Non-Myeloablative T-Cell Depleted (TCD) Haploidentical Hematopoietic Cell Transplantation (HCT) Followed by Donor Leukocyte Infusion(s) for Hematologic Malignancies: The MGH Experience.

We developed a haploidentical HCT protocol based on MHC-mismatched murine models, in which mixed chimerism (MC) is induced as a platform for adoptive immunotherapy via delayed donor leukocyte infusions (DLI). While the scientific concept has remained the same, this haplo-HCT protocol has undergone multiple revisions since its inception, such as substitution of MEDI-507 (a CD2 monoclonal antibody) for ATG, addition of ex vivo TCD of donor graft (via CD34+ cell selection), changes in MEDI-507 doses/schedules and finally addition of fludarabine-all based on evolving clinical experience and new discoveries from murine models. A total of 14 patients with advanced, mostly therapy-refractory disease (NHL, n=7; HD, n=3; t-AML, n=2; ALL, n=1; MDS, n=1), received our most recent nonmyeloablative strategy consisting of cyclophosphamide, fludarabine, MEDI-507, thymic irradiation on day -1 and cyclosporine for GVHD prophylaxis (with taper and discontinuation by day 35 for patients with MC and no evidence of GVHD) followed by GCSF-mobilized ex vivo TCD haplo-HCT (HLA 1/6 mismatched, n=7; HLA 2/6 mismatched, n=7). Median number/kg (range) of infused CD34+ and CD3+ cells were 6.84 x10⁶ (3.19 x 10⁶ – 14.7 x 10⁶) and 4.73 x 10⁴ (0.06 x 10⁴ – 11.8 x 10⁴), respectively. One patient died shortly after the transplantation due to intracranial hemorrhage. Of 13 evaluable patients, all initially achieved MC without GVHD, but 3 lost detectable donor graft despite multiple DLIs. Split lineage MC occurred in 10 patients, with a predominance of early donor granulocyte chimerism (mean 91%, 87%, 96%) and a lower percentage of early donor T-cell chimerism (57%, 60%, 97%) at 30, 90 and 150 days post-HCT. Ten out of 10 patients ultimately achieved full donor chimerism (FDC) in myeloid lineage and 9 achieved FDC in T-cell lineage (spontaneously, n=8; following DLI, n=2). Natural killer cells recovered relatively early, despite the presence of circulating MEDI-507. Eight patients developed acute GVHD: grade I, n=3; grade II, n=4; grade IV, n=1. One died from GVHD-related complications, 1 died of late idiopathic pneumonitis and 5 died from progressive disease. Median overall survival (OS) of all 14 patients is 195 days (range, 31–1028) post-HCT; at 1 year the OS is 39.2% for all 14 patients. Six patients are alive at a median of 604 days (range, 180–1028) post-HCT, including 3 in complete remission of whom 2 had therapy-related MDS/AML. HLA mismatches in the GVH or HVG direction did not influence graft outcome. We also assessed inhibitory killer immunoglobulin-like receptor (KIR)-HLA epitope mismatches (missing ligand) in the GVH and HVG (host versus graft) directions based on HLA and KIR genotyping of patients and their donors. There was a trend in the association between spontaneous FDC and fewer missing donor HLA ligands for host KIR receptor (<2 v. ≥ 2 missing donor ligands, p = 0.075). In conclusion, using our current haploidentical HCT protocol, we reliably achieved initial MC that converted to FDC, either spontaneously or following DLI with manageable GVHD and with the achievement of sustained anti-tumor responses in some patients with therapy-refractory hematologic malignancies.