Historically, myeloablative BMT without T cell depletion from ≥ 2 HLA-antigen-mismatched related (HLA-haploidentical) donors has been associated with excessive rates of severe graft-versus-host disease (GVHD) and non-relapse mortality (NRM). Using the same GVHD prophylaxis regimen that has produced outcomes in non-myeloablative haploidentical BMT similar to those seen in non-myeloablative matched related BMT, we have completed a single-institution phase II clinical trial utilizing high-dose, post-transplantation Cy after myeloablative conditioning and T-cell-replete, HLA-haploidentical BMT. The trial initially enrolled subjects with refractory hematologic malignancies only, with the later addition of high risk leukemias in remission and chemosensitive lymphomas. The median age of the 30 patients enrolled on trial was 43 years (range, 2–64); 13 were male and 19 Caucasian. Diagnoses included acute myeloid (10 refractory, 3 CR1, and 3 CR2), acute lymphocytic (2 CR1), and 1 refractory biphenotypic leukemia; 2 chronic myelogenous leukemia in blast crisis; and non-Hodgkin lymphoma (6 refractory and 2 chemosensitive); and 1 chemosensitive gray zone lymphoma. The majority (67%) of patients were not in remission at the time of transplant. Conditioning consisted of IV Busulfan (pharmacokinetically adjusted) on days −6 to −3, Cy (50 mg/kg/day) on days −2 and −1 in twenty-seven patients or Cy (50 mg/kg/day) on days −5 and −4 and total body irradiation (300 cGy /day) on days −3 to 0 in three patients, followed by T-cell-replete bone marrow in all patients. Postgrafting immunosuppression in all patients consisted of Cy (50 mg/kg/day) on days 3 and 4, followed by mycophenolate mofetil for 30 days, and tacrolimus for 6 months. Donor engraftment at Day 60 occurred in all but one evaluable patient (96%, 24/25). The median times to neutrophil (>500/μL) and platelet recovery (>20,000/μL) were 25 and 32 days, respectively. The cumulative incidences of grades II-IV and grades III-IV acute GVHD at day 100 were 14% (95% CI: 4.3%, 29.4%) and 7.3% (95% CI: 1.2, 21.2%), respectively (Figure a). The cumulative incidence of chronic GVHD at one year was 13% (95% CI: 1.5, 37.6%). The cumulative incidence of NRM at 100 days was 12% (95% CI: 3%, 28%) (Figure b). Non-relapse causes of death were multi-organ system failure in two patients with bulky mediastinal lymphoma and veno-occlusive disease in one patient who had received gemtuzumab ozogamicin 3 weeks before BMT. There were no deaths from infection. The cumulative incidence of relapse at 1 year was 66% (95% CI: 38%, 83.5%), in this poor-risk cohort. The cumulative incidence of relapse among patients in CR prior to transplant was 13% (95% CI: 1.5%, 37.6%) at 1 year. With a median follow-up of surviving patients of 168 days (range 60–729), actuarial overall survival (OS) was 40% at one year. With a median follow-up of event-free patients of 144 days (range 60–729), actuarial event-free survival (EFS) was 23.5% at one year. Myeloablative HLA-haploidentical BMT with T cell replete bone marrow and post-transplantation Cy is associated with promising rates of engraftment, GVHD, and NRM, similar to those seen with non-myeloablative haploidentical BMT with post-transplantation Cy and with conventional myeloablative matched sibling BMT. Based on these data, this approach to myeloablative haploidentical BMT is now being performed in better risk patients. Disease progression remains a problem in patients with refractory leukemia; low rates of GVHD and NRM allow for combining other novel immunotherapies with myeloablative haploidentical BMT in the future to improve disease free survival.
Symons:Otsuka Pharmaceuticals: Research Funding. Chen:Genentech: Membership on an entity's Board of Directors or advisory committees. Luznik:Otsuka Pharmaceuticals: Research Funding.
Asterisk with author names denotes non-ASH members.