Risk Factors and Outcome after Second HLA-Matched Sibling Donor Transplantation for Graft Failure after a First HLA-Matched Sibling Transplant in Severe Aplastic Anemia.
Authors: Horan John , Carreras Jeanette , Tarima Sergey , Camitta Bruce , Gale Robert Peter , Hintergerger Wolfgang , Marsh Judith , Pasquini Ricardo , Pasquini Marcelo , Walters Mark , Eapen Mary 
Published: October 2019

Abstract
Graft failure rates after HLA matched sibling bone marrow (BM) transplants for severe aplastic anemia (SAA) are about 10%. We analyzed factors that may affect rates of hematopoietic recovery, graft-versus-host (GVHD) and overall survival after a second HLA-matched sibling donor transplant in 166 patients with SAA with graft failure after a first HLA-matched sibling donor transplant. Transplantations occurred between 1986 and 2004; median follow up of surviving patients is 8 years. One hundred and forty patients (84%) received their second transplant for secondary graft failure and 26 (16%), for primary graft failure. The median age at second transplantation was 17 years; 90% of patients were younger than 30 years. Sixty-seven percent had performance scores <90%. All patients received T-replete BM grafts for their first transplant; 16% received peripheral blood progenitor cells and 84% BM for their second transplant. Most (88%) second transplants used the original donor. Median time between first and second transplants was 7 months (range 1 – 114). Seventy-four percent received cyclophosphamide (CY) with or without anti-thymocyte globulin (ATG) conditioning for their first transplant. Forty-nine percent received this regimen for second transplant, 19% received CY and limited field irradiation, 10%, busulfan and CY, 11% melphalan and ATG, 4% other combinations of CY and 7% did not receive a second conditioning regimen. For both transplants, most patients (>95%) received GVHD prophylaxis regimen that included a calcineurin-inhibitor. Probabilities of neutrophil recovery at day 28 and platelet recovery at day 60 after second transplantation were 63% and, 62%. Rates of acute grades 2–4 GVHD at day 100 and chronic GVHD at 5 years were 9% and 16%, respectively. Early mortality rates were high, 30% at day-100. Risks of early mortality were lower when pre-transplant performance scores were 90–100% (relative risk [RR] 0.17, 95% CI 0.06–0.47, p=0.001) and when second transplant occurred >3 months from first transplant (RR 0.32, 95% CI 0.15–0.68, p=0.003). Similarly, risks of overall mortality were lower in patients with performance scores 90 – 100% (RR 0.53, 95% CI 0.30–0.95, p=0.033) and when second transplant occurred >3 months from first transplant (RR 0.47, 95% CI 0.29–0.76, p=0.002). Of the 47 patients who received their second transplant ≤ 3 months after their first transplant, 22 had primary graft failure after their first transplant and 25, early secondary graft failure. Fifteen of these 47 patients failed to achieve neutrophil recovery after their second transplant; 12 of 15 had primary graft failure after first transplant. Other factors such as use of a different donor, conditioning regimen, graft type and growth factor administration did not affect outcome after second transplantation. The 5-year probabilities of overall survival in patients with performance scores 90–100% whose second transplants occurred ≤ 3 months and >3 months after their first transplant were 56% and 76%, respectively. Corresponding rates for patients with performance scores <90 were 33% and 61%. We conclude that salvage with second transplantation after primary or early secondary graft failure is suboptimal. Better therapies are required to ensure sustained hematopoietic recovery in these patients.