Trial Information

MULTICENTRE TRIAL OF INTENSIFIED THERAPY FOR ADULT ALL (O5/93)

OBJECTIVES: I. Develop risk-adapted therapy for patients with low-risk, high-risk, T-cell,
or B-cell acute lymphocytic leukemia (ALL). II. Determine the complete remission rate in
these patients treated with the following strategies: increased doses of cyclophosphamide
during induction and reinduction, early use of high-dose cytarabine plus mitoxantrone (for
high-risk patients), and increased doses of methotrexate (for B-cell ALL patients). III.
Determine the duration of remission and survival of patients in all risk groups treated with
intensified consolidation and subtype-specific chemotherapy. IV. Compare the effects of
intensified vs conventional maintenance therapy in patients of all risk groups.

OUTLINE: This is a randomized, multicenter study. Patients are assigned to 1 of 4 treatment
groups based on disease status. Patients in groups 1-3 with a large leukemic cell mass, in
particular those with a WBC greater than 25,000/mm3 and/or marked organomegaly, receive
preinduction therapy comprising oral prednisolone (PRDL) 3 times a day on days 1-7 and
vincristine (VCR) IV on day 1. Group 1 (low-risk acute lymphocytic leukemia (ALL)): First
induction therapy: Patients receive oral PRDL 3 times a day on days 1-7 of weeks 1-4,
asparaginase (ASP) IV over 30 minutes on days 1-7 of weeks 3 and 4, VCR IV and daunorubicin
IV over 30 minutes on day 1 of weeks 1-4, and methotrexate (MTX) IT on day 1 of week 1.
Patients who achieve complete remission (CR) after first induction therapy proceed to first
consolidation therapy on group 1. Second induction therapy: Patients receive oral
cyclophosphamide (CTX) IV on day 1 of weeks 5, 7, and 9; cytarabine (ARA-C) IV over 1 hour
or subcutaneously on days 3-6 and MTX IT on day 3 of weeks 5-8; and oral mercaptopurine (MP)
on days 1-7 of weeks 5-8 and day 1 of week 9. Patients who achieve CR during second
induction therapy undergo prophylactic cranial irradiation 5 days a week for 2.4 weeks.
Patients who achieve CR after second induction therapy proceed to group 3. First
consolidation therapy: Patients receive high-dose MTX IV continuously with leucovorin
calcium (CF) rescue on day 1, ASP IV over 1 hour on day 2, and oral MP on days 1-5 of weeks
13 and 15; and teniposide (VM-26) IV over 1 hour and ARA-C IV over 1 hour on days 1-5 of
week 17. Triple intrathecal therapy (TIT) comprising MTX, ARA-C, and dexamethasone (DM) is
also administered on day 1 of week 17. First reinduction therapy: Patients receive oral PRDL
three times a day on days 1-7 and VCR IV and doxorubicin (DOX) IV over 30 minutes on day 1
of weeks 21-24, and TIT on day 1 of week 21. Second reinduction therapy: Patients receive
CTX IV and TIT on day 1 of week 25, and ARA-C IV over 1 hour on days 3-6 and oral
thioguanine (TG) on days 1-7 of weeks 25 and 26. Second consolidation therapy: Patients
receive oral MP daily and oral MTX weekly during weeks 29-32, 34-38, 40-44, 46-50, and 52;
high-dose MTX, CF rescue, and ASP as in first consolidation therapy during weeks 33 and 45;
and VM-26, ARA-C, and TIT as in first consolidation therapy during weeks 39 and 51. Group 2
(T-cell ALL with or without mediastinal involvement): First induction therapy: Patients
receive treatment as in first induction therapy on group 1. Patients with residual tumor
greater than 2 cm after first induction therapy also undergo mediastinal radiotherapy 5 days
a weeks for 2.4-2.7 weeks concurrently with prophylactic cranial irradiation. Second
induction therapy: Patients receive treatment as in second induction therapy on group 1.
First consolidation therapy: Patients receive high-dose ARA-C IV over 3 hours every 12 hours
on days 1-4 and mitoxantrone (DHAD) IV over 30 minutes on days 3-5 during week 13; and
high-dose MTX, CF rescue, ASP, and MP as in first consolidation therapy on group 1 during
week 17. First reinduction therapy: Patients receive treatment as in first reinduction
therapy on group 1. Second reinduction therapy: Patients receive treatment as in second
