Treatment of Corticosteroid-Refractory Graft-Versus-Host Disease with Ruxolitinib in 95 Patients
Authors: Zeiser Robert , Burchert Andreas , Lengerke Claudia , Verbeek Mareike , Maas-Bauer Kristina , Metzelder Stephan , Spoerl Silvia , Ditschkowski Markus , Ecsedi Matyas , Sockel Katja , Ayuk Francis , Ajib Salem , Sicre de Fontbrune Flore , Na Il-Kang , Penter Livius , Holtick Udo , Wolf Dominik , Schuler Esther , Meyer Everett , Apostolova Petya , Bertz Hartmut , Marks Reinhard , Luebbert Michael , Waesch Ralph M. , Scheid Christof , Stölzel Friedrich , Ordemann Rainer , Bug Gesine , Kobbe Guido , Negrin Robert , Brune Mats L , Spyridonidis Alexandros , Schmitt-Graeff Annette , Velden Walter van der , Huls Gerwin , Mielke Stephan , Grigoleit Goetz Ulrich , Kuball Jurgen , Flynn Ryan P , Ihorst Gabriele , Du Jing , Blazar Bruce R. , Arnold Renate , Kröger Nicolaus , Halter Joerg , Socie Gerard , Beelen Dietrich , Peschel Christian , Neubauer Andreas , Finke Juergen , Duyster Justus , von Bubnoff Nikolas 
Published: October 2019

Abstract
Background: Allogeneic hematopoietic cell transplantation is a potentially curative therapy for patients with hematological malignancies. However a fraction of patients will develop corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) which both cause a high mortality and impaired quality of life. Pre-clinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib by modification of T cells and dendritic cells.
Methods: In this retrospective analysis, 19 stem cell transplant centers in Europe and the United States reported clinical 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 median follow-up times were 26.5 (3-106) for SR-aGVHD and 22.4 (3-135) weeks for SR-cGVHD-patients.
Results: 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). The median time to response was 1.5 (1-11) and 3 (1-25) weeks after initiation of ruxolitinib treatment in SR-aGVHD and SR-cGVHD, respectively. 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. Relapse of the underlying malignancy occurred in 9.3% (5/54) and 2.4% (1/41) of the patients with SR-aGVHD or SR-cGVHD, respectively.
Conclusion: Ruxolitinib constitutes a promising new treatment option for SR-aGVHD and SR-cGVHD. Its activity in SR-aGVHD and SR-cGVHD should be validated in a prospective trials in both, SR-aGvHD and cGvHD.

Disclosures
Bertz: GILEAD Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Scheid:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bug:TEVA Oncology, Astellas: Other: Travel Grant; NordMedica, Boehringer Ingelheim, Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene, Novartis: Research Funding.