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596 Long-Term Outcome of Unrelated Cord Blood Transplantation in Patients with Idiopathic Refractory Severe Aplastic Anemia: A Nationwide Phase 2 Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 723. Allogeneic Transplantation: Long-Term Follow up and Disease Recurrence: Long-term Outcomes Including in Bone Marrow Failure and Rare Diseases
Hematology Disease Topics & Pathways:
Clinical trials, Adult, Research, Clinical Research, Treatment Considerations, Young adult , Study Population, Human
Sunday, December 8, 2024: 12:15 PM

Stephanie Clugston, MBBS1, Sylvie Chevret2*, Charlotte Jubert, MD3,4*, Anne Sirvent5*, Arthur Sterin6*, Virginie Gandemer7*, Jérôme Cornillon8*, Fanny Rialland Battisti, MD9*, Jean-Hugues Dalle, MD, PHD10, Edouard Forcade, MD, PhD4,11*, Benedicte Bruno4,12*, Catherine Paillard, MD, PHD13*, Cecile Pochon14*, Michael Loschi, MD, PhD15*, Raynier Devillier, MD, PhD16*, Marie-Thérèse Rubio, MD, PhD17*, Jacques-Olivier Bay, MD, PhD18*, Eolia Brissot19, Jerome Larghero20*, Éliane Gluckman21, Gerard Socie1,4,22, Flore Sicre De Fontbrune1,4,22* and Regis Peffault De Latour1,4,22,23*

1Bone Marrow Transplantation (BMT) Unit, Saint Louis Hospital, Assistance Publique — Hôpitaux de Paris (AP-HP), Paris, France
2Biostatistics and Medical Information Department, Saint Louis Hospital, Assistance Publique — Hôpitaux de Paris (AP-HP), Paris, France
3Pediatric BMT Unit, Bordeaux University Hospital, Bordeaux, France
4French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Saint Louis Hospital, Paris, France
5Pediatric BMT Unit, Montpellier, France
6Hématologie, immunologie et oncologie pédiatrique, Hôpitaux Universitaires de Marseille, Marseille, France
7Pediatric BMT Unit, Rennes, France
8Département d'hématologie Clinique et de Thérapie Cellulaire, CHU Saint-Etienne, Saint-Etienne, France
9Pediatric BMT Unit, Nantes University Hospital, Nantes, France
10Pediatric BMT Unit, Robert-Debré, AP-HP, Paris, France
11BMT and Cell Therapy Unit, Bordeaux, France
12Pediatric BMT Unit, Lille, France
13Pediatric BMT Unit, Strasbourg, France
14Department of Hematology, Centre Hospitalier Régional Universitaire (CHRU), Vandoeuvre-les-Nancy, France
15Hematology Department, Nice University Hospital, Nice, France
16Hematology and Transplantation, Institut Paoli-Calmettes, Aix Marseille University, Marseille, France
17BMT Unit, Nancy, France
18BMT Unit, Clermont-Ferrand University Hospital, Clermont-Ferrand, France
19Service d’hématologie et des maladies du sang, Hôpital Saint-Antoine, Paris, France
20Cell Therapy Unit, Saint-Louis Hospital, APHP, Paris, France
21Eurocord, Saint Louis Hospital, AP-HP, Paris, France
22University Paris Diderot, Paris, France
23Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation, Leiden, Netherlands

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.

Disclosures: Dalle: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Symbiopharm: Consultancy, Honoraria; Vertex: Consultancy, Honoraria; Orchard: Consultancy, Honoraria; Pierre Fabre Médicaments: Consultancy, Honoraria, Other: travels; Teva: Current equity holder in private company. Forcade: Alexion: Other: Travel support, Speakers Bureau; Novartis: Consultancy; Maat Pharma: Consultancy; Sobi: Speakers Bureau; Sanofi: Other: Travel support, Speakers Bureau; Astellas: Research Funding; Gilead: Other: Travel support, Speakers Bureau; GSK: Speakers Bureau; Jazz: Speakers Bureau; Novartis: Other: Travel support, Speakers Bureau. Sicre De Fontbrune: pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Jazz pharmaceuticals: Consultancy, Honoraria. Peffault De Latour: pfizer: Consultancy, Honoraria, Research Funding; soby: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria, Research Funding; alexion: Consultancy, Honoraria, Research Funding.

*signifies non-member of ASH