Clinical Trials /

Different Therapies in Treating Infants With Newly Diagnosed Acute Leukemia

NCT00550992

Description:

RATIONALE: Giving chemotherapy before a donor stem cell transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine, methotrexate, leucovorin, and antithymocyte globulin before and after transplant may stop this from happening. It is not yet known which treatment regimen is most effective in treating acute leukemia. PURPOSE: This randomized clinical trial is studying how well different therapies work in treating infants with newly diagnosed acute leukemia.

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Unknown status

Phase:

N/A

Trial Eligibility

Document

Different Therapies in Treating Infants With Newly Diagnosed Acute Leukemia

Title

  • Brief Title: Different Therapies in Treating Infants With Newly Diagnosed Acute Leukemia
  • Official Title: International Collaborative Treatment Protocol for Infants Under One Year With Acute Lymphoblastic or Biphenotypic Leukemia
  • Clinical Trial IDs

    NCT ID: NCT00550992

    ORG ID: CDR0000570260

    NCI ID: DCOG-INTERFANT-06

    Trial Conditions

    Leukemia

    Trial Interventions

    Drug Synonyms Arms
    asparaginase
    busulfan
    cyclophosphamide
    cyclosporine
    cytarabine
    daunorubicin hydrochloride
    etoposide
    leucovorin calcium
    melphalan
    mercaptopurine
    methotrexate
    mitoxantrone hydrochloride
    pegaspargase
    prednisolone
    prednisone
    therapeutic hydrocortisone
    thioguanine
    vincristine sulfate

    Trial Purpose

    RATIONALE: Giving chemotherapy before a donor stem cell transplant helps stop the growth of
    cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem
    cells. When the healthy stem cells from a donor are infused into the patient they may help
    the patient's bone marrow make stem cells, red blood cells, white blood cells, and
    platelets. Sometimes the transplanted cells from a donor can make an immune response against
    the body's normal cells. Giving cyclosporine, methotrexate, leucovorin, and antithymocyte
    globulin before and after transplant may stop this from happening. It is not yet known which
    treatment regimen is most effective in treating acute leukemia.

    PURPOSE: This randomized clinical trial is studying how well different therapies work in
    treating infants with newly diagnosed acute leukemia.

    Detailed Description

    OBJECTIVES:

    Primary

    - To compare an early intensification regimen comprising two "acute myeloid leukemia"
    induction therapy blocks with a standard protocol IB regimen administered directly
    after induction therapy in medium-risk (MR) and high-risk (HR) patients with newly
    diagnosed acute lymphoblastic or biphenotypic leukemia.

    Secondary

    - To compare through a randomized study the role of these regimens in treating these
    patients.

    - To compare the overall outcome of the Interfant-06 study with outcomes in the
    historical control series, especially in the Interfant-99 study.

    - To compare the outcomes of low-risk, MR, or HR patients in this study with those of
    patients in the historical control series Interfant-99 study.

    - To study which factors have independent prognostic value in patients treated with these
    regimens.

    - To assess the role of stem cell transplantation in HR patients.

    OUTLINE: This is a multicenter study.

    - Induction therapy:

    - Prednisone phase: Patients receive prednisone orally or IV three times daily on
    days 1-7 and methotrexate (MTX) and prednisolone (PRDL) intrathecally (IT) on day
    1. Patients then proceed to remission induction therapy.

    - Remission induction phase: Patients receive dexamethasone (DEXA) IV or orally
    three times daily on days 8-28 followed by a taper to 0 over 1 week; vincristine
    (VCR) IV on days 8, 15, 22, and 29; cytarabine (ARA-C) IV over 30 minutes on days
    8-21; daunorubicin hydrochloride (DNR) IV over 1 hour on days 8 and 9;
    asparaginase (ASP) IV over 1 hour or intramuscularly (IM) on days 15, 18, 22, 25,
    29, and 33; MTX IT on days 1 and 29*; and ARA-C IT on day 15. Patients also
    receive PRDL or therapeutic hydrocortisone (HC) IT on days 1, 15, and 29.

    NOTE: *Patients with CNS involvement at initial diagnosis also receive MTX IT on days 8 and
    22. If CNS leukemia is still present at day 29, then patients receive weekly MTX IT until
    the CNS is free of leukemia.

    After completion of induction therapy, patients are stratified according to risk group
    (low-risk [LR] vs medium-risk [MR] vs high-risk [HR]). Patients with low-risk disease are
    assigned to treatment arm I. Patients with MR or HR disease that is in complete remission
    (CR) on day 33 are randomized to 1 of 2 treatment arms. These patients are stratified
    according to status (MR with rearranged MLL vs MR with unknown MLL vs HR).

    - Arm I (standard therapy):

    - Protocol IB therapy (beginning on day 36 of induction therapy): Patients receive
    cyclophosphamide (CPM) IV over 1 hour on days 1 and 29 and oral mercaptopurine
    (MP) on days 1-28; ARA-C IV on days 3-6, 10-13, 17-20, and 24-27; ARA-C IT on day
    10; and MTX IT on day 24. Patients also receive PRDL or therapeutic HC IT on days
    10 and 24.

    - MARMA therapy:

    - Part I: Patients receive oral MP once daily on days 1-14; high-dose (HD) MTX
    IV over 24 hours on days 1 and 8; leucovorin calcium orally or IV at 42, 48,
    and 54 hours after each dose of MTX until MTX plasma levels are safe; and MTX
    IT on days 2 and 9. Patients also receive PRDL or therapeutic HC IT on days 2
    and 9.

    - Part II: Patients receive HD ARA-C IV over 3 hours twice daily with 12-hour
    intervals on days 15, 16, 22, and 23; and pegaspargase (PEG-ASP) IV over 1
    hour or IM on day 23.

    - OCTADA(D) reinduction therapy:

    - Part I: At least 2 weeks after the completion of MARMA chemotherapy, patients
    receive oral dexamethasone (DEXA) three times daily on days 1-14, followed by
    a taper to 0 at day 21; oral thioguanine (TG) once daily on days 1-28; VCR IV
    on days 1, 8, 15, and 22; DNR IV over 1 hour on days 1, 8, 15, and 22;
    PEG-ASP IV over 1 hour or IM on day 1; ARA-C IV on days 2-5, 9-12, 16-19, and
    23-26; and ARA-C IT on days 1 and 15. Patients also receive PRDL or
    therapeutic HC IT on days 1 and 15.

    - Part II: Patients receive oral TG once daily on days 36-49; ARA-C IV once
    daily on days 37-40 and 45-48; and CPM IV over 1 hour on days 36 and 49.

    - Maintenance therapy: At least 2 weeks after completion of the last course of
    OCTADA(D) chemotherapy, patients receive oral MP once daily; oral MTX once weekly;
    MTX IT in weeks 1 and 15; and ARA-C IT in week 8. Patients also receive PRDL or
    therapeutic HC IT in weeks 1, 8, and 15. Treatment continues for up to 104 weeks
    after initial diagnosis in the absence of disease progression or unacceptable
    toxicity.

    - Arm II (experimental therapy):

    - ADE therapy (beginning on day 36 of induction therapy: Patients receive ARA-C IV
    every 12 hours on days 1-10; DNR IV over 1 hour on days 1, 3, and 5; etoposide
    (VP-16) IV over 4 hours on days 1-5; and ARA-C IT on day 1. Patients also receive
    PRDL or therapeutic HC IT on day 1.

    - MAE therapy: Patients receive ARA-C IV every 12 hours on days 1-10; mitoxantrone
    hydrochloride IV over 1 hour on days 1, 3, and 5; VP-16 IV over 4 hours on days
    1-5; and MTX IT on day 1. Patients also receive PRDL or therapeutic HC IT on day
    1.

    - MARMA therapy:

    - Part I: Patients receive oral MP once daily on days 1-14; high-dose (HD) MTX
    IV over 24 hours on days 1 and 8; leucovorin calcium orally or IV at 42, 48,
    and 54 hours after each dose of MTX until MTX plasma levels are safe; and MTX
    IT on days 2 and 9. Patients also receive PRDL or therapeutic HC IT on days 2
    and 9.

    - Part II: Patients receive HD ARA-C IV over 3 hours twice daily with 12-hour
    intervals on days 15, 16, 22, and 23; and pegaspargase (PEG-ASP) IV over 1
    hour or IM on day 23.

    - OCTADA reinduction therapy:

    - Part I: At least 2 weeks after the completion of MARMA chemotherapy, patients
    receive oral DEXA three times daily on days 1-14, followed by a taper to 0 at
    day 21; oral TG once daily on days 1-28; VCR IV on days 1, 8, 15, and 22;
    PEG-ASP IV over 1 hour or IM on day 1; ARA-C IV on days 2-5, 9-12, 16-19, and
    23-26; and ARA-C IT on days 1 and 15. Patients also receive PRDL or
    therapeutic HC IT on days 1 and 15.

    - Part II: Beginning 1 week after completion of part I, patients receive oral
    TG once daily on days 36-49; ARA-C IV once daily on days 37-40 and 45-48; and
    CPM IV over 1 hour on days 36 and 49.

    - Maintenance therapy: At least 2 weeks after completion of the last course of
    OCTADA chemotherapy, patients receive oral MP once daily; oral MTX once weekly;
    MTX IT in weeks 1 and 15; and ARA-C IT in week 8. Patients also receive PRDL or
    therapeutic HC IT in weeks 1, 8, and 15. Treatment continues for up to 104 weeks
    after initial diagnosis in the absence of disease progression or unacceptable
    toxicity.

