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305 Improved Outcomes in Paroxysmal Nocturnal Hemoglobinuria Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation in 2011-2020: A Retrospective EBMT-Saawp Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 508. Bone Marrow Failure: Acquired: Emerging Data in the Treatment of Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria
Hematology Disease Topics & Pathways:
Research, Bone Marrow Failure Syndromes, Clinical Research, Paroxysmal Nocturnal Hemoglobinuria, Diseases, Real-world evidence, Registries
Saturday, December 7, 2024: 5:00 PM

Camilla Frieri1,2*, Dirk-Jan Eikema Sr.3*, Joe Tuffnell4*, Brian Piepenbroek5*, Malek Benakli, MD6*, Grzegorz Helbig, MD, PhD7*, Thomas Cluzeau, MD, PhD8*, Cécile Renard, MD9*, Philippe Lewalle10*, Victoria Potter11*, Krzysztof Kalwak Sr.12*, Johan Maertens, MD, PhD13*, Gerard Michel, MD, PhD14*, Andrew Bruce McDonald, MBChB15, Péter Pál Reményi, MD16*, Ladislav Sopko17*, Kazimierz Halaburda18*, Depei Wu, MD, PhD19, Zubeyde Nur Ozkurt20*, Xavier Poiré, MD, PhD21*, Morag Griffin, MBChB, MRCP22*, Mahmoud Aljurf23*, Ashrafsadat Mousavi24*, Jose Antonio Pérez-Simón, MD, PhD25, Henrik Sengeloev26*, Ben Carpenter, MD27*, Eric Deconinck28, Arancha Bermúdez29*, Stéphanie Nguyen-Quoc, MD, PhD30*, Matteo Parma, MD31*, Ibrahim Yakoub-Agha, MD, PhD32*, Shankara Paneesha33*, Lutz Peter Hermann Mueller, MD34*, Regis Peffault De Latour35,36*, Austin G. Kulasekararaj, MD, MBBS, FRCPath, MRCP37 and Antonio M Risitano, MD, PhD38,39

1Hematology and Transplant Unit, A.O.R.N. S. Giuseppe Moscati, Avellino, Italy
2European Bone Marrow Transplantation society, Severe Aplastic Anemia Working Party, Leiden, Netherlands
3EBMT Statistical Unit, Leiden, Netherlands
4EBMT Leiden Study Unit, Leiden, Netherlands
5EBMTClinical Study Unit, Leiden, Netherlands
6Pierre and Marie Curie Center, Algiers, Algeria
7Department of Hematology and Bone Marrow Transplantation, Silesian Medical Academy, Katowice, Poland
8Centre Hospitalier Universitaire de Nice, Nice, France
9Institute of Hematology and Pediatric Oncology, Lyon, France
10Jules Bordet Institute (HUB/ULB), Brussels, Belgium
11Dept. of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, United Kingdom
12Fundacja "Na Ratunek Dzieciom z Choroba Nowotworowa", Wroclaw, Dolnoslaskie, Poland
13Department of Hematology, University Hospital Gasthuisberg, Leuven, Belgium
14CHU de Marseille Hôpital de la Timone Enfants, Marseille, France
15This, Randburg, ZAF
16Department of Hematology and Stem Cell Transplantation, Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
17University Hospital, Bratislava, Slovakia
18Institute of Hematology and Transfusion Medicine, Warsaw, Poland
19Department of Hematology, Collaborative Innovation Center of Hematology, Institute of Blood and Marrow Transplantation, the First Affiliated Hospital of Soochow University, Suzhou, China
20Gazi University Faculty of Medicine, Ankara, Turkey
21Section of Hematology, Institut Roi Albert II, Cliniques Universitaires St-Luc, Brussels, Belgium
22Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
23King Faisal Specialist Hospital & Research Centre, Oncology (Section of Adult Haematolgy/BMT) – Riyadh, Saudi Arabia, Riyadh, Saudi Arabia
24Shariati Hospital, Teheran, Iran (Islamic Republic of)
25Department of Hematology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS), CSIC, University of Sevilla, Sevilla, Spain
26Rigshospitalet, Copenhagen, Denmark
27University College London Hospitals NHS Foundation Trust, London, United Kingdom
28Université de Franche-Comté, EFS, INSERM, UMR RIGHT, Besançon, France
29Department of Hematology, Hospital Universitario Marqués de Valdecilla, Cantabria, Spain
30Hematology Department, Pitié-Salpêtrière University Hospital, AP-HP, Paris, France
31Hematology Department, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
32CHU de Lille, Université de Lille, INSERM U1286, Infinite, 59000, Lille, France
33Birmingham Centre for Cellular Therapy and Transplant (BCCTT), Birmingham, United Kingdom
34Department of Internal Medicine IV, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany
35BMT unit, Hôpital Saint-Louis,, Paris, France
36French Référence Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Paris, France
37King’s College Hospital-NHS Foundation Trust, NIHR/Wellcome King’s Clinical Research Facility, and King’s College London, London, United Kingdom
38Severe Aplastic Anemia Working Party, European Group for Blood and Marrow Transplantation (EBMT), Leiden, Netherlands
39Hematology and BMT Unit, AORN San Giuseppe Moscati, Avellino, Italy

Introduction

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Paroxysmal Nocturnal Hemoglobinuria (PNH) patients has not been investigated in the era of complement inhibitors and available data demonstrated survival rate below 70% (Peffault de Latour et al., Haematologica 2012). Here we describe a retrospective study conducted by the Severe Aplastic Anemia Working Party (SAAWP) looking at the outcomes of PNH patients undergoing HSCT between 2011 and 2020.

