Phase III Randomized Study of Escalating Dose Intravenous Methotrexate Without Leucovorin Rescue Versus Oral Methotrexate and Single Versus Double Delayed Intensification in Children With Acute Lymphoblastic Leukemia
Note: this outline was patched together from the NCI online protocol and input from parents of kids with ALL. It is summarized here for our convenience, so that we can quickly compare our protocols. We do not guarantee the accuracy of this outline - it is not an official document. You can contact your child's oncologist and ask for the complete protocol document if you are interested in the details of your child's protocol.
This trial on the clinicaltrials.gov site.
This trial on the cancer.gov site.
Treatment for standard risk ALL, defined as presenting features of at least one of the following:
- age 1-9 with WBC less than 50,000/microliter
Note the following stipulations:
- Greater than 25% L1 or L2 lymphoblasts (see FAB definition)
- No greater than 25% L3 lymphoblasts
- No patients found to have t(8;14)(q24;q32), t(8;22)(q24;q11), and t(2;8)(p11-p12;q24) (characteristic of Burkitt's lymphoma)
Massive lymphadenopathy, massive splenomegaly, or large mediastinal mass allowed; CNS or testicular leukemia allowed
Specific Aims:
- Compare escalating dose intravenous methotrexate without leucovorin calcium versus oral methotrexate
- Compare two delayed intensification phases versus one delayed intensification phase
- Compare the toxic effects of oral versus intravenous methotrexate
Also:
- Determine the prognostic significance of the rate of disappearance of peripheral lymphoblasts and lymphocytes during the first week of treatment
- Determine the prognostic significance of trisomies of chromosomes 4, 5, 10, and 17 and early treatment response.
- Determine the prognostic significance of the TEL-AML1 fusion transcript and early treatment response.
Protocol Outline
Patients
- without CNS disease at diagnosis
- in remission at day 28 (M1 marrow status of less than 5% blasts in the bone marrow)
- remaining event free with favorable bone marrow status and cytogenetics between day 21 and 28 of consolidation therapy
are randomized to one of four treatment arms.
Patients with CNS disease at diagnosis are assigned to treatment arm II and undergo cranial irradiation.
Patients with any of the following unfavorable bone marrow features and/or unfavorable cytogenetic features are assigned to the augmented treatment regimen by day 21 of induction chemotherapy or at the beginning of consolidation chemotherapy:
Unfavorable marrow status is defined as:
- M2: 5-25% blasts in bone marrow at day 28 of induction chemotherapy (or at day 14 of induction chemotherapy if day 7 status is M3 [>25% blasts])
OR
- M3: Greater than 25% blast cell in bone marrow, regardless of the proportion of mature lymphocytes at day 14 of induction chemotherapy
Unfavorable cytogenetics:
- t(9;22)(q34;q11) OR
- t(4;11)(q21;q23) OR
- Balanced t(1;19)(q23;p13) OR
- Hypodiploidy with less than 45 chromosomes OR
- Other 11q23 translocation involving MLL
Projected Accrual: A total of 2,173 randomized patients will be accrued for this study within 3.5 years.
4 Weeks Induction (All patients receive standard induction chemotherapy)
- cytarabine (ARA-C) intrathecally (IT) on day 0 or up to 72 hours before day 0
- oral dexamethasone (DM) twice daily on days 0-27
- vincristine (VCR) IV on days 0, 7, 14, and 21
- pegaspargase (PEG-ASP) intramuscularly (IM) once between days 3-5.
(Note: Patients without CNS disease at diagnosis receive methotrexate (MTX) IT on days 7 and 28. Patients with CNS disease at diagnosis receive MTX IT on days 7, 14, 21, and 28.)
(Notes: Patients who have achieved M1 marrow status by day 28 of induction therapy and have favorable bone marrow status and cytogenetics receive induction chemotherapy for an additional 14 days and then proceed to standard consolidation therapy once blood counts have recovered. Patients with M3 bone marrow status at day 28 of induction therapy are taken off the protocol. All other patients are assigned to the augmented treatment regimen. These are the "Unfavorable marrow status" patients referred to above.)
4 Weeks Consolidation
- VCR IV on day 0
- oral mercaptopurine (MP) on days 0-27
Patients without CNS disease at diagnosis receive
- MTX IT on days 7, 14, and 21
Patients with CNS disease at diagnosis receive
- MTX IT on day 7 and cranial irradiation 5 days a week for 2 weeks.
Patients with testicular disease receive bilateral testicular radiotherapy 5 days a week for 1 week and then for 3 consecutive days during the next week.
Arm I (standard arm - oral MTX, single delint)
Interim maintenance I (7 weeks)
- oral DM twice daily on days 0-4 and 28-32
- VCR IV on days 0 and 28
- oral MTX on days 0, 7, 14, 21, 28, 35, 42, and 49
- oral MP on days 0-49
- MTX IT on day 28.
Delayed intensification (7 weeks)
- oral DM twice daily on days 0-6 and 14-20
- VCR IV and doxorubicin (DOX) IV over 15 minutes to 2 hours on days 0, 7, and 14
- PEG-ASP IM on day 3
- cyclophosphamide (CTX) IV over 20-30 minutes on day 28
- oral thioguanine (TG) on days 28-41
- ARA-C IV or subcutaneously (SC) daily on days 28-31 and 35-38
- MTX IT on days 0 and 28
Interim maintenance II (7 weeks)
- oral DM twice daily on days 0-4 and 28-32
- VCR IV on days 0 and 28
- oral MTX on days 0, 7, 14, 21, 28, 35, 42, and 49
- oral MP on days 0-49
- MTX IT on days 0 and 28.
Maintenance
- oral DM twice daily on days 0-4, 28-32, and 56-60
- VCR IV on days 0, 28, and 56
- oral MP on days 0-83
- oral MTX on days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, and 77
- MTX IT on day 0.
Arm II (standard + two delayed intensifications)
Interim maintenance I (7 weeks)
- oral DM twice daily on days 0-4 and 28-32
- VCR IV on days 0 and 28
- oral MTX on days 0, 7, 14, 21, 28, 35, 42, and 49
- oral MP on days 0-49
- MTX IT on day 28.
Delayed intensification I (7 weeks)
- oral DM twice daily on days 0-6 and 14-20
- VCR IV and doxorubicin (DOX) IV over 15 minutes to 2 hours on days 0, 7, and 14
- PEG-ASP IM on day 3
- cyclophosphamide (CTX) IV over 20-30 minutes on day 28
- oral thioguanine (TG) on days 28-41
- ARA-C IV or subcutaneously (SC) daily on days 28-31 and 35-38
- MTX IT on days 0 and 28
Interim maintenance II (7 weeks)
- oral DM twice daily on days 0-4 and 28-32
- VCR IV on days 0 and 28
- oral MTX on days 0, 7, 14, 21, 28, 35, 42, and 49
- oral MP on days 0-49
- MTX IT on days 0 and 28.
Delayed intensification II (7 weeks)
- oral DM twice daily on days 0-6 and 14-20
- VCR IV and doxorubicin (DOX) IV over 15 minutes to 2 hours on days 0, 7, and 14
- PEG-ASP IM on day 3
- cyclophosphamide (CTX) IV over 20-30 minutes on day 28
- oral thioguanine (TG) on days 28-41
- ARA-C IV or subcutaneously (SC) daily on days 28-31 and 35-38
- MTX IT on days 0 and 28
Interim maintenance II (7 weeks)
- oral DM twice daily on days 0-4 and 28-32
- VCR IV on days 0 and 28
- oral MTX on days 0, 7, 14, 21, 28, 35, 42, and 49
- oral MP on days 0-49
- MTX IT on days 0 and 28.
Maintenance
- oral DM twice daily on days 0-4, 28-32, and 56-60
- VCR IV on days 0, 28, and 56
- oral MP on days 0-83
- oral MTX on days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, and 77
- MTX IT on day 0.
Arm III (escalating doses of MTX IV w/o leucovorin rescue)
Interim maintenance I (7 weeks)
- VCR IV
- escalating doses of MTX IV on days 0, 10, 20, 30, and 40
- MTX IT on day 30
Delayed intensification (7 weeks)
- oral DM twice daily on days 0-6 and 14-20
- VCR IV and doxorubicin (DOX) IV over 15 minutes to 2 hours on days 0, 7, and 14
- PEG-ASP IM on day 3
- cyclophosphamide (CTX) IV over 20-30 minutes on day 28
- oral thioguanine (TG) on days 28-41
- ARA-C IV or subcutaneously (SC) daily on days 28-31 and 35-38
- MTX IT on days 0 and 28
Interim maintenance II (7 weeks)
- VCR IV
- IV MTX starting at the dose preceding the maximum tolerated dose (MTD) attained in interim maintenance I chemotherapy.
- MTX IT on day 30
Maintenance
- oral DM twice daily on days 0-4, 28-32, and 56-60
- VCR IV on days 0, 28, and 56
- oral MP on days 0-83
- oral MTX on days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, and 77
- MTX IT on day 0.
