Clinical trial NCT00558519: Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Lymphoblastic Leukemia
Official title: An Intergroup Phase II Clinical Trial for Adolescents and Young Adults With Untreated Acute Lymphoblastic Leukemia (ALL)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Leukemia
Keywords: B-cell adult acute lymphoblastic leukemia
T-cell adult acute lymphoblastic leukemia
untreated adult acute lymphoblastic leukemia
Lead sponsor: Alliance for Clinical Trials in Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-11-15
Enrollment: 318
Sex: ALL
Minimum age (years): 16
Maximum age (years): 39
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: 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.

PURPOSE: This phase II trial is studying how well combination chemotherapy works in treating young patients with newly diagnosed acute lymphoblastic leukemia.

Detailed description: OUTLINE: This is a multicenter study. The purpose of this study is to improve the outcome of adolescents and young adults with acute lymphoblastic leukemia (ALL). The objectives of the study are described below.

OBJECTIVES:

* To describe the outcomes (i.e., complete response rate, event-free survival, disease-free survival \[DFS\], and overall survival \[OS\]) of adolescents and young adults with newly diagnosed acute lymphoblastic leukemia (ALL) treated with a pediatric chemotherapy regimen by adult hematologists/oncologists at multiple sites.
* To explore the feasibility of extending the "pediatric approach" to adult patients up to 40 years of age.
* To estimate the DFS and OS of these patients.
* To describe the toxicities observed in these patients.
* To compare the outcomes of patients treated on this protocol with appropriate similar patients (by age and disease characteristics) treated by pediatric oncologists on protocol COG-AALL0232.
* To evaluate the adherence of adult hematologists/oncologists and their patients to a "pediatric" ALL treatment regimen and identify reasons for variances.
* To analyze and describe the outcomes of patients treated on this study according to pretreatment characteristics such as age, gender, white blood cell count, other hematologic parameters, blood chemistry, immunophenotype, cytogenetics and molecular genetic characteristics, and treatment variables such as treatment site (academic center or community), and protocol adherence.
* To analyze and describe the outcomes of patients treated on this study according to baseline psychosocial characteristics, demographics, and family support.

The courses of treatment for the research study are described below.

* Remission induction therapy: Patients receive intrathecal (IT) cytarabine on day 1; vincristine IV on days 1, 8, 15, and 22; prednisone IV or orally twice daily on days 1-28; daunorubicin hydrochloride IV on days 1, 8, 15, and 22; pegaspargase IV or intramuscularly (IM) on day 4 or 5 or 6; and IT methotrexate on days 8 and 29\*. Patients undergo bone marrow aspirate (BMA) and biopsy on day 29 to assess induction response and minimal residual disease status. Patients with M1 marrow (\< 1% lymphoblasts) proceed to remission consolidation therapy. Patients with M2 marrow (\> 5% but \< 25% lymphoblasts) proceed to extended remission induction therapy. Patients with M3 marrow are removed from protocol therapy.

NOTE: \*Patients with CNS3 disease also receive IT methotrexate on days 15 and 22.

* Extended remission induction therapy: Patients receive prednisone IV or orally twice daily on days 1-14; vincristine IV on days 1 and 8; pegaspargase IM or IV on day 4 or 5 or 6; and daunorubicin hydrochloride IV on day 1. Patients undergo BMA and biopsy on day 15. Patients with M1 marrow proceed to remission consolidation therapy. Patients with M2 or M3 bone marrow are removed from protocol therapy.
* Remission consolidation therapy: Patients receive cyclophosphamide IV on days 1 and 29; cytarabine IV or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39; oral mercaptopurine on days 1-14 and 29-42; vincristine IV on days 15, 22, 43, and 50; pegaspargase IM or IV on days 15 and 43; and IT methotrexate on days 1, 8, 15\*, and 22\*. Once blood counts recover, patients proceed to interim maintenance therapy.

NOTE: \*Patients with CNS3 disease do not receive IT methotrexate on days 15 and 22.

* Interim maintenance therapy: Patients receive vincristine IV and methotrexate (Capizzi methotrexate) IV on days 1, 11, 21, 31, and 41; pegaspargase IM or IV on days 2 and 22; and IT methotrexate on days 1 and 31. Once blood counts recover (ANC ≥ 750/mm\^3 and platelet count ≥ 75,000/mm\^3), patients proceed to delayed intensification therapy.
* Delayed intensification therapy: Patients receive vincristine IV on days 1, 8, 15, 43, and 50; dexamethasone IV or orally twice daily on days 1-7 and 15-21; doxorubicin hydrochloride IV on days 1, 8, and 15; pegaspargase IM or IV on day 4 or 5 or 6 AND day 43; cyclophosphamide IV on day 29; cytarabine IV or SC on days 29-32 and 36-39; oral thioguanine on days 29-42; and IT methotrexate on days 1, 29, and 36. Once blood counts recover, patients proceed to maintenance therapy.
* Maintenance therapy: Patients receive vincristine IV on days 1, 29, and 57; dexamethasone IV or orally twice daily on days 1-5, 29-33, and 57-61; mercaptopurine orally on days 1-84; IT methotrexate on day 1\*; and oral methotrexate on days 8, 15, 22, 29\*\*, 36, 43, 50, 57, 64, 71, and 78.

Treatment repeats every 12 weeks for 2 years from the start of interim maintenance (for female patients) or 3 years from the start of interim maintenance (for male patients).

NOTE: \*IT methotrexate is also given on day 29 of the first 4 courses of maintenance therapy.

NOTE: \*\*Oral methotrexate is held on day 29 of the first 4 courses of maintenance therapy (when IT methotrexate is given).

