The Adverse Event Landscape of Stem Cell Transplant: Evidence for AGVHD Driving Early Transplant Associated Toxicities

Background Although unrelated-donor (URD) hematopoietic cell transplantation (HCT) is associated with many toxicities, a detailed analysis of adverse events, as defined by the Common Terminology Criteria for Adverse Events (CTCAE), has not previously been curated. This represents a major unmet need, especially as it relates to assessing the safety of novel agents. Methods We analyzed a detailed AE database from the ‘ABA2’ randomized, double-blind, placebo-controlled clinical trial of abatacept for acute graft-versus-host disease (AGVHD) prevention, for which the FDA mandated a detailed AE assessment through Day+180, and weekly neutrophil and platelet counts through Day+100. These were analyzed for their relationship to key transplant outcomes, with a major focus on the impact of AGVHD on the development/severity of AEs. Results A total of 2102 AEs and 1816 neutrophil/platelet counts were analyzed from 142 8/8-HLA-matched URD HCT recipients on ABA2 (placebo cohort, n=69, abatacept cohort, n=73). This analysis resulted in two major observations. (1) Amongst graft source, conditioning intensity, age, and Grade 2-4 AGVHD, only AGVHD impacted Grade 3-5 AE acquisition after the first month post-transplant. (2) The development of Grade 3-4 AGVHD was associated with thrombocytopenia. Conclusions We have created a detailed resource for the transplant community by which to contextualize clinical toxicities after transplant. It has identified AGVHD as a major driver of post-HCT Grade 3-5 AEs, and underscored a link between AGVHD and thrombocytopenia. This establishes a critical safety framework upon which the impact of novel post-transplant AGVHD therapeutics should be evaluated. This trial was registered at www.clinicaltrials.gov (#NCT01743131).