Nakasone, Hideki

Abstract Overall response (OR) that combines complete (CR) and partial responses (PR) is the conventional end point for acute graft-versus-host disease (GVHD) trials. Because PR includes heterogeneous clinical presentations, reclassifying PR could produce a better end point. Patients in the primary treatment cohort from the Japanese Society for Transplantation and Cellular Therapy (JSTCT) were randomly divided into training and validation sets. In the training set, a classification and regression tree algorithm generated day 28 refined response (RR) criteria based on symptoms at treatment and day 28. We then evaluated RR for primary and second-line treatments, using the area under the receiver operating characteristic curve (AUC) and negative predictive value (NPV) for 6-month nonrelapse mortality as performance measures. RR considered patients with grade 0/1 at day 28 without additional treatment as responders. RR for primary treatment produced higher AUCs than OR with small improvement of NPVs in both validation sets: JSTCT (AUC, 0.73 vs 0.69 [P < .001]; NPV, 92.0% vs 89.6% [P < .001]) and the Mount Sinai Acute GVHD International Consortium (MAGIC; AUC, 0.71 vs 0.68 [P = .032]; NPV, 90.9% vs 89.8% [P = .009]). RR for second-line treatment produced similar AUCs but much higher NPVs than OR in both validation sets of JSTCT (AUC, 0.64 vs 0.63 [P = .775]; NPV, 74.5% vs 66.0% [P < .001]) and MAGIC (AUC, 0.67 vs 0.64 [P = .105]; NPV, 86.8% vs 76.1% [P = .004]). Classifying persistent but mild skin symptoms as responses and residual lower gastrointestinal GVHD as nonresponses were major drivers in improving the prognostic performance of RR. Our externally validated day 28 RR would serve as a better end point than conventional criteria in future first- and second-line treatment trials.

Background Endpoints for GVHD treatment trials use early response (i.e, day (D)28 of treatment) as a surrogate for long term survival. Overall response (OR) that combines complete (CR) and partial responses (PR) at day (D) 28 is the conventional endpoint for primary acute GVHD trials because of similar survival outcomes between CR and PR. D28 OR ignores symptom severity at baseline and D28, however, and the PR category encompasses a wide range of responses from minimal improvement to near complete resolution of symptoms. D28 OR is the only endpoint currently approved by the FDA for efficacy, but it has not been re-evaluated as an endpoint for primary treatment (1L) in fifteen years and little is known regarding the prognostic value of D28 OR as an endpoint for second line treatment (2L) of GVHD. We hypothesized that refinement of the current D28 OR criteria, particularly through recategorization of PR in the GI tract, the main driver of nonrelapse mortality (NRM), would more accurately reflect disease control and better predict survival outcomes than current D28 response. Methods The Japanese Society for Transplantation and Cellular Therapy (JSTCT) collaborated with the Mount Sinai Acute GVHD International Consortium (MAGIC) to develop and validate D28 refined response (RR) criteria for 1L and 2L treatment (tx) in patients with Grades II-IV acute GVHD. To maximize the correlation between treatment success (i.e, response) with long term survival, our primary measured metric was the negative predictive value (NPV). We first randomly divided the 1L tx cohort of JSTCT into the training (n=2341) and validation sets (n=1156). In the training set we used a classification and regression tree (CART) algorithm to generate RR criteria that predicted 6-month (mo) NRM based on symptoms both at tx onset and D28. We then compared the two D28 response endpoints (RR vs OR) as surrogates for 6-mo NRM in two validation sets of both 1L tx (JSTCT: n=1156; MAGIC: n=1141) and 2L tx (JSTCT: n=510; MAGIC: n=196). Results The CART algorithm defined a RR as GVHD Grades 0/I at D28 without additional tx; all other D28 grades were considered refined nonresponses. As expected, RR successfully stratified the risk of 6-mo NRM in both 1L tx validation sets (JSTCT: 8% vs 38%, p<0.01; MAGIC: 9% vs 37%, p<0.01). We defined a discordant nonresponse as a nonresponse by RR criteria but a response by OR criteria, which accounted for the majority (~75%) of differences between RR and OR. 6-mo NRM in discordant nonresponders was four fold higher than in responders (JSTCT: 35%; MAGIC: 30%). The large majority (>80%) of discordant nonresponders had persistent GI GVHD at D28. Because the proportion of discordant nonresponders was small (<7% of the total population) in the 1L setting, the improvements of an already high NPV were small (JSTCT: 93% vs 91%; MAGIC: 91% vs 90%). In the 2L tx validation sets, RR also stratified the risk of 6-mo NRM (JSTCT: 26% vs 56%, p<0.01; MAGIC: 13% vs 55%, p<0.01). At the time of 2L tx, the discordant nonresponders are more common and half of the discordant nonresponders experienced 6-mo NRM (JSTCT: 45%; MAGIC: 59%); as a result, RR achieved much higher NPVs than OR (JSTCT: 75% vs 66%; MAGIC: 87% vs 76%). Deaths in responders from acute GVHD (vs. other causes such as infection) were more frequent in OR than RR in both 2L tx validation sets (JSTCT: 41% vs 20%; MAGIC: 41% vs 13%) and 1L tx validation sets (JSTCT: 25% vs 18%; MAGIC: 32% vs 29%). D28 RR is superior to OR because it more accurately reflects control of serious GVHD in four independent validation cohorts, particularly in patients with GI disease. Conclusion We conclude that RR is a more accurate endpoint than OR in patients with grade II-IV GVHD primarily because it classifies persistent GI GVHD at D28 as a non-response instead of a response, which correlates with 6-mo NRM and achieves a higher NPV. This validated RR metric can serve as a better endpoint than OR in assessing treatment efficacy in both primary treatment trials that enrich for high risk GVHD, e.g. GI involvement, and second line treatment trials.

Key Points Compared with parous female sibling donors, male URDs confer more aGVHD in all patients and more cGVHD in females. There was no difference in survival, relapse, or transplant mortality between recipients of parous female sibling or male URD grafts.