aGvHD,   cGvHD

EHA 2018 | JAK inhibition in steroid–refractory GvHD

Approximately 50% of patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) develop graft-versus-host disease (GvHD), a severe complication which leads to inferior nonrelapse mortality. The current standard for first-line therapy of GvHD are corticosteroids, nevertheless, 50–60% of these patients develop steroid-refractory GvHD (SR-GvHD) later on. Unfortunately, SR-GvHD is associated with very poor survival rates. In order to improve patient outcomes, new second-line therapy options are required.

At the 23rd Annual Congress of EHA (European Hematology Association), Stockholm, Sweden,  Professor Nikolas Bubnoff from the University of Freiburg Medical Center, Freiburg, Germany, gave an overview on the role of JAK inhibition in the treatment of GvHD. Previous studies have demonstrated that proinflammatory cytokines are highly involved in GvHD pathogenesis. Janus kinases (JAKs) play an important role in T effector cell responses, thus inhibition of JAK pathway could effectively decrease acute GvHD. Ruxolitinib, a potent JAK inhibitor, provides a novel therapeutic approach by blocking pro-inflammatory signaling, thus reducing tissue damage as well as stimulating Treg cells in SR-GvHD.1

Key messages about ruxolitinib (RUX)
  • RUX attenuates inflammatory cytokines in myelofibrosis and shows rapid and constant decrease of splenomegaly, improvement of performance status and exercise capacity, weight gain, and ameliorates constitutional symptoms 2
  • RUX suppresses donor T-cell activation in vitro3
  • RUX reduces GvHD via increased Treg numbers in vivo3
  • RUX reduces T-cell expansion and inflammatory cytokines in vivo3
  • RUX induces T-regs leading long-term immunotolerance3,4
  • RUX does not compromise GVL in A20 model5
  • RUX does not compromise protection from graft-versus-tumor (GVT) effect, overall survival and acute GVHD pathologic score at target organs were improved in treated mice6
  • Topical RUX defends Lgr5+ skin stem cells and also improves skin homeostasis in skin GvHD7
  • Retrospective data showed high response rate to RUX in heavily pretreated patients with acute or chronic SR-GvHD (ORR: 81.5% in aGvHD and 85.3% in cGvHD)8
  • Prospective pilot study showed potent activity of RUX in SR-GvHD by blocking proinflammatory signaling and by endorsing tolerogenic Treg cells3
  • RUX has also demonstrated clinical activity in pediatric SR-aGvHD subjects: in a retrospective analysis high rate of reversible adverse effects and a fair overall response rate of RUX were observed9
Active trials of JAK inhibition in GvHD
  • GRAVITAS-301: Phase III multicenter, placebo-controlled, double blind randomized trial (n = 300 patients) to evaluate itacitinib for acute GvHD as first line treatment in combination with steroids
  • REACH2: Phase III multicenter, open-label randomized trial (n = 308 patients) to evaluate ruxolitinib for patients with SR-GvHD as second line of therapy
  • REACH3: Phase III multicenter, open-label randomized trial (n = 324 patients) to evaluate ruxolitinib for patients with SR-GvHD as second line of therapy
  • RIG: Phase II multicenter, open-label, randomized trial (n = 148 patients) to evaluate ruxolitinib for patients with SR-GvHD as second line of therapy

In summary, Professor Bubnoff concluded that JAK inhibition provides clinical benefit and durable responses in patients with SR-GvHD. However, he further highlighted that these results need to be verified in ongoing prospective trials.

References
  1. Bubnoff N. JAK 2 inhibition in the treatment of GvHD. 23rd Congress of the European Hematology Association; 2018 June 14–17; Stockholm, SE.
  2. Verstovsek S. et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med.2010 Sep 16;363(12):1117-27. DOI: 1056/NEJMoa1002028.
  3. Spoerl S. et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. 2014 Jun 12;123(24):3832-42. DOI: 10.1182/blood-2013-12-543736.
  4. Teshima T. JAK inhibitors: a home run for GVHD patients? 2014 Jun 12;123(24):3691-3. DOI: 10.1182/blood-2014-04-570325.
  5. Choi J. et al. Pharmacologic blockade of JAK1/JAK2 reduces GvHD and preserves the graft-versus-leukemia effect. PLoS One.2014 Oct 7;9(10):e109799. DOI: 1371/journal.pone.0109799.
  6. Carniti C. et al. Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects. Clin Cancer Res.2015 Aug 15;21(16):3740-9. DOI: 1158/1078-0432.CCR-14-2758.
  7. Takahashi S. et al. Ruxolitinib protects skin stem cells and maintains skin homeostasis in murine graft-versus-host disease. 2018 May 3;131(18):2074-2085. DOI: 10.1182/blood-2017-06-792614.
  8. Zeiser R. et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. 2015 Oct;29(10):2062-8. DOI: 10.1038/leu.2015.212
  9. Khandelwal P. et al. Ruxolitinib as Salvage Therapy in Steroid-Refractory Acute Graft-versus-Host Disease in Pediatric Hematopoietic Stem Cell Transplant Patients. Biol Blood Marrow Transplant. 2017 Jul;23(7):1122-1127. DOI: 1016/j.bbmt.2017.03.029.
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