Deciphering the efficacy of posttransplant cyclophosphamide in BMT

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

In our work over the past several years, we have overturned the prior paradigm regarding how post-transplantation cyclophosphamide (PTCy) prevents graft-versus-host disease (GVHD) and have worked to develop a new mechanistic framework. Across several active projects, we are continuing to refine and expand this new mechanistic model, which will inform rational translation of new approaches and modifications to improve outcomes for patients. Five related laboratory publications are in preparation and are expected to be submitted within this year or the next fiscal year. Moreover, these and other of our studies have yielded important discoveries that have prompted direct clinical translation, with the most important being 1) the dosing of PTCy can be optimized and may be intermediate rather than very high dosing, and 2) other cell therapies can be combined with PTCy-based transplant in efforts to reduce relapse without increasing GVHD. We published recently results from our first clinical trial showing in patient that intermediate-dose (ID)-PTCy is effective in preventing GVHD, but allows less toxicity, faster engraftment and immune recovery, less infectious complications, and an overall low relapse rate. In this fiscal year, we also completed enrollment on two arms of another study evaluating ID-PTCy for a different transplantation conditioning platform for older/infirm patients. We also showed that pharmacokinetic exposure of 4-hydroxycyclophosphamide, the major active metabolite of cyclophosphamide, with these studies performed as part of a U01, shows excellent correlation with these benefits of reduced-dose PTCy. We have another clinical trial enrolling seeking to optimize PTCy for peripheral blood stem cell transplantation and are nearing the end of phase I for one of the two arms. Two of these studies are multi-institutional. Regarding the second finding, we showed in retrospective data published this year that donor lymphocyte infusions are very safe in PTCy-treated patients but also have low efficacy. However, our preclinical suggested a window for safe and efficacious integration early post-transplant. We are extending this work with another clinical trial, stemming from the work in the laboratory, to integrate prophylactic donor lymphocyte infusion early after transplant and have another study in regulatory review to extend this approach to CAR-T cells. Our goals with these clinical studies and ongoing laboratory research are to use our developing understanding as a basis to explore how to refine this transplant approach clinically towards the clinical goals of further reducing graft-versus-host disease, ensuring reliable engraftment with minimal conditioning, and serving as a platform for other therapies to reduce relapse. We also are exploring the impact of PTCy on human T cells in mixed lymphocyte cultures with the goal of improving our understanding of the immunologic impact of PTCy in order to improve clinical outcomes.