Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease

Abstract

Key Points• We report that ruxolitinib reduces murine GVHD via increased Treg numbers.• We demonstrate the potent activity of ruxolitinib treatment in patients with corticosteroidrefractory GVHD.Graft-versus-host-disease (GVHD) is a severe complication of allogeneic hematopoietic cell transplantation (allo-HCT) characterized by the production of high levels of proinflammatory cytokines. Activated Janus kinases (JAKs) are required for T-effector cell responses in different inflammatory diseases, and their blockade could potently reduce acute GVHD. We observed that inhibition of JAK1/2 signaling resulted in reduced proliferation of effector T cells and suppression of proinflammatory cytokine production in response to alloantigen in mice. In vivo JAK 1/2 inhibition improved survival of mice developing acute GVHD and reduced histopathological GVHD grading, serum levels of proinflammatory cytokines, and expansion of alloreactive luc-transgenic T cells. Mechanistically, we could show that ruxolitinib impaired differentiation of CD4 1 T cells into IFN-g-and IL17A-producing cells, and that both T-cell phenotypes are linked to GVHD. Conversely, ruxolitinib treatment in allo-HCT recipients increased FoxP3 1 regulatory T cells, which are linked to immunologic tolerance. Based on these results, we treated 6 patients with steroid-refractory GVHD with ruxolitinib. All patients responded with respect to clinical GVHD symptoms and serum levels of proinflammatory cytokines. In summary, ruxolitinib represents a novel targeted approach in GVHD by suppression of proinflammatory signaling that mediates tissue damage and by promotion of tolerogenic Treg cells. (Blood. 2014;123(24):3832-3842)

Ruxolitinib for treatment of refractory hemophagocytic lymphohistiocytosis

“…Recent data support the efficacy of ruxolitinib in reducing the symptoms of proinflammatory diseases including rheumatoid arthritis, ulcerative colitis, myeloproliferative disorders, psoriasis, and graft-versus-host disease. 6,7,[15][16][17][18][19][20][21][22] In murine models, ruxolitinib has been shown to both prevent and treat HLH by decreasing cytokine production and inflammation via inhibition of STAT1 signaling. 4,5 There is an active trial using ruxolitinib in adults with secondary HLH, but there have been no reports of pediatric patients who have received ruxolitinib for the treatment of HLH.…”

Allo-SCT for myelofibrosis: reversing the chronic phase in the JAK inhibitor era?

“…50 Conversely, JAK inhibitors appear to reduce acute GVHD in murine models by increasing T-regulatory cells, which has led to the successful treatment of six patients with ruxolitinib for steroidrefractory acute GVHD. 51 Another JAK inhibitor, tofacitinib, a selective JAK3 inhibitor, has been found to reverse CD8 + T-cellmediated mucocutaneous GVHD-like disease in a murine model. 52 IMPACT OF TARGETING THE EPIGENOME Studies on the remarkable complexity of genetic architecture in MPNs have discovered an unexpected degree of differences in individual cases at the epigenetic level.…”

Allogeneic transplantation of hematopoietic stem cells: Perspectives and alternatives, own experience

“…Руксолитиниб также вызыва-ет супрессию многих провоспалительных цитокинов + Т-клеток через сигнальный путь STAT и по-вышает количество FoxP3 + Tregs, что также уменьшает клинические проявления РТПХ [80,81]. В Санкт-Пе-тербурге проводится клиническое исследование со-вместной эффективности руксолитиниба и ПТЦ для профилактики РТПХ при алло-ТГСК у больных миелофиброзом (NCT02806375) [82].…”