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.

Similar incidence of severe acute GVHD and less severe chronic GVHD in PBSCT from unmanipulated, haploidentical donors compared with that from matched sibling donors for patients with haematological malignancies

“…At the end of last century, one of the major concerns in HID HSCT was the occurrence of fatal acute GVHD (aGVHD). However, strategies including T-cell depletion in vitro, antithymoglobulin (ATG)/intensive immunosuppression or, the latest development, post-transplant cyclophosphamide, have achieved acceptable incidences of acute severe GVHD and even similar clinical outcomes in some cohort studies when compared with those of MSD or unrelated HSCT (Aversa et al, 2005;Wang et al, 2009;Munchel et al, 2011). However, data describing the features and risk factors for GVHD, especially chronic GVHD (cGVHD) after HID HSCT are relatively limited.…”

“…Human leucocyte antigen (HLA)-identical siblings have historically been the first choice of donors. More recently, HSCT with haploidentical donors (HIDs) selected from family members has shown promising results for patients lacking an HLA-matched sibling (MSD) or unrelated donor (URD) (Aversa et al, 2005;Munchel et al, 2011;Wang et al, 2013). At the end of last century, one of the major concerns in HID HSCT was the occurrence of fatal acute GVHD (aGVHD).…”

Haploidentical BMT and post-transplant Cy for severe aplastic anemia: a multicenter retrospective study

“…[11][12][13][14][15][16][17][18]20,21 Recently, the use of post-transplant cyclophosphamide (Cy) has permitted transplantation across major HLA barriers for patients receiving BM from a haploidentical donor. [22][23][24][25][26] The use of posttransplant Cy has several advantages compared with traditional methods of ex vivo T-cell depletion, which include lower complexity and cost, and improved immune reconstitution permitting a more widespread adoption of this transplant procedure. 27 Several studies have confirmed the efficacy and safety of this approach, but most reports have focused on patients with hematologic malignancies.…”

Acute graft-versus-host disease: a bench-to-bedside update

“…104 This simple in vivo graft manipulation is able to break the HLA barrier by allowing the infusion of haploidentical donor cells with similar or reduced rates of aGVHD compared with transplants using HLAmatched grafts. 105,106 The results of these studies, as well as the results of 3 recently published novel though preliminary aGVHD prophylaxis trials, have prompted new multicenter comparative clinical trials. First, a phase 1/2 study of maraviroc, a CCR5 inhibitor that blocks lymphocyte chemotaxis while preserving effector functions, demonstrated very low rates of grade II-IV acute GVHD (;15%) and no visceral GVHD at day 100 post-HCT in 35 evaluable patients.…”