Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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The primary objective is to estimate the overall event-free survival of children at least one year of age at diagnosis who are treated with risk-directed therapy and to monitor the molecular remission induction rate.

Detailed Description
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These are the following secondary objectives: To determine if CNS irradiation can be safely omitted in the context of the systemic therapy used in the protocol. To identify whether prolonged (24 hour) intravenous infusions of HDMTX produce greater methotrexate polyglutamate (MTXPG) accumulation than short (4 hour) infusions 42 hours after 1 gm/m2 of HDMTX, stratified for lineage (T- vs B-lineage) and ploidy (hyperdiploid vs non-hyperdiploid B-lineage). To determine whether prolonged (24 hour) intravenous infusions of HDMTX produce greater antileukemic effects than short (4 hour) infusions, based on the inhibition of de novo purine synthesis in bone marrow blasts and the decrease in circulating blasts during the 4 day window prior to initiation of conventional remission induction therapy. MRD Other exploratory objectives Details of Treatment Plan Treatment will consist of three main phases, Remission Induction, Consolidation, and Continuation. Treatment with an Upfront HDMTX Window for research purposes will be optional. All patients will receive IT therapy on day 1, dose is age dependent. Upfront High-Dose Methotrexate Window HDMTX (1 g/m2) as a 4 hour infusion versus as a 24 hour infusion. Leucovorin rescue will be given. Remission Induction Prednisone 40 mg/m2/day PO Days 5 - 32 Vincristine 1.5 mg/m2/week IV Days 5, 12, 19, 26 Daunorubicin 25 mg/m2/week IV Days 5, 12 L-asparaginase 10,000 Unit/m2/dose IM Days 6, 8, 10, 12, 14, 16 (19, 21, 23) Cyclophosphamide 1000 mg/m2/dose IV Day 26 Cytarabine 75 mg/m2/dose IV Days 27-30, 34-37 6-Mercaptopurine 60 mg/m2/dose PO Days 26-39 Imatinib 40 mg/m2 bid for Ph positive patients starting Day 22 of induction. Intrathecal therapy will be administered on day 1 and 19, dose age dependent. Patients with high risk of CNS relapse will receive additional IT treatments on days 8 and 26. Consolidation Treatment High dose methotrexate targeted dose depending on risk status, days 1, 15, 29, and 43 and mercaptopurine 50 mg/m2/day, days 1-56. Reintensification treatment for patients with high risk disease: Patients with high risk disease will be offered the option of hematopoietic stem cell transplant (HSCT) and may receive an additional 1-2 cycles of reintensification treatment prior to maximize the anti-leukemic kill before transplant. Dexamethasone 20 mg/m2 PO days 1-3 Cytarabine 2 g/m2 IV x 4 doses, days 3-5 Etoposide 100 mg/m2 IV x 5 doses, days 3-5 L-asparaginase 25,000 Units/m2 IM day 6 Intrathecal treatment Day 5 Continuation Treatment (lasts 120 weeks for girls and 146 weeks for boys) Treatment will depend on risk classification: low versus standard versus high risk Treatment weeks 1 to 20: Week Standard/High Risk Low Risk DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR 6MP + ASP 6MP + MTX 6MP + ASP 6MP + MTX DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR 6MP + ASP 6MP + MTX 6MP + ASP 6MP + MTX Reinduction I§ Reinduction