Reducing Ptcy Dose in Patients Receiving CAST for GvHD Prevention Results in Accelerated Engraftment at the Cost of Higher Incidence of GvHD

Introduction We previously reported excellent results of post-transplant cyclophosphamide (PTCy), abatacept (A) and a short course of tacrolimus (T) (CAST) for graft-versus-host (GvHD) prevention following peripheral blood (PB) haploidentical transplant. Mechanistic and preliminary clinical data suggest that the dose of PTCy can be decreased to diminish its toxicity while maintaining its efficacy. We sought to explore the feasibility and efficacy of reduced-dose PTCy in patients (pts) receiving CAST. Methods We initiated a phase II Simon 2-stage clinical trial for adult pts with hematological malignancies undergoing haploidentical PB transplants. Pts received PTCy 25 mg/kg days (d) +3 and +4, A 10 mg/kg d +5, +14, +28 and +56 and T starting d +5 and tapered from d +60 until d +90.Primary endpoint is the incidence of grades II-IV acute GvHD (aGvHD) by d +120. Conditioning regimens were of different intensities. Herein, we compare the early results of this ongoing trial to the results of the original CAST trial. Wilcoxon rank-sum tests were used to compare the median d of neutrophil (ANC) and platelet (plt) engraftment. Gray's test was used to compare the cumulative incidence functions of acute and chronic GvHD (cGvHD). The studies were performed sequentially at the same institution and had the same inclusion and exclusion criteria. Results The table summarizes the characteristics of 19 pts enrolled in the re-CAST study as of 12/13/23. Median follow up was 187 d (range 43 – 407). Median time to ANC and plt engraftment were 13 and 18 d, significantly lower than in CAST (18 and 30 d, p<0.0001 for both, fig. panels A and B). There was no graft failure. In the re-CAST study, 14 pts had a follow up >120 d or already developed aGvHD. Four pts developed grade II and 1 grade III aGvHD. Cumulative incidence of grade II-IV aGvHD was 29.4% (95% CI, 13.5%-64%) versus 17.4% (95% CI, 9.2%-50.7%) in the CAST study (p=0.20, figure panel C). There was one case of grade III aGvHD (7.1%, 95% CI, 1%-36%). Median time of onset of aGvHD was 62 d. Eleven pts had a follow-up of >180 d or already diagnosed with moderate to severe (MS) cGvHD. Six pts developed MS cGvHD, mostly with mucocutaneous manifestations. Two pts died without developing cGvHD. Cumulative incidence of MS cGvHD was 67.4% (95% CI, 23.3%-100%) versus 15.9% (95% CI, 8%-31.7%) in the CAST study (p=0.003, figure panel D). There were no cases of steroid-refractory or fatal GvHD. The incidence of CMV and EBV reactivation were 42% and 10%. One pt died of PTLD and 1 of disease relapse. Overall, 2 pts relapsed. Conclusion Our results showed that reducing the total dose of PTCy to 50mg/Kg results in accelerated engraftment at the expense of increased incidence of cGvHD, albeit none life-threatening. This calls for caution in reducing the dose of PTCy in pts receiving PB transplant outside of well-designed clinical trials. The re-CAST study was amended to increase the total dose of PTCy to 75mg/Kg.