Search

Sigbjørn Berentsen,1 Alexander Röth,2 Ulla Randen,3 Bernd Jilma,4 Geir E Tjønnfjord5–71Department of Research and Innovation, Haugesund Hospital, Haugesund, Norway; 2Department of Hematology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; 3Department of Pathology, Akershus University Hospital, Lørenskog, Norway; 4Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; 5Department of Haematology, Oslo University Hospital, Oslo, Norway; 6KG Jebsen’s Center for B-cell Malignancies, University of Oslo, Oslo, Norway; 7Institute of Clinical Medicine, University of Oslo, Oslo, NorwayAbstract: Cold agglutinin disease (CAD) is a complement-dependent, classical pathway-mediated immune hemolytic disease, accounting for 15–25% of autoimmune hemolytic anemia, and at the same time, a distinct clonal B-cell lymphoproliferative disorder of the bone marrow. The disease burden is often high, but not all patients require pharmacological treatment. Several therapies directed at the pathogenic B-cells are now available. Rituximab plus bendamustine or rituximab monotherapy should be considered first-line treatment, depending on individual patient characteristics. Novel treatment options that target the classical complement pathway are under development and appear very promising, and the C1s inhibitor sutimlimab is currently being investigated in two clinical Phase II and III trials. These achievements have raised new challenges and further prospects, which are discussed. Patients with CAD requiring therapy should be considered for clinical trials.Keywords: autoimmune hemolytic anemia, cold agglutinin disease, lymphoproliferative, complement, complement inhibitors, therapy

Competing Interests: I have received advisory board and consultancy honoraria from BeiGene, HillStar Bio, Hummingbird Bioscience, Johnson & Johnson, Sanofi, and Sobi, and lecture honoraria from BeiGene, Janssen-Cilag, Sanofi, and Sobi.

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., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.

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).)

Competing Interests: S.B. has received consultancy and advisory board honoraria from BeiGene, HillStar Bio, Hummingbird Bioscience, Sanofi, and Sobi, and lecture honoraria from BeiGene, Janssen-Cilag, Sanofi, and Sobi. S.S.D. declares no conflicts of interest.

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Immunology.)

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., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

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., Competing Interests: The authors did not receive any funding or writing assistance for this paper. Outside this work, SB has received consultancy and advisory board honoraria from Annexon, BeiGene, Momenta, Sanofi, and Sobi; lecture honoraria from BeiGene, Janssen-Cilag, Sanofi, and Sobi; and royalties from Wolters Kluwer. SSD declares no conflicts of interest., (© 2023 The Author(s).)

