TAC/MTX vs. TAC/MMF/PTCY for Prevention of Graft-versus-Host Disease and Microbiome and Immune Reconstitution Study (BMT CTN 1703/1801)
Condition: Acute Leukemia; Chronic Myelogenous Leukemia (CML); Myelodysplasia; Lymphoma
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Preleukemia; Myelodysplastic Syndromes
Intervention: Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Methotrexate; Tacrolimus; Methotrexate; Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide; Tacrolimus; Mycophenolate Mofetil; Cyclophosphamide
Intervention description: Mobilized 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.; Tacrolimus will be given per institutional practices, orally at a dose of 0.05-0.06 mg/kg/day or intravenously at a dose of 0.02-0.03 mg/kg/day starting on 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 per institutional guidelines with a suggested range of 5-15. If patients are on medications which alter the metabolism of tacrolimus (e.g.concurrent CYP3A4 inhibitors), 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 HCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices and patients should be off tacrolimus by Day 180 post HCT if there is no evidence of active GVHD.; Methotrexate will be administered at the doses of 15 mg/m2 IV bolus on Day +1, and 10 mg/m2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. Methotrexate should be dose reduced, given with leucovorin rescue, or held for complications such as severe mucositis per institutional guidelines.; Mobilized 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.; Tacrolimus will be given per institutional practices, orally at a dose of 0.05-0.06 mg/kg/day or intravenously at a dose of 0.02-0.03 mg/kg/day starting Day +5. Starting tacrolimus dose can be modified to account for possible drug interactions (e.g. concurrent CYP3A4 inhibitor use) according to institutional guides. Serum levels of tacrolimus will be measured at Day +7 and then should be checked weekly thereafter, and the dose adjusted accordingly to maintain a suggested level of 5-15 ng/mL. Tacrolimus taper can be initiated at a minimum of 90 days post HCT if there is no evidence of active GVHD. The rate of tapering will be done according to institutional practices but patients should be off tacrolimus by Day 180 post HCT if there is no evidence of active GVHD; MMF will be given at a dose of 15 mg/kg/dose ter in die (TID) (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1g TID, IV or PO). MMF prophylaxis will start Day +5 and discontinue after the last dose on Day +35, or may be continued if active GVHD is present.; Cyclophosphamide [50 mg/kg ideal body weight (IBW); if actual body weight (ABW) < IBW, use ABW] will be given on Day +3 (between 60 and 72 hours after the start of the PBSC 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).
Intervention MeSH terms: Mycophenolic Acid; Cyclophosphamide; Methotrexate; Tacrolimus
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Patients will be randomized at a ratio of 1:1 between the treatment arms using permuted blocks of random sizes.
Masking: None (Open Label)
Enrollment: 431.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Acute Leukemia; Chronic Myelogenous Leukemia (CML); Myelodysplasia (MDS); Lymphoma; GVHD prophylaxis; Acute GVHD

Summary:

      1703: The study is designed as a randomized, phase III, multicenter trial comparing two acute
      graft-versus-host disease (aGVHD) prophylaxis regimens: tacrolimus/methotrexate (Tac/MTX)
      versus post-transplant cyclophosphamide/tacrolimus/mycophenolate mofetil (PTCy/Tac/MMF) in
      the setting of reduced intensity conditioning (RIC) allogeneic peripheral blood stem cell
      (PBSC) transplantation.

