In Vivo and Ex Vivo T-Cell Depleted (TCD) NonmyeloablativeHaploidentical Stem Cell Transplantation (NSCT) for Hematologic Malignancy (HM).

Abstract

Based on our nonmyeloablative MHC-mismatched murine bone marrow transplant (BMT) models, in which mixed lymphohematopoietic chimerism (MLC) is reliably induced as a platform for adoptive cellular immunotherapy via delayed donor lymphocyte infusions (DLI), we developed a similar clinical strategy for haploidentical NSCT. Conditioning for NSCT has consisted of high dose cyclophosphamide, in vivo T-cell depletion (TCD) with anti-T-cell antibody therapy, pre-transplant thymic irradiation and cyclosporine (CYA) for GVHD prophylaxis (with taper and discontinuation by day 35 for patients with MLC and no evidence of GVHD). Because of a high incidence of ≥ grade II GVHD (10 of 14 patients) using equine anti-thymocyte globulin for in vivo TCD, we substituted MEDI-507 (an anti-CD2 monoclonal antibody) for ATG. Of 8 patients who underwent BMT with MEDI-507 for in vivo TCD, 5 experienced graft loss. The protocol was then modified to include ex vivo T-cell depleted high dose peripheral blood stem cell transplantation (PBSCT). Graft loss occurred in 2 of 4 patients. 2 pts who received DLI for recurrent disease converted to full donor chimerism (FDC) with no (n=1) or grade II (n=1) GVHD. Fludarabine was then added to the conditioning regimen. Ten patients with advanced HM (NHL, n=4; HD, n=3; MDS, n=1; CLL, n=1 CML, n=1) have received NSCT from HLA 5/6 (n=5) or 4/6 (n=5) matched haploidentical donors on a protocol using cyclophosphamide 60 mg/kg x 2, MEDI-507 0.1 mg/kg on day - 8 and 0.6 mg/kg on day 7 and - 6, fludarabine 25 mg/m2 on days - 5 through -1, thymic irradiation on day - 1, and ex vivo TCD (via CD34+ cell selection using the Isolex® device) PBSCT on day 0. Median #/kg (range) of infused CD34+ and CD3+ cells were 6.6X10E6 (3.2X10E6-1.5X10E7) and 3.5X10E4 (6.3X10E2-1.18X10E5), respectively. Of 9 evaluable patients, all initially achieved MLC without GVHD, but 2 patients subsequently lost detectable chimerism. 2 patients with MLC have received DLI, one in conjunction with chemotherapy, for disease progression. 5 pts (n=3 following rapid tapering of immunosuppression to induce a GVT effect, n=2 after DLI) have developed ≥ grade II acute GVHD (3 grade II, 2 grade III-IV). 5 patients have experienced disease progression, of whom one achieved a CR following DLI. Two pts have died due to transplant related complications (GVHD, n=1;late idiopathic pneumonitis, n=1) Split lineage MLC has occurred in each case, with a predominance of early donor granulocyte chimerism (mean 64%,77%,61%,>99% at 2,4,12,26 weeks) and a lower percentage of donor T-cell chimerism (mean 14%,37%,53%,>99% at 2,4,12,26 weeks). Conversion to FDC or near FDC occurred spontaneously in 4 pts and in 2 pts following DLI. Of 22 patients treated with MEDI-507 based haploidentical NSCT regimens, 8 are alive from < 1 to 70 months post-transplant. In conclusion, in vivo and ex vivo TCD haploidentical NSCT reliably leads to split lineage MLC with the potential for spontaneous chimerism conversion or conversion following DLI. Sustained anti-tumor responses in patients with advanced, chemorefractory HM have been achieved.