERAPY): Patients receive methotrexate IT on days 1, 8, 15, and 22; cyclophosphamide IV over 30 minutes on days 1 and 29; cytarabine IV over 15-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO on days 1-14 and 29-42; vincristine sulfate IV on days 15, 22, 43 and 50; and pegaspargase IM or IV over 1-2 hours on days 15 and 43. Patients with DS also receive leucovorin calcium PO at 48 and 60 hours after each methotrexate dose. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy on days 11-12, 15-19, and 22-26. (DS patients excluded as of 09/29/10.) Patients with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo prophylactic CRT (1,200 cGy/dose) QD on days 15-21 and 22-28. Patients with low-risk disease do not undergo conformal radiation therapy (CRT). Patients with standard risk T-LLy received Arm I, and those with high risk T-LLy were randomized between Arm I and Arm II combination chemotherapy.

GROUP I ARM I COMBINATION CHEMOTHERAPY (DELAYED INTENSIFICATION CHEMOTHERAPY): Patients receive vincristine sulfate IV on days 1, 8, 15, 43, and 50; dexamethasone IV or PO BID on days 1-21 (for patients \< 10 years of age) OR on days 1-7 and 15-21 (for patients \>= 10 years of age and for patients with DS); doxorubicin hydrochloride IV on days 1, 8, and 15; pegaspargase IM or IV over 1-2 hours on day 4, 5, OR 6, AND day 43; methotrexate IT on days 1, 29, and 36; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV over 15-30 minutes or SC on days 29-32 and 36-39; and thioguanine PO on days 29-42. Patients with DS also receive leucovorin calcium PO at 48 and 60 hours after each methotrexate dose (DS patients excluded as of 09/29/10). Standard risk T-LLy patients were assigned to Arm I and those with high risk were randomized between Arm I and Arm II.

GROUP I ARM I COMBINATION CHEMOTHERAPY (INTERIM MAINTENANCE CHEMOTHERAPY): Patients receive vincristine sulfate IV and escalating doses of methotrexate IV on days 1, 11, 21, 31, and 41; pegaspargase\* IM or IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31. Patients with DS also receive leucovorin calcium PO 48 and 60 hours after each methotrexate IT dose (DS patients excluded as of 09/29/10).

Note: \*Patients with an allergy to pegaspargase receive Erwinia asparaginase on days 2, 4, 6, 8, 10, 12, 22, 24, 26, 28, 30, and 32.

GROUP I ARM I COMBINATION CHEMOTHERAPY (MAINTENANCE CHEMOTHERAPY): Patients receive vincristine sulfate IV on days 1, 29, and 57; prednisone PO BID on days 1-5, 29-33, and 57-61; mercaptopurine PO QD on days 1-84; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; and methotrexate IT on day 1. Treatment repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 119) (for girls with T-ALL), all patients with T-LLy, and 3 years from the start of interim maintenance therapy (approximately week 171) (for boys with T-ALL).

GROUP I ARM II COMBINATION CHEMOTHERAPY (CONSOLIDATION CHEMOTHERAPY): Patients receive nelarabine IV over 60 minutes on days 1-5 and 43-47; methotrexate IT on days 15, 22, 57, and 64; cyclophosphamide IV over 30 minutes on days 8 and 50; cytarabine IV over 15-30 minutes or SC on days 8-11, 15-18, 50-53 and 57-60; mercaptopurine PO on days 8-21 and 50-63; vincristine sulfate IV on days 22, 29, 64, and 71; and pegaspargase IM or IV over 1-2 hours on days 22 and 64. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy on days 15, 22-26, and 29-33 (DS patients excluded as of 09/29/10). (Patients with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo prophylactic CRT QD on days 22-28 and 29-35. Patients with high risk T-LLy were either randomized to Arm I or Arm II. Patients with T-LLy who failed induction therapy were assigned to Arm II.

GROUP I ARM II COMBINATION CHEMOTHERAPY (DELAYED INTENSIFICATION CHEMOTHERAPY): Patients receive vincristine sulfate IV on days 1, 8, 15, and 50; dexamethasone IV or PO BID on days 1-21 (for patients \< 10 years of age) OR on days 1-7 and 15-21 (for patients \>= 10 years of age); doxorubicin hydrochloride IV on days 1, 8, and 15; pegaspargase IM or IV over 1-2 hours on day 4, 5, OR 6 AND day 50; methotrexate IT on days 1, 36, and 43; nelarabine IV over 60 minutes on days 29-33; cyclophosphamide IV over 30 minutes on day 36; cytarabine IV over 15-30 minutes or SC on days 36-39 and 43-46; and thioguanine PO on days 36-49.

GROUP I ARM II COMBINATION CHEMOTHERAPY (INTERIM MAINTENANCE CHEMOTHERAPY): Patients receive vincristine sulfate IV and escalating doses of methotrexate IV on days 1, 11, 21, 31, and 41; pegaspargase\* IM or IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31.

Note: \*Patients with an allergy to pegaspargase receive Erwinia asparaginase on Monday, Wednesday and Friday for two consecutive weeks starting the day of asparaginase substitution.

GROUP I ARM II COMBINATION CHEMOTHERAPY (MAINTENANCE CHEMOTHERAPY): Patients receive vincristine sulfate, prednisone, mercaptopurine, methotrexate PO, methotrexate IT, and nelarabine in Cycles 1, 2 and 3. Patients then receive treatment (without nelarabine) as follows: vincristine sulfate, prednisone, mercaptopurine, methotrexate PO, and methotrexate IT as in arm II. Treatment (without nelarabine) repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 121) (for girls with T-ALL), and for those with T-LLY, and 3 years from the start of interim maintenance therapy (approximately week 173) (for boys with T-ALL).

GROUP I ARM III COMBINATION CHEMOTHERAPY (CONSOLIDATION CHEMOTHERAPY): Patients receive methotrexate IT on days 1, 8, 15, and 22; cyclophosphamide IV over 30 minutes on days 1 and 29; cytarabine IV over 15-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO on days 1-14 and 29-42; vincristine sulfate IV on days 15, 22, 43 and 50; and pegaspargase IM or IV over 1-2 hours on days 15 and 43. Patients with DS also receive leucovorin calcium PO at 48 and 60 hours after each methotrexate dose. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy on days 11-12, 15-19, and 22-26. (DS patients excluded as of 09/29/10.) Patients with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo prophylactic CRT (1,200 cGy/dose) QD on days 15-21 and 22-28. Patients with low-risk disease do not undergo CRT.

GROUP I ARM III COMBINATION CHEMOTHERAPY (DELAYED INTENSIFICATION CHEMOTHERAPY): Patients receive vincristine sulfate IV on days 1, 8, 15, 43, and 50; dexamethasone IV or PO BID on days 1-21 (for patients \< 10 years of age) OR on days 1-7 and 15-21 (for patients \>= 10 years of age and for patients with DS); doxorubicin hydrochloride IV on days 1, 8, and 15; pegaspargase IM or IV over 1-2 hours on day 4, 5, OR 6, AND day 43; methotrexate IT on days 1, 29, and 36; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV over 15-30 minutes or SC on days 29-32 and 36-39; and thioguanine PO on days 29-42. Patients with DS also receive leucovorin calcium PO at 48 and 60 hours after each methotrexate dose (DS patients excluded as of 09/29/10).

GROUP I ARM III COMBINATION CHEMOTHERAPY (INTERIM MAINTENANCE CHEMOTHERAPY): Patients receive high dose methotrexate (HDMTX) IV over 24 hours and vincristine sulfate IV on days 1, 15, 29, and 43; mercaptopurine PO on days 1-56; and methotrexate IT on days 1 and 29. Beginning 42 hours after the start of HDMTX, patients also receive leucovorin calcium IV or PO once every 6 hours for 3 doses.

GROUP I ARM III COMBINATION CHEMOTHERAPY (MAINTENANCE CHEMOTHERAPY): Patients receive vincristine sulfate IV on days 1, 29, and 57; prednisone PO BID on days 1-5, 29-33, and 57-61; mercaptopurine PO QD on days 1-84; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; and methotrexate IT on day 1. Treatment repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 119) (for girls with T-ALL) and all patients with T-LLy, and 3 years from the start of interim maintenance therapy (approximately week 171) (for boys with T-ALL).

GROUP I ARM IV COMBINATION CHEMOTHERAPY (CONSOLIDATION CHEMOTHERAPY): Patients receive nelarabine IV over 60 minutes on days 1-5 and 43-47; methotrexate IT on days 15, 22, 57, and 64; cyclophosphamide IV over 30 minutes on days 8 and 50; cytarabine IV over 15-30 minutes or SC on days 8-11, 15-18, 50-53 and 57-60; mercaptopurine PO on days 8-21 and 50-63; vincristine sulfate IV on days 22, 29, 64, and 71; and pegaspargase IM or IV over 1-2 hours on days 22 and 64. (DS patients excluded as of 09/29/10). (Patients with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo prophylactic CRT QD on days 22-28 and 29-35.

GROUP I ARM IV COMBINATION CHEMOTHERAPY (DELAYED INTENSIFICATION CHEMOTHERAPY): Patients receive vincristine sulfate IV on days 1, 8, 15, and 50; dexamethasone IV or PO BID on days 1-21 (for patients \< 10 years of age) OR on days 1-7 and 15-21 (for patients \>= 10 years of age); doxorubicin hydrochloride IV on days 1, 8, and 15; pegaspargase IM or IV over 1-2 hours on day 4, 5, OR 6 AND day 50; methotrexate IT on days 1, 36, and 43; nelarabine IV over 60 minutes on days 29-33; cyclophosphamide IV over 30 minutes on day 36; cytarabine IV over 15-30 minutes or SC on days 36-39 and 43-46; and thioguanine PO on days 36-49.

GROUP I ARM IV COMBINATION CHEMOTHERAPY (INTERIM MAINTENANCE CHEMOTHERAPY): Patients receive HDMTX IV over 24 hours and vincristine sulfate IV on days 1, 15, 29, and 43; mercaptopurine PO on days 1-56; and methotrexate IT on days 1 and 29. Beginning 42 hours after the start of HDMTX, patients also receive leucovorin calcium IV or PO once every 6 hours for 3 doses.

GROUP I ARM IV COMBINATION CHEMOTHERAPY (MAINTENANCE CHEMOTHERAPY): Patients receive vincristine sulfate, prednisone, mercaptopurine, methotrexate PO, methotrexate IT, and nelarabine in Cycles 1, 2 and 3. Patients then receive treatment (without nelarabine) as follows: vincristine sulfate, prednisone, mercaptopurine, methotrexate PO, and methotrexate IT as in arm II. Treatment (without nelarabine) repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 121) (for girls with T-ALL), and for those with T-LLY, and 3 years from the start of interim maintenance therapy (approximately week 173) (for boys with T-ALL).

After completion of study therapy, patients are followed periodically for at least 10 years.

Arms: arm 1: All patients (T-ALL and T-LLy) receive cytarabine intrathecally (IT) on day 1; vincristine sulfate IV on days 1, 8, 15, and 22; prednisone IV or PO twice daily BID on days 1-28; pegaspargase IM (may give IV over 1 to 2 hours) on day 4, 5, or 6; daunorubicin hydrochloride IV on days 1, 8, 15 and 22; and methotrexate IT on days 8 and 29 (and days 15 and 22 for patients with CNS3 disease). arm 2: Patients receive nelarabine IV over 60 minutes on days 1-5 and 43-47; methotrexate IT on days 15, 22, 57, and 64; cyclophosphamide IV over 30 minutes on days 8 and 50; cytarabine IV over 15-30 minutes or SC on days 8-11, 15-18, 50-53 and 57-60; mercaptopurine PO on days 8-21 and 50-63; vincristine sulfate IV on days 22, 29, 64, and 71; and pegaspargase IM or IV over 1-2 hours on days 22 and 64. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy on days 15, 22-26, and 29-33 (DS patients excluded as of 09/29/10). (Patients with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo prophylactic CRT QD on days 22-28 and 29-35. arm 3: Patients receive methotrexate IT on days 1, 8, 15, and 22; cyclophosphamide IV over 30 minutes on days 1 and 29; cytarabine IV over 15-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO on days 1-14 and 29-42; vincristine sulfate IV on days 15, 22, 43 and 50; and pegaspargase IM or IV over 1-2 hours on days 15 and 43. Patients with DS also receive leucovorin calcium PO at 48 and 60 hours after each methotrexate dose. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy on days 11-12, 15-19, and 22-26. (DS patients excluded as of 09/29/10.) Patients with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo prophylactic CRT (1,200 cGy/dose) QD on days 15-21 and 22-28. Patients with low-risk disease do not undergo CRT. Patients with standard risk T-LLy received Arm I, and those with high risk T-LLy were randomized between Arm I and Arm II combination chemotherapy. arm 4: Patients receive vincristine sulfate IV on days 1, 8, 15, 43, and 50; dexamethasone IV or PO BID on days 1-21 (for patients \< 10 years of age) OR on days 1-7 and 15-21 (for patients \>= 10 years of age and for patients with DS); doxorubicin hydrochloride IV on days 1, 8, and 15; pegaspargase IM or IV over 1-2 hours on day 4, 5, OR 6, AND day 43; methotrexate IT on days 1, 29, and 36; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV over 15-30 minutes or SC on days 29-32 and 36-39; and thioguanine PO on days 29-42. Patients with DS also receive leucovorin calcium PO at 48 and 60 hours after each methotrexate dose (DS patients excluded as of 09/29/10). Standard risk T-LLy patients were assigned to Arm I and those with high risk were randomized between Arm I and Arm II. arm 5: Patients receive vincristine sulfate IV on days 1, 29, and 57; prednisone PO BID on days 1-5, 29-33, and 57-61; mercaptopurine PO QD on days 1-84; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; and methotrexate IT on day 1. Treatment repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 119) (for girls with T-ALL), all patients with T-LLy, and 3 years from the start of interim maintenance therapy (approximately week 171) (for boys with T-ALL). arm 6: Patients receive vincristine sulfate IV and escalating doses of methotrexate IV on days 1, 11, 21, 31, and 41; pegaspargase\* IM or IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31. Patients with DS also receive leucovorin calcium PO 48 and 60 hours after each methotrexate IT dose (DS patients excluded as of 09/29/10).

Note: \*Patients with an allergy to pegaspargase receive Erwinia asparaginase on days 2, 4, 6, 8, 10, 12, 22, 24, 26, 28, 30, and 32. arm 7: Patients receive nelarabine IV over 60 minutes on days 1-5 and 43-47; methotrexate IT on days 15, 22, 57, and 64; cyclophosphamide IV over 30 minutes on days 8 and 50; cytarabine IV over 15-30 minutes or SC on days 8-11, 15-18, 50-53 and 57-60; mercaptopurine PO on days 8-21 and 50-63; vincristine sulfate IV on days 22, 29, 64, and 71; and pegaspargase IM or IV over 1-2 hours on days 22 and 64. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy on days 15, 22-26, and 29-33 (DS patients excluded as of 09/29/10). (Patients with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo prophylactic CRT QD on days 22-28 and 29-35. Patients with high risk T-LLy were either randomized to Arm I or Arm II. Patients with T-LLy who failed induction therapy were assigned to Arm II. arm 8: Patients receive vincristine sulfate IV on days 1, 8, 15, and 50; dexamethasone IV or PO BID on days 1-21 (for patients \< 10 years of age) OR on days 1-7 and 15-21 (for patients \>= 10 years of age); doxorubicin hydrochloride IV on days 1, 8, and 15; pegaspargase IM or IV over 1-2 hours on day 4, 5, OR 6 AND day 50; methotrexate IT on days 1, 36, and 43; nelarabine IV over 60 minutes on days 29-33; cyclophosphamide IV over 30 minutes on day 36; cytarabine IV over 15-30 minutes or SC on days 36-39 and 43-46; and thioguanine PO on days 36-49. arm 9: Patients receive vincristine sulfate IV and escalating doses of methotrexate IV on days 1, 11, 21, 31, and 41; pegaspargase\* IM or IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31.

Note: \*Patients with an allergy to pegaspargase receive Erwinia asparaginase on Monday, Wednesday and Friday for two consecutive weeks starting the day of asparaginase substitution. arm 10: Patients receive vincristine sulfate, prednisone, mercaptopurine, methotrexate PO, methotrexate IT, and nelarabine in Cycles 1, 2 and 3. Patients then receive treatment (without nelarabine) as follows: vincristine sulfate, prednisone, mercaptopurine, methotrexate PO, and methotrexate IT as in arm II. Treatment (without nelarabine) repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 121) (for girls with T-ALL), and for those with T-LLY, and 3 years from the start of interim maintenance therapy (approximately week 173) (for boys with T-ALL). arm 11: Patients receive methotrexate IT on days 1, 8, 15, and 22; cyclophosphamide IV over 30 minutes on days 1 and 29; cytarabine IV over 15-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO on days 1-14 and 29-42; vincristine sulfate IV on days 15, 22, 43 and 50; and pegaspargase IM or IV over 1-2 hours on days 15 and 43. Patients with DS also receive leucovorin calcium PO at 48 and 60 hours after each methotrexate dose. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy on days 11-12, 15-19, and 22-26. (DS patients excluded as of 09/29/10.) Patients with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo prophylactic CRT (1,200 cGy/dose) QD on days 15-21 and 22-28. Patients with low-risk disease do not undergo CRT. arm 12: Patients receive vincristine sulfate IV on days 1, 8, 15, 43, and 50; dexamethasone IV or PO BID on days 1-21 (for patients \< 10 years of age) OR on days 1-7 and 15-21 (for patients \>= 10 years of age and for patients with DS); doxorubicin hydrochloride IV on days 1, 8, and 15; pegaspargase IM or IV over 1-2 hours on day 4, 5, OR 6, AND day 43; methotrexate IT on days 1, 29, and 36; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV over 15-30 minutes or SC on days 29-32 and 36-39; and thioguanine PO on days 29-42. Patients with DS also receive leucovorin calcium PO at 48 and 60 hours after each methotrexate dose (DS patients excluded as of 09/29/10). arm 13: Patients receive HDMTX IV over 24 hours and vincristine sulfate IV on days 1, 15, 29, and 43; mercaptopurine PO on days 1-56; and methotrexate IT on days 1 and 29. Beginning 42 hours after the start of HDMTX, patients also receive leucovorin calcium IV or PO once every 6 hours for 3 doses. arm 14: Patients receive vincristine sulfate IV on days 1, 29, and 57; prednisone PO BID on days 1-5, 29-33, and 57-61; mercaptopurine PO QD on days 1-84; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; and methotrexate IT on day 1. Treatment repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 119) (for girls with T-ALL) and all patients with T-LLy, and 3 years from the start of interim maintenance therapy (approximately week 171) (for boys with T-ALL). arm 15: Patients receive vincristine sulfate IV on days 1, 8, 15, and 50; dexamethasone IV or PO BID on days 1-21 (for patients \< 10 years of age) OR on days 1-7 and 15-21 (for patients \>= 10 years of age); doxorubicin IV on days 1, 8, and 15; pegaspargase IM or IV over 1-2 hours on day 4, 5, OR 6 AND day 50; methotrexate IT on days 1, 36, and 43; nelarabine IV over 60 minutes on days 29-33; cyclophosphamide IV over 30 minutes on day 36; cytarabine IV over 15-30 minutes or SC on days 36-39 and 43-46; and thioguanine PO on days 36-49. arm 16: Patients receive HDMTX IV over 24 hours and vincristine IV on days 1, 15, 29, and 43; mercaptopurine PO on days 1-56; and methotrexate IT on days 1 and 29. Beginning 42 hours after the start of HDMTX, patients also receive leucovorin calcium IV or PO once every 6 hours for 3 doses. arm 17: Patients receive vincristine sulfate, prednisone, mercaptopurine, methotrexate PO, methotrexate IT, and nelarabine in Cycles 1, 2 and 3. Patients then receive treatment (without nelarabine) as follows: vincristine, prednisone, mercaptopurine, methotrexate PO, and methotrexate IT as in arm II. Treatment (without nelarabine) repeats every 84 days until the total duration of study treatment is 2 years from the start of interim maintenance therapy (approximately week 121) (for girls with T-ALL), and for those with T-LLY, and 3 years from the start of interim maintenance therapy (approximately week 173) (for boys with T-ALL).
Interventions: intervention 1: Asparaginase intervention 2: Cyclophosphamide intervention 3: Cytarabine intervention 4: Daunorubicin Hydrochloride intervention 5: Dexamethasone intervention 6: Doxorubicin Hydrochloride intervention 7: Laboratory Biomarker Analysis intervention 8: Leucovorin Calcium intervention 9: Mercaptopurine intervention 10: Methotrexate intervention 11: Nelarabine intervention 12: Pegaspargase intervention 13: Prednisone intervention 14: Radiation Therapy intervention 15: Thioguanine intervention 16: Vincristine Sulfate
Intervention descriptions: intervention 1: Given IM or IV intervention 2: Given IV intervention 3: Given IT, IV, or SC intervention 4: Given IV intervention 5: Given IV or PO intervention 6: Given IV intervention 7: Correlative studies intervention 8: Given PO intervention 9: Given PO intervention 10: Given IT or PO intervention 11: Given IV intervention 12: Given IM or IV intervention 13: Given IV or PO intervention 14: Some patients undergo testicular and/or prophylactic cranial RT intervention 15: Given PO intervention 16: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
  
 
i 
 
Group Chair 
Peter C. Adamson, M.D. 
adamson@email.chop.edu  
 
Group Vice Chair 
Susan Blaney, M.D. 
smblaney@txch.org  
 
Chief Operating Officer 
Elizabeth O’Connor, M.P.H. 
econnor@childrensoncology 
group.org  
 
Chief Administrative Officer 
Maria Hendricks, M.S.N, R.N. 
C.C.R.P. 
hendricksm@email.chop.edu  
 
Group Statistician 
Todd Alonzo, Ph.D. 
talonzo@childrensoncology 
group.org 
 
Group Chair’s Office 
The Children's Hospital 
of Philadelphia 
3501 Civic Center Blvd 
CTRB 10060 
Philadelphia, PA 19104 
 
P 215 590 6359 
F 215 590 7544 
 
Group Operations Center 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Statistics & Data Center 
Headquarters 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Gainesville Office 
6011 NW 1st Place 
Gainesville, FL 32607 
 
P 352 273 0556 
F 352 392 8162 
 
 
 
A National Cancer Institute  
supported clinical cooperative 
group and Equal Opportunity 
Affirmative Action Institutions 
 
 
 
 
 
June 29, 2018 
 
 
Martha Kruhm, MS, RAC 
Head, Protocol and Information Office  
Operations and Informatics Branch 
Cancer Therapy Evaluation Program 
Division of Cancer Treatment and Diagnosis 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
Re: AALL0434, Intensified Methotrexate, Nelarabine (Compound 506U78; IND# 
52611) and Augmented BFM Therapy for Children and Young Adults with Newly 
Diagnosed T-cell Acute Lymphoblastic Leukemia (ALL) or T-cell Lymphoblastic 
Lymphoma. ~ Amendment #11 
 
Dear Ms. Kruhm, 
 
Enclosed you will find Amendment #11 to the protocol and informed consent 
forms for the study AALL0434. This study is primarily being amended to 
redesign the nelarabine randomization based on better than expected overall 
outcomes. In addition this amendment includes a change in response to Dr. 
Johnson’s July 11, 2014 notice regarding preparation instructions for nelarabine 
(506U78). 
 
Other administrative changes have been made for consistency and clarity 
between documents; specific changes are detailed below. Minor administrative 
updates (such as the correction of typographical errors or updates to the 
numbers of referenced sections) are tracked in the protocol but not specified 
below. 
 
Thanking you in advance for your review of this amendment, 
 
With kind regards, 
 
 
Sarah L. Vargas, Ph.D., Protocol Coordinator (on behalf of) 
 
 
Kimberly Dunsmore, M.D., Study co-Chair, AALL0434 
Stuart Winter, M.D., Study co-Chair, AALL0434 
Robert Hayashi, M.D., Study Vice-Chair, AALL0434 
Meenakshi Devidas, Ph.D., Study Sr. Statistician, AALL0434 
Peter Adamson, Group Chair, Children’s Oncology Group


 
 
 
 
AALL0434 
ii 
 
 
AALL1231 SUMMARY OF CHANGES 
SUMMARY OF CHANGES: PROTOCOL DOCUMENT 
In accordance with the above discussion, the following specific revisions have been made to 
the protocol. Additions are in boldfaced font and deletions in strikethrough font. 
 
Section 
Page 
Comments 
Throughout 
Throughout Update of section numbers and version date. 
Title Page 
1 
Update of version date and amendment number. 
Table of 
Contents 
2-6 
Update of the TOC. 
Study Committee 
9 
The protocol coordinator contact information has been updated. 
4.9.1 
70 
Added * next to “d” on day 29, for proper association with footnote 
instructions. 
6.10 
113 
The nelarabine monograph was revised in response to Dr. Johnson’s 
July 11, 2014 notice regarding preparation instructions for nelarabine 
(506U78). 
10.1.1.1 
129 
Included the new section to describe the study re-design with 
amendment #11. 
10.3.2 
135 
Included the new section to describe the study re-design power 
calculations for nelarabine randomization with amendment #11. 
 
SUMMARY OF CHANGES: INFORMED CONSENT DOCUMENTS 
 
The version date has been updated. 
 
 
 


 
 
 
 
AALL0434 
1 
 
Activated: 
01/22/07 
Version Date: 03/24/16 
Closed: 
7/25/14      
Amendment: 11 
 
 
 
CHIL DREN’S ONCOL OGY GROUP 
 
AALL0434 
 
Intensified Methotrexate, Nelarabine (Compound 506U78; IND # 52611) and Augmented 
BFM Therapy for Children and Young Adults with Newly Diagnosed T-cell Acute 
Lymphoblastic Leukemia (ALL) or T-cell Lymphoblastic Lymphoma 
 
 
A Groupwide Phase III Study 
 
IND sponsor: National Cancer Institute 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR 
ANY OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT 
INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. RESEARCH 
MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, 
DESIGNED TO DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS THE RESEARCH 
PLAN DEVELOPED BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR 
SET OF STUDY QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT. THE 
PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY 
STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT. ANY 
PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING 
PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
STUDY CO-CHAIR 
 
Stuart S. Winter, MD 
Pediatric Oncology Program 
University of New Mexico 
1 University of New Mexico, MSC 10 5590 
Albuquerque, NM 87131-5311 
Phone: 
(505) 272-4461 
Fax: 
(505) 272-8699 
E-mail: 
swinter@salud.unm.edu  
 
STUDY CO-CHAIR 
 
Kimberly P. Dunsmore, MD 
Pediatric Hematology Oncology 
University of Virginia Hospital 
Box 800386 
Charlottesville, VA 22908 
Phone: 
(434) 924-5105 
Fax: 
(434) 982-1927 
E-mail: 
kpd6u@virginia.edu  
 
 
For Statistics and Data Center Contact Person see:  http://members.childrensoncologygroup.org  


 
 
 
 
AALL0434 
Version date: 03/24/16 
 
Page 2 
TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
7 
ABSTRACT 
10 
EXPERIMENTAL DESIGN SCHEMA: T-ALL SAFETY PHASE (COMPLETED) 
11 
EXPERIMENTAL DESIGN SCHEMA: T-ALL EFFICACY PHASE (OPEN) 
12 
EXPERIMENTAL DESIGN SCHEMA: T-NHL EFFICACY PHASE 
13 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
14 
1.1 
Main Clinical Objectives 
14 
1.2 
Secondary Clinical Objective 
14 
2.0 
BACKGROUND 
14 
2.1 
Rationale for Augmented Intensity BFM Therapy 
16 
2.2 
Preliminary Data 
18 
2.3 
Determination of Early Response 
21 
2.4 
Integration of Radiation Therapy 
22 
2.5 
Biological Correlates 
23 
2.6 
Exclusion of Patients with Down syndrome 
24 
2.7 
Phase 1 Safety Phase Data Analysis 
24 
2.7.1 
Toxicity and Adverse Events 
25 
3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
26 
3.1 
Study Enrollment 
26 
3.1.1 
Patient Registration via Remote Date Entry (RDE) 
26 
3.1.2 
IRB Approval 
26 
3.1.3 
Study Enrollment 
27 
3.1.4 
Timing 
27 
3.1.5 
Bilingual Services 
28 
3.1.6 
Randomization 
28 
3.2 
Patient Criteria 
28 
3.2.1 
Classification Study 
28 
3.2.2 
Age 
28 
3.2.3 
Diagnosis 
29 
3.2.4 
Prior Therapy Restrictions 
29 
3.2.5 
Concomitant Medications Restrictions 
29 
3.2.6 
Pregnant/Lactating Females 
30 
3.2.7 
Patients with Down syndrome 
30 
3.2.8 
For T-NHL patients the following additional exclusion criteria apply: 
30 
3.3 
Definitions 
30 
3.3.1 
Hematological Parameters 
30 
3.3.2 
Definitions of Extramedullary Disease 
30 
3.3.3 
Definitions of Bone Marrow Involvement 
32 
3.3.4 
Definitions of Early Response to Treatment 
32 
3.3.5 
Definitions of Risk Stratification 
32 
3.3.6 
Definitions of Relapse 
34 
4.0 
TREATMENT PLAN 
35 
4.1 
Overall Treatment Plan 
35 


 
 
 
 
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Version date: 03/24/16 
 
Page 3 
4.1.1 
Risk Assignment 
35 
4.1.2 
Randomization 
37 
4.2 
INDUCTION (All patients) 
40 
4.2.1 
INDUCTION (All arms) 
43 
4.3 
CONSOLIDATION Arms A (CMTX) and C (HDMTX) (NO Nelarabine) Weeks 6-13 44 
4.3.1 
CONSOLIDATION Arm A (CMTX) and Arm C (HDMTX) 
46 
4.4 
CONSOLIDATION Arms B (CMTX + Nel) and D (HDMTX + Nel) Weeks 6-16 
47 
4.4.1a CONSOLIDATION Arm B (CMTX + Nel) and Arm D (HDMTX + Nel) 
50 
4.4.1b CONSOLIDATION Arm B (CMTX + Nel) and Arm D (HDMTX + Nel) 
51 
4.5 
INTERIM MAINTENANCE Arms A (CMTX) and B (CMTX + Nel) 
52 
4.5.1 
INTERIM MAINTENANCE Arm A (CMTX) & Arm B (CMTX + Nel) 
54 
4.6 
INTERIM MAINTENANCE Arms C (HDMTX) and D (HDMTX + Nel) 
55 
4.6.1 
HD MTX Infusion Guidelines 
56 
4.6.2 
INTERIM MAINTENANCE Arm C (HDMTX) & Arm D (HDMTX + Nel) 
58 
4.7 
DELAYED INTENSIFICATION Arms A (CMTX) and C (HDMTX) (NO Nelarabine) 59 
4.7.1a DELAYED INTENSIFICATION Arm A (CMTX) & Arm C (HDMTX)  
61 
4.7.1b DELAYED INTENSIFICATION Arm A (CMTX) & Arm C (HDMTX)  
62 
4.8 
DELAYED INTENSIFICATION Arms B (CMTX + Nel) and D (HDMTX + Nel) 
63 
4.8.1a DELAYED INTENSIFICATION Arm B (CMTX + Nel) & Arm D  
66 
4.8.1b DELAYED INTENSIFICATION Arm B (CMTX + Nel) & Arm D  
67 
4.9 
MAINTENANCE Arms A (CMTX) and C (HDMTX) (NO Nelarabine)  
68 
4.9.1 
MAINTENANCE Arm A (CMTX) & Arm C (HDMTX) 
70 
4.10 
MAINTENANCE Arms B (CMTX + Nel) and D (HDMTX + Nel) (Weeks 34 – 69) 
71 
4.10.1 MAINTENANCE Arm B (CMTX + Nel) & Arm D (Weeks 34-69) 
73 
4.11 
MAINTENANCE CONTINUED AFTER CYCLE THREE Arms B (CMTX + Nel) and 
D (HDMTX + Nel) 
74 
4.11.1 MAINTENANCE CONTINUED AFTER CYCLE THREE Arm B &   
76 
5.0 
DOSE MODIFICATION FOR TOXICITIES 
77 
5.1 
Asparaginase [Pegaspargase (PEG-Asparaginase) or Erwinia] 
77 
5.2 
Nelarabine (Compound 506U78) 
79 
5.3 
Cyclophosphamide 
80 
5.4 
Cytarabine (ARAC) 
80 
5.5 
Intrathecal Cytarabine 
80 
5.6 
Daunorubicin and Doxorubicin (Anthracyclines) 
80 
5.7 
Intrathecal Methotrexate 
81 
5.8 
High-Dose Methotrexate (HD MTX) and Leucovorin Rescue 
82 
5.8.1 
HD MTX Infusion Guidelines 
83 
5.8.2 
Capizzi Methotrexate Regimens 
85 
5.9 
PO Methotrexate (MTX) and 6-Mercaptopurine (6-MP) 
86 
5.10 
Steroids (Dexamethasone and Prednisone) 
89 
5.11 
PO 6-Thioguanine (6-TG) 
89 
5.12 
Vincristine 
90 
5.13 
Drug Interactions 
91 
6.0 
DRUG INFORMATION 
93 
6.1 
ASPARAGINASE ERWINIA CHRYSANTHEMI 
93 
6.2 
CYCLOPHOSPHAMIDE INJECTION 
95 
6.3 
CYTARABINE         
96 
6.4 
DAUNORUBICIN 
98 
6.5 
DEXAMETHASONE  
6.6 
DOXORUBICIN 
101 


 
 
 
 
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Page 4 
6.7 
LEUCOVORIN CALCIUM  
103 
6.8 
MERCAPTOPURINE 
104 
6.9 
METHOTREXATE 
106 
6.10 
NELARABINE 
108 
6.11 
PEGASPARGASE 
114 
6.12 
PREDNISONE, 
116 
6.13 
THIOGUANINE 
117 
6.14 
VINCRISTINE SULFATE 
119 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
121 
7.1 
Required & Optional Clinical, Laboratory and Disease Evaluations for T-ALL 
121 
7.2 
Required & Optional Clinical, Laboratory and Disease Evaluations for T-NHL 
122 
7.3 
Targeted Toxicities 
123 
7.4 
Studies to be Obtained After Stopping Therapy 
123 
7.5 
At Relapse 
123 
8.0 
SUPPORTIVE CARE GUIDELINES 
123 
8.1 
General Guidelines 
124 
8.1.1 
Blood Components 
124 
8.1.2 
Infection Prophylaxis 
124 
8.1.3 
Treatment of Established or Presumed Infections 
125 
8.1.4 
Antiemetic Protection 
126 
8.1.5 
Use of Filgrastim 
126 
8.2 
Guidelines for Induction 
126 
8.2.1 
Acute Tumor Lysis Syndrome 
126 
8.2.2 
Induction – Infectious Complications 
126 
9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
127 
9.1 
Criteria for Removal From Protocol Therapy 
127 
9.2 
Off Study Criteria 
127 
10.0 
STATISTICAL CONSIDERATIONS 
127 
10.1 
Statistical Design (Amendment #5) 
127 
10.1.1 Study Re-design - (Amendment #9) 
129 
10.1.1.1 Study Re-desing - (Amendment #11) 
 
 
      129 
10.2 
Nelarabine Toxicity Assessment and Duration of Safety and Efficacy Phases 
130 
10.3 
Primary Treatment Comparisons and Statistical Power (Amendment #9) 
131 
10.3.1 Study Re-design Power Calculations (Amendment #9) 
134 
10.3.2 Study Re-design Power Calculations (Amendment #11) 
 
      135 
10.4 
Toxicity Assessment and Monitoring 
135 
10.5 
Analysis and Monitoring of Special Patient Subsets 
136 
10.6 
Analyses of Gender and Ethnicity 
137 
11.0 
EVALUATION CRITERIA 
138 
11.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
138 
11.2 
Response Criteria for T-ALL 
138 
11.3 
Response Criteria for T-NHL 
138 
11.3.1 Complete Response (CR) 
138 
11.3.2 Complete Response Unconfirmed (CRu) 
139 
11.3.3 Partial Response (PR) 
139 
11.3.4 No Response (NR) 
139 
11.3.5 Progressive Disease 
139 


 
 
 
 
AALL0434 
Version date: 03/24/16 
 
Page 5 
12.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
139 
12.1 
Purpose 
139 
12.2 
Determination of reporting requirements 
139 
12.3 
Steps to determine if an adverse event is to be reported in an expedited manner 
140 
12.4 
Reporting methods 
141 
12.5 
When to report an event in an expedited manner 
141 
12.6 
Other recipients of adverse event reports 
142 
12.7 
Reporting of Adverse Events for investigational agents – AdEERS 24-hour notifications, 
and complete report requirements. 
142 
12.8 
Additional Reporting Guidelines and Protocol Specific Requirements 
143 
12.9 
Toxicities and other adverse events that must be reported for all patients via COG remote 
data entry 
144 
12.10 Reporting of Adverse Events for commercial agents – AdEERS abbreviated pathway 144 
13.0 
RECORDS AND REPORTING 
145 
13.1 
Categories of Research Records 
145 
13.2 
CDUS 
145 
13.3 
CTA/CRADA 
145 
14.0 
RADIATION THERAPY GUIDELINES 
148 
14.1 
Cranial Irradiation 
148 
14.1.1 Equipment and Calibration 
148 
14.1.2 Target Volume 
148 
14.1.3 Target Dose 
148 
14.1.4 Dose Uniformity 
149 
14.1.5 Treatment Interruptions 
149 
14.1.6 Treatment Technique 
149 
14.2 
Testicular Radiation 
150 
14.2.1 Equipment and Calibration 
150 
14.2.2 Target Volume 
150 
14.2.3 Target Dose 
150 
14.2.4 Dose Uniformity 
150 
14.2.5 Treatment Interruptions 
151 
14.2.6 Treatment Technique 
151 
14.3 
Quality Assurance Documentation 
151 
14.3.1 QARC Post Treatment Review 
151 
14.3.2 Data must be sent to: 
151 
14.3.3 Questions regarding the dose calculations or documentation should be directed 
to: 
151 
14.3.4 Questions regarding the XRT section of this protocol should be directed to the 
Study Radiation Oncology Coordinator: 
152 
14.4 
Definitions of Deviation in Protocol Performance 
152 
14.4.1 Minor Deviation 
152 
14.4.2 Major Deviation 
152 
15.0 
PATHOLOGY GUIDELINES FOR T-NHL 
152 
15.1 
Pathology Goals 
152 
15.2 
Requirements for Handling Tissue or Cytology Specimens at Primary Institutions 
152 
15.2.1 Tissue Specimens 
152 
15.2.2 Cytology Specimens 
153 
15.3 
Immunophenotyping Recommendations for Primary Institutions 
154 
15.4 
Pathology Staging Criteria 
154 


 
 
 
 
AALL0434 
Version date: 03/24/16 
 
Page 6 
15.5 
Retrospective Central Pathology Review 
154 
15.5.1 Required Materials 
154 
15.5.2 Transmittal Form 
155 
15.5.3 Biopathology Center Address 
156 
15.5.4 Paraffin Blocks and Cytologic Slides-Storage/Return 
156 
15.5.5 Lymphoma Classification 
156 
15.5.6 Review Pathologists 
156 
16.0 
BIOLOGY METHODS AND SPECIMEN SUBMISSION FOR T-NHL 
158 
16.1 
Required Minimal Residual Disease (MRD) Biology Studies 
158 
16.1.1 Sample Collection 
158 
16.1.2 Sample Shipping 
158 
16.2 
Optional Tissue Banking and Subsequent Biologic Studies 
159 
16.3 
Preparation of Tissue Banking Samples at Time of Diagnosis or Relapse 
160 
16.3.1 Specimen Shipping Instructions 
160 
APPENDIX I: MERCAPTOPURINE DOSING GUIDELINES 
162 
APPENDIX II: THIOGUANINE DOSING GUIDELINES 
168 
APPENDIX III: CYP3A4/5 INHIBITORS AND INDUCERS 
170 
APPENDIX IV: HIGH-DOSE METHOTREXATE FLOW CHART 
171 
APPENDIX 
V: 
MODIFIED 
(“BALIS”) 
PEDIATRIC 
SCALE 
OF 
PERIPHERAL 
NEUROPATHIES 
172 
APPENDIX VI: YOUTH INFORMATION SHEETS FOR PATIENTS WITH ALL 
173 
APPENDIX VII: YOUTH INFORMATION SHEETS FOR PATIENTS WITH NHL 
177 
APPENDIX VIII: STAGING CLASSIFICATION OF CHILDHOOD NHL 
181 
APPENDIX IX: AGGREGATE ANALYSIS OF PATIENTS WHO EXPERIENCED 
RHABDOMYOLYSIS IN TRIALS USING NELARABINE 
184 
REFERENCES 
186 


 
 
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AALL0434 
Version date: 03/24/16                         
Page 7 
 
 
STUDY COMMITTEE  
STUDY CO-CHAIR 
STUDY COMMITTEE MEMBERS  
Stuart S. Winter, M.D. 
Marcia Leonard, RN PNP 
Hematology/Oncology 
Nursing 
University of New Mexico 
C.S. Mott Children’s Hospital 
1 University of New Mexico, MSC 10 5590 
Dept of Ped Hem-Onc, D4202 MPB 
Albuquerque, NM 87131-0001 
1500 E. Medical Center Dr. 
Phone: 505-272-4461 
Ann Arbor, Michigan, 48109-5718 
Fax: 
505-272-8699 
Phone: 734-764-7126 
E-mail: swinter@salud.unm.edu  
Fax: 
734-615-0464 
 
E-mail: Marcia@med.umich.edu  
STUDY CO-CHAIR 
 
Kimberly P. Dunsmore, M.D. 
Natia Esiashvili, M.D. 
Hematology/Oncology 
Radiation Oncology 
University of Virginia 
Children’s Healthcare of Atlanta - Egleston 
Pediatric Hematology Oncology 
Radiation Oncology 
University of Virginia Hospital 
1365 Clifton Road, NE 
Box 800386 
Atlanta, GA 30322 
Charlottesville, VA 22908 
Phone: 404-778-5782 
Phone: 434-924-5105 
Fax: 
404-778-3643 
Fax: 
434-982-1927 
E-mail: natia@radonc.emory.org  
E-mail: kpd6u@virginia.edu  
 
 
Nikki J. Briegel 
STUDY VICE CHAIR 
Pharmacy 
Robert J. Hayashi, MD 
Princess Margaret Hospital for Children 
Hematology/Oncology 
Department of Pharmacy 
Washington University School of Medicine 
GPO Box D184 
Pediatrics Hematology/Oncology 
Subiaco 
One Childrens Place 
Perth, Western Australia 6001 
St. Louis, MO 63110 
Australia 
Phone: 314-454-4118 
Phone: 6189340-8875 
Fax: 
314-454-2685 
Fax: 
6189340-8710 
Email: hayashi_r@kids.wustl.edu  
E-mail:  nikki.briegel@health.wa.gov.au 
 
 
STUDY STATISTICIAN 
Douglas K Graham, MD PhD 
Meenakshi Devidas, PhD 
Hematology/Oncology 
Children's Oncology Group - Data Center (Gaines) 
The Children’s Hospital  
6011 NW 1st Place 
Univ of Colorado Denver School of Medicine 
Gainesville, FL 32607 
Pediatrics, Mail Stop 8302, RC-1 North, P18-4108 
Phone: 352-273-0551 
12800 E. 19th Avenue 
Fax: 
352-392-8162 
Aurora, CO 80045 
E-mail: mdevidas@cog.ufl.edu 
Phone: 303-724-4006 
 
Fax: 
303-724-4015 
 
Email: doug.graham@ucdenver.edu  
STUDY COMMITTEE MEMBERS  
 
Michelle Hermiston, MD, PhD 
 
Hematology/Oncology 
 
University of California San Francisco Medical Center-Parnassus  
Pediatrics 
 
505 Parnassus Ave, Box 0106 
 
San Francisco, CA 94143-0106 
 
Phone: 415-476-3831 
 
Fax: 
415-502-4372 
 
Email: hermistonm@peds.ucsf.edu  
 
 
 


 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0434 
Version date: 03/24/16                         
Page 8 
STUDY COMMITTEE MEMBERS 
 
Edward A. Kolb, MD 
Stephen P. Hunger, MD 
Hematology/Oncology 
Hematology/Oncology 
Alfred I duPont Hospital for Children 
The Children’s Hospital 
BBMT 
Center for Cancer & Blood Disorders 
1600 Rockland Rd 
13123 East 16th Street, B115 
Wilmington, DE 19803 
Aurora, CO 80045 
Phone: 302-651-5567 
Phone: 720-777-8855 
Fax: 
302-651-4918 
Fax: 
720-777-7279 
Email: eakolb@nemours.org  
Email: Stephen.Hunger@childrenscolorado.org  
 
 
Robert D. Annett, Ph.D. 
Naomi J. Winick, MD 
Behavioral Science 
Hematology/Oncology 
University of New Mexico 
UT Southwestern Medical Center 
Pediatrics 
Director, Clinical Oncology 
1 Univ. of New Mexico Health Science Center, MSC 10-5590 
Pediatric Hem/Onc 
Albuquerque, NM 87131-0001 
5323 Harry Hines Blvd. 
Phone: 505-272-0311 
Dallas, TX 75390-9063 
Fax: 
505-272-6845 
Phone: 214-456-2382 
E-mail: rdannett@unm.edu  
Fax: 
214-648-2764 
 
Email: naomi.winick@utsouthwestern.edu 
Juliette Hukin, MD 
 
Hematology/Oncology 
William L. Carroll, MD 
British Columbia Children’s Hospital 
Hematology/Oncology 
Neurology-Oncology 
New York University Langone Medical Center 
4480 Oak Street, Room 315 
Director, Hassenfeld Children's Center 
Vancouver, BC V6H 3V4 
160 East 32nd Street, 2nd Floor 
Canada 
New York, NY 10016 
Phone: 604-875-2121 
Phone: 212-263-9906 
Fax: 
604-875-2285 
Fax: 
212-263-8410 
Email: jhukin@cw.bc.ca 
Email: william.carroll@nyumc.org 
 
 
Stacey L. Berg, MD 
Sherrie L. Perkins, MD, PhD 
Hematology/Oncology 
Pathology 
Baylor College of Medicine 
Primary Children’s Medical Center 
Pediatric Oncology 
Department of Pathology 
6621 Fannin Street, MC3-3320 
University of Utah Health Sciences 
Houston, TX 77030 
100 N. Mario Capecchi Dr. 
Phone: 832-824-4588 
Salt Lake City, UT 84132 
Fax: 832-825-4039 
Phone: 801-581-5854 
Email:  sberg@txch.org 
Fax: 
801-662-4707 
 
Email: sherrie.perkins@hsc.utah.edu  
Barbara L. Asselin, MD 
 
Hematology/Oncology 
STUDY CRA 
University of Rochester 
Nancy Lynn Eisenberg, BA 
Pediatric Hematology-Oncology 
Clinical Research Associates 
601 Elmwood Avenue, Box 777 
University of New Mexico 
Rochester, NY 14642 
Pediatrics 
Phone: 585-275-2981 
1 University of New Mexico 
Fax: 585-273-1039 
Albuquerque, NM 87131 
Email: barbara_asselin@urmc.rochester.edu 
Phone: 505-272-5980 
 
Fax: 
505-272-8699 
 
E-mail: neisenberg@salud.unm.edu  
 
 
 
 
 
 


 
 
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AALL0434 
Version date: 03/24/16                         
Page 9 
COG PROTOCOL CONTACT 
 
Sarah L. Vargas, Ph.D. 
AGENT 
 
 NSC#  
AND IND# 
Children's Oncology Group – Operations Center 
Nelarabine 
NSC# 686673 IND#52611 
Study Development Office  
(IND Sponsor: NCI) 
 
 
222 E. Huntington Drive, Suite 100  
Cyclophosphamide 
NSC# 026271 Exempt 
Monrovia, CA 91016 
Cytarabine 
NSC# 063878 Exempt 
Phone: 626-241-1556 
Daunorubicin 
NSC# 082151 Exempt 
Fax: 
626-445-4334 
Dexamethasone 
NSC# 034521 Exempt 
E-mail: svargas@childrensoncologygroup.org  
Doxorubicin 
NSC# 123127 Exempt 
 
Erwinia Asparaginase 
NSC#106977 
Exempt 
COG RESEARCH COORDINATOR 
Leucovorin 
NSC# 003590 Exempt 
Charlotte Wood, CCRP 
6-Mercaptopurine 
NSC# 000755 Exempt 
Clinical Research Associates 
Methotrexate  
NSC# 000740 Exempt 
Children’s Oncology Group – Data Center (Gaines) 
Pegaspargase 
NSC# 624239 Exempt 
CRA & Protocols 
Prednisone 
NSC# 010023 Exempt 
6011 NW 1st Place 
6-Thioguanine 
NSC# 000752 Exempt 
Gainesville, FL 32607 
Vincristine 
NSC# 675574 Exempt 
Phone: 352-273-0573 
 
 
 
Fax: 
352-392-8162 
 
 
 
E-mail: cwood@cog.ufl.edu  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0434 
Version date: 03/24/16                         
Page 10 
The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, which 
will help us protect the privacy of our research subjects.  The Certificate protects against the involuntary release of 
information about your subjects collected during the course of our covered studies.  The researchers involved in the 
studies cannot be forced to disclose the identity or any information collected in the study in any legal proceedings at 
the federal, state, or local level, regardless of whether they are criminal, administrative, or legislative proceedings.  
However, the subject or the researcher may choose to voluntarily disclose the protected information under certain 
circumstances.  For example, if the subject or his/her guardian requests the release of information in writing, the 
Certificate does not protect against that voluntary disclosure.  Furthermore, federal agencies may review our records 
under limited circumstances, such as a DHHS request for information for an audit or program evaluation or an FDA 
request under the Food, Drug and Cosmetics Act. The Certificate of Confidentiality will not protect against 
mandatory disclosure by the researchers of information on suspected child abuse, reportable communicable diseases, 
and/or possible threat of harm to self or others. 
 
ABSTRACT 
 
AALL0434 is a COG group-wide Phase III study designed for patients with T-lineage acute lymphoblastic 
leukemia (T-ALL) or T-lineage lymphoblastic lymphoma (T-NHL) from 1-30 years of age. Although event 
free survival (EFS) and overall survival continue to increase for children and young adults with T-ALL, “On-
Treatment” relapses in the central nervous system (CNS) and bone marrow compartments continue to be 
common causes of treatment failure. There is evidence that both Nelarabine (Compound 506U78) and high 
dose methotrexate (HDMTX) are effective in preventing relapse in T-ALL. To specifically address the early 
treatment failures associated with T-ALL, this study will test the safety and efficacy of these two therapeutic 
interventions. The study utilizes a 2 x 2 factorial design with augmented intensity BFM backbone. After a Day 
29 risk assignment has been determined, patients will become eligible for treatment assignment or 
randomization. Patients will be randomized to receive Capizzi style methotrexate without leucovorin rescue 
(plus PEG Asparaginase) versus high dose methotrexate with leucovorin rescue during the two month Interim 
Maintenance phase of therapy. A safety phase was conducted, during which only the High Risk patients were 
randomized to receive or not receive Nelarabine. During the subsequent efficacy phase of the study (which is 
now open), Intermediate Risk patients will also be randomized to receive or not to receive Nelarabine at a dose 
of 650 mg/m2/day for 5 days during the Consolidation, Delayed Intensification and Maintenance phases of 
therapy. All patients will receive only one Delayed Intensification course and all Intermediate and High Risk 
patients will receive prophylactic cranial radiation (1200 cGy) either during Consolidation (if randomized to 
treatment Arm A (CMTX) or Arm B (CMTX + Nel) or Delayed Intensification (if randomized to treatment 
Arm C (HDMTX) or Arm D (HDMTX + Nel). All Intermediate and High Risk patients classified as CNS3 
will be assigned to receive HD MTX on either Arm C (HDMTX) or Arm D (HDMTX + Nel) and receive 
cranial radiation therapy (CRT) (1800 cGy) during Delayed Intensification. T-NHL patients will be enrolled in 
a separate stratum and will receive the same common Induction therapy given to the T-ALL patients. T-NHL 
patients will be classified as Standard or High Risk, based upon flow cytometry studies performed on 
diagnostic bone marrow samples, an approach piloted in the recently completed lymphoblastic lymphoma 
study (COG A5971). Patients with ≥ 1% disease in the marrow at diagnosis or any level of steroid pre-
treatment will be designated as High Risk and, at the end of Induction, will be randomized to either Arm A 
(CMTX) or Arm B (CMTX + Nel). Patients with < 1% disease in the marrow at diagnosis will be non-
randomly assigned to Arm A (CMTX). Patients who fail to achieve at least a radiologic partial response (PR) 
at the end of Induction (Induction Failures) will be non-randomly assigned to Arm B (CMTX + Nel). T-NHL 
patients will receive treatment for a total of 2 years from the start of Interim Maintenance, regardless of 
gender, and without prophylactic cranial irradiation. T-ALL patients with testicular leukemia will be assigned 
to receive HDMTX on either Arm C (HDMTX) or Arm D (HDMTX + Nel), and will receive testicular 
radiation therapy (TRT) (2400 cGy) during Consolidation therapy, if testicular disease does not resolve by the 
end of Induction therapy. T-NHL patients with CNS3-positive disease and testicular disease patients will not 
be eligible for this study, as only CMTX-based therapy will be offered to T-NHL patients. Low Risk patients, 
who are NCI standard risk by age and WBC, with no testicular disease at diagnosis, CNS1 and rapid early 
responders (RERs) with an M1 marrow by Day 15, and minimal residual disease (MRD) < 0.1% on Day 29, 
have an excellent outcome and therefore will not receive Nelarabine in either the safety or efficacy phases; nor 
will they receive CRT. 
 
 


 
 
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EXPERIMENTAL DESIGN SCHEMA: T-ALL SAFETY PHASE (COMPLETED) 
 
 
 
 
 
High Risk 
AALL03B1 
T-ALL Phenotype 
AALL0434 (on study) 
Induction*
Response Assignment 
M3 
Marrow 
Intermediate 
Risk 
Low Risk 
Randomization 
HDMTX** 
Arm C 
CMTX 
Arm A 
Consolidation 
 
Consolidation 
 
IM† 
HDMTX 
IM† 
CMTX 
Maintenance 
 
DI 
 
Maintenance 
 
DI 
 
Testicular XRT during 
Consolidation if testicular 
disease not resolved by end-
Induction 
CRT& 
Intermediate and High 
Risk pts during DI or 
Consolidation 
Consolidation 
+ Nelarabine 
If M1 Continue as HR 
on ARM D 
HDMTX + Nelarabine†*** 
Randomization 
HDMTX** 
-/+ Nelarabine 
Arm C or D 
CMTX 
-/+ Nelarabine 
Arm A or B  
Consolidation 
-/+ Nelarabine 
Consolidation 
 -/+ Nelarabine 
IM† 
HDMTX 
IM† 
CMTX 
Maintenance 
-/+ Nelarabine 
DI 
-/+ Nelarabine 
Maintenance 
-/+ Nelarabine 
DI 
-/+ Nelarabine  
* Induction evaluation = Day 8 BMA; if not M1 then repeat on Day 15.  
 
 
       Evaluation of BMA and MRD on Day 29.  
** Patients with CNS3 and/or testicular disease at Dx will be assigned to HDMTX arms 
***Patient may also be taken off study for alternate therapy, including BMT 
†Patients must be M1 at end-Consolidation to continue on therapy 
RER = M1 marrow on Day 8 and < 0.1% MRD on Day 29 OR 
            M2/M3 marrow on Day 8 and M1 marrow on Day 15 and 
            < 0.1% MRD on Day 29. 
SER = M2/M3 on Day 15 OR positive MRD on Day 29. 
Low Risk = NCI SR by age & WBC count; RER, M1 on Day 15 and MRD < 0.1% on Day 
29; CNS 1 status; and no testicular disease at diagnosis. 
Intermediate Risk = RER or SER with MRD < 1% on Day 29; any CNS status. 
High Risk = M2 at end of Induction or MRD ≥ 1% on Day 29; any CNS status. 
CMTX = Capizzi escalating MTX  
HDMTX = High dose MTX 
IM = Interim Maintenance 
DI = Delayed Intensification 
 
Patients with a prior seizure disorder will not 
receive Nelarabine. 
 
& CRT = cranial radiation (See Section 14.0 for 
details).   
The safety phase ends when the 1st 20 High Risk pts to receive Nelarabine have been evaluated per Section 
DURING THE SAFETY 
PHASE INTERMEDIATE 
RISK PATIENTS WILL 
NOT RECEIVE 
NELARABINE; 
LOW RISK PTS NEVER 
RECEIVE NELARABINE 
ON THIS STUDY AND 
ARE RANDOMIZED TO 
ARM A OR C ONLY 


 
 
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EXPERIMENTAL DESIGN SCHEMA: T-ALL EFFICACY PHASE (OPEN) 
 
 
 
  
 
AALL08B1 
T-ALL Phenotype 
AALL0434 (on study) 
Induction* 
Response Assignment 
M3 
Marrow 
High Risk 
Intermediate Risk 
Low Risk 
Randomization 
Randomization 
HDMTX 
Arm C 
CMTX 
Arm A 
HDMTX** 
-/+ Nelarabine 
Arm C or D 
CMTX 
-/+ Nelarabine 
Arm A or B  
Consolidation 
 
Consolidation 
 
Consolidation 
-/+ Nelarabine 
Consolidation 
-/+ Nelarabine 
IM† 
HDMTX 
IM† 
CMTX 
IM† 
HDMTX 
IM† 
CMTX 
Maintenance 
 
DI 
 
Maintenance 
 
DI 
 
Maintenance 
-/+ Nelarabine 
DI 
-/+ Nelarabine 
Maintenance 
-/+ Nelarabine 
DI 
-/+ Nelarabine 
Testicular XRT (TRT) during 
Consolidation if testicular 
disease not resolved by end-
Induction 
CRT& 
Intermediate and High 
Risk pts during DI or 
Consolidation 
Consolidation 
+ Nelarabine  
If M1 continue as HR 
on Arm D  
HDMTX + 
Nelarabine†*** 
* Induction evaluation = Day 8 BMA; if not M1 then repeat on Day 15.  
 
 
       Evaluation of BMA and MRD on Day 29.  
** Patients with CNS3 and/or testicular disease at Dx will be assigned to HDMTX arms 
***Patient may also be taken off study for alternate therapy, including BMT 
†Patients must be M1 at end-Consolidation to continue on therapy 
RER = M1 marrow on Day 8 and < 0.1% MRD on Day 29 OR 
            M2/M3 marrow on Day 8 and M1 marrow on Day 15 and 
            < 0.1% MRD on Day 29. 
SER = M2/M3 on Day 15 OR positive MRD on Day 29. 
Low Risk = NCI SR by age & WBC count; RER, M1 on Day 15 and MRD < 0.1% on Day 
29; CNS 1 status; and no testicular disease at diagnosis. 
Intermediate Risk = RER or SER with MRD < 1% on Day 29; any CNS status. 
High Risk = M2 at end of Induction or MRD ≥ 1% on Day 29; any CNS status. 
CMTX = Capizzi escalating MTX  
HDMTX = High dose MTX 
IM = Interim Maintenance 
DI = Delayed Intensification 
 
Patients with a prior seizure disorder will not 
receive Nelarabine. 
 
& CRT = cranial radiation (See Section 14.0 for 
details).  
 
IN THE EFFICACY PHASE 
INTERMEDIATE AND HIGH 
RISK PATIENTS WILL BE 
RANDOMIZED TO ALL 
FOUR ARMS OF THE 
STUDY; LOW RISK PTS 
NEVER RECEIVE 
NELARABINE ON THIS 
STUDY AND ARE 
RANDOMIZED TO ARM A 
OR C ONLY 


 
 
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EXPERIMENTAL DESIGN SCHEMA: T-NHL EFFICACY PHASE 
 
 
Non-Random 
Assignment 
 
Maintenance 
Nelarabine† 
 
CMTX 
Arm B 
Consolidation# 
Nelarabine 
 
IM 
CMTX 
DI 
Nelarabine 
IN THE EFFICACY PHASE 
T-NHL PTS WILL BE 
RANDOMIZED TO ARMS A 
OR B ONLY; STANDARD 
RISK  
T-NHL PTS NEVER 
RECEIVE NELARABINE 
*Patients with testicular disease or CNS3 disease are ineligible for this study. T-NHL patients 
do not receive cranial radial therapy on any arm of this study. 
**Induction evaluation = Day 29 bone marrow (if positive at diagnosis); end of Induction imaging 
(computed tomography (CT) bone scan as indicated per Section 7.2). 
# End of Consolidation evaluation: BM and CT  bone scan as indicated per Section 7.1. Patients 
who are not PR at end of Consolidation are off protocol therapy. 
† Maintenance will be two years from the start of IM for both boys and girls. 
Patients with a prior seizure disorder will not receive Nelarabine. 
End Induction Imaging 
Response Assignment 
AALL0434 (on study) 
Induction** 
BM MRD Risk 
Assignment (At Diagnosis) 
T-NHL Phenotype* 
Induction Failure 
(Any Lymphoblasts BM Day 1) 
Day 29 NR by CT 
 
Maintenance† 
Standard Risk 
(< 1% Lymphoblasts BM Day 1) 
Day 29 CR or PR 
Non-Random 
Assignment 
 
CMTX 
Arm A 
 
Consolidation# 
 
IM 
CMTX 
 
DI 
CMTX = Capizzi escalating MTX  
HDMTX = High dose MTX 
IM = Interim Maintenance 
DI = Delayed Intensification 
High Risk 
(≥ 1% Lymphoblasts BM Day 1 
OR any level steroid pre-treatment) 
Day 29 CR or PR 
 
Maintenance† 
 
CMTX 
Arm A 
 
Consolidation# 
 
IM 
CMTX 
 
DI 
 
Randomization 
 
Maintenance 
Nelarabine† 
 
CMTX 
Arm B 
Consolidation# 
Nelarabine 
 
IM 
CMTX 
DI 
Nelarabine 


 
 
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1.0 
GOALS AND OBJE CTIVES (SCIENTIFIC A IMS) 
 
1.1 
Main Clinical Objectives 
 
1.1.1 
To determine, through randomization, the relative safety and efficacy of the addition of 
Nelarabine (Compound 506U78) to augmented BFM therapy (Regimen C, CCG-1961).  
 
1.1.2 
To determine the relative safety and efficacy of high dose methotrexate (5 g/m2) with leucovorin 
rescue compared to escalating methotrexate without leucovorin rescue plus Pegaspargase 
(Capizzi I) delivered during Interim Maintenance. 
 
1.1.3 
To gain preliminary data on the use of Nelarabine in patients with High Risk T-cell 
lymphoblastic lymphoma and its effect on long-term survival. 
 
1.2 
Secondary Clinical Objective 
 
1.2.1 
To determine the relative safety and efficacy of withholding radiation in patients with Low Risk T-
ALL, while treating Intermediate and High Risk patients with 1200 cGy of prophylactic cranial 
radiation. 
 
 
2.0 
BACKGROUND  
T-cell lymphoid malignancies have distinct biochemical, immunologic and clinical features 
which set them apart from non-T-lymphoid malignancies.1-6 Historically, the diagnosis of T-ALL 
portended a worse prognosis than other forms of non-T childhood ALL.1,7,8 Over the past three 
decades, the introduction of intensive, high-dose, multi-agent pulse chemotherapy has 
significantly improved the EFS for patients with T-ALL from 15%-20% to 40%-73%.9-12 Current 
trials have further improved outcomes for children with T-ALL, but have plateaued in the 70%-
75% EFS range, as shown by Dana Farber Cancer Institute (DFCI) 85-01, 13 DFCI 87-01 and 
Berlin-Frankfurt-Münster (BFM)-86.14 The recent Pediatric Oncology Group (POG) T-cell ALL 
protocol, POG 9404, randomized the addition of high dose methotrexate (HDMTX) to the DFCI 
regimen and found a statistically significant improvement in 4-year EFS rates for NCI High Risk 
patients treated with and without HDMTX of 77.9% vs. 65.5%, respectively. The 76.9% EFS at 
5 years for patients with T-ALL, treated on CCG 1961, regimen C, without HDMTX, is 
comparable to that seen on 9404 with HDMTX. The majority of patients with T-ALL and NCI 
standard-risk features clearly fare better with more aggressive therapy, as demonstrated by EFS 
rates of 71% on CCG 1952/1962 versus 87.4% on POG 9404 (89.2% within the HDMTX arm). 
Based on a projected 2 year EFS rate of 85% for T-cell patients compared to 94% for pre-B ALL 
patients treated on the CCG 1991 study [RHR of 3.12 (p = .002)], T-ALL patients will no longer 
be eligible for COG SR-ALL trials and will be treated on the T-cell specific AALL0434 trial. 
 
Lymphoblastic lymphoma (LL) accounts for approximately 25% of all pediatric non-Hodgkin 
lymphoma (NHL) cases. The history of the treatment for LL over the past 3 decades reflects the 


 
 
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evolution of treatment from conventional lymphoma-based treatment to ALL-based 
treatment.11,15-17 With current therapies for LL, the majority of patients, including those with 
advanced stage disease, can expect a likelihood of 80%-90% disease free survival (DFS) 
utilizing regimens modified from ALL-based regimens. While effective, this intensive 
chemotherapy does produce short- and long-term side effects.18 Unfortunately, identifying risk 
categories for this disease has been difficult.19,20 Even conventional staging classifications have 
failed to segregate High Risk patients from the remaining population as most studies have failed 
to demonstrate major survival differences between patients of different stages. In addition, the 
salvage rate remains poor for LL patients who relapse, with survival of these patients ranging 
from 10%-15%. The ability to identify High Risk patients likely to recur early in the course of 
therapy would provide the opportunity to test novel therapies in these patients. 
 
Rarely does one find a drug with lineage-specific cytotoxicity as recently discovered for 
Nelarabine. Nelarabine (2-amino-9-B-D-arabinofuranosyl-6-methoxy-9H-purine) is a water-
soluble prodrug of araG (9-B-arabinofuranosylguanine), a synthetic deoxyguanosine derivative 
that is resistant to cleavage by endogenous purine nucleoside phosphorylase and is cytotoxic to 
T-lymphoblasts at micromolar concentrations. Cytotoxicity is mediated by the accumulation of 
araG nucleotides, especially d-araGTP, in T-cells greater than in B-cells, resulting in inhibition 
of ribonucleotide reductase and inhibition of DNA synthesis. This differential cytotoxicity 
between B-cells and T-cells has created interest in using this compound to treat T-cell 
malignancies. 
 
Earlier T-ALL studies have not included risk stratification due to the lack of predictive clinical 
or laboratory based prognosticators.6,12 Recently, the international BFM and GIMEMA 
cooperative groups reported that children and adults with Day 29 MRD levels of greater than 1% 
were at a very high risk of relapse.21,22 In the International BFM study, patients who had MRD 
levels of 10-2 or greater had five to ten fold higher relapse rates at 3 years (39% - 86%), and in 
the GIMEMA study, the probability of relapse at 2 years for MRD-positive patients at 
preconsolidation was 81.5% vs., 38.9% for MRD-negative patients. In addition, measurable 
MRD, of prognostic significance, was identified more often in children with T-ALL than those 
with B-lineage ALL.22 Based on these results, MRD-based treatment stratification will be used in 
AALL0434. Low levels of MRD at end Induction (< 0.1%) will be required along with other 
clinical features to be classified as Low Risk (LR), and high levels of end-Induction MRD (≥ 
1%) will be considered equivalent to an M2 (5%-25% blasts) marrow. 
 
In an attempt to develop better prognostic indicators for T-NHL, A5971 tested the feasibility of 
detecting low levels of disease in marrow and peripheral blood at diagnosis and its clearance in 
peripheral blood during Induction, using a BFM leukemia treatment backbone. Analysis from the 
completed trial revealed that 72% of patients had lymphoma cells (CD3+/TdT+ cells) detectable 
in the bone marrow and blood by flow cytometry, although most patients had no lymphoma cells 
detectable morphologically. High levels of disease by flow cytometry were significantly 
associated with a poorer outcome: 2-year EFS was 68.1% ± 11% for patients with > 1% 
lymphoblasts detected in the bone marrow at the time of diagnosis, as compared to 
90.7% ± 4.4% for patients who had less disease detected (P = 0.031). Thus, it appears that 
quantitation of low levels of disease in the bone marrow can identify High Risk patients for 
treatment stratification. 


 
 
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2.1 
Rationale for Augmented Intensity BFM Therapy 
The CCG 1961C or augmented BFM (aBFM) with one Delayed Intensification phase (aBFM) 
regimen will be used as the standard backbone therapy for this study. Patients will be 
randomized to receive high dose methotrexate (HDMTX) versus Capizzi-style methotrexate plus 
PEG Asparaginase (CMTX) in Interim Maintenance and to either receive or not to receive 
Nelarabine in Consolidation, Delayed Intensification and Maintenance. MRD will be monitored 
at the end of Induction, and at the end of Consolidation/beginning of Interim Maintenance for 
observational correlations with response to therapy among patients who are at an increased risk 
of relapse (High Risk patients as defined below, patients with a slow early response and those 
that fail Induction). 
 
The aBFM backbone was chosen over POG 9404 for the following reasons: 1) The overall result 
for aBFM was accomplished without the use of CRT in patients with a rapid early response; 2) 
The aBFM regimen includes significantly less anthracycline; 3) aBFM is most similar to the 
POG pilot study, AALL00P2 which incorporates Nelarabine into a multi-agent backbone, 
allowing for the application of pilot toxicity data to the incorporation of Nelarabine in a 
randomized trial; 4) aBFM is the backbone for COG AALL0232 for patients with High Risk B-
lineage disease. The use of the same aBFM backbone, for patients with B and T-lineage ALL 
will increase provider familiarity with the therapy, enhancing patient care and, importantly, 
allowing for the continued comparison of response measures, including the significance of MRD 
among patients with T- and B-lineage leukemias, and; 5) MRD measurements using the BFM 
backbone have produced compelling European data that response to Induction chemotherapy 
may be useful as a tool for risk-stratification.22 
 
To further assess the toxicity of Nelarabine in the context of multi-agent chemotherapy, 
Nelarabine was incorporated into a modified BFM86 backbone in AALL00P2, which opened for 
accrual in April 2001, using Nelarabine at 400 mg/m2/day, Days 1 through 5. During the first 
phase of AALL00P2, no Grade 3 or higher central or peripheral nervous system toxicities 
attributable to Nelarabine were observed. Based on these results, AALL00P2 was re-opened and 
amended to increase the Nelarabine dose from 400 to the Phase II-recommended dose of 650 
mg/m2. To supplement the data accrued on AALL00P2, MRD positive patients with T-ALL 
(High Risk) will be randomly assigned in AALL0434 to either receive or not to receive 
Nelarabine at 650 mg/m2 IV daily for 5 days. This cohort of patients will be assessed for toxicity 
at approximately 24 months and again at 36 months into the trial. During this analysis, only High 
Risk patients will continue to be randomized to all four arms of the study. If patients receiving 
Nelarabine are found to have an acceptable toxicity profile during this safety phase, the study 
will be opened to also allow randomization of Intermediate Risk patients to all four arms of the 
study during the efficacy phase. 
 
The efficacy phase will include a post-Induction randomization to receive or not receive 
Nelarabine for all Intermediate and High Risk patients. Low Risk patients (NCI standard Risk, 
RER, without testicular disease at diagnosis, CNS1 and Day 29 MRD < 0.1%) will be eligible 
for randomization to aBFM with either Capizzi methotrexate or High Dose methotrexate [Arm A 
(CMTX) or Arm C (HDMTX), respectively]. They will not be eligible for the Nelarabine 
randomization, and will not receive CRT because these patients have an excellent outcome and, 
due to their young age, are more susceptible to neurotoxicity. T-NHL patients will be assessed 


 
 
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for the presence of disease in the bone marrow at diagnosis using flow cytometry. Patients with 
≥ 1% disease in the bone marrow or any level of steroid pre-treatment will be considered High 
Risk and randomized to either Arm A (CMTX) or Arm B (CMTX + Nel). Those with < 1% 
disease in the bone marrow will be considered Standard Risk and will be non-randomly assigned 
to Arm A (CMTX). Results from two prior group wide studies (POG9404 and A5971) have 
failed to demonstrate a superior outcome for patients receiving HDMTX. Thus, a design that 
would include yet another randomization of these patients to the addition of HDMTX is not 
justified. As a result treatment assignment for patients classified as High Risk for T-NHL will be 
restricted to be randomized to either Arm A (CMTX) or Arm B (CMTX + Nel). Please see 
Section 3.3.5 for details regarding T-NHL risk classification. CRT will not be delivered to any 
lymphoma patients on this study as recent reports have demonstrated excellent outcomes without 
radiation. Treatment plans for T-NHL risk groups are designed to closely parallel those for the T-
ALL risk groups. Since patients with high risk T-NHL do not get cranial radiation in contrast to 
patients with T-ALL, those high risk patients randomized to Arm A invariably receive 4 less IT 
Methotrexate administrations during Maintenance compared to patients with standard risk T-
NHL non-randomly assigned to treatment Arm A. This difference in the total number of IT 
administrations (21 for standard risk verses 17 for high risk T-NHL) is not felt to be significantly 
different and is comparable to the number of IT administrations in the recently closed A5971 (19 
for Arms A1 and A2, 13 for Arms B1 and B2) which had excellent CNS disease control. CNS-
positive and testicular disease T-NHL patients will not be eligible for this study. 
 
This study fits in with development of other studies within the ALL committee by using a 
backbone which allows for comparative data, utilizing a new agent with disease specificity and 
allowing for incorporation of biologic questions and cancer control questions within the context 
of the clinical trial. 
 
The use of CRT with aBFM for patients with T-ALL may significantly enhance the outcome for 
patients with T-ALL, whose failures on CCG 1961 disproportionately involved the CNS. 
Additionally, aBFM did not include high dose MTX. In vitro and ex vivo studies of T-
lymphoblasts demonstrate a decrease in accumulation and polyglutamation of MTX when 
compared to B-lineage blasts23-27. Consistent with these observations, POG 9404 demonstrated a 
clear improvement in outcome for T-lineage NCI standard and high risk patients through the 
addition of HD MTX and BFM-90 produced a superior EFS as compared to BFM-86 with an 
increase in the MTX dose from 0.5 to 5.0 gm/m2.28 Thus, it is important to assess, in a 
randomized study, whether the addition of HD MTX to aBFM will enhance outcome. 
 
Osteonecrosis (ON) 
Results from CCG-1961 showed that the use of discontinuous dexamethasone (Days 1-7 and 15-
21, rather than Days 1-21) during DI decreased the rate of ON. Specifically, the rate of ON 
among patients 10+ years of age on CCG-1961, all of whom received prednisone during 
Induction therapy, was 18% for those treated with continuous dexamethasone in a single DI 
(regimen C) vs. 6% for those treated with discontinuous dexamethasone in 2 DI phases (regimen 
D). However, very little ON was observed in CCG-1961 among patients less than 13 years of 
age. Based on these findings, the COG High Risk ALL study (AALL0232) initially used 
discontinuous dexamethasone during DI for patients 13+ years of age, and continuous 
dexamethasone during DI for patients 1-12 years of age. Interim analysis of AALL0232 in 2006 


 
 
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revealed a higher than expected rate of ON in 10-12 year olds receiving continuous 
dexamethasone during DI. Based on these findings, AALL0232 Amendment #3A (09/11/06) 
changed dexamethasone dosing during DI to discontinuous for patients 10-12 years of age. 
 
Ongoing analysis in April 2008 demonstrated higher than expected reported incidence of ON in 
AALL0232 as compared to that observed in CCG-1961. The overall incidence of ON at 24 
months is 10.4%. The incidence of ON is related to patient age and type of Induction steroid. The 
incidence rates by age group are 1-9 years: 2.7%, 10-12 years: 16.0%, and 13+ years: 14.7%. 
Patients who received dexamethasone during Induction have experienced a higher rate of ON 
compared to those who received prednisone (11.6 vs. 8.7%; p-value = 0.014); although there is 
no difference in ON rates in patients 1-9 years of age related to steroid administered during 
Induction therapy (2.2% dexamethasone vs. 2.6% prednisone). 
 
While it is too early in the conduct of AALL0434 to analyze the occurrence of ON in this trial, 
AALL0434 therapy is highly similar to that administered in AALL0232 and the risks for ON are 
likely very similar. Amendment #2A implements several changes in steroid administration to 
attempt to decrease the rate of ON. All patients, regardless of age, will receive discontinuous 
dexamethasone dosing during DI. In addition, all patients, regardless of age, will receive every 4 
week 5-day pulses of prednisone 40 mg/m2/day, rather than dexamethasone 6 mg/m2/day, during 
Maintenance therapy. 
 
2.2 
Preliminary Data 
In a phase I study of Nelarabine a striking response rate was observed.  Fourteen complete (CR) 
and 9 partial responses (PR) were documented among 28 evaluable patients with relapsed T-
ALL. Responses were observed at all dose levels (5 mg/kg - 75 mg/kg), with Nelarabine given 
on Days 1-5. Dose-limiting neurotoxicity, consisting of weakness, ataxia, confusion and coma, 
was observed in 3 of 4 adults treated at the 60 mg/kg dose level, 2 of 31 adults treated at the 40 
mg/kg dose level, and 1 of 11 children treated at the 60 mg/kg dose level. No neurotoxicity was 
observed in children treated at the 40 mg/kg or 1200 mg/m2 level.29 Thirty percent of the adults 
treated at a dose of 40 mg/kg experienced reversible somnolence on Day 6-7 after starting 
therapy with Nelarabine. POG P9673, a pediatric Phase II trial of Nelarabine in T-ALL and T-
NHL accrued 153 (two were ineligible for evaluation) patients from June 1997 to July 2002. By 
definition, all patients treated with Nelarabine on this trial had failed earlier therapy, which 
incorporated other known neurotoxic agents. Patients in first bone marrow relapse had a 
complete response rate of 55%, and 27% of patients with a second or subsequent relapse 
achieved a CR. Available details about the PNS (≥ Grade 2) and CNS (≥ Grade 3) toxicities 
reported from POG 9673 are presented in Tables 1 and 2. Among 151 patients who received at 
least 1 dose of Nelarabine, there were 47 episodes of any Grade of CNS or PNS toxicity in 34 
patients (23%). Twenty-five patients experienced CNS or PNS toxicities that were possibly or 
probably attributable to Nelarabine (Table 1), while 9 patients experienced neurotoxicity unlikely 
to be related to Nelarabine (Table 2). Twelve of the 25 patients experiencing Nelarabine-related 
neurotoxicity, twelve (nearly half) had complete resolution of neurologic signs and symptoms 
within a few hours to one year. Eight experienced toxicity with insufficient follow-up to 
determine the completeness of resolution; four patients died from other causes prior to resolution 
of their neurologic findings and one patient died, comatose, with the death attributed to 
Nelarabine. Based on these data it appears that even in a heavily pretreated group of patients that 
the majority of PNS and/or CNS events will resolve. 


 
 
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Table 1 
(table continues on next page) 
Patient Dose (mg/m2) PNS Grade CNS Grade Comments 
1200 
 
4 
Somnolence; died of progressive disease before resolution 
900 
 
3 
Somnolence; resolved without problem 
900 
2 
 
Lower extremity weakness; resolved within 1 year 
900 
4 
3 
Guillain-Barré like polyneuropathy after 4 doses; died before 
resolution 
650 
 
4 
Seizures 5 days after Nelarabine, 2 days after intrathecal therapy in 
second cycle. Started on anticonvulsants; did not recur. 
650 
2 
 
Lower extremity paresthesias after 7 cycles; resolved within weeks 
650 
3 
 
Lower extremity weakness after 3 cycles; resolved within 3 
months 
650 
3 
1 
Lower extremity paresthesias after 1 cycle; lost to follow-up 
650 
3 
1 
Lower extremity paresthesias after 3 cycles 
650 
2 
1 
Lower extremity weakness after 7 cycles; stable 2 months off 
therapy 
650 
 
5 
Death from Nelarabine preceded by coma; history of 1 prior 
seizure; etiology unknown 
650 
2 
 
Lower extremity paresthesias cycle 4; resolved within 5 months 
650 
3 
 
Painful lower extremity paresthesias cycles 1 and 2; improved 
over 3 months but died prior to complete resolution 
650 
2 
2 
Headache, lower extremity paresthesias with second dose; not 
rechallenged. 
650 
3 
 
Hand numbness/ neck pain attributed to musculoskeletal origin 
650 
 
3 
Hallucination after 1 dose; rechallenged without recurrence 
650 
3 
2 
Lower extremity weakness after 4 doses; improved within days 
650 
 
4 
Seizure 22 days after Nelarabine during metabolic derangement 
650 
2 
2 
Headache, lower extremity paresthesias, in cycle 2. Neurologic 
exam normal 2 months later. 
400 
 
3 
Somnolence during acute illness; resolved 
400 
4 
 
Guillain-Barré like polyneuropathy after high dose cytarabine 6 
weeks after last Nelarabine; died before resolution 
400 
4 
3 
Cranial nerve palsy attributed to Nelarabine by treating physician 
400 
2 
4 
Grade 2 hand and foot pain during course 1; did not recur during 
course 2. 9 weeks after last Nelarabine developed retrobulbar 
neuritis/demyelinating disease after stem cell transplant 
400 
2 
 
Hand/foot numbness during cycle 1, resolved within 24 hours 
400 
 
3 
Headache  during Nelarabine infusion 
 
Table 1.  Details of PNS and CNS adverse events that were likely attributable to Nelarabine on P9673 
 
 


 
 
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Table 2 
Dose 
(mg/m2) 
PNS 
Grade 
CNS 
Grade 
Comments 
900 
 
3 
Hallucinations while septic; resolved 
900 
3 
 
Foot drop attributed to prior vincristine 
400 
4 
 
Weakness, loss of reflexes; associated with fungal brain abscess and hemorrhage during 
first cycle; died before resolution 
400 
3 
3 
Back pain and lower extremity weakness after cycle 1 due to spinal cord metastases 
400 
1 
3 
Seizure (?) due to dilantin toxicity; rechallenged with Nelarabine without problem 
400 
 
3 
Intermittent confusion during terminal illness 
400 
 
3 
Hallucinations attributed to narcotics; resolved 
400 
 
4 
Seizure after first dose of intrathecal therapy on first course; associated with increasing CSF 
blasts 
400 
3 
1 
Due to disease; improved on Nelarabine 
 
Table 2.  Details of CNS and PNS adverse events unlikely to be attributable to Nelarabine on P9673 
 
COG Study AALL00P2 (opened for accrual in April 2001) incorporated Nelarabine into a 
modified BFM86 backbone and gave Nelarabine at 400 mg/m2/daily for 5 days during weeks 6, 
25, 35, 43, 51 and 59 of therapy. In phase I of this study, no Grade 3 or greater central or 
peripheral nervous system toxicities attributable to Nelarabine, given with either 1260 cGy CRT 
(CNS1/CNS2) or 1800 cGy (CNS3) and HDMTX, were observed. Based on this very re-assuring 
absence of significant neurotoxicity, AALL00P2 was re-opened with an amended increase in the 
Nelarabine dose from 400 mg/m2 IV Days 1-5 to the Phase II recommended dose of 650 mg/m2 
IV daily for 5 days. 
 
Several large study groups have reported that MRD analyses are more reliable for risk 
classification in childhood ALL than age, presenting white blood count (WBC), extramedullary 
disease and other existing clinical and biological predictors.30-33 Leukemic cell phenotype 
contributes to the prognostic value of MRD detection, as recently demonstrated by outcome 
predictions that were more accurate for patients with T-ALL than for children having precursor 
B-ALL.22,34 The measurement of MRD at critical time points during the ALL treatment course is 
an important method to gauge the effectiveness of therapy. Using flow-based techniques, the 
detection of one or more leukemic cells among 10,000 normal bone marrow cells was associated 
with an increased risk of relapse, but especially so for patients with more than 1% leukemic 
blasts at the end of Induction.31-34 Alternatively, favorable EFS rates were realized in cases where 
MRD was first detected but later became undetectable during the treatment course, underscoring 
the importance of intensive post-Induction chemotherapy as a means of eradicating residual 
disease burden.33 As previously noted for other patients with higher risk ALL, such as those with 
the Philadelphia chromosome,35,36 children with T-ALL are more likely to have detectable levels 
of MRD at the end of Induction and at later points during treatment.22,34 As a result of this 
supportive data, we propose to use MRD-based risk stratification strategies to either intensify or 
reduce therapy in this study. 
 
Experience on COG P9900 with over 3000 ALL patients has shown that flow cytometric 
detection of end-Induction MRD is feasible in more than 95% of patients, and that end-Induction 


 
 
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MRD burden correlated with 3 years EFS. This method of MRD detection will be used in 
contemporary COG ALL trials. Preliminary data from COG P9900 suggest that MRD 
measurement in peripheral blood (PB) by flow cytometry at Day 8 Induction adds prognostic 
value to Day 29 MRD burden in B-precursor ALL. To confirm and extend these data, frontline 
COG ALL studies (AALL0434, AALL0232 and AALL0331) will include optional Day 8 PB 
MRD determinations. In addition, we also wish to explore whether assessment of BM MRD at 
Day 15 of Induction may help to improve our ability to discriminate between good and bad 
responders. Currently, about 50% of patients have a BM aspiration performed to assess 
morphology at Day 15 of Induction (all patients not M1 at Day 8). Day 15 MRD samples will be 
sent to COG Reference labs for those patients already scheduled to have a BM aspiration 
performed. Consent for these extra specimens is included with AALL08B1. 
 
2.3 
Determination of Early Response 
All T-ALL patients on study will be stratified on the basis of early response as assessed by 
marrow morphology at Day 8/15 and MRD on Day 29. Patients who are M1 on Day 8 will be 
considered rapid early responders (RER) pending the results of Day 29 BM and MRD levels. 
Patients who are M2 or M3 on Day 8 will have a Day 15 BMA and, if M1 on Day 15, they will 
be considered RER pending results of Day 29 MRD. Patients who are M2 or M3 on Day 15 will 
be considered SER, regardless of Day 29 MRD result. All patients with ≥ 0.1% MRD on Day 29 
are considered SER regardless of Day 8/15 marrow morphology. Treatment randomization will 
be affected by categorization into Low, Intermediate and High Risk status. Low Risk patients are 
those who are NCI standard risk by age and WBC, lack testicular disease at diagnosis, are CNS1, 
and are RERs (M1 marrow on Day 8 or 15, and have an M1 marrow with < 0.1% MRD on Day 
29). Low Risk patients are excluded from receiving Nelarabine and CRT (see Sections 4.1.1 and 
10.1 for further details). 
 
High Risk T-ALL patients are those who are either NCI standard or high risk, RER or SER 
status, and have an M2 marrow or ≥ 1% MRD on Day 29. Patients in the High Risk category will 
be eligible for randomization to all four study arms during both the safety and efficacy phases of 
this study. 
 
Intermediate Risk T-ALL patients are those who are NCI standard risk with SER, CNS2 or 
CNS3 disease, or testicular disease, or NCI high risk, RER or SER, any CNS and testicular 
status, but with an M1 marrow on Day 29 with less than 1% MRD. They will be eligible for 
randomization to receive Nelarabine in the efficacy phase (which is now open), but not the safety 
phase of this study (which is now closed). This trial does not include the administration of a 
second Interim Maintenance or Delayed Intensification for the SER patients, as was included in 
CCG 1961. Support for this change in therapy is derived from the absence of any definable 
subset of NCI high risk RER patients that gained benefit from the second IM/DI on CCG 1961. 
Statistically, this suggests that the smaller subset of SER patients, are also unlikely to derive 
significant benefit from the second IM/DI. The continued assessment of RER vs SER status is 
required, however, to allow for an ongoing evaluation of outcome for the SER patients. Should 
they fare poorly on this trial as opposed to 1961; the study will be closed to the SER patients 
while therapy is adjusted. 
 
T-ALL patients with M3 marrow on Day 29 will be considered Induction failures. Given the 
notable responses to Nelarabine for patients with refractory disease, patients who have failed 


 
 
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Induction will be eligible to remain on study, and will be non-randomly assigned to receive 
Nelarabine and HD MTX. If patients in this subset have an M3 marrow after the first block of 
therapy during Consolidation, they are to be taken off study and treated at the investigator’s 
discretion. Moreover investigators may decide on subsequent non-protocol therapy such as bone 
marrow transplantation after exposure to Nelarabine. These patients may be taken off study 
without penalty. 
 
Risk assessment for T-NHL patients will be based upon disease burden in the bone marrow at 
diagnosis and disease response, as measured radiographically and by bone marrow morphology, 
at the end of Induction. The results to date from A5971 indicate that we possess the means to 
detect minimal disease in bone marrow and peripheral blood samples in T-NHL patients, and 
that the extent of disease, as measured by flow cytometry at diagnosis in the bone marrow, may 
predict those patients at increased risk for bone marrow recurrence. Review of data from A5971 
found that all relapses in patients with low or undetectable disease in the bone marrow at 
diagnosis were at the primary site only and not in the bone marrow. Thus, disease quantification 
in the bone marrow at diagnosis may be limited to assessing the risk of relapse in the bone 
marrow and may fail to identify patients at risk for local recurrence. An additional means of 
assessing disease burden using radiologic methods may complement analysis of the marrow to 
fully characterize a patient’s risk status. Thus, conventional CT will be obtained at diagnosis and 
at the end of Induction to assess radiologic clearance of bulky disease. 
 
T-NHL patients with < 1% disease in the marrow at diagnosis will be considered Standard Risk 
and non-randomly assigned to Arm A (CMTX). T-NHL patients with ≥ 1% disease in the 
marrow at diagnosis or any level of steroid pre-treatment will be designated as High Risk and, at 
the end of Induction, will be randomized to either Arm A (CMTX) or Arm B (CMTX + Nel). 
Patients who fail to achieve at least a radiologic partial response (PR) or clearance of their 
marrow by morphology at the end of Induction will be considered Induction Failures and non-
randomly assigned to Arm B (CMTX + Nel). 
 
2.4 
Integration of Radiation Therapy 
Patients with T-ALL have an increased risk of relapse in the central nervous system and CNS 
relapse has become a major cause of treatment failure with improved prevention of BM relapse 
using the ABFM regimen. To date, there have been a total of 77 relapses among 411 T-ALL 
patients enrolled in CCG 1961, including 24 CNS relapses (31% of total relapses) (unpublished 
data, 12/05). Comparison of events between RER patients (who did not receive CRT) and SER 
patients (who received 1200 cGy CRT) suggests a critical role for CRT in CNS control for T-
ALL patients. There were 20 CNS relapses among 252 RER T-ALL patients (7.9%) versus 1 
CNS relapse among 121 SER T-ALL patients (0.8%). Twelve of the 20 CNS relapses in RER 
patients occurred in the first year of therapy, with approximately half occurring in the first 6 
months of therapy. These observations suggest that CRT is a critical component of therapy for T-
ALL patients treated with aBFM therapy and should be delivered relatively early in treatment. 
On this trial, Intermediate and High Risk patients assigned to CMTX (Arms A or B) will receive 
CRT during the Consolidation phase of theapy in the first 2-3 months of treatment. In contrast to 
these results, early administration of HD MTX allows CRT to be delayed in patients with T-
ALL. Among 123 patients with T-ALL enrolled in ALL-BFM 90 that had a good response to a 
prednisone prophase, there were only 3 relapses that involved the CNS (1 isolated CNS, 2 
combined marrow and CNS).37 Based on these and other similar data, CRT will be administered 


 
 
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during the second half of Delayed Intensification in those patients assigned to receive HDMTX 
in order to decrease the risk of neurotoxicity. 
 
CRT will not be delivered to any lymphoma patients on this study as recent reports have demonstrated 
excellent outcomes without radiation.38 The safety of withholding CRT in this study is reinforced by the 
results of the recently completed A5971. Two hundred fifty-seven patients with Stage III/IV disease with 
no CNS disease at diagnosis were treated without prophylactic XRT. Three patients (1.2%) subsequently 
were found to have disease in the CNS at relapse. These results were in the face of an excellent overall 
outcome of the patients in this study (80% 5 year EFS) (personal communication, Dr. Thomas Gross). 
Thus, the exclusion of prophylactic CRT for this population would not be expected to alter the disease 
control for these patients and would spare them of the long term effects of such therapy. 
 
As described above, COG Study AALL00P2 (opened for accrual in April 2001) incorporated 
Nelarabine into a modified BFM86 backbone and gave 1260-cGy CRT (CNS1/CNS2) or 1800 
cGy (CNS3) as well as four courses of HDMTX. In phase I of this study, no Grade 3 or greater 
central or peripheral nervous system toxicities attributable to Nelarabine were observed. Based 
on this very re-assuring absence of significant neurotoxicity, AALL00P2 was re-opened with an 
amended increase in the Nelarabine dose from 400 mg/m2 IV Days 1-5 to the Phase II 
recommended dose of 650 mg/m2 IV daily for 5 days. The study is now closed with only one 
episode of neurotoxicity (Grade 3 Guillain-Barre like syndrome) probably attributable and 2 
episodes of neurotoxicity possibly attributable (Grade 3 PNS, Grade 3 extrapyramidal) to 
Nelarabine among 65 patients enrolled at the 400 mg/m2 dose level and 8 patients enrolled on the 
650 mg/m2 dose level. All of these toxicities occurred at the 400 mg/m2 dosing level. 
 
Testicular leukemia is present in 1%-2% of boys with ALL at the time of initial diagnosis. The 
optimal treatment of testicular leukemia is unknown. While TRT is routinely administered to 
patients with testicular leukemia by some centers and cooperative groups, its role in preventing 
relapse is unproven and this treatment modality is associated with significant late toxicities. For 
these reasons, many large centers and cooperative groups do not routinely prescribe TRT for 
boys with overt testicular leukemia. A recent report from St. Jude Children’s Research Hospital 
concluded that irradiation appears to provide no survival advantage to this patient population.39 
In an effort to decrease the burden of therapy, contemporary COG ALL trials no longer 
recommend routine use of TRT for all boys with testicular leukemia. In this trial, boys with T-
ALL and overt testicular disease will be assigned to HDMTX regimens (Arms C or D). No TRT 
will be given to those patients with testicular leukemia that resolves by the end of Induction 
therapy; those that have persistent testicular involvement at end Induction will receive 2400 cGy 
TRT during Consolidation. T-NHL patients with testicular disease are not eligible for this study. 
 
2.5 
Biological Correlates 
T-ALL arises from transformed progenitors in the bone marrow (BM) microenvironment. Adjusted 
for NCI clinical risk status, patient outcome in High Risk T-ALL remains inferior to other 
childhood leukemias. This study seeks to identify new prognostic markers and identify new targets 
for pharmaceutical intervention. We will couple our previous work with BM stroma-supported 
growth of T-ALL cells and our gene microarray analysis in order to identify novel prognostic 
markers and new therapeutic targets. Our underlying premise is that tumor survival is dependent on 
signaling pathways, communicated in large part through cell-cell contact, that stimulate growth, 
angiogenesis, or the production of anti-apoptotic factors, all of which help sustain tumor cell 


 
 
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growth, spread, and survival. The “setting” in which these cellular interactions take place is often 
termed the microenvironment. The genetic alterations associated with malignancy may alter cellular 
responses to the microenvironment or alter the response of the microenvironment to the malignant 
cells. Thus, targeting the microenvironment for drug therapy has gained considerable interest, 
including small cell carcinoma, multiple myeloma, and other hematopoietic tumors. 
 
T-ALL cell survival in the BM microenvironment is a tightly regulated multistep process that 
involves many of the biologic features of normal T-cell precursor sub populations, as illustrated by 
shared patterns of cell surface protein expression.40-42 The careful analysis of clonal chromosomal 
abnormalities in leukemic blast cells has been a catalyst for the development of new diagnostic and 
therapeutic strategies. Since genetic alterations involving transcriptional regulators and other growth 
regulatory molecules may result in T-cell leukemogenesis43-45 and regulate minimal residual disease 
(MRD) status,21,22 we postulate that genetic alterations might directly or indirectly interfere with 
transcriptional networks that normally regulate T-ALL survival on BM stromal cells as well as 
patient response to therapy as measured by MRD. 
 
For T-NHL, specimens to characterize the biologic nature of the disease will focus on 4 major areas: 
1) immunophenotyping; 2) cytogenetic characterization by fluorescence in situ hybridization 
(FISH); 3) NOTCH mutation analysis; and 4) comparative genomic hybridization and gene 
expression profiling. Tissue should be collected prior to treatment initiation. Patients with T-NHL 
do not enroll onto AALL08B1. It is anticipated that there will be variability in the type and amount 
of tissue submitted, based upon the accessibility of the tumor tissue and the feasibility of obtaining it 
(i.e. patients with large mediastinal masses who are sedation risks will be expected to have limited 
tissue available). Minimum requirements for study entry will include sufficient tissue to confirm the 
diagnosis. Fresh tissue should be obtained whenever possible. All available biologic specimens 
should be sent to the COG Biopathology Center, which will serve as the central repository for this 
component of the study. The study committee will assess the state and quantity of material for 
subsequent studies, with allocation to designated laboratories placing priority in the studies. Please 
see Sections 15 & 16 for details regarding collection, processing, shipping and analysis of the tissue. 
 
2.6 
Exclusion of Patients with Down syndrome 
Due to a high number of toxic deaths seen in Down syndrome patients on AALL0232, and the 
many similarities in the basic therapeutic approaches for patients with Down syndrome between 
AALL0232 and this study, we are excluding this vulnerable patient population from enrollment 
onto AALL0434. At this time, we do not have specific recommendations for the management of 
T-ALL in patients with Down syndrome. 
 
2.7 
Phase 1 Safety Phase Data Analysis 
The required 20 High Risk (HR) patients were randomized to Arms B (CMTX + Nel) and D 
(HDMTX + Nel). Data current as of 02/15/2010 were used in the safety assessments by the 
DSMC. As of 02/15/2010, a total of 57 patients were randomized to either receive or not receive 
Nelarabine; of these 28 randomized to Nelarabine-containing regimens (12 on Arm B [CMTX + 
Nel] and 16 on Arm D [HDMTX + Nel]). A total of 29 patients were randomized to non-
Nelarabine containing regimens (13 on Arm A [CMTX] and 16 on Arm C [HDMTX]). All 
adverse event data submitted as of this date were included in the analyses. 
 
Post-Induction treatment regimens for the 57 High Risk patients: 


 
 
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• Arm A: CMTX, no Nelarabine (13) 
• Arm B: CMTX, plus Nelarabine (12) 
• Arm C: HDMTX, no Nelarabine (16) 
• Arm D: HDMTX, plus Nelarabine (16) 
 
Grade 3 and higher toxicities were examined. There was 1 Grade 5 (death) on Arm D in 
Consolidation due to disseminated intravascular coagulation (DIC), reported as unrelated to 
study drug. 
 
2.7.1 
Toxicity and Adverse Events 
In general, most toxicities occurred for treatment arms A, B, C and D during the Consolidation, 
IM and DI phases of therapy. The toxicities of interest were rather evenly distributed for all 
treatment arms. In comparing the toxicities across all arms, there appears to be an increased 
number of events of elevations of AST/ALT and febrile neutropenia in Arms A and B as 
compared to Arms C and D. However, these events do not seem increased over those reported in 
similar intensive treatment regimens for T-ALL. Importantly, there were few neurological 
toxicities reported for any of the arms. Of note, there were no Grade 4 motor or sensory toxicities 
reported in any of the High Risk patients. The motor and sensory toxicities will be discussed 
separately. 
 
2.7.1.1  Motor Neuropathy 
There were 5 events on Arm A among 13 patients, 6 on Arm B among 12 patients, 1 on Arm C 
among 16 patients, and 4 on Arm D among 16 patients. There were only 2 Grade 3 motor 
neuropathy toxicities reported: 1 in Arm B and 1 in Arm D, both of which were attributed to 
vincristine. The patient in Arm B developed footdrop greater than 3 months after his last 
Nelarabine and in conjunction with vincristine. The patient in Arm D developed vocal cord 
dysfunction in Consolidation after vincristine and prior to Nelarabine. There was 1 Grade 2 
motor neuropathy on Arm A (during DI) in a patient who had a history of neurotoxicity. Another 
patient who experienced a Grade 2 event (on Arm D, IM) did not receive Nelarabine. There does 
not appear to be any difference in overall motor neuropathy rates between Arms A and B and 
also Arms C and D. 
 
2.7.1.2  Sensory Neuropathy 
There were no sensory neuropathies reported on Arm A (N=13). There were 5 on Arm B 
(N=12), 7 on Arm C (N=16), and 5 on Arm D (N=16). There were only 4 Grade 3 sensory 
neuropathy toxicities reported. One was reported in Arm B in DI, 1 in Arm C in Maintenance 
Cycle #1 and 2 in Arm D. The 2 in Arm D were reported on the same patient. The first event 
occurred in DI prior to the administration of Nelarabine, and the second event occurred in 
Maintenance 1. One of the Grade 2 events on Arm B was due to vincristine. With respect to 
sensory neuropathies, Arm B appears to have more when compared to Arm A, but only 1 of 
them was a Grade 3. The rates are similar on Arms C and D.   
 
The data analysis revealed that the addition of Nelarabine to the CMTX and HDMTX arms does 
not result in excessive toxicity for either the targeted neurotoxicities or non-neurologic toxicities. 
While all arms of the protocol are myelosuppressive and thus, produce infectious toxicity, these 
toxicities appear similar to those found on other intensive chemotherapy regimens to treat T-
ALL. The protocol has, therefore, been opened to the efficacy phase. 


 
 
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2.7.1.3 Rhabdomyolysis 
Three cases of rhabdomyolysis have been seen in patients receiving nelarabine; two were 
reported as rhabdomyolysis, and one was reported as elevated alanine aminotransferase (ALT), 
elevated aspartate aminotransferase (AST), elevated creatine phosphokinase (CPK), and myalgia. 
Two cases from AALL0434 are clear cut and isolated incidents; nelarabine administration was 
stopped for these patients and the adverse effects resolved. The third case from a 2004 special 
exception trial (protocol E04-5299) was fatal, but confounded by multi-organ system failure 
resulting in death; direct causality in this case cannot be established. Narratives for these patients 
are provided in Appendix IX.  
 
Thus far, approximately 1175 patients have been treated with nelarabine. Two of the patients 
mentioned above were treated on AALL0434 by the Children’s Oncology Group. They received 
augmented BFM with either Capizzi methotrexate or high dose methotrexate and nelarabine. To 
date, 876 patients have been treated thus far on this study; the targeted accrual is 1580.  Of these 
patients, 126 were randomized to and received nelarabine. 
 
 
3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
 
3.1 
Study Enrollment  
 
3.1.1 
Patient Registration via Remote Date Entry (RDE) 
Prior to enrollment on this study, patients must be assigned a COG patient ID number. This 
number is obtained via the eRDE system once authorization for the release of protected health 
information (PHI) has been obtained. The COG patient ID number is used to identify the patient 
in all future interactions with COG.  If you have problems with the registration, please refer to 
the online help. 
 
In order for an institution to maintain COG membership requirements, every newly diagnosed 
patient needs to be offered participation in ACCRN07, Protocol for the Enrollment on the 
Official COG Registry, The Childhood Cancer Research Network (CCRN). 
 
A Biopathology Center (BPC) number will be assigned as part of the registration process. Each patient will 
be assigned only one BPC number per COG Patient ID. For additional information about the labeling of 
specimens please refer to the Pathology and/or Biology Guidelines in this protocol. 
 
 
3.1.2 
IRB Approval 
Local IRB/REB approval of this study must be obtained by a site prior to enrolling patients. Sites 
must submit IRB/REB approvals to the NCI’s Cancer Trials Support Unit (CTSU) Regulatory 
Office and allow 3 business days for processing. The submission must include a fax coversheet 
(or optional CTSU IRB Transmittal Sheet) and the IRB approval document(s). The CTSU IRB 
Certification Form may be submitted in lieu of the signed IRB approval letter. All CTSU forms 
can be located on the CTSU web page (https://www.ctsu.org). Any other regulatory documents 
needed for access to the study enrollment screens will be listed for the study on the CTSU 
Member’s Website under the RSS Tab. 
 


 
 
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IRB/REB approval documents may be faxed (1-215-569-0206), emailed (CTSURegulatory@ctsu.coccg.org) 
or mailed to the CTSU Regulatory office. 
 
When a site has a pending patient enrollment within the next 24 hours, this is considered a ‘Time 
of Need’ registration. For Time of Need registrations, in addition to marking your submissions as 
‘URGENT’ and faxing the regulatory documents, call the CTSU Regulatory Helpdesk at: 1-866-
651-CTSU. For general (non-regulatory) questions call the CTSU General Helpdesk at: 1-888-
823-5923. 
 
3.1.3 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have been 
met.  Study enrollment is accomplished by going to the Enrollment application in the RDE 
system. If you have problems with enrollment, refer to online help in the Applications area of the 
COG website. 
 
3.1.4 
Timing 
PATIENTS WITH T-ALL MUST BE ENROLLED ON COG AALL08B1 BEFORE 
TREATMENT ON COG AALL0434 BEGINS (with the exception of the first dose of 
intrathecal chemotherapy and/or selected cases for which there has been steroid pretreatment). 
PATIENTS THAT BEGIN PROTOCOL THERAPY FOR LEUKEMIA, PRIOR TO 
ENROLLMENT ON AALL08B1, ARE INELIGIBLE FOR BOTH AALL08B1 AND COG 
ALL THERAPEUTIC TRIALS. 
 
PATIENTS WITH T-NHL ARE INELIGIBLE FOR AALL08B1 AND CAN ENROLL 
DIRECTLY ON AALL0434. EVERY EFFORT SHOULD BE MADE TO ACQUIRE AS 
MUCH TISSUE AS POSSIBLE. SPECIFIC INSTRUCTIONS REGARDING TISSUE 
SUBMISSION ARE OUTLINED IN SECTIONS 15 & 16. 
 
All patients:  
Informed consent: Except for administration of intrathecal cytarabine or allowable steroid 
pretreatment (defined below), informed consent/parental permission MUST be signed before 
protocol therapy begins.  
 
Study enrollment: Study enrollment for AALL0434 must take place within five (5) calendar days 
of beginning protocol therapy. If enrollment takes place before starting therapy, the date protocol 
therapy is projected to start must be no later than five (5) calendar days after enrollment.  
 
Eligibility studies: Patients must meet all eligibility criteria prior to the start of protocol therapy 
or enrollment, whichever occurs first. Unless otherwise indicated in the eligibility section, all 
clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
the start of protocol therapy or enrollment, whichever occurs first. 
 
Initiation of systemic protocol therapy: Systemic induction chemotherapy, with the exception of 
steroid pretreament as outlined below, must begin within 72 hours of the first dose of intrathecal 
chemotherapy 
 


 
 
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3.1.5 
Bilingual Services  
To allow non-English speaking patients to participate in the study, bilingual health care services will 
be provided in the appropriate language. 
 
 
3.1.6 
Randomization 
Randomization/assignment of post-Induction treatment will take place through the eRDE system after Day 29 
risk status has been assigned. For all patients, post-Induction randomization via the RDE Late Randomization 
CRF should be done PRIOR to starting Consolidation therapy. 
 
T-ALL PATIENTS: 
For T-ALL patients, there are four treatment arms in this study. They are identified as follows:  
 
Arm A: Capizzi MTX without Nelarabine (CMTX);  
Arm B: Capizzi MTX with Nelarabine (CMTX + Nel);  
Arm C: High Dose MTX without Nelarabine (HDMTX); and  
Arm D: High Dose MTX with Nelarabine (HDMTX + Nel).   
 
During the safety phase (completed), ONLY High Risk T-ALL patients were randomized to receive 
Nelarabine. 
 
During the efficacy phase (now open), both High and Intermediate Risk T-ALL patients will be included in 
the Nelarabine randomization. Low Risk T-ALL patients do not receive Nelarabine on this protocol. 
 
T-NHL PATIENTS: 
For T-NHL patients, treatment will be restricted to 1 of 2 arms: 
 
 
Arm A: Capizzi MTX without Nelarabine (CMTX) 
 
Arm B: Capizzi MTX with Nelarabine (CMTX + Nel) 
Patients classified as Standard Risk for T-NHL will be non-randomly assigned to Arm A (CMTX). Patients 
classified as High Risk for T-NHL will be randomized to either Arm A (CMTX) or Arm B (CMTX + Nel). 
Please see Section 3.3.5 for details regarding T-NHL risk classification. 
 
3.2 
Patient Criteria 
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived (per COG policy posted 5/11/01). All clinical and laboratory data required for 
determining eligibility of a patient enrolled on this trial must be available in the patient's 
medical/research record which will serve as the source document for verification at the time 
of audit. 
 
INCLUSION CRITERIA 
 
3.2.1 
Classification Study 
T-ALL patients must be enrolled on AALL08B1 prior to treatment and enrollment on 
AALL0434. 
 
3.2.2 
Age 
Patients must be greater than 1.00 and less than 31 years of age. 
 


 
 
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3.2.3 
Diagnosis  
Patients must have newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or T-lineage 
lymphoblastic lymphoma (T-NHL) Stage II-IV (see Appendix VIII). B-lineage lymphoblastic 
lymphoma will not be eligible for this study. A diagnosis of T-ALL is established when leukemic 
blasts lack myeloperoxidase or evidence of B-lineage derivation (CD19/CD22/CD20), and 
express either surface or cytoplasmic CD3 or two or more of the antigens CD8, CD7, CD5, CD4, 
CD2 or CD1a. If surface CD3 is expressed on all leukemic cells, additional markers of 
immaturity, including TdT, CD34 or CD99 will be assessed for expression. Cases with uncertain 
expression will receive additional review within the appropriate COG reference laboratory. 
 
T-NHL PATIENTS: 
For T-NHL patients with tissue available for flow cytometry, the criterion for diagnosis should 
be analogous to T-ALL. For tissue processed by other means (i.e. paraffin blocks), the 
methodology and criteria for immunophenotypic analysis to establish the diagnosis of T-NHL 
defined by the submitting institution will be accepted. 
 
 
3.2.4 
Prior Therapy Restrictions 
Patients shall have had no prior cytotoxic chemotherapy with the exception of steroids and/or IT 
cytarabine. 
 
IT chemotherapy with cytarabine is allowed prior to registration for patient convenience. This is 
usually done at the time of the diagnostic bone marrow or venous line placement to avoid a 
second lumbar puncture. (Note: The CNS status must be determined based on a sample obtained 
prior to administration of any systemic or intrathecal chemotherapy, except for steroid 
pretreatment as discussed in Section 3.3.) Systemic chemotherapy must begin within 72 hours of 
this IT therapy. 
 
Patients diagnosed as having T-NHL or T-ALL with respiratory distress or hyperleukocytosis 
may require steroids prior to the initiation of additional systemic therapy. They are eligible for 
AALL0434 and will be stratified according to Section 3.3.5 below, based on the initial CBC. 
Steroid pretreatment may alter the risk group assessment. If the T-ALL patient’s clinical status 
precludes a lumbar puncture within 48 hours of the initiation of steroid therapy, T-ALL patients 
CANNOT be classified as Low Risk and will be Intermediate or High Risk based on the results 
of the Day 29 marrow as above. Patients with T-NHL who receive steroid pre-treatment will be 
classified as High Risk. The dose and duration of previous steroid therapy should be carefully 
documented. 
 
For the management of airway compromise, patients who have received emergent chest 
irradiation up to 600 cGy will be eligible for this study. 
 
3.2.5 
Concomitant Medications Restrictions 
Patients with a prior seizure disorder requiring anti-convulsant therapy are not eligible to receive 
Nelarabine. In addition, patients with pre-existing Grade 2 (or greater) peripheral neurotoxicity, 
as determined prior to Induction treatment by the treating physician or a neurologist, are not 
eligible to receive Nelarabine. These restrictions in eligibility are designed to prevent excessive 
Nelarabine-induced central and peripheral neurotoxicity in at-risk patients. For the purposes of 
this study, this includes any patient that has received anticonvulsant therapy to prevent/treat 
seizures in the prior two years. 
 


 
 
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EXCLUSION CRITERIA 
 
3.2.6 
Pregnant/Lactating Females 
Pregnant or lactating females are ineligible. The medications used in this protocol may put the 
fetus at risk, and may cross into the breast milk and put the infant at risk. 
 
3.2.7 
Patients with Down syndrome 
Patients with Down syndrome are ineligible to enroll onto this study. 
 
3.2.8 
For T-NHL patients the following additional exclusion criteria apply: 
• B-Precursor lymphoblastic lymphoma 
• Morphologically unclassifiable lymphoma 
• Absence of both B-cell and T-cell phenotype markers in a case submitted as 
lymphoblastic lymphoma 
• CNS3-positive (see Section 3.3.2 for details) or testicular involvement 
 
REGULATORY 
 
3.2.9 
All patients and/or their parents or legal guardians must sign a written informed consent. 
 
3.2.10 
All institutional, FDA, and NCI requirements for human studies must be met. 
 
3.2.11 
For details regarding obtainment of Nelarabine, please see Section 6.11. 
 
3.3 
Definitions 
 
3.3.1 
Hematological Parameters 
 
INITIAL WBC: The first WBC at the treating COG institution. If prior therapy (i.e. steroids) or IV 
hydration has been administered then the initial WBC prior to therapy and/or hydration should be 
used.   
 
INITIAL PLATELET COUNT: The first platelet count at the treating COG institution, or the count 
before transfusion of platelets if transfused prior to arrival. 
 
INITIAL HEMOGLOBIN: The first hemoglobin at the treating COG institution, or the hemoglobin prior 
to intravenous fluid or red cell transfusions, whichever occurred first. 
ABSOLUTE NEUTROPHIL COUNT (ANC): Total WBC count multiplied by the percentage of 
(neutrophils + bands). 
 
3.3.2 
Definitions of Extramedullary Disease 
CNS LEUKEMIA AT DIAGNOSIS: 
 
CNS 1: In cerebral spinal fluid (CSF), absence of blasts on cytospin preparation, regardless of the 
number of white blood cells (WBCs). 
 


 
 
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CNS 2: In CSF, presence of < 5/L WBCs and cytospin positive for blasts or ≥ 5 µL WBCs with 
negative Steinherz Bleyer algorithm. 
CNS 2a: 
< 10/L RBCs; < 5/L WBCs and cytospin positive for blasts; 
CNS 2b: ≥ 10/L RBCs; < 5/L WBCs and cytospin positive for blasts; and 
CNS 2c: 
≥ 10/L RBCs; ≥ 5/L WBCs and cytospin positive for blasts but negative by 
Steinherz/Bleyer algorithm (see below). 
 
CNS3: In CSF, presence of ≥ 5/L WBCs and cytospin positive for blasts and/or clinical signs of 
CNS Leukemia. 
 
(Note: Clinical CNS criteria appear below in CNS 3c): 
CNS 3a: 
< 10/L RBCs; ≥ 5/µL WBCs and cytospin positive for blasts; 
CNS 3b: ≥ 10/µL RBCs, ≥ 5/µL WBCs and positive by Steinherz/Bleyer algorithm  
 
(see below); and 
CNS 3c: 
Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement or 
hypothalamic syndrome). 
 
T-NHL DEFINITION OF CNS3-POSITIVE DISEASE 
Elevated CSF WBC (≥ 5 cell/µL) and a cytocentrifuge preparation demonstrating lymphoma 
cells. CNS lymphoma may also be diagnosed when the CSF WBC is normal but clinical signs of 
CNS involvement are present: 
• Cranial nerve palsy (if not explained by extra cranial tumor) 
• Clinical spinal cord compression 
• Isolated intracerebral mass 
 
CNS3-POSITIVE T-NHL PATIENTS ARE NOT ELIGIBLE FOR THIS STUDY 
 
METHOD OF EVALUATING INITIAL TRAUMATIC LUMBAR PUNCTURES: 
If the patient has leukemic cells in the peripheral blood and the lumbar puncture is traumatic and 
contains  5 WBC/L and blasts, the following algorithm should be used to distinguished 
between CNS2 and CNS3 disease:46 
 
CSF WBC > 2X   Blood WBC 
CSF RBC             Blood RBC 
 
A patient with CSF WBC  5/L blasts, whose CSF WBC/RBC is 2X greater than the blood 
WBC/RBC ratio, has CNS disease at diagnosis. Example: CSF WBC = 60/L; CSF RBC = 
1500/L; blood WBC = 46000/L; blood RBC = 3.0 X 106/L: 
 
60  = 0.04  >  2X   46000   = 0.015 
1500                       3.0 X 106 
 
TESTICULAR LEUKEMIA AT DIAGNOSIS: Unilateral or bilateral testicular disease. Biopsy is 
required if clinical findings are equivocal or suggestive of hydrocele or a non-leukemic mass. 
 
T-NHL PATIENTS WITH TESTICULAR DISEASE ARE NOT ELIGIBLE FOR THIS STUDY. 
 


 
 
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3.3.3 
Definitions of Bone Marrow Involvement 
 
BONE MARROW STATUS: 
M1: < 5% lymphoblasts  
M2: 5 - 25% lymphoblasts 
M3: > 25% lymphoblasts. 
 
BONE MARROW MRD STATUS FOR T-ALL PATIENTS* 
Negative: < 0.1% detectable leukemia cells 
Positive-Intermediate: ≥ 0.1%-1% detectable leukemia cells 
Positive-High: > 1% detectable leukemia cells 
* The definitions for MRD negative, positive-intermediate and positive-high listed above, 
contribute to the classification of marrow results on Day 29 for all patients and the end of 
Conslidation for patients who were M2 or M3 or positive-high (MRD > 1%) on Day 29. 
 
BONE MARROW MRD STATUS FOR T-NHL PATIENTS 
The MRD status of T-NHL patients will be assessed at diagnosis and patients will be risk-
stratified as described in Section 3.3.5. 
 
3.3.4 
Definitions of Early Response to Treatment 
 
T-ALL PATIENTS: 
RAPID EARLY RESPONDER (RER): M1 marrow on either Day 8 or 15, and M1 marrow with 
negative MRD status (< 0.1%) on Day 29. 
 
SLOW EARLY RESPONDER (SER): M2 or M3 marrow on Day 15 OR positive MRD status 
Day 29. M1/M2 marrow on Day 29. 
 
T-NHL PATIENTS: 
T-NHL patients will not be classified based on early response to treatment for risk assignment. 
Patients who fail to respond (< PR; see Section 11.3) will be considered Induction failures. 
 
3.3.5 
Definitions of Risk Stratification 
 
T-ALL PATIENTS: 
LOW RISK T-ALL: NCI Standard Risk by age (1.00 – 9.99 years) and WBC (initial ≤ 
50,000/µL); RER, M1 on Day 15 and M1 marrow with MRD < 0.1% on Day 29; CNS 1 status 
and no testicular disease at diagnosis. 
 
INTERMEDIATE RISK T-ALL: RER or SER, M1 marrow with MRD < 1% on Day 29; any 
CNS status. 
 
HIGH RISK T-ALL: M2 marrow and/or MRD ≥ 1% on Day 29; any CNS status. 
 
INDUCTION FAILURE T-ALL: M3 marrow on Day 29. 
 


 
 
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T-NHL PATIENTS: 
STANDARD RISK T-NHL: < 1% disease in the bone marrow at diagnosis detected by central 
lab flow cytometry. 
HIGH RISK T-NHL: ≥ 1% disease in the bone marrow at diagnosis detected by central lab flow 
cytometry or any level of steroid pre-treatment. 
 
INDUCTION FAILURE T-NHL: Failure to achieve PR, CR or Cru at end of Induction therapy 
(see Section 11.3). 
 
NO RESPONSE (NR) FOR T-NHL: see Section 11.3. 
 
UNFAVORABLE CHARACTERISTICS: 
 
PHILADELPHIA CHROMOSOME POSITIVE (Ph+) 
a) BCR-ABL1 (formerly known as BCR-ABL) fusion transcript determined by FISH or RT-
PCR 
b) t(9;22)(q34;q11) determined by cytogenetics 
 
T-ALL patients entered onto AALL0434 who are later found to meet eligibility criteria for the 
AALL0622 Ph+ ALL study (or successor) should immediately be taken off protocol therapy 
prior to Day 15 of Induction therapy. 
 
T-NHL patients entered onto AALL0434 who are later found to meet the criteria for Ph+ T-NHL 
will be ineligible for post-Induction therapy on AALL0434 and should be removed from 
protocol therapy at the end of Induction. 
 
STEROID PRETREATMENT:  
 
Risk Assessment based on steroid pretreatment for T-ALL patients. Please note: This is different 
from patients with B-precursor ALL. 
 
Patients receiving steroids within the week preceding diagnosis, prior to the diagnosis of T-
ALL: 
i. 
Patients who have received less than 48 hours of oral or IV steroids during the week 
immediately prior to diagnosis will be stratified according to the schema outlined 
above if the results of a CBC obtained prior to the initiation of steroid therapy are 
available. The pre-steroid CBC and age will be used to determine risk assignment. 
ii. 
If the patient has received > 48 hours of oral or IV steroids, whether or not a CBC is 
available prior to therapy, they will be categorized as an SER and assigned to the 
Intermediate Risk group provided their Day 29 BM is M1 and MRD < 1%. If Day 29 
BM is M2 or contains > 1% MRD the patient will be considered to be High Risk. 
Note that on this trial, SER status does not determine treatment assignment. 
iii. 
In the absence of presteroid CBC patients will be considered Intermediate Risk unless 
their Day 29 BM is M2 and/or their MRD is > 1%. These later patients fall into the 
High Risk category. 
Patients who have received steroids within one month of diagnosis (e.g. week -4 to week -1): 
i. 
Patients who receive less than 48 hours of steroids will not have risk assignment 
changed. 


 
 
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ii. 
Patients who receive > 48 hours in weeks -4 to -1 will be assigned to the Intermediate 
or High Risk category depending on the Day 29 bone marrow status. 
 
Any T-NHL patient with a history of steroid pre-treatment in any of the parameters listed above 
will be categorized as High Risk. 
 
3.3.6 
Definitions of Relapse 
 
T-ALL and T-NHL PATIENTS 
Any recurrence of disease whether in marrow or extramedullary site. Relapse should be 
histopathologically confirmed.  
 
CNS Relapse: Positive cytomorphology and > 5 WBC/µL OR positive cytomorphology with CSF 
WBC 0-4/µL on two successive occasions one month apart. If any CSF evaluation shows positive 
cytomorphology and < 5 WBC/µL, a second CSF evaluation is required in 4 weeks. Identification 
of leukemic clone in CSF by flow cytometry (CD2, CD3, CD34, or the same T-cell 
immunophenotypic markers that were identified at diagnosis) or FISH for diagnostic karyotypic 
abnormality is encouraged. 
 
Testicular Relapse: Must be documented by testicular biopsy if the testicular relapse is isolated. 
Biopsy is not mandated if the marrow is also involved. 
 
Bone Marrow Relapse: Patients with an M3 marrow at any point after Day 29.  
 
T-NHL PATIENTS ONLY 
Progressive disease: Greater than 25% increase in the size of any lesions or appearance of new lesion(s). 
  
 


 
 
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4.0 
TREATMENT PLAN 
 
4.1 
Overall Treatment Plan 
 
 
 
All T-ALL and T-NHL patients will receive the same Induction sequence. Subsequent therapy 
will be dependent on risk assignment, as detailed below in Table 3. Since treatment assignment 
is in part dependent on Day 29 MRD status for T-ALL, a radiation oncology consultation should 
be considered for all T-ALL patients during Induction. As specified below, Low Risk T-ALL 
patients (NCI std. risk, CNS1 with RER) do not receive radiation treatment and will, therefore, 
not require a radiation oncology consultation; however, Intermediate and High Risk T-ALL 
patients may be randomized to an arm that includes CRT at Week 8 from the start of 
Induction 
therapy 
(Week 
3 
of 
Consolidation). 
No T-NHL patients will receive CRT. T-NHL patients with CNS3-positive and/or testicular 
disease are not eligible for this study. 
 
