Treatment of hematological malignancies with nonmyeloablative, HLA-haploidentical bone marrow transplantation and high dose, post-transplantation cyclophosphamide

Abstract

Hematopoietic stem cell transplantation provides the only potential curative option in many patients with hematological malignancies. Finding a suitably matched donor in a timely manner is often difficult. However, most patients have a partially HLA-mismatched (HLA-haploidentical) first-degree relative readily available. Historically, HLA-haploidentical bone marrow transplantation (BMT) has been considered extremely high risk due to high rates of life-threatening graft-versus-host disease (GVHD) and non-relapse mortality (NRM). Modifications of the stem cell graft, such as T-cell depletion, have resulted in poor rates of engraftment. We have recently completed a phase II clinical trial of nonmyeloablative HLA-haploidentical hematopoietic BMT followed by post-transplantation high-cyclophosphamide. High-dose cyclophosphamide has been shown to create immunogenic tolerance by specifically killing activated mature T-cells. As a result, alloreactive T-cells in the donor graft are selectively destroyed thereby decreasing the incidence of severe GVHD. As well, host-versus-graft reactive T-cells are also selectively eliminated thereby increasing rates of engraftment. Among 210 patients with hematological malignancies receiving nonmyeloablative, HLA-haploidentical BMT with post-transplantation cyclophosphamide, the rate of sustained donor cell engraftment has been 87%. The cumulative incidence of grade 2-4 acute GVHD is 27%, grade 3-4 acute GVHD is 5% and chronic GVHD is 15%. Interestingly, increasing HLA disparity between donor and recipient was not associated with increasing incidence of GVHD or decreased event-free survival. Nonmyeloablative haploidentical stem cell transplantation with post-transplantation cyclophosphamide seems to be a promising, potentially curative, option for patients with hematological malignancies who either lack an HLA-matched related or unrelated donor, or in whom a myeloablative preparative regimen is contraindicated due to significant co-morbidities or history of extensive pre-treatment.

Conflict of interest statement

Conflict of Interest

The authors declare no conflicts of interest

Published by Elsevier Ltd.

Figures

Figure 1

Treatment schema for nonmyeloablative conditioning regimen in HLA-haploidentical transplantation with post-transplantation cyclophosphamide. MMF=mycophenolate mofetil; TBI=total body irradiation; Cy=cyclophosphamide; G-CSF=granulocyte colony stimulating factor

Figure 2

Cumulative incidence of acute (A) and chronic (B) GVHD after nonmyeloablative haploidentical stem cell transplantation with post-transplantation cyclophosphamide.

Figure 3

Cumulative incidence of relapse and nonrelapse mortality after nonmyeloablative haploidentical stem cell transplantation with post-transplantation cyclophosphamide

Figure 4

Actuarial curves of (A) overall survival (OS) and event-free survival (EFS) in all patients undergoing nonmyeloablative haploidentical stem cell transplantation with post-transplantation cyclophosphamide; (B) overall survival in patients with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) or myeloproliferative disorder (MPD); (C) overall survival in patients with Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) and chronic lymphocytic lymphoma (CLL).

Figure 5

Event-free survival (EFS) of patients undergoing nonmyeloablative haploidentical stem cell transplantation with post-transplantation cyclophosphamide according to number of mismatched HLA-antigens in any direction (GVH or HVG)