Abstract 2591: Ibrutinib can reverse established chronic graft-versus-host disease, which is dependent upon IL-2 inducible T-cell kinase (ITK) and Bruton's tyrosine kinase (BTK)-driven lymphocyte activation
Authors: Dubovsky Jason A. , Flynn Ryan , Du Jing , Harrington Bonnie K. , Zhong Yiming , Yang Carrie , Towns William , Lehman Amy , Johnson Amy , Devine Steven , Jaglowski Samantha , Serody Jonathan S. , Murphy William J. , Munn David H. , Luznik Leo , Hill Geoffrey , MacDonald Kelli K.P. , Maillard Ivan , Koreth John , Cutler Corey , Soiffer Robert J. , Antin Joseph H. , Ritz Jerome , Panoskaltsis-Mortari Angela , Byrd John C. , Blazar Bruce R. 
Published: May 2015

Chronic graft versus host disease (cGVHD) is a life threatening impediment to the otherwise curative potential of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Intensive study has unveiled the lymphoid subsets that drive multifaceted autoimmune and fibrotic cascades which disrupt healthy tissues. Clinical and in-vivo data implicate B-cells and certain subsets of CD4 helper T-cells in the development and progression of cGVHD. These specific immune subsets are unique in their singular dependence upon the TEC-family kinases BTK or ITK for receptor driven activation. Ibrutinib is an irreversible inhibitor of BTK and ITK that has produced durable remissions in B-cell malignancies with minimal toxicity. We sought to examine ibrutinib's potential to attenuate B-cell and CD4 T-cell driven anti-host immunity in the setting of cGVHD. We utilized two complementary murine models independently focused on interrogating sclerodermatous T-cell driven cGVHD (LPJ→C57BL/6) or alloantibody driven bronchiolar obliterans (BO) and multi-organ system disease without skin involvement (C57BL/6→B10.BR). We examined therapeutic administration of 25mg/kg/day ibrutinib initiated when mice first develop signs of cGVHD (25-28 days after allo-HSCT). In the minor-MHC mismatch LPJ→C57BL/6 model, ibrutinib significantly extended median time to cGVHD progression by 14 days and 33% (6 of 18) of ibrutinib treated mice remained progression free as compared to 12% (2 of 18) of mice receiving vehicle and 10% (1 of 11) of mice receiving cyclosporine 10mg/kg/day (p&lt;0.02). Overall survival was also highest in the ibrutinib treatment cohort. Mice receiving ibrutinib showed restoration of external cGVHD criterion including body weight, posture, skin lesions, hair loss, and mobility. There was significant ablation of lymphohistiocytic T- and B-cell pulmonary and renal infiltration in ibrutinib treated animals. Data from the C57BL/6→B10.BR model confirmed the efficacy of ibrutinib in significantly restoring pulmonary compliance, elastance, and resistance to levels indistinguishable from that of a healthy animal and significantly better than cGVHD vehicle treated controls (n=12/group)(p&lt;0.01). These results were associated with significantly decreased alloantibody deposition and decreased fibrosis in the lungs of ibrutinib treated mice. Germinal center (GC) reactions, required for multi-organ system pathology in this model, were also significantly reduced within the spleens of mice receiving therapeutic ibrutinib (p&lt;0.05). Using in-vivo genetic ablation models, we demonstrate the critical nature of BTK and ITK respectively in the development of cGVHD pathognomonic BO. Our data support ibrutinib as a promising therapeutic direction for the treatment of cGVHD by virtue of its ability to suppress BTK and ITK signaling.

Citation Format: Jason A. Dubovsky, Ryan Flynn, Jing Du, Bonnie K. Harrington, Yiming Zhong, Carrie Yang, William Towns, Amy Lehman, Amy Johnson, Steven Devine, Samantha Jaglowski, Jonathan S. Serody, William J. Murphy, David H. Munn, Leo Luznik, Geoffrey Hill, Kelli K.P. MacDonald, Ivan Maillard, John Koreth, Corey Cutler, Robert J. Soiffer, Joseph H. Antin, Jerome Ritz, Angela Panoskaltsis-Mortari, John C. Byrd, Bruce R. Blazar. Ibrutinib can reverse established chronic graft-versus-host disease, which is dependent upon IL-2 inducible T-cell kinase (ITK) and Bruton's tyrosine kinase (BTK)-driven lymphocyte activation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2591. doi:10.1158/1538-7445.AM2014-2591