Acute Leukemia, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Hodgkin's Lymphoma, Lymphoma, B-Cell, Lymphoma, Follicular, Lymphoma, Large B-Cell, Diffuse, Myelodysplasia, Small Lymphocytic Lymphoma
Conditions
Keywords
Acute Lymphoblastic Leukemia/Lymphoma, Acute Myelogenous Leukemia, Mantel-Cell Lymphoma, Hematopoietic Transplant, GVHD Prophylaxis
Brief 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.
Detailed description
GVHD is a complication that can occur after a bone marrow or stem cell transplant. The transplant recipient's body is attacked by the newly introduced cells. Only about 40% of patients with acute GVHD have durable responses when treated with corticosteroid therapy. A strategy that helps fewer people suffer from GVHD, without other adverse effects, would be an effective approach to improve survival after allogeneic transplantation. GVHD incidence can be decreased with various treatment plans. Early transplants were done using post-transplant methotrexate to prevent GVHD. Another drug, cyclosporine, was later shown to work better than methotrexate. Then doctors discovered that the combined use of cyclosporine and methotrexate worked even better than either agent alone. More recently, other calcineurin-inhibitors, such as tacrolimus have been developed as GVHD prophylactic agents due to favorable toxicity profiles in comparison with cyclosporine. Studies have been conducted to compare available treatment combinations for related and unrelated donors. The combination of tacrolimus/methotrexate remains a standard for GVHD prophylaxis. However, improved GVHD prophylaxis remains a significant clinical need in HSCT. The current clinical trial will test three novel GVHD prophylaxis approaches: tacrolimus/methotrexate and bortezomib (Tac/MTX/Bort), tacrolimus/methotrexate and maraviroc (Tac/MTX/MVC) and tacrolimus/mycophenolate mofetil and cyclophosphamide (Tac/MMF/Cy). This randomized Phase II clinical trial will compare each intervention arm with a Tac/MTX control. This study will enroll people who have a cancer of the blood or lymph glands and a stem cell transplant is a treatment option. The study will take at least two years and will include 270 participants - 90 participants in each of three treatment groups. The purpose of this study is to compare three combinations of medications to see whether one or more of them are better than the current standard of care (Tacrolimus/Methotrexate) to prevent GVHD.
Interventions
DRUGTacrolimus (ARM with Methotrexate)
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.
DRUGTacrolimus (ARM with MMF and Cyclophosphamide)
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.
DRUGMethotrexate (ARM with Maraviroc)
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.
DRUGMethotrexate (ARM with Bortezomib)
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.
DRUGMaraviroc
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.
DRUGBortezomib
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.
DRUGMycophenolate mofetil
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.
DRUGCyclophosphamide
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).
Sponsors
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With GVHD/Relapse or Progression-free Survival (GRFS) | 1 Year Post-transplant | GRFS is defined as being free of grade III-IV acute GVHD onset, chronic GVHD onset requiring systemic immunosuppressive therapy, disease relapse or progression, and death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Grade III-IV Acute GVHD | Day 180 Post-transplant | Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995: Skin stage: 0: No rash 1. Rash \<25% of body surface area 2. Rash on 25-50% of body surface area 3. Rash on \> 50% of body surface area 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level)\*: 0: \<2 mg/dL 1.2-3 mg/dL 2.3.01-6 mg/dL 3.6.01-15.0 mg/dL 4.\>15 mg/dL GI stage\*: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus \* If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1. GVHD grade: 0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4 |
| Percentage of Participants With Chronic GVHD | 1 Year Post-transplant | Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification. |
| Percentage of Participants With Chronic GVHD Requiring Immunosupressive Therapy | 1 Year Post-transplant | Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification. This endpoint considers the occurrence of chronic GVHD that necessitated initiation of immunosuppressive therapy for treatment. |
| Percentage of Participants With Disease Relapse or Progression | 1 Year Post-transplant | Relapse is defined by either morphological or cytogenetic evidence of acute leukemia or MDS consistent with pretransplant features, or radiologic evidence of lymphoma. Progression of disease applies to patients with lymphoproliferative diseases (lymphoma or chronic lymphocytic leukemia) not in remission prior to transplantation and is defined as increase in size of prior sites of disease or evidence of new sites of disease. |
| Percentage of Participants With Transplant-Related Mortality (TRM) | 1 Year Post-transplant | TRM is defined as death without prior disease relapse or progression. |
| Percentage of Participants With Disease-free Survival | 1 Year Post-transplant | Disease-free survival is defined as being alive and free of disease relapse or progression. |
| Percentage of Participants With Grade II-IV Acute GVHD | Day 180 Post-transplant | Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995: Skin stage: 0: No rash 1. Rash \<25% of body surface area 2. Rash on 25-50% of body surface area 3. Rash on \> 50% of body surface area 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level)\*: 0: \<2 mg/dL 1. 2-3 mg/dL 2. 3.01-6 mg/dL 3. 6.01-15.0 mg/dL 4. \>15 mg/dL GI stage\*: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus \* If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1. GVHD grade: 0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4 |
| Percentage of Participants With Overall Survival | 1 Year Post-transplant | — |
| Percentage of Participants With Neutrophil Recovery | Days 28 and 100 Post-transplant | Neutrophil recovery is defined as achieving an absolute neutrophil count (ANC) ≥ 500/mm\^3 for three consecutive measurements on three different days. |
| Percentage of Participants With Platelet Recovery | Days 60 and 100 Post-transplant | Platelet recovery is defined as the first day of a sustained platelet count \>20,000/mm\^3 with no platelet transfusion in the preceding seven days. |
| Donor Cell Engraftment | Days 28 and 100 Post-transplant | Donor cell engraftment will be assessed with donor/recipient chimerism. Chimerism may be evaluated in bone marrow, whole blood, or CD3 fractions. Full donor chimerism is defined as the presence of ≥ 95% of donor cells as a proportion of total cells. Mixed chimerism is defined as the presence of donor cells, as a proportion of total cells, of \< 95% but \> 5% in the bone marrow or peripheral blood. Full and mixed chimerism will be evidence of donor cell engraftment. Donor cells of ≤ 5% will be considered as graft rejection. |
| Primary Cause of Death | 1 Year Post-transplant | — |
| Percentage of Participants With GVHD-free Survival | 1 Year Post-transplant | GVHD-free survival is defined as being alive without previous onset of Grade III-IV acute GVHD or chronic GVHD requiring immunosuppressive therapy. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tacrolimus/Methotrexate/Bortezomib Participants will receive a GVHD prophylactic regimen of three agents: Tacrolimus, Methotrexate, and Bortezomib. | 89 |
| Tacrolimus/Methotrexate/Maraviroc Participants will receive a GVHD prophylactic regimen of three agents: Tacrolimus, Methotrexate, and Maraviroc. | 92 |
| Tacrolimus/MMF/Cyclophosphamide Participants will receive a GVHD prophylactic regimen of three agents: Tacrolimus, Mycophenolate Mofetil (MMF), and Cyclophosphamide. | 92 |
| Total | 273 |
Baseline characteristics
| Characteristic | Tacrolimus/Methotrexate/Maraviroc | Total | Tacrolimus/MMF/Cyclophosphamide | Tacrolimus/Methotrexate/Bortezomib |
|---|---|---|---|---|
| Age, Continuous | 64 years | 64 years | 64 years | 64 years |
| Donor/Recipient Cytomegalovirus (CMV) Status Donor Negative / Recipient Negative | 26 Participants | 91 Participants | 34 Participants | 31 Participants |
| Donor/Recipient Cytomegalovirus (CMV) Status Donor Negative / Recipient Positive | 19 Participants | 70 Participants | 26 Participants | 25 Participants |
| Donor/Recipient Cytomegalovirus (CMV) Status Donor Positive / Recipient Negative | 19 Participants | 30 Participants | 7 Participants | 4 Participants |
| Donor/Recipient Cytomegalovirus (CMV) Status Donor Positive / Recipient Positive | 28 Participants | 82 Participants | 25 Participants | 29 Participants |
| Donor/Recipient Sex Matching Female donor / Female Recipient | 19 Participants | 41 Participants | 10 Participants | 12 Participants |
| Donor/Recipient Sex Matching Female donor / Male Recipient | 16 Participants | 49 Participants | 19 Participants | 14 Participants |
| Donor/Recipient Sex Matching Male donor / Female Recipient | 18 Participants | 57 Participants | 20 Participants | 19 Participants |
| Donor/Recipient Sex Matching Male donor / Male Recipient | 39 Participants | 126 Participants | 43 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 11 Participants | 7 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 86 Participants | 252 Participants | 81 Participants | 85 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 10 Participants | 4 Participants | 3 Participants |
| HCT-CI Comorbidity Index 0 | 18 Participants | 68 Participants | 26 Participants | 24 Participants |
| HCT-CI Comorbidity Index 1-2 | 37 Participants | 95 Participants | 27 Participants | 31 Participants |
| HCT-CI Comorbidity Index 3 or greater | 37 Participants | 110 Participants | 39 Participants | 34 Participants |
| HLA Matching and Donor Type Matched Other Relative (6/6) | 1 Participants | 6 Participants | 4 Participants | 1 Participants |
| HLA Matching and Donor Type Matched Sibling (6/6) | 33 Participants | 91 Participants | 29 Participants | 29 Participants |
| HLA Matching and Donor Type Matched Unrelated (8/8) | 48 Participants | 151 Participants | 50 Participants | 53 Participants |
| HLA Matching and Donor Type Mismatched Unrelated (7/8) | 10 Participants | 25 Participants | 9 Participants | 6 Participants |
| Karnofsky Performance Score 100 | 10 Participants | 34 Participants | 11 Participants | 13 Participants |
| Karnofsky Performance Score 70 | 16 Participants | 35 Participants | 11 Participants | 8 Participants |
| Karnofsky Performance Score 80 | 27 Participants | 84 Participants | 28 Participants | 29 Participants |
| Karnofsky Performance Score 90 | 39 Participants | 120 Participants | 42 Participants | 39 Participants |
| Primary Diagnosis Acute Lymphoblastic Leukemia (ALL) | 11 Participants | 31 Participants | 8 Participants | 12 Participants |
| Primary Diagnosis Acute Myeloid Leukemia (AML) | 49 Participants | 144 Participants | 49 Participants | 46 Participants |
| Primary Diagnosis Chronic Lymphocytic Leukemia (CLL) | 3 Participants | 5 Participants | 0 Participants | 2 Participants |
| Primary Diagnosis Chronic Myelogeneous Leukemia (CML) | 2 Participants | 7 Participants | 3 Participants | 2 Participants |
| Primary Diagnosis Diffuse Large B-Cell Lymphoma | 1 Participants | 12 Participants | 7 Participants | 4 Participants |
| Primary Diagnosis Follicular Lymphoma | 6 Participants | 14 Participants | 5 Participants | 3 Participants |
| Primary Diagnosis Hodgkin's Lymphoma | 1 Participants | 3 Participants | 2 Participants | 0 Participants |
| Primary Diagnosis Mantle Cell Lymphoma | 4 Participants | 9 Participants | 1 Participants | 4 Participants |
| Primary Diagnosis Myelodysplastic Syndrome (MDS) | 15 Participants | 48 Participants | 17 Participants | 16 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 6 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 7 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 16 Participants | 5 Participants | 4 Participants |
| Race (NIH/OMB) White | 81 Participants | 242 Participants | 82 Participants | 79 Participants |
| Sex: Female, Male Female | 37 Participants | 98 Participants | 30 Participants | 31 Participants |
| Sex: Female, Male Male | 55 Participants | 175 Participants | 62 Participants | 58 Participants |
| Time from Diagnosis to Transplant | 6.3 months | 7.1 months | 7.4 months | 7.1 months |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 30 / 93 | 31 / 93 | 27 / 93 |
| other Total, other adverse events | 0 / 93 | 0 / 93 | 0 / 93 |
| serious Total, serious adverse events | 21 / 93 | 14 / 93 | 12 / 93 |
Outcome results
Primary
Percentage of Participants With GVHD/Relapse or Progression-free Survival (GRFS)
GRFS is defined as being free of grade III-IV acute GVHD onset, chronic GVHD onset requiring systemic immunosuppressive therapy, disease relapse or progression, and death from any cause.
Time frame: 1 Year Post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus/Methotrexate/Bortezomib | Percentage of Participants With GVHD/Relapse or Progression-free Survival (GRFS) | 35.5 percentage of participants |
| Tacrolimus/Methotrexate/Maraviroc | Percentage of Participants With GVHD/Relapse or Progression-free Survival (GRFS) | 27.2 percentage of participants |
| Tacrolimus/MMF/Cyclophosphamide | Percentage of Participants With GVHD/Relapse or Progression-free Survival (GRFS) | 44.1 percentage of participants |
Secondary
Donor Cell Engraftment
Donor cell engraftment will be assessed with donor/recipient chimerism. Chimerism may be evaluated in bone marrow, whole blood, or CD3 fractions. Full donor chimerism is defined as the presence of ≥ 95% of donor cells as a proportion of total cells. Mixed chimerism is defined as the presence of donor cells, as a proportion of total cells, of \< 95% but \> 5% in the bone marrow or peripheral blood. Full and mixed chimerism will be evidence of donor cell engraftment. Donor cells of ≤ 5% will be considered as graft rejection.