I Reinduction I Reinduction I Reinduction I Reinduction I 6MP + ASP 6MP + MTX DOX + VCR + 6MP + ASP 6MP + MTX 6MP + ASP 6MP + MTX 6MP + ASP 6MP + MTX DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR 6MP + ASP 6MP + MTX 6MP + ASP 6MP + MTX Reinduction II Reinduction II Reinduction II Reinduction II Reinduction II Reinduction II No chemotherapy 6MP + MTX Dexamethasone 12 mg/m2 (std/high risk) or 8 mg/m2 (low risk) PO daily (tid) x 5 days, Days 1-5 Doxorubicin 30 mg/m2 IV, Day 1 Vincristine 2.0 mg/m2 IV push (max. 2 mg), Day 1 Mercaptopurine 50 mg/m2 PO daily x 7 days (std/high risk), Days 1-7 75 mg/m2 PO daily x 7 days (low risk), Days 1-7 L-asparaginase 25,000 Unit/m2 IM, Day 1 Methotrexate 40 mg/m2 IV or IM, Day 1 Reinduction I and II This phase of treatment will be started at weeks 7 and 17 after bone marrow examination confirms complete remission. Reinduction treatment will be given twice: weeks 7 to 9 and weeks 17 to 19 for all patients. Reinduction I for Standard/High Risk ALL: Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8, 15, 21, Vincristine 1.5 mg/m2/week IV (max 2 mg) Days 1, 8, 15, Doxorubicin 30 mg/m2 Days 1, 8, L-asparaginase 25,000 Unit/m2 IM Days 1, 8, 15, Intrathecal chemotherapy, dose age dependent Day 1. Reinduction II for Standard/High Risk ALL: Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8, 15-21, Vincristine 1.5 mg/m2/week IV (max 2 mg) Days 1, 8, 15, L-asparaginase 25,000 Unit/m2, weekly IM Days 1, 8, 17, Intrathecal chemotherapy, dose age dependent Day 1 High-dose cytarabine 2 gm/m2 IV q 12 Days 15, 16 Reinduction I and II for Low Risk ALL Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8, 15-21 Vincristine 1.5 mg/m2/week IV (max 2 mg), Days 1, 8, 15 L-asparaginase 10,000 Unit/m2/thrice weekly IM Days 2, 4, 6, 8, 10, 12, 15, 17, 19 Doxorubicin 30 mg/m2/week IV Day 1 Intrathecal chemotherapy, dose age dependent on Day 1 Treatment Weeks 21 to end of therapy Week Standard/High Risk Low Risk 6MP + MTX 6MP + MTX 6MP + MTX 6MP + MTX Cyclo + Ara-C 6MP + MTX DEX + VCR 6MP + DEX + VCR 6MP + MTX 6MP + MTX 6MP + MTX 6MP + MTX Cyclo + Ara-C 6MP + MTX DEX + VCR 6MP + DEX + VCR Mercaptopurine 75 mg/m2 PO, daily x 7 days, Days 1-7 Methotrexate 40 mg/m2 IV or IM, Day 1 Cyclophosphamide 300 mg/m2 IV, Day 1 Cytarabine 300 mg/m2 IV, Day 1 Dexamethasone 12 mg/m2 (std/high risk) or 8 mg/m2 (low risk) PO daily (tid) x 5, Day 1-5 Vincristine 2.0 mg/m2 IV push (max. 2 mg), Day 1 The same treatment (weeks 21-28) will be repeated for a total of 6 times (until week 68). After week 68, all patients will receive daily 6MP and weekly MTX with pulses of dexamethasone and vincristine every 4 weeks until week 100, after which only 6MP and methotrexate will be given. Intrathecal treatment will be given every 8 weeks only to patients at high risk of CNS relapse after week 48 and will be discontinued after week 96. Continuation therapy will be discontinued after 120 weeks in girls and after 146 weeks in boys Patients who meet the criteria of high-risk ALL are candidates for allogeneic hematopoietic stem cell transplantation. However, if the option is declined by the patients or guardians, or the procedure is deemed unsuitable by the attending physician and the principal investigator, the patient will remain on study and continue to receive chemotherapy