    All HR patients with a suitably matched donor are scheduled for allogeneic stem cell
    transplantation (SCT) after MARMA or before or during OCTADA(D) chemotherapy, provided they
    are in CR1 and no more than 8 months have elapsed since initial diagnosis.

    - Conditioning regimens for allogeneic SCT:

    - Matched sibling donor (MSD): Patients receive oral busulfan (BU) every 6 hours on
    days -7 to -4; CPM IV over 1 hour on days -3 to -2; and melphalan (MEL) IV over 1
    hour on day -1.

    - Matched donors (MD): Patients receive oral BU every 6 hours on days -7 to -4; CPM
    IV over 1 hour on days -3 to -2; MEL IV over 1 hour on day -1; and anti-thymocyte
    globulin (ATG) IV over 4 hours on days -3 to -1.

    - Graft-Versus-Host Disease (GVHD) prophylaxis and therapy:

    - MSD: Patients receive cyclosporine (CsA) IV or orally twice daily beginning on day
    -1 and continuing to day 60 after SCT, followed by a taper in the absence of GVHD
    symptoms.

    - MD: Patients receive CsA as in group MSD; MTX IV on days 1, 3, and 6; leucovorin
    calcium IV on days 2, 4, and 7; and ATG IV on days -3 to -1.

    - Allogeneic SCT: Patients undergo infusion of bone marrow, peripheral blood, or cord
    blood hematopoietic stem cells on day 0.

    After completion of study therapy, patients are followed periodically for up to 2 years.

    Trial Arms

    Name Type Description Interventions

    Eligibility Criteria

    DISEASE CHARACTERISTICS:

    Inclusion criteria:

    - Diagnosis of acute lymphoblastic leukemia (ALL) or biphenotypic leukemia meeting the
    following criteria:

    - Based on European Group for the Classification of Acute Leukemia (EGIL)
    diagnostic criteria

    - Newly diagnosed disease

    - Verified by morphology and confirmed by cytochemistry and immunophenotyping

    - Trephine biopsy is recommended (unless diagnosis can be confirmed by
    peripheral blood examination) in the event that bone marrow aspiration
    results in a "dry tap"

    - Must have MLL gene rearrangements documented by split-signal fluorescence in situ
    hybridization and meets 1 of the following risk criteria:

    - Low-risk disease, defined as all MLL germline cases

    - Medium-risk disease, defined by 1 of the following criteria:

    - MLL status unknown

    - MLL rearranged AND age > 6 months

    - MLL rearranged AND age < 6 months AND WBC < 300 x 10^9/L AND prednisone
    good response

    - High-risk disease, defined by MLL rearrangement AND meets the following
    criteria:

    - Age at diagnosis < 6 months (i.e., < 183 days)

    - WBC 300 x 10^9/L AND/OR prednisone poor response

    - Minimum donor and stem cell requirements for high-risk patients undergoing stem cell
    transplantation:

    - Donor meeting 1 of the following criteria:

    - HLA-identical sibling

    - Very well-matched related or unrelated donor

    - Must be HLA compatible in 10/10 or 9/10 alleles by 4 digit/allele
    high-resolution molecular genotyping

    - Stem cell source

    - Bone marrow (preferred source) OR peripheral blood stem cells of filgrastim
    [G-CSF]-stimulated donors OR cord blood

    - Highly-matched unrelated umbilical cord blood (UCB) (> 7/8 matches
    identified by high-resolution typing) accepted if a sibling donor is
    not able to donate bone marrow AND UCB with a sufficient number of
    nucleated cells (NCs) (i.e., > 1.5 x 10^7/kg recipient body weight
    [BW]) is cryopreserved

    - Must have 3 x 10^8 NCs/kg BW OR 3 x 10^6/kg BW CD34-positive cells available
    for transplantation

    - CNS or testicular leukemia at diagnosis allowed

    Exclusion criteria:

    - Mature B-ALL, defined by the immunophenotypical presence of surface immunoglobulins
    or t(8;14) and breakpoint as in B-ALL

    - Presence of the t(9;22) (q34;q11) or bcr-abl fusion in the leukemic cells (if data
    are not known, patient still may be eligible)

    - Relapsed ALL

    PATIENT CHARACTERISTICS:

    - See Disease Characteristics

    PRIOR CONCURRENT THERAPY:

    - More than 4 weeks since prior systemic corticosteroids

    - Corticosteroids by aerosol are allowed

    Minimum Eligible Age: N/A

    Maximum Eligible Age: 1 Year

    Eligible Gender: Both

    Primary Outcome Measures

    Disease-free survival

    Secondary Outcome Measures

    Survival

    Event-free survival

    Event-free survival within each risk group (i.e., low-risk, medium-risk, or high-risk)

    Trial Keywords

    untreated childhood acute lymphoblastic leukemia

    T-cell childhood acute lymphoblastic leukemia

    acute undifferentiated leukemia