Cold agglutinin disease (CAD) is a rare, autoimmune, classical complement pathway (CP)-mediated hemolytic anemia. Sutimlimab selectively inhibits C1s of the C1 complex, preventing CP activation while leaving the alternative and lectin pathways intact. In Part A (26 weeks) of the open-label, single-arm, Phase 3 CARDINAL study in patients with CAD and a recent history of transfusion, sutimlimab demonstrated rapid effects on hemolysis and anemia. Results of the CARDINAL study Part B (2-year extension) study, described herein, demonstrated that sutimlimab sustains improvements in hemolysis, anemia, and quality of life over a median of 144 weeks of treatment. Mean last-available on-treatment values in Part B were improved from baseline for hemoglobin (12.2 g/dL on-treatment versus 8.6 g/dL at baseline), bilirubin (16.5 μmol/L on-treatment versus 52.1 μmol/L at baseline), and FACIT-Fatigue scores (40.5 on-treatment versus 32.4 at baseline). In the 9-week follow-up period after sutimlimab cessation, CP inhibition was reversed, and hemolytic markers and fatigue scores approached pre-sutimlimab values. Overall, sutimlimab was generally well tolerated in Part B. All 22 patients experienced ≥1 treatment-emergent adverse event (TEAE); 12 (54.5%) patients experienced ≥1 serious TEAE, including seven (31.8%) with ≥1 serious infection. Three patients discontinued due to a TEAE. No patients developed systemic lupus erythematosus or meningococcal infections. After cessation of sutimlimab, most patients reported adverse events consistent with recurrence of CAD. In conclusion, the CARDINAL 2-year results provide evidence of sustained sutimlimab effects for CAD management, but that disease activity reoccurs after treatment cessation. NCT03347396. Registered November 20, 2017., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia and a bone marrow clonal lymphoproliferative disorder. Hemolysis in CAD is complement-dependent and mediated by the classical activation pathway. Patients also frequently suffer from fatigue and cold-induced circulatory symptoms. Although not all patients need treatment, the symptom burden has previously been underestimated. Effective therapies target the clonal lymphoproliferation or the complement activation. Sutimlimab, a humanized monoclonal IgG4 antibody that binds and inactivates complement protein C1s, is the most extensively investigated complement inhibitor for the treatment of CAD. This review addresses the preclinical studies of sutimlimab and the studies of pharmacokinetics and pharmacodynamics. We then describe and discuss the prospective clinical trials that established sutimlimab as a rapidly acting, highly efficacious, and low-toxic therapeutic agent. This complement inhibitor does not improve the cold-induced circulatory symptoms, which are not complement-mediated. Sutimlimab is approved for the treatment of CAD in the US, Japan, and the European Union. A tentative therapeutic algorithm is presented. The choice of therapy for CAD should be based on an individual assessment, and patients requiring therapy should be considered for inclusion in clinical trials., Competing Interests: Outside this work, SB has received advisory board honoraria from Anexon, Momenta Pharmaceuticals, Sanofi-Genzyme, and Sobi, and lecture honoraria from Apellis, BeiGene, Janssen-Cilag, Sanofi-Genzyme, and Sobi. The author has no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Introduction: Cold agglutinin disease (CAD) is a difficult-to-treat autoimmune hemolytic anemia and B cell lymphoproliferative disorder associated with fatigue, acrocyanosis, and a risk of thromboembolic events. Cold-induced binding of autoantibody agglutinates red blood cells and triggers the classical complement pathway, leading to predominantly extravascular hemolysis., Areas Covered: This review summarizes clinical and experimental antibody-based treatments for CAD and analyzes the risks and benefits of B cell and complement directed therapies, and discusses potential future treatments for CAD., Expert Opinion: Conventional treatment of CAD includes a B cell targeted treatment approach with rituximab, yielding only limited treatment success. The addition of a cytotoxic agent (e.g. bendamustine) increases efficacy, but this is accompanied by an increased risk of neutropenia and infection. Novel complement directed therapies have emerged and were shown to have good efficacy against hemolysis and safety profiles but are expensive and unable to address circulatory symptoms. Complement inhibition with sutimlimab may be used as a bridging strategy until B cell directed therapy with rituximab takes effect or continued indefinitely if needed. Future antibody-based treatment approaches for CAD involve the further development of complement directed antibodies, a combination of rituximab and bortezomib, and daratumumab. Non-antibody based prospective treatments may include the use of Bruton tyrosine kinase inhibitors.

Autoimmune hemolytic anemia (AIHA) is defined by increased erythrocyte turnover mediated by autoimmune mechanisms. While corticosteroids remain first-line therapy in most cases of warm-antibody AIHA, cold agglutinin disease is treated by targeting the underlying clonal B-cell proliferation or the classical complement activation pathway. Several new established or investigational drugs and treatment regimens have appeared during the last 1-2 decades, resulting in an improvement of therapy options but also raising challenges on how to select the best treatment in individual patients. In severe warm-antibody AIHA, there is evidence for the upfront addition of rituximab to prednisolone in the first line. Novel agents targeting B-cells, extravascular hemolysis, or removing IgG will offer further options in the acute and relapsed/refractory settings. In cold agglutinin disease, the development of complement inhibitors and B-cell targeting agents makes it possible to individualize therapy, based on the disease profile and patient characteristics. For most AIHAs, the optimal treatment remains to be found, and there is still a need for more evidence-based therapies. Therefore, prospective clinical trials should be encouraged., Competing Interests: Outside this work, SB has received advisory board honoraria from Annexon, Momenta, Sanofi, and Sobi, and lecture honoraria from Apellis, BeiGene, Janssen-Cilag, Sanofi, and Sobi. BF declares consultancies with Amgen, Alexion, Annexon, Apellis, Momenta, Novartis, and Sobi. WB has received consultancy and advisory board honoraria from Agios, Alexion, Biocryst, Incyte, Novartis, and Sanofi; lecture honoraria and congress support from Alexion, Incyte, Novartis, and Sanofi; and research support from Alexion., (Copyright © 2023 Berentsen, Fattizzo and Barcellini.)

Two major steps are identified in the pathogenesis of cold agglutinin disease; clonal B-cell lymphoproliferation and complement-mediated hemolysis. Each of these steps constitutes a target for treatment. In this focused review, we address 2 successful therapeutic approaches; the bendamustine plus rituximab combination as a highly efficacious B-cell directed therapy and the anti-C1s monoclonal antibody sutimlimab as the most extensively studied complement-targeting therapy. We describe and discuss the prospective study of bendamustine plus rituximab and 2 recent, prospective studies of sutimlimab. Bendamustine-rituximab results in a high response rate, frequent complete responses and long median response duration, and the treatment is temporary. However, this therapy is relatively slow-acting and associated with some toxicity. Sutimlimab is also highly efficacious, is far more rapidly acting, and is low-toxic. Disadvantages of sutimlimab are the lack of effect on circulatory symptoms, the probable need for indefinite treatment, and the very high costs. In cold agglutinin disease patients who require treatment, the choice should be based on an individual assessment., Competing Interests: Conflicts of Interest S. Berentsen has received consulting and advisory board honoraria from Anexon, Apellis, Bioverativ, Momenta Pharmaceuticals, Sanofi-Genzyme, and SOBI, and lecture honoraria from Apellis, Janssen-Cilag, Sanofi-Genzyme, and SOBI. G.E. Tjønnfjord has received advisory board honoraria from Alexion Pharmaceuticals and Janssen-Cilag, and lecture honoraria from Novartis, Janssen-Cilag, Alexion Pharmaceuticals, and Mundipharma., (Copyright © 2022. Published by Elsevier Inc.)

Therapies for cold agglutinin disease have been directed at the pathogenic B-cell clone. Sutimlimab, a monoclonal antibody that targets C1s, is the first complement inhibitor to be extensively studied in cold agglutinin disease. Sutimlimab selectively blocks the classical activation pathway and leaves the alternative and lectin pathways intact. Trials have documented high response rates with rapid improvement in hemolysis, hemoglobin levels and fatigue scores and low toxicity. Sutimlimab was recently approved in the USA. This drug appears to be particularly useful in severely anemic patients who require a rapid response, in acute exacerbations that do not resolve spontaneously and in patients in whom chemoimmunotherapy is contraindicated or has failed. The choice of therapy in cold agglutinin disease should be individualized.

Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits the classical complement pathway at C1s, rapidly halted hemolysis in the single-arm CARDINAL study in recently transfused patients with cold agglutinin disease (CAD). CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in patients with CAD without recent (within 6 months prior to enrollment) transfusion history. Forty-two patients with screening hemoglobin ≤10 g/dL, elevated bilirubin, and ≥1 CAD symptom received sutimlimab (n = 22) or placebo (n = 20) on days 0 and 7 and then biweekly. Composite primary endpoint criteria (hemoglobin increase ≥1.5 g/dL at treatment assessment timepoint [mean of weeks 23, 25, 26], avoidance of transfusion, and study-prohibited CAD therapy [weeks 5-26]) were met by 16 patients (73%) on sutimlimab, and 3 patients (15%) on placebo (odds ratio, 15.9 [95% confidence interval, 2.9, 88.0; P < .001]). Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint. Sutimlimab normalized mean bilirubin by week 1. Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization. Twenty-one (96%) sutimlimab patients and 20 (100%) placebo patients experienced ≥1 treatment-emergent adverse event. Headache, hypertension, rhinitis, Raynaud phenomenon, and acrocyanosis were more frequent with sutimlimab vs placebo, with a difference of ≥3 patients between groups. Three sutimlimab patients discontinued owing to adverse events; no placebo patients discontinued. These data demonstrate that sutimlimab has potential to be an important advancement in the treatment of CAD. This trial was registered at www.clinicaltrials.gov as #NCT03347422., (© 2022 by The American Society of Hematology.)

