Early Safety and Feasibility Results from a Phase II Trial of De-Escalated Ptcy and Ruxolitinib for Gvhd Prophylaxis in Older Patients Undergoing Reduced Intensity Conditioning Allogeneic HCT

Background

Post-transplant cyclophosphamide (PTCy) at 50mg/kg on days (D) +3/+4, along with tacrolimus and mycophenolate mofetil (MMF), represents standard of care (SOC) for graft-versus-host disease (GVHD) prophylaxis in adults undergoing reduced intensity conditioning (RIC) allogeneic transplantation (HCT) from an HLA-matched donor. This is based on results of the BMT CTN 1703 study (Bolaños-Meade et al. NEJM 2023). Nearly 25% of patients randomized to PTCy on BMT CTN 1703 developed severe acute GVHD or chronic GVHD by 1 year, and, compared to tacrolimus/methotrexate, these patients experienced significantly more grade 2 infections, and numerically higher rates of severe organ toxicity. Recent studies point to the feasibility of administering PTCy at a reduced dose, 25mg/kg on D+3/+4, preserving GVHD prevention effects and potentially lowering infection rates and organ toxicity. Furthermore, recent studies also suggest that ruxolitinib, a treatment for GVHD, may also be effective for GVHD prophylaxis. Taken together, we initiated a Phase II study where older adults undergoing RIC, HLA-matched HCT, receive PTCy at a lower dose, along with ruxolitinib, to potentially build upon current SOC.

Methods

This is a prospective phase II study (NCT05622318) to de-escalate PTCy and add ruxolitinib for GVHD prophylaxis in adults 60 years and older, with hematologic malignancies, undergoing RIC peripheral blood allogeneic HCT from an HLA-matched donor. GVHD prophylaxis consisted of PTCy, 25mg/kg on D+3/4, tacrolimus (D+5-180), MMF (D+5-35), and ruxolitinib 5mg twice daily (post-engraftment – 1 year). In this analysis, we report on early safety and feasibility parameters on this novel prophylactic GVHD regimen, including primary engraftment, neutrophil and platelet engraftment kinetics, ruxolitinib compliance and dose modifications through the first 100 days, incidence of grade 2-3 infections by D+100, incidence of Grade 2-4 and 3-4 acute GVHD by day +100, and non-relapse mortality (NRM) by D+100.

Results

20 of 54 planned patients have initiated treatment on study. Median age is 67 years (range 61-78 years), 11 patients had AML, 9 patients had MDS. RIC regimens include fludarabine/busulfan (N=19) or fludarabine/melphalan (N=1). Donors included matched related (N=1) or unrelated donors (N=19). Median follow up of survivors is 162 days (range: 20-278 days). Median time to neutrophil and platelet engraftment was 13 days (range: 12-15 days), and 13 days (range: 10-25 days) post-HCT, respectively. Ruxolitinib was initiated at a median 35 days (range: 28-58 days) post-HCT. Median neutrophil and platelet count at initiation was 4,600/µL (range: 1,900-9,200/µL) and 168,000/µL (range: 71,000-340,000/µL) respectively. Zero patients required dose modifications or holds due to ruxolitinib related AEs within the first 100 days. By day 100, the cumulative incidence of grade 2-3 infections was 11.5%, one patient developed bacteremia within the first 30 days; one additional patient developed CMV colitis between day 30 and 100. This case represents the only CMV reactivation/infection event on study. The cumulative incidence of grade 2-4 and 3-4 acute GVHD at D100 was 11.5% and 0%, respectively. Both Grade 2 acute GVHD events were skin only disease. NRM at day 100 is 0%.

Discussion

Among older adults undergoing HLA-matched RIC allo HCT, de-escalated PTCy and ruxolitinib appears feasible, with rapid and reliable engraftment, low rates of infectious complications, and no NRM in the first 100 days. Early and robust engraftment from lower Cy dose along with lower ruxolitinib dosing (5mg twice daily) both facilitate successful continuous ruxolitinib administration in patients thus far. These results support continued investigation on study as currently written.