HLA-mismatched bone marrow transplantation in severe aplastic anemia

Abstract

Hematopoietic stem cell transplantation (SCT) can be curative for patients with severe aplastic anemia (SAA).1, 2 Concerns about graft failure and graft-versus-host disease (GVHD), more so for human leukocyte antigen (HLA) -mismatched donors, have impeded the utility of SCT for these patients. The introduction of post-SCT cyclophosphamide (PTCy) has been shown to decrease alloreactivity in the host-versus-graft and graft-versus-host directions and could be particularly well suited for SAA patients.3 Only a few patients in two recent reports have documented outcomes of patients with SAA treated with a haploidentical transplant and PTCy-based GVHD prophylaxis, both using non-myeloablative (NMA) conditioning with fludarabine, cyclophosphamide and 2 Gy total body irradiation (TBI).4, 5 Concern for higher rejection rate, both primary and secondary, has prompted us to use a more intense conditioning regimen, as previously described.6 Here, we report clinical outcomes in transfusion dependent (n=6, 5 were refractory to first line immunosuppressive therapy, one patient received hypomethylating agent for hypoplastic MDS subsequently diagnosed as AA) SAA patients who underwent HLA-mismatched bone marrow SCT from haploidentical (n=2) and 9/10 matched unrelated donors (n=4) at our center between January 2010 and May 2013. Conditioning regimen consisted of melphalan (140 mg/m2) on day-8, thiotepa (5 mg/kg) on day-7 and fludarabine (160 mg/m2) on days −6 to −3. GVHD prophylaxis consisted of cyclophosphamide (50 mg/kg) on days +3 and +4, tacrolimus for 180 days and mycophenolate mofetil for 100 days post transplant. Median age of patients at the time of SCT was 37 years (range 21–50), median Karnofsky performance score was 90 (range 80–100) and median time from diagnosis to transplant was 9 months (range 2–15 months). Of the six patients, two of them had a concomitant PNH clone>20% prior to SCT. All patients engrafted the donor cells with 100% chimerism noted for both myeloid and T-cell lineage at day +30 post SCT. Of the four-long-term survivors, 100% donor (lymphoid and myeloid) chimerism was noted starting from day 30 until 1 year post SCT in three patients and for up to 6 months for one patient (follow-up care was transferred to an outside institution and was found to be disease-free at 1 year post SCT). Median time to neutrophil and platelet engraftment was 16 and 13 days, respectively (Table 1). Acute GVHD was seen in three patients (grades-1, 2 and 4 each) and led to death in one patient who had a 9/10 MUD SCT (Table 1). No chronic GVHD (cGVHD) or disease relapse was noted. After a median follow-up of 949 days (range 735–1617), 4/6 (66.6%) patients (two haploidentical and two 9/10 MUD) were alive, fully engrafted without cGVHD.