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2180 Sars-Cov-2 Vaccination in Patients with Paroxysmal Nocturnal Hemoglobinuria: An Italian Multicenter Survey

Program: Oral and Poster Abstracts
Session: 508. Bone Marrow Failure: Poster II
Hematology Disease Topics & Pathways:
Acquired Marrow Failure Syndromes, Bone Marrow Failure Syndromes, Diversity, Equity, Inclusion, and Accessibility (DEI/DEIA) , Paroxysmal Nocturnal Hemoglobinuria, Diseases
Sunday, December 12, 2021, 6:00 PM-8:00 PM

Juri Alessandro Giannotta, MD1*, Bruno Fattizzo, MD2,3*, Corrado Girmenia4*, Claudia Ielo, MD5*, Elisabetta Metafuni6,7*, Adele Visentin8*, Paola Bianchi, PhD, BSc9, Vincenzo Apolito10*, Eloise Beggiato11*, Eros Di Bona, MD12*, Simona Sica13,14*, Anna Paola Iori15,16* and Wilma Barcellini17*

1Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy, Milano, Italy
2Department of Oncology and Oncohematology, University of Milan, Italy, Milan, Italy
3Hematology Unit, Pathophysiology of Anemias Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
4Ematologia, Dipartimento di Ematologia, Oncologia e Dermatologia, AOU Policlinico Umberto I, Università Sapienza, Rome, Italy, Roma, ITA
5Hematology, Department of Translational and Precision Medicine, Sapienza University, Policlinico Umberto I, Rome, Italy
6Istituto di Ematologia, Policlinico Universitario A Gemelli IRCCS, Universita’ Cattolica del Sacro Cuore, Roma, Italy
7Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
8UOC Oncoematologia, AULSS7 Pedemontana, Bassano del Grappa, Vicenza, Italy, Vicenza, Italy
9Foundation IRCCS Ca' Granda,, Milano, Italy
10Department of Oncology and Hematology, A.O.U. Città della Salute e della Scienza di Torino, Turin, Italy, Turin, Italy
11Dipartimento di Oncologia/Ematologia, presidio Molinette, Citta della salute e della scienza di Torino, Turin, Italy
12Hematology Department, UOC Oncoematologia, AULSS7 Pedemontana, Bassano del Grappa, Vicenza, Italy, Vicenza, Italy
13Dipartimento di Diagnostica per Immagini, Radioterapia Oncologia ed Ematologia, Fondazione Policlinico A. Gemelli IRCSS, Rome, Italy
14Fondazione Policlinico A. Gemelli IRCCS, Roma, Italy; Istituto di Ematologia, Università Cattolica del Sacro Cuore, Roma, Italy, Roma, Italy
15Department of Haematology, Oncology and Dermatology, “Umberto I” University Hospital, Roma Sapienza University, Rome, Italy, Roma, Italy
16Ematologia, Dipartimento di Ematologia, Oncologia e Dermatologia, AOU Policlinico Umberto I, Rome, Italy
17UOC Ematologia, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy

SARS-CoV-2 infection and vaccination have raised concerns in paroxysmal nocturnal hemoglobinuria (PNH). In fact, PNH patients carry an increased infectious risk secondary to complement inhibition treatment or associated bone marrow failure (BMF), and may therefore benefit from preventive strategies such as vaccinations. On the contrary, vaccines can be numbered among inflammatory complement amplifiers (e.g., infections, traumas, surgery), potentially triggering a disease exacerbation. In PNH patients on complement inhibitors, this phenomenon has been defined pharmacodynamic breakthrough hemolysis (BTH). Based on isolated reports of BTH following SARS-CoV-2 vaccines, we conducted a survey among 5 Italian reference centers to evaluate complications and BTH occurrence in PNH patients who completed the SARS-CoV-2 vaccination schedule from January, 2 2021 until the time of writing. Adverse events, hematologic and hemolytic parameters were recorded within 7-10 days before and after each dose of vaccine. A total of 67 patients (females/males 43/24, median age 47.6 years, range 21-90.5) were eligible for the analysis. According to the International PNH Interest Group classification, 45 patients suffered from hemolytic PNH, 20 from PNH in the context of BMF syndromes (aplastic anemia or myelodysplastic syndrome), and 2 from subclinical PNH. Fifty-five subjects (82%) were on regular complement inhibition therapy, i.e., eculizumab (N=35), ravulizumab (N=13), subcutaneous anti-C5 (N=3), anti-factor B (N=2) and ravulizumab + anti-factor D combination (N=2). Vaccines (Comirnaty/Pfizer-BioNTech N=53, mRNA-1273/Moderna N=12, and ChAdOx1 nCov-19/AstraZeneca N=2) were complessively well-tolerated, with 3 non-hematologic adverse events after the first dose (2 fever and 1 exercise-induced tachycardia, grade 1 according to CTCAE v5.0) and 2 after the second one (fever, accompanied by vomit in one patient, grade 1). During the observation period, 3 BTH and 1 hemolytic exacerbation were recorded (5.9% of patients), as detailed in Table 1. The most severe episode occurred in a young woman (Patient 3) on subcutaneous ravulizumab who experienced a hemoglobin (Hb) drop >2 g/dL, marked clinical signs of intravascular hemolysis and lactate dehydrogenase (LDH) increase >1.5 x upper limit of normal (ULN) from baseline, which is considered a clinical BTH according to the criteria proposed by the Severe Aplastic Anemia Working Party of the European group for Bone Marrow Transplantation. The patient required hospitalization for additional treatment with recombinant erythropoietin and anti-thombotic/bacterial prophylaxis. The second more severe BTH was registered in a male patient (Patient 1) on oral anti-factor B who experienced a Hb drop >2 g/dL without an overt hemolytic flare, and required hospitalization for intravenous antibiotic therapy (concomitant urinary tract infection). The remaining two patients experienced a subclinical BTH (Patient 2) and a hemolytic flare (Patient 4, not on complement inhibition). On the whole, a median delta variation from usual values of Hb and LDH of -25% (range -26+3%) and +80% (+18+105%) were observed, respectively. Of note, 3 episodes occurred after the second dose of vaccine, generally within 24-48 hours. Anti-complement drugs were not modified/discontinued in any of the 3 patients on regular treatment. Patients not experiencing BTH (94.1%) showed stable hematologic parameters after the first dose (Hb/LDH median delta variations from baseline -1%/+1%, range -14+12%/-32+40%) and the second dose of vaccine (Hb/LDH median delta variations from baseline +1%/0%, range -18+47%/-76+41%). Of note, 4 patients with a previous SARS-CoV-2 infection completed the vaccination without any complication/PNH exacerbation.

In conclusion, this survey shows that BTH/hemolytic flares following SARS-CoV-2 vaccines are observed in about 6% of PNH patients, may be clinically relevant but manageable, and should not discourage vaccination. BTH has been registered mostly few days after the second dose of vaccine, suggesting a “booster” effect favoring a higher inflammatory response. Watchful clinical and laboratory monitoring is advised, in order to promptly recognize severe hemolytic flares in both treated and naïve patients.

Disclosures: Fattizzo: Momenta: Honoraria, Speakers Bureau; Apellis: Speakers Bureau; Annexon: Consultancy; Amgen: Honoraria, Speakers Bureau; Alexion: Speakers Bureau; Novartis: Speakers Bureau; Kira: Speakers Bureau. Bianchi: Agios pharmaceutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sica: Jazz Pharma: Consultancy; Alexion: Consultancy. Barcellini: Novartis: Other: Invited speaker, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Other: Invited speaker, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH