Haploidentical related-donor hematopoietic cell transplantation in children using megadoses of CliniMACs-selected CD34+ cells and a fixed CD3+ dose

Abstract

We conducted a prospective phase II trial utilizing the CliniMACs system to perform CD34 þ -cell selection of PBSCs from haploidentical donors to evaluate engraftment and hematoimmunological reconstitution. In total, 21 children with hematological malignancies or nonmalignant conditions underwent conditioning with 1200 cGy TBI, thiotepa, fludarabine and Thymoglobulin. Patients received megadoses of CD34 þ cells (median: 22 Â 10 6 /kg) with a fixed dose of 3 Â 10 4 /kg CD3 þ cells/kg, and engraftment occurred in 90% with prompt recovery of neutrophils and platelets. Grade II acute GVHD (aGVHD) was seen in 32% (95% confidence interval (CI), 15-54%) of evaluable patients, there was no grade III-IV aGVHD, and chronic extensive GVHD was seen in 35% (95% CI, 17-59%) of patients. The estimated 2-year EFS was 62% (95% CI, 48-83%) with a median survivor follow-up of 49 months (range: 18-119 months). Patients with nonmalignant diseases had an estimated 2-year EFS of 100% (95% CI, 56-100%) and patients with malignancies in remission had an estimated 2-year EFS of 56% (95% CI, 22-89%). Megadose CD34 þ cells with a fixed CD3 þ cell dose from haploidentical related donors resulted in good outcomes for pediatric patients with nonmalignant diseases and those with malignant diseases transplanted in remission.

Effects of T-Cell Depletion on Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in AML Patients

“…All patients on this study had neutrophil engraftment, and infection-related mortality at one year was 5%–6%, showing the feasibility of this approach. This approach has also been used in recipients of CD34-selected haplo-identical grafts [68]. The same group previously reported low rates of acute and chronic GVHD in a retrospective series of 16 patients who received DLI (up to 6 × 10 4 CD3+/kg) from haplo-identical donors to enhance immune recovery and/or treat infections [69].…”

Hematopoietic Stem Cell Transplantation for Primary Immunodeficiencies

“…30-32 Infusion of large doses of stem cells as well as other stromal factors aids engraftment of donor stem cells and improves immune reconstitution. 30, 33 Myeloid engraftment, most often achieved following conditioning, facilitates engraftment of donor stem cells, permitting long-term thymopoiesis, even in NK- SCID phenotypes. 32, 34 …”

Haploidentical SCT: the mechanisms underlying the crossing of HLA barriers

“…13,48,49 In brief, anti-third-party CD8 T cells may represent an attractive and effective modality for the induction of transplantation tolerance across major genetic barriers. 5,6 STRATEGIES USED TO OVERCOME HLA BARRIERS Several strategies, such as ex vivo TCD, treatment of healthy donors with G-CSF, post transplant CY (PT/CY) and pharmacological agents, such as ATG and CsA, have been implicated in crossing HLA barriers (Table 1). [35][36][37][38] EX VIVO TCD The Perugia group pioneered an approach for graft TCD via the positive selection of CD34 þ stem cells.…”

“…Each protocol may involve at least two mechanisms relevant to overcoming the HLA barriers and combining different strategies (Tables 1 and 2, and Figure 1). 4,6,17,66,[87][88][89][90][91][92] The Perugia group established a haploidentical protocol that included TCD and a graft that contained a mega-dose of highly purified CD34 þ cells (average X10 Â 10 6 /kg body weight), which was administered following a myeloablative conditioning regimen. This protocol ensured a high engraftment rate, despite the HLA barrier, without triggering GVHD.…”

“…[1][2][3][4][5][6][7] However, the success of haploidentical SCT is hindered by the host and donor T-cell response to allogeneic HLA molecules resulting in unacceptably high incidences of GVHD and graft rejection. The questions of how allografts can avoid rejection from a haploidentical recipient immune system and how normal host tissues can avoid attack by donor alloreactive immune cells have intrigued immunologists and hematologists alike for nearly 30 years.…”