Long-term efficacy and safety of continued complement C1s inhibition with sutimlimab in cold agglutinin disease: CADENZA study Part B.

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.

Cold-antibody Autoimmune Hemolytic Anemia: its Association with Neoplastic Disease and Impact on Therapy.

PURPOSE OF REVIEW: Cold-antibody mediated autoimmune hemolytic anemia (cAIHA) is subclassified as cold agglutinin disease (CAD), secondary cold agglutinin syndrome (CAS), and paroxysmal cold hemoglobinuria (PCH). This review aims to address the occurrence of neoplastic disorders with these three entities and analyze the impact of such neoplasias on treatment for cAIHA. RECENT FINDINGS: "Primary" CAD is a distinct clonal B-cell lymphoproliferative disorder in probably all cases, although not classified as a malignant lymphoma. CAS is secondary to malignant lymphoma in a minority of cases. Recent findings allow a further clarification of these differential diagnoses and the therapeutic consequences of specific neoplastic entities. Appropriate diagnostic workup is critical for therapy in cAIHA. Patients with CAD should be treated if they have symptomatic anemia, significant fatigue, or bothersome circulatory symptoms. The distinction between CAD and CAS and the presence of any underlying malignancy in CAS have essential therapeutic implications.

The impact of individual clinical features in cold agglutinin disease: hemolytic versus non-hemolytic symptoms.

INTRODUCTION: During the last decades, the pathogenesis of cold agglutinin disease (CAD) has been well elucidated and shown to be complex. Several documented or investigational therapies have been made available. This development has resulted in major therapeutic advances, but also in challenges in choice of therapy. AREAS COVERED: In this review, we address each step in pathogenesis: bone marrow clonal lymphoproliferation, composition and effects of monoclonal cold agglutinin, non-complement mediated erythrocyte agglutination, complement-dependent hemolysis, and other effects of complement activation. We also discuss the heterogeneous clinical features and their relation to specific steps in pathogenesis, in particular with respect to the impact of complement involvement. CAD can be classified into three clinical phenotypes with consequences for established treatments as well as development of new therapies. Some promising future treatment approaches - beyond chemoimmunotherapy and complement inhibition - are reviewed. EXPERT OPINION: The patient's individual clinical profile regarding complement involvement and hemolytic versus non-hemolytic features is important for the choice of treatment. Further development of treatment approaches is encouraged, and some candidate drugs are promising irrespective of clinical phenotype. Patients with CAD requiring therapy should be considered for inclusion in clinical trials.

Management of autoimmune haemolytic anaemia in low-to-middle income countries: current challenges and the way forward.

Autoimmune haemolytic anaemia (AIHA) is a common term for several disorders that differ from one another in terms of aetiology, pathogenesis, clinical features, and treatment. Therapy is becoming increasingly differentiated and evidence-based, and several new established and investigational therapeutic approaches have appeared during recent years. While this development has resulted in therapeutic improvements, it also carries increased medical and financial requirements for optimal diagnosis, subgrouping, and individualization of therapy, including the use of more advanced laboratory tests and expensive drugs. In this brief Viewpoint review, we first summarize the diagnostic workup of AIHA subgroups and the respective therapies that are currently considered optimal. We then compare these principles with real-world data from India, the world's largest nation by population and a typical low-to-middle income country. We identify major deficiencies and limitations in general and laboratory resources, real-life diagnostic procedures, and therapeutic practices. Incomplete diagnostic workup, overuse of corticosteroids, lack of access to more specific treatments, and poor follow-up of patients are the rule more than exceptions. Although it may not seem realistic to resolve all challenges, we try to outline some ways towards an improved management of patients with AIHA.

Primary autoimmune haemolytic anaemia is associated with increased risk of ischaemic stroke: A binational cohort study from Denmark and France.

Primary autoimmune haemolytic anaemia (AIHA) causes the destruction of red blood cells and a subsequent pro-thrombotic state, potentially increasing the risk of ischaemic stroke. We investigated the risk of ischaemic stroke in patients with AIHA in a binational study. We used prospectively collected data from nationwide registers in Denmark and France to identify cohorts of patients with primary AIHA and age- and sex-matched general population comparators. We followed the patient and comparison cohorts for up to 5 years, with the first hospitalization of a stroke during follow-up as the main outcome. We estimated cumulative incidence, cause-specific hazard ratios (csHR) and adjusted for comorbidity and exposure to selected medications. The combined AIHA cohorts from both countries comprised 5994 patients and the 81 525 comparators. There were 130 ischaemic strokes in the AIHA cohort and 1821 among the comparators. Country-specific estimates were comparable, and the overall adjusted csHR was 1.36 [95% CI: 1.13-1.65], p = 0.001; the higher rate was limited to the first year after AIHA diagnosis (csHR 2.29 [95% CI: 1.77-2.97], p < 10-9 ) and decreased thereafter (csHR 0.89 [95% CI: 0.66-1.20], p = 0.45) (p-interaction < 10-5 ). The findings indicate that patients diagnosed with primary AIHA are at higher risk of ischaemic stroke in the first year after diagnosis.

Gene expression analysis revealed downregulation of complement receptor 1 in clonal B cells in cold agglutinin disease.

Cold agglutinin disease (CAD) is a rare B-cell lymphoproliferative disorder of the bone marrow, manifested by autoimmune hemolytic anemia caused by binding of monoclonal IgM autoantibodies to the I antigen. Underlying genetic changes have previously been reported, but their impact on gene expression profile has been unknown. Here, we define differentially expressed genes in CAD B cells. To unravel downstream alteration in cellular pathways, gene expression by RNA sequencing was undertaken. Clonal B-cell samples from 12 CAD patients and IgM-expressing memory B cells from 4 healthy individuals were analyzed. Differential expression analysis and filtering resulted in 93 genes with significant differential expression. Top upregulated genes included SLC4A1, SPTA1, YBX3, TESC, HBD, AHSP, TRAF1, HBA2, RHAG, CA1, SPTB, IL10, UBASH3B, ALAS2, HBA1, CRYM, RGCC, KANK2, and IGHV4-34. They were upregulated at least 8-fold, while complement receptor 1 (CR1/CD35) was downregulated 11-fold in clonal CAD B cells compared to control B cells. Flow cytometry analyses further confirmed reduced CR1 (CD35) protein expression by clonal CAD IgM+ B cells compared to IgM+ memory B cells in controls. CR1 (CD35) is an important negative regulator of B-cell activation and differentiation. Therefore, reduced CR1 (CD35) expression may increase activation, proliferation, and antibody production in CAD-associated clonal B cells.