Abstracts Clinical Lymphoma, Myeloma & Leukemia September 2023 S360 instances, using the IPSS-M is unlikely to adversely impact outcomes when used to guide treatment decisions. Keywords: MDS, CMML, risk stratification, CPSS-Mol, IPSS-M, Mayo Molecular Model MDS-273 Oral Iptacopan Monotherapy Increases Paroxysmal Nocturnal Hemoglobinuria (PNH) Red Blood Cell Clone Size Via Control of Intra‑ and Extravascular Hemolysis in Anti‑C5‑Treated PNH Patients With Anemia Antonio M. Risitano MD, PhD1,2, Alexander Röth MD3, Austin Kulasekararaj MBBS, MD, MRCP, FRCPath4,5,6, Phillip Scheinberg MD7, Yasutaka Ueda MD, PhD8, Carlos de Castro MD9, Eros Di Bona MD10, Morag Griffin MBChB, FRCPath11, Saskia MC Langemeijer MD12, Hubert Schrezenmeier MD, PhD13,14, Wilma Barcellini MD15, Vitor AQ Mauad MD, MSc16, Jens Panse MD17,18, Philippe Schafhausen MD19, Suzanne Tavitian MD20, Eloise Beggiato MD21, Anna Gaya MD22, Wei-Han Huang MD23, Toshio Kitawaki MD, PhD24, Abdullah Kutlar MD25, Jaroslaw Maciejewski MD, PhD, FACP26, Rosario Notaro MD27,28, Vinod Pullarkat MD29, Jörg Schubert MD30, Louis Terriou MD31, Michihiro Uchiyama MD32, Flore Sicre de Fontbrune MD33, Luana Marano MD1,2, Ferras Alashkar MD3, Shreyans Gandhi MBBS, MD, DNB, MRCP, FRCPath, M.Phil4, Cécile Kerloeguen MSc34, Rakesh Kumar PhD35, Christine Thorburn N/A36, Samopriyo Maitra PhD35, Marion Dahlke MD, PgDipl34, Régis Peffault de Latour MD, PhD33,37 1AORN Moscati, Avellino, Italy. 2University of Naples Federico II, Naples, Italy. 3West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany. 4King’s College Hospital NHS, London, United Kingdom. 5National Institute for Health and Care Research and Wellcome King’s Research Facility, London, United Kingdom. 6King’s College London, London, United Kingdom. 7Hospital A Beneficência Portuguesa, São Paulo, Brazil. 8Osaka University Graduate School of Medicine, Suita, Japan. 9Duke University School of Medicine, Durham, USA. 10UOC Oncoematologia, AULSS7 Pedemontana, Bassano del Grappa (VI), Vicenza, Italy. 11St James’s University Hospital, Leeds, United Kingdom. 12Radboud University Medical Center, Nijmegen, Netherlands. 13University of Ulm, Ulm, Germany. 14German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen and University Hospital Ulm, Ulm, Germany. 15Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy. 16ABC Medical School, Santo André, Brazil. 17University Hospital RWTH Aachen, Aachen, Germany. 18Center for Integrated Oncology (CIO) Aachen, Bonn, Cologne, Düsseldorf, Germany. 19Medical Center Hamburg-Eppendorf, Hamburg, Germany. 20Toulouse University Hospital Center, Toulouse-Oncopole University Cancer Institute, Toulouse, France. 21University of Torino, Turin, Italy. 22Hospital Clinic of Barcelona, Barcelona, Spain. 23Hualien Tzu Chi Hospital, Hualien, Taiwan. 24Kyoto University, Kyoto, Japan. 25Medical College of Georgia, Augusta, USA. 26Taussig Cancer Institute, Cleveland Clinic, Cleveland, USA. 27Azienda Ospedaliera Universitaria Careggi, Firenze, Italy. 28Instituto per lo Studio, la Prevenzione e la Rete Oncologica, Firenze, Italy. 29City of Hope Medical Center, Duarte, USA. 30Elblandklinikum Riesa, Riesa, Germany. 31CHU Lille, Université de Lille, Lille, France. 32Japanese Red Cross Society Suwa Hospital, Suwa, Japan. 33French Référence Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Paris, France. 34Novartis Pharma AG, Basel, Switzerland. 35Novartis Healthcare Private Limited, Hyderabad, India. 36Novartis Pharmaceuticals UK Limited, London, United Kingdom. 37Assistance Publique Hôpitaux de Paris, Université Paris Cité, Paris, France Background: Anemia caused by C3-mediated extravascular hemolysis (EVH) commonly occurs in patients with PNH receiving standard-of-care (SOC). Iptacopan is an oral complement factor B inhibitor. In the 24-week randomized period of the Ph-3 APPLYPNH trial (NCT04558918), iptacopan monotherapy had superior efficacy to SOC. We report total PNH red blood cell (RBC) clone size and C3-deposition from the 24-week randomized period of APPLY-PNH. Methods: Adults with PNH (N=97) with mean hemoglobin <10g/dL on stable SOC (eculizumab/ravulizumab) for ≥6mo were randomized 8:5 (stratified by SOC and RBC transfusions [RBCTs] in the preceding 6mo) to take iptacopan 200mg twice-a-day (n=62) or continue SOC (n=35). Primary endpoints were defined as a ≥2g/dL hemoglobin increase from baseline and hemoglobin ≥12g/dL, without RBCTs. A prespecified testing procedure adjusted for multiplicity; unadjusted, 2-sided P-values are reported for significant endpoints. Total PNH RBC clone size and C3-deposition were exploratory endpoints. Results: Iptacopan was superior to SOC for both primary endpoints: 82.3% of iptacopan-treated vs 2.0% of SoC-treated patients had a ≥2g/ dL hemoglobin increase from baseline (P<.0001); 68.8% vs 1.8% achieved hemoglobin ≥12g/dL, respectively (P<.0001). Iptacopan was superior for RBCT avoidance (+70.3%; P<.0001), adjusted mean changes from baseline in hemoglobin (+3.63g/dL; P<.0001), FACIT−F score (+8.29; P<.0001) and absolute reticulocyte count (−116.26×109/L; P<.0001), and annualized clinical breakthrough hemolysis (BTH) rate (rate ratio: 0.10; P=.0118). In the iptacopan arm, mean total PNH RBC clone size (baseline, 64.6%) increased by wk4 and stabilized through wk24 (93.2%). Mean C3-deposition (baseline, 19.2%) reduced by wk4 and became negligible through wk24. Through wk24, both were comparable to baseline in the SOC arm. Headache/diarrhea were more commonly reported with iptacopan. Two SOC-treated patients experienced serious hemolysis; none for iptacopan. Conclusions: Iptacopan significantly improved hemoglobin levels vs SOC without RBCTs. By controlling intravascular hemolysis and reducing C3-deposition-mediated EVH, iptacopan led to an expected increase in PNH RBC survival to comprise >90% of the total RBC population. Clinical BTH rate and severity appeared lower with iptacopan. Iptacopan may become a practice-changing outpatient treatment for patients with PNH with a suboptimal response to eculizumab/ravulizumab and a preferred option for patients with hemolytic PNH. Keywords: paroxysmal nocturnal hemoglobinuria, iptacopan, complement inhibitor, hemolysis
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