Adding a Janus kinase 2 (JAK2) inhibitor to standard immunosuppressive drugs may not improve prevention of acute graft-vs-host disease in patients with hematologic malignancies undergoing treatment with allogeneic hematopoietic cell transplantation, according to a recent study published by Pidala et al in Blood.
Background
Hematopoietic cell transplantation may offer a potential cure in patients with hematologic malignancies; however, between 10% and 20% of patients who receive stem cells from a donor through allogeneic hematopoietic cell transplantation develop acute graft-vs-host disease within the first 100 days following transplant. This condition occurs when a donor’s immune cells identify the patient’s cells as foreign and attack them. Apart from disease recurrence, graft-vs-host disease can be life threatening and greatly impact a patient’s quality of life posttransplant.
While JAK inhibition is often effective in treating graft-vs-host disease—the JAK1/2 inhibitor ruxolitinib is indicated for the treatment of refractory graft-vs-host disease—the researchers conducting the recent trial addressed whether JAK inhibitors could have a role in graft-vs-host disease prophylaxis. JAK2 inhibitors are capable of turning off the JAK2 gene—which promotes inflammation and contributes to the development of graft-vs-host disease.
“JAK inhibitors are active in treating [graft-vs-host disease] that does not respond to steroids,” explained senior study author Brian Betts, MD, Vice Chair of Strategic Initiatives for Transplant & Cellular Therapy at the Roswell Park Comprehensive Cancer Center. “But the question over the past 10 years has been whether JAK inhibition could prevent [graft-vs-host disease],” he added.
Study Methods and Results
In the phase II results of a phase I/II clinical trial (ClinicalTrials.gov identifier NCT02891603), the researchers assigned 28 patients with hematologic malignancies or myeloproliferative neoplasms who underwent allogeneic hematopoietic cell transplantation to receive the JAK2 inhibitor pacritinib in combination with the anti-inflammatory drugs sirolimus and tacrolimus.
The patients received pacritinib on the day of transplant and for the following 70 days. Sirolimus was administered the day prior to transplant and then daily for at least 1 year. Tacrolimus was given 3 days prior to transplant and continued for at least 50 days. The researchers sought to determine whether the treatment combination could prevent acute graft-vs-host disease.
The biologic endpoint of the trial was found to be successful. The treatment combination effectively reduced JAK2 activity in donor T cells as well as the development of Th1/Th17 cells—thought to be implicated in graft-vs-host disease onset. Despite achieving this immunologic effect, the incidence of grade 2 to 4 acute graft-vs-host disease was similar to what had been achieved in the past with the use of sirolimus and tacrolimus alone (46% vs 43%), demonstrating that adding pacritinib to the regimen did not improve the prevention of graft-vs-host disease.
Conclusions
The researchers emphasized that further research may be warranted to determine whether this strategy might benefit patients who experience the chronic, more widely systemic type of graft-vs-host disease.
“We show that JAK inhibition with pacritinib does what we expect immunologically. It suppresses JAK2/STAT3 activation and Th1/Th17 cells. However, less-selective approaches like the use of cyclophosphamide after transplantation appear to afford deeper and more durable immune tolerance,” underscored Dr. Betts.
“This work highlights critical biologic differences between [graft-vs-host disease] treatment and … prevention. While our phase II trial shows that JAK inhibition with the sirolimus/tacrolimus regimen does not actually prevent [graft-vs-host disease] after all, we are eager to see how this combination performs in treating chronic [graft-vs-host disease],” he concluded.
Disclosure: For full disclosures of the study authors, visit ashpublications.org.
