A RANDOMIZED PHASE III TRIAL COMPARING DEXAMETHASONE WITH PREDNISONE IN INDUCTION TREATMENT AND BONE MARROW TRANSPLANTATION WITH INTENSIVE MAINTENANCE TREATMENT IN ADOLESCENT AND ADULT ACUTE LYMPHOBLASTIC LEUKEMIA (ALL-4)
- Compare the remission induction, toxicity, and duration of remission in patients with
newly diagnosed acute lymphoblastic leukemia or lymphoblastic lymphoma treated with
prednisone vs dexamethasone plus cyclophosphamide, daunorubicin, and vincristine as
- Compare the survival and disease-free survival of patients treated with autologous bone
marrow transplantation (BMT) followed by low- or high-intensity maintenance
chemotherapy with cranial irradiation after consolidation.
- Determine the relative and disease-free survival of patients treated with autologous or
allogeneic BMT after identical induction, consolidation, and conditioning regimens.
OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
center and risk group (high vs standard).
- Patients are randomized to 1 of 2 treatment arms.
- Arm I:Patients receive daunorubicin IV on days 1-3 and 15 and 16; cyclophosphamide
(CTX) IV on days 1 and 8; vincristine (VCR) IV on days 1, 8, 15, and 22; and
prednisone IV or orally every 8 hours on days 1-7 and 15-21.
- Arm II: Patients receive daunorubicin, CTX, and VCR as in arm I and dexamethasone
IV or orally on days 1-8 and 15-22.
- Patients on both arms without CNS disease at presentation receive CNS prophylaxis
comprising methotrexate (MTX) intrathecally (IT) on days 1, 8, 15, and 22. Patients on
both arms with CNS disease at presentation receive CNS therapy comprising
hydrocortisone (HC) IT and MTX IT alternating with cytarabine (ARA-C) IT twice a week
until CSF clears. After induction, patients on both arms proceed to consolidation,
regardless of response.
- Patients receive ARA-C IV over 2 hours every 12 hours on days 29-34 and mitoxantrone IV
on days 33-35. Patients without CNS disease at presentation receive CNS prophylaxis
comprising MTX IT on day 29. Patients with CNS disease at presentation receive CNS
therapy comprising HC IT and MTX IT alternating with ARA-C weekly for 6 weeks. Patients
who achieve complete response (CR) at day 55-60 receive MTX IV on days 64 and 79,
leucovorin calcium IV or orally every 6 hours on days 65-67 and 80-82, and asparaginase
IV over 1 hour or intramuscularly on days 65 and 80.
- Standard-risk patients who are under age 20 and achieve CR after day 80 are assigned to
arm IV of group A. Patients who achieve CR after day 80 and have a genotypically or
phenotypically HLA-matched family donor, a family donor mismatched at only 1 locus (A,
B, or DR), or an HLA-matched unrelated donor proceed to group B. Patients who achieve
CR after day 80 and are eligible for autologous bone marrow transplantation (BMT)
proceed to group A. Patients found to be at extremely high risk are taken off study.
- Patients are randomized to 1 of 2 treatment arms.
- Arm III: Autologous bone marrow is harvested. Patients receive bone marrow
ablation comprising CTX IV over 1 hour on days -4 and -3 and total body
irradiation on day -1. Autologous bone marrow is reinfused on day 0. Beginning at
month 8 (4 months after BMT), patients receive first maintenance comprising VCR
IV, doxorubicin IV, and dexamethasone IV (VAD) or VCR IV, doxorubicin IV, and
prednisolone IV (VAP) on days 1-4 and 29-32. Patients receive second maintenance
comprising oral mercaptopurine daily and oral MTX daily beginning at month 10 and
continuing through year 3. Patients without CNS disease at presentation receive
CNS prophylaxis comprising MTX IT on days 1 and 29. Patients with CNS disease at
presentation receive CNS therapy comprising ARA-C IT, MTX IT, and HC IT beginning
at 1 month after BMT and continuing monthly for 1 year and then every 3 months
through year 3.
- Arm IV: Patients receive CTX IV and ARA-C IV continuously on day 1, oral
mercaptopurine on days 8-28, and oral MTX on days 8, 15, and 22 during months 4,
7, 11, 13, 17, 21, 25, and 29. Patients receive MTX IV over 30 minutes on day 1,
leucovorin calcium IV or orally every 6 hours on days 2-4, asparaginase IV over 1
hour or intramuscularly on day 2, oral mercaptopurine on days 8-28, and oral MTX
on days 8, 15, and 22 during months 6, 10, 12, 15, 19, 23, and 27. Patients
receive VAD or VAP as in arm III beginning at month 8. Patients without CNS
disease at presentation receive CNS prophylaxis comprising whole brain
radiotherapy and MTX IT on day 1 of radiotherapy during month 5. Patients with CNS
disease at presentation receive CNS therapy as in arm III.
- Allogeneic bone marrow is harvested. Patients receive bone marrow ablation as in arm
III beginning on day 100. Allogeneic bone marrow is infused over 15-30 minutes on day
- Patients in groups A and B with CNS disease at presentation undergo radiotherapy
to focal infiltration at entry or concurrently with total body irradiation, or
whole brain radiotherapy during maintenance (if no prior CNS irradiation). At any
time during the study, patients who develop marrow relapse (more than 5% leukemic
blasts in bone marrow on 2 occasions), CNS relapse (blasts in CSF, cranial nerve
palsy, or CNS mass), or testis or other extramedullary relapse are taken off
PROJECTED ACCRUAL: A total of 392 patients will be accrued for this study within
approximately 6 years.
Allocation: Randomized, Primary Purpose: Treatment
Roel Willemze, MD, PhD
Leiden University Medical Center
United States: Federal Government