Official Title
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Total XV - Total Therapy Study XV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia

Conditions
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Lymphoblastic Leukemia, Acute

Intervention / Treatment
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* Drug: Prednisone, Dexamethasone, Vincristine, Daunorubicin
* Drug: Doxorubicin, L-asparaginase, PEG-L-asparaginase, Erwinia asparaginase
* Drug: Methotrexate, Cyclophosphamide, Cytarabine, Etoposide
* Drug: Mercaptopurine, Imatinib
* Procedure: chemotherapy, intrathecal chemotherapy
* Procedure: steroid therapy, hematopoietic stem cell transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of non-B-cell ALL by immunophenotyping, as determined by the reactivity pattern to a panel of monoclonal antibodies with flow cytometry as well as morphology and cytochemical staining. Age range: 1 to 18 years (inclusive). Exclusion Criteria: • Previously treated with chemotherapy for one week or longer.

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: 1<br> | Drug: Prednisone, Dexamethasone, Vincristine, Daunorubicin<br>* See Detailed Description sections for details on treatment interventions.<br>Drug: Doxorubicin, L-asparaginase, PEG-L-asparaginase, Erwinia asparaginase<br>* See Detailed Description sections for details on treatment interventions.<br>Drug: Methotrexate, Cyclophosphamide, Cytarabine, Etoposide<br>* See Detailed Description sections for details on treatment interventions.<br>Drug: Mercaptopurine, Imatinib<br>* See Detailed Description sections for details on treatment interventions.<br>Procedure: chemotherapy, intrathecal chemotherapy<br>* See Detailed Description sections for details on treatment interventions.<br>Procedure: steroid therapy, hematopoietic stem cell transplantation<br>* See Detailed Description sections for details on treatment interventions.<br>|
| Other: 2<br> | Drug: Prednisone, Dexamethasone, Vincristine, Daunorubicin<br>* See Detailed Description sections for details on treatment interventions.<br>Drug: Doxorubicin, L-asparaginase, PEG-L-asparaginase, Erwinia asparaginase<br>* See Detailed Description sections for details on treatment interventions.<br>Drug: Methotrexate, Cyclophosphamide, Cytarabine, Etoposide<br>* See Detailed Description sections for details on treatment interventions.<br>Drug: Mercaptopurine, Imatinib<br>* See Detailed Description sections for details on treatment interventions.<br>Procedure: chemotherapy, intrathecal chemotherapy<br>* See Detailed Description sections for details on treatment interventions.<br>Procedure: steroid therapy, hematopoietic stem cell transplantation<br>* See Detailed Description sections for details on treatment interventions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Event-free Survival (EFS) | EFS was measured from the start of on-study to the date of first treatment failure of any kind (relapse, death, lineage switch, or second malignancy) or to the last date of follow-up. Failure to enter remission was considered an event at time zero. Measurement was determined by Kaplan-Meyer estimate. | Median follow-up time (range) 5.6 (1.3 to 8.9) years | 
| Continuous Complete Remission Since Week 56 Therapy. | CCR was measured from end of week 56 therapy to the date of first treatment failure of any kind (relapse, death, lineage switch, or second malignancy) or to the last date of follow-up. Measurement was determined by Kaplan-Meyer estimate. | Median follow up time (range) 4.5 (1 to 7.8) years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimal Residual Disease (MRD) | Detection of MRD at end of induction where positive MRD was defined as one or more leukemic cell per 10,000 mononuclear bone-marrow cells (>=0.01%). | End of Induction (Day 46 MRD measurement) | 
| Mean Difference of Active Methotrexate Polyglutamates (MTXPG) in Leukemia Cells Between Two Arms (4 Hours vs. 24 Hours). | Children were randomly assigned to receive initial single-agent treatment with HDMTX (1g/m^2) as either a 24-hour infusion or a 4-hour infusion and the outcome measure was the accumulation of MTXPG in leukemia cells. | 42 hours after start of high dose methotrexate infusion (HDMTX) | 
| Circulating Leukemia Cells in Peripheral Blood Change From Prior to the Methotrexate Infusion to Three Days After Between Two Arms (4 Hours vs. 24 Hours) | White blood cell (leukocytes) counts in peripheral blood by Complete Blood Count Measurement: Percentage change of leukemia cells from baseline | Immediately before the methotrexate infusion and three days after subsequent infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia