https://orcid.org/0000-0001-6825-9340
Key Points
The predictive performance of refined response was superior to the conventional criteria in both primary and second-line treatment settings.
Refined response was externally validated and remained consistent despite differences in patient characteristics and second-line therapy.
Overall response (OR) that combines complete (CR) and partial responses (PR) at day (D) 28 is the conventional endpoint for acute GVHD trials. Since PR includes heterogeneous clinical presentations, reclassifying PR could produce a better endpoint. Patients in the primary treatment cohort from JSTCT were randomly divided into training and validation sets. In the training set, a classification and regression tree algorithm generated D28 refined response (RR) criteria based on symptoms at treatment and D28. We then compared RR for primary and second-line treatments to conventional criteria, using the area under the receiver operating curve (AUC) and negative predictive value (NPV) for 6-month non-relapse mortality as performance measures. RR considered patients with grade 0/I at D28 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<0.001; NPV: 92.0% vs. 89.6%, P<0.001) and MAGIC (AUC: 0.71 vs. 0.68, P=0.032; NPV: 90.9% vs. 89.8%, P=0.009). 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=0.775; NPV: 74.5% vs. 66.0%, P<0.001) and MAGIC (AUC: 0.67 vs. 0.64, P=0.105; NPV: 86.8% vs. 76.1%, P=0.004). Classifying persistent, but mild skin symptoms as responses and residual lower GI GVHD as non-responses were major drivers in improving the prognostic performance of RR. Our externally validated D28 RR would serve as a better endpoint than conventional criteria in future first- and second-line treatment trials.
