Phase III Randomized Study of Multidrug Delayed Intensification Therapy in Children With Newly Diagnosed Standard Risk Acute Lymphocytic 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 cancer.gov site.

Treatment for standard risk ALL, defined as presenting features of:

• 1 to 21 at diagnosis
• not qualifying for POG 9904 and not requiring POG 9906 and not very high risk (e.g., standard risk - not low, high, or very high risk)
• B precursor ALL

Objectives

• Determine if multidrug delayed intensification therapy improves outcome in patients with newly diagnosed standard risk acute lymphocytic leukemia.
• Compare the efficacy and toxicity of methotrexate administered over 4 hours vs methotrexate administered over 24 hours in this patient population.
• Determine the correlation between event free survival, minimal residual disease, and early response in this patient population treated with this multiple drug regimen.

Protocol Outline

All patients receive induction therapy as per POG 9900. (weeks 1-4)

Induction

3-drug induction (vinc, asp, dex) (please double check this outline on the COG or the cancer.gov site)

• ara C IT day 1
• oral dexamethasone twice daily on days 1-28
• vincristine IV weekly on days 1, 8, 15, and 22
• (only for high-risk patients) daunorubicin IV on days 8, 15, 22
• asparaginase IM on days 2, (PEG?) 5, 8, 12, 15, and 19
• methotrexate (MTX) intrathecally (IT) on day and 8
• patients with blasts in the cerebral spinal fluid and inadequate blood counts receive additional intrathecal therapy on days 15 and 22.

Consolidation

After the 4-week induction:

• patients with M1 bone marrow and adequate blood counts immediately proceed to consolidation therapy
• patients with M2 bone marrow receive 2 additional weeks of induction therapy consisting
  • oral prednisone three times a day for 14 additional days
  • vincristine IV bolus
  • daunorubicin IV over 15 minutes on days 29 and 36
  • asparaginase IM on days 29, 32, 36, and 39
  • Patients with M1 bone marrow and adequate blood counts following the above additional induction therapy immediately proceed to consolidation therapy on day 43.
• Patients with M3 bone marrow on day 29 or M2 or M3 bone marrow on day 43 are removed from study.

For consolidation, patients are randomized to one of four treatment arms. Patients with t(1;19) are randomized to either arm III or arm IV.

Arm I: (weeks 5-24)

• IT MTX on day 1 followed by MTX IV over 20 minutes followed by MTX continuously over 23.6 hours on weeks 7, 10, 13, 16, 19, and 22. At 42 hours following the beginning of the MTX infusion, patients receive oral leucovorin calcium every 6 hours for a total of 3 doses.
• oral mercaptopurine daily beginning on week 5 and continuing until the completion of consolidation therapy
• oral dexamethasone twice daily for 7 days on weeks 8 and 17
• vincristine IV on day 1 of weeks 8, 9, 17, and 18.

Arm II: (weeks 5-24)

• MTX IV over 4 hours on weeks 7, 10, 13, 16, 19, and 22. At 42 hours following the beginning of the MTX infusion, patients receive oral leucovorin calcium as in arm I.
• oral mercaptopurine daily beginning on week 5 and continuing until the completion of consolidation therapy
• oral dexamethasone twice daily for 7 days on weeks 8 and 17
• vincristine IV on day 1 of weeks 8, 9, 17, and 18.

Arm III: (weeks 5-32)

• MTX IV as in arm I on weeks 7, 10,13, 24, 27, and 30, leucovorin calcium as in arm I
• asparaginase IM on weeks 16 and 17 for a total of 6 doses
• oral mercaptopurine daily on weeks 5-13, and from week 24 until the completion of consolidation therapy
• IT MTX as in arm I on weeks 7, 10, 13, 16, 20, 21, and 30
• oral dexamethasone twice daily on weeks 8, 16-18, and 28 for a total of 35 days;
• vincristine IV on day 1 of weeks 8, 9, 16, 17, 18, 28, and 29
• daunorubicin IV on day 1 of weeks 16-18
• cyclophosphamide IV over 30 minutes on day 1 of week 20
• cytarabine IV or subcutaneously daily on days 2-5 of weeks 20 and 21
• oral thioguanine daily on weeks 20-21.

Arm IV: (weeks 5-32)

• MTX IV as in arm II on weeks 7, 10, 13, 24, 27, and 30, leucovorin calcium as in arm I
• asparaginase IM on weeks 16 and 17 for a total of 6 doses
• oral mercaptopurine daily on weeks 5-13, and from week 24 until the completion of consolidation therapy
• IT MTX as in arm I on weeks 7, 10, 13, 16, 20, 21, and 30
• oral dexamethasone twice daily on weeks 8, 16-18, and 28 for a total of 35 days;
• vincristine IV on day 1 of weeks 8, 9, 16, 17, 18, 28, and 29
• daunorubicin IV on day 1 of weeks 16-18
• cyclophosphamide IV over 30 minutes on day 1 of week 20
• cytarabine IV or subcutaneously daily on days 2-5 of weeks 20 and 21
• oral thioguanine daily on weeks 20-21.

Intensive continuation therapy

At weeks 25-72 for arms I and II, and at weeks 33-80 for arms III and IV, patients receive intensive continuation therapy consisting of

• MTX every 6 hours for 4 doses on weeks 1, 3, 5, 7, 9, and 11
• oral mercaptopurine daily
• oral leucovorin calcium every 6 hours for 3 doses beginning 42 hours after the start of MTX
• IT MTX on day 1 of week 12
• vincristine IV on day 1 of week 12
• oral dexamethasone twice daily for 7 days beginning with vincristine

Treatment repeats every 12 weeks for 4 courses.

Continuation therapy

At weeks 73-130 for arms I and II, and at weeks 81-130 for arms III and IV, patients receive continuation therapy consisting of:

• oral MTX weekly
• oral mercaptopurine daily
• vincristine IV on day 1 every 12 weeks
• oral dexamethasone as during intensive continuation therapy
• IT MTX on day 1 every 12 weeks, beginning with the last week of the first course, in place of the oral MTX.

Patients are followed monthly for 1 year, every 2 months for 1 year, every 3 months for 1 year, every 6 months for 1 year, and then every 6-12 months for 1 year.

Projected Accrual

A total of 1014 patients will be accrued for this study over 3.22 years.