Acute Leukemia, Chronic Myelogenous Leukemia (CML), Lymphoma, Myelodysplasia
Conditions
Keywords
Acute Leukemia, Chronic Myelogenous Leukemia (CML), Myelodysplasia (MDS), Lymphoma, GVHD prophylaxis, Acute GVHD
Brief 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.
Detailed description
1703: Graft-versus-Host Disease (GVHD) is a complication that affects many hematopoietic stem cell transplant (HSCT) patients; it occurs when the new cells from a transplant attack the recipient's body. The current standard GVHD prophylaxis regimen for patients with hematologic malignancies undergoing HSCT involves a combination of immunosuppressive agents given for the first 6 months after transplant. The standard strategy of Tacrolimus/Methotrexate will be used as a control arm in comparison to one other treatment plan utilizing Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide. Study participants will receive an infusion of mobilized peripheral blood stem cell grafts on both arms. Study participants will be randomized to one of these two treatment arms. 1801: A relationship between the intestinal microbiota and graft-versus-host disease (GVHD) has long been appreciated but is still not well understood. Mice transplanted in germ-free conditions or treated with gut-decontaminating antibiotics developed less severe GVHD. Clinical studies initially suggested a benefit from near-total bacterial decontamination, but later showed no clear benefit and this approach was discontinued in the early 1990s. Partial gut decontamination continues to be practiced at many centers. More recently, the advent of next-generation sequencing (NGS) has resulted in cheaper and easier characterization of complex microbial mixtures. This has led to a renewed interest in evaluating the relationship between the microbiota and human health and disease, including recipients of hematopoietic cell transplantation (HCT). Similarly, NGS has also contributed to significant advancements in the investigator's understanding of immune reconstitution in HCT patients and how this may impact clinica outcomes. 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.
Interventions
PROCEDUREMobilized Peripheral Blood Stem Cell graft with Tacrolimus/Methotrexate
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.
DRUGTacrolimus
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.
DRUGMethotrexate
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.
PROCEDUREMobilized Peripheral Blood Stem Cell graft with Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide
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.
DRUGMycophenolate Mofetil
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.
DRUGCyclophosphamide
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).
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Medical College of Wisconsin
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
Patients will be randomized at a ratio of 1:1 between the treatment arms using permuted blocks of random sizes.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With GVHD/Relapse or Progression-free Survival (GRFS) at One Year | 1 year post randomization | The primary endpoint is GRFS as a time to event endpoint from randomization. All randomized patients will be followed for one year; however, the primary endpoint will be analyzed as a time to event endpoint. The primary analysis will be done using the randomized population. An event for this time to event outcome is defined as grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, disease relapse or progression, or death by any cause, whichever comes first. Time to event analyses were conducted. An unadjusted Kaplan-Meier analysis was done. Additionally, a multivariate Cox regression model adjusting for the following pre-specified covariates: age group (\< 65 vs. 65+), disease risk index (low, intermediate, high/very high), planned RIC conditioning regimen (Fludarabine/Busulfan, Fludarabine/Melphalan, Other), donor type/HLA matching score (related 6/6, unrelated 7/8, unrelated 8/8), and planned use of post-transplant maintenance therapy (Yes vs. no). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Maximum Acute GVHD at One Year Post-transplant | One year post-transplant | Acute GVHD were graded according to Mount Sinai Acute GVHD International Consortium (MAGIC) Criteria (Harris et al. Biology of Blood and Marrow Transplantation 2016; 22:4-10). The higher acute GVHD grade indicates worse outcomes. Grade 0 is no acute GVHD of any organ. Grade I acute GVHD is defined as Skin stage of 1-2 and stage 0 for both GI and liver organs. Grade II is stage 3 of skin, or stage 1 of GI, or stage 1 of liver. Grade III is stage 2-3 for GI, or stage 2-3 of liver. Grade IV is stage 4 of skin, or stage 4 of liver. Max acute GVHD by one-year post-transplant was computed. |
| Number of Participants With Immunosuppression-Free Survival (ISFS) at 1 Year Post-transplant | 1 year post-transplant | Participants who are alive, relapse-free, and do not need ongoing immune suppression (IS) to control GVHD at one year post-transplant are considered successes for the endpoint immunosuppression-free survival (ISFS). Immune suppression is defined as any systemic agents used to control or suppress GVHD. Corticosteroid doses greater than 10 mg were considered active systemic immune suppression treatment. Participants who discontinued immune suppression within 15 days or less prior to the 1-year time point was considered to be on immune suppression for this endpoint. |
| Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Day 100 post-transplant | Organ stages were graded according to Mount Sinai Acute GVHD International Consortium (MAGIC) Criteria (Harris et al. 2016). Higher stage in any organ indicates worse outcomes. For skin, stage 0-no GVHD rash; 1-Maculopapular Rash \<25% BSA; 2-Maculopapular Rash 25-50% BSA; 3-Maculopapular Rash \>50% BSA; 4-Generalized Erythroderma Plus Bullous Formation and Desquamation \>5% BSA. For Lower GI, 0-No Diarrhea or Diarrhea-Adult: \<500 mL/day, \<3 Episodes/day; Child: \<10 mL/kg/day, \<4 Episodes/day; 1-Diarrhea-Adult: 500-999 mL/day, 3-4 Episodes/day; Child: 10-19.9 mL/kg/day, 4-6 Episodes/day; 2-Diarrhea-Adult: 1000-1500 mL/day, 5-7 Episodes/day; Child: 20-30 mL/kg/day, 7-10 Episodes/day; 3-Diarrhea-Adult: \>1500 mL/day, \>7 Episodes/day; Child: \>30 mL/kg/day, \>10 Episodes/day; 4-Severe Abdominal Pain With or Without Ileus or Grossly Bloody Stool. For liver, 0-Bilirubin \<2.0 mg/dL; 1-Bilirubin 2.0-3.0 mg/dL; 2-Bilirubin 3.1-6.0 mg/dL; 3-Bilirubin 6.1-15.0 mg/dL; 4-Bilirubin \>15.0 mg/dL |
| Participants With Maximum Stage of Upper GI at Day 100 Post-transplant | Day 100 post-transplant | Organ stages were graded according to Mount Sinai Acute GVHD International Consortium (MAGIC) Criteria (Harris et al. 2016). Higher stage in any organ indicates worse outcomes. For upper GI, stage 0 is no or intermittent nausea, vomiting, or anorexia; stage 1 is persistent nausea, vomiting, or anorexia. The maximum stages of Upper GI at patient level were summarized at Day 100. |
| Percentage of Participants With Chronic GVHD Post-transplant | 6, 12 months post-transplant | Percentage of participants with chronic GVHD (cGVHD) at one-year will be estimated with 95% confidence intervals for each treatment group using the cumulative incidence estimate with the complementary log-log transformation, treating death prior to cGVHD as a competing event. Chronic GVHD is based on NIH Consensus Criteria (2014 NIH Consensus Criteria) and includes mild, moderate and severe chronic GVHD. Eight organs were scored on a 0-3 scale to reflect degree of cGVHD involvement. Liver and pulmonary function test results and use of systemic therapy for treatment of cGVHD were also recorded. Assessment of cGVHD occurred up to one-year post-transplant. This endpoint considers any cGVHD onset. A multivariate Cox regression model for the cause-specific hazard of cGVHD was used to compare the treatment groups, after adjustment for baseline characteristics as described for the primary endpoint. |
| Number of Participants Experiencing Chronic GVHD With Maximum Severity at 12 Months Post-transplant | 12 months post-transplant | Chronic GVHD data were collected directly from providers and chart review as defined by the NIH Consensus Conference Criteria. Eight organs were scored on a 0-3 scale to reflect degree of chronic GVHD involvement per the NIH global severity scores of mild, moderate and severe chronic GVHD. The maximum severity of chronic GVHD through 12 months post-transplant will be tabulated by treatment arm. |
| Percentage of Participants With Immunosuppression-Free Survival (ISFS) at 1 Year Post-transplant | 1 year post-transplant | Participants who are alive, relapse-free, and do not need ongoing immune suppression to control GVHD at one year post-transplant are considered successes for the endpoint immunosuppression-free survival (ISFS). Percentage of participants alive, relapse free, and off immune suppression at 1 year post-transplant were described for each treatment group, along with 95% Clopper-Pearson confidence intervals. |
| Percentage of Participants With Neutrophil Recovery Post-transplant | Days 28 and day 100 post-transplant | Neutrophil recovery is defined as achieving an absolute neutrophil count (ANC) greater than or equal to 500/mm\^3 for three consecutive measurements on three different days. The first of the three days will be designated the day of neutrophil recovery. The competing event is death without neutrophil recovery. For participants who never drop ANC below 500/mm\^3, the date of neutrophil recovery will be Day +1 post-transplant. The cumulative incidence of neutrophil recovery by Day 28 and Day 100 was described for each treatment group with point estimates and 95% confidence intervals using the complementary log-log transformation and treating death as a competing event. |
| Percentage of Participants With Platelet Recovery Post-transplant | Day 60 and Day 100 post-transplant | Platelet recovery is defined by two different metrics: the first day of a sustained platelet count greater than or equal to 20,000/mm\^3 or greater than or equal to 50,000/mm\^3 with no platelet transfusions in the preceding seven days. The first day of sustained platelet count above these thresholds will be designated the day of platelet engraftment. For participants who never drop their platelet count below 20,000/mm\^3 or 50,000/mm\^3, the date of platelet recovery will be Day +1 post HCT. The competing event is death without platelet recovery. The cumulative incidence estimate of platelet recovery by Day 60 and Day 100 were described by treatment group with 95% confidence intervals (complementary log-log transformation), treating death as a competing event. |
| Percentage of Participants With Lymphocyte Recovery Post-transplant | Day 60, Day 100, 6 Months, and 1 year post-transplant | Lymphocyte recovery is defined as the first day of sustained absolute lymphocyte count greater than or equal to 1000/mm\^3. The competing event is death without lymphocyte recovery. The cumulative incidence estimate of Lymphocyte recovery were described by treatment group with 95% confidence intervals (complementary log-log transformation), treating death as a competing event. |
| Number of Participants With Each Level of Donor Cell Engraftment Post-transplant | Day 28 and Day 100 post-transplant | Donor cell engraftment were assessed with donor/recipient chimerism studies. Mixed chimerism is defined as the presence of donor cells, as a proportion of total cells to be less than 95% but at least 5% in the bone marrow or peripheral blood. Full donor chimerism is defined as greater than or equal to 95% of donor cells. Mixed and full chimerism will be evidence of donor cell engraftment. Donor cells of less than 5% will be considered as graft rejection. The number of participants with each level of chimerism described above is described as part of this outcome. |
| Percentage of Participants With Grades II-IV and III-IV Acute GVHD at Day 100 Post-transplant | Days 100 post-transplant | Acute GVHD was graded according to Mount Sinai aGVHD International Consortium (MAGIC) Criteria (Harris et al. 2016) with higher grade indicating worse outcomes. Grade I aGVHD is defined as Skin stage 1-2 and stage 0 for both GI and liver. Grade II is stage 3 skin, stage 1 GI, or stage 1 liver. Grade III is stage 2-3 GI or stage 2-3 liver. Grade IV is stage 4 skin or stage 4 liver. The cumulative incidence of acute GVHD grade II-IV and III-IV at Day 100 was estimated using the Aalen-Johansen estimator with 95% confidence intervals, treating death prior to aGVHD as a competing event. The cumulative incidences of Minnesota standard and high risk aGVHD at Day 100 were determined with 95% confidence intervals. Time to aGVHD is defined as time from transplant until onset of grades II-IV and III-IV aGVHD, respectively. A multivariate Cox regression model was used to compare the treatment groups, with adjustment for same baseline characteristics as for the primary endpoint. |
| Percentage of Participants With Disease Relapse at 1 Year Post-transplant | 1 year post-transplant | Disease relapse/progression is defined as being alive and free of relapse/progression of the primary disease. The time from transplant until relapse/progression of the primary disease, or cumulative incidence, was estimated at one-year post-transplant along with 95% CIs computed using the complementary log-log transformation, treating death prior to disease relapse as a competing event. A multivariate Cox regression model for the cause-specific hazard of relapse or progression will be used to compare the treatment groups, after adjustment for baseline characteristics as described for the primary endpoint. |
| Percentage of Participants With Treatment-related Mortality (TRM) Post-transplant | Days 100, 180 and 1 year post-transplant | An event for this endpoint TRM is death without evidence of disease progression or recurrence. Disease progression or recurrence will be considered a competing event. The time from transplant until TRM, or cumulative incidence, estimated at specific time points along with 95% CIs computed using the complementary log-log transformation, treating relapse/progression of the primary disease as a competing risk. A multivariate Cox regression model for the cause-specific hazard of TRM was used to compare the treatment groups, after adjustment for baseline characteristics as described for the primary endpoint. |
| Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | 1 year post-transplant | All Grade 3-5 toxicities will be tabulated by grade for each randomized treatment arm, by type of toxicity as well as the peak grade overall. Toxicities were evaluated using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. |
| Frequencies of Infections Categorized by Infection Type | 1 year post-transplant | All Grade 2 and 3 infections were reported according to the BMT CTN Technical Manual of Procedures (MOP) up to 1 year post-transplant. The frequency of Grade 2-3 infections and the number of participants experiencing infections occurring within 1 year post-transplant, are tabulated by treatment arm, organism, time period of infection onset, and severity, with Grade defined per the BMT CTN Technical MOP. |
| Number of Participants With Grade 2 and 3 Infections | 1 year post-transplant | All Grade 2 and 3 infections were reported according to the BMT CTN Technical Manual of Procedures (MOP) up to 1 year post-transplant. The frequency of Grade 2-3 infections and the number of participants experiencing infections occurring within 1 year post-transplant, are tabulated by treatment arm, organism, time period of infection onset, and severity, with Grade defined per the BMT CTN Technical MOP. |
| Percentage of Participants With Grade 2 and 3 Infections | 6 months and 1 year post-transplant | Grade 2 and 3 infections, as defined by the BMT CTN Technical Manual of Procedures (MOP), are reported on the study. The cumulative incidence of infections post transplantation, treating death as a competing risk, were compared between the treatment groups using the Gray's test. |
| Percentage of Participants With CMV at Day 100 Post-transplant | Day 100 post-transplant | The cumulative incidence of initiation of systemic treatment for CMV was compared between the treatment groups using the Gray's test, with death treated as a competing risk. Estimates of the cumulative incidence of CMV reactivation are provided at Day 100 post-transplant. |
| Percentage of Participants With Disease-Free Survival (DFS) at 1 Year Post-transplant | 1 year post-transplant | DFS is defined as being alive and free of relapse/progression of the primary disease. The time from transplant until death or relapse/progression (DFS failure) was described for each treatment arm using the Kaplan-Meier estimator, with numbers of subjects at risk at specific time points presented for each treatment group. A multivariate Cox regression model for the hazard of death will be used to compare the treatment groups, after adjustment for baseline characteristics as described for the primary endpoint. |
| Percentage of Participants With Overall Survival (OS) at 1 Year Post-transplant | 1 year post-transplant | The event for this endpoint OS is death from any cause post-transplant. Time to overall survival is defined as the time interval between date of transplant and date of death from any cause. Surviving participants will be censored at last follow-up or 1 year post-transplant, whichever comes first. The time from transplant until death from any cause was described graphically for each treatment arm using the Kaplan-Meier estimator, with numbers of subjects at risk at specific time points presented for each treatment group. A multivariate Cox regression model for the hazard of death will be used to compare the treatment groups, after adjustment for baseline characteristics as described for the primary endpoint. |
| Percentage of Participants With Lymphoproliferative Disease (PTLD) at 1 Year Post-Transplant | 1 year Post-Transplant | The cumulative incidence of lymphoproliferative disease at 1-year post-transplant is described with 95% confidence intervals for each treatment group using the Aalen-Johansen estimator, treating death as a competing event. |
| Summary Statistics for Donor Chimerism | Day 28 and Day 100 post-transplant | Donor cell engraftment were assessed with donor/recipient chimerism studies. Mixed chimerism is defined as the presence of donor cells, as a percentage of total cells to be less than 95% but at least 5% in the bone marrow or peripheral blood. Full donor chimerism is defined as greater than or equal to 95% of donor cells. Mixed and full chimerism will be evidence of donor cell engraftment. Donor cells of less than 5% will be considered as graft rejection. Donor chimerism at Day 28 and Day 100 after transplant in each of the randomized treatment arms will be described numerically as median and range for those evaluable. |
Countries
United States
Participant flow
Recruitment details
BMT CTN 1703's enrollment was between June 2019 and June 2021 with 431 participants enrolled from 37 centers. The study opened to accrual on June 25, 2019 with 39 centers activated for enrollment. The study closed to accrual on June 18, 2021 and study completed on September 19, 2022. BMT CTN 1801 is a companion study to BMT CTN 1703. The accrual goal was 300 participants. Enrollment to BMT CTN 1801 is performed solely through co-enrollment of BMT CTN 1703 participants.
