Haploidentical Stem Cell Transplantation with CD3 Depleted Mobilized Peripheral Blood Stem Cell Grafts for Children with Hematologic Malignancies.

Allogeneic hematopoietic stem cell transplantation is the only curative therapy for patients with high-risk or recurrent hematologic malignancies. As only 25% of patients have matched siblings and not all have unrelated donors, haploidentical HSCT using mismatched related donors is the only option for many patients. However, historically the risks of GVHD, graft rejection, and prolonged immunocompromise have made this donor option rather limited. More recently, highly purified CD34⁺ hematopoietic cells have been used with decreased GVHD rates, but at the risk of graft rejection and prolonged immunodsuppression with infectious complications. In an attempt to obtain a PBSC graft with higher T-cell content to maintain acceptable GVHD rates while promoting more rapid immune reconstitution, we initiated a prospective clinical trial for patients with hematologic malignancies who lacked a matched related donor or unrelated donor using a novel method of graft processing. The conditioning regimen consisted of TBI (12 Gy in 8 fractions over 4 days), cyclophosphamide (60 mg/kg/day for 2 days), thiotepa (10 mg/kg/day for 1 day), and rabbit ATG (10 mg/kg/course over 4 days). GVHD prophylaxis consisted of cyclosporine initiated at day -2. G-CSF mobilized PBSC grafts from mismatched related donors were infused after ex vivo T-cell depletion using OKT3 on the CliniMACS device. Patients had weekly peripheral blood analysis for evidence of EBV, CMV, or adenovirus DNA by PCR. If positive, pre-emptive therapy was administered. Twenty patients were enrolled with a median age of 11.9 yrs (range, 2.7–22.1). Diagnoses included ALL (2-CR1, 5-CR2, 3-CR3), AML (2-CR1, 1-CR2, 1-persistent disease), MDS (1-CR1, 2-persistent disease), CML (2- first chronic phase) and NHL (1-CR2). Donors and recipients were matched at 3 (n=11), 4 (n=8) or 5 (n=1) of 6 HLA loci. Of the 19 evaluable patients (one patient died prior to engraftment), the median time to attain ANC > 500/mm³ was 13 days (range, 10–19) and the median time to attain a transfusion-independent platelet count of 50,000/mm³ was 18 days (range, 8–37) post-HSCT. Only 3 patients developed grade 1–2 acute GVHD and none developed grade 3–4 acute GVHD. One patient developed limited chronic GVHD. Complications included post-transplant lymphoproliferative disorder (PT-LPD, n=3), VOD (n=2), BOOP (n=1), CMV retinitis (n=1), and adenovirus reactivation (n=7). No patient died of infectious complications or PT-LPD. 6 patients have died of regimen-related toxicities (n=4), or disease recurrence (n=2) at a median of 160 days (range, 4–208) post-HSCT. Fourteen patients remain alive in remission at a median of 162 days (range, 49–947) post-HSCT. OKT3 depleted PBSC grafts from haploidentical donors depleted of T-celss ex vivo results in favorable outcomes and acceptably low rates of GVHD and infectious complications for children undergoing HSCT from parental donors.