title: 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.
authors.affiliation: Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Ashley T
authors.initials: AT
authors.lastname: Munchel
authors.forename: Yvette L
authors.initials: YL
authors.lastname: Kasamon
authors.forename: Ephraim J
authors.initials: EJ
authors.lastname: Fuchs
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D016026:Bone Marrow Transplantation; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage*; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000628:therapy*; D006650:Histocompatibility Testing; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007223:Infant; D008213:Lymphocyte Activation / Q000187:drug effects; D008212:Lymphocyte Depletion / Q000379:methods; D008297:Male; D008875:Middle Aged; D014184:Transplantation, Homologous
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide