Drug Duo Is Efficacious in Treating Posttransplant GVHD

February 24, 2024
Morgan Bayer

Jakafi plus Rezurock showed promise in treating graft-versus-host disease in patients who underwent undergone allogeneic hematopoietic cell transplantation.

More than half of patients responded to treatment with Jakafi (ruxolitinib) plus Rezurock (belumosudil) to treat graft-versus-host disease (GVHD), according to data from a small study presented at the 2024 Tandem Meetings on Transplantation & Cellular Therapy.

“Response was observed with the combination despite progression on both agents as monotherapy, which may suggest synergistic effects in targeting different inflammatory pathways. The combination is tolerable, delays the need for alternative therapies, and facilitates the tapering of corticosteroids,” investigators wrote in the poster.

Among 20 patients observed in the study, the 55% overall response rate (ORR; percentage of patients who had a complete or partial response to treatment), included one (5%) complete response (CR; resolution of GVHD) and seven (35%) partial responses (PR) in patients at any time during the analysis.

However, one patient was excluded due to insufficient treatment time. There were three patients (15%) who experienced PR and then progression, six patients who had no response (30%), two patients who progressed (10%) and one patient who experienced a mixed response (5%).

The median time to response was 91 days, the duration of response was 48 days, and the median time to progression after a response was 28 days. Among the three patients who did not respond to Jakafi or Rezurock monotherapy, the combination therapy led to one patient showing a CR and two patients showing a PR.

There were five patients (25%) who discontinued treatment after a median of 125 days and all other immunosuppressive agents (drugs that impede the immune system to stop GVHD) were either decreased or discontinued in all patients that had a response to the combination.

According to response by organ system, there were seven organ types addressed: upper gastrointestinal (10% of patients had CR), liver (15% of patients had CR), lung (5% had CR, 15% each had either PR or progression), musculoskeletal (5% each had either PR or progression), ocular (5% each had either CR, PR, or progression), oral (10% each had either CR or progression and 15% had PR) and skin (5% each had either CR or PR).

Patients included in the analysis had previously undergone allogeneic hematopoietic cell transplantation, developed GVHD, and received the Jakafi and Rezurock combination between Feb. 1, 2022, and Aug. 30, 2023. Eligible patients could have any disease or transplant type and the effects of the combination therapy were monitored for up to 12 months from initiation.

The majority of patients were female (60%) with either myeloablative (65%) or reduced intensity (35%) conditioning regimens. Patients received either tacrolimus (Prograf) and methotrexate (MTX) (90%) or tacrolimus, MTX, and anti-thymocyte globulin (10%). The graft source received was either peripheral blood (95%) or bone marrow (5%) and the donor type was either matched but unrelated (75%) or related to the patient (25%).

The overall chronic GVHD (cGVHD) grade at diagnosis was either mild (45%), moderate (40%), or severe (15%), and the cGVHD at the onset of the combination was also mild (10%), moderate (25%), or severe (65%). For the best response cGVHD grade 10% of patients had mild best response, 30% had moderate, 55% had severe and 5% had CR.

Regarding side effects, there were no patients who had or developed cytomegalovirus (a common type of virus known as CMV), Epstein-Barr virus, graft failure or relapse disease, and there was no worsening of cytopenia.

However, four patients (20%) developed pneumonia and two developed (10%) an upper respiratory infection. Rezurock was decreased in one patient because of side effects not mentioned in the poster but then tolerated at the decreased dose, and one patient died while receiving the combination therapy.

Historically, Jakafi and Rezurock monotherapy has an ORR of 76%and 65%, respectively, according to prior studies published in Blood and the New England Journal of Medicine. Other commonly used treatments have a lower response rate of 26%, as shown in the REACH3 study. Both Jakafi and Rezurock are well-tolerated medications with different primary targets: Jakafi targets the JAK/Stat pathway, whereas Rezurock targets ROCK2.

“Possible synergistic effects of combination therapy, targeting GVHD from multiple inflammatory pathways may yield higher response rates [and] possible underlying changes in the pathophysiology and manifestations of chronic GVHD over time, [which] could support re-introducing previously failed therapies for use in combination with other agents,” investigators hypothesized.

Moving forward, “large-scale studies [are] warranted to evaluate the efficacy, safety, and durability of response to combination therapy, though there may be overlapping downstream effects of STAT3 and STAT5,” they noted.

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