Introduction: Haploidentical peripheral blood allogeneic hematopoietic cell transplantation (PB haplo-HCT) can be complicated by graft-versus-host disease (GVHD) and cytokine release syndrome (CRS). Acute GVHD rates are improving with modern prophylaxis but still occur and outcomes are poor in steroid refractory cases. Severe CRS occurs in 5-10% of patients receiving PB haplo-HCT and is associated with high non-relapse mortality and dismal one-year overall survival between 25-30%. We previously demonstrated that JAK1 inhibition with itacitinib is effective in preventing aGVHD and CRS, with excellent long term GRFS and OS in a high-risk population undergoing allo-HCT. In this study we are testing ruxolitinib, a JAK1/2 inhibitor, which is approved for treatment of aGVHD and chronic GVHD in the prophylaxis setting. If safe, we will expand this approach to combine ruxolitinib and abatacept and reduce exposure to traditional immunosuppressants mycophenolate mofetil (MMF) and tacrolimus. We hope to establish the safety of this platform, which has the potential to effectively prevent aGVHD and CRS while reducing toxicity and potentially relapse. Here we report the initial clinical outcomes from our study of ruxolitinib +/- abatacept with haplo-HCT (NCT06008808).

Methods: Patients with AML, ALL, MDS, or NHL in remission undergoing PB haplo-HCT are eligible for the study and treated on one of two regimens. Regimen 1: Ruxolitinib 5-10 mg BID on day -3 through 180 followed by a taper in addition to standard MMF days 5-28 and tacrolimus days 5-100 targeting serum level of 3-7 ng/mL. Regimen 2: Ruxolitinib at 5-10 mg BID on day -3 through 180 followed by a taper, abatacept 10 mg/kg IV on days +5, +14, +28, and +56, short course tacrolimus days 5-60, and MMF is eliminated. Myeloablative and reduced intensity conditioning are allowed. All patients received standard dose post-transplant cyclophosphamide. The primary endpoint is safety assessed by graft failure, grade III-IV aGVHD, and non-relapse mortality (NRM), assessed continuously with early stopping rules in place.

Results: Seventeen of the planned 20 patients have completed enrollment to Regimen 1 and underwent haplo-HCT between 7/2024 and 7/2025. Regimen 2 has completed approval and activation and will open for enrollment when Regimen 1 is complete. Median age at transplant was 64 (41-75) and 15/17 patients are male. Diagnoses were AML (12), ALL (1), MDS (3) and NHL (1). Median follow up is 158 days, with 8/17 beyond 180 days. There were no cases of engraftment failure with short median times to neutrophil (14 days, range 12-20) and platelet (14 days, range 7-54) engraftment. There were no cases of grade III-IV acute GVHD. The incidence of grade II acute GVHD through day 100 was 12.5% (95% CI 2-36%). No patients developed aGVHD during their ruxolitinib taper. There were no cases of extensive chronic GVHD. There were no cases of severe CRS with 12 (80%) patients having grade 1 CRS, 1 (7%) having grade 2 CRS, and 2 (13%) having no CRS. There have been no cases of relapsed disease. Four (27%) patients had NRM – aspiration event after engraftment on day 21, influenza pneumonia on day 86, encephalopathy, failure to thrive and multiorgan failure on day 115, and one suicide on day 265. All but one – influenza – were deemed unrelated to ruxolitinib. Overall survival at day 180 was 78% (95% CI 45-92%) by Kaplan-Meier estimate. All evaluable patients (11/11) had full donor engraftment and >95% chimerism at day 100.

Follow up and endpoints will be updated for the ASH 2025 meeting.

Conclusions: Ruxolitinib with PB haplo-HCT appears safe, with no engraftment failure and prompt engraftment. Severe CRS has not been seen in this trial. Rates of acute and chronic GVHD are low, and no patients have relapsed during short follow-up to date. Four patients have experienced NRM, and while three cases were judged as not related to ruxolitinib, we continue to monitor toxicity with each enrollment. Regimen 2 – combining ruxolitinib with abatacept – is approved and will begin enrollment after completion of 20 patients on Regimen 1.

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2025
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