Pre-assignment details
Enrolled participants were randomized in a 1:1 ratio to the two treatment arms. This is an open-label study and not blinded in treatment assignment. The randomized participants were intended to undergo transplant. For various reasons, a small portion of participants did not receive a transplant.
Participants by arm
| Arm | Count |
|---|---|
| PTCY/Tacrolimus/MMF Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide: Mobilized PBSC grafts will be administered on Day 0 to all patients. Stem cells are administered through an indwelling central venous catheter.
Tacrolimus: 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. Serum levels of tacrolimus will be measured at Day +7 and then should be checked weekly thereafter, the dose adjusted accordingly to maintain a suggested level of 5-15 ng/mL. Tacrolimus taper can be initiated at 90 days post HCT if there is no evidence of active GVHD. The tapering rate will be based on institutional practices, patients should be off tacrolimus by Day 180 post HCT if there is no evidence of active GVHD.
Mycophenolate Mofetil: MMF will be given at a dose of 15 mg/kg/dose ter in die (TID) 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: 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. | 214 |
| Tacrolimus/Methotrexate Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Methotrexate: 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: 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. 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, 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: 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. | 217 |
| Total | 431 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Disease Relapse | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Move to Hospice Care | 1 | 0 |
| Overall Study | Off Study | 1 | 0 |
| Overall Study | Screen Failure | 1 | 0 |
| Overall Study | Withdrawal by Subject | 7 | 8 |
Baseline characteristics
| Characteristic | PTCY/Tacrolimus/MMF | Total | Tacrolimus/Methotrexate |
|---|---|---|---|
| Age, Continuous | 64.2 years STANDARD_DEVIATION 8.5 | 64.3 years STANDARD_DEVIATION 8.7 | 64.5 years STANDARD_DEVIATION 8.9 |
| Age, Customized 18-64 years | 94 Participants | 186 Participants | 92 Participants |
| Age, Customized 65 years or older | 120 Participants | 245 Participants | 125 Participants |
| Allogeneic Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) total score 0 | 49 Participants | 102 Participants | 53 Participants |
| Allogeneic Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) total score 1 | 31 Participants | 65 Participants | 34 Participants |
| Allogeneic Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) total score 2 | 60 Participants | 94 Participants | 34 Participants |
| Allogeneic Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) total score 3 | 24 Participants | 57 Participants | 33 Participants |
| Allogeneic Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) total score 4+ | 40 Participants | 95 Participants | 55 Participants |
| Allogeneic Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) total score Missing/Unknown | 10 Participants | 18 Participants | 8 Participants |
| Disease Risk Index High / Very High | 70 Participants | 141 Participants | 71 Participants |
| Disease Risk Index Intermediate | 125 Participants | 250 Participants | 125 Participants |
| Disease Risk Index Low | 19 Participants | 40 Participants | 21 Participants |
| Donor/Recipient ABO Match Bidirectional Mismatch | 66 Participants | 149 Participants | 83 Participants |
| Donor/Recipient ABO Match Major Mismatch | 2 Participants | 3 Participants | 1 Participants |
| Donor/Recipient ABO Match Match | 122 Participants | 233 Participants | 111 Participants |
| Donor/Recipient ABO Match Minor Mismatch | 6 Participants | 7 Participants | 1 Participants |
| Donor/Recipient ABO Match Missing/Unknown | 18 Participants | 39 Participants | 21 Participants |
| Donor/Recipient CMV Status Missing/Unknown | 7 Participants | 11 Participants | 4 Participants |
| Donor/Recipient CMV Status Neg/Neg | 59 Participants | 129 Participants | 70 Participants |
| Donor/Recipient CMV Status Neg/Pos | 67 Participants | 107 Participants | 40 Participants |
| Donor/Recipient CMV Status Pos/Neg | 20 Participants | 52 Participants | 32 Participants |
| Donor/Recipient CMV Status Pos/Pos | 61 Participants | 132 Participants | 71 Participants |
| Donor/Recipient Sex Match F-F | 36 Participants | 71 Participants | 35 Participants |
| Donor/Recipient Sex Match F-M | 47 Participants | 96 Participants | 49 Participants |
| Donor/Recipient Sex Match M-F | 41 Participants | 95 Participants | 54 Participants |
| Donor/Recipient Sex Match Missing/Unknown | 5 Participants | 9 Participants | 4 Participants |
| Donor/Recipient Sex Match M-M | 85 Participants | 160 Participants | 75 Participants |
| Donor Type and HLA Matching Related donor 6/6 | 60 Participants | 128 Participants | 68 Participants |
| Donor Type and HLA Matching Unrelated donor 7/8 | 7 Participants | 15 Participants | 8 Participants |
| Donor Type and HLA Matching Unrelated donor 8/8 | 147 Participants | 288 Participants | 141 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 31 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 203 Participants | 394 Participants | 191 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 6 Participants | 4 Participants |
| Karnofsky / Lansky Performance Score At least 90 | 106 Participants | 214 Participants | 108 Participants |
| Karnofsky / Lansky Performance Score Less Than 90 | 108 Participants | 217 Participants | 109 Participants |
| Planned Post-Transplant Maintenance Therapy Clinical Trial | 1 Participants | 2 Participants | 1 Participants |
| Planned Post-Transplant Maintenance Therapy FLT3 Inhibitor | 10 Participants | 19 Participants | 9 Participants |
| Planned Post-Transplant Maintenance Therapy Monoclonal Antibody | 1 Participants | 1 Participants | 0 Participants |
| Planned Post-Transplant Maintenance Therapy No Planned Post-Transplant Maintenance Therapy | 159 Participants | 329 Participants | 170 Participants |
| Planned Post-Transplant Maintenance Therapy Other | 31 Participants | 53 Participants | 22 Participants |
| Planned Post-Transplant Maintenance Therapy Tyrosine Kinase Inhibitor | 12 Participants | 27 Participants | 15 Participants |
| Planned Reduced Intensity Conditioning Regimen Fludarabine/Busulfan | 58 Participants | 119 Participants | 61 Participants |
| Planned Reduced Intensity Conditioning Regimen Fludarabine/Cyclophosphamide | 6 Participants | 7 Participants | 1 Participants |
| Planned Reduced Intensity Conditioning Regimen Fludarabine/Cyclophosphamide/TBI | 24 Participants | 48 Participants | 24 Participants |
| Planned Reduced Intensity Conditioning Regimen Fludarabine/Melphalan | 125 Participants | 252 Participants | 127 Participants |
| Planned Reduced Intensity Conditioning Regimen Fludarabine/TBI | 1 Participants | 5 Participants | 4 Participants |
| Primary Disease Acute lymphoblastic leukemia (ALL) | 12 Participants | 39 Participants | 27 Participants |
| Primary Disease Acute myelogenous leukemia (AML) | 107 Participants | 207 Participants | 100 Participants |
| Primary Disease Aggressive NHL | 9 Participants | 16 Participants | 7 Participants |
| Primary Disease Biphenotypic leukemia | 1 Participants | 2 Participants | 1 Participants |
| Primary Disease Burkitt lymphoma | 1 Participants | 1 Participants | 0 Participants |
| Primary Disease Chronic myelogenous leukemia (CML) | 6 Participants | 11 Participants | 5 Participants |
| Primary Disease Hodgkin lymphoma | 3 Participants | 6 Participants | 3 Participants |
| Primary Disease Indolent NHL | 3 Participants | 4 Participants | 1 Participants |
| Primary Disease Mantle cell lymphoma | 0 Participants | 1 Participants | 1 Participants |
| Primary Disease Myelodysplastic syndrome (MDS) | 63 Participants | 128 Participants | 65 Participants |
| Primary Disease T-cell NHL | 7 Participants | 12 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 14 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 13 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 23 Participants | 13 Participants |
| Race (NIH/OMB) White | 186 Participants | 379 Participants | 193 Participants |
| Received reduced intensity conditioning regimen Fludarabine/Busulfan | 56 Participants | 117 Participants | 61 Participants |
| Received reduced intensity conditioning regimen Fludarabine/Cyclophosphamide | 5 Participants | 6 Participants | 1 Participants |
| Received reduced intensity conditioning regimen Fludarabine/Cyclophosphamide/TBI | 24 Participants | 48 Participants | 24 Participants |
| Received reduced intensity conditioning regimen Fludarabine/Melphalan | 122 Participants | 245 Participants | 123 Participants |
| Received reduced intensity conditioning regimen Fludarabine/TBI | 1 Participants | 5 Participants | 4 Participants |
| Received reduced intensity conditioning regimen Missing/Unknown | 6 Participants | 10 Participants | 4 Participants |
| Sex: Female, Male Female | 80 Participants | 171 Participants | 91 Participants |
| Sex: Female, Male Male | 134 Participants | 260 Participants | 126 Participants |
| Time from Disease Diagnosis to Transplant | 12.3 months STANDARD_DEVIATION 17 | 12.7 months STANDARD_DEVIATION 19.4 | 13.1 months STANDARD_DEVIATION 21.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 58 / 214 | 70 / 217 |
| other Total, other adverse events | 142 / 208 | 149 / 212 |
| serious Total, serious adverse events | 7 / 208 | 14 / 212 |
Outcome results
Primary
Percentage of Participants With GVHD/Relapse or Progression-free Survival (GRFS) at One Year
The primary endpoint is GRFS as a time to event endpoint from randomization. All randomized patients will be followed for one year; however, the primary endpoint will be analyzed as a time to event endpoint. The primary analysis will be done using the randomized population. An event for this time to event outcome is defined as grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, disease relapse or progression, or death by any cause, whichever comes first. Time to event analyses were conducted. An unadjusted Kaplan-Meier analysis was done. Additionally, a multivariate Cox regression model adjusting for the following pre-specified covariates: age group (\< 65 vs. 65+), disease risk index (low, intermediate, high/very high), planned RIC conditioning regimen (Fludarabine/Busulfan, Fludarabine/Melphalan, Other), donor type/HLA matching score (related 6/6, unrelated 7/8, unrelated 8/8), and planned use of post-transplant maintenance therapy (Yes vs. no).
Time frame: 1 year post randomization
Population: Analysis Population includes all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PTCY/Tacrolimus/MMF | Percentage of Participants With GVHD/Relapse or Progression-free Survival (GRFS) at One Year | 52.3 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With GVHD/Relapse or Progression-free Survival (GRFS) at One Year | 35.5 percentage of participants |
Comparison: This is the result of the Cox proportional hazards analysis. The null hypothesis is that there is no difference of GRFS hazard ratio between treatment groups after adjustment for age group, donor type and HLA Matching Score, disease risk index, Planned RIC Conditioning Regimen, and Planned post-transplant maintenance therapies.p-value: 0.00195% CI: [0.492, 0.835]Regression, Cox
Secondary
Frequencies of Infections Categorized by Infection Type
All Grade 2 and 3 infections were reported according to the BMT CTN Technical Manual of Procedures (MOP) up to 1 year post-transplant. The frequency of Grade 2-3 infections and the number of participants experiencing infections occurring within 1 year post-transplant, are tabulated by treatment arm, organism, time period of infection onset, and severity, with Grade defined per the BMT CTN Technical MOP.
Time frame: 1 year post-transplant
Population: Analysis Population includes transplanted participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PTCY/Tacrolimus/MMF | Frequencies of Infections Categorized by Infection Type | Viral | 70 infections |
| PTCY/Tacrolimus/MMF | Frequencies of Infections Categorized by Infection Type | Protozoal/Parasite | 0 infections |
| PTCY/Tacrolimus/MMF | Frequencies of Infections Categorized by Infection Type | Fungal | 18 infections |
| PTCY/Tacrolimus/MMF | Frequencies of Infections Categorized by Infection Type | Other | 34 infections |
| PTCY/Tacrolimus/MMF | Frequencies of Infections Categorized by Infection Type | Bacterial | 128 infections |
| Tacrolimus/Methotrexate | Frequencies of Infections Categorized by Infection Type | Other | 46 infections |
| Tacrolimus/Methotrexate | Frequencies of Infections Categorized by Infection Type | Bacterial | 118 infections |
| Tacrolimus/Methotrexate | Frequencies of Infections Categorized by Infection Type | Viral | 61 infections |
| Tacrolimus/Methotrexate | Frequencies of Infections Categorized by Infection Type | Fungal | 14 infections |
| Tacrolimus/Methotrexate | Frequencies of Infections Categorized by Infection Type | Protozoal/Parasite | 0 infections |
Secondary
Number of Participants Experiencing Chronic GVHD With Maximum Severity at 12 Months Post-transplant
Chronic GVHD data were collected directly from providers and chart review as defined by the NIH Consensus Conference Criteria. Eight organs were scored on a 0-3 scale to reflect degree of chronic GVHD involvement per the NIH global severity scores of mild, moderate and severe chronic GVHD. The maximum severity of chronic GVHD through 12 months post-transplant will be tabulated by treatment arm.
Time frame: 12 months post-transplant
Population: Analysis Population includes transplanted participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PTCY/Tacrolimus/MMF | Number of Participants Experiencing Chronic GVHD With Maximum Severity at 12 Months Post-transplant | Mild | 29 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Experiencing Chronic GVHD With Maximum Severity at 12 Months Post-transplant | Severe | 3 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Experiencing Chronic GVHD With Maximum Severity at 12 Months Post-transplant | Moderate | 11 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Experiencing Chronic GVHD With Maximum Severity at 12 Months Post-transplant | Unknown | 1 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Experiencing Chronic GVHD With Maximum Severity at 12 Months Post-transplant | None | 164 Participants |
| Tacrolimus/Methotrexate | Number of Participants Experiencing Chronic GVHD With Maximum Severity at 12 Months Post-transplant | Unknown | 2 Participants |
| Tacrolimus/Methotrexate | Number of Participants Experiencing Chronic GVHD With Maximum Severity at 12 Months Post-transplant | None | 139 Participants |
| Tacrolimus/Methotrexate | Number of Participants Experiencing Chronic GVHD With Maximum Severity at 12 Months Post-transplant | Mild | 36 Participants |
| Tacrolimus/Methotrexate | Number of Participants Experiencing Chronic GVHD With Maximum Severity at 12 Months Post-transplant | Moderate | 24 Participants |
| Tacrolimus/Methotrexate | Number of Participants Experiencing Chronic GVHD With Maximum Severity at 12 Months Post-transplant | Severe | 11 Participants |
Secondary
Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant
All Grade 3-5 toxicities will be tabulated by grade for each randomized treatment arm, by type of toxicity as well as the peak grade overall. Toxicities were evaluated using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
Time frame: 1 year post-transplant
Population: Analysis Population includes transplanted participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 General Disorders | 51 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Immune System Disorders | 5 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 GI Disorders | 57 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Renal Disorders | 33 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Hemorrhagic Disorders | 12 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Cardiac Disorders | 71 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Nervous System Disorders | 12 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Blood and Lymphatic Disorders | 3 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Vascular Disorders | 6 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Musculoskeletal and Connective Tissue Disorders | 17 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Respiratory, Thoracic and Mediastinal Disorders | 41 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Metabolism and Nutrition Disorders | 24 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Hepatic Disorders | 24 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Received Dialysis | 11 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Hepatitis | 6 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Liver failure | 2 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Abnormal liver function | 14 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Overall Grade 3 | 141 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Overall Grade 4 | 23 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Overall Grade 5 | 12 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Maximum Toxicity Grade 3 | 113 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Maximum Toxicity Grade 4 | 17 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Maximum Toxicity Grade 5 | 12 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Metabolism and Nutrition Disorders | 33 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 General Disorders | 48 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Overall Grade 3 | 146 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Immune System Disorders | 6 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Hepatic Disorders | 44 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 GI Disorders | 77 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Maximum Toxicity Grade 3 | 116 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Renal Disorders | 30 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Received Dialysis | 8 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Hemorrhagic Disorders | 11 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Overall Grade 4 | 27 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Cardiac Disorders | 72 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Hepatitis | 4 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Nervous System Disorders | 20 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Maximum Toxicity Grade 5 | 11 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Blood and Lymphatic Disorders | 3 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Liver failure | 4 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Vascular Disorders | 12 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Overall Grade 5 | 11 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Musculoskeletal and Connective Tissue Disorders | 12 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Abnormal liver function | 15 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Grades 3-5 Respiratory, Thoracic and Mediastinal Disorders | 42 Participants |
| Tacrolimus/Methotrexate | Number of Participants Reporting Grade 3-5 Toxicities by 1 Year Post-transplant | Maximum Toxicity Grade 4 | 22 Participants |
Secondary
Number of Participants With Each Level of Donor Cell Engraftment Post-transplant
Donor cell engraftment were assessed with donor/recipient chimerism studies. Mixed chimerism is defined as the presence of donor cells, as a proportion of total cells to be less than 95% but at least 5% in the bone marrow or peripheral blood. Full donor chimerism is defined as greater than or equal to 95% of donor cells. Mixed and full chimerism will be evidence of donor cell engraftment. Donor cells of less than 5% will be considered as graft rejection. The number of participants with each level of chimerism described above is described as part of this outcome.
Time frame: Day 28 and Day 100 post-transplant
Population: Analysis Population includes transplanted participants.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| PTCY/Tacrolimus/MMF | Number of Participants With Each Level of Donor Cell Engraftment Post-transplant | Day 28 post-transplant | Full (>95% Donor Cells) | 126 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Each Level of Donor Cell Engraftment Post-transplant | Day 28 post-transplant | Mixed (5-95% Donor Cells) | 39 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Each Level of Donor Cell Engraftment Post-transplant | Day 28 post-transplant | Graft Rejection (<5% Donor Cells) | 4 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Each Level of Donor Cell Engraftment Post-transplant | Day 28 post-transplant | Data missing | 39 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Each Level of Donor Cell Engraftment Post-transplant | Day 100 post-transplant | Full (>95% Donor Cells) | 116 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Each Level of Donor Cell Engraftment Post-transplant | Day 100 post-transplant | Mixed (5-95% Donor Cells) | 48 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Each Level of Donor Cell Engraftment Post-transplant | Day 100 post-transplant | Graft Rejection (<5% Donor Cells) | 5 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Each Level of Donor Cell Engraftment Post-transplant | Day 100 post-transplant | Data missing | 39 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Each Level of Donor Cell Engraftment Post-transplant | Day 100 post-transplant | Data missing | 29 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Each Level of Donor Cell Engraftment Post-transplant | Day 28 post-transplant | Full (>95% Donor Cells) | 129 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Each Level of Donor Cell Engraftment Post-transplant | Day 100 post-transplant | Full (>95% Donor Cells) | 124 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Each Level of Donor Cell Engraftment Post-transplant | Day 28 post-transplant | Mixed (5-95% Donor Cells) | 45 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Each Level of Donor Cell Engraftment Post-transplant | Day 100 post-transplant | Graft Rejection (<5% Donor Cells) | 1 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Each Level of Donor Cell Engraftment Post-transplant | Day 28 post-transplant | Graft Rejection (<5% Donor Cells) | 4 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Each Level of Donor Cell Engraftment Post-transplant | Day 100 post-transplant | Mixed (5-95% Donor Cells) | 58 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Each Level of Donor Cell Engraftment Post-transplant | Day 28 post-transplant | Data missing | 34 Participants |
Comparison: The null hypothesis is that there is no difference of Donor Cell Engraftment at Day 28 after transplantation between the treatment groupsp-value: 0.919Fisher Exact
Comparison: The null hypothesis is that there is no difference of Donor Cell Engraftment at Day 100 after transplantation between the treatment groupsp-value: 0.198Fisher Exact
Secondary
Number of Participants With Grade 2 and 3 Infections
All Grade 2 and 3 infections were reported according to the BMT CTN Technical Manual of Procedures (MOP) up to 1 year post-transplant. The frequency of Grade 2-3 infections and the number of participants experiencing infections occurring within 1 year post-transplant, are tabulated by treatment arm, organism, time period of infection onset, and severity, with Grade defined per the BMT CTN Technical MOP.
Time frame: 1 year post-transplant
Population: Analysis Population includes transplanted participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PTCY/Tacrolimus/MMF | Number of Participants With Grade 2 and 3 Infections | Patients with 2 Infections | 32 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Grade 2 and 3 Infections | Maximum Severity of None | 99 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Grade 2 and 3 Infections | Patients with 4 Infections | 8 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Grade 2 and 3 Infections | Maximum Severity of Grade 1 | 21 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Grade 2 and 3 Infections | Patients with 1 Infection | 46 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Grade 2 and 3 Infections | Maximum Severity of Grade 2 | 57 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Grade 2 and 3 Infections | Patients with 5 Infections | 4 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Grade 2 and 3 Infections | Maximum Severity of Grade 3 | 25 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Grade 2 and 3 Infections | Patients with 3 Infections | 14 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Grade 2 and 3 Infections | CMV Reactivation by Day 100 | 15 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Grade 2 and 3 Infections | Patients with >= 6 Infections | 5 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Grade 2 and 3 Infections | Non-Microbial Infections | 9 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Grade 2 and 3 Infections | Patients with Infections | 109 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Grade 2 and 3 Infections | Non-Microbial Infections | 10 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Grade 2 and 3 Infections | Patients with Infections | 100 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Grade 2 and 3 Infections | Patients with 1 Infection | 46 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Grade 2 and 3 Infections | Patients with 2 Infections | 24 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Grade 2 and 3 Infections | Patients with 3 Infections | 10 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Grade 2 and 3 Infections | Patients with 4 Infections | 7 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Grade 2 and 3 Infections | Patients with 5 Infections | 5 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Grade 2 and 3 Infections | Patients with >= 6 Infections | 8 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Grade 2 and 3 Infections | Maximum Severity of None | 112 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Grade 2 and 3 Infections | Maximum Severity of Grade 1 | 19 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Grade 2 and 3 Infections | Maximum Severity of Grade 2 | 36 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Grade 2 and 3 Infections | Maximum Severity of Grade 3 | 28 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Grade 2 and 3 Infections | CMV Reactivation by Day 100 | 16 Participants |
Secondary
Number of Participants With Immunosuppression-Free Survival (ISFS) at 1 Year Post-transplant
Participants who are alive, relapse-free, and do not need ongoing immune suppression (IS) to control GVHD at one year post-transplant are considered successes for the endpoint immunosuppression-free survival (ISFS). Immune suppression is defined as any systemic agents used to control or suppress GVHD. Corticosteroid doses greater than 10 mg were considered active systemic immune suppression treatment. Participants who discontinued immune suppression within 15 days or less prior to the 1-year time point was considered to be on immune suppression for this endpoint.
Time frame: 1 year post-transplant
Population: Analysis Population includes transplanted and evaluable participants for ISFS
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PTCY/Tacrolimus/MMF | Number of Participants With Immunosuppression-Free Survival (ISFS) at 1 Year Post-transplant | Immunosuppression-Free Survival | 99 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Immunosuppression-Free Survival (ISFS) at 1 Year Post-transplant | Death | 46 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Immunosuppression-Free Survival (ISFS) at 1 Year Post-transplant | Alive & Relapse | 21 Participants |
| PTCY/Tacrolimus/MMF | Number of Participants With Immunosuppression-Free Survival (ISFS) at 1 Year Post-transplant | Alive, no relapse, and still on IS | 32 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Immunosuppression-Free Survival (ISFS) at 1 Year Post-transplant | Alive, no relapse, and still on IS | 45 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Immunosuppression-Free Survival (ISFS) at 1 Year Post-transplant | Immunosuppression-Free Survival | 81 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Immunosuppression-Free Survival (ISFS) at 1 Year Post-transplant | Alive & Relapse | 22 Participants |
| Tacrolimus/Methotrexate | Number of Participants With Immunosuppression-Free Survival (ISFS) at 1 Year Post-transplant | Death | 56 Participants |
Secondary
Participants With Maximum Acute GVHD at One Year Post-transplant
Acute GVHD were graded according to Mount Sinai Acute GVHD International Consortium (MAGIC) Criteria (Harris et al. Biology of Blood and Marrow Transplantation 2016; 22:4-10). The higher acute GVHD grade indicates worse outcomes. Grade 0 is no acute GVHD of any organ. Grade I acute GVHD is defined as Skin stage of 1-2 and stage 0 for both GI and liver organs. Grade II is stage 3 of skin, or stage 1 of GI, or stage 1 of liver. Grade III is stage 2-3 for GI, or stage 2-3 of liver. Grade IV is stage 4 of skin, or stage 4 of liver. Max acute GVHD by one-year post-transplant was computed.
