Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and non-relapse mortality following allogeneic hematopoietic cell transplantation. The clinical staging of GVHD varies greatly between transplant centers and is frequently not agreed upon by independent reviewers. The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multi-center clinical trials. We developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in a large international GVHD research consortium. During the first year of use, the guidance was following discussion of complex clinical phenotypes by experienced transplant physicians and data managers. These guidelines increase the uniformity of GVHD symptom capture which may improve the reproducibility of GVHD clinical trials after further prospective validation.

Despite major improvements in allogeneic hematopoietic cell transplantation over the last decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Pre-clinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage-therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grade III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1–7) and SR-cGVHD (1–10). The ORR was 81.5% (44/54) in SR-aGVHD including 25 CRs (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3%–90.7%,95% CI) and 97.4% (92.3%–100%,95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and CMV-reactivation were observed during ruxolitinib-treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.

The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275.).

Hematotoxicity represents a frequent chimeric antigen receptor (CAR) T-cell related adverse event and remains poorly understood. In this multicenter analysis, we studied patterns of hematopoietic reconstitution and evaluated potential predictive markers in 258 patients receiving Axicabtagene ciloleucel (Axi-cel) or Tisagenlecleucel (Tisa-cel) for relapsed/refractory large B-cell lymphoma. We observed profound (ANC<100/µl) and prolonged (≥day 21) neutropenia in 72 and 64% of patients respectively. The median duration of severe neutropenia (ANC<500/µl) was 9 days. We aimed to identify predictive biomarkers of hematotoxicity using the duration of severe neutropenia until day +60 as the primary endpoint. In the training cohort (n=58), we observed a significant correlation with baseline thrombocytopenia (r= -0.43, P=0.001) and hyperferritinemia (r=0.54, P<0.0001) on uni- and multivariate analysis. Incidence and severity of CRS, ICANS and peak cytokine levels were not associated with the primary endpoint. We calculated the CAR-HEMATOTOX model, which included markers associated with hematopoietic reserve (e.g. platelet count, hemoglobin and ANC) and baseline inflammation (e.g. C-reactive-protein, ferritin). This model was validated in two independent cohorts from Europe (n=91) and the USA (n=109), and discriminated patients with severe neutropenia ≥/<14 days (pooled validation: AUC=0.89, Sensitivity 89%, Specificity 68%). A high CAR-HEMATOTOX score resulted in a longer duration of neutropenia (12 vs. 5.5 days, P<0.001), and a higher incidence of severe thrombocytopenia (87% vs. 34%, P<0.001) and anemia (96% vs. 40%, P<0.001). The score implicates pre-CART bone marrow reserve and inflammatory state as key features associated with delayed cytopenia and will be useful for risk-adapted management of hematotoxicity.