Maintenance Ruxolitinib Is Associated with Low Rates of Chronic Gvhd Requiring Systemic Treatment in Older Adults with AML/MDS Undergoing Allogeneic HCT: Results of a Phase II Multicenter Trial

Abstract

Introduction: Despite recent advances in graft-versus-host disease (GVHD) prophylaxis, novel approaches to effective prevention of chronic GVHD remain of utmost importance. This is particularly true for older transplant recipients,for whom high-dose cyclophosphamide or prolonged treatment with corticosteroids is challenging. Ruxolitinib, an oral selective inhibitor of JAK1/2, is FDA-approved for the treatment of refractory acute and chronic GVHD. However, the clinical efficacy of JAK inhibition in preventing severe chronic GVHD is not well characterized. Methods: In this prospective, multicenter phase II trial (NCT03286530), older adult subjects (age 60-80) with AML in CR1 or MDS undergoing RIC allogeneic HCT were enrolled. Transplants could be conducted from HLA-matched related donors or 7/8 or 8/8 HLA-matched unrelated donors. Transplants were required to use busulfan- or melphalan-based reduced intensity conditioning and peripheral blood stem cells. Standard GVHD prophylaxis consisted of tacrolimus and methotrexate (5-10 mg/m 2 on Days +1, +3, and +6 ± +11). Subjects were enrolled prior to transplant. Ruxolitinib therapy could begin between Day +30 and Day +100, after meeting pre-treatment criteria, which included: donor engraftment, ongoing remission confirmed by biopsy, adequate hematopoietic recovery (Hgb ≥8 g/dL, PLT ≥50K/uL), and the absence of progressive acute GVHD. Ruxolitinib was administered at 10 mg BID continuously in 28-day cycles (allowing for dose reductions due to drug interactions or cytopenias), for up to 24 cycles. The primary objective was to evaluate the GRFS at 1-year after HCT. Key secondary objectives included the cumulative incidence of chronic GVHD, acute GVHD, and relapse, as well as overall survival. Results: Seventy-eight subjects were enrolled, and 63 subjects received ruxolitinib on trial. The reasons for not initiating ruxolitinib were acute GVHD (n=4), physician discretion (n=3), disease relapse (n=2), low chimerism (n=2), death (n=2), primary graft failure (n=1), and subject withdrawal (n=1). In the treated subjects, the median age was 68 years (range, 61-79). Fifty-five (87.3%) subjects had AML and 8 (12.7%) had MDS. Transplants were performed from HLA-matched related (n=16, 25.4%) or unrelated (n=47, 74.6%) donors with either Fludarabine/Melphalan (n=34, 54%) or Fludarabine/Busulfan (n=29, 46%). The median start date of ruxolitinib after HCT was day 45 (range, 32-93). The median follow-up of survivors was 19 months (range, 3-64) at last cutoff (2/14/23). At the time of analysis, the median number of cycles on treatment is 14 (range, 1-24). 17 subjects remain on therapy; the reasons for discontinuation include completed treatment (n=21), disease relapse (n=13), adverse events (n=7), and physician discretion (n=5). The most common (severe grade ≥3) adverse events experienced while on ruxolitinib were neutropenia (n=18, 29% of subjects), thrombocytopenia (n=17, 27% of subjects), and anemia (n=16, 25% of subjects). Seven subjects experienced grade ≥3 infectious events; no fungal infections have occurred. In subjects receiving ruxolitinib, the 6-month cumulative incidence of Grade II-IV acute GVHD was 14% (95%CI, 7-24) and Grade III-IV acute GVHD was 4.8% (95%CI, 1.3-12), with three cases of grade II-IV GVHD occurring prior to initiation of ruxolitinib. While the 12-month incidence of all cases of chronic GVHD is 27% (95%CI, 17-39), the 12-month incidence of chronic GVHD requiring systemic therapy is 8.4% (95%CI, 3.1-17). The 18-month cumulative incidence of NRM is 5.6% (95%CI, 1.4-14); with only one death attributed to GVHD and one death due to infection (COVID-19), thus far. The 18-month cumulative incidence of disease relapse is 27% (95%CI, 16-39). The 12-month GRFS (primary endpoint) is 70% (95%CI, 56-80). The 18-month OS, PFS, and CRFS are 78% (95%CI, 64-88), 68% (95%CI, 53-78) and 64% (95%CI, 50-76), respectively ( Figure 1). Conclusion: Prolonged administration of ruxolitinib following allogeneic HCT is associated with low rates of chronic GVHD requiring systemic treatment. The incidence of relapse is comparable to historical rates, suggesting no compromise of GVL effect. Despite the anticipated cytopenias with therapy, most subjects were able to remain on treatment. The incorporation of JAK inhibition into GVHD prevention approaches warrants further investigation.