Time frame: Days 28 and 100 Post-transplant
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Tacrolimus/Methotrexate/Bortezomib | Donor Cell Engraftment | Day 28 | Full Chimerism | 58 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Donor Cell Engraftment | Day 28 | Mixed Chimerism | 11 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Donor Cell Engraftment | Day 28 | Graft Rejection | 1 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Donor Cell Engraftment | Day 28 | Dead | 2 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Donor Cell Engraftment | Day 28 | No Assay Performed | 17 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Donor Cell Engraftment | Day 100 | Full Chimerism | 63 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Donor Cell Engraftment | Day 100 | Mixed Chimerism | 14 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Donor Cell Engraftment | Day 100 | Graft Rejection | 5 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Donor Cell Engraftment | Day 100 | Dead | 4 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Donor Cell Engraftment | Day 100 | No Assay Performed | 3 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Donor Cell Engraftment | Day 100 | Dead | 10 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Donor Cell Engraftment | Day 28 | Full Chimerism | 56 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Donor Cell Engraftment | Day 100 | Full Chimerism | 56 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Donor Cell Engraftment | Day 28 | No Assay Performed | 21 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Donor Cell Engraftment | Day 28 | Mixed Chimerism | 10 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Donor Cell Engraftment | Day 100 | No Assay Performed | 6 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Donor Cell Engraftment | Day 100 | Graft Rejection | 3 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Donor Cell Engraftment | Day 28 | Graft Rejection | 1 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Donor Cell Engraftment | Day 100 | Mixed Chimerism | 17 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Donor Cell Engraftment | Day 28 | Dead | 4 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Donor Cell Engraftment | Day 100 | Graft Rejection | 3 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Donor Cell Engraftment | Day 28 | Dead | 0 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Donor Cell Engraftment | Day 28 | No Assay Performed | 18 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Donor Cell Engraftment | Day 100 | Full Chimerism | 62 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Donor Cell Engraftment | Day 100 | Dead | 5 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Donor Cell Engraftment | Day 100 | Mixed Chimerism | 13 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Donor Cell Engraftment | Day 28 | Full Chimerism | 64 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Donor Cell Engraftment | Day 100 | No Assay Performed | 9 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Donor Cell Engraftment | Day 28 | Mixed Chimerism | 8 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Donor Cell Engraftment | Day 28 | Graft Rejection | 2 Participants |
Secondary
Percentage of Participants With Chronic GVHD
Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification.
Time frame: 1 Year Post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus/Methotrexate/Bortezomib | Percentage of Participants With Chronic GVHD | 39 percentage of participants |
| Tacrolimus/Methotrexate/Maraviroc | Percentage of Participants With Chronic GVHD | 43 percentage of participants |
| Tacrolimus/MMF/Cyclophosphamide | Percentage of Participants With Chronic GVHD | 28 percentage of participants |
Secondary
Percentage of Participants With Chronic GVHD Requiring Immunosupressive Therapy
Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification. This endpoint considers the occurrence of chronic GVHD that necessitated initiation of immunosuppressive therapy for treatment.
Time frame: 1 Year Post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus/Methotrexate/Bortezomib | Percentage of Participants With Chronic GVHD Requiring Immunosupressive Therapy | 29 percentage of participants |
| Tacrolimus/Methotrexate/Maraviroc | Percentage of Participants With Chronic GVHD Requiring Immunosupressive Therapy | 33 percentage of participants |
| Tacrolimus/MMF/Cyclophosphamide | Percentage of Participants With Chronic GVHD Requiring Immunosupressive Therapy | 22 percentage of participants |
Secondary
Percentage of Participants With Disease-free Survival
Disease-free survival is defined as being alive and free of disease relapse or progression.
Time frame: 1 Year Post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus/Methotrexate/Bortezomib | Percentage of Participants With Disease-free Survival | 58 percentage of participants |
| Tacrolimus/Methotrexate/Maraviroc | Percentage of Participants With Disease-free Survival | 56 percentage of participants |
| Tacrolimus/MMF/Cyclophosphamide | Percentage of Participants With Disease-free Survival | 60 percentage of participants |
Secondary
Percentage of Participants With Disease Relapse or Progression
Relapse is defined by either morphological or cytogenetic evidence of acute leukemia or MDS consistent with pretransplant features, or radiologic evidence of lymphoma. Progression of disease applies to patients with lymphoproliferative diseases (lymphoma or chronic lymphocytic leukemia) not in remission prior to transplantation and is defined as increase in size of prior sites of disease or evidence of new sites of disease.
