HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide

Abstract

We evaluated the safety and efficacy of high-dose, posttransplantation cyclophosphamide (Cy) to prevent graft rejection and graft-versus-host disease (GVHD) after outpatient nonmyeloablative conditioning and T cell-replete bone marrow transplantation from partially HLA-mismatched (haploidentical) related donors. Patients with advanced hematologic malignancies (n = 67) or paroxysmal nocturnal hemoglobinuria (n = 1) received Cy 50 mg/kg i.v. on day 3 (n = 28) or on days 3 and 4 (n = 40) after transplantation. The median times to neutrophil (>500/microL) and platelet recovery (>20,000/microL) were 15 and 24 days, respectively. Graft failure occurred in 9 of 66 (13%) evaluable patients, and was fatal in 1. The cumulative incidences of grades II-IV and grades III-IV acute (aGVHD) by day 200 were 34% and 6%, respectively. There was a trend toward a lower risk of extensive chronic GVHD (cGVHD) among recipients of 2 versus 1 dose of posttransplantation Cy (P = .05), the only difference between these groups. The cumulative incidences of nonrelapse mortality (NRM) and relapse at 1 year were 15% and 51%, respectively. Actuarial overall survival (OS) and event-free survival (EFS) at 2 years after transplantation were 36% and 26%, respectively. Patients with lymphoid malignancies had an improved EFS compared to those with myelogenous malignancies (P = .02). Nonmyeloablative HLA-haploidentical BMT with posttransplantation Cy is associated with acceptable rates of fatal graft failure and severe aGVHD or cGVHD.

Figure 1

Nonmyeloablative haploidentical BMT conditioning and postgrafting immunosuppresive regimen.

Figure 2

Engraftment and chimerism. Cumulative incidence of (A) neutrophil and (B) platelet engraftment. Dashed line represents death without engraftment (competing risk). (C) Percentage of donor chimerism at days 28–30 and 56–60. In Seattle, donor chimerism was analyzed from the CD3⁺ and CD33⁺ fractions of peripheral blood, whereas in Baltimore donor chimerism was analyzed from whole peripheral blood or bone marrow. Bone marrow samples were not obtained from all evaluable patients.

Figure 3

Cumulative incidence of aGVHD and cGVHD. (A) Cumulative incidence of aGVHD grades II–IV and III–IV. (B) Cumulative incidence of extensive cGVHD for patients who received 1 (Seattle) versus 2 (Baltimore) doses of posttransplant Cy.

Figure 4

Outcomes among nonmyeloablative haploidentical BMT recipients. (A) Cumulative incidence of NRM and relapse. (B) OS and EFS. (C) EFS, according to disease category (myeloid versus lymphoid).