Long Term Outcomes of a Randomized Trial of Anti-T Lymphocyte Globulin to Improve Moderate-Severe Chronic Gvhd Free Survival after Unrelated Donor Hematopoietic Cell Transplantation: A CIBMTR Analysis

Background: Results from randomized trials suggest that prophylaxis with anti-T lymphocyte globulin (ATLG) decreased the incidence of chronic graft-versus-host disease (cGVHD) without adversely impacting progression-free (PFS) or overall survival (OS). However, one prospective double blind randomized trial (NCT01295710) in adult recipients of a myeloablative 8/8 HLA matched unrelated donor grafts for acute leukemia or myelodysplastic syndromes who received ATLG with standard GVHD prophylaxis (tacrolimus and methotrexate), that was performed predominantly in the United States, had differing results. Despite significant reductions in grades 2-4 acute and chronic GVHD, there was inferior PFS and OS at 2 years in ATLG recipients. Moderate to severe cGVHD free survival was similar between study arms. The overall aim of this study was to determine the long-term clinical outcomes of patients treated on this trial based on data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).

Methods: CIBMTR contacted US clinical trial centers, and, for those centers agreeing to participate, requested the patient CIBMTR Research ID, drug received (placebo or ATLG), and date of diagnosis of moderate-to-severe cGVHD. Fisher’s exact test was used to compare categorical variables, Kruskal-Wallis for the continuous variable (age), Kaplan-Meier method for survival estimates, and the log-rank test for group comparisons of survival distributions and point estimates. Multivariate analyses were performed using the Cox proportional hazards model with ATLG as the main effect. The threshold for clinical significance was set at .05.

Results: The study population comprised 217 (85.4%) of the 254 initially randomized clinical trial patients, including 108/128 (84.3%) in the placebo arm and 109/126 (86.5%) in the ATLG arm. Median follow-up was 98.8 months (range 27.7-125.6) in the placebo cohort and 97.9 months (range 16.1-125.3) in the ATLG cohort. As in the clinical trial, there were no differences in baseline characteristics between groups except for more males in the placebo group (65.7% vs 46.8%, P = .0061). 93% of patients in both groups identified as White. 4.6% and 3.7% identified as Hispanic in the placebo and ATLG cohorts, respectively. Univariate analysis revealed the probability of moderate-to-severe-cGVHD–free survival was similar between the groups (P = .421) The 2-year probabilities were 41.1% (95% CI, 31.9-50.6) in the placebo group and 46.1% (95% CI, 36.8-55.6) in the ATLG group. The probabilities decreased in both groups over time, being 24.5% (95% CI, 16.4-33.6) at 7 yrs in the placebo group and 33.3% (95% CI, 24.5-42.8) at 7 yrs in the ATLG group (P = .173). There was no difference between the groups at any time point. At 7 yrs after transplant, the probability of OS was similar between the placebo and ATLG groups (P = .290). OS at 2 yrs after transplant was 70.4% (95% CI, 61.4-78.6) in the placebo group and 60.5% (95% CI, 51.2-69.4) in the ATLG group. The probabilities decreased in both groups over time, being 50.4% (95% CI, 40.8-60.0) at 7 yrs in the placebo group and 46.6% (95% CI, 37.1-56.2) at 7 yrs in the ATLG group (P =.584). There was no difference between the groups at any time point. The probability of PFS was similar between the placebo and ATLG groups (P = .146) While PFS at 2 and 3 yrs after transplant was inferior in the ATLG group (P = .010), by 7 yrs the probability of PFS was 44.8% (95% CI, 35.3-54.5) in the placebo group, and 40% (95% CI, 30.9-49.3) in the ATLG group. Disease recurrence was the most common cause of death, 49.2% in the ATLG group and 36.2% in the placebo group. GVHD accounted for 3.2% of deaths in the ATLG group and 12.1% of deaths in the placebo group. In multivariate analysis, prophylaxis with ATLG did not impact moderate-to-severe cGVHD–free survival. (HR 0.644, 95% CI, 0.644-1.242; P = .5068), OS (HR 1.235, 95% CI, 0.857-1.781); P =.2573) or PFS (HR 1.386, 95% CI, 0.974-1.972); P = .07).

Conclusions: This study conducted by the CIBMTR extends the findings of the phase 3 randomized trial clinical trial previously reported. As in the clinical trial, no significant difference was found in moderate to severe cGVHD free survival between the placebo and ATLG groups up to 7 years. In contrast to the clinical trial in which OS and PFS were lower in the ATLG group at 2 years, we found no significant long term differences in OS and PFS up to 7 years after transplant.