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Background: Cold agglutinin disease (CAD) is a rare autoimmune haemolytic anaemia mediated by the classical complement pathway (CP). Sutimlimab selectively targets complement C1s inhibiting classical CP activation. In CADENZA Part A (26-weeks), a placebo-controlled study in patients without recent transfusion history, sutimlimab reduced haemolysis, anaemia, and fatigue, and was generally well tolerated., Methods: The CADENZA study (NCT03347422) started in March 2018 (Part A) and completed in December 2021 (Part B). All patients in Part B were eligible to receive sutimlimab for up to 1 year after the last patient completed Part A. Efficacy and safety was assessed throughout Part B, until the last on-treatment visit with available assessment (LV), and after a 9-week washout., Findings: In total, 32/39 patients completed Part B; median treatment duration: 99 weeks. Similar sustained improvements in haemolysis, anaemia, and quality of life were observed in patients switching to sutimlimab and those continuing sutimlimab. Mean LV values for the combined group (ie, placebo-to-sutimlimab group and sutimlimab-to-sutimlimab group) improved from baseline for haemoglobin (≥11.0 g/dL on-treatment vs 9.3 g/dL at baseline), bilirubin (≤20.0 μmol/L on-treatment vs 35.0 μmol/L at baseline), and FACIT-Fatigue scores. Following a 9-week washout, inhibition of CP activity was reversed, and haemolytic markers approached baseline levels. Overall, sutimlimab was generally well tolerated throughout the study. No patients developed systemic lupus erythematosus or meningococcal infections. During the 9-week washout, most adverse events could be attributed to recurrence of underlying CAD., Interpretation: The CADENZA Part B results support the sustained efficacy and safety of sutimlimab for treatment of CAD; however, upon discontinuation disease activity reoccurs., Funding: Sanofi., Competing Interests: AR has received consultancy fees from Alexion Pharmaceuticals, Inc, Apellis Pharmaceuticals, Bioverativ, a Sanofi company, Novartis, Roche, and Sanofi; honoraria from Alexion, Amgen, Apellis, Novartis, Roche, Sanofi and Sobi, and advisory board fees from Alexion, Amgen, Apellis, Bioverativ, Novartis, Roche, Sanofi, and Sobi. SB has received research support from Mundipharma; lecture honoraria from Apellis, Bioverativ (a Sanofi company), Janssen-Cilag, Momenta Pharmaceuticals and True North Therapeutics; and consultancy and advisory board honoraria from Apellis, Bioverativ, and Momenta Pharmaceuticals. WB has received research support from Alexion; honoraria from Agios, Alexion, Apellis, Biocryst, Incyte, Janssen, Momenta, Novartis, Sanofi, and Sobi; and advisory board fees from Alexion, Novartis, Roche, Sanofi, and Sobi. SD reports speaker fees and research funding from Janssen, BeiGene and Sanofi. BJ has received reimbursement for travel costs related to scientific advice and scientific presentations from Sanofi. MM has received research support for clinical studies from Roche; received fees from Amgen and GlaxoSmithKline for their participation in scientific advisory boards. ICW has received consultancy fees from Alexion, Apellis, Novartis, and Biocryst; and honoraria from Alexion. MY has no disclosures. JN is a member of the advisory board for Chugai Pharmaceuticals and Alexion Pharmaceuticals and has received research funding and honorarium from Alexion Pharmaceuticals. JMIV has received honoraria from Sanofi, Amgen, and BMS; research support from Beigene and AbbVie/Genmab, and advisory board fees from Sanofi and Janssen; all of these are institutional. JC received research funding from Cerus, Kawasumi Laboratories and Sanofi; he also received speaker or advisory fees from Cerus, Fresenius Kabi, Grifols, MacoPharma, Pharm-Olam, Sanofi and Terumo Blood and Cell Technologies. CMB has received research support from Alexion, Argenx, Electra, Novartis, and Sanofi; honoraria from Alexion, Argenx, and Sanofi; and advisory board fees from Argenx, Novartis, and Sanofi. DJ, FS, ML, MS, MW, NW, RY, SS are Sanofi employees and may hold stock and/or stock options in the company., (© 2024 The Author(s).)