4.1.1 
Risk Assignment 
Low Risk T-ALL: These patients will be randomized ONLY to Arm A (CMTX) and Arm C 
(HDMTX) and will NOT receive Nelarabine in either the safety or efficacy phases. They must 
meet the following criteria: Age 1.00-9.99 years and initial WBC count less than 50,000/µL, 
without testicular disease at diagnosis, CNS1 status; RER with an M1 marrow by Day 15; and 
MRD < 0.1% on Day 29. Low Risk patients will NOT receive CRT. Pretreatment with 
steroids may preclude Low Risk status (see Section 3.3). 
 
Intermediate Risk T-ALL: These patients are neither Low Risk, nor High. They will be eligible 
for the Nelarabine randomization during the efficacy phase (which is now open), but did not 
receive Nelarabine during the safety phase (which is now closed). All Intermediate Risk 
patients will receive CRT during either Consolidation (if randomized to Arm A (CMTX) or 
Arm B (CMTX + Nel) or Delayed Intensification (if randomized to Arm C (HDMTX) or 
Arm D (HDMTX + Nel); those with CNS3 status will be assigned to HDMTX on either 
Arm C (HDMTX) or Arm D (HDMTX + Nel) and receive 1800 cGy rather than the 1200 
cGy prophylactic CRT dose during Delayed Intensification. Patients with testicular disease at 
diagnosis will be assigned to HDMTX on either Arm C (HDMTX) or Arm D (HDMTX + Nel), 
and may receive TRT during Consolidation, depending on response. 
 
High Risk T-ALL: These patients will be eligible to receive Nelarabine during both the safety 
and efficacy phases. These patients, regardless of other features, will have a morphologic M2 
marrow or MRD ≥ 1.0% at the end of Induction. All High Risk patients will proceed directly to 
Consolidation, without waiting for count recovery at end-Induction. Given their high risk for 
subsequent failure, the remission status of these patients will be monitored carefully. They will 
have peripheral blood sent at start, mid and end-Consolidation for MRD determination and 
marrow sent at end Consolidation for both morphology and MRD. Patients must have attained an 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are based on 
schedules derived from the experimental design or on established standards of care. Minor unavoidable 
departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and up to 1 week for 
surgery) for valid clinical, patient and family logistical, or facility,  procedure and/or anesthesia scheduling issues 
are acceptable per COG administrative Policy 5.14 (except where explicitly prohibited within the protocol). 


 
 
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M1 marrow by morphology at the end of Consolidation to continue on study. All High Risk 
patients will receive CRT during either Consolidation (if randomized to Arm A (CMTX) or 
Arm B (CMTX + Nel) or Delayed Intensification (if randomized to Arm C (HDMTX) or 
Arm D (HDMTX + Nel); those with CNS3 status will be assigned to HD MTX on either 
Arm C (HDMTX) or D (HDMTX + Nel) and will receive 1800 cGy rather than the 1200 
cGy prophylactic CRT dose during Delayed Intensification. Patients with testicular disease at 
diagnosis will be assigned to HDMTX on either Arm C (HDMTX) or Arm D (HDMTX + Nel) 
and may receive TRT during Consolidation, depending on response. 
 
Induction Failures T-ALL: Patients with an M3 marrow on Day 29 will be non-randomly 
assigned to Arm D (HDMTX + Nel). These patients should proceed directly to Consolidation 
after the Day 29 marrow without waiting for count recovery to occur. They will receive at least 1 
block of Consolidation therapy. Prior to the 2nd course of Nelarabine exposure during 
Consolidation therapy (Day 43), the patients are to have a bone marrow evaluation by local 
morphologic assessment. Bone marrow and peripheral blood samples will also be sent for MRD 
analysis. If M3 status is again observed, the patient is taken off protocol therapy. If the patient 
has an M1 or M2 marrow, they will continue with the second block of Arm D (HDMTX + Nel) 
Consolidation therapy. If the patient has an M1 marrow at end of two blocks of Consolidation 
therapy (ten weeks), they may remain on Arm D (HDMTX + Nel) of the study. These patients 
may also be taken off protocol therapy to receive alternate therapies, such as stem cell 
transplantation, at investigator discretion. Peripheral blood and bone marrow samples for MRD 
are required at end-of-Consolidation. 
 
Standard Risk T-NHL: Patients with < 1% disease in the bone marrow at diagnosis by central 
lab flow cytometry. These patients are NOT eligible for the Nelarabine randomization and will 
be non-randomly assigned ONLY to Arm A (CMTX). 
 
High Risk T-NHL: Patients with ≥ 1% disease in the bone marrow at diagnosis by central lab 
flow cytometry or any level of steroid pre-treatment. These patients are eligible for the 
Nelarabine randomization and will be randomized to either Arm A (CMTX) or Arm B (CMTX + 
Nel). There will be no CRT during Consolidation. T-NHL patients who are CNS-positive or 
who have testicular disease are not eligible for this study. 
 
Induction Failures T-NHL: Patients who fail to achieve at least a PR (see Section 11.3) at the 
end of Induction. These patients will be non-randomly assigned to Arm B (CMTX + Nel). 
Patients who do not attain at least a PR (see Section 11.3) by the end of Condolidation therapy 
will be removed from protocol therapy at that time. 
 
 


 
 
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Table 3 
T-ALL Risk Status NCI Risk Status Day 15 Induction Response; Day 29 MRD 
CNS Status 
Low Risk  
(Must meet all 
criteria and not have 
testicular disease at 
diagnosis, and pre-
treament with 
steroids may 
preclude Low Risk 
status) 
Standard Risk 
(Age 1.00-9.99 
yrs and initial 
WBC less than 
50,000/µL) 
M1 (RER) Day 8 or 15 and M1 marrow with 
MRD < 0.1% on Day 29  
CNS1 
 
Intermediate Risk 
Standard  
Steroid pre-treated, SER or CNS3 or testicular 
disease but M1 with 0.1 to 0.99% MRD on Day 
29 
Any 
High 
RER or SER; M1 with < 1% MRD on Day 29 
Any 
High Risk 
 
Standard or High M2 marrow at end of Induction or MRD ≥ 1% 
on Day 29 
Any 
Induction Failure 
Standard or High M3 marrow at end of Induction 
Any 
T-NHL Risk Status Baseline BM 
MRD 
Day 29 Induction Response 
CNS 
Disease 
Standard Risk 
< 1% 
CR, CRu, PR 
None 
High Risk 
≥ 1% or steroid 
pre-treated 
CR, CRu, PR 
None 
Induction Failure 
Either 
Failure to achieve PR, CR or CRu (see Section 
11.3) 
None 
 
 
Testicular Disease: T-ALL patients with testicular involvement at diagnosis will not receive 
irradiation if testicular disease has resolved completely at the end of Induction (biopsy is 
required if there is any uncertainty regarding the clinical response). Those patients with 
persistent testicular disease at end Induction, based on clinical and/or biopsy findings, will 
receive radiation during Consolidation (2400 cGy to bilateral testes). T-NHL patients with 
testicular disease are not eligible for this study. 
 
4.1.2 
Randomization 
After a risk assignment has been determined for each patient with T-ALL or T-NHL, the patient will become 
eligible for treatment randomization. Randomization will also be determined by whether or not patients have 
T-ALL vs. T-NHL. 
 
4 treatment regimens (for patients with T-ALL): 
Arm A  Augmented BFM with Capizzi MTX, no Nelarabine (CMTX) 
Arm B  Augmented BFM with Capizzi MTX plus Nelarabine (CMTX + Nel) 
Arm C  Augmented BFM with High Dose MTX, no Nelarabine (HDMTX) 
Arm D  Augmented BFM with High Dose MTX plus Nelarabine (HDMTX + Nel) 
 


 
 
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2 treatment regimens (for patients with T-NHL): 
Arm A  Augmented BFM with Capizzi MTX, no Nelarabine (CMTX) 
Arm B  Augmented BFM with Capizzi MTX plus Nelarabine (CMTX + Nel) 
 
4.1.2.1 Safety Phase Randomization (closed) 
During the safety phase of the AALL0434 trial only the High Risk patients received Nelarabine. High Risk 
patients were randomized to all four arms of the study. Toxicity data for the High Risk cohort receiving 
Nelarabine were assessed following administration through Week 43 of the study. If additional data were 
required to assess toxicity in High Risk patients who received Nelarabine, a second assessment would have 
occurred prior to the completion of the third year of the study (see Section 10.2). Completion of the analysis 
of these data ended the safety phase. Grade 2 and greater neurotoxicity was monitored closely during the 
safety phase. During this phase, Low Risk and Intermediate Risk patients were randomized to either Arm A 
(CMTX) or Arm C (HDMTX) and did not receive Nelarabine. NOTE: During the safety phase analysis, High 
Risk patients continued to be randomized to all four treatment arms. 
 
4.1.2.2 Efficacy Phase Randomization (open) 
Analyses of toxicity data have been completed for the initial cohort of High Risk T-ALL patients 
randomized to receive Nelarabine, and the study has been approved to move into the efficacy phase as 
Nelarabine has been deemed safe. The efficacy of Nelarabine will be determined by randomized 
treatment assignment. During the efficacy phase of this study, Intermediate Risk and High Risk T-ALL 
patients (as defined in Table 3) will be randomized to any one of the 4 treatment arms as shown in Table 
4. Low Risk T-ALL patients will not receive Nelarabine and thus will only be randomized to either Arm 
A (CMTX) or Arm C (HDMTX) (Table 4). High Risk T-NHL patients (as defined in Table 3) will be 
randomized to one of two treatmemt arms, as shown below in Table 4. Standard Risk T-NHL patients will 
not receive Nelarabine and thus will be non-randomly assigned to Arm A (CMTX). 
 


 
 
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Table 4 
Intermediate or High Risk T-ALL 
Augmented 
BFM 
Augmented 
BFM/Nelarabine 
Capizzi-Style Methotrexate 
A 
B§ 
High Dose Methotrexate 
C% 
D§ # % 
High Risk T-NHL 
Augmented 
BFM 
Augmented 
BFM/Nelarabine 
Capizzi-Style Methotrexate 
A (NO 
CRT/TRT) 
B§ # (NO CRT/TRT) 
Low Risk T-ALL* 
Augmented 
BFM 
Capizzi-Style Methotrexate 
A 
High Dose Methotrexate 
C% 
Standard Risk T-NHL* 
Augmented 
BFM 
Capizzi-Style Methotrexate 
A (NO 
CRT/TRT) 
§ Children with an anti-convulsant-dependent seizure disorder or those who have Grade 2 or greater peripheral 
neuropathy will NOT be assigned to Nelarabine 
* Children with Low Risk T-ALL or Standard Risk T-NHL will NOT receive Nelarabine or cranial XRT 
% T-ALL patients with CNS3 and/or testicular disease at diagnosis will be ASSIGNED to receive HD MTX 
# T-ALL patients with a Day 29 M3 marrow status will be ASSIGNED to receive HD MTX with Nelarabine;  
T-NHL patients who fail to achieve at least a PR at the end of Induction (see Section 11.3) will be ASSIGNED to 
receive CMTX with Nelarabine. 
 
See Section 7.0 for baseline studies to be obtained prior to starting Induction therapy. 
 
4.1.2.3 Dose Modifications for Obese Patients 
There is no clearly documented adverse impact of treatment of obese patients when dosing is 
performed according to actual body weight. Therefore, all dosing is to be determined by the 
patient’s actual weight. Failure to use actual body weight in the calculation of drug dosages 
will be considered a major protocol deviation. Physicians who are uncomfortable with 
administering chemotherapy doses based on actual body weight should not enroll obese patients 
on this protocol. 
 
 


 
 
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4.2 
INDUCTION (All patients) 
All treatment arms will receive common Induction therapy. 
 
Intrathecal Cytarabine: IT 
Given at time of diagnostic lumbar puncture OR Day 1. 
 
Age-based dosing: 
Age (yrs) 
Dose 
1 – 1.99 
 
30 mg 
2 – 2.99 
 
50 mg 
≥ 3 
 
70 mg 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
1.5 mg/m2/dose (max dose 2 mg) on Days 1, 8, 15 and 22 
 
Special precautions: FOR INTRAVENOUS USE ONLY 
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing 
the statement “Do not remove covering until moment of injection. For intravenous use only - 
Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. 
VinCRIStine VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate 
liposomal injection, VSLI, Marqibo®). Use conventional vincristine only; the conventional and 
liposomal formulations are NOT interchangeable. 
 
PredniSONE: PO* 
30 mg/m2/dose BID (i.e., 60 mg/m2/day, divided BID) on Days 1-28 (do not taper) 
 
* May give IV: substitute methylprednisolone IV at a ratio of 4 mg for each 5 mg of 
predniSONE 
 
DAUNOrubicin: IV push  
25 mg/m2/dose on Days 1, 8, 15 and 22 
 
Administer at a concentration of 5 mg/mL by slow IV push or infusion over 1-15 minutes. Short 
infusion times may be lengthened slightly (and up to 60 minutes) if institutional policies 
mandate. It is suggested that DAUNOrubicin be administered through the tubing of rapidly 
infusing solution of D5W or 0.9% NaCl and that it is infused into a large vein. 
 
Pegaspargase: IM (or IV over 1-2 hours) 
2500 International units/m2/dose x 1 dose on Day 4 [OR 5 OR 6] 
 
For IV: Administer through the tubing of a freely infusing solution of D5W or 0.9% NaCl  
 
Intrathecal Methotrexate: IT 


 
 
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For intrathecal administration, dilute with 5-10 mL preservative-free normal saline or lactated 
Ringer's solution on Days 8 and 29 (CNS3 T-ALL patients also receive IT MTX on Days 15 & 
22). The volume of CSF removed should equal at least half the volume delivered. 
 
Aged-based dosing:  
Age (yrs) 
Dose 
1 – 1.99 
 
8 mg 
2 – 2.99 
 
10 mg 
3 – 8.99 
 
12 mg 
≥ 9 
 
15 mg 
 
The therapy delivery map (TDM) for Induction is on the next page. 
 
Following completion of Induction, the next course (Consolidation, Section 4.3 or 4.4) starts on 
Day 36 or when blood count parameters are met (whichever occurs later). See below for 
additional details regarding risk group assignment and randomization. 
 
Criteria to begin Consolidation 
Once risk assignment occurs, patients must complete and sign informed consent specific to post-
Induction therapy for the appropriate risk group and then undergo randomization. Consolidation 
for Arm A (CMTX) and Arm C (HDMTX) is in Section 4.3; Consolidation for Arm B (CMTX + 
Nel) and Arm D (HDMTX + Nel) is in Section 4.4. 
 
If patient has T-ALL with M1 marrow and MRD < 1% as determined by the COG Reference 
Lab (Low and Intermediate Risk T-ALL), randomize and proceed to Consolidation at Day 36 or 
when peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever 
occurs later). 
 
If patient has Standard Risk T-NHL (< 1% disease in the bone marrow at diagnosis), proceed to 
Consolidation on Arm A (CMTX) (Section 4.3) at Day 36 or when peripheral counts recover 
with ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever occurs later). 
 
If patient has High Risk T-NHL (≥ 1% disease in the bone marrow at diagnosis or any level of 
steroid pre-treatment), randomize and proceed to Consolidation at Day 36 or when peripheral 
counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever occurs later). 
 
High Risk T-ALL 
If the Day 29 marrow is M2 (5%-25% blasts) and/or the central COG reference lab 
determines MRD ≥ 1%, then the patient is defined as High Risk. High Risk patients should 
be randomized as soon as possible and begin Consolidation therapy (as randomized) as 
soon as possible and should not wait until Day 36 or for count recovery to occur. 
 
Induction Failure T-ALL 
If the Day 29 marrow is M3 (≥ 25% blasts), then patient is an Induction Failure. Study 
chair should be notified. The patient will be non-randomly assigned to Arm D (HDMTX + 
Nel) and should begin Consolidation therapy as soon as possible and should not wait until 


 
 
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Day 36 or for count recovery to occur. Patients with Induction Failure must sign the 
appropriate consent form before Consolidation therapy begins. 
 
Induction Failure T-NHL 
If the Day 29 evaluation reveals that the patient’s response status is NR or progressive 
disease (see Section 11.3) then patient is an Induction Failure. Please notify the study chair. 
The patient will be non-randomly assigned to Arm B (CMTX + Nel) and should begin 
Consolidation therapy as soon as possble and should not wait until Day 36 or for count 
recovery to occur. Patients with Induction failure must sign the appropriate consent form 
before Consolidation therapy begins. 
 


 
 
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4.2.1 
INDUCTION (All arms) 
All treatment arms will receive common Induction therapy. 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
This Course lasts 5 weeks (35 days) and this Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Intrathecal 
Cytarabine 
(IT ARAC) 
IT 
Age (yrs) 
Dose 
1 – 1.99 
30 mg 
2 – 2.99 
50 mg 
≥ 3 
70 mg 
Given at time of 
diagnostic lumbar 
puncture (LP) OR 
Day 1 
May give prior to 
randomization 
 
Note age-based dosing 
a. Hx/PE 
b. Weight (BSA) 
c. CBC/diff/platelets 
d. BM eval 
e. CSF cell count, cytospin 
f. PB for host polymorphisms 
(T-ALL only) 
g. PB for MRD (T-ALL only) 
h. Bilirubin, ALT, BUN, 
creatinine 
i. Varicella titers 
j. TPMT genotype (see 
Section 5.9) 
T-NHL only: 
k. Chest/abdomen/pelvis CT 
l. Bone scan 
m. Diagnostic biopsy/cytology 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
VinCRIStine (VCR) 
IV Push  
Over 1 min+ 
1.5 mg/m2/dose 
Days 1, 8, 15 & 22 
+ Or infusion via minibag as 
per institutional policy 
Maximum dose of 2 mg 
PredniSONE (PRED) 
PO 
(may give IV*) 
30 mg/m2/dose BID 
Days 1-28 
(no taper) 
Total daily dose: 60 mg/m2/day, 
divided BID 
*For IV substitution see Sec 4.2 
DAUNOrubicin 
(DAUN) 
IV Push 
Over 15 min 
25 mg/m2/dose 
Days 1, 8, 15 & 22 
See Section 4.2 for 
administration guidelines 
Pegaspargase  
(PEG-ASP) 
IM 
(or IV over 1-2 hours) 
2500 International 
units/m2 x 1 dose 
Day 4 [OR 5 OR 6] 
For IV: Administer through the 
tubing of a freely infusing 
solution of D5W or 0.9% NaCl 
Intrathecal 
Methotrexate (IT 
MTX) 
IT 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
Days 8 & 29 (CNS3 
T-ALL also Days 15 
& 22) 
Note age-based doing 
Therapy Delivery Map  
 
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
IT ARAC 
____mg 
VCR 
____mg 
PRED 
____mg ____mg 
DAUN 
____mg 
PEG-ASP 
____IU 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
____mg 
____mg ____mg ____mg 
____mg 
 
 
a, b, c, d, e, h, i, j, (k, l, m)*  
 
 
2 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
4 
 
 
 
____IU 
(1 dose) 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
8 
 
____mg 
____mg 
 
____mg 
a, c, dβ, e, g^ 
 
 
 
9 
 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
l* 
 
 
 
15 
 
____mg 
____mg 
 
____mg# a, c, dβ, e# 
 
 
 
16 
 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
 
22 
 
____mg 
____mg 
 
____mg# a, c, e# 
 
 
 
23 
 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 
29 
 
 
 
 
 
____mg 
a, c, d^α, e, fβ, g^, (k, l)* 
 
 
 
36 
Start next course (Consolidation, Sec 4.3. or 4.4) on Day 36 or when blood count parameters are met (whichever occurs later). 
^ See Section 7.1 for details 
# CNS3 T-ALL patients ONLY 
* T-NHL patients only (see Section 7.2 for details, including exceptions) 
α T-NHL only, if morphologically positive at diagnosis (see Section 7.2 for details)       β T-ALL only (see Section 7.1 for details) 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 1 of 1 


 
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4.3 
CONSOLIDATION Arms A (CMTX) and C (HDMTX) (NO Nelarabine) Weeks 6-13 
This Consolidation course is for patients randomized or assigned to either treatment arm 
WITHOUT NELARABINE (Arms A and C). 
 
Criteria to begin Consolidation 
Start Consolidation on Day 36 (7 days following Day 29 LP) or when peripheral counts recover 
with ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever occurs later). Once Consolidation 
therapy has begun, interruptions for myelosuppression (ANC ≤ 750/µL and platelets ≤ 
75,000/µL) should occur only at Day 29. Once the Day 1 or Day 29 cyclophosphamide has 
been given, the remainder of the therapy should not be held solely for myelosuppression, which 
is expected to occur. Therapy must be interrupted for patients with serious proven or presumed 
infection and resumed when the signs of infection have abated. 
 
T-ALL patients who are High Risk with MRD > 1% and/or M2 marrow on Day 29, should 
be randomized and proceed directly to Consolidation without waiting for count recovery. 
 
Patients with Induction failure should proceed directly to Consolidation without waiting 
for count recovery. 
 
Intrathecal Methotrexate: IT 
For intrathecal administration, dilute with 5-10 mL preservative-free normal saline or lactated 
Ringer's solution on Days 1++ or 29 ++, 8, 15# and 22# 
 
++if High Risk T-ALL or T-NHL: omit Day 1 and give on Day 29 instead i.e, patients should 
receive IT MTX on Days 8, 15, 22, and 29. 
#if CNS3 T-ALL: omit Days 15 & 22 i.e, patients should receive IT MTX on Days 1 & 8 only. 
All other patients receive IT MTX on Days 1, 8, 15 and 22. 
The volume of CSF removed should equal at least half the volume delivered. 
 
Aged-based dosing:  
Age (yrs) 
Dose 
1 – 1.99 
 
8 mg 
2 – 2.99 
 
10 mg 
3 – 8.99 
 
12 mg 
≥ 9 
 
15 mg 
 
Cyclophosphamide: IV (over 30 minutes) 
1000 mg/m2/dose on Days 1 and 29. Reduce urine specific gravity to ≤ 1.015 prior to 
administering cyclophosphamide and give IV fluids to maintain urine output. Furosemide may 
be given at a dose of 0.25 – 0.5 mg/kg/dose IV for urine output < 3 mL/kg/hr after CPM. See 
Section 5.3 for additional details. 
 
Cytarabine: IV over 1-30 minutes or Subcutaneous 
75 mg/m2/dose on Days 1-4, 8-11, 29-32 and 36-39 
 
Mercaptopurine: PO 


 
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60 mg/m2/dose on Days 1-14 and 29-42. Give at least 1 hour after evening meal. To be taken 
without milk or citrus products. Adjust dose using half tablets and different doses on alternating 
days in order to attain a weekly cumulative dose as close to 420 mg/m2/week as possible. See 
Appendix I for details. Do not escalate or modify dose based on blood counts during this 
course. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
1.5 mg/m2/dose (max dose 2 mg) on Days 15, 22, 43 and 50 
 
Special precautions: FOR INTRAVENOUS USE ONLY 
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing 
the statement “Do not remove covering until moment of injection. For intravenous use only - 
Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. 
VinCRIStine VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate 
liposomal injection, VSLI, Marqibo®). Use conventional vincristine only; the conventional and 
liposomal formulations are NOT interchangeable. 
 
Pegaspargase: IM (or IV over 1-2 hours) 
2500 International units/m2/dose x 1 dose on Days 15 and 43 
 
For IV: Administer through the tubing of a freely infusing solution of D5W or 0.9% NaCl  
 
Testicular Radiation Therapy 
Patients with T-ALL and persistent testicular disease at end-Induction will receive XRT to the 
testes during Consolidation (a testicular biopsy is required if there is any uncertainty regarding 
the clinical response). Within the first two weeks of Consolidation, testicular radiation therapy 
will be given at 2400 cGy in 12 once-daily fractions of 200 cGy (See Section 14.2). Testicular 
radiation must be started during Consolidation and should be completed before the end of this 
phase of therapy. T-NHL patients with testicular disease are not eligible for this study. 
 
Cranial Radiation Therapy 
Prophylactic cranial radiation therapy (1200 cGy in 8 once-daily fractions) for Intermediate/High 
Risk  
T-ALL patients randomized to Arm A (CMTX) should be given during Weeks 3 and 4 of 
Consolidation (see Section 14.0). Cranial XRT (1800 cGy in 10 once-daily fractions) for CNS3 
patients and prophylactic cranial XRT (1200 cGy in 8 once-daily fractions) for 
Intermediate/High Risk T-ALL patients randomized to Arm C (HDMTX) will be given during 
DI. Intrathecal therapy is NOT held during the concomitant administration of CRT. Low Risk T-
ALL patients (defined in Section 4.1) and all T-NHL patients will NOT receive any CRT. 
 
 
The therapy delivery map (TDM) for Consolidation is on the next page. 
 
Following completion of Consolidation, the next course (Interim Maintenance, Section 4.5 or 
4.6) starts on Day 57 or when blood count parameters are met (whichever occurs later). 


 
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4.3.1 
CONSOLIDATION Arm A (CMTX) and Arm C (HDMTX) 
This Consolidation course is for patients randomized or assigned to either treatment arm 
WITHOUT NELARABINE (Arms A and C). 
 
____________________________  __________________________ 
         Patient name or initials                                  DOB 
Start Consolidation on Day 36 (7 days following Day 29 LP) or when peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever 
occurs later). Patients with T-ALL and persistent testicular disease at end-Induction will receive XRT to the testes during Consolidation (a testicular biopsy 
is required if there is any uncertainty regarding the clinical response). Within the first two weeks of Consolidation, testicular radiation therapy will be 
given at 2400 cGy in 12 once-daily fractions of 200 cGy (See Section 14.2). Testicular radiation must be started during Consolidation and should be 
completed before the end of this phase of therapy. This Course lasts 8 weeks (56 days) and this Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Intrathecal 
Methotrexate 
(IT MTX) 
IT 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
Days 8, 15, 22 & 29  
for HR (T-ALL or T-
NHL) 
Note age-based dosing 
 
Please note CNS3 status and risk assignment-
based schedule. See Section 4.1.1 for 
details of risk assignment. 
a. 
Hx/PE 
b. 
Weight (BSA) 
c. 
CBC/diff/platelets 
d. 
CSF cell count, cytospin 
e. 
ALT, creatinine, 
bilirubin 
f. 
BM evaluation† 
g. 
PB for MRD (T-ALL 
only) 
T-NHL only: 
h. 
Chest CT/Chest x-ray 
i. 
Abdomen/Pelvis CT 
j. 
Bone scan  
 
† T-ALL patients are 
considered off protocol 
therapy if not M1 at end-
Consolidation 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
Days 1, & 8  
for CNS3 T-ALL 
Days 1, 8, 15, & 22  
for all other patients 
Cyclophosphamide 
(CPM) 
IV over 30 min 
1000 mg/m2/dose 
Days 1 & 29 
See Section 4.3 for admin guidelines 
Cytarabine (ARAC) 
IV or SubQ 
75 mg/m2/dose 
Days 1-4, 8-11, 29-32 & 
36-39 
 
Mercaptopurine (MP) 
PO 
60 mg/m2/dose 
Days 1-14 & 29-42 
See Sec 4.3 & Appendix I for admin guidelines 
VinCRIStine (VCR) 
IV Push over 
1 min+ 
1.5 mg/m2/dose 
Days 15, 22, 43 & 50 
+ Or infusion via minibag as per institutional 
policy 
Maximum dose of 2 mg 
Pegaspargase  
(PEG-ASP) 
IM 
(or IV over  
1-2 hours) 
2500 International 
units/m2/dose 
Days 15 & 43 
For IV: Administer through the tubing of a freely 
infusing solution of D5W or 0.9% NaCl 
Therapy Delivery Map  
 
 
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
IT MTX@ 
____mg 
CPM 
____mg 
ARAC 
____mg 
MP 
____mg 
VCR 
____mg 
PEG-ASP 
____IU 
Studies 
Comments 
 
 
 
HR (T-ALL 
& T-NHL)  
CNS3 
T-ALL  
All other 
patients  
 
 
 
 
 
 
 
 
 
 
Enter calculated dose above and actual dose administered below  
 
 
 
 
1 
 
____mg 
____mg 
____mg 
____mg 
____mg 
 
 
a, b, c, d, e 
 
 
 
2 
 
 
 
 
____mg 
 
 
 
 
 
 
3 
 
 
 
 
____mg 
 
 
 
 
 
 
4 
 
 
 
 
____mg 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
8 
____mg 
____mg 
____mg 
 
____mg 
 
 
c, d 
 
 
 
9 
 
 
 
 
____mg 
 
 
 
 
 
 
10 
 
 
 
 
____mg 
 
 
 
 
 
 
11 
 
 
 
 
____mg 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
 
 
 
15$ 
____mg 
 
____mg 
 
 
 
____mg 
____IU 
c, d 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
22 
____mg 
 
____mg 
 
 
 
____mg 
 
c, d 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
29 
____mg 
 
 
____mg 
____mg 
____mg 
 
 
c, d, (f, g)& 
 
 
 
30 
 
 
 
 
____mg 
 
 
 
 
 
 
31 
 
 
 
 
____mg 
 
 
 
 
 
 
32 
 
 
 
 
____mg 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
36 
 
 
 
 
____mg 
 
 
c 
 
 
 
37 
 
 
 
 
____mg 
 
 
 
 
 
 
38 
 
 
 
 
____mg 
 
 
 
 
 
 
39 
 
 
 
 
____mg 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
42 
 
 
 
 
 
 
 
 
 
 
 
43 
 
 
 
 
 
 
____mg 
____IU 
a, c 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
50 
 
 
 
 
 
 
____mg 
 
c 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
56 
 
 
 
 
 
 
 
 
c, fβ, &, g&, (h, i, j)γ  
 
 
57 
Start next course (Interim Maintenance, Sec 4.5. or 4.6) on Day 57 or when blood count parameters are met (whichever occurs later). 
@ Please note the different IT MTX schedules according to risk assignment group and CNS status (see Section 4.1.1 for details). 
$ IR/HR T-ALL patients on Arm A are expected to begin prophylactic cranial XRT during Week 3 
& High Risk T-ALL pts ONLY; see Section 7.1 for details 
β Obtain in T-NHL if positive at diagnosis (see Section 7.2 for details) 
 
 
 
γ T-NHL only (see Section 7.2 for details) 
Page 1 of 1 


 
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4.4 
CONSOLIDATION Arms B (CMTX + Nel) and D (HDMTX + Nel) Weeks 6-16 
This Consolidation course is for patients randomized or assigned to either treatment arm PLUS 
NELARABINE (Arms B and D). 
 
Criteria to begin Consolidation 
Start Consolidation on Day 36 (7 days following Day 29 LP) or when peripheral counts recover 
with ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever occurs later). Once Consolidation 
therapy has begun, it may be interrupted for myelosuppression (ANC ≤ 750/µL and 
platelets ≤ 75,000/µL) on Day 43 only. Once the Day 1 or Day 43 Nelarabine has been given, 
the remainder of the therapy should not be held solely for myelosuppression, which is expected 
to occur. Therapy must be interrupted for patients with serious proven or presumed infection and 
resumed when the signs of infection have abated. 
 
T-ALL patients who are High Risk with MRD > 1% and/or M2 marrow on Day 29 should 
be randomized and proceed directly to Consolidation without waiting for count recovery. 
 
T-ALL patients who are Induction failures with an M3 marrow at Day 29 should sign 
consent for post-Induction therapy and start Consolidation therapy [Arm D (HDMTX + 
Nel)] immediately after Day 29 marrow results are known and should not wait for count 
recovery to occur. 
 
T-NHL patients who are Induction failures with NR (see Section 11.3) should sign consent 
for post-Induction therapy and start Consolidation therapy on Arm B (CMTX + Nel) 
immediately after Day 29 evaluation results are known and should not wait for count 
recovery to occur. 
 
Nelarabine: IV (over 60 minutes) 
650 mg/m2/dose on Days 1-5 and 43-47 
 
NOTE: the drug manufacturers of Nelarabine have included as part of the agent’s 
risks/side effects that patients receiving intrathecal chemotherapy or craniospinal 
irradiation with Nelarabine may be at increased risk of neurological adverse events. 
 
Intrathecal Methotrexate: IT 
For intrathecal administration, dilute with 5-10 mL preservative-free normal saline or lactated 
Ringer's solution on Days 15, 22, 57 and 64 (omit Day 22 if CNS3 T-ALL). The volume of CSF 
removed should equal at least half the volume delivered. 
 
Aged-based dosing:  
Age (yrs) 
Dose 
1 – 1.99 
 
8 mg 
2 – 2.99 
 
10 mg 
3 – 8.99 
 
12 mg 
≥ 9 
 
15 mg 
 
Cyclophosphamide: IV (over 30 minutes) 


 
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1000 mg/m2/dose on Days 8 and 50. Reduce urine specific gravity to ≤ 1.015 prior to 
administering. Give IV fluids to maintain urine output. May use Furosemide 0.25 – 0.5 
mg/kg/dose IV for urine output < 3 mL/kg/hr after CPM. See Section 5.3 for additional details. 
 
Cytarabine: IV over 1-30 minutes or Subcutaneous 
75 mg/m2/dose on Days 8-11, 15-18, 50-53 and 57-60 
 
Mercaptopurine: PO 
60 mg/m2/dose on Days 8-21 and 50-63. Give at least 1 hour after evening meal. To be taken 
without milk or citrus products. Adjust dose using half tablets and different doses on alternating 
days in order to attain a weekly cumulative dose as close to 420 mg/m2/week as possible. See 
Appendix I for details. Do not escalate or modify dose based on blood counts during this 
course. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
1.5 mg/m2/dose (max dose 2 mg) on Days 22, 29, 64 and 71 
 
Special precautions: FOR INTRAVENOUS USE ONLY 
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing 
the statement “Do not remove covering until moment of injection. For intravenous use only - 
Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. 
VinCRIStine VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate 
liposomal injection, VSLI, Marqibo®). Use conventional vincristine only; the conventional and 
liposomal formulations are NOT interchangeable. 
 
Pegaspargase: IM (or IV over 1-2hours) 
2500 International units/m2/dose x 1 dose on Days 22 and 64 
 
For IV: Administer through the tubing of a freely infusing solution of D5W or 0.9% NaCl  
 
Testicular Radiation Therapy 
Patients with T-ALL and persistent testicular disease at end-Induction receive XRT to the testes 
during Consolidation (a testicular biopsy is required if there is any uncertainty regarding the 
clinical response). Testicular radiation therapy will be given at 2400 cGy in 12 once-daily 
fractions of 200 cGy (see Section 14.2). Testicular radiation must be started during 
Consolidation and should be completed before the end of this phase of therapy. T-NHL patients 
with testicular disease are not eligible for this study. 
 
Cranial Radiation Therapy 
Prophylactic cranial radiation therapy (1200 cGy in 8 once-daily fractions) for Intermediate/High 
Risk  
T-ALL patients randomized to Arm B (CMTX + Nel) should be given during Weeks 4 and 5 of 
Consolidation (see Section 14.0). Cranial XRT (1800 cGy in 10 once-daily fractions) for CNS3 
T-ALL patients and prophylactic cranial XRT (1200 cGy in 8 once-daily fractions) for 


 
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Intermediate/High 
Risk  
T-ALL patients randomized to Arm D (HDMTX + Nel) will be given during DI. Intrathecal 
therapy is NOT held during the concomitant administration of CRT. Low Risk T-ALL patients 
(defined in Section 4.1) and all T-NHL patients WILL NOT receive any cranial XRT. 
 
 
The therapy delivery maps (TDMs) for Consolidation are on the next two pages. 
 
Following completion of Consolidation, the next course (Interim Maintenance, Section 4.5 or 
4.6) starts on Day 78 or when blood count parameters are met (whichever occurs later). 
 


 
 
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AALL0434 
Version date: 03/24/16                        Page 50 
 
 
4.4.1a 
CONSOLIDATION Arm B (CMTX + Nel) and Arm D (HDMTX + Nel) 
This Consolidation course is for patients randomized or assigned to either treatment arm PLUS 
NELARABINE (Arms B and D). 
 
___________________ 
_________________ 
Patient name or initials 
DOB 
Start Consolidation on Day 36 (7 days following Day 29 LP) or when peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever 
occurs later). Patients with T-ALL and persistent testicular disease at end-Induction receive XRT to the testes during Consolidation (a testicular biopsy is 
required if there is any uncertainty regarding the clinical response). Testicular radiation therapy will be given at 2400 cGy in 12 once-daily fractions of 
200 cGy (see Section 14.2). Testicular radiation must be started during Consolidation and should be completed before the end of this phase of therapy. This 
Course lasts 11 weeks (77 days) and this Therapy Delivery Map is on two (2) pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Nelarabine (Nel) 
IV over 60 min 650 mg/m2/dose 
Days 1-5 & 43-47 
 
a. 
Hx/PE 
b. 
Weight (BSA) 
c. 
CBC/diff/platelets 
d. 
CSF cell count, cytospin 
e. 
ALT, creatinine, 
bilirubin 
f. 
BM evaluation† 
g. 
PB for MRD (T-ALL 
only) 
T-NHL only: 
h. 
Chest CT/Chest x-ray 
i. 
Abdomen/Pelvis CT  
j. 
Bone scan 
 
† T-ALL patients are 
considered off protocol 
therapy if not M1 at end-
Consolidation 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
Intrathecal Methotrexate 
(IT MTX) 
IT 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
Days 15, 22*, 57 & 64 
 
* Omit Day 22 for CNS3 T-ALL 
pts 
Note age-based dosing  
Cyclophosphamide (CPM) IV over 30 min 1000 mg/m2/dose 
Days 8 & 50 
See Section 4.4 for admin 
guidelines 
Cytarabine (ARAC) 
IV or SubQ 
75 mg/m2/dose 
Days 8-11, 15-18, 50-53 & 57-60  
Mercaptopurine (MP) 
PO 
60 mg/m2/dose 
Days 8-21 & 50-63 
See Section 4.4 & Appendix I 
for admin guidelines 
VinCRIStine (VCR) 
IV push over 
1 min+ 
1.5 mg/m2/dose 
Days 22, 29, 64 & 71 
+ Or infusion via minibag as 
per institutional policy 
Maximum dose of 2 mg 
Pegaspargase (PEG-ASP) 
IM 
(or IV over  
1-2 hours) 
2500 International 
units/m2/dose 
Days 22 & 64 
For IV: Administer through the 
tubing of a freely infusing 
solution of D5W or 0.9% NaCl 
Therapy Delivery Map  
 
 
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA______m2 
Date Due 
Date Given 
Day 
Nel 
____mg 
IT MTX 
____mg 
CPM 
____mg 
ARAC 
____mg 
MP 
____mg 
VCR 
____mg 
PEG-ASP 
____IU 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below  
 
 
 
 
1 
____mg 
 
 
 
 
 
 
a, b, c, e 
 
 
 
2 
____mg 
 
 
 
 
 
 
 
 
 
 
3 
____mg 
 
 
 
 
 
 
 
 
 
 
4 
____mg 
 
 
 
 
 
 
 
 
 
 
5 
____mg 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
8 
 
 
____mg 
____mg 
____mg 
 
 
c 
 
 
 
9 
 
 
 
____mg 
 
 
 
 
 
 
10 
 
 
 
____mg 
 
 
 
 
 
 
11 
 
 
 
____mg 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
15 
 
____mg 
 
____mg 
 
 
c, d 
 
 
 
16 
 
 
 
____mg 
 
 
 
 
 
 
17 
 
 
 
____mg 
 
 
 
 
 
 
18 
 
 
 
____mg 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
 
 
22$ 
 
____mg@ 
 
 
 
____mg 
____IU 
c, d@ 
 
 
 
23 
 
 
 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
29 
 
 
 
 
 
____mg 
 
c 
 
 
 
30 
 
 
 
 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
36 
 
 
 
 
 
 
 
c 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
@ Not for CNS3 T-ALL pts                                     $ IR/HR T-ALL pts on Arm B are expected to begin prophylactic cranial XRT during Week 4 
 
 
Page 1 of 2 


 
 
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AALL0434 
Version date: 03/24/16                        Page 51 
 
4.4.1b 
CONSOLIDATION Arm B (CMTX + Nel) and Arm D (HDMTX + Nel) 
This Consolidation course is for patients randomized or assigned to either treatment 
arm PLUS NELARABINE (Arms B and D). 
 
___________________ 
_________________ 
Patient name or initials 
DOB 
Start Consolidation on Day 36 (7 days following Day 29 LP) or when peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL (whichever 
occurs later). Patients with T-ALL and persistent testicular disease at end-Induction receive XRT to the testes during Consolidation (a testicular biopsy is 
required if there is any uncertainty regarding the clinical response). Testicular radiation therapy will be given at 2400 cGy in 12 once-daily fractions of 
200 cGy (see Section 14.2). Testicular radiation must be started during Consolidation and should be completed before the end of this phase of therapy. This 
Course lasts 11 weeks (77 days) and this Therapy Delivery Map is on two (2) pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Nelarabine (Nel) 
IV over 60 
min 
650 mg/m2/dose 
Days 1-5 & 43-47 
 
a. 
Hx/PE 
b. 
Weight (BSA) 
c. 
CBC/diff/platelets 
d. 
CSF cell count, 
cytospin 
e. 
ALT, creatinine, 
bilirubin 
f. 
BM evaluation† 
g. 
PB for MRD (T-ALL 
only) 
T-NHL only: 
h. 
Chest CT/Chest x-ray 
i. 
Abdomen/Pelvis CT  
j. 
Bone scan  
 
† T-ALL patients are 
considered off protocol 
therapy if not M1 at 
end-Consolidation 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
Intrathecal Methotrexate 
(IT MTX) 
IT 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
Days 15, 22*, 57 & 64 
 
* Omit Day 22 for 
CNS3 T-ALL pts 
Note age-based dosing 
Cyclophosphamide (CPM) 
IV over 30 
min 
1000 mg/m2/dose 
Days 8 & 50 
See Section 4.4 for 
administration guidelines 
Cytarabine (ARAC) 
IV or SubQ 75 mg/m2/dose 
Days 8-11, 15-18, 50-53 
& 57-60 
 
Mercaptopurine (MP) 
PO 
60 mg/m2/dose 
Days 8-21 & 50-63 
See Section 4.4 & Appendix I 
for administration guidelines 
VinCRIStine (VCR) 
IV push 
over 1 min+ 
1.5 mg/m2/dose 
Days 22, 29, 64 & 71 
+ Or infusion via minibag as 
per institutional policy 
Maximum dose of 2 mg 
Pegaspargase 
 (PEG-ASP) 
IM 
(or IV over 
1-2hours) 
2500 International 
units/m2/dose 
Days 22 & 64 
For IV: Administer through the 
tubing of a freely infusing solution 
of D5W or 0.9% NaCl 
 
Therapy Delivery Map  
 
 
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA______m2 
Date Due 
Date Given 
Day 
Nel 
____mg 
IT MTX 
____mg 
CPM 
____mg 
ARAC 
____mg 
MP 
____mg 
VCR 
____mg 
PEG-ASP 
____IU 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below  
 
 
 
 
43 
____mg 
 
 
 
 
 
 
a, c, (f, g)** 
 
 
 
44 
____mg 
 
 
 
 
 
 
 
 
 
 
45 
____mg 
 
 
 
 
 
 
 
 
 
 
46 
____mg 
 
 
 
 
 
 
 
 
 
 
47 
____mg 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
50 
 
 
____mg 
____mg 
____mg 
 
 
a, c 
 
 
 
51 
 
 
 
____mg 
 
 
 
 
 
 
52 
 
 
 
____mg 
 
 
 
 
 
 
53 
 
 
 
____mg 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
57 
 
____mg 
 
____mg 
 
 
c, d 
 
 
 
58 
 
 
 
____mg 
 
 
 
 
 
 
59 
 
 
 
____mg 
 
 
 
 
 
 
60 
 
 
 
____mg 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
63 
 
 
 
 
 
 
 
 
 
 
64 
 
____mg 
 
 
 
____mg 
____IU 
c, d 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
71 
 
 
 
 
 
____mg 
 
c 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
77 
 
 
 
 
 
 
 
a, b, c, f β, **, 
g**, (h, i, j)γ 
 
 
 
78 
Start next course (Interim Maintenance, Sec 4.5. or 4.6) on Day 78 or when blood count parameters are met 
(whichever occurs later). 
** HR & IF T-ALL pts only; see Section 7.1 for details 
β Obtain in T-NHL if positive at diagnosis (see Section 7.2 for details) 
γ T-NHL only (see Section 7.2 for details) 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 2 of 2 


 
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AALL0434 
Version date: 03/24/16                        Page 52 
4.5 
INTERIM MAINTENANCE Arms A (CMTX) and B (CMTX + Nel) 
Weeks 14-21 (Arm A) & 17-24 (Arm B) 
 
This Interim Maintenance (IM) course is for patients randomized or assigned to either treatment 
arm with Capizzi methotrexate (Arms A and B). 
 
Criteria to begin Interim Maintenance – Capizzi Methotrexate 
Begin IM when peripheral counts recover with an ANC ≥ 750/µL and platelets ≥ 75,000/µL. All 
therapy should be interrupted for patients with presumed or proven severe infections and 
resumed when the signs of infection have abated. Obtain blood counts 10 days after initial dose 
of methotrexate. 
A) If ANC is < 500/µL or platelets < 50,000/µL, hold all chemotherapy and repeat blood 
counts in 4 days. 
1. If ANC ≥ 500/µL and platelets ≥ 50,000/µL, give same dose of methotrexate as 
previously. 
2. If ANC is still < 500/µL or platelets < 50,000/µL, give VCR, PEG-ASP and IT MTX 
(if due) and repeat counts in 7 days to begin next dose of MTX if counts are adequate. 
If counts now adequate, reduce dose of MTX by 20%. Do not make up missed dose 
of MTX. If counts still too low, hold therapy until counts recover to ANC > 500/µL 
and platelets > 50,000/µL. 
B) If ANC ≥ 500/µL but < 750/µL and platelets ≥ 50,000/µL but < 75,000/µL, give same 
dose of MTX as previously. 
C) If ANC ≥750/µL and platelets ≥ 75,000/µL escalate MTX by 50 mg/m2/dose 
D) If allergic to pegaspargase, give Erwinia L-asparaginase as described in Section 5.1. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
1.5 mg/m2/dose (max dose 2 mg) on Days 1, 11, 21, 31 and 41 
 
Special precautions: FOR INTRAVENOUS USE ONLY 
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing 
the statement “Do not remove covering until moment of injection. For intravenous use only - 
Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. 
VinCRIStine VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate 
liposomal injection, VSLI, Marqibo®). Use conventional vincristine only; the conventional and 
liposomal formulations are NOT interchangeable. 
 
Methotrexate: IV push 
Start dose at 100 mg/m2/dose and escalate by 50 mg/m2/dose (see Section 5.8.2) on Days 1, 11, 
21, 31 and 41. Discontinue escalation and resume at 80% of last dose if delay is necessary for 
myelosuppression and/or Grade 3 mucositis. 
 
Pegaspargase: IM (or IV over 1-2 hours) 
2500 International units/m2/dose on Days 2 and 22. 
 
For IV: Administer through the tubing of a freely infusing solution of D5W or 0.9% NaCl  


 
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Version date: 03/24/16                        Page 53 
 
Note: Continue pegaspargase dosing despite ANC and platelet count. 
 
Intrathecal Methotrexate: IT 
For intrathecal administration, dilute with 5-10 mL preservative-free normal saline or lactated 
Ringer’s solution on Days 1 and 31. The volume of CSF removed should equal at least half the 
volume delivered. 
 
Aged-based dosing:  
Age (yrs) 
Dose 
1 – 1.99 
 
8 mg 
2 – 2.99 
 
10 mg 
3 – 8.99 
 
12 mg 
≥ 9 
 
15 mg 
 
See Section 5.8 for Dose Modifications based on hepatotoxicity and/or mucositis. 
 
The therapy delivery map (TDM) for Interim Maintenance is on the next page. 
 
Following completion of Interim Maintenance, the next course (Delayed Intensification, Section 
4.7 or 4.8) starts on Day 57 or when blood count parameters are met (whichever occurs later). 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
AALL0434 
Version date: 03/24/16                        Page 54 
 
 
4.5.1 
INTERIM MAINTENANCE Arm A (CMTX) & Arm B (CMTX + Nel) 
This IM course is for patients randomized or assigned to either of the treatment 
arms with Capizzi methotrexate (Arms A and B). 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
 
Begin IM when peripheral counts recover with an ANC ≥ 750/µL and platelets ≥ 75,000/µL. All therapy should be 
interrupted for patients with presumed or proven severe infections and resumed when the signs of infection have 
abated. Obtain blood counts 10 days after initial dose of methotrexate. This Course lasts 8 weeks (56 days) and 
this Therapy Delivery Map is on one (1) page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over  
1 min+ 
1.5 mg/m2/dose 
Days 1, 11, 
21, 31 & 41 
+ Or infusion via minibag 
as per institutional policy 
Maximum dose of 2 mg 
a. 
Hx/PE, weight 
(BSA) 
b. 
CBC/diff/platelets* 
c. 
CSF cell count, 
cytospin 
d. 
ALT, creatinine, 
bilirubin 
 
* Obtain repeat counts if 
chemotherapy is held; 
see Section 4.5 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
Methotrexate 
(MTX) 
IV Push 
Start dose @ 100 mg/m2/dose 
then escalate by 50 mg/m2/dose 
Days 1, 11, 
21, 31 & 41 
See Sections 4.5 and 5.8.2 
for details 
Pegaspargase 
(PEG-ASP) 
IM 
(or IV over 
1-2 hours) 
2500 International 
units/m2/dose 
Days 2 & 22 
For IV: Administer 
through the tubing of a 
freely infusing solution of 
D5W or 0.9% NaCl  
Note: Continue PEG-ASP 
dosing despite ANC & plt 
count 
Intrathecal 
Methotrexate  
(IT MTX) 
IT 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
Days 1 & 31 
Note age-based dosing 
 
Therapy Delivery Map   
 
Ht_______cm  
Wt_______kg  
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
VCR 
____mg 
IV MTX 
(escalating dose) 
PEG-ASP 
____IU 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below  
 
 
 
1 
____mg 
____mg 
 
____mg 
a, b, c, d 
 
 
 
2 
 
 
____IU 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
11 
____mg 
____mg 
 
 
b, d 
 
 
 
--- 
 
 
 
 
 
 
 
 
21 
____mg 
____mg 
 
 
b, d 
 
 
 
22 
 
 
____IU 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
31 
____mg 
____mg 
 
____mg 
b, c, d 
 
 
 
--- 
 
 
 
 
 
 
 
 
41 
____mg 
____mg 
 
 
b, d 
 
 
 
--- 
 
 
 
 
 
 
 
 
56 
 
 
 
 
 
 
 
 
57 
Start next course (Delayed Intensification, Sec 4.7. or 4.8) on Day 57 or when blood count parameters are 
met (whichever occurs later). 
 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
 
 


 
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Version date: 03/24/16                        Page 55 
4.6 
INTERIM MAINTENANCE Arms C (HDMTX) and D (HDMTX + Nel) 
Weeks 14-21 (Arm C) & 17-24 (Arm D) 
 
This Interim Maintenance (IM) course is only for T-ALL patients randomized to either treatment 
arm with High-Dose methotrexate (Arms C and D). T-NHL patients DO NOT receive HDMTX 
and will NOT receive therapy on either of these arms. 
 
Criteria to begin Interim Maintenance – High-Dose Methotrexate 
Begin IM when peripheral counts recover with an ANC ≥ 750/µL and platelets ≥ 75,000/µL. All 
therapy should be interrupted for patients with presumed or proven severe infections and 
resumed when the signs of infection have abated. All chemotherapy should be held for ANC < 
750/µL or platelets < 75,000/µL. If counts fail to recover within 2 weeks notify the Study Chair. 
 
Review of BFM and past COG protocols indicates that excess toxicity is not encountered in 
patients who are > 2 m2 and receive more than 10 grams of methotrexate. The methotrexate dose 
should be dosed on the actual meter-squared basis and not capped. 
 
Hold any nonsteroidal anti-inflammatory medications, penicillins, proton pump inhibitors 
aspirin-containing medications, or TMP-SMX on the days of the MTX infusion and until the 
MTX level is less than 0.4 µM. In the presence of delayed clearance, continue to hold TMP-
SMX until the MTX level is less than 0.1 μM. 
 
High-Dose Methotrexate: IV 
5000 mg/m2/dose on Days 1, 15, 29 and 43. See Section 4.6.1 and Appendix IV for High-Dose 
methotrexate infusion and leucovorin rescue guidelines. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
1.5 mg/m2/dose (max dose 2 mg) on Days 1, 15, 29 and 43 
 
Special precautions: FOR INTRAVENOUS USE ONLY 
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing 
the statement “Do not remove covering until moment of injection. For intravenous use only - 
Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. 
VinCRIStine VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate 
liposomal injection, VSLI, Marqibo®). Use conventional vincristine only; the conventional and 
liposomal formulations are NOT interchangeable. 
 
Mercaptopurine: PO 
25 mg/m2/dose on Days 1-56. Give at least 1 hour after evening meal. To be taken without milk 
or citrus products. Adjust dosing using half tablets and different doses on alternating days in 
order to attain a weekly cumulative dose as close to 175 mg/m2/week as possible. See Appendix 
I for details. Do not escalate or modify dose based on blood counts during this course. 
 
Intrathecal Methotrexate: IT 


 
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AALL0434 
Version date: 03/24/16                        Page 56 
For intrathecal administration, dilute with 5-10 mL preservative-free normal saline or lactated 
Ringer’s solution on Days 1 and 29. The volume of CSF removed should equal at least half the 
volume delivered. Deliver within 6 hours of the start of IV MTX (hr -6 to +6). 
 
Aged-based dosing:  
Age (yrs) 
Dose 
1 – 1.99 
 
8 mg 
2 – 2.99 
 
10 mg 
3 – 8.99 
 
12 mg 
≥ 9 
 
15 mg 
 
4.6.1 
HD MTX Infusion Guidelines 
(Please see Section 5.8.1 for additional information.) 
When IT therapy and HDMTX are scheduled for the same day, deliver the IT therapy within 6 
hours of the beginning of the IV MTX infusion (hour -6 to +6, with 0 being the start of the MTX 
bolus). 
 
Hold TMP-SMX on the days of HD MTX infusion and for at least 72 hours after the start of the 
HD MTX infusion and until the MTX level is less than 0.4 μM. In the presence of delayed 
clearance continue to hold TMP-SMX until MTX level is less than 0.1 µM 
 
Hold any nonsteroidal anti-inflammatory medications, penicillins, proton pump inhibitors or 
aspirin-containing medications on the day of HD MTX infusion and for at least 72 hours after the 
start of the HD MTX infusion and until the MTX level is less than 0.4 μM. In the presence of 
delayed clearance continue to hold these drugs until MTX level is less than 0.1 µM 
 
Recommended Prehydration with D5 ¼ NS with 30 mEq NaHCO3/L at 125 mL/m2/hour until 
urine specific gravity is ≤ 1.010 and pH is ≥ 7.0 and ≤ 8.0. Ringers Lactate may be used as the 
initial fluid if a bicarbonate containing solution is unavailable. Adjust fluid volume and sodium 
bicarbonate to maintain urine specific gravity and pH at above parameters. A bicarbonate bolus 
(25 mEq/m2 over 15 minutes) may be given to raise the urine pH relatively quickly; a normal 
saline bolus may also be helpful in facilitating hydration. Continue hydration and alkalinization 
throughout HD MTX infusion, and for a minimum of 48 hours after its completion. In patients 
with delayed MTX clearance, continue hydration until the plasma MTX concentration is below 
0.1 µM. 
 
Hour 0: MTX 500 mg/m2 IV mixed in a final volume of 65 mL/m2 D5 ¼ NS with 30 mEq 
NaHCO3/L and infused over 30 minutes. This is followed, immediately, by MTX 4500 mg/m2 
mixed in a final volume of 2935 mL/m2 D5 ¼ NS with 30 mEq NaHCO3/L given by continuous 
IV infusion over 23.5 hours at 125 mL/m2/hr. Be certain that the HD MTX infusion is completed 
in the 24 hour period. Unintentional prolongation to as long as 26 hours though not encouraged 
is acceptable. 
 
Hours 24, (36), 42 and 48: Draw MTX level and serum creatinine; NOTE: 36 hour level is only 
drawn if needed (see below) 
 


 
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Version date: 03/24/16                        Page 57 
For MTX levels that exceed these expected values modify the rescue regimen as noted 
below and increase hydration to 200 mL/m2/hr, monitor urine pH to assure a value ≥ 7.0 
and monitor urine output to determine if volume is ≥ 80% of the fluid intake, measured 
every 4 hours. If serum creatinine rises significantly, at any time point, assure appropriate 
urine pH and urine volume as above and draw a 42 hour level. If urine output fails to 
continue at 80% of the fluid intake, consider furosemide. Regardless of urine output, also 
consider glucarpidase (carboxypeptidase G2) (see Section 5.8.1). For patients with delayed 
clearance during a previous course, begin the following course with the increased hydration 
(200 mL/m2/hr). If subsequent course is not associated with delayed clearance, attempt to use 
standard hydration. 
 
If the 24 hour level is < 150 µM draw the next level at hour 42 and refer to table in 
Section 5.8.1.If the 24 hour level is ≥ 150 µM and/or creatinine > 125% baseline, repeat 
level if MTX contamination is possible. While waiting for the result and if the value is 
“real” refer to the changes in hydration, etc described above and repeat the level with a 
serum Cr at hour 36. Then refer to the table in Section 5.8.1. 
 
If the 42 and 48 hour levels are ≤ 1 and 0.4 µM, respectively, give leucovorin at 15 mg/m2 
IV/PO at 42, 48 and 54 hours post the start of methotrexate loading dose. No additional levels 
are needed, nor is additional leucovorin. If levels exceed these values, see Section 5.8.1. 
 
See Section 5.8 for Dose Modifications based on hepatotoxicity and/or mucositis. 
 
The therapy delivery map (TDM) for Interim Maintenance is on the next page. 
 
Following completion of Interim Maintenance, the next course (Delayed Intensification, Section 
4.7 or 4.8) starts on Day 57 or when blood count parameters are met (whichever occurs later). 
 


 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
AALL0434 
Version date: 03/24/16                        Page 58 
 
 
4.6.2 
INTERIM MAINTENANCE Arm C (HDMTX) & Arm D (HDMTX + Nel) 
This IM course is only for T-ALL patients randomized to either of the treatment arms with High-
Dose methotrexate (Arms C and D). 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Begin IM when peripheral counts recover with an ANC ≥ 750/µL and platelets ≥ 75,000/µL. All therapy should be interrupted for patients with 
presumed or proven severe infections and resumed when the signs of infection have abated. All chemotherapy should be held for ANC < 750/µL or 
platelets < 75,000/µL. If counts fail to recover within 2 weeks notify the Study Chair. This Course lasts 8 weeks (56 days) and this Therapy 
Delivery Map is on one (1) page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
High-Dose Methotrexate 
(HD MTX) 
IV over 24 
hours 
5000 mg/m2/dose 
Days 1, 15, 29 & 
43 
See Section 4.6.1 for 
administration guidelines 
a. 
Hx/PE, weight 
(BSA) 
b. 
CBC/diff/platelets 
c. 
CSF cell count, 
cytospin 
d. 
ALT, creatinine, 
bilirubin 
 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
Leucovorin (LCV) 
IV/PO 
15 mg/m2/dose 
42, 48 & 54 hrs 
post HDMTX 
See Section 4.6.1 & 
Appendix IV for details 
VinCRIStine (VCR) 
IV push 
over 1 min+ 
1.5 mg/m2/dose 
Days 1, 15, 29 & 
43 
+ Or infusion via minibag 
as per institutional policy 
Maximum dose of 2 mg 
Mercaptopurine (MP) 
PO 
25 mg/m2/dose 
Days 1-56 
See Section 4.6 for 
administration guidelines 
Intrathecal Methotrexate 
(IT MTX) 
IT 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
Days 1 & 29 
Deliver within 6 hours of 
the start of IV MTX (hr -6 
to +6) 
 
Note age-based dosing 
 
Therapy Delivery Map  
 
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date Due Date Given Day 
HD MTX 
____mg 
LCV 
____mg 
VCR 
____mg 
MP 
____mg 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below  
 
 
 
1 
____mg 
 
____mg 
____mg 
____mg 
a, b, c, d 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
____mg 
____mg 
____mg 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
15 
____mg 
 
____mg 
 
b, d 
 
 
 
16 
 
 
 
 
 
 
 
 
17 
 
____mg 
____mg 
____mg 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
29 
____mg 
 
____mg 
____mg 
b, c, d 
 
 
 
30 
 
 
 
 
 
 
 
 
31 
 
____mg 
____mg 
____mg 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
 
34 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
43 
____mg 
 
____mg 
 
b, d 
 
 
 
44 
 
 
 
 
 
 
 
 
45 
 
____mg 
____mg 
____mg 
 
 
 
 
 
 
46 
 
 
 
 
 
 
 
47 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
56 
 
 
 
 
 
 
 
 
57 
Start next course (Delayed Intensification, Sec 4.7. or 4.8) on Day 57 or when blood count parameters are met 
(whichever occurs later). 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 1 of 1 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0434 
Version date: 03/24/16                   
 
 Page 59 
4.7 
DELAYED INTENSIFICATION Arms A (CMTX) and C (HDMTX) (NO Nelarabine) 
Weeks 22-30 
This Delayed Intensification (DI) course is for patients randomized or assigned to either 
treatment arm WITHOUT NELARABINE (Arms A and C). 
 
Criteria to begin Delayed Intensification (NO Nelarabine) 
Patients should have ANC ≥ 750/µL and platelets ≥ 75,000/µL prior to starting therapy on Days 
1 and 29. Once Delayed Intensification has begun, it may be interrupted for 
myelosuppression (ANC ≤ 750/µL and platelets ≤ 75,000/µL) on Day 29 ONLY. Once the 
Day 1 therapy or Day 29 cyclophosphamide has been given, the remainder of the therapy should 
not be held solely for myelosuppression, which is expected to occur. Therapy must be interrupted 
for patients with serious proven or presumed infection and resumed when the signs of infection 
have abated. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
1.5 mg/m2/dose (max dose 2 mg) on Days 1, 8, 15, 43 and 50 
 
Special precautions: FOR INTRAVENOUS USE ONLY 
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing 
the statement “Do not remove covering until moment of injection. For intravenous use only - 
Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. 
VinCRIStine VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate 
liposomal injection, VSLI, Marqibo®). Use conventional vincristine only; the conventional and 
liposomal formulations are NOT interchangeable. 
  