reinduction therapy on group 1. Second consolidation therapy: Patients receive MP and MTX as
in second consolidation therapy on group 1; CTX IV, ARA-C IV continuously, and TIT on day 1
during weeks 33 and 45; and VM-26, ARA-C, and TIT as in first consolidation therapy on group
1 during weeks 39 and 51. Group 3 (high-risk ALL): First induction therapy: Patients receive
treatment as in first induction therapy on group 1. Second induction therapy: Patients
receive CNS-effective chemotherapy comprising high-dose ARA-C every 12 hours on days 1-4 and
DHAD IV over 30 minutes on days 3-5 during week 6. First consolidation therapy: Patients
receive high-dose MTX, CF rescue, and ASP as in first consolidation therapy on group 1; and
CTX, ARA-C, and TIT as in second consolidation therapy on group 2 during week 17. First
reinduction therapy: Patients receive treatment as in first reinduction therapy on group 1.
Second reinduction therapy: Patients receive treatment as in second reinduction therapy on
group 1. Second consolidation therapy: Patients receive MP and MTX as in second
consolidation therapy on group 1; treatment as in second induction therapy on group 3 during
week 33; high-dose MTX, CF rescue, ASP, and MP as in first consolidation therapy on group 1
during week 39; CTX, ARA-C, and TIT as in second consolidation therapy on group 2 during
week 45; and VM-26, ARA-C, and TIT as in first consolidation therapy on group 1 during week
51. Groups 1-3: Patients who are age 15 to 50, achieve first CR, and have a suitable donor
undergo allogeneic bone marrow transplantation. Patients who are under age 40 undergo bone
marrow transplantation from a matched unrelated donor. Patients who have Philadelphia
chromosome/bcr-abl positive disease and no suitable donor undergo purged autologous
peripheral blood stem cell transplantation instead of reinduction therapy during first CR.
CNS therapy: Patients with CNS disease at entry receive TIT 2 or 3 times weekly beginning
immediately upon diagnosis and continuing until 5 doses after blasts are cleared from the
CSF. Patients on group 1 and 2 undergo irradiation of the entire neuraxis 5 days a week for
2.7-3.2 weeks during second induction therapy. Maintenance therapy: After completion of 1
year of treatment on group 1, 2, or 3, patients are randomized to 1 of 2 treatment arms. Arm
I: Patients receive MP daily and MTX weekly on odd-numbered months between months 13-30;
CTX, ARA-C, and TIT as in second consolidation therapy on group 2 during months 14, 20, and
26; VM-26, ARA-C, and TIT as in first consolidation therapy on group 1 during months 16, 22,
and 28; and high-dose MTX, CF rescue, and ASP as in first consolidation therapy on group 1
during months 18, 24, and 30. Arm II: Patients receive MP plus MTX as in second
consolidation therapy on group 1 continuously and TIT every 2 months during months 13-30.
Group 4 (B-cell ALL): Pretreatment: Patients who are age 50 and under receive CTX IV over 1
hour and oral PRDL 3 times a day on days 1-5. Patients who are over age 50 receive CTX IV
and oral DM on days 1, 3, and 5. Treatment: Patients receive alternating therapy on blocks A
and B. Block A therapy consists of VCR IV, MTX IV continuously, and CF rescue on day 1;
ifosfamide IV over 1 hour and oral DM on days 1-5; VM-26 IV over 1 hour and ARA-C IV over 1
hour every 12 hours on days 4 and 5; and TIT on days 1 and 5. Block B therapy consists of
VCR IV, MTX IV continuously, and CF rescue on day 1; CTX IV over 1 hour and oral DM on days
1-5; DOX IV over 15 minutes on days 4 and 5; and TIT on days 1 and 5. Blocks A and B
continue every 3 weeks for a total of 6 courses. Patients who have not achieved CR after 3
courses or who develop disease progression at any time may optionally receive vindesine,
ARA-C, etoposide, and DM. Patients with CNS disease undergo craniospinal irradiation after 2
courses of systemic chemotherapy (block A and B therapy). Patients receive TIT 2-3 times
weekly until CSF is clear after block A therapy only if response is unsatisfactory.

PROJECTED ACCRUAL: Approximately 700 patients will be accrued for this study within 4 years.