Leukemia Clinical Trial
Official title:
ALLR3: An International Collaborative Trial for Relapsed and Refractory Acute Lymphoblastic Leukaemia (ALL)
RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer
cells, either by killing the cells or by stopping them from dividing. It is not yet known
which combination chemotherapy regimen is more effective in treating young patients with
acute lymphoblastic leukemia.
PURPOSE: This partially randomized phase III trial is studying how well combination
chemotherapy works in treating young patients with relapsed or refractory acute
lymphoblastic leukemia.
OBJECTIVES:
Primary
- Evaluate the progression-free survival (defined as the time from study entry to the
first occurrence of progression, relapse, death while in complete clinical remission,
or second malignancy) of United Kingdom patients with relapsed or refractory acute
lymphoblastic leukemia stratified by risk group.
- Evaluate whether a minimal residual disease (MRD) level of 10^-4 is a suitable
criterion at the end of induction therapy on which to decide whether chemotherapy or
stem cell transplantation will be most beneficial to patients with intermediate-risk
disease.
Secondary
- Use MRD as a surrogate marker for response to therapy.
OUTLINE: This is a multicenter study. Patients are stratified by risk group (standard vs
intermediate vs high) and participating country (UK and Ireland vs Australia and New Zealand
vs The Netherlands).
Patients with standard-risk disease receive induction therapy, consolidation therapy,
intensification therapy, interim maintenance therapy, and maintenance therapy. Patients with
intermediate-risk disease receive induction therapy followed by assessment of minimal
residual disease (MRD). Those whose MRD status is < 10^-4 at week 5 (after induction
therapy) proceed to consolidation therapy followed by intensification therapy, interim
maintenance therapy, and maintenance therapy. Those whose MRD status is ≥ 10^-4 at week 5
(after induction therapy) proceed to consolidation therapy followed by intensification
therapy and assessment of MRD at week 13 (after intensification therapy). Those whose MRD
status is ≥ 10^-3 at week 13 proceed to pre-stem cell transplantation cytoreduction (FLAD)
followed by allogeneic stem cell transplant (ASCT). Those whose MRD status is < 10^-3 at
week 13 proceed directly to ASCT. Patients with high-risk disease receive induction therapy,
consolidation therapy, and intensification therapy followed by assessment of MRD at week 13
(after intensification therapy). These patients then proceed to further treatment (FLAD
and/or ASCT) based on the same MRD parameters at week 13 as for patients with
intermediate-risk disease.
- Induction therapy (weeks 1-4): Patients are randomized to 1 of 2 induction therapy
arms.
- Arm I: Patients receive idarubicin IV over 1 hour on days 1 and 2; oral
dexamethasone twice daily on days 1-5 and 15-19; intrathecal (IT) methotrexate on
days 1 and 8; vincristine sulfate IV on days 3, 10, 17, and 24; and pegaspargase
intramuscularly (IM) on days 3 and 17 or asparaginase IM on days 3, 5, 7, 9, 11,
13, 15, 17, 19, 21, 23, and 25.
- Arm II: Patients receive mitoxantrone IV over 1 hour on days 1 and 2. Patients
also receive dexamethasone, methotrexate, vincristine sulfate, and pegaspargase or
asparaginase as in arm I.
- Consolidation therapy (weeks 5-8): Patients receive oral dexamethasone twice daily on
days 1-5; vincristine sulfate IV on day 3; IT methotrexate on day 8; methotrexate IV
continuously over 36 hours beginning on day 8; pegaspargase IM on day 9 or asparaginase
IM on days 9, 11, 13, 15, 17, and 19; leucovorin calcium IV twice on day 10; and
cyclophosphamide IV over 30 minutes and etoposide phosphate IV over 4 hours on days
15-19.
- Intensification therapy (weeks 9-13): Patients receive oral dexamethasone twice daily
on days 1-5; vincristine sulfate IV on 3; IT methotrexate on days 1 and 22; cytarabine
IV over 3 hours twice on days 1, 2, 8, and 9; asparaginase IM on days 2, 4, 9, 11, and
23; methotrexate IV continuously over 36 hours beginning on day 22; and leucovorin
calcium IV twice on day 24.
- Interim maintenance therapy (weeks 14-29): Patients receive oral dexamethasone twice
daily on days 1-5; IT methotrexate* on days 1 and 43; vincristine sulfate IV on day 3;
high-dose oral methotrexate 4 times on day 22; oral leucovorin calcium twice on day 24;
oral mercaptopurine once daily on days 1-42; oral methotrexate on days 8, 15, 29, and
36; oral thioguanine on days 43-49; etoposide phosphate IV over 4 hours and
cyclophosphamide IV over 30 minutes on days 43 and 50; and cytarabine IV or
subcutaneously (SC) on days 44-47 and 51-54. Treatment repeats every 56 days (8 weeks)
for 2 courses.
Patients undergoing cranial irradiation do so before starting interim maintenance therapy.
Patients undergoing testicular irradiation do so concurrently with interim maintenance
therapy.
NOTE: *Patients who undergo cranial irradiation do not receive IT methotrexate.
- Maintenance therapy (weeks 30-117): Patients receive IT methotrexate* on day 15; oral
dexamethasone twice daily on days 1-5, 29-33, and 57-61; vincristine sulfate IV on days
1, 29, and 57; oral mercaptopurine once daily on days 1-84; and oral methotrexate on
days 1, 8, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 84 days (12
weeks) for 7 courses. Patients then receive 4 additional weeks (course 8) of
maintenance therapy without IT methotrexate.
NOTE: *Patients who undergo cranial irradiation do not receive IT methotrexate.
- Pre-stem cell transplantation cytoreduction (FLAD): Patients receive fludarabine
phosphate IV over 30 minutes and cytarabine over 4 hours on days 1-5 and liposomal
daunorubicin citrate IV over 2 hours on day 1. Patients also receive filgrastim IV or
SC beginning on day 7 and continuing until blood counts recover.
- ASCT: Patients undergo ASCT (including conditioning and graft-vs-host disease [GVHD]
prophylaxis) according to national transplant guidelines based on the type of donor.
- Post-transplant immunotherapy: Patients who undergo ASCT may receive incremental doses
of donor lymphocytes by infusion until a response and/or GVHD has occurred.
;
Allocation: Randomized, Primary Purpose: Treatment
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