* Radiotherapy: During the first course of maintenance therapy, patients with testicular disease undergo concurrent radiotherapy to the testes 5 days a week for 2.5 weeks (total dose 2400 cGy given in 12 daily fractions); patients with CNS3 disease undergo concurrent cranial radiotherapy 5 days a week for 2 weeks (total dose of 1800 cGy given in 10 daily fractions); and patients with T-cell ALL undergo concurrent cranial radiotherapy (total dose of 2400 cGy given in 10 daily fractions) 5 days a week for 2 weeks.

Patients may complete surveys at the end of courses 1, 2, and 4, at the end of all protocol treatment, and at 6 and 18 months after the end of all protocol treatment.

After completion of study treatment, patients are followed every 1-3 months for 3 years and then every 6 months for 7 years.

Eligibility criteria: Eligibility Criteria:

1. Diagnosis

   1. Newly diagnosed patients with either B-precursor or T-precursor acute lymphoblastic leukemia (WHO criteria). Burkitt type leukemia as defined per protocol is not eligible. Patients known to have Ph+ ALL at time of diagnosis are not eligible.
   2. CALGB patients entered on CALGB 10403 who are later found to meet the following criteria for Ph+ ALL should have treatment on this trial discontinued and should be encouraged to enroll on CALGB 10001 or its successor trial:

      * BCR-ABL fusion transcript determined by FISH or RT-PCR
      * t(9;22)(q34;q11) or variant determined by cytogenetics

   Non-CALGB study participants who are later found to be Ph+ should have treatment on this trial discontinued and should be encouraged to enroll on an appropriate clinical trial specifically designed for Ph+ ALL.
2. Age: 16 - 39 years
3. ECOG Performance Status 0-2
4. Patients with Down Syndrome are excluded from this study due to the likelihood of excessive toxicity resulting. These patients should be treated in consultation with a pediatric oncologist.
5. Prior Therapy - No prior therapy except for limited treatment with corticosteroids or hydroxyurea and a single dose of intrathecal cytarabine.

   1. No prior therapy for acute leukemia except emergency therapy (corticosteroids or hydroxyurea) for blast cell crisis, superior vena cava syndrome, or renal failure due to leukemic infiltration of the kidneys. When indicated, leukapheresis or exchange transfusion is recommended to reduce the WBC.
   2. Single-dose intrathecal cytarabine is allowed prior to registration or prior to initiation of systemic therapy 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. Systemic chemotherapy must begin within 72 hours of this intrathecal therapy.
   3. Patients receiving prior steroid therapy are eligible for study. The dose and duration of previous steroid therapy should be carefully documented on case report forms.

Primary outcomes:
measure: Complete Response Rate
timeFrame: Up to 8 years post-registration
measure: Event-free Survival
timeFrame: Up to 8 years post-registration
measure: Disease-free Survival
timeFrame: Up to 8 years post-registration
measure: Overall Survival
timeFrame: Up to 8 years post-registration
measure: Number of Participants Who Experienced at Least One Grade 3 or Higher Adverse Event at Least Possibly Related to Treatment (Toxicity)
timeFrame: Up to 10 years post-registration
Secondary outcomes:
Other outcomes:
measure: Analysis and Description of the Outcomes of Patients Treated on This Study According to Baseline Psychosocial Characteristics, Demographics, and Family Support
timeFrame: Up to 10 years post-registration
measure: Outcomes of Patients Treated on This Study According to Pretreatment Characteristics Such as Age, Gender, White Blood Cell Count, Other Hematologic Parameters, Blood Chemistry, Immunophenotype, Cytogenetics and Molecular Genetic Characteristics
timeFrame: Up to 10 years post-registration
measure: Adherence of Adult Hematologists/Oncologists and Their Patients to a "Pediatric" Acute Lymphoblastic Leukemia Treatment Regimen and Identification of Reasons for Variances
timeFrame: Up to 10 years post-registration
measure: Outcomes of Adolescent and Young Adult Patients Treated on This Study Compared With Those of Patients Treated Per COG-AALL0232
timeFrame: Up to 10 years post-registration
Locations:
Study officials:
affiliation: University of Chicago
name: Wendy Stock, M.D.
role: STUDY_CHAIR
References:
citation: Bleyer A: Older adolescents and young adults with acute lymphoblastic leukemia (ALL) in the United States: from the lowest to highest death rate and number of deaths--more rationale for the CALBG-SWOG-ECOG C10403 trial based on COG AALL0232. [Abstract] J Clin Oncol 26 (Suppl 15): A-18034, 2008.
citation: Advani AS, Larsen E, Laumann K, Luger SM, Liedtke M, Devidas M, Chen Z, Yin J, Foster MC, Claxton D, Coffan K, Tallman MS, Appelbaum FR, Erba H, Stone RM, Hunger SP, McNeer JL, Loh ML, Raetz E, Winick N, Carroll W, Larson RA, Stock W. Comparison of CALGB 10403 (Alliance) and COG AALL0232 toxicity results in young adults with acute lymphoblastic leukemia. Blood Adv. 2021 Jan 26;5(2):504-512. doi: 10.1182/bloodadvances.2020002439.
citation: Stock W, Luger SM, Advani AS, Yin J, Harvey RC, Mullighan CG, Willman CL, Fulton N, Laumann KM, Malnassy G, Paietta E, Parker E, Geyer S, Mrozek K, Bloomfield CD, Sanford B, Marcucci G, Liedtke M, Claxton DF, Foster MC, Bogart JA, Grecula JC, Appelbaum FR, Erba H, Litzow MR, Tallman MS, Stone RM, Larson RA. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr 4;133(14):1548-1559. doi: 10.1182/blood-2018-10-881961. Epub 2019 Jan 18.