Calcineurin Inhibitor-Free Interventions BMT CTN 1301 for Prevention of Graft-versus-Host Disease (BMT CTN 1301)
Condition: Acute Leukemia; Myelodysplasia
MeSH terms: Preleukemia; Myelodysplastic Syndromes; Graft vs Host Disease
Intervention: Unmanipulated Bone Marrow Graft with Tacrolimus/Methotrexate; Mobilized CD34-selected Peripheral Blood Stem Cell graft; Unmanipulated Bone Marrow Graft with Cyclophosphamide; Cyclophosphamide; Tacrolimus; Methotrexate
Intervention description: Unmanipulated BM grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.; Mobilized CD34-selected PBSC grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.; Unmanipulated BM grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.; Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide.
Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow infusion) and on Day 4 post-transplant (approximately 24 hours after Day 3 cyclophosphamide). Cyclophosphamide will be given as an IV infusion over 1-2 hours (depending on volume).; Tacrolimus will be given orally or intravenously per institutional standards starting Day -3. The dose of tacrolimus may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of tacrolimus (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tacrolimus taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD.; Methotrexate will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of methotrexate should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices. Leucovorin rescue is allowed according to institutional practices.
Intervention MeSH terms: Cyclophosphamide; Methotrexate; Tacrolimus
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 346.0
Sex: All
Minimum age: 1 Year
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Acute Leukemia; Myelodysplasia; GVHD Prophylaxis; Chronic GVHD

Summary:

      The study is designed as a three arm randomized Phase III, multicenter trial comparing two
      calcineurin inhibitor (CNI)-free strategies for Graft-versus-Host Disease (GVHD) prophylaxis
      to standard tacrolimus and methotrexate (Tac/Mtx) in patients with hematologic malignancies
      undergoing myeloablative conditioning hematopoietic stem cell transplantation.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Males and females aged ≥ 1.0 year and < 66.0 years

          2. Patients with acute leukemia in morphologic complete remission with or without
             hematologic recovery or with myelodysplasia (MDS) with no circulating blasts and with
             less than 5% blasts in the bone marrow. Patients with CMML must have a WBC count ≤
             10,000 cells/µL and < 5% blasts in the marrow. Patients with ≥ 5% blasts due to a
             regenerating marrow must contact the protocol chairs for review.

          3. Planned myeloablative conditioning regimen

          4. Patients must have a related or unrelated donor as follows:

               1. 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 (product to
                  be determined by randomization post enrollment) and must meet institutional
                  criteria for donation.

               2. 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. (Selection of unrelated donors is to be performed according to
                  institutional practice. It is recommended that the time from collection to
                  initiation of the cell processing be considered when prioritizing donors, as data
                  shows better results for CD34 selection when cell processing begins within 36
                  hours of the end of collection)

          5. Cardiac function: Ejection fraction at rest ≥ 45.0% or shortening fraction of ≥ 27.0%
             by echocardiogram or radionuclide scan (MUGA).

          6. 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 < 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.

          7. 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.

          8. Liver function: total bilirubin < 2x the upper limit of normal (unless elevated
             bilirubin is attributed to Gilbert's Syndrome) and alanine aminotransferase (ALT) /
             aspartate aminotransferase (AST) < 2.5x the upper limit of normal.

          9. Signed informed consent.

        Exclusion Criteria:

          1. Prior autologous or allogeneic hematopoietic stem cell transplant

          2. Karnofsky or Lansky Performance Score < 70%

          3. Active central nervous system (CNS) involvement by malignant cells

          4. Patients with uncontrolled bacterial, viral or fungal infections (currently taking
             medication and with progression or no clinical improvement) at time of enrollment

          5. Presence of fluid collection (ascites, pleural or pericardial effusion) that
             interferes with methotrexate clearance or makes methotrexate use contraindicated

          6. Patients seropositive for HIV-1 or -2

          7. Patients seropositive for Human T-Lymphotrophic Virus (HTLV)-I or -II

          8. Patients with active Hepatitis B or C viral replication by polymerase chain reaction
             (PCR)

          9. Documented allergy to iron dextran or murine proteins

         10. Women who are pregnant (positive serum or urine βHCG) or breastfeeding

         11. 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

         12. History of uncontrolled autoimmune disease or on active treatment

         13. Patients with 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 < 5 years previously will not be allowed
             unless approved by the Protocol Officer or one of the Protocol Chairs.

         14. Patient unable to comply with the treatment protocol including appropriate supportive
             care, follow-up and research tests

         15. Planned post-transplant maintenance therapy except for FLT3 inhibitors or TKIs must be
             declared prior to randomization.

         16. If it is known prior to enrollment that the hematopoietic stem cell product will need
             to be cryopreserved, the patient should not be enrolled.

         17. German centers only: Treatment with any known non-marketed drug substance or
             experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment,
             whichever is longer, or participation in any other interventional clinical study.