Short Course of Post-Transplantation Cyclophosphamide and Bortezomib for Graft-versus-Host Disease Prevention after Allogeneic Peripheral Blood Stem Cell Transplantation Is Feasible and Yields Favorable Results: A Phase I Study

Abstract

An effective graft-versus-host disease (GVHD) preventative approach that preserves the graft-versus-tumor effect after allogeneic hematopoietic stem cell transplantation (HSCT) remains elusive. Standard GVHD prophylactic regimens suppress T cells indiscriminately and are suboptimal. Conversely, post-transplantation high-dose cyclophosphamide selectively destroys proliferating alloreactive T cells, allows the expansion of regulatory T cells, and induces long-lasting clonal deletion of intrathymic antihost T cells. It has been successfully used to prevent GVHD after allogeneic HSCT. Bortezomib has antitumor activity on a variety of hematological malignancies and exhibits a number of favorable immunomodulatory effects that include inhibition of dendritic cells. Therefore, an approach that combines post-transplantation cyclophosphamide and bortezomib seems attractive. Herein, we report the results of a phase I study examining the feasibility and safety of high-dose post-transplantation cyclophosphamide in combination with bortezomib in patients undergoing allogeneic peripheral blood HSCT from matched siblings or unrelated donors after reduced-intensity conditioning. Cyclophosphamide was given at a fixed dose (50 mg/kg on days +3 and +4). Bortezomib dose was started at .7 mg/m2, escalated up to 1.3 mg/m2, and was administered on days 0 and +3. Patients receiving grafts from unrelated donors also received rabbit antithymocyte globulin. The combination was well tolerated and allowed prompt engraftment in all patients. The incidences of acute GVHD grades II to IV and grades III and IV were 20% and 6.7%, respectively. With a median follow-up of 9.1 months (range, 4.3 to 26.7), treatment-related mortality was 13.5% with predicted 2-year disease-free survival and overall survival of 55.7% and 68%, respectively. The study suggests that the combination of post-transplantation cyclophosphamide and bortezomib is feasible and may offer an effective and practical GVHD prophylactic regimen. The combination, therefore, merits further examination.

Approaches for the Prevention of Graft-Versus-Host Disease Following Hematopoietic Cell Transplantation

“…Further studies aim to more clearly define the optimal patient population, conditioning intensity, and graft source of post-transplant cyclophosphamide for GVHD prevention, including investigating its use in combination with cyclosporine after myeloablative conditioning (NCT01427881) or with tacrolimus-MMF after myeloablative or reduced-intensity conditioning (NCT01010217). One recent trial also demonstrated that post-transplantation cyclophosphamide and bortezomib were feasible and may be effective GVHD prophylaxis after reduced-intensity transplantation from matched donors [93]. …”

“…A randomized phase II trial of bortezomib combined with either tacrolimus-methotrexate or tacrolimus-sirolimus compared with tacrolimus-methotrexate in this patient population is underway (NCT01754389). A recent phase I study also reported that bortezomib in combination with high-dose cyclophosphamide after HCT from matched siblings or unrelated donors after reduced-intensity conditioning was safe and resulted in encouraging levels of acute GVHD that merit further evaluation [93]. …”

A phase 2 study of weekly temsirolimus and bortezomib for relapsed or refractory B‐cell non‐Hodgkin lymphoma: A Wisconsin Oncology Network study

“…An immunomodulatory effect of bortezomib has also been suggested in the allogeneic HCT setting, based on the observation of decreased incidence of graft-versus-host disease when patients receive bortezomib after transplantation. 22,23 Our data demonstrate that combined bortezomib and temsirolimus had activity in patients with heavily pretreated NHL, with manageable toxicities. This combination could be explored further in the future by adding additional agents to the regimen or by replacing bortezomib with newer proteasome inhibitors, such as carfilzomib or ixazomib.…”

“…This observation suggests that temsirolimus/bortezomib may have created an immunomodulatory/antilymphoma effect that persisted even after the completion of protocol therapy. An immunomodulatory effect of bortezomib has also been suggested in the allogeneic HCT setting, based on the observation of decreased incidence of graft‐versus‐host disease when patients receive bortezomib after transplantation …”

Post-Transplantation Cyclophosphamide and Ixazomib Combination Rescues Mice Subjected to Experimental Graft-versus-Host Disease and Is Superior to Either Agent Alone

“…However, unfavorable rates of acute GVHD have been reported when PTC is used alone, in particular in the setting of reduced-intensity conditioning and peripheral blood grafts [16]. This has prompted several investigators to examine the role of PTC in combination with cyclosporine [21], sirolimus [22,23], or bortezomib [24].…”