Risk-Adjusted Combination Chemotherapy in Treating Young Patients With Acute Lymphoblastic Leukemia

OBJECTIVES:

• To test in a randomized way the type and intensity of reintensification therapy for pediatric patients with acute lymphoblastic leukemia in each risk group: standard-risk (SR), intermediate-risk (IR), and high-risk (HR) group.
• To compare two shorter elements of reintensification (protocol III x 2 courses) to one (protocol II x 1 course) in terms of effectiveness when cumulative dose of most drugs are the same in both regimen in patients in the standard-risk group.
• To determine if the increased risk of failure in patients in the intermediate-risk group can be curtailed by a third reintensification element (protocol III x 3 courses vs protocol II x 1 course).
• To determine if the three reintensification elements (protocol III x 3 courses) achieve the same or better results in high-risk group patients, as compared with current applied HR approach in Berlin-Frankfurt-Münster Group (BFM) or Italian Association of Pediatric Hematology and Oncology (AIEOP).

OUTLINE: This is a partially randomized, multicenter study. Patients are stratified according to risk group (standard risk [SR] vs intermediate risk [IR] vs high risk [HR]). Patients are randomized in reinduction part of the treatment.

• Induction therapy:
• Protocol I' (SR B-cell precursor [BCP] ALL ): Patients receive methotrexate intrathecally (IT) on days 1, 12, and 33 (and possibly on days 18 and 27); prednisone or prednisolone orally or IV on days 1-28 followed by a taper; vincristine sulfate IV on days 1, 8, 15, 22, and 29; daunorubicin hydrochloride IV over 1 hour on days 8 and 15; and asparaginase IV over 1 hour on days 12, 15, 18, 21, 24, 27, 30, and 33. Patients then receive cyclophosphamide IV over 1 hour on days 36 and 64; oral mercaptopurine once daily on days 36-63; cytarabine IV continuously on days 38-41, 45-48, 52-55, and 59-62; and methotrexate IT on days 45 and 59.
• Protocol I (SR T-cell ALL, IR, or HR): Patients receive therapy as in Protocol I' except that they also receive daunorubicin hydrochloride on days 22 and 29.

Approximately 2 weeks after completion of induction therapy, patients proceed to consolidation therapy.

• Consolidation: Patients who have achieved complete cytomorphologic remission proceed to protocol mM or protocol M. Patients in HR group proceed to 3-block consolidation regimen.
• Protocol mM (BCP-ALL) (SR or IR): Patients receive oral mercaptopurine once daily on days 1-56; medium-dose methotrexate IV over 24 hours and methotrexate IT on days 8, 22, 36, and 50; and leucovorin calcium IV every 6 hours on days 9, 23, 37, and 51.
• Protocol M (T-cell ALL) (SR or IR): Patients receive mercaptopurine, methotrexate IT, and leucovorin calcium as in protocol mM, and they also receive high-dose (HD) methotrexate IV over 24 hours on days 8, 22, 36, and 50.
• 3-block consolidation regimen (HR): Patients receive 3 regimen blocks with 2 weeks between blocks. Treatment continues in the absence of unacceptable toxicity.
• Block HR-1': Patients receive dexamethasone orally or IV 3 times daily on days 1-5; vincristine sulfate IV on days 1-6; HD methotrexate IV over 24 hours on day 1; leucovorin calcium IV every 6 hours, beginning 42 hours after the start of HD methotrexate, for 3 doses; cyclophosphamide IV over 1 hour, every 12 hours, on days 2-4; HD cytarabine IV over 3 hours, every 12 hours, on day 5 (2 doses); asparaginase IV over 2 hours on days 6 and 11; and triple intrathecal therapy (TIT) comprising methotrexate, cytarabine, and prednisone, 3 times on day 1.
• Block HR-2': Patients receive dexamethasone, HD methotrexate, leucovorin calcium, and asparaginase as in block HR-1'. Patients receive TIT once on day 1 (CNS-negative patients) or twice on days 1 and 5 (CNS-positive patients). Patients also receive vindesine IV on days 1 and 6; ifosfamide IV over 1 hour, every 12 hours, on days 2-4; and daunorubicin hydrochloride IV over 24 hours on day 5.
• Block HR-3': Patients receive dexamethasone and asparaginase as in block HR-1'; TIT 3 times on day 5; HD cytarabine IV over 3 hours, every 12 hours, on days 1 and 2; and etoposide IV over 1 hour, every 12 hours, on days 3-5.

Approximately 2 weeks after completion of consolidation therapy, patients proceed to reinduction therapy.