Methods

All consecutive first HSCT for PNH performed at EBMT centers were evaluated in retrospective analysis. Data were retrieved from the EBMT registry Promise (looking specifically for the diagnosis of PNH), which includes detailed information about the underlying disease, the HSCT procedure, and treatment outcomes, including engraftment, graft failure, acute and chronic graft versus host disease (GVHD), overall survival (OS), as well as event-free survival (EFS; events: primary and secondary graft failure, second transplant, relapse and death) and GvHD/relapse-free survival (GRFS; events: aGvHD III-IV, extensive cGvHD, relapse, graft failure (any)/no engraftment and death). Death was a competing event for engraftment, graft failure and GVHD.

Results

A total of 240 PNH patients underwent HSCT in the decade 2011-2020 in 125 EBMT transplant centers, with a slight imbalance between the two quinquennia (60% vs 40%). Median age at HSCT was 26.4 years (IQR, 18.6 to 37.2 years). The median time from diagnosis to allo-HSCT was 10.3 months (IQR, 4.8 to 34.7 months). Median follow up was 2.9 years. Patients were transplanted either from an HLA-matched sibling (MSD; 46.7%), matched unrelated (MUD; 37.1%), mismatched-unrelated (MMUD; 12.9%) or mismatched haplo-identical (Haplo; 3.3%) donor. The stem cell source was peripheral blood (PB) in 52.9% and bone marrow (BM) in 45.8%; 76.6% of patients received reduced-intensity conditioning (RIC) and 23.4% myeloablative conditioning (MAC) regimen. GvHD prophylaxis was based on calcineurin inhibitors alone (CNI; 23.7%), or associated to serotherapy (anti-thymocyte globulin 67.8%, alemtuzumab 3.4%) or to post-transplant cyclophosphamide (5.1%). The cumulative incidence of engraftment by day 28 was 87% for neutrophils (median time 18 days (16-19) and 85% by day 60 for platelets (median time 22 days (18-24). The 3-years OS was 79%, with infections and GVHD as main causes of death. Strikingly, donor type and patient age were associated with survival with 3-years estimates of OS 86% for MSD, 78% for MUD, 62% for MMUD (p=0.003). Three-year OS was 83% in patients <20 years, 82% 20-40 years, 67% >40 years (p=0.047). Interval between diagnosis and transplant (>1 years) was also associated with OS (73% vs 84% <1 year; p=0.036), while conditioning regimen, comorbidity index (HCT-CI), stem cell source and GVHD prophylaxis (CNI vs serotherapy) was not.

Rate of grade II-IV acute GVHD was 14% (MSD 12%; MUD 10%; MMUD 28%; p=0.046), and chronic GVHD was 13% (MSD 15%; MUD 5%; MMUD 25%; p=0.06). As a result, 3-years GRFS was 66%, with an impact of donor type (MSD 74%; MUD 65%; MMUD 46%; p=0.025) and of interval between diagnosis and transplant (>1 year 57% vs 73% £1 year; p=0.02). Primary (at 30 days) and secondary (at 3 years) graft failure were 8% and 6%, respectively. Donor type impacted primary graft (MSD 2%; MUD 14%, MMUD 3%; p<0.001) but not secondary graft failure, whereas stem cell source impacted only secondary graft failure (BM 10%, PB 3%; p=0.008).

The 3-years EFS was 69%. Here, donor type (MSD 80%, MUD 65%, MMUD 54% (p=0.006) and interval between diagnosis and transplant (>1 year 61% vs 76% <1 year; p=0.015) impacted EFS; conditioning regimen, patient’s age, HCT-CI, stem cell source and GvHD prophylaxis did not.

Out of the 8 patients transplanted from an Haplo donor, 4 experienced graft failure (1 died, 2 rescued by second HSCT), 2/8 suffered from aGVHD and 1/7 from cGVHD (1 fatal), with 3/8 being alive free of GVHD and relapse.

Conclusions

The outcome of PNH patients receiving allogeneic HSCT has meaningfully improved in the last decade with increasing OS rate in HLA-identical donors (both related and unrelated), especially in young patients; a RIC regimen was as good as a MAC regimen. Complement inhibitors remain the standard of care for hemolytic PNH patients, however allogeneic HSCT can be considered an alternative option in case of non-availability of complement inhibitors, or in specific clinical settings.

Disclosures: Renard: Jazz pharmaceuticals: Consultancy, Honoraria; Medac: Consultancy, Honoraria; Pierre Fabre: Honoraria, Other: travels. McDonald: MSD: Other: Travel expenses, Research Funding. Griffin: Sobi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biocryst: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Regeneron Pharmaceuticals: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pérez-Simón: Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; J&J: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Carpenter: Bluebird Biotech: Honoraria; Vertex Pharmaceuticals Incorporated: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Deconinck: ImmunoGen: Research Funding; Menarini-Stemline: Other: consultancy, Research Funding; Abbvie: Research Funding; Novartis: Research Funding. Yakoub-Agha: Kite, a Gilead Company: Honoraria, Other: Travel Support; Janssen: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria. Mueller: Pfizer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: travel grant; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Other: travel grant; BMS: Honoraria, Other: Travel grant; Squibb: Honoraria, Other: travel grant. Peffault De Latour: pfizer: Consultancy, Honoraria, Research Funding; soby: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria, Research Funding; alexion: Consultancy, Honoraria, Research Funding. Kulasekararaj: Janssen: Consultancy; Samsung: Consultancy, Honoraria, Speakers Bureau; BioCryst: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Akari: Consultancy, Honoraria, Speakers Bureau; Silence Therapeutics: Honoraria; Agios: Honoraria; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Achillion: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Risitano: Apellis: Speakers Bureau; Amyndas: Consultancy; Omeros: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Speakers Bureau.

*signifies non-member of ASH