Association of Rabbit Anti-Thymocyte (rATG) Exposure and Outcomes after Hematopoietic Cell Transplantation for Malignant Indications: Ancillary Analysis from BMT CTN 1202

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Background Rabbit Anti-thymocyte globulin (rATG) is used to prevent graft rejection and graft versus host disease (GVHD) in hematopoietic cell transplantation (HCT). Weight (<40kg) and pre-ATG absolute lymphocyte count (ALC) are predictors of rATG pharmacokinetics (PK). Weight-based dosing leads highly variable rATG exposures and impacts outcomes. Objective To determine whether simulated estimated post-HCT rATG exposure associates with outcomes after T-replete HCT. Methods We estimated post-HCT rATG exposures as area under the curve (arbitrary unit per day/milliliter [AUxday/mL]) by using a validated population PK model for patients enrolled on BMT CTN 1202 and who received unmanipulated bone marrow or peripheral blood stem cell HCT for a malignant indication. Results were compared to a control group that did not receive ATG. Previously defined post-HCT rATG exposure groups: A: <30, B: 30-55 and C: ≥55 AUxday/mL were correlated with outcomes of interest: overall survival (OS), CD4+immune reconstitution (CD4+IR) defined as CD4 + >50/uL by Day+100, transplant-related mortality (TRM), acute GVHD 2-4, chronic GVHD (cGVHD), and relapse. Cox proportional hazard and cause-specific hazards models adjusted on clinical factors were used to assess previously defined AUC groups while splines and maximally selected log-rank statistics were used to search for new thresholds. Results 325 patients (median age 51 years; myeloablative conditioning 60%) were included: 228 received rATG and 97 did not. Median post-HCT rATG exposure was 44.1 (range 6.15-125). Five-year OS declined with increasing post-HCT rATG (group A: 67%; B: 49%; C:34%, p=0.007; no ATG OS was 51% (Figure 1). Higher rATG exposure also correlated with increasing 5-year relapse rate (A: 27%; B: 42%; C: 58%, p<0.001) and a lower rate of CD4 + IR (A: 73%; B: 51%; C: 19%, p=0.003). For context, no ATG relapse rate was 31% and CD4 + IR was 64%. A new, lower threshold for rATG (≤23) was identified by maximal log-rank difference and stratified patients for GVHD leukemia free survival (GLFS) into two distinct risk groups (GLFS: 50% vs 15%, corresponding HR 0.41 [95% CI: 0.21, 0.84]; p=0.008). GLFS was 16% in the no ATG group. rATG exposure (any threshold) was associated with less extensive cGVHD in patients receiving rATG [HR: 0.63 (95% CI: 0.42, 0.94), p=0.025)]. Conclusions Low post-HCT rATG exposure correlates with higher OS, lower relapse, and higher GLFS compared to higher exposure and no ATG. The optimal post-HCT exposure needs to be determined, but both low thresholds (≤23 and <30) created favorable risk strata. Model-based dosing could be used to target low post-HCT rATG exposure but needs to be validated prospectively.

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