Arm IV (escalating doses of MTX IV w/o leucovorin rescue, 2 delayed intensifications)
Interim maintenance I (7 weeks)
- VCR IV
- escalating doses of MTX IV on days 0, 10, 20, 30, and 40
- MTX IT on day 30
Delayed intensification I (7 weeks)
- oral DM twice daily on days 0-6 and 14-20
- VCR IV and doxorubicin (DOX) IV over 15 minutes to 2 hours on days 0, 7, and 14
- PEG-ASP IM on day 3
- cyclophosphamide (CTX) IV over 20-30 minutes on day 28
- oral thioguanine (TG) on days 28-41
- ARA-C IV or subcutaneously (SC) daily on days 28-31 and 35-38
- MTX IT on days 0 and 28
Interim maintenance II (7 weeks)
- VCR IV
- IV MTX starting at the dose preceding the maximum tolerated dose (MTD) attained in interim maintenance I chemotherapy.
- MTX IT on day 3
Delayed intensification II (7 weeks)
- oral DM twice daily on days 0-6 and 14-20
- VCR IV and doxorubicin (DOX) IV over 15 minutes to 2 hours on days 0, 7, and 14
- PEG-ASP IM on day 3
- cyclophosphamide (CTX) IV over 20-30 minutes on day 28
- oral thioguanine (TG) on days 28-41
- ARA-C IV or subcutaneously (SC) daily on days 28-31 and 35-38
- MTX IT on days 0 and 28
Maintenance
- oral DM twice daily on days 0-4, 28-32, and 56-60
- VCR IV on days 0, 28, and 56
- oral MP on days 0-83
- oral MTX on days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, and 77
- MTX IT on day 0
Augmented Treatment
Patients receive induction chemotherapy:
- daunorubicin IV continuously for 48 hours beginning no later than day 21
- oral DM twice daily on days 14-27
- VCR IV on days 14 and 21
Patients without CNS disease at diagnosis receive MTX IT on days 21 and 35. Patients with CNS disease at diagnosis receive MTX IT on days 21 and 28.
Consolidation therapy
- CTX IV over 20-30 minutes on days 0 and 28
- oral MP on days 0-13 and 28-41
- ARA-C IV or SC daily on days 0-3, 7-10, 28-31, and 35-38
- VCR IV on days 14, 21, 42, and 49
- PEG-ASP IM on days 14 and 42.
Patients without CNS disease at diagnosis receive MTX IT on days 7, 14, and 21. Patients with CNS disease at diagnosis receive MTX IT on day 7 and cranial irradiation as in the randomized treatment section. Patients with testicular leukemia receive radiotherapy as in the randomized treatment section.
Interim maintenance I
- VCR IV on days 0, 10, 20, 30, and 40
- escalating doses of MTX IV on days 10, 20, 30, and 40
- PEG-ASP IM on days 1 and 21
- MTX IT on days 0 and 30.
Delayed intensification I chemotherapy
- oral DM twice daily on days 0-6 and 14-20
- VCR IV on days 0, 7, 14, 42, and 49
- DOX IV over 15 minutes to 2 hours on days 0, 7, and 14
- PEG-ASP IM on days 3 and 42
- CTX IV over 20-30 minutes on day 28
- oral TG on days 28-41
- ARA-C IV or SC daily on days 28-31 and 35-38
- MTX IT on days 0 and 28.
Interim maintenance II chemotherapy
- VCR IV on days 0, 10, 20, 30, and 40
- IV MTX starting at the dose preceding the MTD attained in interim maintenance I chemotherapy
- PEG-ASP IM on days 1 and 21
- MTX IT on days 0 and 30.
Delayed intensification II chemotherapy
- oral DM twice daily on days 0-6 and 14-20
- VCR IV on days 0, 7, 14, 42, and 49
- DOX IV over 15 minutes to 2 hours on days 0, 7, and 14
- PEG-ASP IM on days 3 and 42
- CTX IV over 20-30 minutes on day 28
- oral TG on days 28-41
- ARA-C IV or SC daily on days 28-31 and 35-38
- MTX IT on days 0 and 28.
Maintenance
- oral DM twice daily on days 0-4, 28-32, and 56-60
- VCR IV on days 0, 28, and 56
- oral MP on days 0-83
- oral MTX on days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, and 77
- MTX IT on day 0.
Follow-up:
Patients are followed every 4-8 weeks for one year, every 3 months for one year, every 6 months for one year, and then annually thereafter.
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Last Updated 4/06
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