TAC/MTX vs. TAC/MMF/PTCY for Prevention of Graft-versus-Host Disease and Microbiome and Immune Reconstitution Study (BMT CTN 1703/1801)

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.

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.

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

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 (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.

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.

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 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.