Post-transplant cyclophosphamide (PTCy) has emerged as a cornerstone of graft-versus-host disease (GvHD) prophylaxis in reduced intensity (RIC) allogeneic hematopoietic cell transplantation (HCT), yet infection and GvHD continue to be major challenges. Studies suggest that itacitinib, a selective JAK1 inhibitor, holds potential for preventing GvHD with reduced impact on hematopoietic recovery compared to other JAK inhibitors. We conducted a single-center pilot study (NCT05364762) to evaluate the safety of adding itacitinib to PTCy-based prophylaxis with tacrolimus, schedule for 60 or 90 days, in patients undergoing matched (related or unrelated) donor peripheral blood stem cell (PBSC) HCT using fludarabine (25 mg/m2: days -7 to -3) and melphalan (100 mg/m2: day -2) as conditioning.

GvHD prophylaxis consisted of PTCy (50 mg/kg: days +3 and +4), itacitinib (200 mg, oral, daily from day +5 to +100), and tacrolimus beginning on day +6. Two cohorts were evaluated: cohort 1 (n=10) received tacrolimus until day +95, and cohort 2 (n=10) until day +65. Supportive care including antibiotics and growth factors were provided per institution guidelines. The primary objective was to assess the safety of adding itacitinib at a fixed dose to PTCy-based GvHD prophylaxis after 90 (cohort 1) or 60 (cohort 2) days of tacrolimus administration. Primary safety event (PSE) was defined as grade 3-4 acute GvHD per MAGIC criteria. Observation period was from first dose of PTCy until grade 3-4 acute GVHD or competing risk events (relapse, NRM, donor lymphocyte infusion or second HCT), or until day +100 post-HCT, whichever came first.

A total of 20 patients were enrolled. Median age at the time of HCT was 63 years (range: 56–77), with 55% being male, and 80% being non-Hispanic. Most patients (80%) received HCT from an unrelated donor. KPS was 90-100 in 16 (80%) of patients and HCT-CI was ≥ 3 in 50% (n=10). The underlying diagnoses included AML in CR1/2? (n=8; 40%), MDS (n=7; 35%), ALL in CR1/2 (n=2; 10%), CMML (n=2; 10%), or MF (n=1; 5%). All patients achieved engraftment with median time to neutrophile engraftment of 16 days (range: 13-25) and platelet engraftment of 27 days (range: 17-137). Grade ≥3 adverse events (AEs) considered at least possibly related to Itacitinibincluded anemia (n=14), febrile neutropenia (n=3), sepsis (n=3), and acute kidney injury (n=2). Grade ≥3 thrombocytopenia occurred in the majority of patients (n=18), most commonly within the first 6 weeks following HCT, with a median duration of 16 days (range= 8–102). All cases resolved without clinically significant bleeding. Importantly, no unexpected safety signals or protocol-specified safety events (PSEs) were observed with either 60-day or 90-day tacrolimus administration schedules. Cytokine release syndrome (CRS) occurred in 3 patients (15%; all grade 1–2). During the first 100 days bacterial infections were reported in 35% (BMT CTN grade 1; 10% and grade 2; 25%), fungal infection in 5% (grade 1), and viral infection in 20% (grade 1; 5% and grade 2; 15%). No BMT CTN grade 3 infections were reported.

At the time of abstract submission, 17/20 patients have completed their 12-months follow-up, and the rest (n=3) completed their 6-months follow-up. One-year overall survival (OS) and relapse-free survival (RFS) for all patients were 88% (95% CI: 61–97) and 85% (95% CI: 60–95), respectively. Cumulative incidence of relapse and non-relapse mortality at 1-year post-HCT were 15% (95% CI: 3.6–34.0) and was 0%, respectively. Day 180 cumulative incidence of grade 2-4 and 3-4 acute GvHD was 10% (n=2) and 0%, respectively. Cumulative incidence of 1 year moderate to severe chronic GvHD was 6% (95% CI 0–2.5). None of the patients were on immunosuppressive therapy at 1 year post HCT. The 1-year GVHD-free and relapse-free survival (GRFS) was 79% (95% CI: 53–92).

The addition of itacitinib to PTCy and tacrolimus-based GVHD prophylaxis (ICT) was safe and well-tolerated, with low incidence of acute and chronic GVHD, no NRM, and promising 1-year GRFS and survival outcomes. These results support further study of JAK1 inhibition in combination with PTCy platform for GVHD prophylaxis regimens to optimize immune tolerance post-HCT.

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2025
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