Background: Cold agglutinin disease (CAD) is a rare subtype of autoimmune haemolytic anaemia characterised by classical complement pathway-mediated haemolysis, fatigue, and poor quality of life (QoL). Sutimlimab, a C1s inhibitor, rapidly halted haemolysis, and improved patient-reported outcomes (PROs) in patients with CAD in two phase 3 trials (CARDINAL and CADENZA). Here we report PROs from the CADENZA open-label extension (Part B)., Methods: The first patient was enrolled in CADENZA (NCT03347422) in March 2018 (Part A) and the last patient completed the study in December 2021 (Part B). All patients who completed the 26-week Part A were eligible to receive biweekly doses of sutimlimab in Part B for up to 1 year after the last patient completed Part A. PROs were assessed throughout Part B, until the last on-treatment visit with available assessment (LV), and after a 9-week washout., Findings: In total, 32/39 patients completed Part B; median Part B treatment duration: 99 weeks. Patients switching from placebo to sutimlimab in Part B experienced rapid improvement in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score and other PROs. Sustained, clinically important improvements in FACIT-Fatigue were observed throughout Part B in patients who switched to sutimlimab and those continuing sutimlimab treatment (combined-group mean [SE] change from baseline at LV: 8.8 [2.1]). Similarly, the combined-group mean [SE] change for 12-Item Short Form Health Survey physical (4.9 [1.7]) and mental (4.0 [1.8]) component scores exceeded clinically important changes from baseline at LV. EuroQol visual analogue scale showed consistent and sustained increases from baseline with sutimlimab treatment. Following a 9-week washout, all PROs approached baseline values., Interpretation: Continued inhibition of the classical complement pathway with sutimlimab results in meaningful long-term improvements in PROs (fatigue and QoL) in patients with CAD., Funding: Sanofi., Competing Interests: AR has received consultancy fees from Alexion Pharmaceuticals, Inc, Apellis Pharmaceuticals, Bioverativ, a Sanofi company, Novartis, Roche, and Sanofi; honoraria from Alexion, Amgen, Apellis, Novartis, Roche, Sanofi and Sobi, and advisory board fees from Alexion, Amgen, Apellis, Bioverativ, Novartis, Roche, Sanofi, and Sobi. CMB has received research support from Alexion, Argenx, Electra, Novartis, and Sanofi; honoraria from Alexion, Argenx, and Sanofi; and advisory board fees from Argenx, Novartis, and Sanofi. WB has received research support from Alexion; honoraria from Agios, Alexion, Apellis, Biocryst, Incyte, Janssen, Momenta, Novartis, Sanofi, and Sobi; and advisory board fees from Alexion, Novartis, Roche, Sanofi, and Sobi. BJ has received reimbursement for travel costs related to scientific advice and scientific presentations from Sanofi. QAH has received research support from Alexion; consultancy fees from Amgen, Argenx, Gliknik, Grifols, Incyte, Immunovant, Janssen, Novartis, ReAlta, Sanofi, and Sobi; and honoraria from Amgen, Argenx, Bioverativ, Gliknik, Grifols, Incyte, Immunovant, Janssen, Novartis, ReAlta, Sanofi, Shire, and Sobi. DC has received research support to his institution from Astellas and consulting fees from Sanofi. THAT has received honoraria from Ablynx, Alexion, and Novartis. MY has no disclosures. IM has received consultancy fees and honoraria from Alexion, Apellis, Momenta/Janssen, Novartis, Rigel, Sanofi. ICW has received consultancy fees from Alexion, Apellis, Novartis, and Biocryst; and honoraria from Alexion. ML, FS, MW, DJ, RY and JM are Sanofi employees and may hold stock and/or stock options in the company., (© 2024 The Author(s).)

Please visit https://bit.ly/AJHpodcast to complete the accredited learning activity and receive CME credit or NCPD contact hours. Because immune-mediated rare blood disorders are uncommon, healthcare providers often lack the knowledge and experience necessary to identify, diagnose, and treat them in accordance with best practices. As a result, there are significant gaps in care, including delays in diagnosis and suboptimal treatment. To ensure that more patients with these rare disorders are offered quality, evidence-based care, it is essential that healthcare providers possess up-to-date information about best practices and new developments in this area of medicine. In this activity, composed of three podcasts, an expert moderator will interview three expert faculty members about evidence-based guidelines for the diagnosis and treatment of acquired thrombotic thrombocytopenic purpura; developments in the diagnosis and treatment of cold agglutinin disease; and the challenges of achieving enduring remission in patients with immune thrombocytopenia., (© 2024 Wiley Periodicals LLC.)