Combination Ruxolitinib and Belumosudil Is Tolerable and Induces Responses Despite Treatment Failure As Monotherapies

Background FDA approved agents for the treatment of chronic GVHD including ruxolitinib and belumosudil are effective steroid-sparing agents, with overall response rates (ORR) of 76% and 65% respectively. The ORR of other commonly used therapies is 26% as seen in REACH3 BAT arm. Ruxolitinib and belumosudil (rux + bel) are well tolerated with different primary targets; ruxolitinib targets JAK/Stat pathway while belumosudil targets ROCK2. Little data is available on the use of ruxolitinib and belumosudil in tandem but may have implication to practice. Methods This is a single center, retrospective analysis of 20 treatment-refractory patients (pts) s/p allogeneic HCT with chronic GVHD treated with combination rux + bel between 2/1/22 and 8/30/23. Pts with any disease or transplant type were eligible. Data was collected via EMR and included demographics, disease characteristics, treatment response, and clinical outcomes. Data outcome measures extended up to 12 months from initiation of combination therapy. Results A total of 20 pts were evaluable. 1 pt was excluded due to insufficient treatment time. Refer to Table 1 for demographics. The ORR including complete response (CR) and partial response (PR) at any time was 55% (11/20) [95% CI: 0.32-0.77]. 1 pt (5%) achieved CR, 7 pts (35%) had PR, 3 pts (15%) had PR then progression, 6 pts (30%) did not respond, 2 pts (10%) had progression and 1 (5%) pt had mixed response. Refer to Table 2 for response by organ system. The median time to response was 91 days, duration of response until end of follow up period was 48 days, and time to progression after initial response was 28 days. In patients who had previously failed monotherapy, time to resuming as combination was 218 days. 3/3 patients who previously failed both as monotherapies had ORR 100% (1 CR, 2 PR) to rux + bel combination. Among responding pts, other immunosuppressive agents were tapered or discontinued in all pts, barring 3 pts not on other immune suppression. Of the 6 pts with no response, 3 pts remained on therapy to allow more time for response. 5 pts (25%) discontinued after a median of 125 days. None of the pts developed EBV or CMV reactivation requiring treatment or infection with gram negative rods. 4 pts (20%) developed pneumonia and 2 pts (10%) developed viral URI. Cytopenias were not exacerbated. No pts had graft failure or relapsed disease. Belumosudil was tapered in 1 pt due to side effects. 1 pt expired while on combination therapy. Conclusion Combination rux + bel despite progression on either as monotherapies showed ORR of 55% in our small, single center retrospective analysis. The combination is tolerable, may be utilized after failure of both as monotherapies with excellent response, delays the need for alternative therapies, and facilitates tapering of corticosteroids. Continued analysis is warranted to assess durability of response, though there may be overlapping downstream effects of STAT3 and STAT5.