Long-Term Outcome of Unrelated Cord Blood Transplantation in Patients with Idiopathic Refractory Severe Aplastic Anemia: A Nationwide Phase 2 Study
Authors: Clugston Stephanie , Chevret Sylvie , Jubert Charlotte , Sirvent Anne , Sterin Arthur , Gandemer Virginie , Cornillon Jérôme , Rialland Battisti Fanny , Dalle Jean-Hugues , Forcade Edouard , Bruno Benedicte , Paillard Catherine , Pochon Cecile , Loschi Michael , Devillier Raynier , Rubio Marie-Thérèse , Bay Jacques-Olivier , Brissot Eolia , Larghero Jerome , Gluckman Éliane , Socie Gerard , Sicre De Fontbrune Flore , Peffault De Latour Regis 
Published: December 2024

Introduction:
We previously conducted a prospective nationwide phase 2 study to assess the efficacy and safety of unrelated cord blood transplantation (CBT) in 26 refractory severe aplastic anemia (SAA) patients (APCORD protocol, NCT01343953). With a median follow-up of 38.8 months, engraftment occurred in 23 patients (88%); cumulative incidences of grade II-IV acute and chronic graft-versus-host disease (GVHD) were 45.8% and 36%, respectively. The overall survival (OS) was 88.5% at 1 year (Peffault de Latour, Blood 2018). In this follow-up analysis we examined the long-term outcomes in patients treated in the APCORD study.
Method:
Patients with primary refractory SAA at 6 months after antithymocyte globulin (ATG) and cyclosporine (CSA) or in relapse without an available matched unrelated donor were included. Cord blood selection required at least 1-2 unrelated cord blood units containing a total of at least 4x10^7 nucleated cells per kilogram, no more than 2 out of 6 HLA mismatches between each cord blood unit and the patient, and negative donor-specific HLA antibodies. Conditioning comprised fludarabine (FLU) 30 mg/m2/day and cyclophosphamide (CY) 30 mg/kg/day on days -6 to -3, ATG 2.5 mg/kg/day on day -3 and -2 and total body irradiation (TBI) 2-Gy on day -2. Graft-versus-host disease prophylaxis comprised cyclosporine alone.
Results:
Twenty-six patients underwent CBT between June 2011 and October 2015, with median age of 16 years (interquartile range (IQR) 9.3-23.4) and median time from initial SAA diagnosis to CBT of 12 months (IQR 8.7-17.8). Two patients have been lost to follow-up, at 31 and 45 months post-CBT. The actual median follow-up is 100.8 (IQR 76.4-117.8) months. Overall, 4 patients died during the first two years post-CBT (2 deaths from infection after non-engraftment and 2 from GVHD). Thus 22 of the 26 patients were included in this extended follow-up study.
There have been no further deaths since the initial follow-up period, resulting in an 8-year overall survival of 90.2% (95% confidence interval 78.2-100). There has been no new episode of graft failure or late graft rejection. No patient has newly presented chronic GVHD and all patients with prior chronic GVHD no longer have active GVHD and have stopped immunosuppressive therapy.
Cardiovascular complications have occurred in 2 patients (9%), one with a myocardial infarction and cardiac failure subsequently undergoing cardiac transplantation at 9 years post-CBT and the other with a stroke secondary to inflammatory vasculitis treated with corticosteroids and anti-TNFa therapy, who has regained function.
Osteonecrosis has affected 4 (18%) and endocrine disorders 6 (27%) patients (diabetes mellitus, growth hormone deficiency, ovarian insufficiency and osteoporosis). One case of secondary malignancy occurred, a thyroid papillary carcinoma; this patient is alive at last follow-up. One case of immune mediated thrombocytopenia, successfully treated with intravenous immunoglobulins, occurred at 6 months post-CBT.
Two patients (9%) have presented 4 infections since the first report, one case of ophthalmic varicella zoster and one patient with three acute infections post cardiac transplant. Post-transplant lymphoproliferative disorder has not occurred. Immune reconstitution has been favourable with normal median T cell counts and raised median B cell count at time of last assessment. Lastly, 20 patients have restarted either schooling or work activities. At last follow-up, only one patient continues immunosuppressive therapy following successful cardiac transplantation.
Conclusion:
Unrelated CBT following FLU-CY-TBI-ATG conditioning regimen for patients with refractory SAA is associated with an excellent long-term overall survival and importantly almost all patients regain functional activity in the long-term.