A Phase II Study of Sirolimus-Based Calcineurin Inhibitor-Free Gvhd Prophylaxis after Peripheral Blood Haploidentical Transplantation with Post-Transplant Cyclophosphamide

Haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide (PTCy) is increasingly offered as a curative treatment for patients with hematological malignancies. In a recent registry study (Bashey et al. JCO 2017), peripheral blood (PB) as a graft source compared to bone marrow reduced the risk of relapse but increased acute and chronic GVHD after haplo-HCT with PTCy in combination with calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF). In this phase II trial we aimed to assess the efficacy of Sirolimus (Sir) in combination with PTCy and MMF as a CNI-free GVHD prophylaxis after PB haplo-HCT (NCT03018223). The primary end point was the cumulative incidence of grade II-IV acute GVHD at day 100 after HCT. With 32 evaluable patients enrolled, the study had a 90% power (α = 0.1) to demonstrate a reduction in 100-day grade II-IV acute GVHD from the historical benchmark of 40% (haplo-HCT and PTCy/Tac/MMF) to 20%. Sir was administrated from days +5 to +90 at target level of 8-14 ng/ml, followed by taper by day +180 in the absence of acute GVHD. A total of 32 patients with hematological malignancies were treated on trial 2/2017- 8/2018. The median age at HCT was 50 years (range, 23-75) and 59% of patients were racial/ethnic minorities. AML (50.0%) was the most common indication for HCT.  The majority (66%) received myeloablative Fludarabine (Flu) and Busulfan (AUC of 5300), while 34% received non-myeloablative Flu/Cy/TBI 200 cGy. There were no graft failure events and the median time of neutrophil engraftment was 17 days (range, 12 - 30). With a median follow-up of 15.4 months, the primary endpoint was met with day 100 grade II-IV acute GVHD cumulative incidence of 18.8% (95% CI 7.5 - 34.0; grade III-IV = 9.4%). The cumulative incidence of 1-year NIH moderate/severe chronic GVHD was 20.0% (95% CI 7.9-36.0) (Figure). Only 3 patients required systemic glucocorticoids for chronic GVHD therapy. At last follow up, all immunosuppression was successfully discontinued in 43% (n=12) of all surviving study patients.  The 1-year probability of non-relapse mortality was 19.7% (95% CI 7.8 - 35.5), relapse was 23.7% (95% CI 10.2 - 40.4), disease-free survival was 56.6% (95% CI 41.3 - 77.7) and overall survival was 70.2% (95% CI 55.5 - 88.6) for the entire cohort. These data demonstrate that PTCy/Sir/MMF GVHD prophylaxis effectively prevents grade II-IV acute GVHD after PB haplo-HCT and results in successful hematopoietic engraftment. Furthermore, the initial chronic GVHD, relapse and survival outcomes appear favorable. These findings warrant prospective comparison of PTCy/Sir/MMF with PTCy/Tac/MMF after PB haplo-HCT.