Dexamethasone: PO (may give IV) 
All patients, regardless of age, receive discontinuous dexamethasone: 5 mg/m2/dose BID (i.e., 
10 mg/m2/day, divided BID) on Days 1-7 and 15-21. 
 
DOXOrubicin: IV push  
25 mg/m2/dose on Days 1, 8 and 15 
 
Administer at a concentration not to exceed 2 mg/mL by slow IV push or infusion over 1-15 
minutes. Short infusion times may be lengthened slightly (and up to 60 minutes) if institutional 
policies mandate. It is suggested that DOXOrubicin be administered through the tubing of rapidly 
infusing solution of D5W or 0.9% NaCl and that it is infused into a large vein. 
 
Pegaspargase: IM (or IV over 1-2 hours) 
2500 International units/m2/dose on Day 4 [OR 5 OR 6] AND Day 43 
 
For IV: Administer through the tubing of a freely infusing solution of D5W or 0.9% NaCl  
 
Intrathecal Methotrexate: IT 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0434 
Version date: 03/24/16                   
 
 Page 60 
For intrathecal administration, dilute with 5-10 mL preservative-free normal saline or lactated 
Ringer's solution on Days 1, 29 and 36. The volume of CSF removed should equal at least half 
the volume delivered. 
 
Aged-based dosing:  
Age (yrs) 
Dose 
1 – 1.99 
 
8 mg 
2 – 2.99 
 
10 mg 
3 – 8.99 
 
12 mg 
≥ 9 
 
15 mg 
 
Cyclophosphamide: IV (over 30 minutes) 
1000 mg/m2/dose on Day 29. 
 
Reduce urine specific gravity to ≤ 1.015 prior to administering. Give IV fluids to maintain urine 
output. May use Furosemide 0.25 – 0.5 mg/kg/dose IV for urine output < 3 mL/kg/hr after CPM. 
See Section 5.3 for additional details. 
 
Cytarabine: IV over 1-30 minutes or Subcutaneous 
75 mg/m2/dose on Days 29-32 and 36-39 
 
Thioguanine: PO 
60 mg/m2/dose on Days 29-42.  
 
Give at least 1 hour after evening meal. To be taken without milk or citrus products. Adjust dose 
using half tablets and different doses on alternating days in order to attain a weekly cumulative 
dose as close to 420 mg/m2/week as possible. See Appendix II for details. Do not escalate or 
modify dose based on blood counts during this course. Please note: TG should not be 
administered to any patient receiving CRT during this stage of therapy (i.e. IR/HR T-ALL 
patients randomized to Arm C and all CNS3 T-ALL patients). 
 
 
Cranial Radiation Therapy 
Prophylactic cranial XRT (1200 cGy in 8 once-daily fractions) for Intermediate/High Risk T-
ALL patients randomized to Arm C (HDMTX) and cranial XRT (1800cGy in 10 once-daily 
fractions) for CNS3 T-ALL patients should start on Day 50 of DI. Intermediate and High Risk T-
ALL patients randomized to Arm A (CMTX) received CRT in Consolidation and WILL NOT 
receive prophylactic cranial XRT during this phase of therapy. Low Risk T-ALL patients 
(defined 
in 
Section 
4.1) 
and 
all  
T-NHL patients WILL NOT receive any cranial XRT. Please see Section 14.0 for all CRT 
details. 
 
The therapy delivery maps (TDMs) for Delayed Intensification are on the next two pages. 
 
Following completion of Delayed Intensification, the next course (Maintenance, Section 4.9) 
starts on Day 64 or when blood count parameters are met (whichever occurs later). 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
AALL0434 
Version date: 03/24/16                   
 
 Page 61 
 
 
4.7.1a 
DELAYED INTENSIFICATION Arm A (CMTX) & Arm C (HDMTX) (NO Nelarabine) 
This Delayed Intensification course is for patients randomized or assigned to either treatment arm 
WITHOUT NELARABINE. 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Patients should have ANC ≥ 750/µL and platelets ≥ 75,000/µL prior to starting therapy on Days 1 and 29. Once Delayed Intensification has begun, it 
may be interrupted for myelosuppression on Day 29 ONLY. Once the Day 1 therapy or Day 29 cyclophosphamide has been given, the remainder of 
the therapy should not be held solely for myelosuppression, which is expected to occur. Therapy must be interrupted for patients with serious proven 
or presumed infection and resumed when the signs of infection have abated. This Course lasts 9 weeks (63 days) and this Therapy Delivery Map is on 
two (2) pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 min+ 
1.5 mg/m2/dose 
Days 1, 8, 15, 43 & 50 
+ Or infusion via minibag 
as per institutional policy 
Maximum dose of 2 mg 
a. 
Hx/PE, weight 
(BSA) 
b. CBC/diff/platelet
s 
c. 
CSF cell count, 
cytospin 
d. Bilirubin, ALT, 
creatinine 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Dexamethasone 
(DEX) 
PO 
(may give IV) 
5 mg/m2/dose BID 
Days 1-7 & 15-21 
Total daily dose: 
10 mg/m2/day, divided BID 
DOXOrubicin 
(DOXO) 
IV Push 
Over 15 min 
25 mg/m2/dose 
Days 1, 8, & 15 
See Section 4.7 for 
administration guidelines 
Pegaspargase 
 (PEG-ASP) 
IM 
(or IV over 1-2 hours) 
2500 International 
units/m2/dose 
Day 4 [OR 5 OR 6] AND 
Day 43 
For IV: Administer through 
the tubing of a freely 
infusing solution of D5W or 
0.9% NaCl 
Intrathecal 
Methotrexate  
(IT MTX) 
IT 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
Days 1, 29 & 36 
Note age-based doing 
Cyclophosphamide 
(CPM) 
IV over 30 min 
1000 mg/m2/dose 
Day 29 
See Section 4.7 for 
administration guidelines 
Cytarabine (ARAC) 
IV or SubQ 
75 mg/m2/dose 
Days 29-32 & 36-39 
 
Thioguanine (TG) 
PO 
60 mg/m2/dose 
Days 29-42 (omit all TG 
for IR/HR T-ALL pts 
receiving CRT on Arm C) 
See Section 4.7 & Appendix 
II for administration 
guidelines 
 
Therapy Delivery Map  
 
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date Due 
Date Given 
Day 
VCR 
____mg 
DEX 
____mg ____mg 
DOXO 
____mg 
PEG-ASP 
____IU 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
____mg 
____mg ____mg 
____mg 
 
____mg 
a, b, c, d 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
____IU 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
8 
____mg 
 
____mg 
 
 
b 
 
 
 
9 
 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
 
15 
____mg 
____mg ____mg 
____mg 
 
 
b 
 
 
 
16 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
b 
 
 
 
This therapy delivery map continues on the next page with Day 29. 
Page 1 of 2 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
AALL0434 
Version date: 03/24/16                   
 
 Page 62 
 
 
4.7.1b 
DELAYED INTENSIFICATION Arm A (CMTX) & Arm C (HDMTX) (NO Nelarabine) 
This Delayed Intensification course is for patients randomized or assigned to either 
treatment arm WITHOUT NELARABINE. 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Patients should have ANC ≥ 750/µL and platelets ≥ 75,000/µL prior to starting therapy on Days 1 and 29. Once Delayed Intensification has 
begun, it may be interrupted for myelosuppression on Day 29 ONLY. Once the Day 1 therapy or Day 29 cyclophosphamide has been given, the 
remainder of the therapy should not be held solely for myelosuppression, which is expected to occur. Therapy must be interrupted for patients 
with serious proven or presumed infection and resumed when the signs of infection have abated. This Course lasts 9 weeks (63 days) and this 
Therapy Delivery Map is on two (2) pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 min+ 1.5 mg/m2/dose 
Days 1, 8, 15, 43 & 50 
+ Or infusion via minibag as per 
institutional policy 
Maximum dose of 2 mg 
a. 
Hx/PE, weight 
(BSA) 
b. 
CBC/diff/platelets 
c. 
CSF cell count, 
cytospin 
d. 
Bilirubin, ALT, 
creatinine 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Dexamethasone (DEX) 
PO 
(may give IV) 
5 mg/m2/dose BID Days 1-7 & 15-21 
Total daily dose: 
10 mg/m2/day, divided BID 
DOXOrubicin (DOXO) 
IV Push 
Over 15 min 
25 mg/m2/dose 
Days 1, 8, & 15 
See Section 4.7 for 
administration guidelines 
Pegaspargase 
(PEG-ASP) 
IM  
(or IV over 1- 2 hours) 
2500 International 
units/m2/dose 
Day 4 [OR 5 OR 6] AND 
Day 43 
For IV: Administer through the 
tubing of a freely infusing 
solution of D5W or 0.9% NaCl 
Intrathecal Methotrexate  
(IT MTX) 
IT 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
Days 1, 29 & 36 
Note age-based dosing 
Cyclophosphamide (CPM) 
IV over 30 min 
1000 mg/m2/dose 
Day 29 
See Section 4.7 for 
administration  guidelines 
Cytarabine (ARAC) 
IV or SubQ 
75 mg/m2/dose 
Days 29-32 & 36-39 
 
Thioguanine (TG) 
PO 
60 mg/m2/dose 
Days 29-42 (omit all TG for 
IR/HR T-ALL pts receving 
CRT on Arm C) 
See Sec 4.7 & Appendix II for 
administration guidelines 
Therapy Delivery Map  
 
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
VCR 
____mg 
PEG-ASP 
____IU 
IT MTX 
____mg 
CPM 
____mg 
ARAC 
____mg 
TG$ 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
29 
 
 
____mg 
____mg ____mg 
____mg$ 
a, b, c, d 
 
 
 
30 
 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
 
 
34 
 
 
 
 
 
 
 
 
 
35 
 
 
 
 
 
 
 
 
 
36 
 
 
____mg 
 
____mg 
b, c 
 
 
 
37 
 
 
 
 
 
 
 
 
38 
 
 
 
 
 
 
 
 
39 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
42 
 
 
 
 
 
 
 
 
 
43 
____mg 
____IU 
 
 
 
 
b 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
50$ 
____mg 
 
 
 
 
 
b 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
57 
 
 
 
 
 
 
b 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
63 
 
 
 
 
 
 
 
 
 
 
64 
Start next course (Maintenance, Sec 4.9) on Day 64 or when blood count parameters are met (whichever occurs later) 
$ IR/HR T-ALL patients on Arm C and all CNS3 T-ALL patients are expected to begin cranial XRT on Day 50. Hold all thioguanine (Days 29-42) for pts 
receiving cranial XRT. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 2 of 2 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0434 
Version date: 03/24/16                   Page 63 
4.8 
DELAYED INTENSIFICATION Arms B (CMTX + Nel) and D (HDMTX + Nel)  
Weeks 25-33 
This Delayed Intensification (DI) course is for patients randomized or assigned to either 
treatment arm PLUS NELARABINE (Arms B and D). 
 
Criteria to begin Delayed Intensification 
Patients should have ANC ≥ 750/µL and platelets ≥ 75,000/µL prior to starting therapy on Days 
1 and 29. Once Delayed Intensification has begun, it may be interrupted for 
myelosuppression (ANC ≤ 750/µL and platelets ≤ 75,000/µL) on Day 29 ONLY. Once the 
Day 1 therapy or Day 29 Nelarabine has been given, the remainder of the therapy should not be 
held solely for myelosuppression, which is expected to occur. Therapy must be interrupted for 
patients with serious proved or presumed infection and resumed when the signs of infection have 
abated. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
1.5 mg/m2/dose (max dose 2 mg) on Days 1, 8, 15 and 50 
 
Special precautions: FOR INTRAVENOUS USE ONLY 
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing 
the statement “Do not remove covering until moment of injection. For intravenous use only - 
Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. 
VinCRIStine VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate 
liposomal injection, VSLI, Marqibo®). Use conventional vincristine only; the conventional and 
liposomal formulations are NOT interchangeable. 
 
Dexamethasone: PO (may give IV) 
All patients, regardless of age, received discontinuous dexamethasone: 5 mg/m2/dose BID (i.e., 
10 mg/m2/day, divided BID) on Days 1-7 and 15-21 
 
DOXOrubicin: IV push 
25 mg/m2/dose on Days 1, 8 and 15 
 
Administer at a concentration not to exceed 2 mg/mL by slow IV push or infusion over 1-15 
minutes. Short infusion times may be lengthened slightly (and up to 60 minutes) if institutional 
policies mandate. It is suggested that DOXOrubicin be administered through the tubing of rapidly 
infusing solution of D5W or 0.9% NaCl and that it is infused into a large vein. 
 
Pegaspargase: IM (or IV over 1-2 hours) 
2500 International units/m2/dose on Day 4 [OR 5 OR 6] AND Day 50 
 
For IV: Administer through the tubing of a freely infusing solution of D5W or 0.9% NaCl  
 
Intrathecal Methotrexate: IT 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0434 
Version date: 03/24/16                   Page 64 
For intrathecal administration, dilute with 5-10 mL preservative-free normal saline or lactated 
Ringer's solution on Days 1, 36 and 43. The volume of CSF removed should equal at least half 
the volume delivered. 
 
Aged-based dosing:  
Age (yrs) 
Dose 
1 – 1.99 
 
8 mg 
2 – 2.99 
 
10 mg 
3 – 8.99 
 
12 mg 
≥ 9 
 
15 mg 
 
Nelarabine: IV (over 60 minutes) 
650 mg/m2/dose on Days 29-33 
 
NOTE: the drug manufacturers of Nelarabine have included as part of the agent’s 
risks/side effects that patients receiving intrathecal chemotherapy or craniospinal 
irradiation with Nelarabine may be at increased risk of neurological adverse events. 
 
Cyclophosphamide: IV (over 30 minutes) 
1000 mg/m2/dose on Day 36. 
 
Reduce urine specific gravity to ≤ 1.015 prior to administering. Give IV fluids to maintain urine 
output. May use Furosemide 0.25 – 0.5 mg/kg/dose IV for urine output < 3 mL/kg/hr after CPM. 
See Section 5.3 for additional details. 
 
Cytarabine: IV over 1-30 minutes or Subcutaneous 
75 mg/m2/dose on Days 36-39 and 43-46 
 
Thioguanine: PO 
60 mg/m2/dose on Days 36-49. 
 
Give at least 1 hour after evening meal. To be taken without milk or citrus products. Adjust dose 
using half tablets and different doses on alternating days in order to attain a weekly cumulative 
dose as close to 420 mg/m2/week as possible. See Appendix II for details. Do not escalate or 
modify dose based on blood counts during this course. Please note: TG should not be 
administered to any patient receiving CRT during this stage of therapy (i.e. IR/HR T-ALL 
patients randomized to Arm D and all Induction Failures/CNS3 T-ALL patients). 
 
Cranial Radiation Therapy 
Prophylactic cranial XRT (1200 cGy in 8 once-daily fractions) for Intermediate/High Risk T-
ALL patients randomized to Arm D (HDMTX + Nel) and cranial XRT (1800cGy in 10 once-
daily fractions) for CNS3 T-ALL patients should start on Day 50 of DI. Intermediate/High Risk 
T-ALL patients randomized to Arm B (CMTX + Nel) received CRT in Consolidation and WILL 
NOT receive prophylactic cranial XRT during this phase of therapy. Low Risk T-ALL patients 
(defined in Section 4.1) and all T-NHL patients WILL NOT receive any cranial XRT. Please see 
Section 14.0 for all CRT details. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0434 
Version date: 03/24/16                   Page 65 
 
The therapy delivery maps (TDMs) for Delayed Intensification are on the next two pages. 
 
Following completion of Delayed Intensification, the next course (Maintenance, Sections 4.10 
and 4.11) starts on Day 64 or when blood count parameters are met (whichever occurs later). 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
AALL0434 
Version date: 03/24/16                   Page 66 
 
 
4.8.1a 
DELAYED INTENSIFICATION Arm B (CMTX + Nel) & Arm D (HDMTX + Nel) 
This Delayed Intensification course is for patients randomized or assigned to either treatment arm 
PLUS NELARABINE (Arms B and D). 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Patients should have ANC ≥ 750/µL and platelets ≥ 75,000/µL prior to starting therapy on Days 1 and 29. Once Delayed Intensification has 
begun, it may be interrupted for myelosuppression on Day 29 ONLY. Once the Day 1 therapy or Day 29 Nelarabine has been given, the 
remainder of the therapy should not be held solely for myelosuppression, which is expected to occur. Therapy must be interrupted for patients 
with serious proved or presumed infection and resumed when the signs of infection have abated. This Course lasts 9 weeks (63 days) and this 
Therapy Delivery Map is on two (2) pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 min+ 
1.5 mg/m2/dose 
Days 1, 8, 15 & 50 
+ Or infusion via minibag as 
per institutional policy 
Maximum dose of 2 mg 
a. 
Hx/PE 
b. 
Weight (BSA) 
c. 
CBC/diff/platelets 
d. 
CSF cell count, 
cytospin 
e. 
Bilirubin, ALT, 
creatinine 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Dexamethasone 
(DEX) 
PO 
(may give IV) 
5 mg/m2/dose BID 
Days 1-7 & 15-21 
Total daily dose: 
10 mg/m2/day, divided BID 
DOXOrubicin 
(DOXO) 
IV Push 
Over 15 min 
25 mg/m2/dose 
Days 1, 8, & 15 
See Section 4.8 for 
administration guidelines 
Pegaspargase 
(PEG-ASP) 
IM 
(or IV over 1-2 hours) 
2500 International 
units/m2/dose 
Day 4 [OR 5 OR 6] AND 
Day 50 
For IV: Administer through 
the tubing of a freely infusing 
solution of D5W or 0.9% NaCl 
Intrathecal 
Methotrexate 
(IT MTX) 
IT 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
Days 1, 36 & 43 
Note age-based dosing 
Nelarabine (Nel) 
IV over 60 min 
650 mg/m2/dose 
Days 29-33 
 
Cyclophosphamide 
(CPM) 
IV over 30 min 
1000 mg/m2/dose 
Day 36 
See Section 4.8 for 
administration guidelines 
Cytarabine (ARAC) 
IV or SubQ 
75 mg/m2/dose 
Days 36-39 & 43-46 
 
Thioguanine (TG) 
PO 
60 mg/m2/dose 
Days 36-49 (omit all TG 
for IR/HR T-ALL pts 
receiving CRT on Arm D) 
See Section 4.8 & Appendix II 
for administration guidelines 
 
Therapy Delivery Map  
 
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date Due 
Date Given 
Day 
VCR 
____mg 
DEX 
____mg ____mg 
DOXO 
____mg 
PEG-ASP 
____IU 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
____mg 
____mg ____mg 
____mg 
 
____mg 
a, b, c, d, e 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
____IU 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
8 
____mg 
 
____mg 
 
 
c 
 
 
 
9 
 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
 
15 
____mg 
____mg ____mg 
____mg 
 
 
c 
 
 
 
16 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
c 
 
 
 
This therapy delivery map continues on the next page with Day 29. 
Page 1 of 2 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
AALL0434 
Version date: 03/24/16                   Page 67 
 
 
4.8.1b 
DELAYED INTENSIFICATION Arm B (CMTX + Nel) & Arm D (HDMTX + Nel) 
This Delayed Intensification course is for patients randomized or assigned to either treatment arm PLUS 
NELARABINE (Arms B and D) 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Patients should have ANC ≥ 750/µL & plts ≥ 75,000/µL prior to starting therapy on Days 1 and 29. Once Delayed Intensification has begun, it may be 
interrupted for myelosuppression on Day 29 ONLY. Once the Day 1 therapy or Day 29 Nelarabine has been given, the remainder of the therapy should not be 
held solely for myelosuppression, which is expected to occur. Therapy must be interrupted for patients with serious proved or presumed infection and resumed 
when the signs of infection have abated. This Course lasts 9 weeks (63 days) and this Therapy Delivery Map is on two (2) pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 min+ 1.5 mg/m2/dose 
Days 1, 8, 15 & 50 
+ Or infusion via minibag as 
per institutional policy 
Maximum dose of 2 mg 
a. Hx/PE 
b. Weight (BSA) 
c. CBC/diff/platelets 
d. CSF cell count, 
cytospin 
e. Bilirubin, ALT, 
creatinine 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Dexamethasone (DEX) 
PO 
(may give IV) 
5 mg/m2/dose BID Days 1-7 & 15-21 
Total dose: 10 mg/m2/day, 
divided BID 
DOXOrubicin (DOXO) 
IV push over 15 min 25 mg/m2/dose 
Days 1, 8, & 15 
See Section 4.8 for 
administration guidelines 
Pegaspargase 
(PEG-ASP) 
IM 
(or IV over 1-2 hours) 
2500 International 
units/m2/dose 
Day 4 [OR 5 OR 6] AND Day 
50 
For IV: Administer through the 
tubing of a freely infusing 
solution of D5W or 0.9% NaCl 
Intrathecal 
Methotrexate (IT MTX) 
IT 
Age (yrs) Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
Days 1, 36 & 43 
Note age-based dosing 
Nelarabine 
IV over 60 min 
650 mg/m2/dose 
Days 29-33 
 
Cyclophosphamide 
(CPM) 
IV over 30 min 
1000 mg/m2/dose Day 36 
See Section 4.8 for 
administration guidelines 
Cytarabine (ARAC) 
IV or SubQ 
75 mg/m2/dose 
Days 36-39 & 43-46 
 
Thioguanine (TG) 
PO 
60 mg/m2/dose 
Days 36-49 (omit all TG for 
IR/HR T-ALL pts receiving CRT 
on Arm D) 
See Section 4.8 & Appendix II 
for administration guidelines 
Therapy Delivery Map  
 
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date Due 
Date Given 
Day 
VCR 
____mg 
PEG-ASP 
____IU 
IT MTX 
_____mg 
Nel 
____mg 
CPM 
____mg 
ARAC 
_____mg 
TG$ 
_____mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
29 
 
 
 
____mg 
 
 
 
a, b, c, e 
 
 
30 
 
 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
36 
 
 
_____mg 
 
____mg _____mg 
_____mg$ 
a, c, d 
 
 
37 
 
 
 
 
 
 
 
 
38 
 
 
 
 
 
 
 
 
39 
 
 
 
 
 
 
 
 
40 
 
 
 
 
 
 
 
 
 
41 
 
 
 
 
 
 
 
 
 
42 
 
 
 
 
 
 
 
 
 
43 
 
 
_____mg 
 
 
_____mg 
c, d 
 
 
44 
 
 
 
 
 
 
 
 
45 
 
 
 
 
 
 
 
 
46 
 
 
 
 
 
 
 
 
47 
 
 
 
 
 
 
 
 
 
48 
 
 
 
 
 
 
 
 
 
49 
 
 
 
 
 
 
 
 
 
50$ 
____mg 
____IU 
 
 
 
 
 
c 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
57 
 
 
 
 
 
 
 
c 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
63 
 
 
 
 
 
 
 
 
 
 
64 
Start next course (Maintenance, Sec 4.10 & 4.11) on Day 64 or when blood count parameters are met (whichever 
occurs later) 
$ T-ALL IR/HR pts on Arm D and all T-ALL Induction Failures/CNS3 pts are expected to begin cranial XRT on Day 50. Hold all thioguanine (Days 36-49)  
for pts receiving cranial XRT.   SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 2 of 2 


 
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AALL0434 
Version date: 03/24/16                   Page 68 
4.9 
MAINTENANCE Arms A (CMTX) and C (HDMTX) (NO Nelarabine) Week 30 until End of 
Therapy 
This Maintenance course is for patients randomized or assigned to either treatment arm 
WITHOUT NELARABINE (Arms A and C). 
 
Maintenance begins when peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 
75,000/µL. Only mercaptopurine and PO methotrexate will be interrupted for myelosuppression 
as outlined in Section 5.9. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
1.5 mg/m2/dose (max dose 2 mg) on Days 1, 29 and 57 
 
Special precautions: FOR INTRAVENOUS USE ONLY 
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing 
the statement “Do not remove covering until moment of injection. For intravenous use only - 
Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. 
VinCRIStine VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate 
liposomal injection, VSLI, Marqibo®). Use conventional vincristine only; the conventional and 
liposomal formulations are NOT interchangeable. 
 
PredniSONE: PO 
20 mg/m2/dose BID (i.e., 40 mg/m2/day, divided BID) x 5 days every 4 weeks on Days 1-5, 29-
33 and 57-61 
 
Mercaptopurine: PO 
75 mg/m2/dose on Days 1-84. 
 
Give at least 1 hour after evening meal. To be taken without milk or citrus products. Adjust dose 
using half tablets and different doses on alternating days in order to attain a weekly cumulative 
dose as close to 525 mg/m2/week as possible. See Appendix I for details. See Section 5.9 for 
dose escalation during Maintenance. 
 
Methotrexate: PO 
20 mg/m2/dose weekly on Days 8, 15, 22, 29*, 36, 43, 50, 57, 64, 71 and 78. See Section 5.9 for 
dose escalation during Maintenance. 
 
* Omit Day 29 of FIRST 4 CYCLES FOR LOW RISK T-ALL & STANDARD RISK T-NHL 
PATIENTS ONLY 
 
Intrathecal Methotrexate: IT 
For intrathecal administration, dilute with 5-10 mL preservative-free normal saline or lactated 
Ringer’s solution on Day 1 (also on Day 29 of the first 4 cycles of Maintenance for Low Risk 
T-ALL and Standard Risk T-NHL patients ONLY). The volume of CSF removed should 
equal at least half the volume delivered. 
 
Aged-based dosing:  


 
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AALL0434 
Version date: 03/24/16                   Page 69 
Age (yrs) 
Dose 
1 – 1.99 
 
8 mg 
2 – 2.99 
 
10 mg 
3 – 8.99 
 
12 mg 
≥ 9 
 
15 mg 
The therapy delivery map (TDM) for Maintenance is on the next page. 
 
Begin subsequent Maintenance cycles regardless of counts. Only mercaptopurine and PO 
methotrexate will be interrupted for myelosuppression as outlined in Section 5.9. 
 
GIRLS T-ALL: Continue to repeat 12-week cycles of Maintenance therapy until the total 
duration of therapy is two years from the start of Interim Maintenance (~ Week 119). 
BOYS T-ALL: Continue to repeat 12-week cycles of Maintenance therapy until the total 
duration of therapy is three years from the start of Interim Maintenance (~ Week 171). 
T-NHL patients (regardless of gender): Continue to repeat 12-week cycles of Maintenance 
therapy until the total duration of therapy is two years from the start of Interim Maintenance 
(~Week 119) 
May stop therapy on anniversary date if prednisone is completed for the 5-day prednisone pulse. 
Anniversary date is defined as the date marking two (2) years (for T-ALL girls and all T-NHL 
patients, regardless of gender) and three (3) years (for T-ALL boys) from the start of Interim 
Maintenance. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
AALL0434 
Version date: 03/24/16                   Page 70 
 
 
4.9.1 
MAINTENANCE Arm A (CMTX) & Arm C (HDMTX) 
This Maintenance course is for patients randomized or assigned to either of the treatment arms WITHOUT 
NELARABINE (Arms A and C). Maintenance is given in 12-week cycles and is repeated until two (2) years (for  
T-ALL girls and all T-NHL patients, regardless of gender) and three (3) years (for T-ALL boys) from the start of 
Interim Maintenance. 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Maintenance begins when peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL. Only Mercaptopurine and PO Methotrexate will 
be interrupted for myelosuppression as outlined in Section 5.9. This Cycle lasts 12 weeks (84 days) and this Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 
1 min+ 
1.5 mg/m2/dose 
Days 1, 29 & 57 
+ Or infusion via minibag as per 
institutional policy 
Maximum dose of 2 mg 
a. Hx/PE 
b. Weight (BSA) 
c. CBC/diff/platelets 
d. CSF cell count, 
cytospin 
e. ALT, creatinine, 
bilirubin 
T-NHL only: 
f. Chest CT/Chest x-ray 
g. Abdomen/Pelvis CT 
h. Bone scan  
 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
PredniSONE (PRED) 
PO 
20 mg/m2/dose 
BID 
Days 1-5, 29-33 & 57-61 
Total daily dose: 
40 mg/m2/day, divided BID 
Mercaptopurine (MP) 
PO 
75 mg/m2/dose 
Days 1-84 
See Appendix I for admin guidelines; 
see Sec 5.9 regarding dose escalation 
Methotrexate (MTX) 
PO 
20 mg/m2/dose 
weekly 
Days 8, 15, 22, 29@, 36, 43, 50, 
57, 64, 71 & 78 
See Section 5.9 regarding dose 
escalation 
@ Omit Day 29 of first 4 cycles only 
(for Low Risk T-ALL & Standard Risk  
T-NHL pts) 
Intrathecal 
Methotrexate 
(IT MTX) 
IT 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
Day 1 
Day 29 (Cycles 1-4) Low Risk 
T-ALL & Standard Risk T-
NHL pts ONLY 
Note age-based dosing 
See Section 2.1 for rationale on 
omitting Day 29 IT MTX in certain 
risk groups.  
Enter Cycle # ________ 
 
Ht_____________cm 
 
Wt____________kg 
 
BSA__________m2 
Date 
Due 
Date 
Given 
Day 
VCR 
_____mg 
PRED 
___mg ___mg 
MP 
____mg 
PO MTX 
____mg 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
_____mg 
___mg ___mg 
____mg 
 
____mg 
(a, c)^  (b, d, e)# 
 
 
 
--- 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
8 
 
 
____mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
15 
 
 
____mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
22 
 
 
____mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
29 
_____mg 
___mg ___mg 
____mg@ 
____mg** 
(a, c)^, d** 
 
 
 
--- 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
36 
 
 
____mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
43 
 
 
____mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
50 
 
 
____mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
57 
_____mg 
___mg ___mg 
____mg 
 
(a, c)^ 
 
 
 
--- 
 
 
 
 
 
 
 
61 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
64 
 
 
____mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
71 
 
 
____mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
78 
 
 
____mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
84 
 
 
 
 
(a, c)^ (f, g, h)& 
 
 
 
85 
Begin next cycle on Day 85 regardless of counts and repeat until two years (for T-ALL girls and all  
T-NHL pts, regardless of gender) and three years (for T-ALL boys) from the start of Interim Maintenance. Only MP & PO MTX will be 
interrupted for myelosuppression during subsequent Maintenance cycles as outlined in Section 5.9. 
# Start of each 12-week cycle 
^ Every 4 weeks each 12-week cycle 
** First 4 cycles only (Low Risk T-ALL & Standard Risk T-NHL pts ONLY) 
@ Omit in first 4 cycles only for Low Risk T-ALL & Standard Risk T-NHL pts 
& T-NHL pts only at completion of Maintenance therapy (see Section 7.2) 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 1 of 1 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0434 
Version date: 03/24/16                   Page 71 
4.10 
MAINTENANCE Arms B (CMTX + Nel) and D (HDMTX + Nel) CYCLES 1-3  
(Weeks 34 – 69) 
 
This Maintenance course is for patients randomized or assigned to either treatment arm PLUS 
NELARABINE (Arms B and D). 
 
Maintenance begins when peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 
75,000/µL. Only mercaptopurine and PO methotrexate will be interrupted for myelosuppression 
as outlined in Section 5.9. If delays exceed two weeks or interfere with Nelarabine 
administration, please notify the Study Chair. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
1.5 mg/m2/dose (max dose 2 mg) on Days 1 and 57 
 
Special precautions: FOR INTRAVENOUS USE ONLY 
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing 
the statement “Do not remove covering until moment of injection. For intravenous use only - 
Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. 
VinCRIStine VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate 
liposomal injection, VSLI, Marqibo®). Use conventional vincristine only; the conventional and 
liposomal formulations are NOT interchangeable. 
  
PredniSONE: PO 
20 mg/m2/dose BID (i.e., 40 mg/m2/day, divided BID) on Days 1-5 and 57-61. 
 
Mercaptopurine: PO 
75 mg/m2/dose on Days 1-28 and 36-84. 
 
Give at least 1 hour after evening meal. To be taken without milk or citrus products. Adjust dose 
using half tablets and different doses on alternating days in order to attain a weekly cumulative 
dose as close to 525 mg/m2/week as possible. See Appendix I for details. See Section 5.9 for 
dose escalation during Maintenance. 
 
Methotrexate: PO 
20 mg/m2/dose weekly on Days 8, 15, 22, 36, 43, 50, 57, 64, 71 & 78. See Section 5.9 for dose 
escalation during Maintenance. 
 
Intrathecal Methotrexate: IT 
For intrathecal administration, dilute with 5-10 mL preservative-free normal saline or lactated 
Ringer’s solution on Day 1. The volume of CSF removed should equal at least half the volume 
delivered. 
 
Aged-based dosing:  
Age (yrs) 
Dose 
1 – 1.99 
 
8 mg 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0434 
Version date: 03/24/16                   Page 72 
2 – 2.99 
 
10 mg 
3 – 8.99 
 
12 mg 
≥ 9 
 
15 mg 
 
Nelarabine: IV (over 60 minutes) 
650 mg/m2/dose on Days 29-33. DO NOT administer concomitantly with other 
chemotherapy agents. 
 
NOTE: the drug manufacturers of Nelarabine have included as part of the agent’s 
risks/side effects that patients receiving intrathecal chemotherapy or craniospinal 
irradiation with Nelarabine may be at increased risk of neurological adverse events. 
 
Repeat above cycle two (2) times for a total of three (3) cycles with Nelarabine. Then proceed to 
additional 12-week Maintenance cycles (Section 4.11) until End of Therapy. 
 
The therapy delivery map (TDM) for this block of Maintenance therapy is on the next page. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
AALL0434 
Version date: 03/24/16                   Page 73 
 
4.10.1 MAINTENANCE Arm B (CMTX + Nel) & Arm D (HDMTX + Nel) CYCLES 1-3 
             (Weeks 34-69) 
This Maintenance therapy block is for patients randomized or assigned to either of the treatment arms PLUS 
NELARABINE (Arms B and D). This block of Maintenance therapy is repeated twice for a total of three (3) cycles 
with Nelarabine. 
 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Maintenance begins when peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL. Only Mercaptopurine and PO Methotrexate will be 
interrupted for myelosuppression as outlined in Section 5.9. If delays exceed two weeks or interfere with Nelarabine administration, please notify the 
Study Chair. This Cycle lasts 12 weeks (84 days) and this Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push 
over 1 min+ 
1.5 mg/m2/dose 
Days 1 & 57 
+ Or infusion via minibag as per institutional policy 
Maximum dose of 2 mg 
a. 
Hx/PE 
b. 
Weight (BSA) 
c. 
CBC/diff/ 
platelets 
d. 
CSF cell count, 
cytospin 
e. 
ALT, 
creatinine, 
bilirubin 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
PredniSONE (PRED) 
PO 
20 mg/m2/dose BID Days 1-5 & 57-61 
Total daily dose: 40 mg/m2/day, divided BID 
Mercaptopurine (MP) 
PO 
75 mg/m2/dose 
Days 1-28 & 36-84 
See Appendix I for admin guidelines; see Section 
5.9 regarding dose escalation 
Methotrexate (MTX) 
PO 
20 mg/m2/dose 
weekly 
Days 8, 15, 22, 36, 43, 
50, 57, 64, 71 & 78 
See Section 5.9 regarding dose escalation 
Intrathecal 
Methotrexate 
(IT MTX) 
IT 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
Day 1 ONLY 
 
Note age-based dosing 
Nelarabine (Nel) 
IV over 60 
min 
650 mg/m2/dose 
Days 29-33 
Note: only three (3) cycles of Nelarabine 
DO NOT administer concomitantly with other 
chemotherapy agents 
 
Enter Cycle # ________ 
 
Ht___________cm 
 
Wt___________kg 
 
BSA________m2 
Date 
Due 
Date 
Given 
Day 
VCR 
____mg 
PRED 
__mg __mg 
MP 
____mg 
PO MTX 
____mg 
IT MTX 
____mg 
Nel 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
____mg 
__mg __mg 
____mg 
 
____mg 
 
(a, c)^  (b, d, e)# 
 
 
 
--- 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
8 
 
 
____mg 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
15 
 
 
____mg 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
22 
 
 
____mg 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 
29 
 
 
 
 
 
____mg 
(a, c)^ 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
36 
 
 
____mg 
____mg 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
43 
 
 
____mg 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
50 
 
 
____mg 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
57 
____mg 
__mg __mg 
____mg 
 
 
(a, c)^ 
 
 
 
--- 
 
 
 
 
 
 
 
 
61 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
64 
 
 
____mg 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
71 
 
 
____mg 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
78 
 
 
____mg 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
84 
 
 
 
 
 
(a, c)^ 
 
 
 
85 
Begin next cycle on Day 85 and repeat two times for a total of three (3) cycles with Nelarabine 
^ Every 4 weeks 
# Every 12 weeks 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 1 of 1 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0434 
Version date: 03/24/16         
 
           Page 74 
4.11 
MAINTENANCE CONTINUED AFTER CYCLE THREE Arms B (CMTX + Nel) and D 
(HDMTX + Nel) 
This Maintenance course is for patients randomized or assigned to either treatment arm PLUS 
NELARABINE (Arms B and D). 
 
Maintenance continues when peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 
75,000/µL. Only mercaptopurine and PO methotrexate will be interrupted for myelosuppression 
as outlined in Section 5.9. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional policy 
1.5 mg/m2/dose (max dose 2 mg) on Days 1, 29 and 57 
 
Special precautions: FOR INTRAVENOUS USE ONLY 
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing 
the statement “Do not remove covering until moment of injection. For intravenous use only - 
Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. 
VinCRIStine VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate 
liposomal injection, VSLI, Marqibo®). Use conventional vincristine only; the conventional and 
liposomal formulations are NOT interchangeable. 
  
PredniSONE: PO 
20 mg/m2/dose BID (i.e., 40 mg/m2/day, divided BID) x 5 days every 4 weeks on Days 1-5, 29-
33 and 57-61. 
 
Mercaptopurine: PO 
75 mg/m2/dose on Days 1-84. 
 
Give at least 1 hour after evening meal. To be taken without milk or citrus products. Adjust dose 
using half tablets and different doses on alternating days in order to attain a weekly cumulative 
dose as close to 525 mg/m2/week as possible. See Appendix I for details. See Section 5.9 for 
dose escalation during Maintenance. 
 
Methotrexate: PO 
20 mg/m2/dose weekly on Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 & 78. See Section 5.9 for 
dose escalation during Maintenance. 
 
Intrathecal Methotrexate: IT 
For intrathecal administration, dilute with 5-10 mL preservative-free normal saline or lactated 
Ringer’s solution on Day 1. The volume of CSF removed should equal at least half the volume 
delivered. 
 
Aged-based dosing:  
Age (yrs) 
Dose 
1 – 1.99 
 
8 mg 
2 – 2.99 
 
10 mg 
3 – 8.99 
 
12 mg 
≥ 9 
 
15 mg 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0434 
Version date: 03/24/16         
 
           Page 75 
 
The therapy delivery map (TDM) for Maintenance continued after Cycle Three is on the next 
page. 
 
Begin subsequent Maintenance cycles regardless of counts. Only mercaptopurine and PO 
methotrexate will be interrupted for myelosuppression as outlined in Section 5.9. 
 
GIRLS T-ALL: Continue to repeat 12-week cycles of Maintenance therapy until the total 
duration of therapy is two years from the start of Interim Maintenance (~ Week 121). 
BOYS T-ALL: Continue to repeat 12-week cycles of Maintenance therapy until the total 
duration of therapy is three years from the start of Interim Maintenance (~ Week 173). 
T-NHL patients (regardless of gender): Continue to repeat 12-week cycles of Maintenance 
therapy until the total duration of therapy is two years from the start of Interim Maintenance 
(~Week 121). 
May stop therapy on anniversary date if prednisone is completed for the 5-day prednisone pulse. 
Anniversary date is defined as the date marking two (2) years (for T-ALL girls and all T-NHL 
patients, regardless of gender) and three (3) years (for T-ALL boys) from the start of Interim 
Maintenance. 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
 
AALL0434 
Version date: 03/24/16         
 
           Page 76 
 
4.11.1 MAINTENANCE CONTINUED AFTER CYCLE THREE Arm B (CMTX + 
 
Nel) & Arm D (HDMTX + Nel) 
This Maintenance therapy block is for patients randomized or assigned to either of the treatment arms 
PLUS NELARABINE (Arms B and D). Maintenance is given in 12-week cycles and is repeated until two 
(2) years (for T-ALL girls and all T-NHL patients, regardless of gender) and three (3) years (for T-ALL 
boys) from the start of Interim Maintenance. 
 
____________________________ 
Patient name or initials 
 
____________________________ 
DOB 
Maintenance continues when peripheral counts recover with ANC ≥ 750/µL and platelets ≥ 75,000/µL. Only Mercaptopurine and PO Methotrexate will  
be interrupted for myelosuppression as outlined in Section 5.9. This Cycle lasts 12 weeks (84 days) and this Therapy Delivery Map is on one (1) page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push 
over 1 min+ 
1.5 mg/m2/dose 
Days 1, 29 & 57 
+ Or infusion via minibag as per institutional 
policy 
Maximum dose of 2 mg 
a. Hx/PE 
b. Weight (BSA) 
c. CBC/diff/platelets 
d. CSF cell count, 
cytospin 
e. ALT, creatinine, 
bilirubin 
T-NHL only: 
f. Chest CT/Chest x-ray 
g. Abdomen/Pelvis CT 
h. Bone scan  
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
PredniSONE (PRED) 
PO 
20 mg/m2/dose BID Days 1-5, 29-33 & 57-61 Total daily dose: 40 mg/m2/day, divide BID 
Mercaptopurine (MP) 
PO 
75 mg/m2/dose 
Days 1-84 
See Appendix I for admin guidelines; see 
Section 5.9 regarding dose escalation 
Methotrexate (MTX) 
PO 
20 mg/m2/dose 
weekly 
Days 8, 15, 22, 29, 36, 
43, 50, 57, 64, 71 & 78 
See Section 5.9 regarding dose escalation 
Intrathecal 
Methotrexate 
(IT MTX) 
IT 
Age (yrs) 
Dose 
1 – 1.99 
8 mg 
2 – 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
Day 1 ONLY 
 
Note age-based dosing 
 
Enter Cycle # ________ 
 
 
Ht_______cm 
 
Wt_______kg 
 
 
BSA____m2 
Date Due Date 
Given 
Day 
VCR 
____mg 
PRED 
___mg ___mg 
MP 
____mg 
PO MTX 
____mg 
IT MTX 
____mg 
Studies 
Comments 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
____mg 
___mg ___mg 
____mg 
 
____mg 
(a, c)^  (b, d, e)# 
 
 
 
--- 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
8 
 
 
____mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
15 
 
 
____mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
22 
 
 
____mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
29 
____mg 
___mg ___mg 
____mg 
 
(a, c)^ 
 
 
 
--- 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
36 
 
 
____mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
43 
 
 
____mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
50 
 
 
____mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
57 
____mg 
___mg ___mg 
____mg 
 
(a, c)^ 
 
 
 
--- 
 
 
 
 
 
 
 
61 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
64 
 
 
____mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
71 
 
 
____mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
78 
 
 
____mg 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
84 
 
 
 
 
(a, c)^ (f, g, h)& 
 
 
 
85 
Begin next cycle on Day 85 regardless of counts and repeat until 2 years (for T-ALL girls and all  
T-NHL pts, regardless of gender) and 3 years (for T-ALL boys) from the start of Interim Maintenance. Only MP & 
PO MTX will be interrupted for myelosuppression during subsequent cycles of Maintenance as outlined in Sec 5.9. 
^ Every 4 weeks 
# Every 12 weeks  
& T-NHL pts only at completion of Maintenance therapy (see Section 7.2) 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE SECTION 8.0 FOR SUPPORTIVE CARE 
Page 1 of 1 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0434 
Version date: 03/24/16         
 
           Page 77 
 
5.0 
DOSE MODIFICATION FOR TOXICIT IES 
 
Notify the Study Chair at the time of removing a patient from protocol therapy for toxicity. The 
drugs are listed in alphabetical order 
 
5.1 
Asparaginase [Pegaspargase (PEG-Asparaginase) or Erwinia] 
Allergy 
Local Allergic Reactions (inflammation at injection site, swelling): Continue pegaspargase 
administration in the presence of Grade 1 allergy (transient flushing or rash; drug fever < 38ºC).  
 
Systemic Allergic Reactions: Discontinuation may be considered for severe Grade 2 or higher 
allergic reactions as defined by CTCAE v4.0. 
 
Note: Pre-medication with antihistamines to decrease the risk of overt allergy symptoms is 
strongly discouraged since anti-histamine use may mask the appearance of systemic allergy. 
Systemic allergy is frequently associated with the presence of asparaginase neutralizing 
antibodies, which render asparaginase therapy ineffective. In the event of severe systemic or 
recurrent local allergic reaction, Erwinia asparaginase (now FDA-approved for this indication) 
should be substituted.  
 
Anaphylaxis: Discontinue pegaspargase if the patient develops Grade 3 anaphylaxis as defined 
by CTCAE v4.0 (symptomatic bronchospasm, with or without urticaria; parenteral intervention 
indicated; allergy-related edema/angioedema; hypotension). If this occurs, Erwinia asparaginase 
(now FDA-approved for this indication) should be substituted. 
 
Erwinia asparaginase has a shorter half life and is associated with a shorter duration of 
asparagine depletion than native E. coli asparaginase, with “head-to-head” comparisons of 
Erwinia and E. coli asparaginase, using the same dose and schedule for both preparations, 
demonstrating a superior outcome, favoring E. coli asparaginase47,48. Pegaspargase has a longer 
half-life and is associated with more prolonged asparagine depletion than native E. coli 
asparaginase, but the largest randomized trial comparing weekly native to bi-weekly 
pegaspargase wasn’t powered to detect a difference in outcome49 Current COG trials have 
adopted pegaspargase as the preparation of choice, based on the results of CCG 1962. COG 
AALL07P2 showed that Erwinia asparaginase was well tolerated and achieved nadir serum 
asparaginase activity at both 48 and 72 hours after dosing that was similar to that achieved with 
pegaspargase. Based on these and other data, the FDA approved Erwinia asparaginase for use 
following allergy to pegaspargase, with a dose of Erwinia 25,000 IU/m2 x 6 doses IM on a 
Monday/Wednesday/Friday schedule substituted for a single dose of pegaspargase 
 
The dose modification guidelines for ALL trials recommend the substitution for replacement of 
Erwinia asparaginase for either native or pegaspargase utilizing the following schedule: 
 
Phase(s) of Treatment 
Drug(s) 
Replacement Schedule 
for Erwinia 
asparaginase# 
Standard Induction, Re-Induction, Interim 
One or more 
25,000 IU/m2/dose IM 


 
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Maintenance, Delayed Intensification, or phases 
of therapy in which pegaspargase doses are 13+ 
days apart 
doses of 
pegaspargase 
(2,500 IU/m2) 
M/W/F x 6 doses for each 
dose of pegaspargase 
#If a patient develops a Grade 3 or higher anaphylaxis to Erwinia, discontinue future asparaginase therapy. Consider 
discontinuation for severe Grade 2 or higher allergic reactions. 
 
To replace a dose of intravenous pegaspargase that was discontinued during the infusion due to an allergic 
reaction, the following recommendations may be used to guide patient care.  
 
In the event that a pegaspargase infusion is discontinued for an allergic reaction, regardless of amount 
received, substitution with Erwinia asparaginase should begin approximately 48 hours after pegaspargase 
has been discontinued and preferably to coincide with the recommended Monday/Wednesday/Friday 
administration schedule detailed above in patients who are clinically stable. Up to 6 doses of Erwinia 
asparaginase may be administered, as tolerated, to replace the incomplete intravenous pegaspargase dose. 
Of note, Erwinia asparaginase is recommended only for pegaspargase hypersensitivity reactions, and not 
for pancreatitis, hepatitis, coagulation abnormalities, or other non-hypersensitivity toxicities associated 
with pegaspargase. To best suit the needs of each individual patient, additional modifications to these 
recommendations may be made at the discretion of the treating physician. 
 
Coagulopathy: If symptomatic, hold asparaginase until symptoms resolve, then resume with the 
next scheduled dose. Consider factor replacement (FFP, cryoprecipitate, factor VIIa). Do not 
withhold dose for abnormal laboratory findings without clinical symptoms.   
 
Hyperbilirubinemia: asparaginase may need to be withheld in patients with an elevated direct 
bilirubin, since asparaginase has been associated with hepatic toxicity. There are no specific 
guidelines available. 
 
Hyperglycemia: Do not modify dose. Treat hyperglycemia as medically indicated. 
 
Hyperlipidemia: Do not modify dose. 
 
Ketoacidosis: Hold asparaginase until blood glucose can be regulated with insulin. 
 
Pancreatitis (Grade 3-4): Discontinue asparaginase in the presence of hemorrhagic pancreatitis or 
severe pancreatitis. In the case of mild pancreatitis, asparaginase should be held until symptoms 
and signs subside, and amylase levels return to normal and then resumed. Severe pancreatitis is a 
contraindication to additional asparaginase administration. 
 
Thrombosis: Withhold asparaginase until resolved, and treat with appropriate anti-thrombotic 
therapy, as indicated. Upon resolution of symptoms consider resuming asparaginase, while 
continuing LMWH or anti-thrombotic therapy. Do not withhold dose for abnormal laboratory 
findings without clinical correlate. For significant thrombosis, not line related, consider evaluation 
for inherited predisposition to thrombosis. 
 
CNS Events (bleed, thrombosis or infarction): Hold asparaginase. Treat with FFP, factors or 
anticoagulation as appropriate. Resume at full dose when all symptoms have resolved (and evidence 
of recanalization in case of thrombosis by CT/MRI). Consider evaluation for inherited 
predisposition to thrombosis.  


 
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5.2 
Nelarabine (Compound 506U78)  
If neurologic toxicity develops prior to the completion of 5 days of therapy, Nelarabine 
should be halted and the study chair should be called immediately. If Grade 4 Nelarabine-
related neurotoxicity develops, the patient will be taken off Nelarabine indefinitely. 
 
NOTE: THE DRUG MANUFACTURERS OF NELARABINE HAVE INCLUDED AS 
PART OF THE AGENT’S RISKS/SIDE EFFECTS THAT PATIENTS RECEIVING 
INTRATHECAL CHEMOTHERAPY OR CRANIOSPINAL IRRADIATION WITH 
NELARABINE MAY BE AT INCREASED RISK OF NEUROLOGICAL ADVERSE 
EVENTS. 
 
Peripheral Neurotoxicity 
Investigators are cautioned to monitor patients carefully for the development of signs and 
symptoms of peripheral neuropathy. In the event that a patient develops initial signs or 
symptoms of peripheral neuropathy attributed to the administration of Nelarabine, the agent 
should be discontinued for the course. Only resume Nelarabine if peripheral neuropathy resolves 
to less than Grade 2 toxicity. Nelarabine should NOT be continued in patients who develop signs 
or symptoms suggestive of an ascending polyneuropathy, including a Guillain-Barré-like 
syndrome, even if these symptoms resolve. It is recommended that patients who develop 
neurotoxicity in association with Nelarabine undergo a thorough neurologic evaluation to 
establish a diagnosis and to exclude other potential etiologies (e.g. disease progression, 
concomitant illness, etc.). If a Guillain-Barré-like syndrome is suspected, therapeutic measures 
considered appropriate for the individual patients (i.e. intravenous immunoglobulin, 
plasmapheresis, steroids, and supportive care) should be instituted as soon as possible. It is 
strongly recommended that you consult with your institution’s neurologist. 
 
Central Neurotoxicity  
In patients who develop Grade 3 CNS events (e.g., somnolence, mood alteration, irritability, 
confusion, etc.) that return to < Grade 2 severity prior to the next planned course of Nelarabine, 
the Nelarabine dose is to be prescribed without treatment interruption. 
 
Nelarabine will not be made up if any doses are missed during a 5-day treatment course. Patients 
who are unable to receive a 5-day course of Nelarabine because of toxicity should proceed to the 
next planned course of protocol therapy as soon as recovery allows. 
 
Rhabdomyolysis 
If patient(s) develop myalgia or myoglobinuria, they should be evaluated for the potential of 
having rhabdomyolysis. The patient should receive a workup that includes AST, ALT, 
creatinine, and creatine kinase (CK)/(CPK) at a minimum. Consideration should be given to 
consulting a nephrologist. The Study Chair(s) should be notified if the patient develops either of 
the above symptoms, and the nelarabine should be held. If the patient is stable, other protocol 
therapy may continue while the patient is undergoing evaluation. Following study chair 
notification and evaluation for rhabdomyolysis, a decision should be rendered regarding 
permanently discontinuing the nelarabine. 
 


 
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5.3 
Cyclophosphamide 
Hematuria: Omit in the presence of macroscopic hematuria. If there is a history of previous 
significant hematuria, hydrate before cyclophosphamide until specific gravity is < 1.010 and 
hydrate at 125 mL/m2/hr for 24 hours after dose. Monitor for adequate urine output as per 
institution guidelines. Give IV mesna at a total dose that is 60% of the cyclophosphamide dose 
divided to 3 doses (eg, if the cyclophosphamide dose is 1000 mg/m2, the total mesna dose is 600 
mg/m2 or 200 mg/m2). Give the first mesna dose 15 minutes before or at the same time as the 
cyclophosphamide dose and repeat 4 and 8 hours after the start of cyclophosphamide. This total 
daily dose of mesna can also be administered as IV continuous infusion. The continuous infusion 
should be started 15-30 minutes before or at the same time as cyclophosphamide and finished no 
sooner than 8 hours after the end of cyclophosphamide infusion. 
 
5.4 
Cytarabine (ARAC) 
ARAC Syndrome: Do not withhold ARAC for fever if it is likely to have been caused by the 
ARAC. Obtain blood cultures if a central line is present. For rash or conjunctivitis, withhold for 
Grade 3-4 toxicity until resolved. Make up missed doses and consider concurrent treatment with 
hydrocortisone or dexamethasone, and/or with dexamethasone ophthalmic drops for 
conjunctivitis. 
 
5.5 
Intrathecal Cytarabine 
Do not withhold dose given on Day 1 of Induction. 
 
5.6 
Daunorubicin and Doxorubicin (Anthracyclines)  
Cardiac Toxicity: Discontinue for clinical or echocardiographic evidence of cardiomyopathy (SF 
< 27% or EF < 50%) or Grade 3-4 left ventricular systolic dysfunction (LVSD) per CTCAE 
version 4.0. 
 
Note: use the following updated term to report decreases in the SF or EF: Cardiac disorders-
other. 
 
Myelosuppression (beyond Induction): If patient has severe infection or severe mucositis (Grade 3-4) and 
an ANC < 500/μL delay anthracycline during phases other than Induction. During Induction, continue 
with anthracycline administration. Subsequent doses should be given at full dose. 
Hyperbilirubinemia:50  
Direct bilirubin <1.2 mg/dL -Full dose 
Direct bilirubin 1.2-3.0 mg/dL 
-50% dosage decrease. 
Direct bilirubin 3.1-5.0 mg/dL 
-75% dosage decrease. 
Direct bilirubin >5 mg/dL 
-Withhold dose and administer next scheduled dose if toxicity has 
resolved. Do not make up missed doses. 
 
Extravasation: 
In the event of an extravasation, discontinue the IV administration of the drug and institute appropriate 
measures to prevent further extravasation and damage according to institutional guidelines. Also see 
https://members.childrensoncologygroup.org/_files/disc/Nursing/extravasationguidelines.pdf for COG 
guidelines. 
 


 
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5.7 
Intrathecal Methotrexate 
Systemic toxicity: The dosage for IT chemotherapy will not be reduced for systemic toxicity 
(myelosuppression, mucositis, etc.). Instead, leucovorin may be used at a dose of 5mg/m2/dose 
every 12 hours x 2 doses, beginning 48 hours after the IT therapy has been delivered. This may 
reduce the risk of worsening already existent myelosuppression (ANC < 500/L) or mucositis. Do 
not administer leucovorin solely to prevent myelosuppression. 
 
Dose modifications following an episode of acute neurotoxicity: 
Neurotoxicity has extremely protean manifestations, ranging from transient events, seizures or 
episodes of acute hemiparesis, to severe necrotizing encephalopathies.51-53 These toxicities are 
poorly understood and currently it is impossible to predict who will suffer these complications. 
In addition, there are no data clearly linking the occurrence of an acute neurotoxic event with an 
increased risk of long-term neurocognitive dysfunction, nor do changes present on MRI at the 
time of an acute event clearly correlate with or predict outcome.53-58 It is clear however, that 
CNS prophylaxis is a mandatory component of curative therapy for children with ALL. Effective 
prophylaxis generally takes 2 forms; cranial, or less commonly, craniospinal radiation, with a 
limited number of doses of IT therapy or prolonged IT therapy with either IT MTX or triple IT 
therapy (MTX, ARAC and hydrocortisone). Certain protocols, for example BFM 200028, include 
fewer doses of IT MTX, with an acceptably low frequency of CNS relapse, but the backbone of 
the BFM therapies is not the same as those currently used by the Children’s Oncology Group. 
The exclusive use of IT ARAC has not been studied or described in the context of ALL therapy 
nor can one demonstrate the safety of omitting multiple doses of IT therapy without concomitant 
use of cranial irradiation or high dose Methotrexate. 
 
The following guidelines are offered for consideration following an acute event, but it must be 
recognized that there are little data to support these approaches or any others. Thus the treating 
physician must evaluate the patient and, with the family, make the best possible decision with 
respect to the relative risk and benefit of continued therapy. 
 
Following an acute neurotoxic event, a history and physical exam should guide the differential 
diagnosis. A neurology consult may be of value and should be considered.  Seizures and other 
transient events may be linked to fever, infection, encephalitis, meningitis, hypertension, 
electrolyte disturbance, hypoglycemia, trauma, intracranial hemorrhage or thrombosis, narcotic 
withdrawal, illicit drug use, or other causes in addition to the direct side effects of chemotherapy. 
Appropriate laboratory studies may include, but are not limited to, blood cultures, a CBC, 
electrolytes, including glucose, calcium, magnesium and phosphorus, renal and liver function 
studies and/or an examination of the CSF. Imaging studies may include a CT scan and/or an 
MRI. The CT is commonly normal, in the absence of stroke, but if calcifications are present, this 
finding may be indicative of a more severe mineralizing leukoencephalopathy.59 MRI 
abnormalities may be pronounced, but transient. Posterior reversible encephalopathy may be 
present on MR with extensive diffusion abnormalities, but these do not appear to correlate with 
subsequent demyelination or gliosis.60-62 Additional studies, including MR angiography and/or 
venogram should be considered, if clinically indicated (e.g. focal deficits). 
 
Many acute events, seizures or episodes of transient hemiparesis, are temporally related to the 
administration of intrathecal therapy, commonly 9 to 11 days after the IT administration.63 For 
patients who return to their “pre-event” status, without residual deficits on physical or neurologic 


 
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exam, there are few data to support or guide therapeutic interventions. It is reasonable to hold the 
next dose of IT therapy, or, substitute IT ARAC for 1 dose of IT MTX, or triple IT therapy. It is 
also reasonable to include leucovorin rescue at a dose of 5 mg/m2 q 12 hrs x 2 doses beginning 
48 hours after the LP. This pattern of rescue was associated with a clear diminution in the 
incidence of acute neurotoxicity in one case series.63 There have been questions about potential 
interference of leucovorin with the efficacy of the IT MTX, but there are little data to support or 
refute this position. Moreover, the administration 48 hours later would minimize any potential 
interference. If the event does not recur, resumption of standard therapy should be considered, 
following one modified or omitted IT dose. In the face of multiply recurrent events, or evidence 
of progressive encephalopathy, another evaluation is warranted and the treating physician may 
consider a more prolonged or definitive change in therapy. These decisions are extremely 
difficult and may hinge on an individuals view of the importance of quality of life versus an 
increase in the risk of relapse. Since the greatest impact of CNS prophylaxis occurs early in 
therapy, the timing of these events may also influence clinical decisions. Cranial radiation has 
been suggested as an alternative to continued IT therapy though much of the literature on long-
term neurocognitive dysfunction supports a more deleterious effect from CRT than IT therapy.64-
67 Dramatic deviations from protocol recommended therapy might result in the child being taken 
off protocol therapy. 
 
The use of dextromethorphan (DM) has been suggested as a neuroprotectant, capable of 
preventing NMDA mediated neurotoxicity without prohibitive toxicity. Low dose therapy has 
been recommended, in part, based on data suggesting that DM is concentrated in brain relative to 
serum. However, the literature on the use of DM supports a tight dose response relationship, with 
the likelihood of sparing an initially unaffected area, following ischemic damage, linked to dose, 
in both clinical trials and animal models of CNS ischemia.68-71 At doses thought to be 
therapeutic, side effects have included nystagmus, nausea and vomiting, distorted vision, ataxia, 
and dizziness. In addition, Hollander and others72 have raised concerns about the potential 
deleterious effects of long-term NMDA receptor blockade on memory because hippocampal 
long-term potentiation is dependent on the activation of the NMDA receptor. Thus in the absence 
of a clinical trial there are few data to support the addition of DM. 
 
 
Hydrocephalus, microcephaly or known abnormality of CSF flow precluding intrathecal chemotherapy 
via lumbar puncture: 
Intraventricular chemotherapy via Ommaya catheter may be used in place of intrathecal therapy delivered 
by LP. Intraventricular chemotherapy should be given according to the same schedule, but at 50% of the 
corresponding age-based doses that would be given by LP. NOTE: Obstruction to CSF flow may be a 
contraindication to intrathecal and/or intraventricular therapy. 
 
Viral, bacterial, or fungal meningitis: Omit until resolved. 
 
 
5.8 
High-Dose Methotrexate (HD MTX) and Leucovorin Rescue 
[Please note that HD MTX refers to IV MTX 5 g/m2 given over 24 hrs] 
Review of methotrexate dosing on BFM-based protocols indicated that excessive methotrexate 
toxicity has not been encountered in patients larger than 2 m2 who receive more than 10 grams of 
methotrexate. The investigator should base the methotrexate on the patient's meter-squared 
dosing and not cap at 10 grams of methotrexate. 


 
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5.8.1 
HD MTX Infusion Guidelines 
See Appendix IV for a flowchart of the HDMTX/LCV guidelines. 
 
