Trial Information

ACUTE MYELOID LEUKAEMIA TRIAL 12

OBJECTIVES:

- Compare the remission rate, duration of remission, survival, toxicity, and supportive
care requirements associated with induction chemotherapy with cytarabine, daunorubicin,
and etoposide vs mitoxantrone, cytarabine, and etoposide in patients with acute myeloid
leukemia.

- Assess filgrastim (G-CSF) support in the recovery phase after the first induction
course with respect to remission rate, reasons for failure, hematologic regeneration,
febrile incidents, supportive care requirements, and overall survival in these
patients.

- Compare 4 vs 5 courses of total treatment, with either chemotherapy or bone marrow
transplantation (BMT) as the final course, with respect to remission duration, relapse
rate, disease free mortality, and overall survival in these patients.

- Compare allogeneic or autologous BMT vs conventional chemotherapy with respect to
remission duration, relapse rate, disease free mortality, and overall survival in these
patients.

- Evaluate the prognostic significance of blood and bone marrow morphology, cytogenetics,
molecular genetics, and immunophenotype assessed at diagnosis, at second randomization,
and at relapse.

OUTLINE: This is a randomized study. Patients are stratified by center, age (15-29 vs 30-39
vs 40-49 vs 50-59), performance status, and disease status (de novo vs secondary). Patients
who are eligible for the second randomization are also stratified by first randomization
treatment (arm I vs II) and prognostic risk group (good vs standard).

Original first randomization (closed as of 11/1998): Patients are randomized to 1 of 2
induction treatment arms.

- Arm I: During course 1, patients receive cytarabine IV every 12 hours on days 1-10,
daunorubicin IV on days 1, 3, and 5, and etoposide IV over 1 hour on days 1-5. Patients
are further randomized to receive either filgrastim (G- CSF) or placebo subcutaneously
(SQ) beginning on day 18 and continuing until 2 days after blood counts have recovered
(G-CSF randomization closed as of 8/15/2000). During course 2, patients receive
daunorubicin and etoposide as in course 1 and cytarabine IV every 12 hours on days 1-8,
but no G-CSF or placebo unless peripheral blood stem cells (PBSC) are harvested.

- Arm II: During course 1, patients receive mitoxantrone IV on days 1, 3, and 5 and
cytarabine, etoposide, and G-CSF or placebo as in course 1 of arm I. During course 2,
patients receive mitoxantrone and etoposide as in course 1 of arm II, cytarabine as in
course 2 of arm I, but no G-CSF or placebo unless PBSC are harvested.

Patients who have poor prognostic risk after course 1 or fail to achieve complete remission
(CR) after course 2 are taken off this study and should be entered in the MRC
refractory/relapse study. Patients who achieve CR after course 1 proceed to the harvest
phase after completion of course 2. Patients who achieve CR after course 2 proceed to the
postinduction chemotherapy phase. New first randomization (opened as of 12/1998): Patients
are randomized to 1 of 2 induction treatment arms.

- Arm I: During course 1, patients receive daunorubicin IV on days 1, 3, and 5 and lower
dose cytarabine IV every 12 hours and thioguanine IV every 12 hours on days 1-10.
During course 2, patients receive treatment as in course 1, but with cytarabine and
thioguanine on days 1-8.

- Arm II: During courses 1 and 2, patients receive treatment as in arm I, but with higher
dose cytarabine.

Both arms may be further randomized to receive no tretinoin or tretinoin for 60 days. Acute
prophylactic subgroups are not randomized and all receive tretinoin.

- Postinduction chemotherapy: Patients receive amsacrine IV over 1 hour, cytarabine IV
continuously, and etoposide IV over 1 hour on days 1-5.

- Harvest: Patients who have an HLA matched sibling donor undergo allogeneic bone marrow
transplantation (BMT), otherwise autologous BMT is planned. PBSC may also be harvested.
Patients who undergo harvest of PBSC also receive G-CSF on days 18-30 of induction and
days 13-25 of postinduction.

- Second randomization: Patients are randomized to 1 of 4 consolidation treatment groups.
Good risk patients are randomized to arm II or IV. Standard risk patients for whom BMT
is considered inappropriate are randomized to arm II or IV and those for whom BMT is
considered appropriate are randomized to arm I or III. Patients for whom 4 total
courses of therapy are preferred are randomized to arm I or II and those for whom 5
total courses of therapy are preferred are randomized to arm III or IV.

- Arm I: Six to eight weeks following completion of induction, patients receive a
fourth course of therapy comprised of cyclophosphamide IV over 1 hour for 2 days,
followed 24 hours later by total body irradiation (TBI) for 4 days, and followed
24 hours later by reinfusion of bone marrow. Patients receive cranial irradiation
daily for 3-5 days prior to TBI.

- Arm II: Patients receive a fourth course comprised of mitoxantrone IV on days 1-5
and cytarabine IV over 2 hours every 12 hours on days 1-3.

- Arm III: Patients receive a fourth course comprised of idarubicin IV on days 1 and
2, cytarabine as in arm II, and etoposide IV over 1 hour on days 1-3 and then a
fifth course comprised of cranial irradiation, TBI, and BMT as in arm I.

- Arm IV: Patients receive a 4th course comprised of idarubicin, cytarabine, and
etoposide as in arm III and then a 5th course comprised of mitoxantrone and
cytarabine as in arm II.

- PBSC support: Optional PBSC are reinfused after completion of course 4 (arm I or
II) or course 5 (arm III or IV) beginning no sooner than 24 hours after completion
of BMT.

- CNS therapy: Patients receive cytarabine intrathecally at the time of diagnostic
lumbar puncture, then 3 days a week until cerebral spinal fluid clears, and then
every 2 weeks until completion of consolidation.

PROJECTED ACCRUAL: A minimum of 2,000 patients will be accrued for this study over 5 years.