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Acute Lymphoblastic Leukemia – Therapy for First Relapse

AALL0434: A Phase III Randomized Study of Augmented Berlin-Frankfurt-Münster-86 Multiagent Chemotherapy, Intensified Methotrexate, and Nelarabine in Younger Patients with Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia

Basic Study Information

PhaseType of TrialStatus of TrialAge Range (yrs.)Sponsor of TrialProtocol ID
IIITreatmentActive1 to 30COGAALL0434

Outline

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

  • Induction therapy (weeks 1-5): Patients receive cytarabine intrathecally (IT) on day 1; vincristine IV and daunorubicin hydrochloride IV on days 1, 8, 15, and 22; prednisone IV or orally twice daily on days 1-28; pegaspargase intramuscularly (IM) on day 4, 5, OR 6; and methotrexate (MTX) IT on days 8 and 29*. Patients with Down syndrome (DS) also receive oral leucovorin calcium at 48 and 60 hours after each MTX dose.
    After completion of induction therapy, patients undergo risk assessment. Patients with M1 marrow and minimal residual disease (MRD) < 1% (defined as low- and intermediate-risk) proceed to consolidation therapy at day 36 or when blood counts recover (whichever occurs later). Patients with M2 marrow (5-25% blasts) and/or MRD ≥ 1% (defined as high-risk) proceed to consolidation therapy as soon as possible (i.e., they should not wait until day 36 or for blood counts to recover). Patients with M3 marrow (≥ 25% blasts) (defined as induction failure) proceed to consolidation therapy as soon as possible.
     [Note: *Patients with CNS3 disease also receive MTX IT on days 15 and 22.]
  • Consolidation therapy (weeks 6-13): During the safety phase portion of the study, patients with low-risk or intermediate-risk disease are randomized to arms I or III. Patients with high-risk disease are randomized to arms I, II, III, or IV. During the efficacy phase portion of the study, patients with low-risk disease are randomized to arms I and III. Patients with intermediate-risk or high-risk disease are randomized to arms I, II, III, or IV. The safety phase ends when the first 20 high-risk patients to receive nelarabine have been evaluated. Patients with DS are nonrandomly assigned to arm I. Patients with induction failure are nonrandomly assigned to arm IV.
  • Arm I: Patients receive MTX IT on days 1, 8, 15, and 22*; cyclophosphamide IV over 30 minutes 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; and pegaspargase IM on days 15 and 43. Patients with DS also receive oral leucovorin calcium at 48 and 60 hours after each MTX dose. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy on days 11-12, 15-19, and 22-26. Patients with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo prophylactic cranial radiotherapy (CRT) (1,200 cGy/dose) once daily on days 15-19 and 22-24. Patients with low-risk disease do not undergo CRT.
     [Note: *Patients with CNS3 disease omit MTX IT on days 15 and 22; patients with high-risk disease omit MTX IT on day 1 and add an extra dose at day 29. ]
  • Arm II: Patients receive nelarabine IV over 60 minutes on days 1-5 and 43-47; MTX IT on days 15, 22*, 57, and 64; cyclophosphamide IV over 30 minutes on days 8 and 50; cytarabine IV or SC on days 8-11, 15-18, 50-53 and 57-60; oral mercaptopurine on days 8-21 and 50-63; vincristine IV on days 22, 29, 64, and 71; and pegaspargase IM 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. Patients with intermediate-risk or high-risk disease (CNS1 or CNS2) undergo prophylactic CRT once daily on days 22-26 and 29-31.
     [Note: *Patients with CNS3 disease omit MTX IT on day 22.]
  • Arm III: Patients receive MTX, cyclophosphamide, cytarabine, mercaptopurine, vincristine, and pegaspargase as in arm I. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy as in arm I.
  • Arm IV: Patients receive nelarabine, MTX, cyclophosphamide, cytarabine, mercaptopurine, vincristine, and pegaspargase as in arm II. Patients with persistent testicular disease or with DS and testicular disease undergo testicular radiotherapy as in arm II.

Once blood counts recover, patients proceed to interim maintenance therapy according to their randomized/assigned arm. Patients not achieving M1 marrow by the end of consolidation therapy are removed from the study.

  • Interim maintenance therapy (weeks 14-21 for arms I and III; weeks 17-24 for arms II and IV):
  • Arm I: Patients receive vincristine IV and escalating doses of MTX IV on days 1, 11, 21, 31, and 41; pegaspargase* IM on days 2 and 22; and MTX IT on days 1 and 31. Patients with DS also receive oral leucovorin calcium 48 and 60 hours after each MTX IT dose.
     [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 II: Patients receive vincristine, escalating doses of MTX, pegaspargase, and MTX IT as in arm I.
  • Arm III: Patients receive high-dose methotrexate (HDMTX) IV over 24 hours and vincristine IV on days 1, 15, 29, and 43; oral mercaptopurine on days 1-56; and MTX IT on days 1 and 29. Beginning 42 hours after the start of HDMTX, patients also receive leucovorin calcium IV or orally once every 6 hours for 3 doses.
  • Arm IV: Patients receive HDMTX, vincristine, mercaptopurine, MTX IT, and leucovorin calcium as in arm III.

Once blood counts recover, patients proceed to delayed instensification therapy according to their randomized/assigned arm.

  • Delayed intensification therapy (weeks 22-30 for arms I and III; weeks 25-33 for arms II and IV):
  • Arm I: Patients receive vincristine IV on days 1, 8, 15, 43, and 50; dexamethasone IV or orally twice daily 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 over 15 minutes on days 1, 8, and 15; pegaspargase IM on day 4, 5, OR 6, AND day 43; MTX IT on days 1, 29, and 36; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV or SC on days 29-32 and 36-39; and oral thioguanine on days 29-42. Patients with DS also receive oral leucovorin calcium at 48 and 60 hours after each MTX dose.
  • Arm II: Patients receive vincristine IV on days 1, 8, 15, and 50; dexamethasone IV or orally twice daily 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 over 15 minutes on days 1, 8, and 15; pegaspargase IM on day 4, 5, OR 6 AND day 50; MTX 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 or SC on days 36-39 and 43-46; and oral thioguanine on days 36-49.
  • Arm III: Patients receive vincristine, dexamethasone, doxorubicin hydrochloride, pegaspargase, MTX IT, cyclophosphamide, cytarabine, and thioguanine as in arm I. Patients with intermediate- or high-risk disease (CNS1 or CNS2 disease) undergo prophylactic CRT (1,200 cGy/dose) once daily on days 50-54 and 57-59.
  • Arm IV: Patients receive vincristine, dexamethasone, doxorubicin hydrochloride, pegaspargase, MTX IT, nelarabine, cyclophosphamide, cytarabine, and thioguanine as in arm II. Patients with intermediate- or high-risk disease (CNS 1 or CNS2 disease) undergo prophylactic CRT on days 50-54 and 57-59.
    All patients with CNS3 disease at diagnosis undergo CRT (1,800cGy/dose) once daily on days 50-54 and 57-61.
    Once blood counts recover, patients proceed to maintenance therapy according to their randomized/assigned arm.
  • Maintenance therapy (week 31- until the end of therapy for arms I and III; weeks 34-69 for arms II and IV):
  • Arm I: Patients receive vincristine IV on days 1, 29, and 57; oral dexamethasone twice daily on days 1-5, 29-33, and 57-61; oral mercaptopurine once daily on days 1-84; oral MTX on days 8, 15, 22, 29*, 36, 43, 50, 57, 64, 71, and 78; and MTX 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) and 3 years from the start of interim maintenance therapy (approximately week 171) (for boys).
     [Note: *Patients with low-risk disease receive MTX IT, instead of oral MTX, on day 29 during the first 4 courses of therapy.]
  • Arm II: Patients receive vincristine IV on days 1 and 57; oral dexamethasone on days 1-5 and 57-61; oral mercaptopurine once daily on days 1-84; oral MTX on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; MTX IT on day 1; and nelarabine IV over 60 minutes on days 29-33. Treatment (that includes nelarabine) repeats every 84 days for 3 courses. Patients then receive treatment (without nelarabine) as follows: vincristine IV on days 1 and 57; oral dexamethasone on days 1-5, 29-33, and 57-61; oral mercaptopurine on days 1-84; oral MTX on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; and MTX IT on day 1. 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) and 3 years from the start of interim maintenance therapy (approximately week 173) (for boys).
  • Arm III: Patients receive vincristine, dexamethasone, mercaptopurine, oral MTX*, and MTX IT as in arm I. 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) and 3 years from the start of interim maintenance therapy (approximately week 171) (for boys).
     [Note: *Patients with low-risk disease receive MTX IT, instead of oral MTX, on day 29 during the first 4 courses of therapy.]
  • Arm IV: Patients receive vincristine, dexamethasone, mercaptopurine, oral MTX, MTX IT, and nelarabine as in arm II. Patients then receive treatment (without nelarabine) as follows: vincristine, dexamethasone, mercaptopurine, oral MTX, and MTX 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) and 3 years from the start of interim maintenance therapy (approximately week 173) (for boys).


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

Objectives

Primary
1. Compare the relative safety and efficacy of augmented Berlin-Frankfurt-Münster-86 multiagent chemotherapy with or without nelarabine in younger patients with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL).
2. Compare the relative safety and efficacy of interim maintenance therapy comprising high-dose methotrexate (with leucovorin calcium rescue) and mercaptopurine vs escalating-dose methotrexate ( without leucovorin calcium rescue) and pegaspargase in these patients.

Secondary
1. Determine the relative safety and efficacy of withholding radiotherapy in patients with low -risk T-ALL and administering prophylactic cranial radiotherapy in patients with intermediate- or high-risk T-ALL.

Expected Enrollment

1380
A total of 1,380 patients will be accrued for this study.

Entry Criteria

Disease Characteristics:

Newly diagnosed T-cell acute lymphoblastic leukemia, meeting the following criteria:

  • 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
  • Concurrently enrolled on protocol COG-AALL03B1

Prior/Concurrent Therapy:

  • See Disease Characteristics
  • Prior steroid therapy allowed
  • No prior cytotoxic chemotherapy except intrathecal cytarabine
  • At least 2 years since prior and no concurrent anticonvulsant therapy (for patients randomized to receive nelarabine)
  • No concurrent milk or citrus products during thioguanine or mercaptopurine administration
  • No concurrent intensity-modulated radiotherapy
  • No concurrent nonsteroidal anti-inflammatory drugs, penicillin, or acetylsalicyclic acid-containing medications for at least 3 days after high-dose methotrexate

Patient Characteristics:

  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No peripheral neurotoxicity ≥ grade 2 (for patients randomized to receive nelarabine)
  • No prior seizure disorder (for patients randomized to receive nelarabine

Trial Contact Information

Rebecca Turner, MS, CCRP
Cincinnati Children's Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039
Phone: 513-636-2799
cancer@cchmc.org