      1801: The goal of this protocol is to test the primary hypothesis that the engraftment stool
      microbiome diversity predicts one-year non-relapse mortality in patients undergoing reduced
      intensity allogeneic HCT.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age 18.0 years or older at the time of enrollment on Segment A

          2. Patients with acute leukemia or chronic myelogenous leukemia with no circulating
             blasts and with less than 5% blasts in the bone marrow

          3. Patients with myelodysplasia/chronic myelomonocytic leukemia with no circulating
             blasts and with less than 10% blasts in the bone marrow (higher blast percentage
             allowed in MDS due to lack of differences in outcomes with <5% vs. 5-10% blasts in
             this disease)

          4. Patients with relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma with
             chemosensitive disease at time of transplantation

          5. Patients with lymphoma [follicular lymphoma, Hodgkin lymphoma, diffuse large B cell
             lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, angioimmunoblastic T-cell
             lymphoma and anaplastic large cell lymphoma] with chemosensitive disease at the time
             of transplantation

          6. Planned reduced intensity conditioning regimen (see eligible regimens in Table 2.4a)

          7. Patients must have a related or unrelated peripheral blood stem cell donor as follows:

               1. Sibling donor must be a 6/6 match for Human Leukocyte Antigen-A (HLA)-A and -B at
                  intermediate (or higher) resolution, and -DRB1 at high resolution using DNA-based
                  typing, and must be willing to donate peripheral blood stem cells and meet
                  institutional criteria for donation.

               2. Unrelated donor must be a 7/8 or 8/8 match at HLA-A, -B, -C and -DRB1 at high
                  resolution using DNA-based typing. Unrelated donor must be willing to donate
                  peripheral blood stem cells and meet National Marrow Donor Program (NMDP)
                  criteria for donation.

          8. Cardiac function: Left ventricular ejection fraction at least 45%

          9. Estimated creatinine clearance acceptable per institutional guidelines

         10. Pulmonary function: Diffusing capacity of lung for carbon monoxide (DLCO) corrected
             for hemoglobin at least 40% and forced expiratory volume at one second (FEV1)
             predicted at least 50%

         11. Liver function acceptable per institutional guidelines

         12. Karnofsky Performance Score at least 60%

         13. Female patients (unless postmenopausal for at least 1 year before the screening visit,
             or surgically sterilized), agree to practice two (2) effective methods of
             contraception at the same time, or agree to completely abstain from heterosexual
             intercourse, from the time of signing the informed consent through 12 months
             post-transplant (see Section 2.6.4 for definition of postmenopausal)

         14. Male patients (even if surgically sterilized), of partners of women of childbearing
             potential must agree to one of the following: practice effective barrier contraception
             (see Section 2.6.4 for list of barrier methods), or abstain from heterosexual
             intercourse from the time of signing the informed consent through 12 months
             post-transplant

         15. Plans for the use of post-transplant maintenance therapy must be disclosed upon
             enrollment and must be used irrespective of the outcome of the randomization. Please
             note that THIS DOES NOT INCLUDE INVESTIGATIONAL AGENTS and maintenance therapy with
             investigational treatment requires approval by the study chairs.

         16. Voluntary written consent obtained prior to the performance of any study-related
             procedure that is not a part of standard medical care, with the understanding that
             consent may be withdrawn by the patient at any time without prejudice to future
             medical care.

        Exclusion Criteria:

          1. Prior allogeneic transplant

          2. Active central nervous system (CNS) involvement by malignant cells

          3. Patients with secondary acute myeloid leukemia arising from myeloproliferative
             disease, including chronic myelomonocytic leukemia (CMML)

          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 clinically significant fluid collection (ascites, pleural or pericardial
             effusion) that interferes with methotrexate clearance or makes methotrexate use
             contraindicated

          6. Patients seropositive for human immunodeficiency virus (HIV) with detectable viral
             load. HIV+ patients with an undetectable viral load on antiviral therapy are eligible.

          7. Myocardial infarction within 6 months prior to enrollment or New York Heart
             Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe
             uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
             ischemia.

          8. Female patients who are pregnant (as per institutional practice) or lactating

          9. Patients with a serious medical or psychiatric illness likely to interfere with
             participation in this clinical study

         10. Patients with prior malignancies except resected non-melanoma skin cancer 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 must be
             reviewed and approved by the Protocol Officer or Chairs.

         11. Planned use of antithymocyte globulin (ATG) or alemtuzumab in conditioning regimen