Novel Approaches for Graft-versus-Host Disease Prevention Compared to Contemporary Controls (BMT CTN 1203)
Condition: Acute Leukemia; Chronic Myelogenous Leukemia; Myelodysplasia; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Lymphoma, B-Cell; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Hodgkin's Lymphoma
MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Graft vs Host Disease
Intervention: Tacrolimus (ARM with Methotrexate); Tacrolimus (ARM with MMF and Cyclophosphamide); Methotrexate (ARM with Maraviroc); Methotrexate (ARM with Bortezomib); Maraviroc; Bortezomib; Mycophenolate mofetil; Cyclophosphamide
Intervention description: Tacrolimus will be given orally at a dose of 0.05 mg/kg or intravenously at a dose of 0.03 mg/kg 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. The dose should be adjusted accordingly to maintain a suggested level 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.; Tacrolimus will be given orally at a dose of 0.05 mg/kg or intravenously at a dose of 0.03 mg/kg starting Day +5. 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 HSCT 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 HSCT if there is no evidence of active GVHD.; Methotrexate will be administered, per institutional practices, 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. The Day +1 dose of methotrexate will be given at least 24 hours after the hematopoietic stem cell infusion and at least 30 minutes after the first dose of maraviroc. 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.; Methotrexate will be administered, per institutional practices, 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. The Day +1 dose of methotrexate will be given at least 24 hours after the hematopoietic stem cell infusion and at least 30 minutes after the first dose of bortezomib. 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.; Maraviroc will be dosed at 300 mg orally twice a day and will start on Day -3 prior to hematopoietic stem cell infusion, and continue until Day 30 post HSCT. If the patient requires a two-day stem cell infusion, maraviroc treatment will end 30 days after the first infusion day.; Bortezomib will be administered at the dose of 1.3 mg/m2 based upon actual body weight (ABW) as an approximately 3-5 second IV push on Days +1, +4, and +7 after hematopoietic stem cell infusion. There must be at least 72 hours between each dose of bortezomib. Subcutaneous administration of bortezomib is not allowed on this protocol.; MMF will be given at a dose of 15 mg/kg three times a day (TID) based upon ABW 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.; Hydration prior to cyclophosphamide may be given according to institutional standards.
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 ideal body weight (IBW); if ABW < IBW, use ABW] will be given on Day 3 post-transplant (between 60 and 72 hours after the start of the HSCT) 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; Maraviroc; Cyclophosphamide; Methotrexate; Bortezomib; Tacrolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 279.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Acute Lymphoblastic Leukemia/Lymphoma; Acute Myelogenous Leukemia; Mantel-Cell Lymphoma; Hematopoietic Transplant; GVHD Prophylaxis

Summary:

      Acute Graft-versus-Host-Disease (GVHD) is an important cause of morbidity and mortality after
      allogeneic hematopoietic stem cell transplantation (HSCT). This study aims to determine if
      any of three new GVHD prophylaxis approaches improves the rate of GVHD and relapse free
      survival at one year after transplant compared to the current standard prophylaxis regimen.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age 18-75 years (patient is older than 18.0 and less than 76.0 years old)

          2. Patients with acute leukemia, chronic myelogenous leukemia or myelodysplasia with no
             circulating blasts and with less than 5% blasts in the bone marrow.

          3. Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular,
             marginal zone, diffuse large B-cell, Hodgkin's Lymphoma,or mantle cell lymphoma with
             chemosensitive disease at time of transplantation

          4. Planned reduced intensity conditioning regimen (see eligible regimens in Table 2.4a)

          5. Patients must have a related or unrelated peripheral blood stem cell donor as follows:

               1. Sibling donor must be a 6/6 match for 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 be medically cleared to donate stem cells
                  according to National Marrow Donor Program (NMDP) criteria.

          6. Cardiac function: Ejection fraction at rest ≥ 45%

          7. Estimated creatinine clearance greater than 50 mL/minute (using the Cockcroft-Gault
             formula and actual body weight)

          8. Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 40%
             (adjusted for hemoglobin) and forced expiratory volume in one second (FEV1) ≥ 50%

          9. Liver function: total bilirubin < 1.5 x the upper limit of normal and alanine
             aminotransferase (ALT)/aspartate aminotransferase (AST) < 2.5x the upper normal limit.
             Patients who have been diagnosed with Gilbert's Disease are allowed to exceed the
             defined bilirubin value of 1.5x the upper limit of normal.

         10. Female subjects (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).

         11. Male subjects (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.

         12. Signed informed consent

        Exclusion Criteria:

          1. Prior allogeneic transplant

          2. Karnofsky 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 with transformed lymphoma (e.g., Richters transformation arising in
             follicular lymphoma or chronic lymphocytic leukemia)

          7. Patients seropositive for the human immunodeficiency virus (HIV)

          8. Patient with active Hepatitis B or C determined by serology and/or nucleic acid
             amplification tests (NAAT)

          9. Patients with hypersensitivity to bortezomib, boron or mannitol

         10. Patients with ≥ grade 2 sensory peripheral neuropathy

         11. Myocardial infarction within 6 months prior to enrollment or New York Heart
             Association (NYHA) Class III or IV heart failure (see Appendix D), uncontrolled
             angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence
             of acute ischemia or active conduction system abnormalities. Prior to study entry, any
             ECG abnormality at screening must be documented by the investigator as not medically
             relevant.

         12. Female patients who are lactating or pregnant

         13. Patients with a serious medical or psychiatric illness likely to interfere with
             participation in this clinical study

         14. Patients with prior malignancies except resected basal cell carcinoma 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.

         15. Planned use of anti-thymocyte globulin (ATG) or alemtuzumab in conditioning regimen.

         16. Planned post-transplant therapy, including use of tyrosine-kinase inhibitors (TKI).

         17. Inability to withhold agents that may interact with hepatic cytochrome P450 enzymes
             (CYP3A4), or glutathione S-transferases involved in bortezomib and/or busulfan
             metabolism during day -5 through day +7. It is acceptable to use alternative
             non-interacting medications during this period, and then resume prior medications.

         18. Patients with secondary acute myeloid leukemia arising from myeloproliferative
             disease, including Chronic myelomonocytic leukemia (CMML), with evidence of active
             myeloproliferative features or myelofibrosis in the background.