NIH Chronic GVHD Study Group

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Over recent years we made substantial contributions to the world literature in providing the first descriptions of specific, rare and most severe chronic GVHD manifestations or medical complications. This robust publication output has continued over last year. The studies of biology included peripheral blood and target tissues research biopsies (skin, oral mucosa) which is a unique characteristics of this program. This study protocol enrolled more than 450 well characterized chronic GVHD patients with 90% of them referred from across the US and some internationally (Europe). These years long efforts of this program resulted in August of 2017 with the first in history FDA approval of an agent with an indication for chronic GVHD, which pivotal trial used the NIH response criteria developed here, as the primary endpoint. Our team specifically contributed to the planning and implementation of the belumosudil pivotal clinical trial which led to the FDA approval for refractory chronic GVHD in summer of 2021. Our ongoing program development strategies are focusing on expanding multi-center trial collaborations in developing reliable biomarkers and novel therapies for chronic GVHD. The current cross-sectional natural history study of chronic GVHD will continue to be a continuous source of publications and a backbone of the NIH chronic GVHD study group. In a collaborative effort, we have proposed a new model of chronic GVHD pathogenesis, whereby interferon (IFN)-mediated processes drive expansion and differentiation of T-effectors and their emigration into tissues. In collaboration with colleagues from the NIDCR laboratory (Dr. Jackie Mays) we conducted a pilot study of the salivary proteomics profile in chronic GVHD to identify disease biomarkers and study the salivary environment and biopsies in the larger cohort of chronic GVHD patients. Future studies will focus on the utilization of high sensitivity assays to develop chronic GVHD cytokine biomarkers and the genomic techniques to determine the biological patterns and clinical phenotypes using the natural history study patient samples. We recently completed accrual to three in-house prospective therapy studies and the date are being analyzed: a) prevention of chronic GVHD (unrelated donor transplant protocol) phase 1 study using dose escalation of KGF, b) treatment of steroid refractory chronic GVHD with pomalidomide, and c) treatment of refractory oral chronic GVHD (clobetasol rinses). The key goal of this program is to develop new and safer molecularly targeted therapies which will allow us to depart from current toxic drugs such as steroids or calcineurin inhibitors and allow more specific interference in the disease process and to develop better salvage treatments. This approach will also allow entry of new pharmacological immunomodulators in the clinical allogeneic transplantation in general by defining initial safety, PK, PD and dosing properties. Two NCI phase 2 investigator initiated studies are in advanced stages of enrolling patients - alvelestat (MPH966) neutrophil elastase inhibitor for lung chronic GVHD (Mereo CTA) and the baricitinib (Lilly), JAK 1-2 inhibitor. We are currently opening several new clinical trials exploring novel and less toxic agents: Pacritinib (CTI) a JAK 2 inhibitor with also potent anti-malignancy effects; planned as a small multicenter study coordinated by our group. KD025 a randomized multi-center phase 2 study of a ROCK2 inhibitor. The front line pilot targeting B-cell and T-cell signaling pathways by ibrutinib before steroids is also in the process of enrolling. To better understand nature of immune dysregulation in chronic GVHD and after allotransplant in general, over last year we stared robustly enrolling on to a long term follow-up longitudinal protocol which by now accrued more than 40 patients in a 12 month period. We are also seeking broader new collaborations across the intramural NIH programs to address in a translational way, future challenges in the field of cellular and other immunotherapies for hematologic malignancies. In July 2018 Dr Pavletic spearheaded the first ASH summit on emerging new immunotherapies held in Washington DC. Our contributions to national and international collaborations and initiatives in chronic GVHD will continue. During 2019 Dr Noa Holtzman joined the program as a major contributor and staff clinician. We also initiated the 3rd NIH 2020 Consensus project aiming and developing fundamentally new strategies to research and combat chronic GVHD which sic papers have been published in 2021.