Background: Cold agglutinin disease is a rare autoimmune hemolytic anemia characterized by hemolysis that is caused by activation of the classic complement pathway. Sutimlimab, a humanized monoclonal antibody, selectively targets the C1s protein, a C1 complex serine protease responsible for activating this pathway., Methods: We conducted a 26-week multicenter, open-label, single-group study to assess the efficacy and safety of intravenous sutimlimab in patients with cold agglutinin disease and a recent history of transfusion. The composite primary end point was a normalization of the hemoglobin level to 12 g or more per deciliter or an increase in the hemoglobin level of 2 g or more per deciliter from baseline, without red-cell transfusion or medications prohibited by the protocol., Results: A total of 24 patients were enrolled and received at least one dose of sutimlimab; 13 patients (54%) met the criteria for the composite primary end point. The least-squares mean increase in hemoglobin level was 2.6 g per deciliter at the time of treatment assessment (weeks 23, 25, and 26). A mean hemoglobin level of more than 11 g per deciliter was maintained in patients from week 3 through the end of the study period. The mean bilirubin levels normalized by week 3. A total of 17 patients (71%) did not receive a transfusion from week 5 through week 26. Clinically meaningful reductions in fatigue were observed by week 1 and were maintained throughout the study. Activity in the classic complement pathway was rapidly inhibited, as assessed by a functional assay. Increased hemoglobin levels, reduced bilirubin levels, and reduced fatigue coincided with inhibition of the classic complement pathway. At least one adverse event occurred during the treatment period in 22 patients (92%). Seven patients (29%) had at least one serious adverse event, none of which were determined by the investigators to be related to sutimlimab. No meningococcal infections occurred., Conclusions: In patients with cold agglutinin disease who received sutimlimab, selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue. (Funded by Sanofi; CARDINAL ClinicalTrials.gov number, NCT03347396.)., (Copyright © 2021 Massachusetts Medical Society.)

The last decades have seen great progress in the treatment of cold agglutinin disease (CAD). Comparative trials are lacking, and recommendations must be based mainly on nonrandomized trials and will be influenced by personal experience. Herein, current treatment options are reviewed and linked to 3 cases, each addressing specific aspects of therapy. Two major steps in CAD pathogenesis are identified, clonal B-cell lymphoproliferation and complement-mediated hemolysis, each of which constitutes a target of therapy. Although drug treatment is not always indicated, patients with symptomatic anemia or other bothersome symptoms should be treated. The importance of avoiding ineffective therapies is underscored. Corticosteroids should not be used to treat CAD. Studies on safety and efficacy of relevant drugs and combinations are briefly described. The author recommends that B cell-directed approaches remain the first choice in most patients requiring treatment. The 4-cycle bendamustine plus rituximab combination is highly efficacious and sufficiently safe and induces durable responses in most patients, but the time to response can be many months. Rituximab monotherapy should be preferred in frail patients. The complement C1s inhibitor sutimlimab is an emerging option in the second line and may also find its place in the first line in specific situations., (© 2021 by The American Society of Hematology.)

We retrospectively studied 232 patients with cold agglutinin disease (CAD) at 24 centers in 5 countries. In Norway and a northern region of Italy, the study was close to being population-based. For the first time, we demonstrate fourfold differences between cold and warmer climates regarding prevalence (20 vs 5 cases/million) and incidence (1.9 vs 0.48 cases/million per year). Mean baseline hemoglobin level was 9.3 g/dL, but 27% had hemoglobin <8 g/dL. Identification of typical features of CAD-associated lymphoproliferative disorder in the bone marrow was greatly increased by centralized biopsy assessment. CAD seems to be associated with a slightly increased risk of venous thrombosis. This work includes a follow-up study of therapies, focusing on the long-term outcomes of the rituximab plus bendamustine and rituximab plus fludarabine regimens. Rituximab plus bendamustine therapy resulted in responses in 35 (78%) of 45 patients; 24 (53%) achieved complete response. Interestingly, these rates were still higher than observed in the original (2017) prospective trial, and we also found a shift toward deeper responses with time. This is explained by the prolonged time to response seen in many patients, probably related to long-lived plasma cells. In patients responding to rituximab-bendamustine, median response duration was not reached after 88 months, and estimated 5-year sustained remission was 77%. The regimen appeared safe regarding late-occurring malignancies. Rituximab plus fludarabine therapy seems to carry a higher risk of long-term adverse effects., (© 2020 by The American Society of Hematology.)