Trial Information

A Phase III Trial Comparing ARA-C/High-Dose Mitoxantrone ("ALL-2') to A Standard Vincristine/Prednisone Based Regimen ('L-20') as Induction Therapy For Adult Patients With Acute Lymphoblastic Leukemia (ALL): The ALL-4 Protocol

OBJECTIVES:

- Compare the incidence of complete remission (CR) following induction with the ALL-2
regimen (cytarabine and high-dose mitoxantrone) vs the L-20 regimen (vincristine and
prednisone) in previously untreated adult patients with acute lymphoblastic leukemia
(ALL), lymphoblastic lymphoma, and lymphoid blast crisis chronic myelogenous leukemia.

- Compare the time to CR, length of hospital stay, efficacy of treatment in Philadelphia
chromosome-positive ALL, and the proportion of patients achieving durable (greater than
5 years) remission in each treatment regimen.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
participating institution and antecedent lymphoid blast crisis of chronic myelogenous
leukemia (yes vs no). Patients are randomized to one of two treatment arms.

Arm I:

- Patients receive induction therapy consisting of cytarabine IV over 3 hours on days 1-5
with high-dose mitoxantrone IV on day 3 and methotrexate intrathecally on days 2 and 4.
Patients receive sargramostim (GM-CSF) subcutaneously or IV over 4 hours beginning on
day 7 and continuing until blood counts recover.

- At 7-14 days following induction therapy, patients receive consolidation therapy
consisting of vincristine IV on days 1, 8, 15, 22, and 29, oral prednisone 2-3 times
daily on days 1-30 and methotrexate intrathecally on days 8, 15, 22, and 29.

- At 2-3 weeks following the last dose of vincristine, patients receive an additional
course of consolidation therapy consisting of cyclophosphamide IV on day 1 and GM-CSF
subcutaneously beginning on day 3 and continuing until blood counts recover.

- At 3-4 weeks following the second consolidation course, patients receive a third course
of consolidation therapy consisting of cytarabine IV bolus on day 1 followed by
continuous infusion cytarabine on days 1-4 with etoposide IV over 1 hour on days 1-3
and methotrexate intrathecally on days 2 and 4. Patients receive GM-CSF subcutaneously
beginning on day 6 and continuing until blood counts recover.

- Following recovery from the third consolidation course, patients receive a fourth
consolidation course consisting of pegaspargase IV or intramuscularly (IM) on day 1.

- Following recovery from consolidation therapy patients receive 2 sequences of
maintenance therapy with sequence one consisting of vincristine IV on days 1 and 8,
oral prednisone 2-3 times daily on days 1-8, doxorubicin IV on day 15, oral
mercaptopurine 2-3 times daily on days 36-64, oral methotrexate on days 39, 46, 53, and
60, dactinomycin IV on day 85, and methotrexate intrathecally on days 36 and 43.

- At 2 weeks following sequence one of maintenance therapy, patients receive sequence two
consisting of the same regimen as in the first sequence with the addition of
cyclophosphamide IV and carmustine IV on day 15.

- Patients with CNS involvement receive whole brain radiotherapy in addition to
chemotherapy regimens.

Arm II:

- Patients receive induction therapy consisting of vincristine IV on days 1, 8, 15, 22,
and 29, oral prednisone 2-3 times daily on days 1-29, cyclophosphamide IV on day 5,
doxorubicin IV on days 23-25 and 42, methotrexate intrathecally on days 3, 5, 13, 16,
32, and 34 and GM-CSF subcutaneously or IV over 4 hours beginning from days 7 and 27
and continuing until blood counts recover.

- At approximately 3 weeks following induction therapy, patients receive consolidation
therapy consisting of cytarabine IV bolus on day 1 followed by continuous infusion
cytarabine on days 1-5, with daunorubicin IV on days 1-3 and methotrexate intrathecally
on days 2 and 4. Patients receive GM-CSF subcutaneously beginning on day 7 and
continuing until blood counts recover.

- At 6-8 weeks following the first course of consolidation therapy, patients receive a
second consolidation course consisting of cytarabine IV bolus on day 1 followed by
continuous infusion cytarabine on days 1-4 with methotrexate IV on days 1-4 and
methotrexate intrathecally on days 2 and 4. Patients receive GM-CSF subcutaneously
beginning on day 6 and continuing until blood counts recover.

- At 6-8 weeks following the second course of consolidation therapy, patients receive a
third consolidation course consisting of pegaspargase IV or IM on day 1.

- At 3-4 weeks following the third course of consolidation therapy, patients receive a
fourth consolidation course consisting of cyclophosphamide IV on day 1.

- At 3 weeks following the completion of consolidation therapy, patients receive the same
maintenance regimen as in Arm I.

Treatment continues in patients achieving complete response. Patients in both arms receive
alternating sequences of maintenance therapy over 2 years.