Clinical Trial 19143

Cancer Type: Malignant Hematology
Interventions:ATG; Alkeran (Melphalan); FK506 (Tacrolimus); MESNA; Melphalan; Tacrolimus; busulfan; cyclophosphamide; cytoxan (cyclophosphamide); fludarabine (Fludarabine phosphate); methotrexate

Study Type: Prevention
Phase of Study: Phase III

  • Farhad Khimani


Study Title

A Randomized, Multi-Center, Phase III Trial of Calcineurin Inhibitor-Free Interventions for Prevention of Graft-versus Host-Disease


The purpose of this study is to compare three different combinations of treatment plans to see whether one or more of them are better than a standard transplant procedure. The procedures being studied have the objective to reduce the occurrence of chronic GVHD. The procedures included in this clinical trial are: Treatment Group A: CD34 Selected Peripheral Blood Stem Cell Transplant. Treatment Group B: Bone Marrow Transplant followed by Post-Transplant Cyclophosphamide. Treatment Group C: Bone Marrow Transplant with Tacrolimus and Methotrexate as GVHD Prevention.


The Primary Objective of the randomized trial is to compare chronic GVHD/relapse-free survival [CRFS] as a time to event endpoint after hematopoietic stem cell transplant (HSCT) between each of the CNI-free interventions and a Tac/Mtx control. Secondary Objectives are: Comparison of rates of grade II-IV and III-IV acute GVHD, chronic GVHD, chronic GVHD-free survival, immunosuppression-free survival at one year, neutrophil and platelet engraftment, disease relapse, transplant related mortality, rates of Grade >/= 3 toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0; incidence of CMV and EBV reactivation, incidence of infections; immune reconstitution, quality of life and overall survival.

Inclusion Criteria

  • Males and females aged > 1.0 year and less than 66.0 years
  • Patients with acute leukemia, in morphologic complete remission with or without hematologic recovery or myelodysplasia with less than 5% blasts in the marrow and no circulating blasts. Patients with CMML must have a WBC count ≤10,000 cells/μL and less than 5% blasts in the marrow. Patients with > 5% blasts due to a regenerating marrow must contact the protocol chairs for review.
  • Planned myeloablative conditioning regimen
  • Patients must have a related or unrelated donor as follows: a.) Related donor must be an 8/8 match for human leukocyte antigen (HLA)-A, -B, and -C at intermediate (or higher) resolution, and -DRB1 at high resolution using DNA-based typing. Pediatric related donors must weigh ≥ 25.0 kg., must have adequate peripheral venous catheter access for leukapheresis or must agree to placement of a central catheter, must be willing to (1) donate bone marrow and (2) receive G-CSF followed by donation of peripheral blood stem cells and must meet institutional criteria for donation. B.) Unrelated donor must be an 8/8 match at HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing. Unrelated donor must be medically eligible to donate according to National Marrow Donor Program (NMDP) (or equivalent donor search organization) criteria. At time of enrollment, the donor should not have any known preferences or contraindications to donate bone marrow or peripheral blood stem cells.
  • Cardiac function: Ejection fraction at rest ≥ 45.0% or shortening fraction of ≥ 27.0% by echocardiogram or radionuclide scan (MUGA).
  • Estimated creatinine clearance (for patients > 12 years) greater than 50.0 mL/minute (using the Cockcroft-Gault formula and actual body weight); for pediatric patients (> 1 year to 12 years), Glomerular Filtration Rate (GFR) estimated by the updated Schwartz formula ≥ 90.0 mL/min/1.73 m^2. If the estimated creatinine clearance is less than 90 mL/min/1.73 m^2, then renal function must be measured by 24-hour creatinine clearance or nuclear GFR, and must be > 70.0 mL/min/1.73 m^2.
  • Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 50% (adjusted for hemoglobin), and forced expiratory volume in one second (FEV1) or forced vital capacity (FVC) ≥ 50%; for children who are unable to perform for Pulmonary Function Tests (PFTs) due to age or developmental ability, there must be no evidence of dyspnea and no need for supplemental oxygen, as evidenced by O2 saturation ≥ 92% on room air.
  • Liver function: total bilirubin less than 2x the upper limit of normal (unless elevated bilirubin is attributed to Gilbert's Syndrome) and alanine aminotransferase (ALT) / aspartate aminotransferase (AST) less than 2.5x the upper limit of normal.
  • Signed informed consent.

  • Exclusion Criteria

  • Prior autologous or allogeneic hematopoietic stem cell transplant
  • Karnofsky or Lansky Performance Score less than 70%
  • Active central nervous system (CNS) involvement by malignant cells
  • Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment
  • Presence of fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated
  • Patients seropositive for HIV-1 or -2
  • Patients seropositive for Human T-Lymphotrophic Virus (HTLV)-I or -II
  • Patients with active Hepatitis B or C viral replication by polymerase chain reaction (PCR)
  • Documented allergy to iron dextran or murine proteins
  • Women who are pregnant (positive serum or urine βHCG) or breastfeeding
  • Females of childbearing potential (FCBP) or men who have sexual contact with FCBP unwilling to use 2 effective forms of birth control or abstinence for one year after transplantation
  • History of uncontrolled autoimmune disease or on active treatment
  • Prior malignancies, except resected non-melanoma or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent less than 5 years previously will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs.
  • Unable to comply with the treatment protocol including appropriate supportive care, follow-up and research tests
  • Planned post-transplant maintenance therapy except for FLT3 inhibitors or TKIs