an ALinC #16 study

Phase III Randomized Study of Delayed Intensification With Twice Weekly Oral Methotrexate (MTX) Versus Standard Weekly Intramuscular MTX and of Twice Daily Versus Standard Daily Mercaptopurine (MP) During Delayed Intensification and Continuation Therapy in Children With Standard Risk Acute Lymphocytic Leukemia: An ALinC #16 Study.

This trial on the cancer.gov site.

Treatment for standard risk pre-B and B-cell ALL, risk defined as:

• no CNS involvement (fewer than 5 WBC/microliter with or without blasts in CSF sediment) and no cranial nerve palsy
• no testicular involvement
• no chormosomal translocation (1;19), 4;11), or (9,22)

And one of the following groups of characteristics:

• age 1-9, WBC less than 50,000 and
  • either no simultaneous trisomies 4 and 10 or DNA index no greater than 1.16
• Age 10-21, WBC less than 50,000 and
  • either simultaneous trisomies 4 and 10 or DNA index greater than 1.16
• age 1-21, WBC 50,000 or greater and
• either simultaneous trisomies 4 and 10 or DNA index greater than 1.16

note: this means that DNA index greater than 1.16 and trisomies 4 and 10 are good, older kids with them can go on the standard risk along with the younger kids that do not have them. They also override WBC greater than 50,000.

Objectives

Determine whether the addition of delayed intensification therapy with divided dose oral methotrexate (MTX) improves event free survival in children with newly diagnosed standard risk acute lymphoblastic leukemia.

Compare the effect of delivering oral mercaptopurine (MP) on a twice daily vs once daily schedule during delayed intensification and continuation therapy on event free survival of these patients.

Date initiated, # of patients: 905 patients over 2.7 years; is current 12/97, started??

Protocol Chair: Beverly Ann Bell, 404-727-4451

Specific Aims:

• delint with divided-dose oral methotrexate
• oral MP twice a day vs once a day during delint and continuation

Also:

• correlate with POG 9400 (pool with 9201, 9405, 9406)
• identify patients at risk of treatment failure through in vitro studies of lymphoblast methotrexate and MP metabolism and through erythrocyte drug and enzyme levels (as selected institutions).
• assess the prognostic significance of the marrow blast content after 2 weeks of induction
• correlate elevation of transaminases with treatment outcome

4 arms of treatment:

• standard late intensification and continuation
• oral MTX in late intensification, standard continuation
• divided dose MP in late intensification and continuation
• oral MTX in late intensification, divided dose MP in late intensification and continuation

POG 9605

• 4 weeks induction (all studies, hospital version)
  • 3 drug combination systemic chemotherapy plus 3 drug IT (TIT: "triple intraethical")
    • prednisone, oral, TID (three times a day) for 28 days, no taper
    • vincristine, IV push, days 1, 8, 15, 22
    • asparaginase, IM days 2, 5, 8, 12, 15, 19
    • plus TIT, methotrexate, hydrocortisone, and ara C, day 1.
• Weeks 5-24, consolidation (all studies, hospital version)
  • 4 drug combination chemotherapy plus 3 drug IT
    • every 3 weeks (requires 3-4 days in-patient treatment): methotrexate as a 24 hr continuous IV infusion; leucovorin rescue begins 42 hrs after the start of the IV MTX
    • daily: 6-MP, oral, once a day
    • TMP/SMZ, oral, bid (twice a day), on 3 consecutive days per week
    • weeks 8 to 9 and 17 to 18: prednisone, oral, TID for 7 days
    • vincristine, IV push days 1 and 8 each pulse, weeks 8, 9, 17, 18
    • plus TIT, weeks 5, 6, 9, 12, 15, 18
• Weeks 25-52, late intensification (hospital versions, regimen 4)
  • regimen 1: standard late intensification and continuation
    • Late Intensification: 2-drug combination systemic chemotherapy with pulses of 2-drug combination systemic chemotherapy plus 3-drug intrathecal chemotherapy The methotrexate is given IM.
      • MTX/MP; with PRED/VCR; plus TIT
  • regimen 2: oral MTX in late intensification, standard continuation
    • Late Intensification: 2-drug combination systemic chemotherapy with pulses of 2-drug combination systemic chemotherapy plus 3-drug intrathecal chemotherapy with oral MTX twice weekly.
      • 6-MP, oral
      • methotrexate, oral, divided doses for 4 doses every other week. Leucovorin given 48 hours after the start of methotrexate (oral).
      • vincristine, IV push days 1 and 8 each pulse
      • prednisone, tid for 7 days.
  • regimen 3: divided dose MP in late intensification and continuation. Divided dose MP means that it is given twice a day: "MP bid".
    • Late Intensification: 2-drug combination systemic chemotherapy with pulses of 2-drug combination systemic chemotherapy plus 3-drug intrathecal chemotherapy with MP bid. (The methotrexate is given IM.)
      • MTX/MP; with PRED/VCR; plus TIT with MP bid.
  • regimen 4: oral MTX in late intensification, divided dose MP (given twice a day) in late intensification and continuation.
    • Late Intensification: 2-drug combination systemic chemotherapy with pulses of 2-drug combination systemic chemotherapy plus 3-drug intrathecal chemotherapy with oral MTX with MP bid.
      • 6-MP, oral, bid, every day.
      • methotrexate, oral, 4 doses every other week. Leucovorin given 48 hours after the start of methotrexate (oral).
      • vincristine, IV push days 1 and 8 each pulse, weeks 25, 26, 41, 42
      • prednisone weeks 25 to 26 and 41 to 42, for one week (7 days), tid
      • TIT weeks 25, 33, 41, 49
• Weeks 53-130, continuation (regimens 3 and 4)
  • regimens 1 and 2: standard continuation
    • 2-drug combination systemic chemotherapy with pulses of 2-drug combination systemic chemotherapy plus 3-drug intrathecal chemotherapy
      • MTX/MP; with PRED/VCR; plus TIT
  • regimens 3 and 4: divided dose MP in late intensification and continuation. Divided dose MP means that it is given twice a day: "MP bid".
    • 2-drug combination systemic chemotherapy with pulses of 2-drug combination systemic chemotherapy plus 3-drug intrathecal chemotherapy with MP bid.
      • 6MP, oral, bid for 7 days
      • methotrexate, IM, weekly
      • vincristine, IV push, days 1 and 8 each pulse, weeks 57-58, 73-74, 89-90, 105-106
      • prednisone, tid for 7 days,
        • 1: week 57 to 58, for one week (7 days)
        • 2: week 73 to 74, for one week (7 days)
        • 3: week 89 to 90, for one week (7 days)
        • 4: week 105 to 106, for one week (7 days)
      • TIT, every 8 weeks

Notes:

"Trisomies 4 and 10" means that the leukemic cells have 3 copies each (instead of the usual 2) of the chromosomes numbers 4 and 10 (normally there are 23 pairs of chromosomes = 46 total). For more information on this, see the journal Blood, 1992, Jun 15;79 (12):3316-3324 "Trisomy of leukemic cell chromosomes 4 and 10 identifies children with B-progenitor cell acute lymphoblastic leukemia with a very low risk of treatment failure: a Pediatric Oncology Group study." Harris MB, Shuster JJ, Carroll A, Look AT, Borowitz MJ, Crist WM, Nitschke R, Pullen J, Steuber CP, Land VJ.

DNA index greater than 1.16 is "hyperploidy", meaning there are more than 46 chromosomes in the leukemic clones, which is considered a good prognostic indicator.

Comments:

No anthracyclines! No cytoxin! Even the low risk CCG protocols use these.