Excellent Outcomes of Combined Haploidentical and Cord-Blood (Haplo-Cord) Transplantation and HLA-Matched Sibling (Matched-Sib) Donor Transplantation for High-Risk Patients with Severe Aplastic Anemia (SAA) Refractory to Immunosuppressive Therapy
Authors: Purev Enkhtsetseg , Aue Georg , Vo Phuong , Kotecha Ritesh , Wilder Jennifer S. , McDuffy Emily , Wells Brian , Shalabi Reem , Prince Patricia , Bergerson Sarah , Khuu Hahn M. , Stroncek David , Kurlander Roger , Reger Robert N. , Flagel Willy , Adams Sharon , Cho Elena , Worthy Tatyana , Cook Lisa , Ramos Catalina , Pantin Jeremy M , Young Neal S. , Tian Xin , Childs Richard W. 
Published: October 2019

Abstract
Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for SAA unresponsive to immunosuppressive therapy (IST). For SAA patients (pts) with a HLA-identical sibling donor, the use of peripheral-blood (PB) grafts have been reported to have increased risk of graft-versus-host disease (GVHD) compared with using the bone marrow (BM) as the stem cell source. For pts lacking an HLA-identical donor, transplantation using unrelated cord blood (UCB) or haplo-identical donors has historically been associated with high graft failure rates and poor survival. Here we report and compare the clinical outcomes for two novel transplantation strategies under investigation at our center aimed at improving engraftment and survival and reducing GVHD in high-risk SAA pts refractory to IST: combined haploidentical and cord-blood (haplo-cord) transplants vs. HLA-matched sibling (matched-sib) donor PB HSCT with partial T-cell depletion.
Methods: Forty-seven pts with SAA or SAA evolved to MDS that was unresponsive to IST underwent HSCT at a single center between 2008 and 2016, and received either a haplo-cord transplant (n= 28; pt eligibility included lack a HLA-matched donor but availability of a haploidentical relative, a ≥4/6 HLA matched UCB unit and severe neutropenia with an ANC<500 cells/µL) or an HLA matched-sib transplant (n=19). Both cohorts were treated with cyclophosphamide, ATG, and fludarabine, with the haplo-cord cohort also receiving 200 cGy of total body irradiation. For the haplo-cord cohort, pts received a CD34-selected G-CSF mobilized haplo-donor allograft combined with a ≥ 4/6 HLA-matched UCB unit (minimum TNC dose ≥1.5x107 cells/kg). For the matched-sib cohort, pts received G-CSF-mobilized PBSC-allograft containing high numbers of CD34+ selected cells combined with BM transplant equivalent-dose of non-mobilized CD3+T-cells/kg from a ≥9/10 HLA-matched sibling donor. GVHD prophylaxis included tacrolimus and MMF (haplo-cord) or CSA and MTX (matched-sib). Results: The median age at transplant was 20 years (range 5-49) in haplo-cord and 22 years (6-67) in matched-sib. Pts were heavily transfused and allo-immunized: pre-transplant serum ferritin was markedly elevated at a median 3368 µg/l (range 980-21465) and 1978 µg/l (161-13928) for haplo-cord and matched-sib cohorts, respectively. For the haplo-cord cohort, 18 pts received a 4/6 and 10 pts received a ≥5/6 HLA-matched UCB unit; UCB units contained a median of 3.6x107 TNCs/kg and 1.5x105 CD34+ cells/kg; haplo-grafts contained a median of 3.2x106 CD34+ cells/kg and 1.0x103 CD3+ T-cells/kg. For the matched-sib cohort, PBSC allografts from 10/10 (n=18) or 9/10 (n=1) HLA-matched donors contained a median of 8x106CD34+ cells/kg and 2x107 non-mobilized CD3 T-cells/kg. At a median follow-up of 40 months in haplo-cord and 32 months in matched-sib, most post-transplant clinical outcomes were comparable between two cohorts. In both cohorts, all pts (100%) had donor engraftment with neutrophil recovery occurring at a median of 10 days (range 6-28) in haplo-cord and 14 days (10-23) in matched-sib (Figure); median times to platelet recovery were 28 and 18 days. No patients in the matched-sib and only one pt (4%) in haplo-cord group developed late graft failure. The 200-day survival were 100% and 95%, and overall survival at 5 years were 91% and 87% in haplo-cord and matched-sib cohorts, respectively (Figure, P=0.7). The cumulative incidences of grade II-IV and III-IV acute GVHD were 37% and 4% in haplo-cord, compared to 21% and 11% in matched-sib. The cumulative incidence of chronic GVHD was higher in haplo-cord than matched-sib (45% vs.12%), however, only 8% and 0% extensive chronic GVHD occurred in two cohorts, respectively. Conclusion: Both transplant regimens being studied our center for SAA pts with high-risk ATG-refractory disease resulted in rapid neutrophil recovery, durable donor engraftment and excellent long-term survival. Despite pts being heavily transfused, iron overloaded and HLA allo-immunized, adverse outcomes of graft failure, severe acute grade III-IV GVHD and extensive chronic GVHD rarely occurred with either transplant approach. Remarkably, most transplant outcomes including survival were similar between haplo-cord and matched-sib cohorts, establishing haplo-cord transplantation to be a viable and promising transplant strategy for SAA pts who lack an HLA identical sibling.
Figure Figure.

Disclosures
Young: GSK/Novartis: Research Funding.