When IT therapy and HDMTX are scheduled for the same day, deliver the IT therapy within 6 
hours of the beginning of the IV MTX infusion (hour -6 to +6, with 0 being the start of the MTX 
bolus). 
 
Hold TMP-SMX on the days of HD MTX infusion and for at least 72 hours after the start of the HD MTX 
infusion and until the MTX level is less than 0.4 μM. In the presence of delayed clearance continue to hold 
these medications until MTX level is less than 0.1 µM. 
 
Hold any nonsteroidal anti-inflammatory medications, penicillins, proton pump inhibitors,  TMP/SMX or 
aspirin-containing medications on the day of HD MTX infusion and for at least 72 hours after the start of 
the HD MTX infusion and until the MTX level is less than 0.4 μM. In the presence of delayed clearance 
continue to hold these medications until MTX level is less than 0.1 µM. 
 
Recommended Prehydration with D5 ¼ NS with 30 mEq NaHCO3/L at 125 mL/m2/hour until 
urine specific gravity is ≤ 1.010 and pH is ≥ 7.0 and ≤ 8.0. Ringers Lactate may be used as the 
initial fluid if a bicarbonate containing solution is unavailable. Adjust fluid volume and sodium 
bicarbonate to maintain urine specific gravity and pH at above parameters. A bicarbonate bolus 
(25 mEq/m2 over 15 minutes) may be given to raise the urine pH relatively quickly; a normal 
saline bolus may also be helpful in facilitating hydration. Continue hydration and alkalinization 
throughout HD MTX infusion, and for a minimum of 48 hours after its completion. In patients 
with delayed MTX clearance, continue hydration until the plasma MTX concentration is below 
0.1 µM. 
 
Hour 0: MTX 500 mg/m2 IV mixed in a final volume of 65 mL/m2 D5 ¼ NS with 30 mEq 
NaHCO3/L and infused over 30 minutes. This is followed, immediately, by MTX 4500 mg/m2 
mixed in a final volume of 2935 mL/m2 D5 ¼ NS with 30 mEq NaHCO3/L given by continuous 
IV infusion over 23.5 hours at 125 mL/m2/hr. Be certain that the HD MTX infusion is completed 
in the 24 hour period. Unintentional prolongation to as long as 26 hours though not encouraged 
is acceptable. 
 
Hours 24, (36), 42 and 48: Draw MTX level and serum creatinine; NOTE: 36 hour level is only 
drawn if needed (see below) 
 
 
For MTX levels that exceed these expected values modify the rescue regimen as 
noted below and increase hydration to 200 mL/m2/hr, monitor urine pH to assure a 
value ≥ 7.0 and monitor urine output to determine if volume is ≥ 80% of the fluid intake, 
measured every 4 hours. If serum creatinine rises significantly, at any time point, assure 
appropriate urine pH and urine volume as above and draw a 42 hour level. If urine output 
fails to continue at 80% of the fluid intake, consider furosemide. Regardless of urine 
output, also consider glucarpidase (carboxypeptidase G2) (see below). For patients with 
delayed clearance during a previous course, begin the following course with the increased 
hydration (200 mL/m2/hr). If subsequent course is not associated with delayed clearance, 
attempt to use standard hydration. 
 
If the 24 hour level is < 150 M draw the next level at hour 42 and refer to table below.   


 
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If the 24 hour level is ≥ 150 M and/or creatinine > 125% baseline, repeat level if 
MTX contamination is possible. While waiting for the result and if the value is “real” 
refer to the changes in hydration, etc described above and repeat the level with a serum 
Cr at hour 36. Then refer to the table below. 
 
If the 42 and 48 hour levels are ≤ 1 and 0.4 M, respectively, give leucovorin at 15 
mg/m2 IV/PO at 42, 48 and 54 hours post the start of methotrexate loading dose. No 
additional levels are needed, nor is additional leucovorin. 
 
(36 hr MTX level) 
42 hr MTX 
level 
48 hr MTX 
level 
Leucovorin Rescue++ 
Only required if 24 
hr level is ≥ 150 µM.   
See below for 
guidelines** 
1.01 to 9.9 µM  
0.41 to 5.9 µM 
Continue 15 mg/m2 q 6h until MTX 
level < 0.1 M (draw q12-24 h). 
 
10 to 19.9 µM 
6 to 9.9 µM 
Increase to 15 mg/m2 q 3h until 
MTX level < 0.1 M (draw q 6-24 
h). 
Consider glucarpidase. 
 
20 to 200 µM 
10 to 100 µM 
Increase to 100 mg/m2 q 6h until 
MTX level < 0.1 M (draw q 6-24 
h). 
Consider glucarpidase. 
 
> 200 µM 
> 100 µM 
Increase to 1000 mg/m2 q 6h until 
MTX level < 0.1 M (draw q 6-24 
h). 
Consider glucarpidase. 
** If the 36 hour level exceeds 3 M, increase hydration to 200 mL/m2/hr, monitor urine pH to assure a value 
> 7.0 and monitor urine output to determine if volume is > 80% of the fluid intake, measured every 4 hours. 
If urine output fails to continue at 80% of the fluid intake, consider furosemide. Regardless of urine output, 
also consider glucarpidase if 36 hour MTX level exceeds 10 M (see below). 
 
++ If the level is high at hour 36 or 42, but then the patient “catches up” and the level falls to the expected 
values of ≤ 1 µM and/or ≤ 0.4 µM at hours 42 and 48, respectively, resume standard leucovorin and 
hydration as long as urine output remains satisfactory. 
 
Nephrotoxicity: Postpone course if pre-treatment (MTX) serum creatinine is > 1.5 x baseline or 
GFR creatinine clearance < 65 mL/minute/1.73m2. If renal function does not recover, omit MTX.  
Do not give HDMTX to a patient with this degree of renal impairment, assuming that prolonged 
excretion can be managed with glucarpidase. Patients who must omit more than one course of 
HDMTX will be removed from protocol therapy. 
 
NOTE: For patients who have markedly delayed MTX clearance secondary to renal dysfunction, 
consider using glucarpidase (carboxypeptidase G2, Voraxaze).73,74 ASD Healthcare is the sole 
supplier of glucarpidase in the US. To obtain supplies of glucarpidase in the US contact the 
Voraxaze 24-hour Customer Service line at 855-786-7292. Additional information can be found at 


 
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http://www.btgplc.com/products/specialty-pharmaceuticals/voraxaze. Canadian sites should 
contact McKesson at (877) 384-7425 for further information. Sites in Australia and New Zealand 
should contact Hospira at 1300-046-774 (local) or medicalinformationAUS@hospira.com. 
Patients requiring glucarpidase rescue will remain on study.  
 
Liver Dysfunction: Samples for the determination of ALT value must be drawn within 72 hours, PRIOR to 
a course of intravenous MTX. Blood samples for ALT should not be drawn following the start of MTX 
infusions as MTX causes significant short term elevations in ALT levels. 
 
 
ALT 
IV MTX 
< 10 X ULN 
Continue with therapy as scheduled 
10 – 20 X ULN 
Continue with therapy as scheduled for 1 cycle 
10 – 20 X ULN for 2 consecutive cycles 
Discontinue TMP/SMX* 
Hold therapy until ALT < 10 X ULN, then resume at full doses at point 
of interruption. 
Do not skip doses. 
> 20 X ULN 
Discontinue TMP/SMX* 
Hold therapy until ALT < 10 X ULN, then resume at full doses at point 
of interruption.   
Do not skip doses. 
> 20 X ULN for > 2 weeks 
Evaluate with AST, Bili, Alkaline phosphatase, PT, albumin, total 
protein, and hepatitis A, B, C, CMV, and EBV serologies. 
Consider liver biopsy before additional therapy given.   
* Please see Section 8.1.2 for TMP/SMX substitutions 
 
Hold IV MTX for direct hyperbilirubinemia of > 2.0 mg/dL. 
 
For patient's allergic to or experiencing excessive myelosuppression with TMP/SMX, alternative 
prophylaxis with dapsone (1-2 mg/kg/day, maximum dose 100 mg/day), aerosolized pentamidine 
(300 mg/q month ≥ 5 years of age), or atovaquone (30 mg/kg/day if 1-3 mo. or > 2 years, 45 
mg/kg/day if between 3 mo. & 2 years) may be considered. 
 
Mucositis: For Grade 3-4 mucositis, withhold IV MTX until resolved. Increase leucovorin rescue 
following the next course from three to five doses on a q6 hr schedule. If subsequent course is not 
associated with Grade 3-4 mucositis, attempt to decrease the leucovorin. If mucositis recurs despite 
the extended leucovorin, decrease the dose of MTX by 25%, increase hydration to 200mL/m2/hr 
and continue increased leucovorin as above. Should subsequent courses be well tolerates, use a 
stepwise approach to resuming a standard approach to drug delivery.  Consider culturing lesions for 
herpes simplex if mucositis persists or recurs. 
 
Myelosuppression: All chemotherapy should be held for ANC < 750/µL or platelets < 
75,000/µL. 
 
5.8.2 
Capizzi Methotrexate Regimens  
 
Liver Dysfunction: Samples for the determination of ALT value must be drawn within 72 hours, 
PRIOR to a course of intravenous MTX. Blood samples for ALT should not be drawn following 
the start of MTX infusions as MTX causes significant short term elevation in ALT levels. 
 
 


 
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ALT 
IV MTX 
< 10 X ULN 
Continue with therapy as scheduled 
10 – 20 X ULN 
Continue with therapy as scheduled for 1 cycle 
10 – 20 X ULN for 2 
consecutive cycles 
Discontinue TMP/SMX* 
Hold therapy until ALT < 10 X ULN, then resume at full doses at point of 
interruption. 
Do not skip doses. 
> 20 X ULN 
Discontinue TMP/SMX* 
Hold therapy until ALT < 10 X ULN, then resume at full doses at point of 
interruption. 
Do not skip doses. 
> 20 X ULN for > 2 weeks 
Evaluate with AST, Bili, Alkaline phosphatase, PT, albumin, total protein, and 
hepatitis A, B, C, CMV, and EBV serologies.  Consider liver biopsy before 
additional therapy given. 
* Please see Section 8.1.2 for TMP/SMX substitutions 
 
Hold IV MTX for direct hyperbillirubinemia of > 2.0 mg/dL 
 
Mucositis: For Grade 3-4 mucositis, withhold IV MTX until resolved. Discontinue MTX dose 
escalation and resume at 80% of last dose if therapy is delayed for myelosuppression or Grade 3 or 
greater mucositis. If mucositis recurs, consider culturing lesions for herpes simplex. 
 
Myelosuppression:   
A) If ANC is < 500/µL or platelets < 50,000/µL, hold all chemotherapy and repeat blood counts 
in 4 days. 
1. If ANC ≥ 500/µL and platelets ≥ 50,000/µL, give same dose of methotrexate as previous 
cycle. 
2. If ANC is still < 500/µL or platelets < 50,000/µL, give VCR, PEG-ASP and IT MTX (if 
due) and repeat counts in 7 days to begin next dose of MTX if counts are adequate. If 
counts now adequate, reduce dose of MTX by 20%. Do not make up missed dose of 
MTX. If counts still too low, hold therapy until counts recover to ANC > 500/µL and 
platelets > 50,000/µL. 
B) If ANC ≥ 500/µL but < 750µL and platelets ≥50,000/µL but < 75,000/µL, give same dose of 
MTX as previously.  
C) If ANC ≥ 750/µL and platelets ≥ 75,000/µL escalate MTX by 50 mg/m2/dose. 
 
 
5.9 
PO Methotrexate (MTX) and 6-Mercaptopurine (6-MP) 
 
Interim Maintenance with HD MTX: 
If ANC is < 750/µL and/or platelets < 75 000/µL, hold mercaptopurine. Restart mercaptopurine 
at full dose with next cycle of HD MTX when ANC is  750/L and platelets are  75 000/L. 
Do not make up missed doses. Consider a marrow evaluation in the face of persistent or 
prolonged cytopenias. 
 
If patient develops severe or unexpected myelosuppression, see section below on thiopurine 
pharmacology testing. 
 
Maintenance: 


 
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If neutrophil count falls below 500/L or if platelet count falls below 50,000/L during Maintenance, 6-
MP and MTX only will be held until recovery above these levels. For the first drop in ANC or platelets, 
resume chemotherapy (both 6-MP and MTX) at the same dose the patient was taking prior to the episode 
of myelosuppression. If neutrophil count falls below 500/L or if platelet count falls below 50,000/L for 
a second (or greater) time, discontinue doses of MP and MTX until ANC is ≥ 750/µL and platelets are 
≥ 75,000/µL. Restart both 6-MP and MTX at 50% of the dose prescribed at the time the medication was 
stopped. Then continue to increase to 75% and then 100% of the dose prescribed prior to stopping the 
medication at 2-4 week intervals provided ANC remains ≥ 750/µL and platelets remain ≥ 75,000/µL. 
Consider discontinuing TMP/SMX as per supportive care guidelines in Section 8.1.2. If neutrophil count 
falls below 500/µL or if platelet count falls below 50,000/µL on > 2 occasions during Maintenance, 
perform thiopurine pharmacology testing as described below. Should therapy be withheld for 
myelosuppression or elevated transaminase, do not “make up” that week. Resume therapy at the correct 
point, chronologically. 
 
Dose escalation during Maintenance: 
No dose escalations are recommended during the first cycle of Maintenance. Thereafter, for ANC ≥ 
1500/L on 3 CBC(s) done over 6 weeks or 2 successive monthly CBC(s) alternately increase doses 
of MTX or MP by 25%. If both MTX and 6-MP are increased once without a fall in ANC, consider 
noncompliance as a possibility. Noncompliance can be assessed by obtaining a sample for RBC 
thioguanine nucleotides (TGNs). Consider observing the administration of an oral dose of MTX and 
checking plasma MTX concentration 2-4 hours later. This will document whether or not poor 
absorption contributes to lack of response and may facilitate discussions about noncompliance. 
 
Mucositis Grade 3-4: 
MTX should be reduced to 50% if Grade 3 toxicity develops; withhold in the presence of Grade 4 
toxicity until there is a resolution, then resume at 50% of original dose with gradual dose escalation. 
If mucositis persists or recurs, consider culturing for herpes simplex. 
 
Liver Dysfunction: 
For increase in hepatic transaminases (SGPT/ALT or SGOT/AST) to greater than 5x ULN 
consistent with Grade 3 toxicity, obtain total bilirubin.  Monitor SGPT/ALT or SGOT/AST and 
total bilirubin every 2 weeks during Consolidation and every 4 weeks during Maintenance as long 
as transaminases remain over 5x ULN. 
 
Continue full dose therapy unless either of the following occurs: 
1) Direct bilirubin > 2.0 mg/dL  
2) SGPT/ALT or SGOT/AST > 20x ULN (consistent with Grade 4 toxicity) on 2 determinations at 
least 1 week apart. 
 
If either of these occurs, hold MTX and monitor labs as above, weekly. Restart at full dose therapy when the 
transaminase is less than 5x ULN, if bilirubin is normal. If liver dysfunction persists, consider a trial period 
with MTX but without 6-MP, especially if red cell 6-MP methylated derivatives are elevated. If liver 
function improves in the absence of MP, consider resuming MP dose at 50% and escalating every two weeks 
as tolerated. Also consider liver biopsy. 
 
Exclude infectious hepatitis (A, B, C) for persistent (> 1 month) elevations in SGPT/ALT or 
SGOT/AST above 5x ULN. 
 


 
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Thiopurine Pharmacology Testing and Dosage Adjustments:  
6-MP and 6-TG are methylated directly by thiopurine methyltransferase (TPMT) to an inactive 
metabolite. TPMT activity varies tremendously among patients, because of a common inherited 
genetic defect in TPMT. One in 300 patients is completely deficient (homozygous defective) and 
10% of the population are moderately deficient in TPMT activity because they have inherited one 
variant (non-functional) TPMT allele (i.e., heterozygotes).75-78 Patients with low TPMT form 
higher concentrations of the thioguanine nucleotides (TGNs) and are more susceptible to acute 
thiopurine toxicity (primarily myelosuppression, involving neutropenia, thrombocytopenia, and 
anemia). Patients with the complete deficiency of TPMT tolerate less than 10% of protocol doses 
of 6MP (10 to 30 mg/m2/day 3 days per week). About 35% of heterozygotes require a lower dose 
of 6MP to avoid dose-limiting myelosuppression.79  
 
There are now CLIA certified tests for TPMT genotype and phenotype, and for thiopurine 
metabolites (6-methyl mercaptopurine [6-MMP] and 6-TGN) measurements. Only 3 SNPs 
constitute well over 90% of the inactivating mutations in the gene, based on studies in numerous 
racial and ethnic groups worldwide.75,80-83 Thus, the genotyping test has a low false negative rate, 
and may be preferable to TPMT phenotype testing in cases where a history of red cell 
transfusions would potentially confound assessments of RBC TPMT activity. When the 
genotyping result is coupled with a phenotyping test for TPMT or with thiopurine metabolite 
concentrations in erythrocytes, the reliability of the tests will be even greater. Moreover, 
metabolite levels can provide an index of patient compliance with thiopurine therapy. 
 
Recommendations for Thiopurine Monitoring and Dosage Adjustments: 
Since 6-MP is first introduced during Consolidation, concomitantly with myelosuppressive 
therapy, TPMT genotyping should be considered during Induction, prior to the initiation of 6-MP 
administration. If TPMT testing has not been performed, consider TPMT testing and/or an 
assessment of 6-TGN and methlymercaptopurine metabolites when myelosuppression has led to 
significant delays in therapy (> 2 weeks) or is disproportionate to the therapy being delivered: 
-  For patients who have received full dose thiopurine therapy during the 2 weeks 
immediately preceding the test, RBC thiopurine metabolites will likely predict TPMT 
status and actual thiopurine exposure. 
-  In the absence of RBC transfusions for 3 months prior, TPMT activity will accurately 
reflect TPMT status 
-  TPMT genotyping will be informative in all patients, if at least one mutant allele is 
identified. If not, and myelosuppression continues, send samples for TPMT activity 
and/or metabolites since TPMT genotyping will miss 5%-10% of mutants. NOTE: 
Genotyping can be done despite recent transfusions. 
 
Suggested Dose Adjustments in Patients with Unacceptable Myelosuppression: 
-  If the patient is homozygous deficient for TPMT, the thiopurine dose should be 
reduced to 10-20 mg/m2/day 3 days per week. If the patient is heterozygous for TPMT 
and has experienced significant myelosuppression, the thiopurine dose should be 
reduced by 30%-50%. Do not increase the dose in response to a high ANC for 4 
weeks to allow for achievement of steady state. All other myelosuppressive 
medications should be delivered at full dose, and the thiopurine dose should be 
titrated based on blood counts. Further thiopurine pharmacologic measures are not 
often necessary.  


 
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-  If the patient is homozygous wild-type (high activity) for TPMT, then discontinue 
TMP/SMX and use pentamidine or dapsone. For modifications of the oral 6-MP and 
MTX see the beginning of this section (5.9). 
 
5.10 
Steroids (Dexamethasone and Prednisone) 
Hypertension: Dose should not be reduced. Sodium restriction and anti-hypertensives should be 
employed in an effort to control hypertension. Avoid calcium channel blockers due to their 
potential prohemorrhagic effect.  
 
Hyperglycemia: Dose should not be reduced for hyperglycemia. Rather, insulin therapy should be 
employed to control the blood glucose level. 
 
Pancreatitis: Do not modify dose for asymptomatic elevations of amylase and/or lipase. Discontinue 
steroids, except for stress doses, in the presence of hemorrhagic pancreatitis or severe pancreatitis 
(abdominal pain > 72 hours and > Grade 3 amylase elevation (> 2.0x ULN).   
 
Osteonecrosis (ON): Do not modify corticosteroid therapy for osteonecrosis (also referred to as 
avascular necrosis) during Induction or Delayed Intensification. Consider omitting Maintenance 
steroid for osteonecrosis Grade 1 (clinically asymptomatic, radiographic finding only). Omit 
Maintenance steroid for osteonecrosis Grade 2 or greater, and notify study chair. Consider resuming 
Maintenance steroid after 6 months if joint symptoms have resolved and if MRI findings have 
significantly improved or normalized. 
 
Varicella: Steroids should be held during active infection except during Induction. Do not hold 
during incubation period following exposure. 
 
Inability to use oral doses: 
For dexamethasone, substitute the IV preparation mg for mg. For prednisone, substitute IV 
methylprednisolone at 80% of the oral prednisone dose. Note that if substituting oral 
prednisolone for prednisone, the doses are the same; prednisone is converted in the liver to 
prednisolone. 
 
Severe infection: Do not hold or discontinue steroids during Induction without serious 
consideration, as this is a critical period in the treatment of ALL. Later in therapy, one may consider 
holding steroid until patient achieves cardiovascular stability, except for “stress doses.” 
 
Severe psychosis: Steroid dose may be decreased by 50% for severe psychosis. 
 
5.11 
PO 6-Thioguanine (6-TG) 
Delayed Intensification: 
Oral 6-TG will be held for suspected or proven serious infection. 
 
For severe and/or unexpected myelosuppression, evaluate for TPMT activity as described in 
Section 5.9. 
 


 
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5.12 
Vincristine 
 
** PLEASE USE “BALIS” SCALE FOR GRADING NEUROPATHY (SEE APPENDIX V) 
 
Severe neuropathic pain (Grade 3 or greater): Hold dose(s). When symptoms subside, resume at 
50% previous calculated dose (maximum dose: 1 mg), then escalate to full dose as tolerated. NOTE: 
neuropathic pain can be not only severe but difficult to treat. However, since vincristine is an 
important component of curative therapy and the majority of neuropathies are ultimately reversible, 
vincristine therapy may be given at full dose at investigator discretion. Severe peripheral 
neuropathies, with or without a positive family history might suggest the need for a molecular 
diagnostic evaluation to rule out Charcot Marie Tooth Disease (CMT), Type 1A or Hereditary 
neuropathy with liability to pressure palsies.  Drugs such as gabapentin may be of value. 
 
Vocal Cord paralysis: Hold dose(s). When symptoms subside, resume at 50% previous calculated 
dose (maximum dose: 1 mg), then escalate to full dose as tolerated. See above for comment on 
CMT. 
 
Foot Drop, paresis: Should be Grade 3 to consider holding or decreasing dose. These toxicities are 
largely reversible but over months to years. Accordingly, holding doses of vincristine and/or 
lowering the dose may not result in rapid resolution of symptoms and may compromise cure. See 
above for comment on CMT. Physical therapy may be beneficial to maintain range of motion and 
provide AFO’s and other forms of support. Drugs such as gabapentin may be of value. 
 
Jaw pain: Treat with analgesics; do not modify vincristine dose. 
 
 
Hyperbilirubinemia:84,85 
 
Direct bilirubin  
 
Dose reduction  
< 3.1 mg/dL  
Full dose (maximum dose: 2 mg) 
3.1-5.0 mg/dL  
50% of calculated dose (maximum dose: 1 mg) 
5.1-6.0 mg/dL  
75% of calculated dose (maximum dose: 0.5 mg) 
> 6 mg/dL 
Withhold dose and administer next scheduled dose if toxicity has 
resolved. Do not make up missed doses. 
 
Constipation or ileus (> Grade 3) or typhlitis: Hold dose(s); institute aggressive regimen to treat 
constipation if present. When symptoms abate resume at 50% of calculated dose (maximum dose: 
1 mg) and escalate to full dose as tolerated. 
 
Extravasation: 
In the event of an extravasation, discontinue the IV administration of the drug and institute appropriate 
measures to prevent further extravasation and damage according to institutional guidelines. Also see 
https://members.childrensoncologygroup.org/_files/disc/Nursing/extravasationguidelines.pdf for COG 
guidelines. 


 
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5.13 
Drug Interactions 
Since concurrent use of enzyme inducing anticonvulsants (e.g. phenytoin, phenobarbital, and 
carbamazepine) with antileukemic therapy has recently been associated with inferior EFS, every 
effort should be made to avoid these agents, as well as rifampin, which also induces many drug 
metabolizing enzymes 86,87. Neither Gabapentin nor Levetiracetam induce hepatic drug 
metabolizing enzymes and may be suitable alternative anticonvulsant. Azole antifungals 
(fluconazole, itraconazole, ketoconazole, posaconazole, and voriconazole) and the macrolide 
group of antibiotics (e.g. erythromycin, clarithromycin, and azithromycin) may have potent 
inhibitory effects on drug-metabolizing enzymes. Patients receiving some antileukemic drugs 
(e.g. vincristine, anthracyclines, etoposide) may experience excess toxicity when these agents are 
given concomitantly; alternate antifungal and antibacterial therapy should be used where 
possible (see table below).  
 
DRUGS 
POTENTIAL INTERACTION 
ACTION TO BE TAKEN 
Anticonvulsants 
Induction of drug metabolizing 
enzymes 
Lowered EFS 
AVOID phenytoin, Phenobarbital, 
carbamazepine 
Consider Gabapentin or Levetiracetam 
(Keppra) as alternative 
Rifampin 
Induction of drug metabolizing 
enzymes  
DO NOT USE 
Azole Antifungals 
(fluconazole, 
itraconazole*, 
posaconazole, 
voriconazole, 
ketoconazole) 
Inhibition of drug metabolizing 
enzymes 
CONSIDER ALTERNATIVE 
MEDICATIONS. 
May need dose reductions of vincristine*, 
anthracyclines, etoposide, steroids 
Macrolide Antibiotics 
(erythromycin, 
clarithromycin, 
azithromycin 
roxithromycin 
telithromycin) 
Inhibition of drug metabolizing 
enzymes 
CONSIDER ALTERNATIVE 
MEDICATIONS. 
May need dose reductions of vincristine, 
anthracyclines, etoposide, steroids 
*Itraconazole should NOT be used in patients who are receiving vincristine due to a serious drug-drug 
interation leading to severe neurotoxicity.88,89 
 
For more complete list of CYP 3A 4/5 Inhibitors and Inducers see Appendix III. 
 
Possible Drug Interactions with Capizzi Methotrexate: 
Avoid non-steroidal anti-inflammatory drugs (NSAIDs), trimethoprim/sulfamethoxazole 
(TMP/SMX), penicillins, probenecid, IV contrast media, proton pump inhibitors, phenytoin and 
fosphenytoin. Urinary acidifiers can cause methotrexate to precipitate in the urinary tract. 
 
Possible Drug Interactions with High Dose Methotrexate: 
When IT therapy and high dose methotrexate are scheduled for the same day, deliver the IT 
therapy within 6 hours of the beginning of the IV methotrexate infusion (hour -6 to +6, with 0 
being the start of the methotrexate bolus). 
 
Hold non-steroidal anti-inflammatory drugs (NSAIDs), trimethoprim/sulfamethoxazole (TMP/SMX), 
penicillins, probenecid, IV contrast media, proton pump inhibitors, phenytoin and fosphenytoin on the days 
of high dose methotrexate infusion and for at least 72 hours after the start of the high dose methotrexate 


 
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infusion and until the methotrexate level is less than 0.4 M. In the presence of delayed clearance, continue 
to hold TMP/SMX until methotrexate level is less than 0.1 M. 
 
 
 


 
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6.0 
DRUG INFORMATION 
 
6.1 
ASPARAGINASE 
ERWINIA  
CHRYSANTHEMI 
(ERWINIA  
CHRYSANTHEMI, 
ERWINASE®, ERWINAZETM, CRISANTASPASE)  NSC #106977  
 
 
 
 
(02/29/12) 
Source and Pharmacology: 
L-asparagine is a nonessential amino acid synthesized by the transamination of L-aspartic acid 
by a reaction catalyzed by the enzyme L-asparagine synthetase. Neoplastic cells associated with 
acute lymphoblastic leukemia, acute myeloid leukemia and lymphoblastic lymphosarcoma are 
asparagine-dependent but lack asparagine synthetase activity. The administration of L-
asparaginase produces an anti-neoplastic effect by catalyzing asparagine into aspartic acid and 
ammonia. As a result, these cells lack the ability to produce the asparagine necessary for protein 
metabolism and survival. Deamination of glutamine may also play a role in the antineoplastic 
activity of asparaginase. 
 
Asparaginase Erwinia chrysanthemi (ErwinazeTM) is asparaginase derived from cultures of 
Erwinia chrysanthemi. L-asparaginase is a tetrameric enzyme; each of the four identical subunits 
has a molecular weight of approximately 35 kDa. Asparaginase Erwinia chrysanthemi is 
immunologically distinct from E. coli L-asparaginase and may allow continued asparaginase 
therapy when a hypersensitivity reaction occurs to Escherichia coli-derived asparaginase. The 
package labeling states that there is insufficient information to characterize the incidence of 
antibodies to asparaginase Erwinia chrysanthemi. Several factors are involved in 
immunogenicity assay results and the assessment of antibodies, including assay methodology, 
assay sensitivity and specificity, sample handling, timing of sample collection, concomitant 
medications, and the underlying disease state. The following data have been reported on each of 
the three preparations of asparaginase: 
 
Clinical 
Pharmacology of 
Asparaginase 
Formulation 
Elimination half-life (IM) 
% Anti-Asparaginase Antibody 
positive patients 
Native Escherichia Coli 
26-30 hours 
45-75 
Pegylated-asparaginase 
5.5-7 days 
5-18 
Erwinia Asparaginase 
16 hours (7-13 hrs package insert) 
30-50 
From: Avramis, V; Panosyan, E; Pharmacokinetic/Pharmacodynamic Relationships of Asparaginase Formulations: The Past, 
the Present and Recommendations for the Future. Clin Pharmacokinet 2005; 44 (4): 367-393. 
 
Effective asparaginase levels have been defined as activity of ≥ 0.1 International Units per mL. 
Clinical trials with asparaginase Erwinia chrysanthemi demonstrated that 100% of patients 
achieved effective asparaginase levels at 48 and 72 hours (n=35 and n=13, respectively) 
following the third total dose when given on a Monday, Wednesday, Friday schedule. No formal 
drug interaction studies have been performed with asparaginase Erwinia chrysanthemi. 


 
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Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Allergic reactions, 
anaphylaxis,  urticaria 
Local injection site reactions 
Fever 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
 
 
Pancreatitis, glucose intolerance, 
thrombosis, hemorrhage, transient ischemic 
attack, disseminated intravascular 
coagulation, hyperbilirubinemia, alanine 
aminotransferase increased, aspartate 
aminotransferase increased, hyperglycemia, 
hyperammonemia, vomiting, nausea, 
abdominal pain, headache, diarrhea, seizure.  
Unknown 
Frequency and 
Timing:  
Fetal toxicities and teratogenic effects of L-asparaginase have been noted in animals. It is 
unknown whether the drug is excreted in breast milk. Adequate, well-controlled studies of 
asparaginase Erwinia chrysanthemi have NOT been conducted. It is not known whether 
asparaginase Erwinia chrysanthemi will cause fetal harm or affect the ability to reproduce. It is 
not known if asparaginase Erwinia chrysanthemi is excreted into breast milk. The use of 
asparaginase Erwinia chrysanthemi should be avoided in pregnant or lactating patients. 
(L) Toxicity may also occur later. 
 
Formulation and Stability: 
Asparaginase Erwinia chrysanthemi is supplied as a sterile, white lyophilized powder for 
reconstitution in a clear glass vial with a 3 mL capacity. Each vial contains 10,000 International 
Units of asparaginase Erwinia chrysanthemi and the following inactive ingredients: glucose 
monohydrate (5.0 mg), sodium chloride (0.5 mg). Store intact vials between 2°C and 8°C (36° to 
46ºF). Protect from light. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
 
Use appropriate precautions for preparation of a hazardous agent. Visually inspect the powder in 
vial for foreign particles or discoloration prior to reconstitution. The contents of each vial should 
be reconstituted by slowly adding 1 mL or 2 mL of sterile, preservative-free NS to the inner vial 
wall. The final concentration is 10,000 International Units per mL when using 1 mL for 
reconstitution or 5,000 International Units per mL when using 2 mL for reconstitution. Gently mix 
or swirl the contents to dissolve the contents of the vial. Do not shake or invert the vial. The 
resulting solution should be clear and colorless. Discard if any particulate matter or protein 
aggregates are visible. Withdraw the appropriate dosing volume into a polypropylene 
syringe within 15 minutes of reconstitution. Polycarbonate luer-lok syringes from B-D (1 mL) 
are also acceptable (personal communication, EUSA Pharma). Discard any unused drug; do not 
save or use any unused drug remaining in the vial.  
 
Administer the dose within a 4 hour time period from reconstitution. If the dose is not used 
within this time period, discard the dose. Do not freeze or refrigerate the reconstituted solution.   
 
Administer the dose intramuscularly (IM). No more than 2 mL should be given at any one injection 
site. Doses larger than 2 mL should be divided and given in separate administration sites. 
 


 
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Drug Ordering: 
In the United States, asparaginase Erwinia chrysanthemi (ErwinazeTM) is distributed by Accredo 
Health Group, Inc. An institutional contract with Accredo is required in order to purchase the 
product. Accredo’s contact information is as follows: 
 
Accredo Health Group, Inc. 
1640 Center Parkway, Suite 8 
Memphis, TN  38134 
Phone: 1-877-900-9223 
Fax: 1-866-628-8942 
Email: wholesalefax@accredohealth.com 
 
CANADIAN SITES 
Asparaginase Erwinia chrysanthemi is commercially available in Canada. Canadian sites may 
purchase the Canadian commercial supply from EUSA via CGF Pharmatech, Montreal, Quebec, 
a subsidiary of EUSA (order desk phone: 1-514-343-0344 or 1-866-343-0344, fax: 1-514-343-
0340). CGF requests that a site fax a Purchase Order number. There is no special fax order form. 
Shipments are sent Monday to Wednesday only and usually arrive at the site within 48-72 hours. 
 
6.2 
CYCLOPHOSPHAMIDE INJECTION 
(Cytoxan) NSC #26271                         (03/05/13) 
Source and Pharmacology:  
Cyclophosphamide is an alkylating agent related to nitrogen mustard. Cyclophosphamide is 
inactive until it is metabolized by P450 isoenzymes (CYP2B6, CYP2C9, and CYP3A4) in the 
liver to active compounds. The initial product is 4-hydroxycyclophosphamide (4-HC) which is in 
equilibrium with aldophosphamide which spontaneously releases acrolein to produce 
phosphoramide mustard. Phosphoramide mustard, which is an active bifunctional alkylating 
species, is 10 times more potent in vitro than is 4-HC and has been shown to produce interstrand 
DNA cross-link analogous to those produced by mechlorethamine. Approximately 70% of a dose 
of cyclophosphamide is excreted in the urine as the inactive carboxyphosphamide and 5-25% as 
unchanged drug. The plasma half-life ranges from 4.1 to 16 hours after IV administration.  
 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of every 
100 
Immediate: 
Within 1-2 days of 
receiving drug 
Anorexia, nausea & vomiting 
(acute and delayed) 
Abdominal discomfort, 
diarrhea 
Transient blurred vision, nasal 
stuffiness with rapid administration, 
arrhythmias (rapid infusion), skin 
rash, anaphylaxis, SIADH 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Leukopenia, alopecia, immune 
suppression 
Thrombocytopenia, 
anemia, hemorrhagic 
cystitis (L) 
Cardiac toxicity with high dose (acute 
– CHF hemorrhagic myocarditis, 
myocardial necrosis) (L), 
hyperpigmentation, nail changes, 
impaired wound healing, infection 
secondary to immune suppression 
Delayed: 
Any time later 
during therapy 
Gonadal dysfunction: 
azoospermia or oligospermia 
(prolonged or permanent)1 (L) 
Amenorrhea1 
Gonadal dysfunction: ovarian 
failure1 (L), interstitial pneumonitis, 
pulmonary fibrosis2 (L)  
Late: 
 
 
Secondary malignancy (ALL, ANLL, 


 
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Any time after 
completion of 
treatment 
AML), bladder carcinoma (long term 
use > 2 years), bladder fibrosis  
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of cyclophosphamide (alone or in combination with other 
antineoplastic agents) have been noted in humans. Toxicities include: chromosomal 
abnormalities, multiple anomalies, pancytopenia, and low birth weight. Cyclophosphamide is 
excreted into breast milk. Cyclophosphamide is contraindicated during breast feeding because of 
reported cases of neutropenia in breast fed infants and the potential for serious adverse effects. 
1 Dependent on dose, age, gender, and degree of pubertal development at time of treatment. 
2 Risk increased with pulmonary chest irradiation and higher doses. 
(L) Toxicity may also occur later. 
 
Formulation and Stability:  
Cyclophosphamide for injection is available as powder for injection or lyophilized powder for 
injection in 500 mg, 1 g, and 2 g vials. The powder for injection contains 82 mg sodium 
bicarbonate/100 mg cyclophosphamide and the lyophilized powder for injection contains 75 mg 
mannitol/100 mg cyclophosphamide. Storage at or below 25ºC (77ºF) is recommended. The 
product will withstand brief exposures to temperatures up to 30ºC (86ºF). 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
Cyclophosphamide for Injection:  
If the drug will be administered as undiluted drug at the 20 mg/mL concentration, then reconstitute to 20 
mg/mL with NS ONLY to avoid a hypotonic solution.  If the drug will be further diluted prior to 
administration, then first reconstitute with NS, SWFI, or Bacteriostatic Water for Injection (paraben 
preserved only) to a concentration of 20 mg/mL.  Following reconstitution further dilute in dextrose or 
saline containing solutions for IV use.  
 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
 
6.3 
CYTARABINE (Cytosine arabinoside, Ara-C, Cytosar®) NSC #063878 
           (05/06/11) 
Source and Pharmacology: Cytarabine appears to act through the inhibition of DNA 
polymerase. A limited, but significant, incorporation of cytarabine into both DNA and RNA has 
also been reported. It exhibits cell phase specificity, primarily killing cells undergoing DNA 
synthesis (S-phase) and under certain conditions blocking the progression of cells from the G1 
phase to the S-phase. Cytarabine is metabolized by deoxycytidine kinase and other nucleotide 
kinases to the nucleotide triphosphate (Ara-CTP), an effective inhibitor of DNA polymerase. 
Ara-CTP is inactivated by a pyrimidine nucleoside deaminase, which converts it to the nontoxic 
uracil derivative (Ara-U). It appears that the balance of kinase and deaminase levels may be an 
important factor in determining sensitivity or resistance of the cell to cytarabine. It has an initial 
distributive phase t½ of about 10 minutes, with a secondary elimination phase t½ of about 1 to 3 
hours. Peak levels after intramuscular or subcutaneous administration of cytarabine occur about 20 
to 60 minutes after injection and are lower than IV administration. Intrathecally administered doses 
are metabolized and eliminated more slowly with a t½ of about 2 hours. 
 
 


 
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Toxicity: (Intravenous, SubQ, IM) 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children out 
of every 100 
Rare 
Happens to < 5 children out of every 
100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, 
anorexia 
 
Flu-like symptoms with 
fever, rash 
Ara-C syndrome (fever, myalgia, 
bone pain, occasionally chest pain, 
maculopapular rash,  malaise, 
conjunctivitis), anaphylaxis 
 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Myelosuppression 
(anemia, 
thrombocytopenia, 
leukopenia, 
megaloblastosis, 
reticulocytopenia), 
stomatitis, alopecia 
Diarrhea, hypokalemia, 
hypocalcemia, 
hyperuricemia 
 
Hepatotoxicity, sinusoidal obstruction 
syndrome (SOS, formerly VOD), 
urinary retention, renal dysfunction, 
pain and erythema of the palms and 
soles 
Delayed: 
Any time later 
during therapy, 
excluding the above 
conditions 
 
 
Asymptomatic nonoliguric 
rhabdomyolysis 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of cytarabine have been noted in humans. It is unknown 
whether the drug is excreted in breast milk. 
 
Toxicity: (Intrathecal) 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, fever, 
headache 
Arachnoiditis 
Rash, somnolence, meningismus, 
convulsions, paresis 
Prompt: 
Within 2-3 weeks, prior 
to the next course 
 
 
Myelosuppression, ataxia 
Delayed: 
Any time later during 
therapy, excluding the 
above condition 
 
 
Necrotizing leukoencephalopathy, 
paraplegia, blindness (in combination 
with XRT & systemic therapy) 
 
Formulation and Stability: Cytarabine for Injection is available in vials of 100 mg, 500 mg, 1 g, 
and 2 g containing a sterile powder for reconstitution. It is also available at a 20 mg/mL 
concentration with benzyl alcohol (25 mL per vial) or as a preservative free solution (5 mL, 50 mL 
per vial),, and at a 100 mg/mL concentration with benzyl alcohol (20 mL vial) or as preservative 
free solution (20 mL vial). Hydrochloric acid and/or sodium hydroxide may be added to adjust 
the pH. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Cytarabine solutions 
should be protected from light. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
 
 
IV Infusion: 
Reconstitute the lyophilized powder with Bacteriostatic Water for Injection or NS. Solution 


 
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containing bacteriostatic agent should not be used for the preparation of doses > 200 mg/m2. May 
be further diluted with dextrose or sodium chloride containing solutions. May give by IV push 
injection, by IV infusion, or by continuous infusion. 
 
Low Dose (≤ 200 mg/m²/dose): For administration by IV push, reconstitute to a concentration of 
20-100 mg/mL. 
 
Stability: When reconstituted with Bacteriostatic Water for Injection, cytarabine is stable for 48 
hours at room temperature. Solutions reconstituted without a preservative should be used 
immediately. Discard if solution appears hazy. Diluted solutions in D5Wor NS are stable for 
8 days at room temperature; however, the diluted cytarabine should be used within 24 hours for 
sterility concerns. 
 
Subcutaneous: 
Dilute with Bacteriostatic Water for Injection or NS to a concentration not to exceed 100 mg/mL. 
Rotate injection sites for subcutaneous administration.  
 
Intrathecal: 
For intrathecal administration, dilute with 5-10 mL (or volume per institutional practice) 
preservative free NS, lactated Ringer’s injection, Elliot’s B solution. The volume of CSF removed 
should be equal to at least ½ the volume delivered. 
 
Patient Age 
(years) 
Recommended 
volume 
10% CSF 
volume 
CSF Volume* 
1 – 1.99 
5–10 mL 
5 mL 
50  + 10 mL  (babies) 
2 – 2.99 
5-10 mL 
8 mL 
80  + 20 mL (younger 
children) 
3 – 8.99 
5-10 mL 
10 mL 
100 + 20 mL (older children) 
9 or greater 
5-10 mL 
13 mL 
130  + 30 mL (adults) 
* Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection; N Engl J Med. 1962 Dec 20; 267:1273-8 
 
Of note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, 
with the patient remaining prone after the procedure may facilitate drug distribution.  These 
procedures have not been validated in clinical trials. They are allowed but not mandated for patients 
on COG studies. 
 
Intrathecal cytarabine mixed in NS, lactated Ringer’s injection, or Elliot’s B solution is stable for 
24 hours at 25ºC but contains no preservative and should be administered as soon as possible after 
preparation. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
6.4 
DAUNORUBICIN (Daunomycin, rubidomycin, Cerubidine®) NSC #82151 
(05/09/11) 
Source and Pharmacology: Daunorubicin is an anthracycline antibiotic isolated from cultures of 
Streptomyces coeruleorubidus. Daunorubicin is closely related structurally to doxorubicin only 
differing in that the side chain of daunorubicin terminates in a methyl group rather than an alcohol. 


 
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The cytotoxic effect of daunorubicin on malignant cells and its toxic effects on various organs 
are similar to those of doxorubicin and are thought to be related to nucleotide base intercalation 
and cell membrane lipid binding activities. Intercalation inhibits nucleotide replication and action 
of DNA and RNA polymerases. The interaction of daunorubicin with topoisomerase II to form 
DNA-cleavable complexes appears to be an important mechanism of cytocidal activity. 
Daunorubicin cellular membrane binding may affect a variety of cellular functions. Enzymatic 
electron reduction of daunorubicin by a variety of oxidases, reductases and dehydrogenases 
generate highly reactive species including the hydroxyl free radical (OH•) which may lead to 
DNA damage or lipid peroxidation. Daunorubicin is metabolized more rapidly by 
aldoketoreductases to the active metabolite, daunorubicinol, than is doxorubicin. Daunorubicin 
hydrochloride is rapidly and widely distributed in tissues, with the highest levels in the spleen, 
kidneys, liver, lungs, and heart. Daunorubicin serum decay pattern is multiphasic. The initial t½ 
is approximately 45 minutes followed by a terminal t½ of 18.5 hours. By 1 hour after drug 
administration, the predominant plasma species is daunorubicinol, which disappears with a half-
life of 26.7 hours. Twenty-five percent of an administered dose of daunorubicin is eliminated in 
an active form by urinary excretion and an estimated 40% by biliary excretion. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of every 
100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, pink or 
red color to urine, sweat, 
tears and saliva 
Hyperuricemia, sclerosis 
of the vein 
Diarrhea, anorexia, abdominal pain, 
extravasation (rare) but if occurs = 
local ulceration, anaphylaxis, fever, 
chills, rash, urticaria, acute 
arrhythmias  
Prompt: 
Within 2-3 weeks, 
prior to the next course 
Myelosuppression 
(leukopenia, 
thrombocytopenia, 
anemia), alopecia  
Mucositis (stomatitis and 
esophagitis), 
hepatotoxicity  
Radiation recall reactions, 
myocarditis-pericarditis syndrome, 
conjunctivitis and lacrimation 
Delayed: 
Any time later during 
therapy 
 
 
Cardiomyopathy1 (uncommon at 
cumulative doses ≤ 550 mg/m², 
400 mg/m² with mediastinal radiation, 
300 mg/m² in children, or 10 mg/kg 
in children < 2 yrs or 0.5 m²) (L), 
hyper-pigmentation of nail beds 
Late: 
Any time after 
completion of 
treatment 
 
Subclinical cardiac 
dysfunction 
CHF (on long term follow up in 
pediatric patients), secondary 
malignancy (in combination 
regimens) 
Unknown Frequency 
and Timing:  
Fetal toxicities and teratogenic effects of daunorubicin have been noted in animals. It is 
unknown whether the drug is excreted in breast milk. 
1 Risk increases with cardiac irradiation, exposure at a young or advanced age 
(L) Toxicity may also occur later. 
 
Formulation and Stability: Daunorubicin is available as red-orange lyophilized powder1 for 
injection in 20 mg single dose vials and a preservative free 5 mg/mL solution2 in 20 mg (4 mL) and 
50 mg (10 mL) vials. 
¹ Each vial contains 21.4 mg of daunorubicin hydrochloride (equivalent to 20 mg of daunorubicin) and 100 mg mannitol. 
² Each mL contains 5.3 mg daunorubicin hydrochloride (equivalent to 5 mg of daunorubicin), 9 mg of sodium chloride, 
sodium hydroxide or hydrochloric acid to adjust pH, and Sterile Water for Injection. 
 


 
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Powder for Injection: 
Store intact unreconstituted vial at room temperature 15°C-30°C (59°F-86°F). Protect from light. 
Retain in carton until contents are used. Reconstitute a 20 mg vial with 4 mL SWFI to a final 
concentration of 5 mg/mL. After adding the diluent, the vial should be shaken gently and the 
contents allowed to dissolve. The reconstituted solution is stable for 24 hours at room 
temperature and 48 hours refrigerated. Protect from exposure to sunlight. 
 
Aqueous Solution: 
Store refrigerated 2°-8°C (36°-46°F). Protect from light. Retain in carton until contents are used. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
Administer by IV side arm into a rapidly flowing infusion solution. Alternately, daunorubicin 
may be further diluted in saline or dextrose containing solutions and administered by infusion. 
Protect final preparation from light. To avoid extravasation, the use of a central line is suggested. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
 
6.5 
DEXAMETHASONE (Decadron®, Hexadrol®, Dexone®, Dexameth®) NSC #34521 (05/09/11) 
Source and Pharmacology: Dexamethasone is a synthetic fluorinated glucocorticoid devoid of 
mineralocorticoid effects. Dexamethasone, 0.75 mg, has potent anti-inflammatory activity 
equivalent to approximately 5 mg of prednisone. Glucocorticoids produce widespread and 
diverse physiologic effects on carbohydrate, protein, and lipid metabolism, electrolyte and water 
balance, functions of the cardiovascular system, kidney, skeletal muscle, and the nervous 
systems. Glucocorticoids reduce the concentration of thymus-dependent lymphocytes (T-
lymphocytes), monocytes, and eosinophils. Glucocorticoids selectively bind to the cortisol 
receptors on human lymphoid cells which are found in larger numbers on leukemic 
lymphoblasts. They also decrease binding of immunoglobulin to cell surface receptors and 
inhibit the synthesis and/or release of interleukins, thereby decreasing T-lymphocyte 
blastogenesis and reducing expansion of the primary immune response. The specific cellular 
mechanisms that act to halt DNA synthesis are thought to be related to inhibition of glucose 
transport or phosphorylation, retardation of mitosis, and inhibition of protein synthesis. 
Elimination half-lives for the following age groups have been reported to be: infants and children 
under 2 years of age: 2.3 to 9.5 hours, 8 to 16 years: 2.82 to 7.5 hours, and adults (age not 
specified): 3 to 6 hours. The biologic half-life is 36-72 hours. It is primarily metabolized in the 
liver and excreted by the kidneys. 
 
Toxicity: 
 
Common 
Happens to 21-100 children out 
of every 100 
Occasional 
Happens to 5-20 children out 
of every 100 
Rare 
Happens to < 5 children out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Insomnia, hyperphagia 
Gastritis 
Hyperuricemia 
Prompt: 
Within 2-3 weeks, 
prior to the next course 
Immunosuppression, 
personality changes (mood 
swings, euphoria, anxiety, 
depression), pituitary-adrenal 
axis suppression, acne (L) 
Hyperglycemia, facial 
erythema, poor wound 
healing, infections (bacterial, 
fungal, parasitic, viral), 
edema 
Pancreatitis (L), increased intraocular 
pressure (L), hypertension, psychosis, 
vertigo, headache 
Delayed: 
Any time later during 
Cushing’s syndrome (moon 
facies, truncal obesity) 
Striae and thinning of the 
skin, easy bruising, muscle 
Spontaneous fractures (L), growth 
suppression, peptic ulcer and GI bleeding, 


 
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therapy 
weakness, osteopenia  
pseudotumor cerebri (increased 
intracranial pressure with papilledema, 
headache), aseptic necrosis of the femoral 
and humeral heads (L), urolithiasis1 (L) 
Late: 
Any time after 
completion of 
treatment 
 
Cataracts (which may be 
reversible on discontinuation 
of dexamethasone in 
children) 
 
Unknown Frequency 
and Timing: 
Fetal and teratogenic toxicities: dexamethasone crosses the placenta with 54% metabolized by enzymes 
in the placenta. In animal studies, large doses of cortisol administered early in pregnancy produced cleft 
palate, stillborn fetuses, and decreased fetal size. Chronic maternal ingestion during the first trimester has 
shown a 1% incidence of cleft palate in humans. There are no reports of dexamethasone excretion into 
breast milk in humans; however, it is expected due to its low molecular weight that it would partition into 
breast milk. 
1 Mainly reported in pediatric patients with ALL.  Howard SC et al.  Urolithiasis in pediatric patients with acute lymphoblasic 
leukemia. Leukemia 2003; 17: 541-6. 
(L) Toxicity may also occur later. 
 
Formulation and Stability:  
Oral: Available in 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, and 6 mg tablets; liquid 
formulations are available in 0.5 mg/5 mL and 1 mg/1 mL concentration. Inactive ingredients vary 
depending on manufacturer but tablet formulations may include: calcium or magnesium stearate, 
corn starch, lactose, and various dyes. Liquid formulations may include: 5%-30% alcohol, benzoic 
acid, sorbitol, sodium saccharin, glycerin, purified water, and various dyes.  
 
Injection: Dexamethasone Sodium Phosphate Solution for Injection is available as 4 mg/mL (1 
mL, 5 mL, and 30 mL vials), and 10 mg/mL (1mL and 10 mL vial sizes). Four milligrams of 
dexamethasone sodium phosphate is equivalent to 3.33 mg of dexamethasone. Vials are available 
in multi-dose vials as well as unit of use vials and syringes. Inactive ingredients vary depending 
on manufacturer but include creatinine, sodium citrate, sodium hydroxide to adjust pH, Water for 
Injection, sodium sulfite, bisulfite and metabisulfite, methyl and propyl paraben, benzyl alcohol, 
and EDTA. 
 
Guidelines for Administration: See Treatment and Dose Modifications section of the protocol. 
 
Dexamethasone Sodium Phosphate for Injection may be given IV, or IM undiluted. For IV use, it 
may be further diluted in dextrose or saline containing solutions. Avoid using benzyl alcohol 
containing dexamethasone solutions for use in neonates. Diluted solutions that contain no 
preservatives should be used within 24 hours, but maintain stability for at least 14 days in PVC 
bags at room temperature protected from light. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information  
 
6.6 
DOXORUBICIN (Adriamycin®) NSC #123127 
(05/09/11) 
Source and Pharmacology: An anthracycline antibiotic isolated from cultures of Streptomyces 
peucetius. The cytotoxic effect of doxorubicin on malignant cells and its toxic effects on various 
organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding 
activities of doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and 
RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable 
complexes appears to be an important mechanism of doxorubicin cytocidal activity. Doxorubicin 
cellular membrane binding may affect a variety of cellular functions. Enzymatic electron 


 
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reduction of doxorubicin by a variety of oxidases, reductases and dehydrogenases generate 
highly reactive species including the hydroxyl free radical (OH•). Free radical formation has 
been implicated in doxorubicin cardiotoxicity by means of Cu (II) and Fe (III) reduction at the 
cellular level. Cells treated with doxorubicin have been shown to manifest the characteristic 
morphologic changes associated with apoptosis or programmed cell death. Doxorubicin-induced 
apoptosis may be an integral component of the cellular mechanism of action relating to 
therapeutic effects, toxicities, or both. 
 
Doxorubicin serum decay pattern is multiphasic. The initial distributive t½ is approximately 5 
minutes suggesting rapid tissue uptake of doxorubicin. The terminal t½ of 20 to 48 hours reflects 
a slow elimination from tissues. Steady-state distribution volumes exceed 20 to 30 L/kg and are 
indicative of extensive drug uptake into tissues. Plasma clearance is in the range of 8 to 20 
mL/min/kg and is predominately by metabolism and biliary excretion. The P450 cytochromes 
which appear to be involved with doxorubicin metabolism are CYP2D6 and CYP3A4. 
Approximately 40% of the dose appears in the bile in 5 days, while only 5 to 12% of the drug 
and its metabolites appear in the urine during the same time period. Binding of doxorubicin and 
its major metabolite, doxorubicinol to plasma proteins is about 74 to 76% and is independent of 
plasma concentration of doxorubicin. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of every 
100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, pink or 
red color to urine, sweat, 
tears and saliva 
Hyperuricemia, facial 
flushing, sclerosis of the 
vein 
Diarrhea, anorexia, erythematous 
streaking of the vein (flare reaction), 
extravasation (rare) but if occurs = 
local ulceration, anaphylaxis, fever, 
chills, urticaria, acute arrhythmias 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Myelosuppression 
(leukopenia, 
thrombocytopenia, 
anemia), alopecia  
Mucositis (stomatitis and 
esophagitis), 
hepatotoxicity  
Radiation recall reactions, 
conjunctivitis and lacrimation 
Delayed: 
Any time later during 
therapy 
 
Cardiomyopathy1 (CHF 
occurs in 5-20% at 
cumulative doses 
≥ 450 mg/m²) (L) 
Cardiomyopathy1 (CHF occurs in 
< 5% at cumulative doses 
≤ 400 mg/m²) (L), ulceration and 
necrosis of colon, hyper-pigmentation 
of nail bed and dermal crease, 
onycholysis 
Late: 
Any time after 
completion of 
treatment 
Subclinical cardiac 
dysfunction 
CHF (on long term 
follow up in pediatric 
patients) 
Secondary malignancy (in combination 
regimens) 
Unknown Frequency 
and Timing: 
Fetal and teratogenic toxicities. Carcinogenic and mutagenic effects of doxorubicin have been 
noted in animal models. Doxorubicin is excreted into breast milk in humans. 
1 Risk increases with cardiac irradiation, exposure at a young or advanced age 
(L) Toxicity may also occur later. 
 
Formulation and Stability:  
Doxorubicin is available as red-orange lyophilized powder for injection in 10 mg¹, 20 mg¹, 50 mg¹ 
vials and a preservative-free 2 mg/mL solution in 10 mg¹, 20 mg¹, 50 mg¹, 200 mg² vials. 
¹ Contains lactose monohydrate, 0.9 NS, HCl to adjust pH to 3. The Adriamycin RDF (rapid dissolution formula) 
also contains methylparaben 1 mg per each 10 mg of doxorubicin to enhance dissolution. 


 
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² Multiple dose vial contains lactose, 0.9% NS, HCl to adjust pH to 3. 
 
Aqueous Solution: 
Store refrigerated 2°-8°C (36°-46°F). Protect from light. Retain in carton until contents are used. 
 
Powder for Injection: 
Store unreconstituted vial at room temperature 15°-30°C (59°-86°F). Retain in carton until 
contents are used. Reconstitute with preservative-free NS to a final concentration of 2 mg/mL. 
After adding the diluent, the vial should be shaken and the contents allowed to dissolve. The 
reconstituted solution is stable for 7 days at room temperature and 15 days under refrigeration 
2°-8°C (36°-46°F) when protected from light. Doxorubicin further diluted in 50-1000 mL of NS 
or D5W is stable for up to 48 hours at room temperature (25°C) when protected from light. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol.  
 
Administer IV through the tubing of rapidly infusing solution of D5W or NS preferably into a 
large vein. Protect the diluted solution from sunlight. To avoid extravasation, the use of a central 
line is suggested. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
6.7 
LEUCOVORIN 
CALCIUM 
(LCV, 
Wellcovorin®, 
citrovorum 
factor, 
folinic 
acid)  
NSC #003590 
(05/09/11) 
Source and Pharmacology:  Leucovorin is a mixture of the diastereoisomers of the 5-formyl 
derivative of tetrahydrofolic acid (THF). The biologically active compound of the mixture is the 
(-)- l-isomer, known as Citrovorum factor or (-)-folinic acid. Leucovorin does not require 
reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing 
folates as a source of “one-carbon” moieties. Administration of leucovorin can counteract the 
therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by 
inhibiting dihydrofolate reductase. In contrast, leucovorin can enhance the therapeutic and toxic 
effects of fluoropyrimidines used in cancer therapy, such as 5-fluorouracil. Leucovorin is readily 
converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the 
binding of fluorodeoxyuridylic acid (an active metabolite of 5-FU) to thymidylate synthase and 
thereby enhances the inhibition of this enzyme. Peak serum levels of 5-methyl THF (an active 
metabolite) were reached at approximately 1.3-1.5 hours (IV/IM) and 2.3 hours for the oral form. 
The terminal half-life of total reduced folates was approximately 6.2 hours. Following oral 
administration, leucovorin is rapidly absorbed and expands the serum pool of reduced folates. At 
a dose of 25 mg, almost 100% of the l-isomer (the biologically active form) but only 20% of the 
d-isomer is absorbed. Oral absorption of leucovorin is saturable at doses above 25 mg. The 
apparent bioavailability of leucovorin was 97% for 25 mg, 75% for 50 mg, and 37% for 100 mg 
doses. Both oral and parenteral leucovorin raise the CSF folate levels. 
 
 


 
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Toxicity: 
 
Common 
Happens 
to 
21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of receiving 
drug 
 
 
Anaphylaxis, urticaria,seizure 
Unknown Frequency and 
Timing:  
Fetal toxicities and teratogenic effects of leucovorin in humans are unknown. It is 
unknown whether the drug is excreted in breast milk. 
 
Injection: Because of the calcium content of the leucovorin solution, no more than 160 mg of 
leucovorin should be injected intravenously per minute (16 mL of a 10 mg/mL solution per 
minute). IV leucovorin and sodium bicarbonate are incompatible. 
 
Oral: Oral leucovorin should be spaced evenly (e.g. every six hours) throughout the day and may 
be taken without regard to meals. Doses > 25 mg should be given IV due to the saturation of 
absorption. 
 
Leucovorin should not be administered < 24 hours after intrathecal injections which contain 
methotrexate unless there are special circumstances. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
6.8 
MERCAPTOPURINE (6-MP, Purinethol®, 6-mercaptopurine) NSC #000755 
(11/26/12) 
Source and Pharmacology: Mercaptopurine is an analogue of the purine bases adenine and 
hypoxanthine. The main intracellular pathway for MP activation is catalyzed by the enzyme 
hypoxanthine-guanine phosphoribosyl transferase (HGPRT) which catalyzes the conversion of 
MP to several active nucleotide metabolites including thioinosinic acid, a ribonucleotide which 
can interfere with various metabolic reactions necessary for nucleic acid (RNA and DNA) 
biosynthesis. It can also cause pseudofeedback inhibition of the first step in de novo purine 
biosynthesis or convert to another ribonucleotide which can cause feedback inhibition. 
Mercaptopurine can be incorporated into DNA in the form of TG nucleotides as well and thus 
produce toxicity. The absorption of an oral dose of MP is incomplete and variable, with only 
about 16%-50% of an administered dose reaching the systemic circulation secondary to a first 
pass metabolism in the liver. Food intake and co-administration with cotrimoxazole (TMP/SMX) 
significantly reduces absorption of MP. After IV administration, MP has a plasma half-life of 21 
minutes in children and 47 minutes in adults. Approximately 19% is bound to protein. 
Mercaptopurine is well distributed into most body compartments except the CSF. (With high dose 
IV MP the CSF to plasma ratio is 0.15.) MP is metabolized by xanthine oxidase in the liver to 6-
Thiouric acid an inactive metabolite. In patients receiving both MP and allopurinol (a xanthine 
oxidase inhibitor) the dose of MP must be reduced by 50-75%. Since TPMT, 6-thiopurine 
methyltransferase, is also one of the enzymes involved in the metabolism of MP, those 
individuals who have an inherited deficiency of the enzyme may be unusually sensitive to the 
myelosuppressive effects of MP and prone to develop rapid bone marrow suppression following 
the initiation of treatment. Mercaptopurine is excreted in urine as metabolites and some 
unchanged drug; about half an oral dose has been recovered in 24 hours. A small proportion is 
excreted over several weeks. 


