Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
Condition: Lymphoblastic Leukemia, Acute
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Study type: Interventional
Phase: Phase 3

Summary: 
      The primary objective is to estimate the overall event-free survival of children at least one
      year of age at diagnosis who are treated with risk-directed therapy and to monitor the
      molecular remission induction rate.
    

Detailed description: 
      These are the following secondary objectives:

        -  To determine if CNS irradiation can be safely omitted in the context of the systemic
           therapy used in the protocol.

        -  To identify whether prolonged (24 hour) intravenous infusions of HDMTX produce greater
           methotrexate polyglutamate (MTXPG) accumulation than short (4 hour) infusions 42 hours
           after 1 gm/m2 of HDMTX, stratified for lineage (T- vs B-lineage) and ploidy
           (hyperdiploid vs non-hyperdiploid B-lineage).

        -  To determine whether prolonged (24 hour) intravenous infusions of HDMTX produce greater
           antileukemic effects than short (4 hour) infusions, based on the inhibition of de novo
           purine synthesis in bone marrow blasts and the decrease in circulating blasts during the
           4 day "window" prior to initiation of conventional remission induction therapy.

        -  MRD

        -  Other exploratory objectives

      Details of Treatment Plan

      Treatment will consist of three main phases, Remission Induction, Consolidation, and
      Continuation. Treatment with an Upfront HDMTX Window for research purposes will be optional.

      All patients will receive IT therapy on day 1, dose is age dependent.

      Upfront High-Dose Methotrexate Window

      HDMTX (1 g/m2) as a 4 hour infusion versus as a 24 hour infusion. Leucovorin rescue will be
      given.

      Remission Induction

      Prednisone 40 mg/m2/day PO Days 5 - 32 Vincristine 1.5 mg/m2/week IV Days 5, 12, 19, 26
      Daunorubicin 25 mg/m2/week IV Days 5, 12 L-asparaginase 10,000 Unit/m2/dose IM Days 6, 8, 10,
      12, 14, 16 (19, 21, 23) Cyclophosphamide 1000 mg/m2/dose IV Day 26 Cytarabine 75 mg/m2/dose
      IV Days 27-30, 34-37 6-Mercaptopurine 60 mg/m2/dose PO Days 26-39 Imatinib 40 mg/m2 bid for
      Ph positive patients starting Day 22 of induction. Intrathecal therapy will be administered
      on day 1 and 19, dose age dependent. Patients with high risk of CNS relapse will receive
      additional IT treatments on days 8 and 26.

      Consolidation Treatment

      High dose methotrexate targeted dose depending on risk status, days 1, 15, 29, and 43 and
      mercaptopurine 50 mg/m2/day, days 1-56.

      Reintensification treatment for patients with high risk disease:

      Patients with high risk disease will be offered the option of hematopoietic stem cell
      transplant (HSCT) and may receive an additional 1-2 cycles of reintensification treatment
      prior to maximize the anti-leukemic kill before transplant.

      Dexamethasone 20 mg/m2 PO days 1-3 Cytarabine 2 g/m2 IV x 4 doses, days 3-5 Etoposide 100
      mg/m2 IV x 5 doses, days 3-5 L-asparaginase 25,000 Units/m2 IM day 6 Intrathecal treatment
      Day 5

      Continuation Treatment (lasts 120 weeks for girls and 146 weeks for boys)

      Treatment will depend on risk classification: low versus standard versus high risk

      Treatment weeks 1 to 20:

      Week Standard/High Risk Low Risk

        1. DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR

        2. 6MP + ASP 6MP + MTX

        3. 6MP + ASP 6MP + MTX

        4. DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR

        5. 6MP + ASP 6MP + MTX

        6. 6MP + ASP 6MP + MTX

        7. Reinduction I§ Reinduction I

        8. Reinduction I Reinduction I

        9. Reinduction I Reinduction I

       10. 6MP + ASP 6MP + MTX

       11. DOX + VCR + 6MP + ASP 6MP + MTX

       12. 6MP + ASP 6MP + MTX

       13. 6MP + ASP 6MP + MTX

       14. DEX + DOX + VCR + 6MP + ASP 6MP + DEX + VCR

       15. 6MP + ASP 6MP + MTX

       16. 6MP + ASP 6MP + MTX

       17. Reinduction II Reinduction II

       18. Reinduction II Reinduction II

       19. Reinduction II Reinduction II

       20. No chemotherapy 6MP + MTX

           Dexamethasone 12 mg/m2 (std/high risk) or 8 mg/m2 (low risk) PO daily (tid) x 5 days,
           Days 1-5 Doxorubicin 30 mg/m2 IV, Day 1 Vincristine 2.0 mg/m2 IV push (max. 2 mg), Day 1
           Mercaptopurine 50 mg/m2 PO daily x 7 days (std/high risk), Days 1-7 75 mg/m2 PO daily x
           7 days (low risk), Days 1-7 L-asparaginase 25,000 Unit/m2 IM, Day 1 Methotrexate 40
           mg/m2 IV or IM, Day 1

           Reinduction I and II

           This phase of treatment will be started at weeks 7 and 17 after bone marrow examination
           confirms complete remission. Reinduction treatment will be given twice: weeks 7 to 9 and
           weeks 17 to 19 for all patients.

           Reinduction I for Standard/High Risk ALL:

           Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8, 15, 21, Vincristine 1.5 mg/m2/week IV
           (max 2 mg) Days 1, 8, 15, Doxorubicin 30 mg/m2 Days 1, 8, L-asparaginase 25,000 Unit/m2
           IM Days 1, 8, 15, Intrathecal chemotherapy, dose age dependent Day 1.

           Reinduction II for Standard/High Risk ALL:

           Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8, 15-21, Vincristine 1.5 mg/m2/week IV
           (max 2 mg) Days 1, 8, 15, L-asparaginase 25,000 Unit/m2, weekly IM Days 1, 8, 17,
           Intrathecal chemotherapy, dose age dependent Day 1 High-dose cytarabine 2 gm/m2 IV q 12
           Days 15, 16

           Reinduction I and II for Low Risk ALL Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8,
           15-21 Vincristine 1.5 mg/m2/week IV (max 2 mg), Days 1, 8, 15 L-asparaginase 10,000
           Unit/m2/thrice weekly IM Days 2, 4, 6, 8, 10, 12, 15, 17, 19 Doxorubicin 30 mg/m2/week
           IV Day 1 Intrathecal chemotherapy, dose age dependent on Day 1

           Treatment Weeks 21 to end of therapy Week Standard/High Risk Low Risk

       21. 6MP + MTX 6MP + MTX

       22. 6MP + MTX 6MP + MTX

       23. Cyclo + Ara-C 6MP + MTX

       24. DEX + VCR 6MP + DEX + VCR

       25. 6MP + MTX 6MP + MTX

       26. 6MP + MTX 6MP + MTX

       27. Cyclo + Ara-C 6MP + MTX

       28. DEX + VCR 6MP + DEX + VCR

      Mercaptopurine 75 mg/m2 PO, daily x 7 days, Days 1-7 Methotrexate 40 mg/m2 IV or IM, Day 1
      Cyclophosphamide 300 mg/m2 IV, Day 1 Cytarabine 300 mg/m2 IV, Day 1 Dexamethasone 12 mg/m2
      (std/high risk) or 8 mg/m2 (low risk) PO daily (tid) x 5, Day 1-5 Vincristine 2.0 mg/m2 IV
      push (max. 2 mg), Day 1

      The same treatment (weeks 21-28) will be repeated for a total of 6 times (until week 68).
      After week 68, all patients will receive daily 6MP and weekly MTX with pulses of
      dexamethasone and vincristine every 4 weeks until week 100, after which only 6MP and
      methotrexate will be given. Intrathecal treatment will be given every 8 weeks only to
      patients at high risk of CNS relapse after week 48 and will be discontinued after week 96.
      Continuation therapy will be discontinued after 120 weeks in girls and after 146 weeks in
      boys

      Patients who meet the criteria of high-risk ALL are candidates for allogeneic hematopoietic
      stem cell transplantation. However, if the option is declined by the patients or guardians,
      or the procedure is deemed unsuitable by the attending physician and the principal
      investigator, the patient will remain on study and continue to receive chemotherapy
    

Intervention name(s): Prednisone, Dexamethasone, Vincristine, Daunorubicin; Doxorubicin, L-asparaginase, PEG-L-asparaginase, Erwinia asparaginase; Methotrexate, Cyclophosphamide, Cytarabine, Etoposide; Mercaptopurine, Imatinib; chemotherapy, intrathecal chemotherapy; steroid therapy, hematopoietic stem cell transplantation
Intervention type(s): Drug; Drug; Drug; Drug; Procedure; Procedure
Intervention description(s): See Detailed Description sections for details on treatment interventions.; See Detailed Description sections for details on treatment interventions.; See Detailed Description sections for details on treatment interventions.; See Detailed Description sections for details on treatment interventions.; See Detailed Description sections for details on treatment interventions.; See Detailed Description sections for details on treatment interventions.
Intervention MeSH terms: Cytarabine; Dexamethasone; Prednisone; Cyclophosphamide; Doxorubicin; Methotrexate; Etoposide; Vincristine; Daunorubicin; Asparaginase; Mercaptopurine; Pegaspargase
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Leukemia