Time frame: 1 Year Post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus/Methotrexate/Bortezomib | Percentage of Participants With Disease Relapse or Progression | 24 percentage of participants |
| Tacrolimus/Methotrexate/Maraviroc | Percentage of Participants With Disease Relapse or Progression | 31 percentage of participants |
| Tacrolimus/MMF/Cyclophosphamide | Percentage of Participants With Disease Relapse or Progression | 28 percentage of participants |
Secondary
Percentage of Participants With Grade III-IV Acute GVHD
Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995: Skin stage: 0: No rash 1. Rash \<25% of body surface area 2. Rash on 25-50% of body surface area 3. Rash on \> 50% of body surface area 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level)\*: 0: \<2 mg/dL 1.2-3 mg/dL 2.3.01-6 mg/dL 3.6.01-15.0 mg/dL 4.\>15 mg/dL GI stage\*: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus \* If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1. GVHD grade: 0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4
Time frame: Day 180 Post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus/Methotrexate/Bortezomib | Percentage of Participants With Grade III-IV Acute GVHD | 8 percentage of participants |
| Tacrolimus/Methotrexate/Maraviroc | Percentage of Participants With Grade III-IV Acute GVHD | 9 percentage of participants |
| Tacrolimus/MMF/Cyclophosphamide | Percentage of Participants With Grade III-IV Acute GVHD | 2 percentage of participants |
Secondary
Percentage of Participants With Grade II-IV Acute GVHD
Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995: Skin stage: 0: No rash 1. Rash \<25% of body surface area 2. Rash on 25-50% of body surface area 3. Rash on \> 50% of body surface area 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level)\*: 0: \<2 mg/dL 1. 2-3 mg/dL 2. 3.01-6 mg/dL 3. 6.01-15.0 mg/dL 4. \>15 mg/dL GI stage\*: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus \* If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1. GVHD grade: 0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4
Time frame: Day 180 Post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus/Methotrexate/Bortezomib | Percentage of Participants With Grade II-IV Acute GVHD | 26 percentage of participants |
| Tacrolimus/Methotrexate/Maraviroc | Percentage of Participants With Grade II-IV Acute GVHD | 32 percentage of participants |
| Tacrolimus/MMF/Cyclophosphamide | Percentage of Participants With Grade II-IV Acute GVHD | 27 percentage of participants |
Secondary
Percentage of Participants With GVHD-free Survival
GVHD-free survival is defined as being alive without previous onset of Grade III-IV acute GVHD or chronic GVHD requiring immunosuppressive therapy.
Time frame: 1 Year Post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus/Methotrexate/Bortezomib | Percentage of Participants With GVHD-free Survival | 43 percentage of participants |
| Tacrolimus/Methotrexate/Maraviroc | Percentage of Participants With GVHD-free Survival | 34 percentage of participants |
| Tacrolimus/MMF/Cyclophosphamide | Percentage of Participants With GVHD-free Survival | 53 percentage of participants |
Secondary
Percentage of Participants With Neutrophil Recovery
Neutrophil recovery is defined as achieving an absolute neutrophil count (ANC) ≥ 500/mm\^3 for three consecutive measurements on three different days.
Time frame: Days 28 and 100 Post-transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tacrolimus/Methotrexate/Bortezomib | Percentage of Participants With Neutrophil Recovery | Day 28 | 94 percentage of participants |
| Tacrolimus/Methotrexate/Bortezomib | Percentage of Participants With Neutrophil Recovery | Day 100 | 96 percentage of participants |
| Tacrolimus/Methotrexate/Maraviroc | Percentage of Participants With Neutrophil Recovery | Day 28 | 93 percentage of participants |
| Tacrolimus/Methotrexate/Maraviroc | Percentage of Participants With Neutrophil Recovery | Day 100 | 95 percentage of participants |
| Tacrolimus/MMF/Cyclophosphamide | Percentage of Participants With Neutrophil Recovery | Day 28 | 95 percentage of participants |
| Tacrolimus/MMF/Cyclophosphamide | Percentage of Participants With Neutrophil Recovery | Day 100 | 98 percentage of participants |
Secondary
Percentage of Participants With Overall Survival
Time frame: 1 Year Post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus/Methotrexate/Bortezomib | Percentage of Participants With Overall Survival | 68 percentage of participants |
| Tacrolimus/Methotrexate/Maraviroc | Percentage of Participants With Overall Survival | 66 percentage of participants |
| Tacrolimus/MMF/Cyclophosphamide | Percentage of Participants With Overall Survival | 71 percentage of participants |
Secondary
Percentage of Participants With Platelet Recovery
Platelet recovery is defined as the first day of a sustained platelet count \>20,000/mm\^3 with no platelet transfusion in the preceding seven days.