 
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Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children out of 
every 100 
Immediate: 
Within 1-2 days of receiving drug 
 
Anorexia, nausea, 
vomiting, diarrhea, malaise 
Urticaria, hyperuricemia,  
Prompt: 
Within 2-3 weeks, prior to the next 
course 
Myelosuppression (L) 
Erythematous rash (L) 
Oral lesions resembling thrush, 
toxic hepatitis(L), increased 
AST/ALT, hyperpigmentation (L), 
pancreatitis  
Delayed: 
Any time later during therapy, 
excluding the above conditions 
 
Oligospermia 
Hepatic fibrosis(L), 
hyperbilirubinemia, alopecia 
Late: 
Any time after the completion of 
treatment 
 
 
Pulmonary fibrosis, secondary 
malignancies 
Unknown Frequency and 
Timing:   
Fetal toxicities and teratogenic effects of mercaptopurine have been noted in animals.  
Women receiving mercaptopurine in the first trimester of pregnancy have an increased 
incidence of abortion. It is unknown whether the drug is excreted in breast milk 
(L) Toxicity may also occur later. 
 
Formulation and Stability: 
Mercaptopurine is available as a 50 mg tablet containing mercaptopurine and the inactive 
ingredients corn and potato starch, lactose, magnesium stearate, and stearic acid. Store at 
15°-25°C (59°-77°F) in a dry place. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
Do not give oral mercaptopurine with food or milk. Concurrent milk products can decrease 
absorption and mercaptopurine effect is enhanced if given at bedtime on an empty stomach. If 
allopurinol is also given, the oral dose of mercaptopurine should be reduced by 67-75%. Patients 
with severe myelosuppression should have their thiopurine S-methyltransferase (TPMT) status 
and/or their thiopurine metabolite concentrations evaluated, so that the dose of mercaptopurine can 
be reduced in patients with a TPMT defect. Patients with the rare homozygous deficient TPMT 
phenotype may tolerate only 1/10th to 1/20th the average mercaptopurine dose. TPMT testing and 
thiopurine metabolite measurements are commercially available. 
 
Suspension: 
For children unable to swallow the tablets whole, a 50 mg/mL oral suspension can be 
compounded. The suspension is prepared by crushing 50 mercaptopurine 50 mg tablets in a mortar 
and adding 8.5 mL sterile water for irrigation. The mixture is triturated to form a smooth paste. 
Next, 16.5 mL simple syrup (pH=7) are added with continuous mixing and finally cherry syrup 
(pH=7.1) is added to a total volume of 50 mL. The suspension is stable in amber glass bottles at 
room temperature (19ºC -23ºC) for up to 5 weeks. The suspension should be shaken well before 
each use. Procedures for proper handling and disposal of cytotoxic drugs should be used when 
preparing the suspension. (Aliabadi HM, Romanick M, Desai S et al. Effect of buffer and 
antioxidant on stability of mercaptopurine suspension. Am J Heath-Syst Pharm. 65:441-7, 2008.) 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 


 
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6.9 
METHOTREXATE (MTX, amethopterin, Trexall®) NSC #000740 
(02/29/12) 
Source and Pharmacology: A folate analogue which reversibly inhibits dihydrofolate reductase, 
the enzyme that reduces folic acid to tetrahydrofolic acid. Inhibition of tetrahydrofolate formation 
limits the availability of one carbon fragments necessary for the synthesis of purines and the 
conversion of deoxyuridylate to thymidylate in the synthesis of DNA and cell reproduction. The 
polyglutamated metabolites of MTX also contribute to the cytotoxic effect of MTX on DNA repair 
and/or strand breaks. MTX cytotoxicity is highly dependent on the absolute drug concentration 
and the duration of drug exposure. MTX is actively transported across cell membranes. At serum 
methotrexate concentrations exceeding 0.1 µmol/mL, passive diffusion becomes a major means of 
intracellular transport of MTX. The drug is widely distributed throughout the body with the highest 
concentration in the kidney, liver, spleen, gallbladder and skin. Plasma concentrations following 
high dose IV MTX decline in a biphasic manner with an initial half-life of 1.5-3.5 hours, and a 
terminal half life of 8-15 hours. About 50% is bound to protein. After oral administration, 
approximately 60% of a 30 mg/m2 dose is rapidly absorbed from the GI tract, with peak blood 
levels at 1 hour. At doses > 30 mg/m² absorption decreases significantly. Even at low doses 
absorption may be very erratic, varying between 23% and 95%. The elimination of MTX from the 
CSF after an intrathecal dose is characterized by a biphasic curve with half-lives of 4.5 and 14 
hours. After intrathecal administration of 12 mg/m², the lumbar concentration of MTX is ~ 100 
times higher than in plasma. (Ventricular concentration is ~ 10% of lumbar concentration.) MTX is 
excreted primarily by the kidneys via glomerular filtration and active secretion into the proximal 
tubules. Renal clearance usually equals or exceeds creatinine clearance. Small amounts are 
excreted in the feces. There is significant entero-hepatic circulation of MTX. The distribution of 
MTX into third-space fluid collections, such as pleural effusions and ascitic fluid, can substantially 
alter MTX pharmacokinetics. The slow release of accumulated MTX from these third spaces over 
time prolongs the terminal half-life of the drug, leading to potentially increased clinical toxicity.  
 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Transaminase elevations 
Nausea, vomiting, 
anorexia 
Anaphylaxis, chills, fever, dizziness, malaise, 
drowsiness, blurred vision, acral erythema, urticaria, 
pruritis, toxic epidermal necrolysis, Stevens-Johnson 
Syndrome, tumor lysis syndrome, seizures1, 
photosensitivity 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
 
Myelosuppression, 
stomatitis, gingivitis, 
photosensitivity, fatigue 
Alopecia, folliculitis, acne, renal toxicity (ATN, 
increased creatinine/BUN, hematuria), enteritis, GI 
ulceration and bleeding, acute neurotoxicity1 
(headache, drowsiness, aphasia, paresis, blurred 
vision, transient blindness, dysarthria, hemiparesis, 
decreased reflexes), diarrhea, conjunctivitis 
Delayed: 
Any time later 
during therapy, 
excluding the above 
conditions 
 
Learning disability1 (L) 
Pneumonitis, pulmonary fibrosis (L), hepatic fibrosis 
(L), osteonecrosis (L), leukoencephalopathy1 (L), 
pericarditis, pericardial effusions, hyperpigmentation 
of the nails 
Late: 
Any time after the 
completion of 
therapy 
 
 
Progressive CNS deterioration1 
Unknown 
Methotrexate crosses the placenta. Fetal toxicities and teratogenic effects of methotrexate have been noted 


 
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Frequency and 
Timing: 
in humans. The toxicities include: congenital defects, chromosomal abnormalities, severe newborn 
myelosuppression, low birth weight, abortion, and fetal death. Methotrexate is excreted into breast milk in 
low concentrations 
1 May be enhanced by HDMTX and/or cranial irradiation. 
(L) Toxicity may also occur later. 
 
Intrathecal Therapy (Methotrexate Single Agent) 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, headache 
Arachnoditis: (headache, 
fever, vomiting, 
meningismus, nuchal 
rigidity, and pleocytosis) 
Anaphylaxis, vomiting, seizures(L), 
malaise, confusion, back pain, rash, 
bleeding into subarachnoid or subdural 
space (risk >with platelet counts <20,000) 
Prompt: 
Within 2-3 weeks, prior 
to the next course 
 
 
Myelosuppression, ataxia, somnolence, 
cranial nerve palsy, subacute myelopathy 
(paraparesis/paraplegia), speech disorders, 
pain in the legs, bladder dysfunction 
Delayed: 
Any time later during 
therapy, excluding the 
above condition 
 
Cognitive disturbances 
(L)1, learning disability 
(L)1 
Leukoencephalopathy1 (L) 
Late: 
Any time after the 
completion of treatment 
 
 
Progressive CNS deterioration1 
1 May be enhanced by HDMTX and/or cranial irradiation. 
(L) Toxicity may also occur later. 
 
Formulation & Stability:  
Methotrexate for oral use is available as 2.5 mg, 5 mg, 7.5 mg, 10 mg and 15 mg tablets. Inactive 
ingredients vary depending on manufacturer but tablet formulations may include: anhydrous 
lactose, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline 
cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, sodium carbonate 
monohydrate, talc and titanium dioxide and various dyes. Store at controlled room temperature 
15°-30°C (59°-86°F) and protect from light.  
 
Methotrexate for Injection is available as a lyophilized powder for injection in 1000 mg vials. 
The powder for injection contains approximately 7 mEq sodium in the 1000 mg vial. 
Methotrexate for Injection is also available as a 25 mg/mL solution in 2, 4, 8, 10, and 40 mL 
preservative free vials and 2 and 10 mL vials with preservative. The 2, 4, 8, 10, and 40 mL 
solutions contain approximately 0.43, 0.86, 1.72, 2.15, and 8.6 mEq sodium per vial, 
respectively. The preserved vials contain 0.9% benzyl alcohol as a preservative.  
 
Sterile methotrexate powder or solution is stable at 20º-25ºC (68º-77ºF); excursions permitted to 
15º-30ºC (59- 86 Fº). Protect from light  
 
Guidelines for Administration: See Treatment and Dose Modifications sections of protocol. 
Leucovorin rescue may be necessary with certain doses of methotrexate. 
 
Oral administration: Food or milk delays absorption and reduces peak concentration. 
Methotrexate for oral use should preferentially be given on an empty stomach, 1 hour before or 2 


 
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hours after food or milk and at the same time each day. Methotrexate injection diluted in water 
can be used for oral administration (Marshall PS, Gertner E. Oral administration of an easily 
prepared solution of injectable methotrexate diluted in water: a comparison of serum 
concentrations vs methotrexate tablets and clinical utility. J Rheumatol 23:455-8, 1996). 
 
For IV use: Powder for injection: Dilute 1000 mg vial with 19.4 mL of preservative free SWFI, 
D5W or NS to a 50 mg/mL concentration. The powder for injection may be further diluted in NS 
or dextrose containing solutions to a concentration of ≤ 25 mg/mL for IV use. 
 
The 25 mg/mL solution may be given directly for IM administration or further diluted in Saline 
or Dextrose containing solutions for IV use. Do not use the preserved solution for high dose 
methotrexate administration due to risk of benzyl alcohol toxicity. Methotrexate dilutions are 
chemically stable for at least 7 days at room temperature but contain no preservative and should 
be used within 24 hours. Diluted solutions especially those containing bicarbonate exposed to 
direct sunlight for periods exceeding 4 hours should be protected from light. 
 
High dose methotrexate requires alkalinization of the urine, adequate hydration and leucovorin 
rescue. Avoid probenecid, penicillins, cephalosporins, aspirin, proton pump inhibitors, and 
NSAIDS as renal excretion of MTX is inhibited by these agents. 
 
For Intrathecal use: Use preservative free 25 mg/mL solution.  
 
For intrathecal administration, dilute with 5-10 mL preservative free NS, lactated Ringer’s, or 
Elliot’s B solution, as per institutional standard of practice. The volume of CSF removed should be 
equal to at least half the volume delivered. 
 
Patient Age (years) Methotrexate dose Recommended volume 10% CSF volume 
CSF Volume* 
1–1.99 
8 mg  
5–10 mL 
5 mL 
50 + 10 mL  (babies) 
2–2.99 
10 mg  
5-10 mL 
8 mL 
80 + 20 mL (younger children) 
3–8.99 
12 mg  
5-10 mL 
10 mL 
100 + 20 mL (older children) 
9 or greater 
15 mg  
5-10 mL 
13 mL 
130 + 30 mL (adults) 
* Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection; N Engl J Med. 1962 Dec 20; 267:1273-8 
 
Of note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, 
with the patient remaining prone after the procedure may facilitate drug distribution. These 
procedures have not been validated in clinical trials. They are allowed but not mandated for patients 
on COG studies. 
 
Diluted methotrexate for intrathecal administration is stable in normal saline for 24 hours at 25ºC 
but contains no preservative and should be administered as soon as possible after preparation. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
6.10 
NELARABINE (2-Amino-9--D arabinofuranosyl-6-methoxy-9H-purine, Compound 506U78) 
NSC# 686673; IND# 52611 
(03/24/16) 
Source and Pharmacology: Nelarabine (compound 506U78) is a water soluble pro-drug of 9-β-
D-arabinofuranosylguanine (ara-G), a deoxyguanosine analog being developed for the treatment 


 
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of patients with T-cell and B-cell leukemias and lymphomas. Nelarabine is rapidly converted by 
adenosine deaminase in the peripheral blood to ara-G. In Vitro studies and biochemical studies 
have demonstrated that intracellular ara-G is phosphorylated via deoxycytosine kinase (dCK) 
and deoxyguanosine kinase (dGK) to its active 5’-triphosphate (ara-GTP). Ara-GTP 
incorporation into DNA is a primary cause of cell death. 
 
The pharmacokinetics of nelarabine in humans are characterized by a rapid and extensive 
conversion to ara-G. The average elimination half-lives for nelarabine and ara-G were 
approximately 20-25 minutes and 2.6-4.0 hours, respectively. Virtually all nelarabine was 
converted to ara-G. Peak plasma concentration and area under the curve for both nelarabine and 
ara-G was essentially proportional to the administered dose. The steady-state volume of 
distribution of ara-G was similar in adult and pediatric patients. Neither compound showed 
accumulation with the dosing studies used in the pre-clinical trials with this agent. The 
pharmacokinetics of both nelarabine and ara-G appeared to be independent of diagnosis and 
gender. Intracellular leukemic blast concentrations of ara-GTP were characterized by a long 
elimination half-life (median approximately 24 hours) and diagnosis dependent accumulation; 
with T-lymphoblasts generally demonstrating greater accumulation of ara-GTP than other cell 
types. Nelarabine and ara-G is < 25% bound to human plasma proteins. 
 
Toxicity: 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Nelarabine (Compound 506U78, NSC 686673) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI via AdEERS (except as noted below).  
Refer 
to 
the 
'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for 
further clarification. Frequency is provided based on 458 patients. Below is the CAEPR for 
nelarabine (Compound 506U78). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
 


 
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Version 2.2, July 10, 2013 
 
 Adverse Events with Possible  
 Relationship to Nelarabine (Compound 506U78) 
 (CTCAE 4.0 Term) 
[n= 458] 
 
 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr. 3) 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr. 3) 
CARDIAC DISORDERS 
  
 
Sinus tachycardia 
 
 Sinus tachycardia (Gr. 3) 
EYE DISORDERS 
  
 
Blurred vision 
 
 Blurred vision (Gr. 3) 
 
Eye pain 
 
 Eye pain (Gr. 3) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr. 3) 
 
Anal mucositis 
 
 Anal mucositis (Gr. 3) 
 
Diarrhea 
 
 Diarrhea (Gr. 3) 
 
Mucositis oral 
 
 Mucositis oral (Gr. 3) 
Nausea 
 
 
 Nausea (Gr. 3) 
 
Pancreatitis 
 
 Pancreatitis (Gr. 3) 
 
Rectal mucositis 
 
 Rectal mucositis (Gr. 3) 
 
Small intestinal mucositis 
 
 Small intestinal mucositis (Gr. 3) 
 
Vomiting 
 
 Vomiting (Gr. 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
 Edema limbs (Gr. 3) 
Fatigue 
 
 
 Fatigue (Gr. 3) 
 
Fever 
 
 Fever (Gr. 3) 
 
Gait disturbance 
 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection2 
 
 Infection2 (Gr. 3) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase increased (Gr. 3) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase increased (Gr. 
3) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr. 3) 
 
CPK increased 
 
 CPK increased (Gr. 3) 
Lymphocyte count decreased  
 
 Lymphocyte count decreased (Gr. 3) 
Neutrophil count decreased 
 
 
 Neutrophil count decreased (Gr. 3) 
Platelet count decreased 
 
 
 Platelet count decreased (Gr. 3) 
 
Serum amylase increased 
 
 Serum amylase increased (Gr. 3) 
 
Weight gain 
 
 Weight gain (Gr. 3) 
White blood cell decreased 
 
 
 White blood cell decreased (Gr. 3) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr. 3) 
 
Dehydration 
 
 Dehydration (Gr. 3) 
 
Hyperglycemia 
 
 Hyperglycemia (Gr. 3) 
 
Hyperuricemia 
 
 Hyperuricemia (Gr. 3) 
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr. 3) 


 
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Hypocalcemia 
 
  
 
Hypokalemia 
 
 Hypokalemia (Gr. 3) 
 
Hyponatremia 
 
 Hyponatremia (Gr. 3) 
 
Tumor lysis syndrome 
 
 Tumor lysis syndrome (Gr. 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr. 3) 
 
Bone pain 
 
 Bone pain (Gr. 3) 
 
Generalized muscle weakness  
 Generalized muscle weakness (Gr. 3) 
 
Musculoskeletal and 
connective tissue disorder -  
Other (muscle twitching) 
 
 Musculoskeletal and connective tissue 
disorder -  Other (muscle twitching) (Gr. 3) 
 
 
Musculoskeletal and connective 
tissue disorder -  Other 
(rhabdomyolysis) 
  
 
Myalgia 
 
 Myalgia (Gr. 3) 
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Ataxia 
 
 Ataxia (Gr. 3) 
Depressed level of 
consciousness 
 
 
 Depressed level of consciousness (Gr. 3) 
 
Dizziness 
 
 Dizziness (Gr. 3) 
 
Dysphasia 
 
 Dysphasia (Gr. 3) 
 
Encephalopathy 
 
 Encephalopathy (Gr. 3) 
 
Headache 
 
 Headache (Gr. 3) 
 
Memory impairment 
 
 Memory impairment (Gr. 3) 
 
Nervous system disorders - 
Other (Guillian-Barre 
syndrome) 
 
 Nervous system disorders - Other (Guillain-
Barre syndrome) (Gr. 3) 
 
Paresthesia 
 
  
 
Peripheral motor neuropathy  
 Peripheral motor neuropathy (Gr. 3) 
Peripheral sensory neuropathy  
 
 Peripheral sensory neuropathy (Gr. 3) 
 
Pyramidal tract syndrome 
 
 Pyramidal tract syndrome (Gr. 3) 
 
Seizure 
 
 Seizure (Gr. 3) 
 
Tremor 
 
 Tremor (Gr. 3) 
PSYCHIATRIC DISORDERS 
  
 
Agitation 
 
 Agitation (Gr. 3) 
 
Anxiety 
 
 Anxiety (Gr. 3) 
 
Confusion 
 
 Confusion (Gr. 3) 
 
Depression 
 
 Depression (Gr. 3) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Epistaxis 
 
 Epistaxis (Gr. 3) 
 
Laryngeal mucositis 
 
 Laryngeal mucositis (Gr. 3) 
 
Pharyngeal mucositis 
 
 Pharyngeal mucositis (Gr. 3) 
 
Tracheal mucositis 
 
 Tracheal mucositis (Gr. 3) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Purpura 
 
 Purpura (Gr. 3) 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal 
Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
2Infection may include all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
3Gastrointestinal hemorrhage may include Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal 


 
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hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper 
gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
 
Also reported on nelarabine (Compound 506U78) trials but with the relationship to 
nelarabine (Compound 506U78) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (pancytopenia) 
CARDIAC DISORDERS - Cardiac arrest; Left ventricular systolic dysfunction 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (ear 
hemorrhage); Hearing impaired; Middle ear inflammation 
EYE DISORDERS - Conjunctivitis; Eye disorders - Other (blindness); Keratitis 
GASTROINTESTINAL 
DISORDERS 
- 
Constipation; 
Dry 
mouth; 
Gastrointestinal 
hemorrhage3; Ileus 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Pain 
INVESTIGATIONS - Alkaline phosphatase increased; Creatinine increased; Fibrinogen 
decreased; Investigations - Other (hypobicarbonatemia); Lipase increased 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyperkalemia; 
Hypoglycemia; Hypomagnesemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 
(lymphoma) 
NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Dysarthria; Intracranial 
hemorrhage; Oculomotor nerve disorder 
PSYCHIATRIC DISORDERS - Insomnia; Psychosis 
RENAL AND URINARY DISORDERS - Acute kidney injury; Urinary incontinence 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Genital edema 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; 
Hypoxia; Laryngeal hemorrhage; Pleural effusion; Pneumonitis; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Skin and 
subcutaneous tissue disorders - Other (dermatitis allergic); Skin and subcutaneous tissue 
disorders - Other (herpes zoster) 
VASCULAR DISORDERS - Hypertension; Hypotension 
 
Note: Nelarabine (Compound 506U78) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent. 
 
Pregnancy and Lactation: 
Fetal toxicities and teratogenic effects of nelarabine are unknown. It is unknown whether the 
drug is excreted in breast milk. 
 
Formulation and Stability: 
Nelarabine (compound 506U78) is formulated to provide 5 mg of nelarabine per mL in 0.45% 
saline solution. Nelarabine Injection consists of a clear, colorless solution, contained in a clear 50 
mL glass vial with a gray rubber closure and lacquered overseals made of polypropylene and 


 
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aluminum. The drug is supplied as a 5 mg/mL liquid in 50 mL vials with a total of 250 mg 
nelarabine per vial. The pH of the solution is between 5 and 7. 
 
Intact 50 mL glass vials containing 250 mg of nelarabine for injection should be stored at or 
below 30C (86F). Do not store vials in the refrigerator as crystallization of the product may 
occur. Nelarabine as a clear colorless solution is stable in glass vials for at least 30 months at 
30C.  
 
Guidelines for Administration: See the Treatment and Dose Modifications Sections of the 
protocol.  
 
All vials should be visually inspected for any particulate matter prior to use. The solution is 
intended to be used full strength directly from the vials with no further dilution. Glass or 
plastic containers may be used. Nelarabine is stable in polyvinylchloride (PVC) infusion bags, 
ethyl vinyl acetate (EVA) infusion bags and glass containers for up to 8 hours at up to 30C.  
 
CAUTION: The single-use dosage form contains no antibacterial preservatives. Therefore, it is 
advised that the product be discarded 8 hours after initial entry.  
 
Supplier: Supplied by GlaxoSmithKline and distributed by the NCI DTCD. Do not use 
commercially available drug. 
 
Obtaining the Agent 
NCI supplied agent may be requested by the Principal Investigator (or their authorized designee) 
at each participating institution. Pharmaceutical Management Branch (PMB) policy requires that 
agent be shipped directly to the institution where the patient is to be treated. PMB does not 
permit the transfer of agents between institutions (unless prior approval from PMB is obtained.) 
The CTEP assigned protocol number must be used for ordering all CTEP supplied 
investigational agents. The responsible investigator at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and Financial 
Disclosure Form (FDF). If there are several participating investigators at one institution, CTEP 
supplied investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees must submit agent requests through the PMB Online Agent Order Processing 
(OAOP) application < https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx>. Access to OAOP 
requires the establishment of a CTEP Identity and Access Management (IAM) account < 
https://eapps-ctep.nci.nih.gov/iam/ > and the maintenance of an “active” account status and a 
“current” password. For questions about drug orders, transfers, returns, or accountability call 
(240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime.  
 
Agent Accountability 


 
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Agent Inventory Records - The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record Form (DARF). (See the CTEP 
home page at http://ctep.cancer.gov/protocolDevelopment/default.htm#agents_drugs for the 
Procedures for Drug Accountability and Storage and http://ctep.cancer.gov/forms/default.htm to 
obtain a copy of the DARF and Clinical Drug Request form.) 
 
Investigational Agent Returns 
Investigators/Designees must return unused DCTD supplied investigational agent to the NCI 
clinical repository as soon as possible when: the agent is no longer required because the study is 
completed or discontinued and the agent cannot be transferred to another DCTD sponsored 
protocol; the agent is outdated or the agent is damaged or unfit for use. Regulations require that 
all agents received from the DCTD, NCI be returned to the DCTD, NCI for accountability and 
disposition. Return only unused vials/bottles. Do NOT return opened or partially used 
vials/bottles unless specifically requested otherwise in the protocol. See the CTEP web site for 
Policy 
and 
Guidelines 
for 
Investigational 
agent 
Returns 
at 
http://ctep.cancer.gov/protocolDevelopment/default.htm#agents_drugs. The appropriate forms 
may be obtained at: http://ctep.cancer.gov/forms/docs/return_form.pdf. 
 
6.11 
PEGASPARGASE 
(PEG-asparaginase, PEGLA, PEG-L-asparaginase, polyethylene glycol-
L-asparaginase, Oncaspar®)  
NSC #624239  
 
 
 
 
 
 
 
 
(03/13/13) 
Source and Pharmacology: 
Pegaspargase is a modified version of the enzyme L-asparaginase. L-asparaginase is modified by 
covalently conjugating units of monomethoxypolyethylene glycol (PEG), molecular weight of 5000, to 
the enzyme, forming the active ingredient PEG-L-asparaginase. The L-asparaginase (L-asparagine 
amidohydrolase, type EC-2, EC 3.5.1.1) used in the manufacture of Pegaspargase is derived from 
Escherichia coli which is purchased in bulk from Merck, Sharp and Dohme. L-asparagine is a 
nonessential amino acid synthesized by the transamination of L-aspartic acid by a reaction catalyzed by 
the enzyme L-asparagine synthetase. The ability to synthesize asparagine is notably lacking in 
malignancies of lymphoid origin. Asparaginase depletes L-asparagine from leukemic cells (especially 
lymphoblasts) by catalyzing the conversion of L-asparagine to aspartic acid and ammonia. In 
predominately L-asparaginase naive adult patients with leukemia and lymphoma, initial plasma levels of 
L-asparaginase following intravenous administration of pegaspargase were determined. Apparent volume 
of distribution was equal to estimated plasma volume. L-asparaginase was measurable for at least 15 days 
following the initial treatment with Pegaspargase. The approximate t½ in adult patients is 5.73 days. The 
enzyme could not be detected in the urine. The half-life is independent of the dose administered, disease 
status, renal or hepatic function, age, or gender. In a study of newly diagnosed pediatric patients with 
ALL who received either a single intramuscular injection of pegaspargase (2500 IU/m2), E. coli 
L-asparaginase (25000 IU/m2), or Erwinia (25000 IU/m2), the plasma half-lives for the three forms of 
L-asparaginase were: 5.73 ± 3.24 days, 1.24 ± 0.17 days, and 0.65 ± 0.13 days respectively. The plasma 
half-life of pegaspargase is shortened in patients who are previously hypersensitive to native 
L-asparaginase as compared to non-hypersensitive patients. L-asparaginase is cleared by the 
reticuloendothelial system and very little is excreted in the urine or bile. Cerebrospinal fluid levels are < 1% 
of plasma levels.  


 
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Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Allergic reactions (total 
likelihood of local, and or 
systemic reaction especially if 
previous hypersensitivity 
reaction to native 
asparaginase), pain at 
injection site, weakness, 
fatigue, diarrhea  
Allergic reactions (total 
likelihood of local, and 
or systemic reaction if no 
previous hypersensitivity 
reaction to native 
asparaginase), rash  
Anaphylaxis, hyper/hypotension, 
tachycardia, periorbital edema, 
chills, fever, dizziness, dyspnea, 
bronchospasm, lip edema, arthralgia, 
myalgia, urticaria, mild 
nausea/vomiting, abdominal pain, 
flatulence, somnolence, lethargy, 
headache, seizures (L), 
hyperuricemia  
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Hyperammonemia (L), 
coagulation abnormalities 
with prolonged PTT, PT and 
bleeding times (secondary to 
decreased synthesis of 
fibrinogen, AT-III & other 
clotting factors) (L) 
Hyperglycemia, 
abnormal liver function 
tests, pancreatitis (L), 
increased serum 
lipase/amylase 
Hemorrhage (L), DIC, thrombosis, 
anorexia, weight loss, CNS ischemic 
attacks, edema, azotemia and 
decreased renal function, mild 
leukopenia, granulocytopenia, 
thrombocytopenia, pancytopenia, 
hemolytic anemia, infections (sepsis 
with/without septic shock, subacute 
bacterial endocarditis [SBE], URI), 
CNS changes including irritability, 
depression, confusion, EEG changes, 
hallucinations, coma and stupor, 
paresthesias, hypertriglyceridemia, 
hyperlipidemia, Parkinson-like 
syndrome with tremor and increase 
in muscular tone, 
hyperbilirubinemia, chest pain  
Delayed: 
Any time later 
during therapy 
 
 
Renal failure, urinary frequency, 
hemorrhagic cystitis, elevated 
creatinine and BUN, fatty liver 
deposits, hepatomegaly, liver failure 
Unknown 
Frequency and 
Timing:  
Animal reproduction studies have not been conducted with pegaspargase. It is not known whether 
pegaspargase can cause fetal harm when administered to a pregnant woman or can affect 
reproduction capacity. However, fetal toxicities and teratogenic effects of asparaginase have been 
noted in animals. It is unknown whether the drug is excreted in breast milk. 
(L)Toxicity may also occur later. 
 
Formulation and Stability: 
Each milliliter of pegaspargase contains: PEG-L-asparaginase 750 IU ± 20%, monobasic sodium 
phosphate, USP 1.20 mg ± 5% dibasic sodium phosphate, USP 5.58 mg ± 5%, sodium chloride, USP 
8.50 mg ± 5% , Water for Injection, USP qs to 1 mL. The specific activity of pegaspargase is at least 
85 IU per milligram protein. Available in 5 mL vials as Sterile Solution for Injection in ready to use 
single-use vials, preservative free. Keep refrigerated at 2°-8°C (36°-46°F). Do not use if stored at room 
temperature for more than 48 hours. DO NOT FREEZE. Do not use product if it is known to have been 
frozen. Freezing destroys activity, which cannot be detected visually.  
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
For IM administration: the volume at a single injection site should be limited to 2 mL. If the volume to be 
administered is greater than 2 mL, multiple injection sites should be used.  
 
For IV administration: dilute pegaspargase in 100 mL of NS or D5W and infuse over 1 to 2 hours through 
a NS or D5W running infusion line. Pegaspargase admixed in 100 mL of NS or D5W is stable for 


 
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48 hours at room temperature. Pegaspargase diluted in 100 mL of NS is stable for up to 72 hours 
refrigerated (4ºC [39°F]) (refrigerated stability data on file with Sigma-Tau). Avoid excessive agitation. 
DO NOT SHAKE. Do not use if cloudy or if precipitate is present.  
 
Have available during and after the infusion: antihistamine, epinephrine, oxygen, and IV corticosteroids. 
Observe patient for ONE hour after administration for signs of hypersensitivity reactions. 
 
Supplier: 
Pegaspargase 
(Oncaspar®) 
is 
commercially 
available 
from 
Sigma-Tau 
Pharmaceuticals. US sites can purchase the drug through their usual ordering channels 
(wholesalers). If needed, the Sigma Tau Customer Service phone number for the US is 1-888-
276-2217.  
 
CANADIAN SITES 
Pegaspargase is not commercially available in Canada. Sites may purchase and import the USA 
commercial supply directly from Sigma Tau Pharmaceuticals under the authority of the 
protocol’s No Objection Letter (NOL). The Canadian Senior Medical Officer (SMO)’s office is 
responsible for coordinating the “Fax Back” for all lot numbers and expiry dates to Health 
Canada’s Biologics and Genetic Therapies Directorate for approval for use in Canada on behalf 
of all Canadian sites. A list of approved lot numbers is distributed to all Canadian sites by the 
SMO’s office. If an unapproved lot is received from Sigma Tau Pharmaceuticals, quarantine the 
lot and contact the COG Canada Regulatory Affairs Office at 1-780-492-7064.  Note: 
Pegaspargase may have orders placed and Drug Accountability Logs maintained on a multiple 
protocol basis (Multiple Protocol—Imported Biologic) as long as each protocol has a NOL. Drug 
Accountability Logs (DAL) must record Lot #’s and expiry dates of shipments received and 
doses dispensed. Sites may use their own DAL as long as it complies with all elements of ICH 
GCP and Division 5 of the Food and Drugs Act.  Sites may import and manage a single clinical 
trial supply for multiple protocols as long as each protocol has an NOL and the protocol the 
patient is registered on is recorded on the DAL. 
 
6.12 
PREDNISONE (Deltasone, Meticorten, Orasone®, Liquid Pred, Pediapred®, Sterapred®)      
NSC #010023  
(05/10/11) 
Source and Pharmacology: Prednisone is a synthetic compound closely related to hydrocortisone. 
Glucocorticoids produce widespread and diverse physiologic effects on carbohydrate, protein, and 
lipid metabolism, electrolyte and water balance, functions of the cardiovascular system, kidney, 
skeletal muscle, and the nervous systems. Glucocorticoids reduce the concentration of thymus-
dependent lymphocytes (T-lymphocytes), monocytes, and eosinophils. Glucocorticoids 
selectively bind to the cortisol receptors on human lymphoid cells which are found in larger 
numbers on leukemic lymphoblasts. They also decrease binding of immunoglobulin to cell 
surface receptors and inhibit the synthesis and/or release of interleukins, thereby decreasing T-
lymphocyte blastogenesis and reducing expansion of the primary immune response. The specific 
cellular mechanisms that act to halt DNA synthesis are thought to be related to inhibition of 
glucose transport or phosphorylation, retardation of mitosis, and inhibition of protein synthesis. 
Peak blood levels occur within 2 hours of oral intake. Prednisone is approximately 75% protein 
bound with a plasma t½ of 3.2 to 4 hours (biologic half-life is 12-36 hours). 


 
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Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Insomnia, hyperphagia 
Gastritis 
Hyperuricemia 
Prompt: 
Within 2-3 weeks, prior 
to the next course 
Immunosuppression, 
personality changes (mood 
swings, euphoria, anxiety, 
depression), pituitary-
adrenal axis suppression, 
acne (L) 
Hyperglycemia, facial 
erythema, poor wound 
healing, infections 
(bacterial, fungal, 
parasitic, viral), edema 
Pancreatitis (L), electrolyte 
imbalance (Na retention, 
hypokalemia, hypocalcemia) (L), 
increased intraocular pressure (L), 
hypertension, psychosis, vertigo,  
headache 
Delayed: 
Any time later during 
therapy 
Cushing’s syndrome (moon 
facies, truncal obesity) 
Striae and thinning of the 
skin, easy bruising, 
muscle weakness, 
osteopenia  
Spontaneous fractures (L), growth 
suppression, peptic ulcer and GI 
bleeding, pseudotumor cerebri 
(increased intracranial pressure 
with papilledema, headache), 
aseptic necrosis of the femoral and 
humeral heads (L), urolithiasis1 (L) 
Late: 
Any time after 
completion of treatment 
 
Cataracts (which may be 
reversible on 
discontinuation of 
prednisone in children) 
 
Unknown Frequency 
and Timing:  
Fetal and teratogenic toxicities: Corticosteroids cross the placenta (prednisone has the 
poorest transport). In animal studies, large doses of cortisol administered early in pregnancy 
produced cleft palate, stillborn fetuses, and decreased fetal size. Chronic maternal ingestion 
during the first trimester has shown a 1% incidence of cleft palate in humans. Prednisone is 
excreted into breast milk in humans; however, several studies suggest that amounts excreted 
in breast milk are negligible with prednisone doses ≤ 20 mg/day.  
1 Mainly reported in pediatric patients with ALL.  Howard SC et al.  Urolithiasis in pediatric patients with acute lymphoblastic 
leukemia. Leukemia 2003; 17: 541-6. 
(L) Toxicity may also occur later. 
 
Formulation and Stability: 
Available in 1 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, and 50 mg tablets. Also available as a solution in 
1 mg/1 mL or 5 mg/mL concentrations. Inactive ingredients vary depending on manufacturer but 
tablet formulations may include: calcium or magnesium stearate, corn starch, lactose, erythrosine 
sodium, mineral oil, sorbic acid, sucrose, talc and various dyes. The solution may include: 5-30% 
alcohol, fructose, sucrose, saccharin, and sorbitol. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
Supplier: Commercially available from various sources. See package insert for further 
information.  
 
6.13 
THIOGUANINE (6-TG, 6-thioguanine, 2-amino-1, 7-dihydro-6H-purine-6-thione, WR-1141, 
Tabloid®, Lanvis®) NSC #752 
(10/28/12) 
Source and Pharmacology: Thioguanine is a purine analogue of the nucleic acid guanine with the 
substitution of a thiol group in place of the hydroxyl group on guanine. The main intracellular 
pathway for 6-TG activation is catalyzed by the enzyme hypoxanthine-guanine phosphoribosyl 
transferase (HGPRT) which catalyzes the conversion of 6-TG to the active nucleotide, 6-


 
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thioguanylic acid. The monophosphate nucleotide form of 6-TG inhibits de novo purine synthesis 
and purine interconversion reactions, whereas the nucleotide triphosphate metabolite is 
incorporated directly into nucleic acids. Incorporation of fraudulent nucleotides into DNA 
interferes with DNA replication and results in the formation of DNA strand breaks. The net 
consequence of its action is a sequential blockade of the synthesis and 
utilization of the purine nucleotides. The relative contribution of each of these 
actions to the mechanism of cytotoxicity of 6-TG is unclear. The absorption of an oral 
dose of 6-TG is incomplete and variable, averaging approximately 30% of the 
administered dose (range: 14% to 46%). 
 
Thioguanine undergoes deamination by the enzyme guanine deaminase resulting in 6-
thioxanthene, which is then oxidized by xanthine oxidase to 6-thiouric acid. In contrast to 
mercaptopurine, 6-TG is not a direct substrate for xanthine oxidase. Because the inhibition of 
xanthine oxidase results in the accumulation of 6-thioxanthene, an inactive metabolite, 
adjustments in 6-TG dosage are not required for patients receiving allopurinol. Since TPMT, 6-
thiopurine methyltransferase, is one of the enzymes involved in the deactivation of 6-TG, those 
individuals who have an inherited deficiency of the enzyme may be unusually 
sensitive to the myelosuppressive effects of 6-TG and prone to developing 
rapid bone marrow suppression following the initiation of treatment. 
 
Peak levels occur 2 to 4 hours after oral administration with a median half-life is about 90 minutes 
(range: 25-240 minutes). Very little unchanged drug is excreted renally.  
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children out 
of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of receiving drug 
 
Anorexia, nausea, vomiting, 
diarrhea, malaise 
Urticaria, rash, hyperuricemia 
Prompt: 
Within 2-3 weeks, prior to next 
course 
Myelosuppression 
 
Toxic hepatitis (L), increased 
SGOT (AST)/SGPT (ALT), 
ataxia, mucositis 
Delayed: 
Anytime later during therapy 
 
 
Hepatic fibrosis(L), sinusoidal 
obstruction syndrome (SOS, 
formerly VOD) (L), 
hyperbilirubinemia 
Unknown Frequency and 
Timing:   
Fetal toxicities and teratogenic effects of thioguanine have been noted in animals.  It is 
unknown whether the drug is excreted in breast milk. 
(L) Toxicity may also occur later. 
 
Formulation and Stability:  
Each greenish-yellow, scored tablet contains 40 mg thioguanine. Store at 15°-25°C (59°-77°F) in 
a dry place. 
 
For patients unable to swallow tablets, a 20 mg/mL oral suspension may be compounded. Crush 
fifteen (n=15) 40 mg tablets in a mortar and reduce to a fine powder. Add 10 mL methylcellulose 
1% in incremental proportions and mix to a uniform paste. Transfer to a graduated cylinder, rinse 
mortar with simple syrup, and add quantity of simple syrup sufficient to make 30 mL. Dispense 


 
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in an amber glass bottle and label "shake well" and "refrigerate". If methylcellulose is not 
available, substitute 15 mL of Ora-Plus in place of the methylcellulose and qs with Ora-Sweet (in 
place of simple syrup) to a final volume of 30 mL. Both preparations are stable for 63 days at 
19°C – 23°C. (Aliabadi HM, Romanick M, Somayah V, et al. Stability of compounded 
thioguanine oral suspensions. Am J Health Syst Pharm 2011;68:1278. Dressman JB, Poust RI. 
Stability of Allopurinol and Five Antineoplastics in Suspension. Am J Hosp Pharm 
1983;40(4):616-8.) 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
Administer on an empty stomach, preferably at bedtime. 
Substantial dosage reductions may be required in patients with an inherited deficiency of the 
enzyme thiopurine methyltransferase (TPMT) due to accumulation of active thioguanine 
metabolites resulting in a higher incidence of myelosuppression. 
 
Supplier: Commercially available. See package insert for more detailed information.  
 
6.14 
VINCRISTINE SULFATE 
(8/16/12) 
(Oncovin®, VCR, LCR) NSC #67574 
Source and Pharmacology: Vincristine is an alkaloid isolated from Vinca rosea Linn 
(periwinkle). It binds to tubulin, disrupting microtubules and inducing metaphase arrest. Its serum 
decay pattern is triphasic. The initial, middle, and terminal half-lives are 5 minutes, 2.3 hours, 
and 85 hours respectively; however, the range of the terminal half-life in humans is from 19 to 
155 hours. The liver is the major excretory organ in humans and animals; about 80% of an 
injected dose of vincristine sulfate appears in the feces and 10% to 20% can be found in the 
urine. The p450 cytochrome involved with vincristine metabolism is CYP3A4. Within 15 to 30 
minutes after injection, over 90% of the drug is distributed from the blood into tissue, where it 
remains tightly, but not irreversibly bound. It is excreted in the bile and feces. There is poor CSF 
penetration. 
 
Toxicity: 
 
Common 
Happens to 21-100 children out 
of every 100 
Occasional 
Happens to 5-20 children out of 
every 100 
Rare 
Happens to < 5 children out of every 
100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Jaw pain, headache 
Extravasation (rare) but if occurs = 
local ulceration, shortness of breath and 
bronchospasm 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Alopecia, constipation 
Weakness, abdominal pain, mild 
brief myelosuppression 
(leukopenia, thrombocytopenia, 
anemia) 
Paralytic ileus, ptosis, diplopia, night 
blindness, hoarseness, vocal cord 
paralysis, SIADH, seizure, defective 
sweating 
Delayed: 
Any time later 
during therapy 
Loss of deep tendon reflexes 
Peripheral paresthesias  
including numbness, tingling and 
pain; clumsiness; wrist drop, foot 
drop, abnormal gait 
Difficulty walking or inability to walk; 
sinusoidal obstruction syndrome (SOS, 
formerly VOD) (in combination); 
blindness, optic atrophy; urinary tract 
disorders (including bladder atony, 
dysuria, polyuria, nocturia, and urinary 
retention);  autonomic neuropathy with 
postural hypotension; 8th cranial nerve 
damage with dizziness, nystagmus, 
vertigo and hearing loss 


 
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Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of vincristine (either alone or in combination with other antineoplastic 
agents) have been noted in humans. The toxicities include: chromosome abnormalities, malformation, 
pancytopenia, and low birth weight. It is unknown whether the drug is excreted in breast milk. 
 
Formulation and Stability: 
Vincristine is supplied in 1 mL and 2 mL vials in which each mL contains vincristine sulfate 1 
mg (1.08 µmol), mannitol 100 mg; SWFI; acetic acid and sodium acetate are added for pH 
control. The pH of vincristine sulfate injection, USP ranges from 3.5 to 5.5. This product is a 
sterile, preservative free solution. Store refrigerated at 2°-8°C or 36°-46°F. Protect from light and 
retain in carton until time of use. 
 
Do not mix with any IV solutions other than those containing dextrose or saline. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of protocol. 
 
The World Health Organization, the Institute of Safe Medicine Practices (United States) and the 
Safety and Quality Council (Australia) all support the use of minibag rather than syringe for the 
infusion of vincristine. The delivery of vincristine via either IV slow push or minibag is 
acceptable for COG protocols. Vincristine should NOT be delivered to the patient at the same 
time with any medications intended for central nervous system administration. Vincristine is 
fatal if given intrathecally.  
 
Injection of vincristine sulfate should be accomplished as per institutional policy. Vincristine 
sulfate must be administered via an intact, free-flowing intravenous needle or catheter. Care 
should be taken to ensure that the needle or catheter is securely within the vein to avoid 
extravasation during administration. The solution may be injected either directly into a vein or 
into the tubing of a running intravenous infusion. 
 
Special precautions: FOR INTRAVENOUS USE ONLY. 
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing 
the statement “Do not remove covering until moment of injection. For intravenous use only - 
Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and vinBLAStine. 
VinCRIStine VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate 
liposomal injection, VSLI, Marqibo®). Use conventional vincristine only; the conventional and 
liposomal formulations are NOT interchangeable. 
 
Supplier: Commercially available from various manufacturers. See package insert for more 
detailed information. 


 
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7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
 
7.1 
Required & Optional Clinical, Laboratory and Disease Evaluations for T-ALL 
STUDIES**  
Induction 
Consolidation3 
Arms A and C 
Consolidation3 
Arms B and D 
Interim Maintenance* 
Delayed 
Intensification 
Maintenance 
Hx/PE 
Weekly 
As shown 
As shown 
As shown 
As shown 
Every 4 weeks 
BSA 
Start of Course 
Start of Course 
Start of Course 
Start of Course 
Day 1, 29 
Every 12 weeks 
CBC/diff/plts 
Weekly 
Weekly 
Weekly 
Prior to each MTX dose 
Weekly 
Every 4 weeks 
MTX Levels 
 
 
 
Arm C (HDMTX) & 
Arm D (HDMTX + Nel) ONLY4 
 
 
Peripheral Blood for Host 
Polymorphisms 
Day 295 
 
 
 
 
 
Bone Marrow 
Cytomorphology 
Baseline and 
Days 8, 151, 29 
Day 29 & End of 
Course for HR 
patients 
Day 43 & End of 
Course for HR & IF 
patients 
 
 
 
Bone Marrow MRD 
Assessment 
Day 151,2 & 
292 
Day 292 & End of 
Course2 for HR 
patients 
Day 432 & End of 
Course2 for HR & IF 
patients 
 
 
 
Peripheral Blood MRD 
Assessment# 
Day 82 & 292 
Day 292 & End of 
Course2 for HR 
patients 
Day 432 & End of 
Course2 for HR & IF 
patients 
 
 
 
CSF cell count & cytospin 
With each IT  
With each IT 
With each IT 
With each IT 
With each IT 
With each IT 
Bilirubin, ALT, creatinine, 
BUN 
Baseline 
Start of Course 
Start of Course 
Prior to each MTX dose 
Day 1, 29 
Prior to each 12 wk 
cycle 
TPMT testing 
Baseline (see 
Section 5.9) 
 
 
 
 
 
Varicella titer 
Baseline 
 
 
 
 
 
1 If Day 8 BMA was M2 or M3 obtain additional bone marrow for morphology & MRD on Day 15. 
2 Send Induction Day 15 BM and Day 8 PB samples to ALL Flow Cytometry Reference Lab ONLY for MRD; send Induction Day 29 BM/PB, Consolidation Day 29 BM/PB 
(Arms A/C) or Day 43 BM/PB (Arms B/D) and End of Course samples to ALL Flow Cytometry Reference Lab for MRD (see AALL08B1 for shipping requirements and 
addresses) for patients that are High Risk or Induction Failures. 
3 During Consolidation obtain BM for morphology at Day 29 (Arms A/C) or Day 43 (Arms B/D) and End of Course for patients that are High Risk or Induction Failures.  Patients 
not in remission at end-Consolidation are off protocol therapy. 
4 See HD MTX Infusion Guidelines Section 4.6.1. 
5 Obtain if patient consented on AALL08B1: send to ALL Molecular Reference Lab for host polymorphisms (see AALL08B1 for shipping requirements) 
* See Section 5.8.1 regarding MTX levels for HD MTX (Arms C and D only) 
# Send to ALL Flow Cytometry Reference Lab ONLY for MRD 
**If patient(s) develop myalgia or myoglobinuria, they should be evaluated for the potential of having rhabdomyolysis, as described in Section 5.2. 
 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are based on schedules derived from the experimental design or on established standards 
of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable per COG administrative Policy 5.14 (except where explicitly prohibited within the protocol). 


 
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7.2 
Required & Optional Clinical, Laboratory and Disease Evaluations for T-NHL 
 
STUDIES**  
Induction 
Consolidation3 
Arm A  
Consolidation3 
Arm B  
Interim 
Maintenance 
Delayed 
Intensification 
Maintenance 
Relapse 
Hx/PE 
Weekly 
As shown 
As shown 
As shown 
As shown 
Every 4 weeks 
 
BSA 
Start of Course 
Start of Course 
Start of Course 
Start of Course 
Day 1, 29 
Every 12 weeks 
 
CBC/diff/plts 
Weekly 
Weekly 
Weekly 
Prior to each 
MTX dose 
Weekly 
Every 4 weeks 
 
Bone Marrow Cytomorphology 
Baseline &  
Day 291 
End of Course if 
positive at diagnosis 
End of Course if 
positive at diagnosis 
 
 
 
At relapse 
Bone Marrow MRD 
Assessment 
Baseline2  
 
 
 
 
 
 
CSF cell count & cytospin 
With each IT  
With each IT 
With each IT 
With each IT 
With each IT 
With each IT 
 
Bilirubin, ALT creatinine, 
BUN 
Baseline 
Start of Course 
Start of Course 
Prior to each 
MTX dose 
Day 1, 29 
Prior to each  
12-week cycle 
 
TPMT testing 
Baseline  
(see Section 5.9) 
 
 
 
 
 
 
Varicella titer 
Baseline 
 
 
 
 
 
 
Chest CT/Chest x-ray3 
Baseline3 &  
end-Induction3 
End of Course3 
End of Course3 
 
 
Completion of 
Therapy3 
 
Abdomen/Pelvis CT 
Baseline &  
end-Induction4 
End of Course4 
End of Course4 
 
 
Completion of 
Therapy4 
 
Bone scan5 
Baseline & 
end-Induction 
End of Course 
End of Course 
 
 
Completion of 
Therapy 
 
Diagnostic Biopsy/Cytology6 
Baseline7 
 
 
 
 
 
At relapse7 
Optional Banking/Biology6 
Baseline7 
 
 
 
 
 
At relapse7 
 
1 Obtain in T-NHL beyond Day 1 only if morphologically positive at diagnosis. 
2 Send baseline BM sample to ALL Flow Cytometry Reference Lab ONLY for MRD; see Section 16 for shipping requirements and address. 
3 Obtain chest CT for all patients at Baseline and at end-Induction. The baseline chest CT may be delayed until the patient is stable. If patient has CR at end-
Induction, no subsequent chest CT is required but a chest x-ray will be performed at end-Consolidation and end of therapy. If patient does not have CR at end-
Induction, a chest CT will be performed at end-Consolidation. If patient has CR at end-Consolidation, a chest x-ray will be performed at end of therapy. If 
patient does not have CR at end-Consolidation, a chest CT will be performed at end of therapy. Note: Patients who have NR and have not achieved at least a 
PR at end-Consolidation are off protocol therapy. 
4 Many patients will have no disease below the diaphragm; if the abdominal and pelvic CTs at Baseline are negative, no repeat scans are required. 
5 Bone scan only if patient has bone symptoms; follow-up exams only if baseline demonstrates disease. 
6 See Sections 15 and 16 for guidelines regarding tissue acquisition, processing and shipping. NOTE: This study includes retrospective central pathology review. 
7 Obtain extra tissue samples in patients who consent to specimen banking; see Sections 15 & 16. 
**If patient(s) develop myalgia or myoglobinuria, they should be evaluated for the potential of having rhabdomyolysis, as described in Section 5.2. 
 
 


 
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7.3 
Targeted Toxicities 
Neurological adverse events for Nelarabine are: ataxia (incoordination), confusion, depressed 
level of consciousness, dizziness/lightheadedness, memory loss, mood alternation/anxiety, 
agitation, 
encephalopathy, 
disequilibrium, 
Guillain-Barré-like 
syndrome, 
neuropathy 
motor/sensory, seizures, speech impairment (slurred speech), tremor or vertigo and visual 
disturbances. 
 
Non-neurological toxicities also described to occur with Nelarabine include the following (by 
system): 
cardiovascular, 
constitutional, 
gastroenterological, 
hemorrhage, 
metabolic 
(pancreatitis), ocular/visual and pain.  Any Grade 3-5 non-hematologic toxicities affecting these 
systems would also require reporting. 
 
Collection of data for targeted toxicities may include additional information to that obtained through the 
usual CTCAE information that will be routinely collected (see Section 12.0). Expedited reporting rules 
apply to patients experiencing any Grade 3, Grade 4 or Grade 5 neurological toxicities after receiving 
Nelarabine.  
 
If patient(s) develop myalgia or myoglobinuria, they should be evaluated for rhabdomyolysis, as 
described in Section 5.2. 
  
7.4 
Studies to be Obtained After Stopping Therapy 
Note: Refer to COG’s Long term follow-up Guidelines for monitoring cardiac function. Found 
at: http://www.survivorshipguidelines.org/ 
 
1st year  
 
PE, CBC/diff/plts q month, ALT q 2 months until normal 
BMA, CSF, as clinically indicated 
 
2nd year 
 
PE, CBC/diff/plts q 2 months 
 
3rd year 
 
PE, CBC/diff/plts q 3 months 
 
4th year 
PE, CBC/diff/plts q 6 months 
 
5th year 
PE, CBC/diff/plts q 6-12 months.  
 
7.5 
At Relapse 
T-ALL patients who relapse should have samples of blood and bone marrow sent to the 
appropriate Molecular Reference Laboratory (see AALL08B1 for details).   
T-NHL patients: see Section 7.2 for instructions. 
 
 
8.0 
SUPPORTIVE CARE GUIDELINES 
 
Aggressive supportive care improves outcome, particularly in High Risk patient populations 
receiving very intensive therapy as incorporated in this trial. The following guidelines are intended 
to give general direction for optimal patient care and to encourage uniformity in the treatment of this 
study population. Investigators are requested to report unexpected or unusually severe 
complications to Study Chair. Please also see the supportive care manual developed by CCG/POG 
(Supportive Care of Children with Cancer, A Altman ed, 3rd ed).   


 
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8.1 
General Guidelines 
Patients are recommended to have central venous access with either a totally implantable devide 
(port-a-cath) or a tunneled catheter (Broviac, Groshong or Hickman). The risks and benefits 
associated with these devices should be discussed with the patient by members of the oncology 
and surgical care teams. The goal is to select a venous access catheter that will have the least 
likelihood of developing catheter-related complications for each individual patient. 
 
8.1.1 
Blood Components 
 
Blood products should be irradiated following current FDA guidelines found at: 
http://www.fda.gov/cber/gdlns/gamma.htm  
 
Investigators in Canadian institutions need to follow the CSA standards for Blood and Blood 
Components CAN/CSA-Z902-04 issued in March 2004 and available at: http://www.shopcsa.ca.  
 
Red blood cells (RBCs) 
Transfusion with RBCs is indicated to correct severe or symptomatic anemia or acute blood loss. 
In the setting of extreme hyperleukocytosis investigators should be mindful that PRBC’s may 
contribute to hyperviscosity. 
 
Platelets 
Transfusion with platelets is indicated to correct bleeding manifestations and may be indicated 
for severe thrombocytopenia without bleeding particularly in the setting of an invasive 
procedure. 
 
8.1.2 
Infection Prophylaxis 
 
Pneumocystis carinii 
All patients should receive trimethoprim/sulfamethoxazole (TMP/SMX) at a dose of TMP 5 
mg/kg/day divided bid three sequential days per week. For patient’s allergic to or experiencing 
excessive myelosuppression with TMP/SMX, alternative prophylaxis with dapsone (1-2 
mg/kg/day, maximum dose 100 mg/day), aerosolized pentamidine (300 mg/q month ≥ 5 years of 
age), or atovaquone (30 mg/kg/day if < 3 mo. or > 2 years, 45 mg/kg/day if between 3 mo. & 2 
years) may be considered. 
 
Varicella Vaccine 
May be given to the siblings of patients in remission and stable at the physician’s discretion. 
Administration to the non-immune patients is not recommended. 
 
Gamma globulin 
If clinically indicated, IgG levels may be monitored throughout treatment. If the IgG level falls 
below age-determined normal levels, IVIG at 400 mg/kg may be administered at the discretion 
of the investigator. Note of IVIG administration should be made on data form. 
 
Antifungals 


 
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Azole antifungal agents (i.e. fluconazole, itraconazole, voriconazole) given concurrently with 
vincristine may increase the risk of neurotoxicity. Investigator caution is advised if azole 
antifungals are used.   
 
8.1.3 
Treatment of Established or Presumed Infections 
 
Fever with Neutropenia 
For patients with ANC < 500/µL and temperature between 38.0°C and 38.5°C twice in 12 hours, 
or ≥ 38.5°C, empiric parenteral broad spectrum antibiotics should be instituted after obtaining 
appropriate cultures. The risk of sepsis is higher during Induction and while the peripheral 
neutrophil count is falling rather than rising. The specific choice of antibiotics to be used in 
empiric treatment of febrile neutropenia is dependent on each of your institution’s experience 
regarding the type of infecting organisms and their antibiotioc sensitivity patterns. Duration of 
therapy should be determined by site of infection (if identified), culture results, and response to 
treatment. If fever and neutropenia persist, systemic antifungal therapy with amphotericin B 
should be initiated after 3-5 days. When severe mucositis or a sepsis syndrome is present in 
patients with their initial febrile neutropenia, or a patient has a history of prior alpha hemolytic 
sepsis, consider inclusion of Vancomycin in the empiric antibiotic regimen. 
 
Primary Varicella Infection (Chickenpox) 
Patients should be treated promptly with acyclovir 1500 mg/m²/day intravenously divided q 8 
hours, and monitored closely for the development of invasive systemic disease. 
 
Empiric Management of Pulmonary Infiltrates 
Pulmonary infiltrates should be evaluated in the context of the patients clinical and laboratory 
profile. If the patient is not neutropenic, and the pulmonary lesions on CT scan are not 
particularly suggestive of a mold infection (Aspergillus, mucor), consider using broad spectrum 
antibiotics. If the patient develops progressively worsening clinical or laboratory features then 
more aggressive diagnostic measures should be undertaken. Pulmonary infiltrates should then be 
evaluated with bronchoscopy and biopsy, lavage or open lung biopsy. If a procedure cannot be 
tolerated, begin empiric treatment with amphotericin B given89 the high likelihood of fungal 
disease during Induction. It is advisable to seek an infectious disease consult under these 
circumstances. Empiric coverage should include treatment for gram-negative and positive 
bacteria, 
Legionella 
(erythromycin), 
Pneumocystis 
(TMP/SMX), 
and 
fungi 
(amphotericin/ambesome) pending culture results. If fungal pulmonary disease is documented, 
surveillance radiographic imaging studies of the sinuses, abdomen/pelvis and brain are indicated. 
Surgical excision of pulmonary lesions should be considered at the discretion of the treating 
physician. Treatment of fungal infections with amphotericin B and/or other antifungal agents 
will be at the discretion of the treating physician. Azole antifungal agents (i.e. fluconazole, 
itraconazole, voriconazole) given concurrently with vincristine may INCREASE the risk of 
neurotoxicity and myelosuppression.88,89 Investigator caution is advised if azole antifungals 
are used. 
 
Management of Mucositis/Perirectal Cellulitis 
Mucositis should be managed with IV hydration and hyperalimentation if indicated, effective 
analgesia, broad-spectrum gram-positive and gram-negative antibiotic therapy and empiric 
antiviral and antifungal therapy as indicated. Management of perirectal cellulitis should include 


 
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broad-spectrum antibiotic therapy with dual gram-negative coverage as well as anaerobic 
coverage (i.e. ceftazidime + aminoglycoside + metronidazole; or piperacillin-tazobactam + 
aminoglycoside), Sitz baths, a strong barrier technique and effective analgesia. 
 
8.1.4 
Antiemetic Protection 
Antiemetics should be given as needed. The routine use of steroids is discouraged, including 
dexamethasone, but may be appropriate in select patients with demonstrated intolerance to 
higher-dose chemotherapeutic agents. 
 
8.1.5 
Use of Filgrastim 
The routine use of filgrastim is not generally recommended, but may be used at the discretion of 
the investigator in situations of serious infection with neutropenia. 
 
8.2 
Guidelines for Induction 
 
8.2.1 
Acute Tumor Lysis Syndrome 
The risk for serious acute tumor lysis syndrome (TLS) is usually restricted to the first 72 hrs after 
initiation of therapy; however, it may spontaneously occur prior to treatment. To manage the 
metabolic derangements caused by hyperuricemia, hyperkalemia, hyperphosphatemia and 
hypocalcemia, the following steps should be intiated: 
1. Begin allopurinol at a dose of 300 mg/m²/day in 3 divided doses and continue until 
peripheral blasts and extramedullary disease are reduced. In some situations it may be 
appropriate to use Rasburicase.  
2. Hydrate at 2400-3000 mL/m²/day to maintain urine output > 100 mL/m²/hour until 
peripheral blasts and extramedullary disease are reduced. 
3. Alkalinize urine with NaHCO3 20-40 mEq/L IV fluid to maintain urine pH between 6.5 and 
7.5. Alkalinization is not recommended when treating with Rasburicase. 
4. If the patient has oliguria or severe renal dysfunction, consider the use of Rasburicase at 
0.15 to 0.2 mg/kg/dose and obtaining a nephrology consult.  
5. While patients are on steroid therapy they should receive an H2 blocker. 
 
Refer also to the discussion of TLS in the Supportive Care Manual (Supportive Care of Children 
with Cancer, ed A Altman, 3rd edition, 2004) 
 
8.2.2 
Induction – Infectious Complications 
Since steroid-containing 4 drug ALL inductions may be associated with higher rates of toxicity, 
investigators are cautioned to pay close attention to a number of factors during the early phases of 
treatment. Patients may experience profound myelosuppression and immune suppression during this 
time. Since prednisone may mask fever, as well as other components of the inflammatory response 
sepsis during Induction, the warning signs of septic shock may be associated with very mild and 
subtle symptoms. Caregivers must also be made aware that patients may experience very rapid 
clinical deterioration. This suggests the need for a supportive care network that can recognize and 
respond to sudden changes in a patient’s condition. In addition it should be noted that several 
serious toxic events have had an intestinal component. Patients with subtle GI symptoms should be 
monitored very closely. 
 


 
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In this population with High Risk ALL, rapidly assess patients clinically and by appropriate 
laboratory parameters for evidence of symptomatic hyperleukocytosis, tumor lysis syndrome, and 
coagulopathy. Patients at greatest risk will be those with WBC > 100,000/L and extramedullary 
disease. Suggested initial studies to be obtained prior to initiating antileukemia therapy include 
complete blood count (CBC), prothrombin and activated partial thromboplastin times, fibrinogen, 
D-dimer, and serum electrolytes, including creatinine, BUN, uric acid, phosphorous, and calcium. 
Continued monitoring of these studies should be carried out at suitable intervals until abnormalities 
have resolved or the risk has abated. 
 
 
9.0 
CRITE RIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITE RIA 
 
9.1 
Criteria for Removal From Protocol Therapy 
 
a) 
T-ALL patients found to meet criteria for the AALL0622 Ph+ ALL study (or successor) 
b) 
T-NHL patients found to meet criteria for Ph+ T-NHL 
c) 
Recurrent leukemia following complete remission. 
d) 
For T-NHL: Progressive lymphoma 
e) 
For T-ALL: Induction failure patients may be removed from therapy following 
Consolidation at investigator discretion 
f) 
For T-NHL: NR at end of Consolidation therapy (see Section 11.3) 
g) 
Refusal of further protocol therapy by patient/parent/guardian. 
h) 
Completion of planned therapy. 
i) 
Physician determines it is in patient’s best interest. 
j) 
Development of a second malignancy. 
k) 
Adverse Event/Side Effects/Complications 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study 
(see below).  Follow-up data will be required unless consent was withdrawn. 
 
9.2 
Off Study Criteria 
 
a) 
Death. 
b) 
Lost to follow-up. 
c) 
Enrollment onto another COG study with tumor therapeutic intent (eg, at recurrence). 
d) 
Withdrawal of consent for any further data submission. 
e) 
Tenth anniversary of the date the patient was enrolled on this study. 
 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
10.1 
Statistical Design (Amendment #5) 
The anticipated number of newly diagnosed T-lineage ALL patients is estimated to be 230/year 
(~19/month). About 25% and 75% of T-lineage patients would be in the age/WBC defined NCI criteria 
for standard risk (age 1-9 and WBC < 50,000/µL) and high risk (age 10+ or WBC > 50,000/µL) groups, 
respectively. 


 
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The long term EFS result in the overall T-lineage group in recent COG studies is approximately 80%, 
with the vast majority of EFS events occurring in the first three years. Unlike the pattern of outcome seen 
for B-precursor ALL, it is rare to see events occur beyond 4 years among patients with T-ALL. This 
outcome can be modeled reasonably well by a linear decreasing hazard rate with no appreciable risk of 
failure after completion of year 4. 
 
For this study, definitions of T-lineage risk groups have been chosen to conduct the study in a manner that 
provides appropriate treatment strategies for these different groups. The Low Risk subset of T-lineage is 
defined for this study as those who are age 1-9.99 with WBC ≤ 50,000/µL (i.e., NCI standard risk), but 
who in addition have CNS1 status at diagnosis and have no testicular leukemia at diagnosis, who have a 
morphologic M1 marrow by Day 14, and who have MRD < 0.1% at end of Induction. We estimate that 
this will result in approximately 18% of the overall T-lineage group being in the “Low Risk” group for 
this study. The “High Risk” subset for this study will be those patients with either M2 morphologic 
marrow status or MRD > 1% at the end of Induction. This group is estimated to be approximately 20% of 
the overall T-lineage group, leaving 62% in the “Intermediate Risk” subset. 
 
European data from the BFM group have suggested a poor outcome for T-lineage patients with MRD 
levels > 1%. Data from COG studies on MRD status suggest that about 15%-20% of T-lineage patients 
will have MRD > 1% at end of Induction. However, insufficient follow-up is currently available to 
determine their ultimate EFS outcome. Data from COG studies suggest that most traditional prognostic 
factors in B-precursor ALL have minimal effect on outcome for T-lineage ALL. Patients in recent COG 
studies with M2 marrow status at the end of Induction had a 4 year EFS of 56%. It is expected there will 
be substantial overlap in the two criteria for High Risk (HR) status with many patients who are in both the 
MRD > 1% and end Induction marrow status of M2. We estimate that approximately 20% of patients will 
be High Risk by these combined criteria. We will assume that the 4 year EFS outcome for the High Risk 
subset is 56%. We also assume that the 4 year EFS for the Low Risk (LR) and Intermediate Risk (IR) 
subsets will be 92% and 84%, respectively. These assumptions would give an EFS of 80% for the overall 
T-lineage population which is reasonably consistent with the observed results in recent COG studies. 
Since randomization in this study will occur after successful completion of Induction (about 2.5% are 
estimated to have either Induction death or M3 non-response), the EFS post-randomization will be a bit 
higher. The assumed EFS post-randomization for the 3 risk groups are 93%, 86% and 60% - resulting in 
an overall post-randomization 4 year EFS of approximately 82%. 
 
The basic therapy backbone for all the patients in this study will use the ABFM regimen. The 
initial design at the start of this study (safety phase) will involve a randomization at the 
completion of Induction for all patients achieving remission to two regimens that will differ only 
in the dose and schedule of MTX delivery: either HDMTX or CMTX. Children who are in the 
LR subset will be excluded from CNS irradiation and will be non-randomly assigned to regimens 
without Nelarabine throughout all stages of this study. IR patients will receive prophylactic CNS 
irradiation, but they will not receive Nelarabine during the safety phase of the study. During the 
safety phase, HR risk patients will be randomized to receive Nelarabine or no Nelarabine in 
addition to randomization to receive HDMTX or CMTX. Once sufficient accrual and follow-up 
is available (described in following section), an assessment of the toxicity profile for Nelarabine 
will be performed. If Nelarabine is found to be safe in the context of this treatment backbone and 
the MTX regimens, the initial study randomization to HDMTX vs. CMTX would be modified to 
a larger 2x2 randomization in an expanded efficacy phase which includes the IR risk patients. 
 
  
  
 
 
                 Safety Phase 
 
                 Efficacy Phase 


 
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T-ALL Risk  
ABFM 
MTX 
question 
Nelarabin
e 
question 
CNS 
XRT 
MTX 
question 
Nelarabin
e 
question 
CNS 
XRT 
Low Risk  
yes 
Yes 
No 
No 
yes 
no 
no 
Intermediate 
Risk 
yes 
Yes 
No 
Yes 
yes 
yes 
yes 
High Risk 
yes 
Yes 
Yes 
Yes 
yes 
yes 
yes 
 
T-cell Lymphoblastic Lymphoma Patients 
The T-NHL patients will be stratified separately on this study, and will also be analyzed 
separately without impacting the analyses for the T-ALL patients. The number of T-NHL 
patients to be accrued during the Efficacy Phase of AALL0434 is projected to be around 68/year. 
Adjusting for loss to randomization, about 35 patients/year will be classified as High Risk at the 
end of Induction and will be randomized to CMTX ± Nelarabine. Those classified as Standard 
Risk (17 patients/year) will be assigned to Arm A (CMTX, no Nelarabine). About 2 patients/year 
will be classified as Induction failures (no PR, CR or CRu by Day 29 of Induction) and will be 
assigned to Arm B (CMTX + Nelarabine). Over a 4-year accrual period, approximately 140 High 
Risk patients will be accrued. There will be insufficient power for any formal comparison of 
outcomes between randomized regimens for these patients, but informal comparisons will be 
made. Outcome analyses for the 68 Standard Risk and 8 Induction Failure patients will 
essentially be descriptive due to small numbers. 
 
10.1.1 Study Re-design - (Amendment #9) 
Overall accrual rate (as of 09/30/2011) for the T-ALL patients has been around 256 per year over 
the past year compared to the projected 230/year in the protocol; and the actual loss to post-
Induction randomization/assignment is around 20% instead of the estimated 10%. In addition, 
the distribution of post-Induction risk assignments - Low risk (LR), Intermediate risk (IR), and 
High risk (HR) is currently 9%, 71%, and 20% respectively, differing from what was projected 
above (18%, 62%, and 20% respectively). Due to this, the annual accrual rate to the MTX and 
nelarabine randomizations are currently the same – around 175 patients/year (compared to the 
prior estimates of 201 and 165 patients, respectively). 
 
Per the current design in the protocol, the MTX question is to accrue 1206 patients to ensure that 
we get the required 615 patients for the nelarabine randomization during that accrual duration. 
This results in the MTX randomization being well over-powered at 91.6% power. This 
amendment modifies the statistical considerations for the 2 randomizations as detailed below in 
Section 10.3, in order to cater to the change in distribution of risk groups. The baseline event free 
survival (EFS) rates and detectable improvement in EFS remain the same as was originally 
specified. Both randomizations will have the same efficacy and futility monitoring procedures as 
was previously specified, using the updated expected total events for each.  
 
The annual accrual rate for T-NHL patients has also been higher than expected and is around 68 
patients per year. With the increased accrual rates for T-ALL and T-NHL, the target accrual on 
this study will be 1707, in order accrual of the required eligible, evaluable patients for study 
objectives.  


 
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10.1.1.1 Study re-design (Amendment #11) 
On April 17th 2015, following review of a planned protocol specified interim monitoring, the Data Safety 
Monitoring Committee released the results of the randomized comparison of Capizzi versus High Dose 
Methotrexate (HDM) regimens on study. Per protocol specified interim monitoring 4-year disease-free 
survival rates (DFS) are 92.5% (SE 1.8%) for the CM regimen vs. 86.1% (SE 2.4%) for the HDM regimen 
(p = 0.0173). Although the efficacy monitoring boundary (was not crossed (the p-value is equal to the 
boundary), the conditional probability of proving HDMTX is superior to CMTX given the current data 
(12/31/2015 data freeze), was very small (<0.0001). The baseline outcomes for patients on this study are 
higher than projected. Hence the expected total number of events for both the MTX randomization and the 
Nelarabine randomization are lower than projected in the original study design. This amendment is to 
update the study design to reflect the lower expected event horizon for the Nelarabine randomization (which 
would impact the interim monitoring for outcomes. The details of the redesign done by an independent 
statistician who does not have knowledge of the interim results for the nelarabine randomization and was 
provided with the updated event rate for the control arm, are provided in section 10.3.2 below. 
 
 
10.1.2 Amended study accrual (Amendment #10) 
The total target accrual for the study has been increased from 1707 to 1900 patients. This 
increase is necessary in order to get the required eligible, evaluable patients (as given in Section 
10.3.1 below) for the Methotrexate and Nelarabine post-induction randomizations. The reasons 
for this increase in projected total accrual, are: a) The projected accrual rates for T-ALL and T-
NHL on study were 256 and 68 patients per year, respectively while the actual rates (as of 
9/9/2013) are 247 and 86 patients per year. The T-NHL patients do not participate in the two 
randomized study questions, but their increased accrual rate has taken up accrual slots that would 
have been taken otherwise by T-ALL patients who would likely get randomized. b) The loss at 
the end of induction to the post-induction randomizations was higher (24%) than that projected 
(20%). c) The actual accrual rates for each of the randomizations are both around 
145 patients/year as opposed to the projected rates (175 pts/year). Based on data as of 9/9/2013, 
an additional 115 patients are needed for EACH of the post-induction randomizations. This 
translates to about 270 (200 T-ALLs, 70 T-NHLs) enrollments to the overall study (adjusting for 
losses end of induction and for the 30 patients currently on induction therapy yet to be risk 
assigned). As of 9/9/2013, 77 accrual slots were still available before current target accrual of 
1707 is met. Hence the required increase in target accrual is by 193 (270-77), to give a new 
target accrual of 1900. The study is projected to meet the new accrual target by September 2014. 
No changes are required to any of the statistical analyses plans and power calculations given in 
the following sections.  
 
10.2 
Nelarabine Toxicity Assessment and Duration of Safety and Efficacy Phases  
The initial assessment of Nelarabine toxicity will occur for the first 20 HR patients receiving 
Nelarabine with 10 in both the HDMTX and CMTX regimens. An adequate period of follow-up 
in these patients is necessary to judge the toxicity. The delivery of Nelarabine starts in the first 
week of the Consolidation phase (at 6 weeks from study entry) and the last dose will be given at 
week 60, which is early in Maintenance. During the evaluation period for the Safety Phase, HR 
patients will continue to randomize to all four treatment arms. This approach will allow us to 
gain further experience with Nelarabine in HR patients. We will evaluate the HR patients in the 
Safety Phase of the study at approximately 8 weeks following the week 36 dose of Nelarabine 


 
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(through week 43 in the Maintenance phase). The rationale for choosing this time-point is that it 
will allow patients to have resolved radiation-induced somnolence syndrome and other 
potentially confounding neurotoxicities. It has been our experience on AALL00P2 that 
Nelarabine toxicities occurred acutely after exposure and we do not anticipate significant 
additional Nelarabine toxicities occurring after the Week 43 observational time point. In 
addition, this will shorten the time interval for follow-up required before proceeding to the 
Efficacy Phase. Based on the anticipated annual accrual rate, we estimate that it will take about 
12 months to obtain this initial cohort of 20 HR patients randomized to Nelarabine. Then an 
additional 10 months after the last of this group is entered will be needed to reach the time in 
Maintenance with adequate follow-up for toxicity assessment. The HR patients receiving 
Nelarabine will be compared directly to their randomized HR controls who are not receiving 
Nelarabine with the comparison further stratified by the methotrexate regimen received. These 
toxicity analyses and any recommendations from the ALL Steering Committee regarding the 
opening of the Nelarabine randomization to the IR subset will be provided to the COG DSMC 
for their review and approval before any decision to open the randomization further. If results at 
this first toxicity comparison require additional patient entries for further assessment, the original 
randomization to Nelarabine will continue in just the HR patients. If this second stage of toxicity 
assessment is needed, it will take place at approximately one year after the initial assessment, at 
which time a decision to either open or not open the Nelarabine randomization to include the IR 
patients will occur. The total planned length of the safety phase HR randomization is intended to 
not exceed 3 years. HR T-ALL patients will continue to be randomized for the Nelarabine 
question throughout the safety phase. 
 
10.3 
Primary Treatment Comparisons and Statistical Power (Amendment #9)  
The primary endpoint for the study analyses and the endpoint used for the subsequent power 
calculations is event-free survival (EFS) following initial remission since randomization occurs 
after Induction. EFS events include any type of relapse, death in remission or second malignant 
neoplasm. Since CNS relapse has been an important event in many studies of T-lineage patients, 
that outcome will be a secondary endpoint which will be examined for various treatment regimen 
comparisons, and in the subset of patients who will not receive XRT CNS prophylaxis. “Intent-
to-treat” analyses (i.e. based on the regimen to which patients are initially randomized) will be 
the primary approach used to assess treatment efficacy. 
 
The following calculations allow for a 2.5% failure rate in Induction (the combined M3 non-
response rate and Induction death rate) and a 10% rate of randomization refusal. This provides 
201 patients per year (approximately 36 LR, 125 IR and 40 HR) who will be available for the 
MTX randomization after allowing for the attrition due to Induction failure and those who refuse 
randomization. The planned study accrual duration will be approximately 6 years providing a 
total of 1206 patients who will be randomized to HDMTX versus CMTX. The power calculation 
for this comparison is based on a 2-sided log rank test (alpha = 0.05) with the first analysis 
occurring when approximately 20% of the expected events from the projected EFS event horizon 
have occurred. Four subsequent analyses will occur at approximately 40%, 60%, 80% and 100% 
of the expected event total. A t2 spending function for the stopping boundary (with truncation at 
3 standard deviations) will be used to allocate greater importance to the later analyses. For the 
MTX comparison, the long term EFS baseline outcome in these patients is expected to be 82% at 
4 years. In this study, a clinically important difference is assumed to be an improvement to 89% 
EFS which represents a relative EFS event reduction of approximately 41% for the better 


 
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regimen (viz., relative hazard rate, RHR = 0.587). The event horizon is calculated using the 
previous EFS outcome assumptions and assuming an accrual of 6 years with a follow-up of 3 
years after the last patient is randomized. For this situation, one would expect a total of 174 EFS 
events which results in a cumulative power to detect a difference by the last analysis of 91.6%. 
The z-value upper and lower monitoring boundaries for the 5 looks at the data are ± 3, 2.744, 
2.477, 2.281, and 2.115. If a slightly smaller improvement to 88% EFS occurs (RHR = 0.644), 
the cumulative power to detect a difference by the last analysis would be 80.4%. 
 
Upon completion of the study, smaller differences in EFS outcome than those described above 
might occur. In that case, it would still be useful to identify which of the 2 methotrexate 
treatment approaches might be selected for use in future T-ALL studies. Part of this selection 
process would involve the overall comparison of toxicity and complications data for HDMTX 
and CMTX, but another part of the evaluation would relate to the final EFS results for the 
regimens. If the final EFS efficacy comparison described above does not achieve the 
conventional significance level used (overall alpha = 0.05), the regimens would also be 
compared using a more liberal significance criterion (p ≤ 0.20) to choose which regimen is 
better. With this criterion and the sample size for the methotrexate randomization, true EFS 
differences in the neighborhood of 4% would permit identification of the better regimen with 
high probability. For example, if one of the methotrexate regimens has an EFS of 82% and the 
other has an EFS of 86%, the probability that the better regimen is selected would be .852 and 
the probability that the poorer regimen would be selected is only 0.003 (with a .145 probability 
that no regimen would be selected based on the criterion being used). The table below (Table 1) 
shows that the selection rates remain reasonably stable for this 4% EFS difference if the baseline 
outcome departs somewhat from the assumed 82%. If a slightly smaller EFS difference of 3% 
occurs (with one regimen at 82% and the other at 85%), the selection probabilities are still in a 
reasonable range with the probability that the better regimen is selected being 0.737 and the 
probability that the poorer regimen would be selected is 0.001. Of course, this type of 
comparison would need to be considered in conjunction with the toxicity and complications 
analysis in order to decide which regimen is preferable to the other for choice in a future study. 
 
Table 1: Regimen Selection Probabilities with a True 4% Difference in EFS Outcome: 
 
 
Poorer Regimen 
True EFS 
 
Better Regimen 
True EFS 
Probability 
of 
Selecting Better 
Regimen 
Probability 
of 
Selecting Poorer 
Regimen 
 
Probability of No 
Selection 
82% 
86% 
0.852 
0.003 
0.145 
80% 
84% 
0.832 
0.004 
0.164 
84% 
88% 
0.875 
0.002 
0.123 
 
The power calculation for the randomized Nelarabine versus no Nelarabine comparison is based 
on a  
1-sided log rank test (alpha = 0.05) since we wish to see if the addition of Nelarabine improves 
the outcome of T-lineage patients. The Nelarabine comparison will also have 5 planned analyses 
of the data and utilize the same type of t2 spending function. The following calculations assume a 
3 year period of randomization to the Nelarabine question for the HR subset before the 
randomization is expanded to include the IR group. If the study duration is approximately 6 
years, this would eventually result in about 615 patients randomized to this comparison (240 HR 


 
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patients over 6 years, 375 IR patients over 3 years). Since the more favorable LR subset of T-
lineage patients will be excluded from this randomization (i.e., those who are aged 1-10 years 
and CNS1 and no testicular disease and RER and MRD- are excluded), the assumed long term 
EFS outcome in this group of patients is assumed to be 76% at 4 years (resulting from the above 
mixture of the IR and HR groups). A clinically important difference is an improvement to 85% 
EFS, representing a relative EFS event reduction of approximately 41% for the better regimen 
(viz., RHR = 0.592). The number of expected EFS events with 3 years of follow-up after the last 
randomized patient is enrolled would be 119 events. In this situation, the cumulative power to 
detect a difference by the last analysis is 85.9%. The 1-sided z-value monitoring boundaries for 
the 5 looks at the data are 2.878, 2.470, 2.200, 1.982 and 1.790. If the IR patients can be enrolled 
sooner than 3 years into the study because the Nelarabine safety is established before that time, 
this would increase the statistical power figures given above. 
 
With the planned study duration, there should also be reasonable statistical power to examine 
some of the treatment differences within the risk group subsets. This would be of particular 
interest for the Nelarabine randomization. In the HR subset, the cumulative power to detect a 
change in EFS outcome from 60% to 75% (RHR = 0.563) would be 77.2%. For the IR subset the 
power to detect a change in EFS outcome will be less since those patients would only begin 
enrollment after the safety phase is completed. For example, in the IR subset the power to detect 
a change in EFS outcome from 86% to 93% (RHR = 0.481) for the Nelarabine regimen 
comparison would be 68.4%. 
 
Secondary comparisons of the incidence of CNS relapse will be examined. This will be 
performed for the comparison of the 2 MTX regimens and also for comparing Nelarabine versus 
no Nelarabine. Comparison of overall survival (OS) will also be a secondary endpoint for the 
regimen comparisons. 
 
Based on the treatment regimens chosen for this design and experience with factorial designs in 
numerous other COG ALL studies, the occurrence of an important statistical interaction effect on 
EFS for the 2 main treatment factors is thought to be unlikely. Hence, the preceding power 
calculations are based on the assumption that the stratified analysis of either factor across levels 
of the other factor will allow the “pooled” analysis to be valid. However, analyses will be 
performed regularly to assess the possibility of an interaction effect (using a Cox regression 
likelihood ratio test) which will assess the four individual treatment regimens in the 2 x 2 design 
to see if a non-proportional hazards effect occurs for the combinations of the two main effect 
factors. If strong evidence exists for the presence of a statistical interaction of the MTX and 
Nelarabine regimens, then separate analyses of a regimen effect would need to be done within 
each level of the other treatment factor. This would result in substantial attenuation of the 
statistical power and might necessitate extension of the study duration to achieve better power to 
detect treatment differences. 
 
Since the comparison of the methotrexate regimens utilizes a selection type analysis, no futility 
testing will be used for that comparison. However, futility testing boundaries will be used for the 
comparison of “Nelarabine” versus “No Nelarabine” to decide if stopping should occur for 
similarity of outcome. This will be tested with a Pampallona-Tsiatis type lower monitoring 
boundary when approximately 20%, 40%, 60% and 80% of the EFS event information is 


 
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available. This boundary has the property that the probability of rejecting HA (i.e. relative hazard 
of 0.5237 favoring Nelarabine) when HA is true is 5%. The z-values corresponding to stopping 
for futility at the four interim analyses are -1.595, -0.656, +0.021 and +0.584, respectively. 
 
The proportional hazards assumption underlying the log rank test appears to have been 
reasonably valid for the treatments studied in many previous COG trials in ALL. However, that 
assumption for this trial will be regularly examined at the times the treatment regimens are 
compared. Should it not appear valid, other statistics will be used for comparing treatment 
outcome (e.g., cure model statistics and/or 4-year EFS comparisons). 
 
If during the conduct of the trial, results emerge which establish the superiority of one of the 
regimens for a particular comparison in the factorial design (i.e., either for the methotrexate 
regimen comparison or for the Nelarabine comparison), the entire study would not be stopped. In 
this case, the study will continue the randomization for the remaining comparison with all 
additional patients assigned to the better regimen for the part of the randomization which was 
terminated. 
 
10.3.1 Study Re-design Power Calculations (Amendment #9) 
The distribution of post-Induction risk assignments - Low risk (LR), Intermediate risk (IR), and 
High risk (HR) is currently 9%, 71%, and 20% respectively, differing from what was projected 
above (18%, 62%, and 20% respectively). Due to this, the annual accrual rate to the MTX and 
nelarabine randomizations are currently the same – around 175 patients/year (compared to the 
prior estimates of 201 and 165 patients, respectively). The updated power calculations reflecting 
this, and interim monitoring rules are given below.  
 
MTX randomization: Using a 2-sided alpha of 5%, there is power of 85.3%, to detect an 
improvement in 4-year EFS from 82% to 89%. A total of 980 patients will be accrued (total 
expected events: 142) with minimum followup of 3 years. As of 09/30/2011 a total of 580 
patients have already been accrued to this randomization. Hence the remaining 400 patients can 
be accrued to this post-Induction randomization over 2.3 years (projected study closure date of 
02/01/2014 instead of the currently projected date of 04/15/2015). Overall, a total of 605 patients 
will be enrolled at study entry during this time period, to give 590 eligible, evaluable patients for 
the post-Induction randomizations/treatment assignments. Interim analyses will be done as 
specified earlier in Section 10.3, with the first analysis occurring when approximately 20% of the 
expected events from the projected EFS event horizon have occurred. Four subsequent analyses 
will occur at approximately 40%, 60%, 80% and 100% of the expected event total. A t2 spending 
function for the stopping boundary (with truncation at 3 standard deviations) will be used to 
allocate greater importance to the later analyses. Since the comparison of the methotrexate 
regimens utilizes a selection type analysis, no futility testing will be used for that comparison. 
 
Nelarabine randomization: With a 1-sided alpha of 5%, there is 85.9% power, to detect an 
improvement in 4-year EFS from 76% to 85%. The total number of patients required is the same 
as currently specified in Section 10.3 (615 patients) (total expected events: 119) with minimum 
followup of 3 years. As of 09/30/2011 a total of 215 patients have been accrued to this 
randomization. Hence the remaining 400 patients can also be accrued over 2.3 years as specified 
for the MTX randomization. The Nelarabine comparison will also have 5 planned interim 


 
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analyses of the data for efficacy (at 20%, 40%, 60%, and 100% information) and utilize the same 
type of t2 spending function as for the MTX randomization. 
 
Futility testing boundaries will be used for the comparison of “Nelarabine” versus “No 
Nelarabine” to decide if stopping should occur for similarity of outcome. This will be tested with 
a Pampallona-Tsiatis type lower monitoring boundary when approximately 20%, 40%, 60% and 
80% of the EFS event information is available. This boundary has the property that the 
probability of rejecting HA (i.e. relative hazard of 0.5237 favoring Nelarabine) when HA is true is 
5%. The z-values corresponding to stopping for futility at the 4 interim analyses are -1.595, -
0.656, +0.021 and +0.584, respectively. 
 
10.3.2 Study Re-design Power Calculations for Nelarabine randomization (Amendment #11) 
The study closed to accrual on 07/25/2014. Total expected accrual for the study was determined based 
on estimating losses during/at the end of induction and the required sample sizes for the two randomized 
study questions. Due to a lower rate of loss than projected, a higher number of (n= 659) patients than the 
projected 615 were randomized to +/- nelarabine. A total of 336 and 323 patients were randomized to no 
nelarabine vs. nelarabine regimens. 
 
It is assumed that the 336 and 323 patients randomized to the two arms were accrued uniformly 
during the 3.83 years (from 9/22/2010 to 7/25/2014) when the efficacy phase of the nelarabine 
randomization was open, with a minimum follow up of 3 years. Assuming a cure rate model for 
each arm that has exponential distribution for the first four years and reaches a plateau at 4 
years; accounting for 5 interim analyses (using an alpha t2 spending function) at approximate 
20%, 40%, 60%, 80% and 100%, there is 80% power to detect improvement in 4-year EFS from 
82% to 89% (93 events) with a one sided significance level of 0.05. Given the additional 
expected toxicities due to the addition of nelarabine, 7% is considered to be a clinically 
meaningful improvement in outcome to plan for. Three interim analyses for efficacy have 
already occurred thus far. The next planned interim analysis for efficacy and futility will be 
conducted at 80% information (74 events). Final analysis will be conducted when the specified 
event horizon (93 events) is reached or when the last patient randomized to +/- nelarabine has 3 
years of follow-up, whichever comes first. 
 
10.4 
Toxicity Assessment and Monitoring  
Neurological toxicities are of special concern with Nelarabine. The toxicities for the Nelarabine 
patients will be examined in two primary ways: First, they will be compared directly to their 
randomized control not receiving Nelarabine with additional examination of the comparison 
within the separate methotrexate regimen subsets. These comparisons will focus on Grade 3 or 
higher non-hematologic toxicities. Next, the overall incidence of selected neurologic toxicities 
will also be monitored since these represent an important target category for Nelarabine toxicity 
(see Section 7.3). 
 
For toxicity monitoring rules related to Nelarabine, any death clearly attributable to Nelarabine will lead 
to closure of the Nelarabine randomization with subsequent review and consideration given to re-opening 
the randomization at a lower dose and/or restricting patient entry to only those with High Risk disease. A 
second monitoring rule will look for 10% Grade 4 or 20% Grade 3 peripheral neuropathies that fail to 
resolve within one week, attributable to Nelarabine and not matched by a similar neurologic toxicity rate 
on the regimens without Nelarabine. Should this occur, it will lead to a temporary closure of the 


 
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randomization with consideration to be given to re-opening the randomization at a lower dose and/or 
restricting patient entry to only those with High Risk disease. 
 
Patients with CNS disease at diagnosis (CNS3) might be at higher risk of neurologic problems with 
Nelarabine. Thus, specific toxicity comparisons of this small group will be examined for the randomized 
Nelarabine and no Nelarabine regimens, and those analyses will be provided together with the regular 
overall study toxicity assessments. 
 
Detailed toxicity data as described above will be regularly provided to the COG DSMC at each of their 
twice yearly meetings and an ad hoc basis as required for judging the safety of Nelarabine. 
 
10.4.1  Amended monitoring for toxic deaths (Amendment # 10) 
A formal statistical monitoring rule for toxic deaths attributed to Nelarabine, during post 
Induction therapy is given below. Based on the rule given in Section 10.4 above, on 09/05/2012, 
accrual to the study and randomization to Nelarabine was suspended following a death during 
consolidation of a patient assigned to the Nelarabine + HDMTX arm. The AALL0434 study 
committee reviewed the data on Nelarabine related toxicities. Although there was one death 
related to Nelarabine, there were only two other nervous system toxicities (1 Grade 3 seizure and 
1 Grade 3 somnolence) for which attribution to Nelarabine was scored as possible, and none that 
were scored as probable or definite among over 180 patients randomized /assigned to receive 
Nelarabine on study. The rate of neurological toxicities is well below the level defined as 
concerning in Section 10.4. The COG DSMC reviewed the data and approved re-opening 
randomization/assignment of patients on study to Nelarabine containing arms as in the original 
study design. The DSMC also recommended at the time that with the next amendment a more 
formal monitoring rule for deaths related to Nelarabine be added to the statistical consideration. 
Of note, no additional deaths attributed to Nelarabine have occurred after the sole death that 
occurred in September 2012.  
 
The death rate related to Nelarabine during post-Induction therapy will be closely monitored. 
About 335 patients will be randomized or assigned to Nelarabine containing regimens for post 
Induction therapy on this study. If four remission deaths attributed to Nelarabine occur, then the 
Nelarabine randomization will be temporarily closed to accrual. The deaths will be reviewed by 
the study committee and the COG data safety monitoring committee, and a decision made with 
respect to possible therapy modifications and reopening the randomization or permanent closure 
of the Nelarabine randomization. With this rule, the probability of stopping is 9% if the true toxic 
death rate is 0.5%. The probability of stopping is 90% if the true toxic death rate due to 
Nelarabine is 2%.  
 
10.5 
Analysis and Monitoring of Special Patient Subsets 
There are various patient subsets in this study that will be examined regularly. These subsets 
were selected either because the AALL0434 treatment is very different than in previous studies 
for the subset, or the subset is of interest for other reasons. 
 
Patients in the LR subset: 
The outcome of the Low Risk patients who do not receive prophylactic CNS irradiation will be 
contrasted to the historical control experience from recent studies of T-lineage ALL that 
provided such treatment (POG 9404). 
 


 
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SER patients: 
Since SER patients in this study will not receive a second DI phase and previously treated SER 
T-lineage patients in the CCG-1961 study received 2 DI phases, a comparison of outcome for 
this subset will be made with that historical control. 
 
Induction failure patients: 
In this study, patients failing Induction with an M3 marrow continue to stay on the study and 
they will receive Nelarabine+HDMTX in a Consolidation phase which might be followed 
thereafter by BMT.  This subset is expected to be a very small group based on the M3 rate at end 
of Induction for the CCG-1961 T-ALL patients receiving the ABFM chemotherapy (1.2%). Only 
very limited data is available from previous COG studies about these patients such as the 
survival outcome following Induction failure. Thus, examination of outcome for this group will 
be primarily descriptive, but their toxicity experience will be examined separately and their 
survival outcome will be compared to a similar group of patients treated on previous studies. 
 
10.6 
Analyses of Gender and Ethnicity  
Using national incidence data (SEER, 1986-1990) one can calculate the sex ratio incidence for 
male: female cases in childhood ALL to be approximately 1.24 for ages 0-14 or 1.31 for ages 0-
19.91 Data from recent COG trials (CCG-1950/60s) show that the ratio of male to female patients 
entered on ALL trials is 1.31:1, so the ALL population registered by COG institutions is in 
excellent agreement with national data for the relative incidence of ALL by sex group. In the 
subset of patients to be treated in this T-lineage ALL study the estimated sex ratio is 2.32:1 since 
the male: female sex ratio is much higher in T-lineage ALL which is known to have a male 
predominance. National data for the ethnicity distribution of the overall US population (1986-
1990) suggests that 84.3% of the overall US population are white, 12.2% are black, and 3.5% are 
non-white, non-black.91 The relative ethnicity distribution in T-lineage childhood ALL (from the 
CCG-1950/60s series of studies) was 77.4% whites, 6.0% blacks, 11.0% Hispanics, 3.3% Asians, 
and 2.3% “other”. Using the SEER classification of race, probably most of the Hispanics in the 
COG racial category classification would be classified as “whites”. These data suggest that the 
racial composition of patients entered in COG ALL trials is similar to what would be expected 
from national incidence data. One would expect this to be the case since some reports have 
suggested that 80%-90% of children in the US diagnosed with ALL are enrolled on COG trials. 
 
As has been done in previous COG ALL trials, analyses of effects of sex group and ethnicity on 
outcome will be examined for this study. Extensive data exists in the literature showing that for 
all children with ALL, females generally have a better prognosis than males.92-94 However, it is 
less clear that this effect also occurs in T-lineage ALL (viz., for the CCG-1950/60s series it was 
a non-significant difference, p = 0.42, relative event rate for males 1.18 times that for females). 
Numerous reports also exist suggesting certain types of outcome differences by racial category 
for childhood ALL. The most consistent theme in these reports is a somewhat poorer outcome 
for black patients as compared to whites.95,96 The size of this difference is in the neighborhood of 
10%-15% lower EFS at late periods of follow-up. Again it is not clear that this is the case in T-
lineage ALL (viz., for the CCG-1950/60s blacks had a non-significant difference in EFS 
compared to whites with a relative event rate for blacks of only 1.19 times that in whites). With a 
sex ratio of male: female patients in T-lineage patients of approximately 2.32, the overall size of 
the AALL0434 study (N = 1900 patients) will provide adequate statistical power in this study to 
examine any overall prognostic difference in outcome by sex. Examination of prognostic 


 
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differences in ethnicity categories will be more of a problem because of the relatively small 
proportions for some ethnicity groups, resulting in adequate statistical power only for larger 
differences in outcome for certain comparisons. However, analyses will be performed for both 
gender and ethnicity outcome differences recognizing the above statistical analysis caveats. No a 
priori evidence exists suggesting that the therapies to be used in this study will have differing 
effects on either gender groups or ethnicity categories. Nevertheless, examination of different 
prognostic patterns for sex group or racial category outcome according to treatment regimen will 
be examined and statistical tests for interaction effects will be used. However, the small subsets 
that will result for some comparisons and the multiple comparison nature of this type of analysis 
will require cautious interpretation of any findings. 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
106 
+ 
102 
= 
208 
Not Hispanic or Latino 
465 
+ 
1227 
= 
1692 
Ethnic Category: Total of all subjects 
571 
 
(A1) 
+ 
1329 
 
(B1) 
= 
1900 
 
(C1) 
Racial Category 
 
American Indian or Alaskan Native 
2 
+ 
9 
= 
11 
Asian 
23 
+ 
40 
= 
63 
Black or African American 
43 
+ 
72 
= 
115 
Native Hawaiian or other Pacific Islander 
0 
+ 
0 
= 
0 
White 
503 
+ 
1208 
= 
1711 
Racial Category: Total of all subjects 
571 
 
(A2) 
+ 
1329 
 
(B2) 
= 
1900 
 
(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
Data derived from T-lineage population in CCG-1950/60s studies 
 
 
11.0 
EVALUATI ON CRI TER IA  
 
11.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize the CTCAE of the National Cancer Institute (NCI) for toxicity and 
performance reporting. The descriptions and grading scales found in the revised CTCAE version 
4.0 will be utilized for AE reporting beginning July 1, 2011. All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0 which can be downloaded from the 
CTEP web site (http://ctep.cancer.gov). Additionally, toxicities are to be reported on the 
appropriate data collection forms. 
 
11.2 
Response Criteria for T-ALL 
See definitions in Section 3.3. 
 
11.3 
Response Criteria for T-NHL 
 
11.3.1 Complete Response (CR) 
Defined as disappearance of all evidence of disease from all sites for at least 4 weeks. This will 
be determined by physical exam and appropriate imaging studies. Bone marrow aspirate/biopsy 


 
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must be morphologically normal and any macroscopic nodules in any organs detectable on CT 
should no longer be present. 
 
11.3.2 Complete Response Unconfirmed (CRu) 
A residual lymph node mass > 1.5 cm in greatest transverse diameter that has regressed by 
> 75% in sum of the products of the greatest perpendicular diameters (SPD), or any residual 
lesions in organs that have decreased by > 75%. 
 
11.3.3 Partial Response (PR) 
Partial response > 50% decrease in the SPD of the lesions for at least 4 weeks. No new lesions. 
 
11.3.4 No Response (NR) 
Failure to qualify for a PR. No new lesions. 
 
11.3.5 Progressive Disease 
Greater than 25% increase in the size of any lesions or appearance of new lesion(s). 
 
 
 
12.0 
ADVERSE EVENT REPORTING REQUIRE MENTS  
 
12.1 
Purpose 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Certain adverse events must be reported in an expedited 
manner to allow for timelier monitoring of patient safety and care. The following sections 
provide information about expedited reporting. 
 
12.2 
Determination of reporting requirements 
Reporting requirements may include the following considerations: 1) whether the patient has 
received an investigational or commercial agent; 2) the characteristics of the adverse event 
including the Grade (severity), the relationship to the study therapy (attribution), and the prior 
experience (expectedness) of the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) 
whether or not hospitalization or prolongation of hospitalization was associated with the event.  
 
An investigational agent is a protocol drug administered under an Investigational New Drug 
Application (IND). In some instances, the investigational agent may be available commercially, 
but is actually being tested for indications not included in the approved package label.  
 
Commercial agents are those agents not provided under an IND but obtained instead from a 
commercial source. The NCI, rather than a commercial distributor, may on some occasions 
distribute commercial agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules apply. 
• 
Concurrent administration: When an investigational agent is used in combination 
with a commercial agent, the combination is considered to be investigational and 
expedited reporting of adverse events would follow the guidelines for 
investigational agents. 


 
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• 
Sequential administration: When a study includes an investigational agent and a 
commercial agent on the same study arm, but the commercial agent is given for a 
period of time prior to starting the investigational agent, expedited reporting of 
adverse events which occur prior to starting the investigational agent would follow 
the guidelines for commercial agents. Once therapy with the investigational agent is 
initiated, all expedited reporting of adverse events follow the investigational agent 
reporting guidelines. 
 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (eg, treatment with 
investigational agent/intervention, radiation or chemotherapy). A metastasis of the initial neoplasm is not 
considered a secondary malignancy.  
 
All secondary malignancies that occur following treatment need to be reported via AdEERS. Three 
options are available to describe the event:  
• 
Leukemia secondary to oncology chemotherapy   
• 
Myelodysplastic syndrome  
• Treatment related secondary malignancy 
 
12.3 
Steps to determine if an adverse event is to be reported in an expedited manner 
 
Step 1: Identify the type of event using the NCI Common Terminology Criteria (CTCAE) [use 
version 4.0 beginning 07/01/11]. 
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting and are located on the 
CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
All 
appropriate 
treatment areas should have access to a copy of the CTCAE. 
 
Step 2: Grade the event using the NCI CTCAE. 
 
Step 3: Determine the attribution of adverse event in relation to the protocol therapy. Attribution 
categories are: Unrelated, Unlikely, Possible, Probable, and Definite. 
 
Step 4: Determine the prior experience of the adverse event.   
Expected events for a CTEP IND agent are defined as those listed in the ASAEL 
(Agent Specific Adverse Event List), a subset of the CAEPR (Comprehensive Adverse 
Event and Potential Risks). For investigational agents that are not commercially available 
and are being studied under a company’s IND, expected AEs are usually based on the 
Investigator’s Brochure. 
 
Unexpected events for a CTEP IND agent are defined as those NOT listed in the 
ASAEL. 
 
Guidance on expectedness of the agent is provided in the Drug Information Section of this 
protocol. 
 


 
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Step 5: Review Tables A and/or B in this section to determine if: 
 
• 
there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 
• 
there are any protocol-specific exceptions to the reporting requirements. 
 
Step 6: Determine if the protocol treatment given prior to the adverse event included an 
investigational agent, a commercial agent, or a combination of investigational and commercial 
agents.  
 
Note: If the patient received at least one dose of investigational agent, follow the guidelines in 
Table A. If no investigational agent was administered, follow the guidelines in Table B. 
 
12.4 
Reporting methods 
 
• 
Use the NCI’s Adverse Event Expedited Reporting System (AdEERS). The NCI’s 
guidelines for AdEERS can be found at: 
http://ctep.cancer.gov/protocolDevelopment/default.htm 
 
 
An AdEERS report must be submitted by the following method: 
 
 Electronically submit the report via the AdEERS Web-based application located 
at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adeers.htm 
 
• 
Fax supporting documentation for AEs related to investigational agents to: 
o The NCI for agents supplied under a CTEP IND only (fax # 301-230-0159)  
o and 
to 
COG 
for 
all 
studies 
(fax# 
626-303-1768; 
email: 
COGAdEERS@childrensoncologygroup.org; Attention: COG AdEERS 
Coordinator). 
 
• 
DO NOT send the supporting documentation for AEs related to commercial 
agents to the NCI. Fax or email this material to COG (fax # 626-303-1768; email: 
COGAdEERS@childrensoncologygroup.org; 
Attention: 
COG 
AdEERS 
Coordinator). 
 
• 
ALWAYS include the ticket number on all faxed documents. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided 
during trial registration on all reports. 
 
12.5 
When to report an event in an expedited manner 
 
• Some adverse events require notification within 24 hours (refer to Table A) to NCI 
via the web based application and/or by telephone call to the Study Chair. 
 
In the rare situation where Internet connectivity is disrupted, the 24-hour notification 
is to be made to the NCI for agents supplied under a CTEP IND by telephone call to 


 
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301-897-7497. In addition, once Internet connectivity is restored, a 24-hour 
notification that was phoned in must be entered into the electronic AdEERS system 
by the original submitter of the report at the site. 
 
• Submit the report within 5 calendar days of learning of the event. 
 
12.6 
Other recipients of adverse event reports 
COG will forward reports and supporting documentation to the Study Chair, to the FDA (when 
COG holds the IND) and to the pharmaceutical company (for industry sponsored trials).  
 
Adverse events determined to be reportable must also be reported according to the local policy 
and procedures to the Institutional Review Board responsible for oversight of the patient. 
 
12.7 
Reporting of Adverse Events for investigational agents – AdEERS 24-hour notifications, 
and complete report requirements. 
 
Expedited reporting is required if the patient has received at least one dose of the investigational 
agent as part of the trial. Reporting requirements are provided in Table A. The investigational 
agent used in this study is Nelarabine (Compound 506U78; IND # 52611); the IND holder is 
the NCI. 
 
Table A 
Phase 2 and 3 Trials and COG Group-wide Pilot Studies utilizing an Agent under a CTEP 
IND or a Non-CTEP IND: AdEERS Expedited Reporting Requirements for Adverse 
Events That Occur Within 30 Days1 of the Last Dose of the Investigational Agent 
 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 33 
 
Grade 33 
Grades 
4 & 52 
Grades 
43 & 52 
Unexpected 
and 
Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Unex-
pected 
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
5 
Calendar 
Days 
5 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
5 
Calendar 
Days 
5 
Calendar 
Days 
5 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
5 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after 
the last dose of treatment with an agent under a CTEP IND or non-CTEP IND require reporting as 
follows: 
AdEERS 24-hour notification (via AdEERS for CTEP IND agents; via e-mail to COG AE Coordinator for 
agents in Non-CTEP IND studies) followed by complete report within 5 calendar days for: 
• Grade 4 and Grade 5 unexpected events  
 
AdEERS 5 calendar day report: 
• Grade 3 unexpected events with hospitalization or prolongation of hospitalization (see exceptions 
below 
• Grade 5 expected events 
2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full 
report is required as outlined in the table. 
3 Please see exceptions below under section entitled “Additional Instructions or Exceptions.” 
March 2005 


 
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Note: All deaths on study require timely reporting to COG via RDE regardless of causality. Attribution to 
treatment or other cause must be provided. 
• 
Expedited AE reporting timelines defined: 
➢ 
“24 hours; 5 calendar days” – The investigator must initially report the AE 
(via AdEERS for CTEP IND agents; via e-mail to COG AE Coordinator for 
agents in non-CTEP IND studies) within 24 hours of learning of the event 
followed by a complete AdEERS report within 5 calendar days of the initial 
24-hour report. 
➢ 
“5 calendar days” - A complete AdEERS report on the AE must be 
submitted within 5 calendar days of the investigator learning of the event.  
 
• 
Any medical event equivalent to CTCAE Grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via AdEERS if the event occurs following 
treatment with an agent under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
 
• 
Protocol specific reporting of AEs, in addition to the AdEERS requirements, are to be 
entered in the COG remote data entry system.   
 
Additional Instructions or Exceptions to AdEERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND or Non-CTEP IND: 
 
• Any death that occurs more than 30 days after the last dose of treatment with an investigational 
agent which can be attributed (possibly, probably, or definitely) to the agent and is not due to 
cancer recurrence/progression must be reported via AdEERS for an agent under a CTEP IND 
[and via AdEERS for non-CTEP IND agent] per the timelines outlined in the table above. 
 
• Grades 1-4 myelosuppression do not require expedited reporting unless unexpected. 
 
12.8 
Additional Reporting Guidelines and Protocol Specific Requirements  
 
The adverse events listed below do not require expedited reporting via AdEERS: 
 
Grade 4 myelosuppression 
Grade 3 hemoglobinemia (ie, anemia), leukopenia, neutropenia or thrombocytopenia with 
hospitalization  
Grade 3 infection with hospitalization 
Grade 3 mucositis with hospitalization 
Grade 3 fever/neutropenia with hospitalization 
Grade 3 transfusion with hospitalization 
Grade 3 nausea and/or vomiting with hospitalization 
Grade 3 diarrhea or gastritis with hospitalization 
Grade 4 fever/neutropenia ± hospitalization 


 
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Grade 4 hemoglobinemia (ie, anemia), leukopenia, neutropenia or thrombocytopenia ± 
hospitalization  
 
Neurological toxicities are of special concern with Nelarabine. The Study Chair should also 
be notified immediately of patients experiencing any Grade 3 or Grade 4 neurological 
toxicity after receiving Nelarabine.  
 
Rhabdomyolysis has been rarely reported with the use of nelarabine. Routine reporting 
will include any Grade 3 or higher hepatobiliary enzyme elevation associated with highly 
elevated creatinine phosphokinase elevation. The CTCAE 4.0 Terms to list are: 1) Liver 
dysfunction (AST, ALT, CK elevations); 2) Muscle pain/weakness; AND 3) 
Musculoskeletal other: rhabdomyolysis. 
 
12.9 
Toxicities and other adverse events that must be reported for all patients via COG remote 
data entry 
 
The following toxicities and adverse events must be reported for all patients on study, whether or 
not they have received any doses of an investigational agent on this study. 
 
Report all Grade 3 and 4 non-hematologic toxicities. 
 
Report all Grade 3 and 4 hematologic toxicities that result in hospitalization or a delay in 
therapy of > 1 week. 
 
Report all CNS toxicities, Grade 1 and greater. 
 
 
Report all grades of peripheral neuropathy (neurological toxicities are of special concern 
with nelarabine. The Study Chair should also be notified immediately of patients 
experiencing any Grade 3 or Grade 4 neurological toxicity after receiving nelarabine). 
 
Report all Grade 3 and higher infection toxicities. 
 
Report all osteonecrosis (avascular necrosis) Grade 1 and greater that has been confirmed 
by imaging. If a new site of osteonecrosis (avascular necrosis) is diagnosed during a 
subsequent reporting period please report each occurrence of toxicity on the AE form and 
the Osteonecrosis (Avascular Necrosis) Data Form again for the reporting period during 
which the new site of toxicity was identified. Likewise, during subsequent reporting periods 
submit these forms if toxicity grade increases, and also if an orthopedic surgical procedure 
is performed. 
 
If the patient is off protocol therapy and has a newly diagnosed osteonecrosis (avascular 
necrosis) or develops a new site of osteonecrosis (avascular necrosis) the Osteonecrosis 
(Avascular Necrosis) CRF should be completed. 
 
12.10 Reporting of Adverse Events for commercial agents – AdEERS abbreviated pathway 
The following are expedited reporting requirements for adverse events experienced by patients 
on study who have not received any doses of an investigational agent on this study. 
Commercial reporting requirements are provided in Table B.  
 


 
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COG requires the AdEERS report to be submitted within 5 calendar days of learning of the 
event. 
 
Table B  
Reporting requirements for adverse events experienced by patients on study who have 
NOT received any doses of an investigational agent on this study. 
 
AdEERS Reporting Requirements for Adverse Events That Occur During Therapy With a 
Commercial Agent or Within 30 Days1 
 
 
Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated or Unlikely 
 
 
AdEERS 
Possible, Probable, 
Definite 
AdEERS 
 
AdEERS 
1This includes all deaths within 30 days of the last dose of treatment with a 
commercial agent, regardless of attribution.  Any death that occurs more than 30 
days after the last dose of treatment with a commercial agent which can be 
attributed (possibly, probably, or definitely) to the agent and is not due to cancer 
recurrence must be reported via AdEERS. 
 
13.0 
RECORDS AND REPORTING 
 
13.1 
Categories of Research Records 
Research records for this study can be divided into three categories: 
 
1. 
Non-computerized Information: Pathology Narrative Reports and Surgical Reports. 
These forms are submitted through the Imaging Document System in the eRDES. 
 
2. 
Reference Labs’ required reports and QARC data: These data accompany submissions to these 
centers, which forward their review data electronically to the COG Statistics and Data Center. 
 
3. 
Computerized Information Electronically Submitted: All other computerized data will be 
entered in the COG Remote Data Entry System with the aid of schedules and worksheets 
(essentially paper copies of the RDE screens) provided in the data form packet. 
 
See separate Data Form Packet posted on the COG web site, which includes submission schedule. 
 
13.2 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative CDUS data will 
be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31 and 
October 31. This is not a responsibility of institutions participating in this trial. 
 
13.3 
CTA/CRADA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the 


 
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“Intellectual Property Option to Collaborator” (http://ctep.cancer.gov/industry) contained within 
the terms of award, apply to the use of the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators. The protocol documents for studies 
utilizing investigational Agents contain confidential information and should not be shared 
or distributed without the permission of the NCI. If a copy of this protocol is requested by 
a patient or patient’s family member participating on the study, the individual should sign 
a confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data”): 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NIH, 
the design of the proposed combination protocol, and the existence of any 
obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party 
Data 
solely 
for 
development, 
regulatory 
approval, 
and 
commercialization of its own investigational Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA, 
as appropriate and unless additional disclosure is required by law or court order. 
Additionally, all Clinical Data and Results and Raw Data will be collected , used and 
disclosed consistent with all applicable federal statutes and regulations for the protection 
of human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, 
who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or 
PI for other studies) of Collaborator's wish to contact them. 
 


 
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5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is 
a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP for 
immediate delivery to Collaborator(s) for advisory review and comment prior to 
submission for publication. Collaborator(s) will have 30 days from the date of receipt for 
review. Collaborator shall have the right to request that publication be delayed for up to 
an additional 30 days in order to ensure that Collaborator’s confidential and proprietary 
data, in addition to Collaborator(s)’s intellectual property rights, are protected. Copies of 
abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy review 
as soon as possible and preferably at least three (3) days prior to submission, but in any 
case, prior to presentation at the meeting or publication in the proceedings. Press releases 
and other media presentations must also be forwarded to CTEP prior to release. Copies of 
any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland  20892 
FAX 301-402-1584 
Email: anshers@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator(s) confidential/ 
proprietary information. 
 
 
 


 
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14.0 
RADIATION THERAPY GUIDELINES 
Radiation Therapy for patients on COG protocols can only be delivered at approved COG RT 
facilities (per COG administrative policy 3.9) 
 
 
 
All Intermediate and High Risk T-ALL patients randomized to Arms C (HD MTX) and D (HD 
MTX + Nel) will receive prophylactic cranial radiation therapy (CRT) (1200 cGy) starting on 
Day 50 of Delayed Intensification (DI). All Intermediate and High Risk T-ALL patients 
randomized to Arms A (CMTX) and B (CMTX + Nel) will receive prophylactic cranial radiation 
therapy (CRT) (1200 cGy) during Weeks 3 and 4 (Arm A) and Weeks 4 and 5 (Arm B) of 
Consolidation. All T-ALL patients who were CNS 3 at diagnosis will receive CRT (1800 cGy) 
starting on Day 50 of DI. T-ALL patients with testicular disease at diagnosis that has not 
resolved by end Induction (biopsy is required if there is any uncertainty regarding clinical 
response) will receive testicular irradiation (2400 cGy) during Consolidation. T-ALL patients 
with testicular disease at diagnosis that resolves by end-Induction will not receive testicular 
irradiation. No patients with Low Risk T-ALL or T-NHL disease will receive radiation therapy. 
 
14.1 
Cranial Irradiation 
 
14.1.1 Equipment and Calibration 
 
14.1.1.1 Modality 
X-ray beams with a nominal energy between 4 and 6 MV. The use of IMRT is not permitted in 
this study. 
 
14.1.1.2 Calibration  
Calibrations of therapy units used in this protocol will be verified by the Radiological Physics 
Center (RPC). 
 
14.1.2 Target Volume 
Target volume consists of entire brain and meninges, including frontal lobe as well as posterior 
halves of globes of eyes, with optic disk and nerve, extending superior to vertex and posterior to 
occiput. Caudal border will be below skull base at C2 vertebral level. 
 
The target volume shall be defined by means of a CT simulator or conventional simulator. Care 
must be taken to avoid shielding the posterior orbit and cribriform plate. In case of conventional 
simulation, radio-opaque markers should be placed on the surface of the fleshy canthus to aid in 
localizing this point. 
 
14.1.3 Target Dose 
 
14.1.3.1 Prescription Point 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are based on 
schedules derived from the experimental design or on established standards of care. Minor unavoidable departures 
(up to 72 hours) from protocol directed therapy and/or disease evaluations (and up to 1 week for surgery) for valid 
clinical, patient and family logistical, or facility,  procedure and/or anesthesia scheduling issues are acceptable per 
COG administrative Policy 5.14 (except where explicitly prohibited within the protocol). 


 
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The prescription point in the cranial volume is at or near the center. For multi-convergent beams, 
the prescription point is usually at intersection of the beam axis. Note: Regardless of the location 
of central axis, dose should be prescribed at the center of the cranial volume (midway between 
the maximum separation). 
 
14.1.3.2 Dose Definition 
Absorbed dose is specified in centigrays (cGy)-to-muscle. 
 
14.1.3.3 Tissue Heterogeneity 
No corrections for bone attenuation will be made. 
 
14.1.3.4 Prescribed Dose and Fractionation 
 
14.1.3.4.1 Intermediate and High Risk Patients 
These patients will receive prophylactic cranial radiation, consisting of a total dose of 1200 cGy 
given in 8 daily fractions of 150 cGy per fraction, administered Monday through Friday. 
 
14.1.3.4.2 CNS 3 Patients 
All patients who present with CNS 3 leukemia at diagnosis will receive cranial radiation 
consisting of a total dose of 1800 cGy given in 10 daily fractions of 180 cGy per fraction, 
administered Monday through Friday. 
 
14.1.4 Dose Uniformity 
Dose variations in target volume will be within +7%, -5% of prescription-point dose. (From 
ICRU Report 50: small high-dose volumes can be excluded from evaluation of dose uniformity 
but not small low-dose volumes.) 
 
14.1.5 Treatment Interruptions 
No corrections will be made for treatment interruptions less than 7 days. For interruptions greater 
than 7 days, contact the Study Radiation Oncology Coordinator. 
 
14.1.6 Treatment Technique 
 
14.1.6.1 Patient Position 
It is recommended that the patient be treated in supine with immobilization appropriate for the 
child such as a face mask. 
 
14.1.6.2 Beam Configuration 
Cranial volume is treated with two lateral, equally weighted photon beams. Fields will extend at 
least 1 cm beyond periphery of scalp.  
 
14.1.6.3 Field Shaping 
Field-shaping will be done with blocks which are at least 5 HVL thick. Multi-leaf collimators are 
acceptable. 
 
14.1.6.4 Eye Protection 


 
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A simple method to minimize lens irradiation, while treating posterior halves of eyes, is to let 
central axes of horizontal cranial beams go through both orbits. Anterior edges of beams are 
defined by external block or by independently controlled collimator and meet at a point 1 cm 
anterior to frontal lobe meninges. Shielding blocks cover anterior halves of eyes and protect nose 
and mouth. Essentially the same geometry can be achieved with central axes through center of 
head by angling lateral fields so rays through the eyes lie in the same horizontal plane. It is 
acceptable to use parallel-opposed beam-pair, without such angling, with shielding blocks that 
cover anterior half of proximal eye. (Dose to contralateral lens will then increase.) 
 
 
14.2 
Testicular Radiation 
Only patients with persistent testicular disease at end-Induction (based on clinical and/or 
biopsy findings) will receive testicular irradiation. 
 
14.2.1 Equipment and Calibration 
 
14.2.1.1 Modality 
High-energy photon or electron beams. Selection of energy is determined by dose uniformity 
criterion, and with electrons, lowest possible energy should be used to spare tissues outside target 
volume. IMRT is not permitted. 
 
14.2.1.2 Calibration 
Calibrations of therapy machines used in this protocol will be verified by the Radiological 
Physics Center. 
 
14.2.2 Target Volume 
Planning target volume consists of testes in scrotal sac. (N.B. Cremasteric reflex may move 
testes high up in inguinal canal.) The field may be reduced as the palpably enlarged mass 
decreases in size during treatment. 
 
14.2.3 Target Dose 
 
14.2.3.1 Prescription point is at or near center of planning target volume. 
 
14.2.3.2 Dose Definition 
Absorbed dose is specified as centigrays (cGy)-to-muscle. 
 
14.2.3.3 Prescribed Dose and Fractionation 
Total dose to prescription point will be 2400 cGy in 12 fractions. Patient will be treated with one 
daily fraction per day of 200 cGy for five days a week. 
 
14.2.4 Dose Uniformity 
Variations of dose within planning target volume will be within +7%, -5% of dose to 
prescription point Uniformity requirement can be met with electron beam of appropriate energy 
provided bolus is used, which is simplest technique. Bolus may also be needed for photon beams 
to fulfill dose uniformity requirement. (From ICRU Report 50: small high-dose volumes can be 
excluded from evaluation of dose uniformity, but not small low-dose volumes.) 
 


 
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14.2.5 Treatment Interruptions 
No corrections will be made for treatment interruptions less than 7 days. For interruptions greater 
than 7 days, contact the Study Radiation Oncology Coordinator.  
 
14.2.6 Treatment Technique 
 
14.2.6.1 Patient Position 
Patient will be treated in supine position. 
 
14.2.6.2 Field Shaping 
Field shaping can be done with blocks of at least 5 HVL thick.  Multi-leaf collimators are 
acceptable. 
 
14.2.6.3 Normal Tissue Sparing 
Testes will be supported posteriorly and, if possible, extended caudally in order to minimize 
perineal irradiation.  Field will not be angled towards perineum. The penis will be excluded from 
field by fixing it to skin over the symphysis pubis. 
 
14.3 
Quality Assurance Documentation 
 
14.3.1 QARC Post Treatment Review 
Patients receiving RT on this study will have a simple review of the treatment delivered. There is 
no on-treatment review in this study. There is no film review required. Within one week of the 
completion of radiotherapy, the following data will be submitted: 
 
• “RT-2 Radiotherapy Total Dose Record” form. 
• Copy of patient’s radiation therapy chart, including prescription, and daily and 
cumulative doses. 
 
14.3.2 Data must be sent to: 
 
Quality Assurance Review Center 
Building A, Suite 201 
640 George Washington Highway 
Lincoln, RI 02865-4207 
Phone: (401) 753-7600 
Fax: 
(401) 753-7601 
 
14.3.3 Questions regarding the dose calculations or documentation should be directed to: 
 
COG Protocol Dosimetrist 
Building A, Suite 201 
Quality Assurance Review Center 
640 George Washington Highway 
Lincoln, RI 02865-4207 
Phone: (401) 753-7600 
Fax: 
(401) 753-7601 


 
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14.3.4 Questions regarding the XRT section of this protocol should be directed to the Study Radiation 
Oncology Coordinator: 
 
Natia Esiashvili, MD 
Emory Radiation Oncology Department 
1365 Clifton road, NE 
Atlanta, GA, 30322 
Phone: (404) 778-5782 
Fax: 
(404) 778-3643 
E-mail: natia@radonc.emory.org  
 
14.4 
Definitions of Deviation in Protocol Performance 
 
14.4.1 Minor Deviation 
Dose to prescription point differs from that in protocol between 6% and 10%. 
 
14.4.2 Major Deviation 
Dose to the prescription point differs from that in the protocol by more than 10%. 
 
 
15.0 
PATHOLOGY GUIDELINES FOR T-NHL 
 
15.1 
Pathology Goals 
1. Provide quality control by central pathologic review with accurate diagnosis and 
classification of pediatric non-Hodgkin lymphoma. This is to be based on both morphologic 
and immunophenotypic criteria. This study is limited to T-cell lymphoblastic lymphoma. 
Patients with B-lineage lymphoblastic lymphoma are not eligible for this study. 
2. Employ the recently described World Health Organization (WHO) Lymphoma 
Classification97 to facilitate concordance in diagnosis. 
3. Correlate morphologic, immunophenotypic and cytogenetic data for the lymphomas included 
in this treatment protocol. 
 