Time frame: One year post-transplant
Population: Analysis Population includes transplanted participants
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PTCY/Tacrolimus/MMF | Participants With Maximum Acute GVHD at One Year Post-transplant | Grade I | 27 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Acute GVHD at One Year Post-transplant | Grade III | 11 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Acute GVHD at One Year Post-transplant | Grade II | 99 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Acute GVHD at One Year Post-transplant | Grade IV | 5 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Acute GVHD at One Year Post-transplant | Grade 0 | 66 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Acute GVHD at One Year Post-transplant | Grade IV | 14 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Acute GVHD at One Year Post-transplant | Grade 0 | 60 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Acute GVHD at One Year Post-transplant | Grade I | 32 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Acute GVHD at One Year Post-transplant | Grade II | 81 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Acute GVHD at One Year Post-transplant | Grade III | 25 Participants |
Secondary
Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant
Organ stages were graded according to Mount Sinai Acute GVHD International Consortium (MAGIC) Criteria (Harris et al. 2016). Higher stage in any organ indicates worse outcomes. For skin, stage 0-no GVHD rash; 1-Maculopapular Rash \<25% BSA; 2-Maculopapular Rash 25-50% BSA; 3-Maculopapular Rash \>50% BSA; 4-Generalized Erythroderma Plus Bullous Formation and Desquamation \>5% BSA. For Lower GI, 0-No Diarrhea or Diarrhea-Adult: \<500 mL/day, \<3 Episodes/day; Child: \<10 mL/kg/day, \<4 Episodes/day; 1-Diarrhea-Adult: 500-999 mL/day, 3-4 Episodes/day; Child: 10-19.9 mL/kg/day, 4-6 Episodes/day; 2-Diarrhea-Adult: 1000-1500 mL/day, 5-7 Episodes/day; Child: 20-30 mL/kg/day, 7-10 Episodes/day; 3-Diarrhea-Adult: \>1500 mL/day, \>7 Episodes/day; Child: \>30 mL/kg/day, \>10 Episodes/day; 4-Severe Abdominal Pain With or Without Ileus or Grossly Bloody Stool. For liver, 0-Bilirubin \<2.0 mg/dL; 1-Bilirubin 2.0-3.0 mg/dL; 2-Bilirubin 3.1-6.0 mg/dL; 3-Bilirubin 6.1-15.0 mg/dL; 4-Bilirubin \>15.0 mg/dL
Time frame: Day 100 post-transplant
Population: Analysis Population includes transplanted participants
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| PTCY/Tacrolimus/MMF | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Skin | 4 | 3 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Lower GI | 3 | 10 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Skin | 1 | 54 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Lower GI | 4 | 1 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Lower GI | 0 | 155 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Liver | 0 | 198 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Skin | 3 | 14 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Liver | 1 | 9 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Lower GI | 1 | 33 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Liver | 2 | 0 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Skin | 2 | 16 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Liver | 3 | 1 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Lower GI | 2 | 9 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Liver | 4 | 0 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Skin | 0 | 121 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Liver | 4 | 0 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Skin | 0 | 125 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Skin | 1 | 40 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Skin | 2 | 18 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Skin | 3 | 21 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Skin | 4 | 8 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Lower GI | 0 | 159 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Lower GI | 1 | 27 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Lower GI | 2 | 11 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Lower GI | 3 | 11 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Lower GI | 4 | 4 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Liver | 0 | 192 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Liver | 1 | 7 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Liver | 2 | 8 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant | Liver | 3 | 5 Participants |
Secondary
Participants With Maximum Stage of Upper GI at Day 100 Post-transplant
Organ stages were graded according to Mount Sinai Acute GVHD International Consortium (MAGIC) Criteria (Harris et al. 2016). Higher stage in any organ indicates worse outcomes. For upper GI, stage 0 is no or intermittent nausea, vomiting, or anorexia; stage 1 is persistent nausea, vomiting, or anorexia. The maximum stages of Upper GI at patient level were summarized at Day 100.
Time frame: Day 100 post-transplant
Population: Analysis Population includes transplanted participants
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PTCY/Tacrolimus/MMF | Participants With Maximum Stage of Upper GI at Day 100 Post-transplant | 0 | 136 Participants |
| PTCY/Tacrolimus/MMF | Participants With Maximum Stage of Upper GI at Day 100 Post-transplant | 1 | 72 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Stage of Upper GI at Day 100 Post-transplant | 0 | 137 Participants |
| Tacrolimus/Methotrexate | Participants With Maximum Stage of Upper GI at Day 100 Post-transplant | 1 | 75 Participants |
Secondary
Percentage of Participants With Chronic GVHD Post-transplant
Percentage of participants with chronic GVHD (cGVHD) at one-year will be estimated with 95% confidence intervals for each treatment group using the cumulative incidence estimate with the complementary log-log transformation, treating death prior to cGVHD as a competing event. Chronic GVHD is based on NIH Consensus Criteria (2014 NIH Consensus Criteria) and includes mild, moderate and severe chronic GVHD. Eight organs were scored on a 0-3 scale to reflect degree of cGVHD involvement. Liver and pulmonary function test results and use of systemic therapy for treatment of cGVHD were also recorded. Assessment of cGVHD occurred up to one-year post-transplant. This endpoint considers any cGVHD onset. A multivariate Cox regression model for the cause-specific hazard of cGVHD was used to compare the treatment groups, after adjustment for baseline characteristics as described for the primary endpoint.
Time frame: 6, 12 months post-transplant
Population: Analysis Population includes transplanted participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PTCY/Tacrolimus/MMF | Percentage of Participants With Chronic GVHD Post-transplant | 6 months post transplant | 11.3 percentage of participants |
| PTCY/Tacrolimus/MMF | Percentage of Participants With Chronic GVHD Post-transplant | 12 months post transplant | 21.9 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Chronic GVHD Post-transplant | 6 months post transplant | 13.9 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Chronic GVHD Post-transplant | 12 months post transplant | 35.1 percentage of participants |
Comparison: This is the unadjusted analysis. The null hypothesis is that there is no difference of chronic GVHD post-transplantation between the treatment groupsp-value: 0.005Gray's test for cumulative Incidence
Comparison: This is the result of the Cox proportional hazards analysis. The null hypothesis is that there is no difference of the chronic GVHD hazard ratio between treatment groups after adjustment for age group, donor type and HLA Matching Score, disease risk index, Planned RIC Conditioning Regimen, and Planned post-transplant maintenance therapiesp-value: 0.00295% CI: [0.381, 0.813]Regression, Cox
Secondary
Percentage of Participants With CMV at Day 100 Post-transplant
The cumulative incidence of initiation of systemic treatment for CMV was compared between the treatment groups using the Gray's test, with death treated as a competing risk. Estimates of the cumulative incidence of CMV reactivation are provided at Day 100 post-transplant.
Time frame: Day 100 post-transplant
Population: Analysis Population includes transplanted participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PTCY/Tacrolimus/MMF | Percentage of Participants With CMV at Day 100 Post-transplant | 7.3 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With CMV at Day 100 Post-transplant | 7.1 percentage of participants |
Comparison: The null hypothesis is that there is no difference of CMV between the treatment groupsp-value: 0.825Gray's test for cumulative Incidence
Secondary
Percentage of Participants With Disease-Free Survival (DFS) at 1 Year Post-transplant
DFS is defined as being alive and free of relapse/progression of the primary disease. The time from transplant until death or relapse/progression (DFS failure) was described for each treatment arm using the Kaplan-Meier estimator, with numbers of subjects at risk at specific time points presented for each treatment group. A multivariate Cox regression model for the hazard of death will be used to compare the treatment groups, after adjustment for baseline characteristics as described for the primary endpoint.
Time frame: 1 year post-transplant
Population: Analysis Population includes transplanted participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PTCY/Tacrolimus/MMF | Percentage of Participants With Disease-Free Survival (DFS) at 1 Year Post-transplant | 67.0 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Disease-Free Survival (DFS) at 1 Year Post-transplant | 62.6 percentage of participants |
Comparison: This is the unadjusted analysis. The null hypothesis is that there is no difference of Disease-Free Survival between the treatment groupsp-value: 0.351Log Rank
Comparison: This is the result of the Cox proportional hazards analysis. The null hypothesis is that there is no difference of Disease-Free Survival hazard ratio between treatment groups after adjustment for age group, donor type and HLA Matching Score, disease risk index, Planned RIC Conditioning Regimen, and Planned post-transplant maintenance therapiesp-value: 0.3295% CI: [0.61, 1.176]Regression, Cox
Secondary
Percentage of Participants With Disease Relapse at 1 Year Post-transplant
Disease relapse/progression is defined as being alive and free of relapse/progression of the primary disease. The time from transplant until relapse/progression of the primary disease, or cumulative incidence, was estimated at one-year post-transplant along with 95% CIs computed using the complementary log-log transformation, treating death prior to disease relapse as a competing event. A multivariate Cox regression model for the cause-specific hazard of relapse or progression will be used to compare the treatment groups, after adjustment for baseline characteristics as described for the primary endpoint.
Time frame: 1 year post-transplant
Population: Analysis Population includes transplanted participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PTCY/Tacrolimus/MMF | Percentage of Participants With Disease Relapse at 1 Year Post-transplant | 20.8 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Disease Relapse at 1 Year Post-transplant | 20.2 percentage of participants |
Comparison: This is the unadjusted analysis. The null hypothesis is that there is no difference of Disease Relapse between the treatment groupsp-value: 0.906Gray's test for cumulative Incidence
Comparison: This is the result of the Cox proportional hazards analysis. The null hypothesis is that there is no difference of Disease Relapse hazard ratio between treatment groups after adjustment for age group, donor type and HLA Matching Score, disease risk index, Planned RIC Conditioning Regimen, and Planned post-transplant maintenance therapiesp-value: 0.94795% CI: [0.641, 1.515]Regression, Cox
Secondary
Percentage of Participants With Grade 2 and 3 Infections
Grade 2 and 3 infections, as defined by the BMT CTN Technical Manual of Procedures (MOP), are reported on the study. The cumulative incidence of infections post transplantation, treating death as a competing risk, were compared between the treatment groups using the Gray's test.
Time frame: 6 months and 1 year post-transplant
Population: Analysis Population includes transplanted participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PTCY/Tacrolimus/MMF | Percentage of Participants With Grade 2 and 3 Infections | 6 months post-transplant | 36.4 percentage of participants |
| PTCY/Tacrolimus/MMF | Percentage of Participants With Grade 2 and 3 Infections | 1 year post-transplant | 40.0 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Grade 2 and 3 Infections | 6 months post-transplant | 24.1 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Grade 2 and 3 Infections | 1 year post-transplant | 30.4 percentage of participants |
Comparison: The null hypothesis is that there is no difference of Grade 2 and 3 infections between the treatment groupsp-value: 0.018Gray's test for cumulative Incidence
Secondary
Percentage of Participants With Grades II-IV and III-IV Acute GVHD at Day 100 Post-transplant
Acute GVHD was graded according to Mount Sinai aGVHD International Consortium (MAGIC) Criteria (Harris et al. 2016) with higher grade indicating worse outcomes. Grade I aGVHD is defined as Skin stage 1-2 and stage 0 for both GI and liver. Grade II is stage 3 skin, stage 1 GI, or stage 1 liver. Grade III is stage 2-3 GI or stage 2-3 liver. Grade IV is stage 4 skin or stage 4 liver. The cumulative incidence of acute GVHD grade II-IV and III-IV at Day 100 was estimated using the Aalen-Johansen estimator with 95% confidence intervals, treating death prior to aGVHD as a competing event. The cumulative incidences of Minnesota standard and high risk aGVHD at Day 100 were determined with 95% confidence intervals. Time to aGVHD is defined as time from transplant until onset of grades II-IV and III-IV aGVHD, respectively. A multivariate Cox regression model was used to compare the treatment groups, with adjustment for same baseline characteristics as for the primary endpoint.
Time frame: Days 100 post-transplant
Population: Analysis Population includes transplanted participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PTCY/Tacrolimus/MMF | Percentage of Participants With Grades II-IV and III-IV Acute GVHD at Day 100 Post-transplant | MAGIC aGVHD Grade II-IV | 53.8 percentage of participants |
| PTCY/Tacrolimus/MMF | Percentage of Participants With Grades II-IV and III-IV Acute GVHD at Day 100 Post-transplant | MAGIC aGVHD Grade III-IV | 6.3 percentage of participants |
| PTCY/Tacrolimus/MMF | Percentage of Participants With Grades II-IV and III-IV Acute GVHD at Day 100 Post-transplant | Standard risk aGVHD | 64.1 percentage of participants |
| PTCY/Tacrolimus/MMF | Percentage of Participants With Grades II-IV and III-IV Acute GVHD at Day 100 Post-transplant | High risk aGVHD | 13.1 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Grades II-IV and III-IV Acute GVHD at Day 100 Post-transplant | High risk aGVHD | 18.5 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Grades II-IV and III-IV Acute GVHD at Day 100 Post-transplant | MAGIC aGVHD Grade II-IV | 51.9 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Grades II-IV and III-IV Acute GVHD at Day 100 Post-transplant | Standard risk aGVHD | 64.3 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Grades II-IV and III-IV Acute GVHD at Day 100 Post-transplant | MAGIC aGVHD Grade III-IV | 14.7 percentage of participants |
Comparison: This is the unadjusted analysis. The null hypothesis is that there is no difference of grade II-IV acute GVHD post-transplantation between the treatment groups.p-value: 0.995Gray's test for cumulative Incidence
Comparison: This is the unadjusted analysis. The null hypothesis is that there is no difference of grade III-IV acute GVHD post-transplantation between the treatment groupsp-value: 0.001Gray's test for cumulative Incidence
Comparison: This is the result of the Cox proportional hazards analysis. The null hypothesis is that there is no difference of grade II-IV acute GVHD post-transplantation between the treatment groups using a Cox regression model for the cause-specific hazard of aGVHDp-value: 0.87995% CI: [0.758, 1.267]Regression, Cox
Comparison: This is the result of the Cox proportional hazards analysis. The null hypothesis is that there is no difference of grade III-IV aGVHD hazard ratio between treatment groups after adjustment for age group, donor type and HLA Matching Score, disease risk index, Planned RIC Conditioning Regimen, and Planned post-transplant maintenance therapies.p-value: 0.00195% CI: [0.215, 0.691]Regression, Cox
Secondary
Percentage of Participants With Immunosuppression-Free Survival (ISFS) at 1 Year Post-transplant
Participants who are alive, relapse-free, and do not need ongoing immune suppression to control GVHD at one year post-transplant are considered successes for the endpoint immunosuppression-free survival (ISFS). Percentage of participants alive, relapse free, and off immune suppression at 1 year post-transplant were described for each treatment group, along with 95% Clopper-Pearson confidence intervals.
Time frame: 1 year post-transplant
Population: Analysis Population includes transplanted and evaluable participants for ISFS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PTCY/Tacrolimus/MMF | Percentage of Participants With Immunosuppression-Free Survival (ISFS) at 1 Year Post-transplant | 50 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Immunosuppression-Free Survival (ISFS) at 1 Year Post-transplant | 39.7 percentage of participants |
Comparison: The null hypothesis is that there is no difference of Immunosuppression-Free Survival between the treatment groupsp-value: 0.038Chi-squared
Secondary
Percentage of Participants With Lymphocyte Recovery Post-transplant
Lymphocyte recovery is defined as the first day of sustained absolute lymphocyte count greater than or equal to 1000/mm\^3. The competing event is death without lymphocyte recovery. The cumulative incidence estimate of Lymphocyte recovery were described by treatment group with 95% confidence intervals (complementary log-log transformation), treating death as a competing event.
Time frame: Day 60, Day 100, 6 Months, and 1 year post-transplant
Population: Analysis Population includes transplanted participants with lymphocyte recovery data provided.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PTCY/Tacrolimus/MMF | Percentage of Participants With Lymphocyte Recovery Post-transplant | Day 60 post-transplant | 29.6 percentage of participants |
| PTCY/Tacrolimus/MMF | Percentage of Participants With Lymphocyte Recovery Post-transplant | Day 100 post-transplant | 32.5 percentage of participants |
| PTCY/Tacrolimus/MMF | Percentage of Participants With Lymphocyte Recovery Post-transplant | 6 Months post-transplant | 41.5 percentage of participants |
| PTCY/Tacrolimus/MMF | Percentage of Participants With Lymphocyte Recovery Post-transplant | 1 Year post-transplant | 47.1 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Lymphocyte Recovery Post-transplant | 1 Year post-transplant | 63.2 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Lymphocyte Recovery Post-transplant | Day 60 post-transplant | 48.2 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Lymphocyte Recovery Post-transplant | 6 Months post-transplant | 58.3 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Lymphocyte Recovery Post-transplant | Day 100 post-transplant | 52.5 percentage of participants |
Comparison: The null hypothesis is that there is no difference of Lymphocyte Recovery between the treatment groupsp-value: <0.001Gray's test for cumulative Incidence
Secondary
Percentage of Participants With Lymphoproliferative Disease (PTLD) at 1 Year Post-Transplant
The cumulative incidence of lymphoproliferative disease at 1-year post-transplant is described with 95% confidence intervals for each treatment group using the Aalen-Johansen estimator, treating death as a competing event.
Time frame: 1 year Post-Transplant
Population: Analysis Population includes transplanted participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PTCY/Tacrolimus/MMF | Percentage of Participants With Lymphoproliferative Disease (PTLD) at 1 Year Post-Transplant | 0.5 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Lymphoproliferative Disease (PTLD) at 1 Year Post-Transplant | 0 percentage of participants |
Secondary
Percentage of Participants With Neutrophil Recovery Post-transplant
Neutrophil recovery is defined as achieving an absolute neutrophil count (ANC) greater than or equal to 500/mm\^3 for three consecutive measurements on three different days. The first of the three days will be designated the day of neutrophil recovery. The competing event is death without neutrophil recovery. For participants who never drop ANC below 500/mm\^3, the date of neutrophil recovery will be Day +1 post-transplant. The cumulative incidence of neutrophil recovery by Day 28 and Day 100 was described for each treatment group with point estimates and 95% confidence intervals using the complementary log-log transformation and treating death as a competing event.
Time frame: Days 28 and day 100 post-transplant
Population: Analysis Population includes transplanted participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PTCY/Tacrolimus/MMF | Percentage of Participants With Neutrophil Recovery Post-transplant | Day 28 post-transplant | 90.3 percentage of participants |
| PTCY/Tacrolimus/MMF | Percentage of Participants With Neutrophil Recovery Post-transplant | Day 100 post-transplant | 92.7 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Neutrophil Recovery Post-transplant | Day 28 post-transplant | 93.4 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Neutrophil Recovery Post-transplant | Day 100 post-transplant | 97.2 percentage of participants |
Comparison: The null hypothesis is that there is no difference of Neutrophil Recovery between the treatment groupsp-value: 0.032Gray's test for cumulative Incidence
Secondary
Percentage of Participants With Overall Survival (OS) at 1 Year Post-transplant
The event for this endpoint OS is death from any cause post-transplant. Time to overall survival is defined as the time interval between date of transplant and date of death from any cause. Surviving participants will be censored at last follow-up or 1 year post-transplant, whichever comes first. The time from transplant until death from any cause was described graphically for each treatment arm using the Kaplan-Meier estimator, with numbers of subjects at risk at specific time points presented for each treatment group. A multivariate Cox regression model for the hazard of death will be used to compare the treatment groups, after adjustment for baseline characteristics as described for the primary endpoint.
Time frame: 1 year post-transplant
Population: Analysis Population includes transplanted participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PTCY/Tacrolimus/MMF | Percentage of Participants With Overall Survival (OS) at 1 Year Post-transplant | 76.8 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Overall Survival (OS) at 1 Year Post-transplant | 72.6 percentage of participants |
Comparison: This is the unadjusted analysis. The null hypothesis is that there is no difference of Overall Survival between the treatment groupsp-value: 0.335Log Rank
Comparison: This is the result of the Cox proportional hazards analysis. The null hypothesis is that there is no difference of the Overall Survival hazard ratio between treatment groups after adjustment for age group, donor type and HLA Matching Score, disease risk index, Planned RIC Conditioning Regimen, and Planned post-transplant maintenance therapiesp-value: 0.25295% CI: [0.541, 1.175]Regression, Cox
Secondary
Percentage of Participants With Platelet Recovery Post-transplant
Platelet recovery is defined by two different metrics: the first day of a sustained platelet count greater than or equal to 20,000/mm\^3 or greater than or equal to 50,000/mm\^3 with no platelet transfusions in the preceding seven days. The first day of sustained platelet count above these thresholds will be designated the day of platelet engraftment. For participants who never drop their platelet count below 20,000/mm\^3 or 50,000/mm\^3, the date of platelet recovery will be Day +1 post HCT. The competing event is death without platelet recovery. The cumulative incidence estimate of platelet recovery by Day 60 and Day 100 were described by treatment group with 95% confidence intervals (complementary log-log transformation), treating death as a competing event.
Time frame: Day 60 and Day 100 post-transplant
Population: Analysis Population includes transplanted participants with platelet recovery data provided
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PTCY/Tacrolimus/MMF | Percentage of Participants With Platelet Recovery Post-transplant | Day 60 post-transplant of Platelet Recovery to >20k | 88.3 percentage of participants |
| PTCY/Tacrolimus/MMF | Percentage of Participants With Platelet Recovery Post-transplant | Day 100 post-transplant of Platelet Recovery to >20k | 90.3 percentage of participants |
| PTCY/Tacrolimus/MMF | Percentage of Participants With Platelet Recovery Post-transplant | Day 60 post-transplant of Platelet Recovery to >50k | 77.6 percentage of participants |
| PTCY/Tacrolimus/MMF | Percentage of Participants With Platelet Recovery Post-transplant | Day 100 post-transplant of Platelet Recovery to >50k | 79.5 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Platelet Recovery Post-transplant | Day 100 post-transplant of Platelet Recovery to >50k | 83.7 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Platelet Recovery Post-transplant | Day 60 post-transplant of Platelet Recovery to >20k | 91.8 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Platelet Recovery Post-transplant | Day 60 post-transplant of Platelet Recovery to >50k | 82.7 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Platelet Recovery Post-transplant | Day 100 post-transplant of Platelet Recovery to >20k | 92.8 percentage of participants |
Comparison: The null hypothesis is that there is no difference of Platelet Recovery greater than or equal to 20,000/mm\^3 between the treatment groupsp-value: <0.001Gray's test for cumulative Incidence
Comparison: The null hypothesis is that there is no difference of Platelet Recovery greater than or equal to 50,000/mm\^3 between the treatment groupsp-value: <0.001Gray's test for cumulative Incidence
Secondary
Percentage of Participants With Treatment-related Mortality (TRM) Post-transplant
An event for this endpoint TRM is death without evidence of disease progression or recurrence. Disease progression or recurrence will be considered a competing event. The time from transplant until TRM, or cumulative incidence, estimated at specific time points along with 95% CIs computed using the complementary log-log transformation, treating relapse/progression of the primary disease as a competing risk. A multivariate Cox regression model for the cause-specific hazard of TRM was used to compare the treatment groups, after adjustment for baseline characteristics as described for the primary endpoint.
Time frame: Days 100, 180 and 1 year post-transplant
Population: Analysis Population includes transplanted participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PTCY/Tacrolimus/MMF | Percentage of Participants With Treatment-related Mortality (TRM) Post-transplant | Day 100 post-transplant | 6.8 percentage of participants |
| PTCY/Tacrolimus/MMF | Percentage of Participants With Treatment-related Mortality (TRM) Post-transplant | Day 180 post-transplant | 8.8 percentage of participants |
| PTCY/Tacrolimus/MMF | Percentage of Participants With Treatment-related Mortality (TRM) Post-transplant | 12 Months post-transplant | 12.3 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Treatment-related Mortality (TRM) Post-transplant | Day 100 post-transplant | 7.6 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Treatment-related Mortality (TRM) Post-transplant | Day 180 post-transplant | 13.3 percentage of participants |
| Tacrolimus/Methotrexate | Percentage of Participants With Treatment-related Mortality (TRM) Post-transplant | 12 Months post-transplant | 17.2 percentage of participants |
Comparison: This is the unadjusted analysis. The null hypothesis is that there is no difference of Treatment-related Mortality between the treatment groupsp-value: 0.167Gray's test for cumulative Incidence
Comparison: This is the result of the Cox proportional hazards analysis. The null hypothesis is that there is no difference of Treatment-related Mortality hazard ratio between treatment groups after adjustment for age group, donor type and HLA Matching Score, disease risk index, Planned RIC Conditioning Regimen, and Planned post-transplant maintenance therapiesp-value: 0.13395% CI: [0.404, 1.127]Regression, Cox
Secondary
Summary Statistics for Donor Chimerism
Donor cell engraftment were assessed with donor/recipient chimerism studies. Mixed chimerism is defined as the presence of donor cells, as a percentage of total cells to be less than 95% but at least 5% in the bone marrow or peripheral blood. Full donor chimerism is defined as greater than or equal to 95% of donor cells. Mixed and full chimerism will be evidence of donor cell engraftment. Donor cells of less than 5% will be considered as graft rejection. Donor chimerism at Day 28 and Day 100 after transplant in each of the randomized treatment arms will be described numerically as median and range for those evaluable.
Time frame: Day 28 and Day 100 post-transplant
Population: Analysis Population includes transplanted participants who submitted post-transplant assessments.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| PTCY/Tacrolimus/MMF | Summary Statistics for Donor Chimerism | Day 28 post-transplant | 100 percentage of donor cells |
| PTCY/Tacrolimus/MMF | Summary Statistics for Donor Chimerism | Day 100 post-transplant | 99 percentage of donor cells |
| Tacrolimus/Methotrexate | Summary Statistics for Donor Chimerism | Day 28 post-transplant | 100 percentage of donor cells |
| Tacrolimus/Methotrexate | Summary Statistics for Donor Chimerism | Day 100 post-transplant | 99 percentage of donor cells |
Comparison: The null hypothesis is that there is no difference of quantitative donor chimerism at Day 28 after transplantation between the treatment groupsp-value: 0.67Wilcoxon (Mann-Whitney)
Comparison: The null hypothesis is that there is no difference of quantitative donor chimerism at Day 100 after transplantation between the treatment groupsp-value: 0.607Wilcoxon (Mann-Whitney)