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Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease.

ABSTRACT: Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia with limited epidemiological and clinical data. We used the Danish National Patient Registries to examine CAD occurrence and risk of thromboembolic events (TEs) and mortality in CAD patients compared with a matched cohort from the general population in Denmark. We identified 72 patients diagnosed with CAD and 720 matched controls between 1999 and 2013. For 2013, the most recent year of study, crude incidence of CAD was 0.18 per 100 000 inhabitants per year and prevalence was 1.26 per 100 000 inhabitants. Risk of TEs was higher in the CAD patient cohort than in the comparison cohort at 1 year (7.2% of CAD patients had TEs vs 1.9% of comparisons), 3 years (9.0% vs 5.3%), and 5 years (11.5% vs 7.8%) after the index date. The median survival was 8.5 years. CAD patients had increased mortality compared with the general population cohort (adjusted hazard ratio [aHR], 1.84; 95% confidence interval [CI], 1.10-3.06; P = .020), with the highest mortality observed during the first 5 years after diagnosis (aHR, 2.27; 95% CI, 1.32-3.89; P = .003). Mortality rates 1 and 5 years after diagnosis were 17% and 39% in the CAD group vs 3% and 18% in the comparison cohort, respectively. CAD is a rare illness characterized by increased risk of TEs and mortality.

SUBMITTER: Bylsma LC

PROVIDER: S-EPMC6849939 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Cold agglutinin disease.

Project description:Primary chronic cold agglutinin disease (CAD) is a well-defined clinicopathologic entity in which a specific, clonal lymphoproliferative B-cell bone marrow disorder results in autoimmune hemolytic anemia. The immune hemolysis is entirely complement-dependent, predominantly mediated by activation of the classical pathway and phagocytosis of erythrocytes opsonized with complement protein C3b. Typical clinical features in CAD have diagnostic and therapeutic implications. Pharmacologic treatment should be offered to patients with symptom-producing anemia or disabling circulatory symptoms. CAD should not be treated with corticosteroids. Based on an individualized approach, rituximab monotherapy or rituximab-fludarabine in combination is recommended as first-line therapy. Rituximab-bendamustine is still an investigational therapy. Although complement-modulating agents are still to be considered experimental in CAD, therapy with the anti-C1s monoclonal antibody TNT009 seems promising.

| S-EPMC6142439 | biostudies-other

Necrosis secondary to cold agglutinin disease.

Project description: Not available

| S-EPMC9001000 | biostudies-literature

Cold agglutinin disease: current challenges and future prospects.

Project description: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.

| S-EPMC6497508 | biostudies-literature

Sutimlimab for the Treatment of Cold Agglutinin Disease.

Project description: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.

| S-EPMC10155901 | biostudies-literature

Increased risk of thrombotic events in cold agglutinin disease: A 10-year retrospective analysis.

Project description:BackgroundCold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia mediated by IgM autoantibodies that trigger hemolysis via classical complement pathway. Increased incidence of thrombotic events (TEs) has been reported in patients with other forms of hemolysis. The incidence of TEs in patients with CAD is unknown.ObjectiveEvaluate TE risk in patients with CAD.Patients/methodsThis is a matched cohort comparison study evaluating the risk of TEs in patients with CAD and without CAD over a 10-year period. A total of 608 patients with CAD were identified in the Optum Claims-Clinical data set by reviewing clinical notes for CAD terms and matched with up to 10 patients without CAD (N = 5873). TEs were defined as the first medical claim for a TE using International Classification of Diseases, Ninth and Tenth Revision codes. Cox regression models were used to estimate time to first TE. Sensitivity analyses were conducted to estimate TE risk among patients with primary CAD.ResultsAt least 1 TE occurred in 29.6% of patients with CAD and 17.6% of patients without CAD. The proportion of patients experiencing venous, arterial, and cerebral TEs were each higher among CAD patients. The overall risk of having TEs was higher in patients with CAD (adjusted hazard ratio [aHR], 1.94; 95% confidence interval [CI], 1.64-2.30). Patients with presumed primary CAD also demonstrated an increased risk of TEs (aHR, 1.80; 95% CI, 1.46-2.22). Patients with CAD with the fewest comorbidities had 2.44-fold higher risk of having a TE (95% CI, 1.70-3.52).ConclusionsPatients with CAD have an increased risk of TEs when compared with a matched non-CAD population.

| S-EPMC7292660 | biostudies-literature

Sustained hematologic remission after discontinuation of sutimlimab treatment in patients with cold agglutinin disease.

Project description: Not available

| S-EPMC10189382 | biostudies-literature

The Burden of Cold Agglutinin Disease on Patients' Daily Life: Web-Based Cross-sectional Survey of 50 American Patients.

Project description:BackgroundCold agglutinin disease (CAD) is a rare disorder, affecting 15% of patients with autoimmune hemolytic anemia. Few studies have assessed CAD symptoms and their impact on daily life, but these studies did not address the patients' perspectives.ObjectiveThe aims of this study were to increase the knowledge about CAD through a patient-centric survey and to gain a better understanding of the burden of this disease.MethodsWe conducted an internet-based survey in September 2020 among American patients registered on the CAD Unraveled website and members of the Cold Agglutinin Disease Foundation.ResultsA total of 50 respondents were included in this study. Totally, 90% (45/50) of the patients reported having experienced fatigue. Fatigue was mainly reported on a daily basis, and approximately one-third of these patients (13/45, 29%) said that their fatigue was constant throughout the day. It has also been shown that CAD has a great impact on patients' physical well-being, emotional well-being, social life, and household finances. The disease varies over time, with or without symptoms. A total of 88% (44/50) of the patients reported previous episodes of the increased intensity or sensitivity of their CAD symptoms, with a mean of 4.5 (SD 5.4) episodes reported during the past year. More than half of the patients (27/50, 54%) considered their disease to be moderate or severe, and 42% (21/50) of the study group reported that their symptoms had worsened since the time of diagnosis.ConclusionsOur study has provided new data on CAD symptoms, particularly data on the importance and type of fatigue and the fluctuation of CAD symptoms.

| S-EPMC9356335 | biostudies-literature

Inhibition of complement C1s in patients with cold agglutinin disease: lessons learned from a named patient program.

Project description:Cold agglutinin disease (CAD) causes predominantly extravascular hemolysis and anemia via complement activation. Sutimlimab is a novel humanized monoclonal antibody directed against classical pathway complement factor C1s. We aimed to evaluate the safety and efficacy of long-term maintenance treatment with sutimlimab in patients with CAD. Seven CAD patients treated with sutimlimab as part of a phase 1B study were transitioned to a named patient program. After a loading dose, patients received biweekly (once every 2 weeks) infusions of sutimlimab at various doses. When a patient's laboratory data showed signs of breakthrough hemolysis, the dose of sutimlimab was increased. Three patients started with a dose of 45 mg/kg, another 3 with 60 mg/kg, and 1 with a fixed dose of 5.5 g every other week. All CAD patients responded to re-treatment, and sutimlimab increased hemoglobin from a median initial level of 7.7 g/dL to a median peak of 12.5 g/dL (P = .016). Patients maintained near normal hemoglobin levels except for a few breakthrough events that were related to underdosing and which resolved after the appropriate dose increase. Four of the patients included were eventually treated with a biweekly 5.5 g fixed-dose regimen of sutimlimab. None of them had any breakthrough hemolysis. All patients remained transfusion free while receiving sutimlimab. There were no treatment-related serious adverse events. Overlapping treatment with erythropoietin, rituximab, or ibrutinib in individual patients was safe and did not cause untoward drug interactions. Long-term maintenance treatment with sutimlimab was safe, effectively inhibited hemolysis, and significantly increased hemoglobin levels in re-exposed, previously transfusion-dependent CAD patients.

| S-EPMC7094024 | biostudies-literature

Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial.

Project description: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.

| S-EPMC9437710 | biostudies-literature

Cold agglutinin disease secondary to severe SARS-CoV-2 treated with eculizumab.

Project description:Impaired immune response with uncontrolled inflammation and various immunological disorders have been reported during SARS-CoV-2 infection. Here, we report a case of cold agglutinin disease occurring during a severe coronavirus disease 2019 (COVID-19) in a French intensive care unit. A patient was presented with acute respiratory distress syndrome, acute renal failure and haemolytic anaemia. Direct antiglobulin test was positive with a cold agglutinin titre of 1/512. No other cause than COVID-19 explained the occurrence of cold agglutinin disease; however, causality could not be formally established. Persistent anaemia despite transfusion therapy and the short-term life-threatening, prompted the infusion of a monoclonal anti-C5 antibody (eculizumab). Eculizumab therapy quasi-fully resolved haemolysis within a few days, but ultimately the patient died from his severe COVID-19 infection. Data regarding the specific treatment of cold agglutinin disease during COVID-19 are rare. Although additional studies are warranted, eculizumab may be considered in critical situations.

| S-EPMC9058691 | biostudies-literature

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