15.2 
Requirements for Handling Tissue or Cytology Specimens at Primary Institutions 
 
15.2.1 Tissue Specimens 
Tissue should preferentially, whenever possible, be obtained fresh and delivered immediately to 
the Pathology Laboratory for optimal handling and distribution (fixation, snap freezing, 
cytogenetics, etc.). Refer to diagram entitled ‘Lymph Node Processing For Institutional 
Diagnosis And Research Studies In Children’s Oncology Group’ (Figure 15.1). Submit 
representative tissue sections for fixation including at least one block with 10% buffered 
formalin. 
 
 
 


 
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Figure 15.1 
 
 
15.2.2 Cytology Specimens 
Cytology or body fluid specimens (i.e. pleural fluid) should be delivered promptly to the 
pathology laboratory, and handled per primary institutional procedures. Sufficient material 
should be utilized for morphologic evaluation by cytocentrifuge preparations stained with a 
Romanowsky stain (i.e. Giemsa or Wright’s stains). Provided enough specimen is available, at 
least one cell block should be prepared with specification of the fixative utilized and the time in 
fixative. 
  
 


 
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15.3 
Immunophenotyping Recommendations for Primary Institutions 
For eligibility in this study, the methodology and criteria for immunophenotypic analysis defined 
by the submitting institution will be accepted. Recognized methods include: paraffin section 
immunohistochemistry, frozen section immunohistochemistry, cytocentrifuge (cytospin) 
immunocytochemistry, and flow cytometry. 
 
For eligibility in this study, an extensive panel of antibodies should be employed for 
immunophenotypic 
evaluation. 
This 
can 
be 
done 
on 
snap 
frozen 
tissue 
by 
immunohistochemistry, and body fluid/cytology specimens by flow cytometry or cytocentrifuge 
(cytospin) immunocytochemistry. This panel of antibodies is listed as follows: 
 
T-Cell: CD1, CD2, CD3, CD4, CD5, CD7, CD8. 
B-Cell: CD19, CD20, Kappa, Lambda. 
Myeloid: CD13, CD14, CD33. 
Other: CD10, CD25, CD34, CD45, TdT. 
 
The method of TdT evaluation should be specified (i.e. flow cytometry, immunofluorescence, 
immunohistochemistry). 
 
For cases in which no paraffin embedded tissue has been prepared, and only stained cytospin 
slides remain available, these cases will be acceptable for protocol submission and pathology 
review when adequate immunophenotypic data is available from the primary institution. This 
situation may occur with cases evaluated by cytospin immunocytochemistry or flow cytometry 
immunophenotyping. 
 
If specimen is limited, preventing a complete immunophenotypic evaluation, a recommended 
minimum panel of antibodies should include: CD3, CD5, CD19, CD79a and TdT. If specimen is 
limited to paraffin embedded tissue only, a preferred panel of antibodies should include at least: 
CD45RO (UCHL-1), CD79a, and TdT. If additional antibodies that may be utilized in paraffin 
embedded tissue are available at the primary institution, the panel may include: CD3 
(polyclonal), CD43 (Leu22), CD22, PAX598,99, and CD45RA (4KB5). If immunophenotyping 
studies are not available locally, the case may be sent as a consultation case for evaluation 
including immunophenotyping studies to Dr. Sherrie Perkins (see address in Section 15.5.6). 
 
15.4 
Pathology Staging Criteria 
Cerebrospinal Fluid: Leukocyte count greater than or equal to 5/μL, with presence of blasts. TdT 
evaluation is strongly recommended. 
 
Bone Marrow: The presence of greater than 5% and less than 25% blasts in a bone marrow 
aspirate, or focal infiltration in a bone marrow biopsy, represents involvement of the marrow by 
lymphoblastic lymphoma. 
 
15.5 
Retrospective Central Pathology Review 
 
15.5.1 Required Materials 
Materials to be submitted for retrospective pathology review to the COG Biopathology Center 
include the following: 
1. Initial diagnostic material prior to therapy 
2. Specimens demonstrating relapse of lymphoma at any time 


 
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3. Specimens from residual masses demonstrating residual lymphoma or complete response 
to therapy 
4. A copy of all final pathology reports (see details in Section 15.5.1.4) 
5. Pathology Data Collection Form 
6. Transmittal Form 
 
Please label all materials with the patient’s COG patient identification number and the 
institutional pathology number and block number found on the corresponding pathology report. 
The materials to be submitted are described below and listed in Table 15-1. 
 
15.5.1.1  Paraffin Blocks 
If possible, it is preferred that paraffin blocks be submitted to the COG Biopathology Center. For 
surgical biopsy specimens, this should include a paraffin block of tissue prepared in 10% 
Buffered Formalin (as described in Section 15.2.1). For cytology specimens, a paraffin block 
may be available as a cell block preparation (see Section 15.2.2). If paraffin blocks cannot be 
submitted, then submit twenty (20) unstained sections (4 microns thick) of unbaked slides air-
dried at room temperature and two (2) H&E stained slides from each block. These sections 
should be place on sialinized slides (i.e. Fisher Superfrost Plus). 
 
15.5.1.2  Cytology Slides 
When paraffin blocks have not been prepared, a cytologic preparation of one stained, air-dried 
cytospin slide (i.e. Romanowsky stain such as Giemsa or Wright’s stain) and 10 unstained slides 
should be submitted. 
 
15.5.1.3  Biopsies of Residual Masses 
For these biopsy specimens, send a recut slide (hematoxylin and eosin stain) from all of the 
paraffin blocks for review. The corresponding pathology report should accompany the slides for 
review. 
 
15.5.1.4  Pathology Reports 
A copy of all pathology reports on each case should be submitted. This should include: 
1. Final reports of diagnostic biopsy and bone marrow specimens (even if negative) 
2. All immunophenotyping reports of diagnostic biopsy and bone marrow specimens (if 
available); also include copies of flow cytometry histograms (if available) 
3. Results of any genotypic studies (i.e. gene rearrangement studies) 
4. Results of any cytogenetic (karyotypic) analysis 
 
15.5.1.5  Pathology Data Collection Forms/COG Pathology Center 
A separate pathology data collection form (Institutional Pathology Form) should be completed 
and submitted along with the above materials. Also, indicate the primary institution pathology 
diagnosis utilizing the WHO Lymphoma Classification97 on the data collection form. 
 
15.5.2 Transmittal Form 
A specimen transmittal form must be submitted along with the pathology review materials. 
 


 
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15.5.3 Biopathology Center Address 
All material submitted for central pathology review should be sent via regular mail or using your 
institutional courier account to: 
 
COG Biopathology Center 
Nationwide Children’s Hospital 
700 Children's Drive, WA 1340* 
Columbus, OH 43205 
Phone: (614) 722-2894 
Fax: (614) 722-2897 
 
* The room number is required. Packages not listing the room number could be denied and returned to sender. 
 
15.5.4 Paraffin Blocks and Cytologic Slides-Storage/Return 
Paraffin blocks and cytologic slides will be retained at the COG Biopathology Center 
indefinitely, unless the institution requests their return. 
 
15.5.5 Lymphoma Classification 
Morphologic evaluation and classification of the study cases will utilize the criteria described in 
the WHO Lymphoma Classification.97 Eligible pediatric lymphomas will be classified as 
precursor T-cell lymphoblastic lymphoma. 
 
15.5.6 Review Pathologists 
For any questions regarding the pathology protocol, please contact: 
 
Sherrie Perkins, MD, PhD 
University of Utah and ARUP Laboratories 
Department of Hematology 
500 Chipeta Way 
Salt Lake City, UT 84108 
Phone: (801) 581-5854 
Fax: (801) 585-3831 
 
 
 


 
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TABLE 15-1: MATERIALS TO SEND FOR CENTRAL PATHOLOGY REVIEW 
 
1. Paraffin Blocks 
Send one of the following: 
a. Surgical biopsy specimen: One paraffin block (formalin preferred). 
b. Cytology cell block: One paraffin block (specify fixative). 
c. If blocks cannot be sent, submit twenty unstained and unbaked sections 
(4 μm) and two H&E stained sections from each block on sialinized 
slides. 
 
2. Cytology Slides 
Send one stained slide (Romanowsky stain) and 10 unstained slides 
 
3. Biopsies of Residual Masses 
a. Send a recut slide (hematoxylin and eosin stain) from all of the paraffin 
blocks from each of these types of biopsy specimens. 
b. Send corresponding pathology report. 
 
4. Pathology Reports 
Send all of the following: 
a. Final reports of diagnostic biopsy and bone marrow specimens (even if 
negative). 
b. All immunophenotyping reports of diagnostic biopsy, and bone marrow 
specimens (if available); also include copies of flow cytometry 
histograms (if available). 
c. Results of any genotypic studies (i.e. gene rearrangement studies). 
d. Results of any cytogenetic (karyotypic) analysis. 
 
5. Pathology Data Collection Form  
 
6. Transmittal Form 
 
 


 
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16.0 
BIOLOGY METHODS AND SPECIMEN SUBMISSION FOR T-NHL 
 
16.1 
Required Minimal Residual Disease (MRD) Biology Studies 
 
16.1.1 Sample Collection 
A single bone marrow specimen will be obtained at diagnosis to assess disease involvement in 
the bone marrow for subsequent risk stratification. This sample will be shipped to the COG ALL 
Reference Flow Cytometry Lab using the same shipping and handling requirements as T-ALL 
patients enrolled on this study. 
 
Samples are to be shipped to Dr. Brent Wood at the University of Washington, Flow Cytometry 
Laboratory. The Specimen Transmittal Form is to be submitted with each sample submitted to 
the COG Reference Laboratory. The specimen transmittal form information should always 
include the name and telephone number of a person designated by the PI to receive calls from the 
Reference Laboratory directors. The PI’s FAX number must also be noted on each sample 
inclusion form. Because clinical recommendations will be made on these samples, always 
include the patient’s initials and COG number on any sample submitted. This is a CLIA 
requirement. COG ALL Reference Laboratories may be unable to analyze specimens if adequate 
patient identifiers are not provided. 
 
T-NHL samples for the Reference Laboratories are to be collected in special 15 mL conical tubes 
(SM) containing EDTA/RPMI as the anticoagulant and media diluent. These tubes will be 
prepared in the Reference Laboratories and mailed in batches to each participating institution, 
where they can be stored frozen at -20°C until use. Tubes are stable for 3 months if refrigerated 
and stable for 1 year if frozen. 
 
To request prepared and pre-packaged sample shipping tubes, click on the ‘Biopathology Center 
Application’ link on either the Protocol or the CRA Home Page of the COG web site. On the 
Biopathology Center Applications page, select the BPC Kit Management link to enter the Kit 
Management application. Please select the protocol ‘AALL08B1’ to order the shipping tubes 
required for MRD samples. Even though T-NHL patients are not enrolled on AALL08B1, the 
supplies are still ordered through that protocol. 
 
Bone Marrow Collection Procedures for Reference Laboratories for T-NHL: 
a. Collect BM into a syringe and transfer the specimen immediately into the 15 mL shipping 
media conical tube with RPMI/EDTA. 
b. Mix well. Up to 5 mL of BM can be placed in one 15 mL tube with RPMI/EDTA. If you 
don’t have shipping media tubes, you can place the BM into large purple EDTA tubes 
that are commonly available in most hospitals. However, the viability of the cells is 
greatly enhanced in the shipping media tubes. 
c. 5 mL of BM will be sufficient for MRD analysis at diagnosis. 
 
16.1.2 Sample Shipping 
T-NHL bone marrow samples for MRD studies will be shipped to one place: 
 
Western Flow Cytometry Reference Laboratory 
Brent Wood, MD, PhD 
SCCA 


 
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Hematopathology Laboratory 
Room G7-800 
825 Eastlake Ave. E. 
Seattle, WA 98109-1028 
Phone: 206-288-7060 
FAX: 206-288-7127 
 
 
SAMPLES THAT ARE EXPECTED TO BE DELAYED FOR MORE THAN 48 
HOURS— 
PLACE A COLD PACK (NOT ICE PACK) IN SHIPMENT. ALL TUBES SHOULD BE 
LABELED WITH AT LEAST TWO PATIENT IDENTIFIERS, INCLUDING THE 
NAME AND THE COG NUMBER/BIOPATHOLOGY NUMBER. IN ADDITION, A 
SPECIMEN TRANSMITTAL FORM AVAILABLE ON THE RDE SHOULD ALWAYS 
BE SUBMITTED WITH EACH SAMPLE. 
 
Call Reference Laboratories only when shipping a sample to be delivered on Saturday. 
 
Samples for the Flow Cytometry Reference Laboratory should be mailed by FEDERAL 
EXPRESS PRIORITY (DELIVERY BEFORE 10 AM) using the COG Federal Express account 
number available at: 
https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf 
 
16.2 
Optional Tissue Banking and Subsequent Biologic Studies 
Specimens to characterize the biologic nature of the disease will focus on four major areas: 
1) immunophenotyping; 2) cytogenetic characterization by FISH; 3) NOTCH mutation analysis; 
and 4) CGH and gene expression profiling. Tissue collection is requested prior to treatment 
initiation and also at the time of relapse. It is anticipated that there will be variability in the type 
and amount of tissue submitted based upon the accessibility of the tumor tissue and the 
feasibility of obtaining it (i.e. patients with large mediastinal masses who are sedation risks will 
be expected to have limited tissue available). Minimum requirements for study entry will include 
sufficient tissue to confirm the diagnosis. Fresh tissue will be obtained whenever possible. All 
available biologic specimens will be sent to the COG Biopathology Center, which will serve as 
the central repository for this component of the study. The study committee will assess the state 
and quantity of material for subsequent studies with allocation to designated laboratories, placing 
priority in the studies in the rank order listed below. The collection, processing, shipping and 
analysis of the tissue have been incorporated into the AALL0434 protocol in order to prevent 
any modification or amendment of the ALL Classification Study (AALL08B1). Specific details 
of the biologic studies include: 
  
1. Immunophenotyping: Immunophenotyping will focus on the characterization of the 
thymic developmental stage of a particular patient’s disease to determine whether this has 
prognostic significance. Emphasis will be placed on those surface markers that can be 
obtained from paraffin embedded tissue that should be available from all patients 
enrolled. This will include CD4-CD8-sCD3-CD1a to establish the developmental stage of 
the disease for each patient. Data from recently completed A5971 suggests that a 


 
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phenotype expressing CD1, CD5, and CD8 may correlate with a poor outcome.100 This 
observation will be examined in this proposal to determine its validity. 
2. Cytogenetic Analysis: Limited cytogenetic analysis (via FISH) will be obtained in all 
specimens with sufficient tissue given the great paucity of data available characterizing 
the nature of cytogenetic abnormalities in LL. Conventional cytogenetic analysis on fresh 
tissue will not be attempted as prior studies have failed to yield sufficient specimens to 
warrant a commitment of resources to this endeavor. This combined with CGH studies 
below will allow a more detailed characterization of the cytogenetic abnormalities in LL. 
3. NOTCH Mutation Analysis: Specimens will be collected to characterize both the 
incidence and prognostic value of the presence of NOTCH mutations and NOTCH 
expression in patients with LL. Data collected from these studies will be correlated to 
disease outcome and gene expression analysis to gain further insight on the relevance of 
NOTCH mutations and the biologic and clinical behavior of the disease. 
4. Comparative Genomic Hybridization (CGH) and Gene Expression Profiling: The 
recently completed A5971 study piloted the feasibility of comparative genomic analysis 
to characterize genetic alterations in a small number of LLs to assess whether this 
technique can identify important genetic alternations, which have been difficult to assess 
due to the limited availability of tissue typically available for cytogenetic analysis. A 
recent COG analysis comparing T-cell ALL to LL utilizing gene expression profiling 
demonstrated that there may be several non overlapping genes expressed, distinguishing 
these two diseases.101 Based upon the findings of A5971, and the availability of 
resources, a targeted approach will be expanded to gain more extensive characterization 
of the incidence of genetic aberrations in LL and their correlation to clinical outcome. 
This may potentially lead to insight of the important genetic features of high risk disease 
and possibly reveal potential targets for new therapies. 
 
For cases with a limited amount of tissue available for analysis, the AALL0434 and NHL 
Biology Committee will prioritize specimens for studies.  
 
16.3 
Preparation of Tissue Banking Samples at Time of Diagnosis or Relapse 
At diagnosis, at least one square centimeter of snap frozen tumor is requested in addition to the 
material required for central review (described in Section 15.5). If more than 1 gram is available, 
cut tissue into 1 gram aliquots. Wrap tissue in foil and snap freeze in liquid nitrogen or cold 
isopentane. Place tissue in zip-loc bag and, using a waterproof marker, label the bag with the 
patient’s BPC number, specimen type and date obtained. Store specimens at -70°C or colder 
until shipped. Include a transmittal form with each shipment of specimens. 
 
If tumor tissue is obtained at the time of relapse for clinical purposes, additional material (as 
described above for diagnosis) is requested for banking and subsequent biologic studies. 
 
The Biopathology Center (BPC) will bank the tissue for future distribution and use including the 
studies listed above. 
 
16.3.1 Specimen Shipping Instructions 
Specimen procurement kits for shipping frozen tumor tissue to the BPC are provided upon 
request. To request a Specimen Procurement Kit, click on the ‘Biopathology Center Application’ 
link on either the Protocol or the CRA Home Page of the COG web site. On the Biopathology 


 
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Center Applications page, select the BPC Kit Management link to enter the Kit Management 
application. Select ‘AALL0434’ to order kits for the submission of frozen tumor tissue. 
Specimen procurement kits must be shipped to the BPC, Monday through Thursday for delivery 
Tuesday through Friday. 
 
1. Before the frozen tissue is placed into the Specimen Procurement Kit, it must first be 
placed in three separate layers of packaging : 
a. Place the tissue in a zip-loc bag. 
b. Place the zip-loc bag in the plastic watertight biohazard diagnostic envelope and seal 
the envelope securely. 
c. Place the clear plastic biohazard diagnostic envelope inside the pressure-proof Tyvek 
diagnostic envelope and seal securely. 
 
2. Place the tissue inside the kit compartment with dry ice. Layer the bottom of the 
compartment with dry ice until it is approximately one-third full. Place the frozen 
specimens on top of the dry ice. Cover the specimens with the dry ice until the 
compartment is almost completely full. 
 
3. Place the transmittal form inside the compartment. 
 
4. Place the stryofoam lid on top to secure specimns during shipment. 
 
5. Close the outer lid of the Specimen Procurement Kit and tape with filament or other 
durable sealing tape. 
 
6. Access the BPC Kit Management application to print a Federal Express shipping label. A 
blank adhesive label is provided in the Specimen Procurement Kit to use when printing 
the shipping label. Attach the shipping label to the top of the kit. Complete the dry ice 
label (UN 1845). Stick the dry ice and Exempt Human Specimen labels to the side of the 
kit.. Arrange for Federal Express pick-up per your usual institutional procedure or by 
calling 1-800-238-5355.  
 
Ship specimens to: 
COG Biopathology Center 
Nationwide Children’s Hospital 
700 Children’s Drive, Room WA1340* 
Columbus, OH 43205 
Phone: (614) 722-2865 
 
* The room number is required. Packages not listing the room number could be denied and 
returned to sender. 
 
 


 
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APPENDIX I:  MER CAPTOPURINE DOSING GUIDELINES 
 
MERCAPTOPURINE 25 mg/m2  
 
Body Surface Area 
(m²)* 
Daily Dose (d) for 7 days 
(1 tablet = 50 mg) 
Cumulative Weekly 
Dose 
0.36 - 0.49 
½ tab / d x 3 
75 mg/wk 
0.50 - 0.64 
½ tab / d x 4 
100 mg/wk 
0.65 - 0.78 
½ tab / d x 5 
125 mg/wk 
0.79 - 0.92 
½ tab / d x 6 
150 mg/wk 
0.93 – 1.07 
½ tab / d x 7 
175 mg/wk 
1.08 – 1.21 
1 tab / d x 1; ½ tab / d x 6 
200 mg/wk 
1.22 – 1.35 
1 tab / d x 2; ½ tab / d x 5 
225 mg/wk 
1.36 – 1.49 
1 tab / d x 3; ½ tab / d x 4 
250 mg/wk 
1.50 – 1.64 
1 tab / d x 4; ½ tab / d x 3 
275 mg/wk 
1.65 – 1.78 
1 tab / d x 5; ½ tab / d x 2 
300 mg/wk 
1.79 – 1.92 
1 tab / d x 6; ½ tab / d x 1 
325 mg/wk 
1.93 – 2.07 
1 tab / d x 7 
350 mg/wk 
2.08 – 2.21 
1½ tab / d x 1; 1 tab / d x 6 
375 mg/wk 
2.22 - 2.35 
1½ tab / d x 2; 1 tab / d x 5 
400 mg/wk 
2.36 – 2.49 
1½ tab / d x 3; 1 tab / d x 4 
425 mg/wk 
2.50 – 2.64 
1½ tab / d x 4; 1 tab / d x 3 
450 mg/wk 
2.65 – 2.78 
1½ tab / d x 5; 1 tab / d x 2 
475 mg/wk 
2.79 – 2.92 
1½ tab / d x 6; 1 tab / d x 1 
500 mg/wk 
2.93 – 3.00* 
1½ tab / d x 7 
525 mg/wk 
*Patients exceeding a BSA of 3.00 m2 should have their MP doses calculated on actual BSA with no 
maximum dose. 


 
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MERCAPTOPURINE  60 mg/m2 
 
Body Surface Area 
(m²)* 
Daily Dose (d) for 7 days 
(1 tablet = 50 mg) 
Cumulative 
Weekly Dose 
0.33 - 0.38 
½ tab / d x 6 
150 mg/wk 
0.39 - 0.44 
½ tab / d x 7 
175 mg/wk 
0.45 - 0.50 
½ tab / d x 6; 1 tab / d x 1 
200 mg/wk 
0.51 - 0.56 
½ tab / d x 5; 1 tab / d x 2 
225 mg/wk 
0.57 - 0.62 
½ tab / d x 4; 1 tab / d x 3 
250 mg/wk 
0.63 - 0.68 
1 tab / d x 4; ½ tab / d x 3 
275 mg/wk 
0.69 - 0.74 
1 tab / d x 5; ½ tab / d x 2 
300 mg/wk 
0.75 - 0.80 
1 tab / d x 6; ½ tab / d x 1 
325 mg/wk 
0.81 - 0.86 
1 tab / d x 7 
350 mg/wk 
0.87 - 0.92 
1 tab / d x 6; 1½ tab / d x 1 
375 mg/wk 
0.93 - 0.98 
1 tab / d x 5; 1½ tab / d x 2 
400 mg/wk 
0.99 - 1.04 
1 tab / d x 4; 1½ tab / d x 3 
425 mg/wk 
1.05 - 1.10 
1½ tab / d x 4; 1 tab / d x 3 
450 mg/wk 
1.11 - 1.16 
1½ tab / d x 5; 1 tab / d x 2 
475 mg/wk 
1.17 - 1.22 
1½ tab / d x 6; 1 tab / d x 1 
500 mg/wk 
1.23 - 1.27 
1½ tab / d x 7 
525 mg/wk 
1.28 - 1.33 
1½ tab / d x 6; 2 tab / d x 1 
550 mg/wk 
1.34 - 1.39 
1½ tab / d x 5; 2 tab / d x 2 
575 mg/wk 
1.40 - 1.45 
1½ tab / d x 4; 2 tab / d x 3 
600 mg/wk 
1.46 - 1.51 
2 tab / d x 4; 1½ tab / d x 3 
625 mg/wk 
1.52 - 1.57 
2 tab / d x 5; 1½ tab / d x 2 
650 mg/wk 
1.58 - 1.63 
2 tab / d x 6; 1½ tab / d x 1 
675 mg/wk 
1.64 - 1.69 
2 tab / d x 7 
700 mg/wk 
1.70 - 1.75 
2 tab / d x 6; 2½ tab / d x 1 
725 mg/wk 
1.76 - 1.81 
2 tab / d x 5; 2½ tab / d x 2 
750 mg/wk 


 
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1.82 - 1.87 
2 tab / d x 4; 2½ tab / d x 3 
775 mg/wk 
1.88 - 1.93 
2½ tab / d x 4; 2 tab / d x 3 
800 mg/wk 
1.94 - 1.99 
2½ tab / d x 5; 2 tab / d x 2 
825 mg/wk 
2.00 - 2.05 
2½ tab / d x 6; 2 tab / d x 1 
850 mg/wk 
2.06 - 2.11 
2½ tab/ d x 7 
875 mg/wk 
2.12 - 2.17 
2½ tab/ d x 6; 3 tab / d x 1 
900 mg/wk 
2.18 - 2.23 
2½ tab/ d x 5; 3 tab / d x 2 
925 mg/wk 
2.24 - 2.29 
2½ tab/ d x 4; 3 tab / d x 3 
950 mg/wk 
2.30 - 2.35 
3 tab/ d x 4; 2½ tab / d x 3 
975 mg/wk 
2.36 - 2.41 
3 tab/ d x 5; 2½ tab / d x 2 
1000 mg/wk 
2.42 - 2.47 
3 tab/ d x 6; 2½ tab / d x 1 
1025 mg/wk 
2.48 - 2.52 
3 tab/ d x 7 
1050 mg/wk 
2.53 - 2.58 
3 tab/ d x 6; 3½ tab / d x 1 
1075 mg/wk 
2.59 - 2.64 
3 tab/ d x 5; 3½ tab / d x 2 
1100 mg/wk 
2.65 - 2.70 
3 tab/ d x 4; 3½ tab / d x 3 
1125 mg/wk 
2.71 - 2.76 
3½ tab/ d x 4; 3 tab / d x 3 
1150 mg/wk 
2.77 - 2.82 
3½ tab/ d x 5; 3 tab / d x 2 
1175 mg/wk 
2.83 - 2.88 
3½ tab/ d x 6; 3 tab / d x 1 
1200 mg/wk 
2.89 - 2.94 
3½ tab/ d x 7 
1225 mg/wk 
2.95 - 3.00 
3½ tab/ d x 6; 4 tab / d x 1 
1250 mg/wk 
*Patients exceeding a BSA of 3.00 m2 should have their MP doses calculated on actual 
BSA with no maximum dose. 
 


 
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MERCAPTOPURINE 75 mg/m2  
 
Body Surface 
Area (m²)* 
Daily Dose (d) for 7 days 
(1 tablet = 50 mg) 
Cumulative 
Weekly Dose 
0.36 - 0.40 
½ tab / d x 6; 1 tab / d x 1 
200 mg/wk 
0.41 - 0.45 
½ tab / d x 5; 1 tab / d x 2 
225 mg/wk 
0.46 - 0.49 
½ tab / d x 4; 1 tab / d x 3 
250 mg/wk 
0.50 - 0.54 
1 tab / d x 4; ½ tab / d x 3 
275 mg/wk 
0.55 - 0.59 
1 tab / d x 5; ½ tab / d x 2 
300 mg/wk 
0.60 - 0.64 
1 tab / d x 6; ½ tab / d x 1 
325 mg/wk 
0.65 - 0.69 
1 tab / day 
350 mg/wk 
0.70 - 0.73 
1 tab / d x 6; 1½ tab / d x 
1 
375 mg/wk 
0.74 - 0.78 
1 tab / d x 5; 1½ tab / d x 
2 
400 mg/wk 
0.79 - 0.83 
1 tab / d x 4; 1½ tab / d x 
3 
425 mg/wk 
0.84 - 0.88 
1½ tab / d x 4; 1 tab / d x 
3 
450 mg/wk 
0.89 - 0.92 
1½ tab / d x 5; 1 tab / d x 
2 
475 mg/wk 
0.93 - 0.97 
1½ tab / d x 6; 1 tab /d x 
1 
500 mg/wk 
0.98 - 1.02 
1½ tab / day 
525 mg/wk 
1.03 - 1.07 
1½ tab / d x 6; 2 tab / d x 
1 
550 mg/wk 
1.08 - 1.11 
1½ tab / d x 5; 2 tab / d x 
2 
575 mg/wk 
1.12 - 1.16 
1½ tab / d x 4; 2 tab / d x 
3 
600 mg/wk 
1.17 - 1.21 
2 tab / d x 4; 1½ tab / d x 
3 
625 mg/wk 
1.22 - 1.26 
2 tab / d x 5; 1½ tab / d x 
2 
650 mg/wk 
1.27 - 1.30 
2 tab / d x 6; 1½ tab / d x 
1 
675 mg/wk 
1.31 - 1.35 
2 tab / day 
700 mg/wk 
1.36 - 1.40 
2 tab / d x 6; 2½ tab / d x 
1 
725 mg/wk 
1.41 - 1.45 
2 tab / d x 5; 2½ tab / d x 
2 
750 mg/wk 
1.46 – 1.49 
2 tab / d x 4; 2½ tab / d x 
3 
775 mg/wk 
1.50 – 1.54 
2½ tab/ d x 4; 2 tab / d x 
3 
800 mg/wk 


 
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1.55 – 1.59 
2½ tab/ d x 5; 2 tab / d x 
2 
825 mg/wk 
1.60 – 1.64 
2½ tab/ d x 6; 2 tab / d x 
1 
850 mg/wk 
1.65 – 1.69 
2½ tab/ d 
875 mg/wk 
1.70 – 1.73 
2½ tab/ d x 6; 3 tab / d x 
1 
900 mg/wk 
1.74 – 1.78 
2½ tab/ d x 5; 3 tab / d x 
2 
925 mg/wk 
1.79 – 1.83 
2½ tab/ d x 4; 3 tab / d x 
3 
950 mg/wk 
1.84 – 1.88 
3 tab/ d x 4; 2½ tab / d x 
3 
975 mg/wk 
1.89 – 1.92 
3 tab/ d x 5; 2½ tab / d x 
2 
1000 mg/wk 
1.93 – 1.97 
3 tab/ d x 6; 2½ tab / d x 
1 
1025 mg/wk 
1.98 – 2.02 
3 tab/ d x 7 
1050 mg/wk 
2.03 – 2.07 
3 tab/ d x 6; 3½ tab / d x 
1 
1075 mg/wk 
2.08 – 2.11 
3 tab/ d x 5; 3½ tab / d x 
2 
1100 mg/wk 
2.12 – 2.16 
3 tab/ d x 4; 3½ tab / d x 
3 
1125 mg/wk 
2.17 – 2.21 
3½ tab/ d x 4; 3 tab / d x 
3 
1150 mg/wk 
2.22 – 2.26 
3½ tab/ d x 5; 3 tab / d x 
2 
1175 mg/wk 
2.27 – 2.30 
3½ tab/ d x 6; 3 tab / d x 
1 
1200 mg/wk 
2.31 – 2.35 
3½ tab/ d x 7 
1225 mg/wk 
2.36 – 2.40 
3½ tab/ d x 6; 4 tab / d x 
1 
1250 mg/wk 
2.41 – 2.45 
3½ tab/ d x 5; 4 tab / d x 
2 
1275 mg/wk 
2.46 – 2.49 
3½ tab/ d x 4; 4 tab / d x 
3 
1300 mg/wk 
2.50 – 2.54 
4 tab/ d x 4; 3½ tab / d x 
3 
1325 mg/wk 
2.55 – 2.59 
4 tab/ d x 5; 3½ tab / d x 
2 
1350 mg/wk 
2.60 – 2.64 
4 tab/ d x 6; 3½ tab / d x 
1 
1375 mg/wk 
2.65 – 2.69 
4 tab/ d x 7 
1400 mg/wk 
2.70 – 2.73 
4 tab/ d x 6; 4½ tab / d x 
1 
1425 mg/wk 


 
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2.74 – 2.78 
4 tab/ d x 5; 4½ tab / d x 
2 
1450 mg/wk 
2.79 – 2.83 
4 tab/ d x 4; 4½ tab / d x 
3 
1475 mg/wk 
2.84 – 2.88 
4½ tab/ d x 4; 4 tab / d x 
3 
1500 mg/wk 
2.89 – 2.92 
4½ tab/ d x 5; 4 tab / d x 
2 
1525 mg/wk 
2.93 – 2.97 
4½ tab/ d x 6; 4 tab / d x 
1 
1550 mg/wk 
2.98 – 3.00 
4½ tab/ d x 7 
1575 mg/wk 
*Patients exceeding a BSA of 3.00 m2 should have their MP doses calculated 
on actual BSA with no maximum dose. 
 


 
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Version date: 03/24/16                   Page 168 
APPENDIX II : THIOGUANINE DOSING GUIDELINES 
 
 
THIOGUANINE  60 mg/m2 
 
Body Surface 
Area (m²)* 
Daily Dose (d) for 7 days 
(1 tablet = 40 mg) 
Cumulative 
Weekly Dose 
0.31 - 0.35 
½ tab / d x 7 
140 mg/wk 
0.36 - 0.40 
½ tab / d x 6; 1 tab / d x 1 
160 mg/wk 
0.41 - 0.45 
½ tab / d x 5; 1 tab / d x 2 
180 mg/wk 
0.46 - 0.49 
½ tab / d x 4; 1 tab / d x 3 
200 mg/wk 
0.50 - 0.54 
1 tab / d x 4; ½ tab / d x 3 
220 mg/wk 
0.55 - 0.59 
1 tab / d x 5; ½ tab / d x 2 
240 mg/wk 
0.60 - 0.64 
1 tab/ d x 6; ½ tab / d x 1 
260 mg/wk 
0.65 - 0.69 
1 tab / day 
280 mg/wk 
0.70 - 0.73 
1 tab / d x 6; 1½ tab / d x 1 
300 mg/wk 
0.74 - 0.78 
1 tab / d x 5; 1½ tab / d x 2 
320 mg/wk 
0.79 - 0.83 
1 tab/ d x 4; 1½ tab / d x 3 
340 mg/wk 
0.84 - 0.88 
1½ tab / d x 4; 1 tab / d x 3 
360 mg/wk 
0.89 - 0.92 
1½ tab / d x 5; 1 tab /d x 2 
380 mg/wk 
0.93 - 0.97 
1½ tab / d x 6; 1 tab / d x 1 
400 mg/wk 
0.98 - 1.02 
1½ tab /day 
420 mg/wk 
1.03 - 1.07 
1½ tab / d x 6; 2 tab / d x 1 
440 mg/wk 
1.08 - 1.11 
1½ tab / d x 5; 2 tab / d x 2 
460 mg/wk 
1.12 - 1.16 
1½ tab / d x 4; 2 tab / d x 3 
480 mg/wk 
1.17 - 1.21 
2 tab / d x 4; 1½ tab / d x 3 
500 mg/wk 
1.22 - 1.26 
2 tab / d x 5; 1½ tab / d x 2 
520 mg/wk 
1.27 - 1.30 
2 tab / d x 6; 1½ tab / d x 1 
540 mg/wk 
1.31 - 1.35 
2 tab / day 
560 mg/wk 
1.36 - 1.40 
2 tab / d x 6; 2½ tab / d x 1 
580 mg/wk 
1.41 - 1.45 
2 tab / d x 5; 2½ tab / d x 2 
600 mg/wk 
1.46 - 1.49 
2 tab / d x 4; 2½ tab / d x 3 
620 mg/wk 
1.50 - 1.54 
2½ tab / d x 4; 2 tab / d x 3 
640 mg/wk 
1.55 - 1.59 
2½ tab / d x 5; 2 tab / d x 2 
660 mg/wk 
1.60 - 1.64 
2½ tab / d x 6; 2 tab / d x 1 
680 mg/wk 
1.65 - 1.69 
2½ tab / d 
700 mg/wk 
1.70 - 1.73 
2½ tab / d x 6; 3 tab / d x 1 
720 mg/wk 
1.74 - 1.78 
2½ tab / d x 5; 3 tab / d x 2 
740 mg/wk 
1.79 - 1.83 
2½ tab / d x 4; 3 tab / d x 3 
760 mg/wk 
1.84 - 1.88 
3 tab / d x 4; 2½ tab / d x 3 
780 mg/wk 
1.89 - 1.92 
3 tab / d x 5; 2½ tab / d x 2 
800 mg/wk 
1.93 - 1.97 
3 tab / d x 6; 2½ tab / d x 1 
820 mg/wk 
1.98 - 2.02 
3 tab / d x 7 
840 mg/wk 
2.03 - 2.07 
3 tab / d x 6; 3½ tab / d x 1 
860 mg/wk 
2.08 - 2.11 
3 tab / d x 5; 3½ tab / d x 2 
880 mg/wk 


 
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2.12 - 2.16 
3 tab / d x 4; 3½ tab / d x 3 
900 mg/wk 
2.17 - 2.21 
3½ tab / d x 4; 3 tab / d x 3 
920 mg/wk 
2.22 - 2.26 
3½ tab / d x 5; 3 tab / d x 2 
940 mg/wk 
2.27 – 2.30 
3½ tab / d x 6; 3 tab / d x 1 
960 mg/wk 
2.31 – 2.35 
3½ tab / d x 7 
980 mg/wk 
2.36 – 2.40 
3½  tab / d x 6; 4 tab / d x 1 
1000 mg/wk 
2.41 – 2.45 
3½  tab / d x 5; 4 tab / d x 2 
1020 mg/wk 
2.46 – 2.49 
3½ tab / d x 4; 4 tab / d x 3 
1040 mg/wk 
2.50 – 2.54 
4 tab / d x 4; 3½  tab / d x 3 
1060 mg/wk 
2.55 – 2.59 
4 tab / d x 5; 3½  tab / d x 2 
1080 mg/wk 
2.60 – 2.64 
4 tab / d x 6; 3½  tab / d x 1 
1100 mg/wk 
2.65 – 2.69 
4 tab / d x 7 
1120 mg/wk 
2.70 – 2.73 
4  tab / d x 6; 4½ tab / d x 1 
1140 mg/wk 
2.74 – 2.78 
4  tab / d x 5; 4½ tab / d x 2 
1160 mg/wk 
2.79 – 2.83 
4 tab / d x 4; 4½ tab / d x 3 
1180 mg/wk 
2.84 – 2.88 
4½ tab / d x 4; 4  tab / d x 3 
1200 mg/wk 
2.89 – 2.92 
4½ tab / d x 5; 4  tab / d x 2 
1220 mg/wk 
2.93 – 2.97 
4½ tab / d x 6; 4  tab / d x 1 
1240 mg/wk 
2.98 – 3.00 
4½ tab / d x 7 
1260 mg/wk 
*Patients exceeding a BSA of 3.00 m2 should have their TG doses calculated on 
actual BSA with no maximum dose. 
 
 


 
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AALL0434 
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APPENDIX III: CYP3A4/5 INHIBITORS AND INDUCERS 
 
 
Adapted from Cytochrome P-450 Enzymes and Drug Metabolism. In: Lacy CF, Armstrong LL, Goldman MP, 
Lance LL eds. Drug Information Handbook 8th edition. Hudson, OH; LexiComp Inc. 2000: 1364-1371. 
 
CYP3A4/5 Inhibitors:  
 
CYP3A4/5 Inducers: 
Amiodarone  
Anastrozole  
Azithromycin  
Cannabinoids 
Cimetidine 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delaviridine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazem 
Dirithromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole (weak) 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
Indinavir 
Isoniazid 
Itraconazole 
Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole (moderate) 
Nefazodone 
Nelfinavir 
Nevirapine 
Norfloxacin 
Norfluoxetine 
Omeprazole (weak) 
Oxiconazole 
Paroxetine (weak) 
Posaconazole 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir 
Roxithromycin 
Saquinavir 
Sertindole 
Sertraline 
Telithromycin 
Troleandomycin 
Valproic acid (weak) 
Verapamil 
Voriconazole 
Zafirlukast 
Zileuton 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carbamazepine 
Dexamethasone 
Ethosuximide 
Glucocorticoids 
Griseofulvin 
Modafinil 
Nafcillin 
Nelfinavir 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenylbutazone 
Phenytoin 
Primidone 
Progesterone 
Rifabutin 
Rifapentine 
Rifampin 
Rofecoxib (mild) 
St. John’s Wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
This list may not be comprehensive due to new agents coming to market. Below is a link to a list of drugs that 
are metabolized by cytochrome P450 isoform. Drug names are hyperlinks to specific literature references, 
most of which include a link to the abstract of the article in the NLM's PubMed database.  
 
http://medicine.iupui.edu/flockhart/ 


 
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Draw 24-hr MTX level 
& Creatinine 
 
MTX <150 µM 
 
MTX >150 µM 
or 
Cr > 125% baseline 
Draw 36-hr MTX level++ 
(& Creatinine) 
MTX >3 µM 
MTX >10 µM 
Consider glucarpidase 
Increase hydration 
to 200 mL/m2/hr 
Draw MTX level (& Creatinine) 
at Hr 42++ & Hr 48 
Continue standard hydration 
(i.e @ 125 mL/m2/hr) 
MTX <3 µM 
Hr 42 ≤1 µM 
  
  Hr 48 ≤0.4 µM 
LCV 15 mg/m2 at 
hrs 42, 48, & 54, 
then stop LCV 
 
- No further MTX 
levels required 
LCV 15 mg/m2 at 
hrs 42, 48, & 54 and 
continue q6hrs until 
MTX level < 0.1 
µM 
 
- Repeat MTX 
levels q12-24 hrs 
Hr 42 = 10-19.9 µM 
  
Hr 48 = 6-9.9 µM 
Hr 42 = 20-200 µM 
  
Hr 48 = 10-100 µM 
Hr 42 >200 µM 
   
    Hr 48 >100 µM 
Hr 42 = 1.01-9.9 µM 
 
Hr 48 = 0.41-5.9 µM 
LCV 15 mg/m2 
starting at hr 42 and 
continue q3hrs, until 
MTX level < 0.1 µM 
 
Repeat MTX levels 
q6-24 hrs 
 
Consider 
glucarpidase 
LCV 100 mg/m2 
starting at hr 42 and 
continue q6hrs, until 
MTX level < 0.1 µM 
 
Repeat MTX levels 
q6-24 hrs 
 
Consider 
glucarpidase 
LCV 1000 mg/m2 
starting at hr 42 and 
continue q6hrs, until 
MTX level < 0.1 µM 
 
Repeat MTX levels 
q6-24 hrs 
 
Consider 
glucarpidase 
++ If the level is high at hour 36 or 42, but then the patient “catches up” and the level falls to the expected values of ≤1 and/or 
≤0.4 µM at hours 42 and 48, respectively, resume standard leucovorin and hydration as long as urine output remains satisfactory. 
Consider repeat 
MTX level to r/o 
contamination. 
Increase 
hydration while 
awaiting result  
APPENDIX IV: HIGH-DOSE MET HOTREXATE FLOW CHART 
(Please refer to Section 5.8 for complete details; all levels are timed from the start of the 
HDMTX infusion) 
 
 


 
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Version date: 03/24/16                   Page 172 
APPENDIX 
V: 
MODIFIED 
(“BALIS”) 
PEDIATRIC 
SCALE 
OF 
PERIPHERAL 
NEUROPATHIES 
 
 
Peripheral Motor Neuropathy: 
• Grade 1: Subjective weakness, but no deficits detected on neurological exam, other than 
abnormal deep tendon reflexes. 
 
• Grade 2: Weakness that alters fine motor skills (buttoning shirt, coloring, writing or drawing, 
using eating utensils) or gait without abrogating ability to perform these tasks. 
 
• Grade 3: Unable to perform fine motor tasks (buttoning shirt, coloring, writing or drawing, 
using eating utensils) or unable to ambulate without assistance. 
 
• Grade 4: Paralysis. 
 
Peripheral Sensory Neuropathy: 
• Grade 1: Paresthesias, pain, or numbness that do not require treatment or interfere with 
extremity function. 
 
• Grade 2: Paresthesias, pain, or numbness that are controlled by non-narcotic medications 
(without causing loss of function), or alteration of fine motor skills (buttoning shirt, writing or 
drawing, using eating utensils) or gait, without abrogating ability to perform these tasks. 
 
• Grade 3: Paresthesias or pain that are controlled by narcotics, or interfere with extremity 
function (gait, fine motor skills as outlined above), or quality of life (loss of sleep, ability to 
perform normal activities severely impaired). 
 
• Grade 4: Complete loss of sensation, or pain that is not controlled by narcotics. 
  
 


 
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APPENDIX VI: YOUTH INFORMA TION SHEE TS FOR PATIENTS WIT H T-CELL ALL 
 
INFORMATION SHEET REGARDING RESEARCH STUDY AALL0434 
(for children from 7 through 12 years of age) 
 
Intensified Methotrexate, Nelarabine and Augmented Therapy for Children and Young Adults 
with T-cell Acute Lymphoblastic Leukemia (ALL) or T-cell Lymphoblastic Lymphoma 
 
1. We have been talking with you about a type of cancer called T-cell acute lymphoblastic 
leukemia or T-ALL. T-ALL is a type of cancer that only affects T-cells (a special kind of cell 
of your immune system). T-cell ALL grows in the bone marrow. The bone marrow is inside 
your bones. It is where your blood is made. After doing tests, we have found that you have 
this type of cancer. 
 
2. We are asking you to take part in a research study because you have T-ALL. A research 
study is when doctors work together to try out new ways to help people who are sick. In this 
study, we are trying to learn more about how to treat T-ALL. We will do this by comparing 4 
ways to treat T-ALL. Some of the children in this study will get the usual treatment for T-
ALL. Some of the children will get extra chemotherapy. We don’t know which way is better. 
That is why we are doing this study. 
 
3. Children who are part of this study will be treated with chemotherapy. Chemotherapy is a 
type of medicine that destroys cancer cells. Sometimes X-ray treatments are also given to 
patients to help kill cancer that is in the brain and/or testicles (if you are a male) or to keep 
the cancer from moving into the brain. You will have regular blood tests and several bone 
marrow tests and spinal taps during your treatment. The bone marrow tests and spinal taps 
may hurt some, but medicines will be given to keep it from hurting too much. 
 
4. Sometimes good things can happen to people when they are in a research study. These good 
things are called ‘benefits’. We hope that a benefit to you of being part of this study is 
keeping the cancer away for as long as possible, but we don’t know for sure if there is any 
benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad 
things are called ‘risks’. The risks to you from this study are increased toxicities that can 
cause infections or make it harder for a patient to fight off infections, loss of healthy blood 
cells and damage to bones or joints. Steroid drugs, such as the dexamethasone (and less 
frequently prednisone), are known causes of a disease called “osteonecrosis” (ON). 
Osteonecrosis results from the temporary or permanent loss of the blood supply to the bones. 
Without blood, the bone tissue dies and causes the bone to breakdown. ON is most 
commonly seen in the hip joint. If the bones near a joint breakdown it can cause the joint to 
collapse. The exact reason why corticosteroids cause ON is not known. For patients receiving 
extra chemotherapy, there is also the risk of side effects involving the nerves, such as 
numbness and tingling and weakness. Most of the time these side effects are mild and go 
away within a few days. In rare cases the nerve side effects may be very severe, and then 
may last for a long time and may not completely go away. It is also possible that your 


 
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AALL0434 
Version date: 03/24/16                   Page 174 
treatment plan may increase the side effects of treatment without improving the chances of 
getting rid of the cancer for as long as possible.  
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop 
being in this study at any time once you start. There may be other treatments for your illness 
that your doctor can tell you about. Make sure to ask your doctors any questions that you 
have. 
 
 
 


 
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AALL0434 
Version date: 03/24/16                   Page 175 
INFORMATION SHEET REGARDING RESEARCH STUDY AALL0434 
(for teens from 13 through 17 years of age) 
 
Intensified Methotrexate, Nelarabine and Augmented BFM Therapy for Children and Young 
Adults with Newly Diagnosed T-cell Acute Lymphoblastic Leukemia (ALL) or T-cell 
Lymphoblastic Lymphoma 
 
1. We have been talking with you about a type of cancer called T-cell acute lymphoblastic 
leukemia or T-ALL. T-ALL is a type of cancer that only affects T-cells (a special kind of cell 
of your immune system). T-cell ALL grows in the bone marrow. The bone marrow is inside 
your bones. It is where your blood is made. After doing tests, we have found that you have 
this type of cancer. 
 
2. We are asking you to take part in a research study because you have T-ALL. A research 
study is when doctors work together to try out new ways to help people who are sick. In this 
study, we are trying to learn more about how to treat T-ALL. We will do this by comparing 4 
ways to treat T-ALL: 
• 
Standard chemotherapy for T-ALL 
• 
Standard chemotherapy for T-ALL, plus an experimental drug called Nelarabine 
• 
Augmented chemotherapy for T-ALL, which is standard chemotherapy with high-
dose methotrexate substituted for methotrexate 
• 
Augmented chemotherapy for T-ALL, plus Nelarabine 
 
Some of the children and teens in this study will get the usual treatment for T-ALL. Some of 
the children and teens will get extra chemotherapy. We don’t know which way is better. That 
is why we are doing this study. 
 
3. Children and teens who are part of this study will be treated with chemotherapy. 
Chemotherapy is a type of medicine that destroys cancer cells. Sometimes X-ray treatments 
are also given to patients to help kill cancer that is in the brain and/or testicles (if you are a 
male) or to keep the cancer from moving into the brain. You will have regular blood tests and 
several bone marrow tests and spinal taps during your treatment. The bone marrow tests and 
spinal taps may hurt some, but medicines will be given to keep it from hurting too much. 
 
4. Sometimes good things can happen to people when they are in a research study. These good 
things are called ‘benefits’. We hope that a benefit to you of being part of this study is 
keeping the cancer away for as long as possible, but we don’t know for sure if there is any 
benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad 
things are called ‘risks’. The risks to you from this study are increased toxicities that can 
cause infections or make it harder for a patient to fight off infections, loss of healthy blood 
cells and damage to bones or joints. 
 
Steroid drugs, such as the dexamethasone (and less frequently prednisone), are known causes 
of a disease called “osteonecrosis” (ON). Osteonecrosis results from the temporary or 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0434 
Version date: 03/24/16                   Page 176 
permanent loss of the blood supply to the bones. Without blood, the bone tissue dies and 
causes the bone to breakdown. ON is most commonly seen in the hip joint. If the bones near 
a joint breakdown it can cause the joint to collapse. The exact reason why corticosteroids 
cause ON is not known. 
 
For patients receiving Nelarabine, there is also the risk of side effects involving the nerves, 
such as numbness and tingling and weakness. Most of the time these side effects are mild and 
go away within a few days. In rare cases the nerve side effects may be very severe, and then 
may last for a long time and may not completely go away. It is also possible that adding 
Nelarabine and/or high-dose methotrexate to your treatment plan may increase the side 
effects of treatment without improving the chances of getting rid of the cancer for as long as 
possible. Adding Nelarabine and/or high-dose methotrexate to your treatment plan could also 
reduce how well your treatment works. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop 
being in this study at any time once you start. There may be other treatments for your illness 
that your doctor can tell you about. Make sure to ask your doctors any questions that you 
have. 
 
 
 
 


 
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Version date: 03/24/16                   Page 177 
APPENDIX VII: YOUTH INFORMA TION SHEETS FOR PATIENTS WITH T-CELL NHL 
 
INFORMATION SHEET REGARDING RESEARCH STUDY AALL0434 
(for children from 7 through 12 years of age) 
 
Intensified Methotrexate, Nelarabine and Augmented Therapy for Children and Young Adults 
with T-cell Acute Lymphoblastic Leukemia (ALL) or T-cell Lymphoblastic Lymphoma 
 
1. We have been talking with you about a type of cancer called T-cell lymphoblastic lymphoma 
or  
T-NHL. T-NHL is a type of cancer that occurs in the lymph system, which is made up of the 
lymph nodes and other lymph tissue throughout the body. Lymph tissue makes and stores 
infection-fighting white blood cells called lymphocytes. These cells become cancerous when 
a subject has lymphoma. After doing tests, we have found that you have this type of cancer. 
 
2. We are asking you to take part in a research study because you have T-NHL. A research 
study is when doctors work together to try out new ways to help people who are sick. In this 
study, we are trying to learn more about how to treat T-NHL. We will do this by comparing 2 
ways to treat T-NHL. Some of the children in this study will get the usual treatment for T-
NHL. Some of the children will get extra chemotherapy. We don’t know which way is better. 
That is why we are doing this study. 
 
3. Children who are part of this study will be treated with chemotherapy. Chemotherapy is a 
type of medicine that destroys cancer cells. You will have regular blood tests and several 
bone marrow tests and spinal taps during your treatment. You will also have scans performed 
to make sure the T-NHL is responding to treatment. The bone marrow tests and spinal taps 
may hurt some, but medicines will be given to keep it from hurting too much. 
 
4. Sometimes good things can happen to people when they are in a research study. These good 
things are called ‘benefits’. We hope that a benefit to you of being part of this study is 
keeping the cancer away for as long as possible, but we don’t know for sure if there is any 
benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad 
things are called ‘risks’. The risks to you from this study are increased toxicities that can 
cause infections or make it harder for a patient to fight off infections, loss of healthy blood 
cells and damage to bones or joints. Steroid drugs, such as the dexamethasone (and less 
frequently prednisone), are known causes of a disease called “osteonecrosis” (ON). 
Osteonecrosis results from the temporary or permanent loss of the blood supply to the bones. 
Without blood, the bone tissue dies and causes the bone to breakdown. ON is most 
commonly seen in the hip joint. If the bones near a joint breakdown it can cause the joint to 
collapse. The exact reason why corticosteroids cause ON is not known. For patients receiving 
extra chemotherapy, there is also the risk of side effects involving the nerves, such as 
numbness and tingling and weakness. Most of the time these side effects are mild and go 
away within a few days. In rare cases the nerve side effects may be very severe, and then 
may last for a long time and may not completely go away. It is also possible that your 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0434 
Version date: 03/24/16                   Page 178 
treatment plan may increase the side effects of treatment without improving the chances of 
getting rid of the cancer for as long as possible.  
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop 
being in this study at any time once you start. There may be other treatments for your illness 
that your doctor can tell you about. Make sure to ask your doctors any questions that you 
have. 
 
 
 


 
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AALL0434 
Version date: 03/24/16                   Page 179 
INFORMATION SHEET REGARDING RESEARCH STUDY AALL0434 
(for teens from 13 through 17 years of age) 
 
Intensified Methotrexate, Nelarabine and Augmented BFM Therapy for Children and Young 
Adults with Newly Diagnosed T-cell Acute Lymphoblastic Leukemia (ALL) or T-cell 
Lymphoblastic Lymphoma 
 
1. We have been talking with you about a type of cancer called T-cell lymphoblastic lymphoma 
or  
T-NHL. T-NHL is a type of cancer that occurs in the lymph system, which is made up of the 
lymph nodes and other lymph tissue throughout the body. Lymph tissue makes and stores 
infection-fighting white blood cells called lymphocytes. These cells become cancerous when 
a subject has lymphoma. After doing tests, we have found that you have this type of cancer. 
 
2. We are asking you to take part in a research study because you have T-NHL. A research 
study is when doctors work together to try out new ways to help people who are sick. In this 
study, we are trying to learn more about how to treat T-NHL. We will do this by comparing 2 
ways to treat T-NHL: 
• 
Standard chemotherapy for T-NHL 
• 
Standard chemotherapy for T-NHL, plus an experimental drug called Nelarabine 
 
Some of the children and teens in this study will get the usual treatment for T-NHL. Some of 
the children and teens will get extra chemotherapy. We don’t know which way is better. That 
is why we are doing this study. 
 
3. Children and teens who are part of this study will be treated with chemotherapy. 
Chemotherapy is a type of medicine that destroys cancer cells. You will have regular blood 
tests and several bone marrow tests and spinal taps during your treatment. You will also have 
scans performed to make sure the T-NHL is responding to treatment. The bone marrow tests 
and spinal taps may hurt some, but medicines will be given to keep it from hurting too much. 
 
4. Sometimes good things can happen to people when they are in a research study. These good 
things are called ‘benefits’. We hope that a benefit to you of being part of this study is 
keeping the cancer away for as long as possible, but we don’t know for sure if there is any 
benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad 
things are called ‘risks’. The risks to you from this study are increased toxicities that can 
cause infections or make it harder for a patient to fight off infections, loss of healthy blood 
cells and damage to bones or joints. 
 
Steroid drugs, such as the dexamethasone (and less frequently prednisone), are known causes 
of a disease called “osteonecrosis” (ON). Osteonecrosis results from the temporary or 
permanent loss of the blood supply to the bones. Without blood, the bone tissue dies and 
causes the bone to breakdown. ON is most commonly seen in the hip joint. If the bones near 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AALL0434 
Version date: 03/24/16                   Page 180 
a joint breakdown it can cause the joint to collapse. The exact reason why corticosteroids 
cause ON is not known. 
 
For patients receiving Nelarabine, there is also the risk of side effects involving the nerves, 
such as numbness and tingling and weakness. Most of the time these side effects are mild and 
go away within a few days. In rare cases the nerve side effects may be very severe, and then 
may last for a long time and may not completely go away. It is also possible that adding 
Nelarabine to your treatment plan may increase the side effects of treatment without 
improving the chances of getting rid of the cancer for as long as possible. Adding Nelarabine 
to your treatment plan could also reduce how well your treatment works. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop 
being in this study at any time once you start. There may be other treatments for your illness 
that your doctor can tell you about. Make sure to ask your doctors any questions that you 
have. 
 
 
 
 


 
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APPENDIX 
VIII: 
STAGING 
CLASSIFICATION 
OF 
CHILDHOOD 
NON-HODGKIN 
LYMPHO MA 
 
 


 
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APPENDIX 
IX: 
AGGREGATE 
ANALYSIS 
OF 
PATIENTS 
WHO 
EXPERIENCED 
RHABDOMYOLYSIS IN TRIALS USING NELARABINE 
 
AE #1147179 (Protocol AALL0434): 
A 4-year-old male with precursor T-cell acute lymphoblastic leukemia (T-cell ALL) experienced elevated 
alanine aminotransferase (ALT), elevated aspartate aminotransferase (AST), bilateral lower limb muscle 
weakness, and rhabdomyolysis while on the consolidation arm of a phase 2/3 study using the 
investigational agent nelarabine in combination with methotrexate, cyclophosphamide, cytarabine, 
mercaptopurine, vincristine, pegaspargase, and radiation therapy.   
 
The patient received nelarabine as scheduled from April 19, 2011 to April 23, 2011, and tolerated the 
treatment well while in the hospital. On April 23, 2011 (Cycle 2, Day 5), laboratory results showed 
elevated AST and ALT levels immediately following his last dose of nelarabine. On April 26, 2011, the 
patient presented with abdominal pain associated with dark urine, nonspecific pain in his upper neck, and 
bilateral leg pain causing difficulty with walking. The neck and leg pain had been present since he left the 
hospital. His urinalysis showed a protein of 30 mg/dL (reference range: 0-8 mg/dL) and was positive for 
hemoglobin. His creatine kinase (CK) was 56,846 IU/L (reference range:  60-294 IU/L), his ALT was 770 
IU/L (reference range: 1-52 IU/L), and his AST was 1880 IU/L (reference range: 1-51 IU/L).  He was 
admitted to the hospital and started on aggressive hydration, along with alkalinization of his urine.  
Chemotherapy and his prophylactic Bactrim® were held. It was felt that the patient was experiencing 
acute rhabdomyolysis due to the nelarabine. On May 1, 2011 (Cycle 2, Day 8 with dose delay), the patient 
restarted his chemotherapy receiving cyclophosphamide and cytarabine, which he tolerated. By May 2, 
2011, the patient’s condition had improved; his CK was 1,559 IU/L and his ALT and AST were 321 IU/L 
and 76 IU/L, respectively, and he was discharged. On May 10, 2011, his ALT and AST were 68 IU/L and 
47 IU/L, respectively. Treatment with nelarabine was permanently discontinued. Per the site, as of 
July 12, 2011, the patient has had no residual side effects from the event. 
 
AE #1668452 (Protocol AALL0434): 
A 16-year-old male with Non-Hodgkin’s Lymphoma experienced elevated ALT, elevated AST, elevated 
creatine phosphokinase (CPK), and myalgia while on the consolidation arm of a phase 2/3 study using the 
investigational agent nelarabine in combination with methotrexate, cyclophosphamide, cytarabine, 
mercaptopurine, vincristine, pegaspargase, and radiation therapy. 
 
The patient completed Cycle 2, Day 47 of consolidation, which included a 5-day course of nelarabine, on 
April 26, 2011. He had experienced diffuse but mainly abdominal and chest muscle pain which improved 
by April 29, 2011 (Cycle 2, Day 50). The patient’s symptoms were thought to initially be an episode of 
myositis associated with nelarabine. Evaluation revealed an elevated CPK of 56,760 IU/L (ULN = 
400 IU/L), AST of 1178 IU/L (ULN = 41 IU/L), ALT of 246 IU/L (reference range not provided), and 
lactate dehydrogenase (LDH) of 1298, consistent with rhabdomyolysis. A previous urinalysis had shown 
blood without RBCs on microscopic examination; a current urinalysis was unremarkable. He was given 
IV fluids and increased oral fluids. On May 4, 2011, the patient’s CPK was 1086 IU/L. By May 6, 2011, 
his CPK was 342 IU/L and the rhabdomyolysis was deemed resolved. The patient had no further muscle 
pain.  Nelarabine was permanently discontinued. The patient relapsed with bony metastatic disease in 
June of 2011. 
 
AE # 1720816 (Protocol E04-5299): 
A 12-year-old male with pre-cursor T-cell acute lymphocytic leukemia (ALL) developed motor 
neuropathy, psychosis, seizure, and rhabdomyolysis before dying of adult respiratory distress syndrome 
(ARDS) while on a special exception trial using the investigational agent nelarabine. 
 


 
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The patient, who received 4 of the 5 planned doses of nelarabine, tolerated the treatment well until 
September 17, 2004 (Cycle 1, Day 3), when he experienced a single episode of hallucinations and 
developed leg weakness. By Cycle 1, Day 5, the patient was experiencing increased leg pain and 
weakness and was unable to move his legs. The last day of study drug was held. He experienced further 
hallucinations as well as confusion, then seizure. On September 20, 2004, his creatinine increased to 
3.7 mg/dL (reference range: 0.8-1.2 mg/dL), his myoglobin was 4,258.8 ng/mL (reference range: 0-
110 ng/mL), and his CPK was 1,653 U/L (reference range: 55-370 U/L), consistent with rhabdomyolysis. 
Myoglobin decreased to 191.9 ng/mL on September 24, 2004. The patient went into respiratory failure 
and gradually deteriorated until he expired on October 12, 2004. 
 
 
 
  
 


 
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