Time frame: Days 60 and 100 Post-transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tacrolimus/Methotrexate/Bortezomib | Percentage of Participants With Platelet Recovery | Day 60 | 91 percentage of participants |
| Tacrolimus/Methotrexate/Bortezomib | Percentage of Participants With Platelet Recovery | Day 100 | 91 percentage of participants |
| Tacrolimus/Methotrexate/Maraviroc | Percentage of Participants With Platelet Recovery | Day 60 | 92 percentage of participants |
| Tacrolimus/Methotrexate/Maraviroc | Percentage of Participants With Platelet Recovery | Day 100 | 92 percentage of participants |
| Tacrolimus/MMF/Cyclophosphamide | Percentage of Participants With Platelet Recovery | Day 60 | 90 percentage of participants |
| Tacrolimus/MMF/Cyclophosphamide | Percentage of Participants With Platelet Recovery | Day 100 | 96 percentage of participants |
Secondary
Percentage of Participants With Transplant-Related Mortality (TRM)
TRM is defined as death without prior disease relapse or progression.
Time frame: 1 Year Post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus/Methotrexate/Bortezomib | Percentage of Participants With Transplant-Related Mortality (TRM) | 17 percentage of participants |
| Tacrolimus/Methotrexate/Maraviroc | Percentage of Participants With Transplant-Related Mortality (TRM) | 16 percentage of participants |
| Tacrolimus/MMF/Cyclophosphamide | Percentage of Participants With Transplant-Related Mortality (TRM) | 11 percentage of participants |
Secondary
Primary Cause of Death
Time frame: 1 Year Post-transplant
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tacrolimus/Methotrexate/Bortezomib | Primary Cause of Death | Infection | 4 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Primary Cause of Death | Organ Failure | 2 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Primary Cause of Death | Toxicity - Not Specified | 0 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Primary Cause of Death | Acute GVHD | 3 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Primary Cause of Death | Hemorrhage | 1 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Primary Cause of Death | Still Alive | 61 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Primary Cause of Death | Recurrence/Persistence | 11 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Primary Cause of Death | Interstitial Pneumonia | 1 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Primary Cause of Death | Squamous Cell Carcinoma | 1 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Primary Cause of Death | Metastatis Breast Cancer | 1 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Primary Cause of Death | Adult Respiratory Distress Syndrome | 2 Participants |
| Tacrolimus/Methotrexate/Bortezomib | Primary Cause of Death | Chronic GVHD | 2 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Primary Cause of Death | Adult Respiratory Distress Syndrome | 1 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Primary Cause of Death | Metastatis Breast Cancer | 0 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Primary Cause of Death | Squamous Cell Carcinoma | 0 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Primary Cause of Death | Infection | 7 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Primary Cause of Death | Still Alive | 61 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Primary Cause of Death | Toxicity - Not Specified | 1 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Primary Cause of Death | Acute GVHD | 7 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Primary Cause of Death | Organ Failure | 2 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Primary Cause of Death | Chronic GVHD | 1 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Primary Cause of Death | Hemorrhage | 0 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Primary Cause of Death | Interstitial Pneumonia | 0 Participants |
| Tacrolimus/Methotrexate/Maraviroc | Primary Cause of Death | Recurrence/Persistence | 12 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Primary Cause of Death | Still Alive | 66 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Primary Cause of Death | Chronic GVHD | 1 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Primary Cause of Death | Acute GVHD | 2 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Primary Cause of Death | Recurrence/Persistence | 15 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Primary Cause of Death | Infection | 4 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Primary Cause of Death | Organ Failure | 2 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Primary Cause of Death | Hemorrhage | 1 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Primary Cause of Death | Interstitial Pneumonia | 1 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Primary Cause of Death | Adult Respiratory Distress Syndrome | 0 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Primary Cause of Death | Metastatis Breast Cancer | 0 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Primary Cause of Death | Squamous Cell Carcinoma | 0 Participants |
| Tacrolimus/MMF/Cyclophosphamide | Primary Cause of Death | Toxicity - Not Specified | 0 Participants |