A Novel Protocol for Haploidentical HSCT Without in Vitro T Cell Depletion in the Treatment of Severe Acquired Aplastic Anemia

Mismatched related donor HSCT for severe aplastic anemia (SAA) presents challenges, mainly associated with graft failure and GVHD. Non-engraftment and graft rejection after allo-HSCT for SAA has been strongly associated with higher degrees of histoincompatibility and allosensitization to histocompatibility antigens due to previous blood product transfusions. Earlier reports have suggested that the greater the HLA disparity, the poorer the overall survival (OS), less than 20% survival for two or more loci-mismatched recipients. Recently, progress has been made in haploidentical HSCT, which is now used to perform haploidentical non-T-cell-depleted HSCT for patients with hematological malignancies, it is not known whether the similar procedure could be used for patients with SAA. We report the results of 19 consecutive SAA/VSAA patients who received haploidentical-HSCT. All cases failed to previous therapy and were heavily transfused prior to transplantation. Among these, 9 cases had 3 loci mismatches, 9 cases had 2 loci mismatches, and 1 case had 1 locus mismatch. All patients were treated with a regimen which consisted of the following: busulfan (6.4mg/kg i.v. in 8 doses); cyclophosphamide (200mg/kg, i.v. in 4 doses); and ATG (10mg/kg i.v.,rabbit, of the Sangstat product or 80mg/kg i.v.,porcine,the Bioproduct, Wuhan, in 4 doses).All recipients received CsA, mycophenolate mofetil, and short-term MTX for GVHD prophylaxis. The source of stem cell grafts was a combination of G-CSF-primed BM and G-CSF-mobilized peripheral blood stem cells. All patients achieved 100% donor myeloid engraftment; the median time for myeloid engraftment was 12 days (ranging from 10-29 days) and 18 days (ranging from 8-180 days) for platelets, with a cumulative platelet engraftment incidence of 84.21 ± 10.53%. Two patients (10.5%) suffered late graft rejection. The cumulative incidence was 42.1 ± 11.3% for grade II-IV acute GVHD (aGVHD) and 21.1 ± 9.4% for grade III-IV aGVHD. The cumulative incidence was 56.2 ± 12.4% for chronic GVHD (cGVHD) and 12.5 ± 8.3% for extensive cGVHD. Of 13 surviving patients with a median 746 d (90-1970) follow-up, OS was 64.6 ± 12.4%. The independent high risk factors to OS are grade II-IV aGVHD and mononuclear cells (MNC) infused <8.84x108/kg. These limited data suggest that HLA-mismatched/haploidentical HSCT for SAA patients without an HLA-identical sibling donor may be feasible. Properly controlled trials will be needed to confirm this conclusion. Mismatched related donor HSCT for severe aplastic anemia (SAA) presents challenges, mainly associated with graft failure and GVHD. Non-engraftment and graft rejection after allo-HSCT for SAA has been strongly associated with higher degrees of histoincompatibility and allosensitization to histocompatibility antigens due to previous blood product transfusions. Earlier reports have suggested that the greater the HLA disparity, the poorer the overall survival (OS), less than 20% survival for two or more loci-mismatched recipients. Recently, progress has been made in haploidentical HSCT, which is now used to perform haploidentical non-T-cell-depleted HSCT for patients with hematological malignancies, it is not known whether the similar procedure could be used for patients with SAA. We report the results of 19 consecutive SAA/VSAA patients who received haploidentical-HSCT. All cases failed to previous therapy and were heavily transfused prior to transplantation. Among these, 9 cases had 3 loci mismatches, 9 cases had 2 loci mismatches, and 1 case had 1 locus mismatch. All patients were treated with a regimen which consisted of the following: busulfan (6.4mg/kg i.v. in 8 doses); cyclophosphamide (200mg/kg, i.v. in 4 doses); and ATG (10mg/kg i.v.,rabbit, of the Sangstat product or 80mg/kg i.v.,porcine,the Bioproduct, Wuhan, in 4 doses).All recipients received CsA, mycophenolate mofetil, and short-term MTX for GVHD prophylaxis. The source of stem cell grafts was a combination of G-CSF-primed BM and G-CSF-mobilized peripheral blood stem cells. All patients achieved 100% donor myeloid engraftment; the median time for myeloid engraftment was 12 days (ranging from 10-29 days) and 18 days (ranging from 8-180 days) for platelets, with a cumulative platelet engraftment incidence of 84.21 ± 10.53%. Two patients (10.5%) suffered late graft rejection. The cumulative incidence was 42.1 ± 11.3% for grade II-IV acute GVHD (aGVHD) and 21.1 ± 9.4% for grade III-IV aGVHD. The cumulative incidence was 56.2 ± 12.4% for chronic GVHD (cGVHD) and 12.5 ± 8.3% for extensive cGVHD. Of 13 surviving patients with a median 746 d (90-1970) follow-up, OS was 64.6 ± 12.4%. The independent high risk factors to OS are grade II-IV aGVHD and mononuclear cells (MNC) infused <8.84x108/kg. These limited data suggest that HLA-mismatched/haploidentical HSCT for SAA patients without an HLA-identical sibling donor may be feasible. Properly controlled trials will be needed to confirm this conclusion.