• Reinduction (randomized): Patients in continuous complete remission proceed to protocol II or III. Patients from SR and IR group are randomized to arms I and II; patients from HR group are randomized to arms II and III.
• Arm I (protocol II x 1 course) (SR-1 or IR-1): Patients receive dexamethasone orally or IV on days 1-21 followed by a taper; vincristine sulfate IV and doxorubicin hydrochloride IV over 1 hour on days 8, 15, 22, and 29; asparaginase IV over 1 hour on days 8, 11, 15, and 18; and methotrexate IT on days 1 and 18. Patients then receive cyclophosphamide IV over 1 hour on day 36; oral thioguanine once daily on days 36-49; cytarabine IV continuously on days 38-41 and 45-48; and methotrexate IT on days 38 and 45.
• Arm II (protocol III x 2 or 3 courses and interim maintenance therapy [IMT]) (SR-2, IR-2, or HR-1): Patients receive dexamethasone orally or IV three times daily on days 1-14 followed by a taper; vincristine sulfate IV and doxorubicin hydrochloride IV over 1 hour on days 1 and 8; and asparaginase IV over 1 hour on days 1, 4, 8, and 11. Patients then receive cyclophosphamide IV over 1 hour on day 15; oral thioguanine once daily on days 15-28; cytarabine IV continuously on days 17-20 and 24-27; and methotrexate IT on days 17 and 21 (and day 1 if there is initial CNS involvement). Approximately 1 week after completion of protocol III (course 1), patients receive IMT for 10 weeks (SR group) or 4 weeks (IR and HR groups) as described below. Approximately 1 week after completion of IMT, patients receive protocol III as above (course 2). Approximately 1 week after completion of protocol III (course 2), patients in IR and HR group receive IMT for another 4 weeks followed by another course of protocol III (course 3) 1 week later.
• IMT: Patients receive oral methotrexate once weekly and oral mercaptopurine daily.
• Arm III (HR-2): Patients receive 1 of the following regimens according to local practices:
• Regimen HR-2A: Patients receive protocol II as in arm I, rest 1 week and receive IMT for 4 weeks. Approximately 1 week later, patients receive another course of protocol II.
• Regimen HR-2B: Patients receive treatment as in 3-block consolidation regimen with 3 weeks between each block. Approximately 3 weeks later, patients receive protocol II as in arm I.
• Cranial radiotherapy (CRT) during reinduction: CNS positive patients (CNS status 3) receive CRT after completion of protocol II (SR, IR, HR-2B) or during the first 1.5-2.5 weeks of IMT (SR, IR, HR-2A). SR and IR patients with T-cell ALL and HR patients receive prophylactic CRT at these same time periods.

Beginning 2 weeks after completion of reinduction (some patients in HR group also undergo allogeneic stem cell transplantation, as described below), patients proceed to maintenance therapy.

• Maintenance therapy (MT): Patients receive oral mercaptopurine once daily and methotrexate IV once weekly. Each patient subgroup (except HR patients undergoing transplantation) receives MT for a period that brings the total weeks of treatment to 104 weeks, as follows:
• SR: Patients receive MT for 74 weeks (SR-1) or 61 weeks (SR-2).
• IR: Patients receive MT for 74 weeks (IR-1) or 57 weeks (IR-2).
• HR: Patients receive MT for 58 weeks (HR-1), 62 weeks (HR-2A), or 63 weeks (HR-2B).

Patients with BCP-ALL and in group SR-1 or IR-1 also receive methotrexate IT once in weeks 4, 8, 12, and 16 of MT. Patients with BCP-ALL and in group SR-2 receive methotrexate IT in weeks 4 and 8 of MT.

• Allogeneic stem cell transplantation (ASCT): Some patients in HR group may undergo ASCT (usually bone marrow, but may be peripheral blood or umbilical cord stem cells), (at the time of reinduction therapy) beginning 3-4 weeks after the completion of second protocol III (HR-1), the first protocol II (HR-2A), or completion of the 3-block consolidation regimen (HR-2B).
• Under 2 years old: Patients receive oral busulfan every 6 hours on days -8 to -5, etoposide IV over 4 hours on day -4, and cyclophosphamide IV over 1 hour on days -3 and -2, and then undergo ASCT on day 0.
• At least 2 years old: Patients undergo total body irradiation twice daily on days -6 to -4 and receive etoposide IV over 4 hours on day -3, and then undergo ASCT on day 0. Fractionated local radiotherapy, if required, is administered on days -14 to -7.