Busulfan, Cyclophosphamide, and Melphalan or Busulfan and Fludarabine Phosphate Before Donor Hematopoietic Cell Transplant in Treating Younger Patients With Juvenile Myelomonocytic Leukemia
Condition: Juvenile Myelomonocytic Leukemia
MeSH terms: Leukemia; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile
Study type: Interventional
Phase: Phase 2

Summary: 
      This randomized phase II trial studies how well giving busulfan, cyclophosphamide, and
      melphalan or busulfan and fludarabine phosphate before donor hematopoietic cell transplant
      works in treating younger patients with juvenile myelomonocytic leukemia. Giving chemotherapy
      before a donor hematopoietic transplant helps stop the growth of cancer cells. It may also
      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. It is not yet known whether
      giving busulfan, cyclophosphamide, and melphalan or busulfan and fludarabine phosphate before
      a donor stem cell transplant is more effective in treating juvenile myelomonocytic leukemia.
    

Detailed description: 
      PRIMARY OBJECTIVES:

      I. To compare ? in a randomized fashion ? the day 100 treatment related mortality (TRM)
      incidence for two myeloablative conditioning regimens, busulfan-fludarabine (fludarabine
      phosphate) (BU-FLU) and busulfan-cyclophosphamide-melphalan (BU-CY-MEL), prior to
      hematopoietic cell transplant (HCT) for children with juvenile myelomonocytic leukemia
      (JMML), in order to determine the preferred regimen for future trials.

      II. To compare ? in a randomized fashion ? the 18-month event-free survival (EFS) following
      two different myeloablative conditioning regimens (BU-FLU vs. BU-CY-MEL) prior to HCT for
      children with JMML, in order to determine the preferred regimen for future trials.

      SECONDARY OBJECTIVES:

      I. To determine the 18-month relapse incidence (RI) following two different myeloablative
      conditioning regimens (BU-FLU vs. BU-CY-MEL) prior to HCT for children with JMML.

      II. To determine the graft failure rates following two different myeloablative conditioning
      regimens (BU-FLU vs. BU-CY-MEL) prior to HCT for children with JMML.

      TERTIARY OBJECTIVES:

      I. To determine the rates of severe toxicities (grade 3/4) at day 100 post-HCT between the
      two myeloablative conditioning regimens (BU-FLU vs. BU-CY-MEL).

      II. To determine the rates of acute and chronic (at 18 months post-HCT) graft-versus-host
      disease (GVHD) following HCT using two different conditioning regimens (BU-FLU vs. BU-CY-MEL)
      in children with JMML.

      III. To create a JMML-specific pre-HCT index to allow better risk-stratification of future
      patients.

      IV. To determine the feasibility of assessing post-transplant disease burden by donor
      chimerism measurements and allele-specific polymerase chain reaction (PCR) in mononuclear and
      sorted cell subsets.

      V. To validate gene expression and methylation classifiers predictive of relapse in patients
      with JMML.

      VI. To comprehensively assess genetic and biochemical alterations amongst patients with JMML
      who are treated on this transplant protocol.

      OUTLINE: Patients are randomized to 1 of 2 treatment arms.

      ARM I:

      CONDITIONING REGIMEN: Patients receive busulfan intravenously (IV) over 2-3 hours once daily
      (QD), every 12 hours, or every 6 hours on days -8 to -5, cyclophosphamide IV over 60 minutes
      QD on days -4 and -3, and melphalan IV over 15-30 minutes on day -1.

      TRANSPLANT: Patients undergo allogeneic HCT on day 0.

      Patients receive tacrolimus IV or orally (PO) on days -1 to 98 (related donor) or 180
      (unrelated donor) and mycophenolate mofetil IV over 2 hours or PO every 8 hours on days 1-30
      (related donor) or 45 (unrelated donor).

      ARM II:

      CONDITIONING REGIMEN: Patients receive busulfan as in Arm I and fludarabine phosphate IV over
      30-60 minutes on days -5 to -2.

      TRANSPLANT: Patients undergo allogeneic HCT as in Arm I.

      Patients receive tacrolimus IV or PO on days -1 to 98 (related donor) or 180 (unrelated
      donor) and mycophenolate mofetil IV over 2 hours or PO every 8 hours on days 1-30 (related
      donor) or 45 (unrelated donor).

      After completion of study treatment, patients are followed up for 5 years.
    

Intervention name(s): Allogeneic Hematopoietic Stem Cell Transplantation; Busulfan; Cyclophosphamide; Fludarabine Phosphate; Laboratory Biomarker Analysis; Melphalan; Mycophenolate Mofetil; Pharmacological Study; Tacrolimus
Intervention type(s): Procedure; Drug; Drug; Drug; Other; Drug; Drug; Other; Drug
Intervention description(s): Undergo allogeneic HCT; Given IV; Given IV; Given IV; Correlative studies; Given IV; Given IV or PO; Correlative studies; Given IV or PO
Other intervention name(s): Allogeneic Hematopoietic Cell Transplantation; Allogeneic Stem Cell Transplantation; HSC; HSCT; 1, 4-Bis[methanesulfonoxy]butane; BUS; Bussulfam; Busulfanum; Busulfex; Busulphan; CB 2041; CB-2041; Glyzophrol; GT 41; GT-41; Joacamine; Methanesulfonic Acid Tetramethylene Ester; Methanesulfonic acid, tetramethylene ester; Mielucin; Misulban; Misulfan; Mitosan; Myeleukon; Myeloleukon; Myelosan; Mylecytan; Myleran; Sulfabutin; Tetramethylene Bis(methanesulfonate); Tetramethylene bis[methanesulfonate]; WR-19508; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CTX; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Cytoxan; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; 2-F-ara-AMP; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; Beneflur; Fludara; SH T 586; Alanine Nitrogen Mustard; CB-3025; L-PAM; L-Phenylalanine Mustard; L-sarcolysin; L-Sarcolysin Phenylalanine mustard; L-Sarcolysine; Melphalanum; Phenylalanine Mustard; Phenylalanine nitrogen mustard; Sarcoclorin; Sarkolysin; WR-19813; Cellcept; MMF; FK 506; Fujimycin; Hecoria; Prograf; Protopic
Intervention MeSH terms: Mycophenolic Acid; Cyclophosphamide; Melphalan; Busulfan; Mechlorethamine; Nitrogen Mustard Compounds; Fludarabine; Fludarabine phosphate; Tacrolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment