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.

Monoclonal antibodies for treatment of cold agglutinin disease.

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.

Sutimlimab for the Treatment of Cold Agglutinin Disease.

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.

The choice of new treatments in autoimmune hemolytic anemia: how to pick from the basket?

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.

Sustained inhibition of complement C1s with sutimlimab over 2 years in patients with cold agglutinin disease.

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.

Current Treatment Options in Cold Agglutinin Disease: B-Cell Directed or Complement Directed Therapy?

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.

Sutimlimab for treatment of cold agglutinin disease: why, how and for whom?

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.

In cold agglutinin disease (CAD), red blood cells are destroyed by cold agglutinin, a type of antibody against the patient's own red blood cells. Previous treatments for CAD have aimed at killing the cold agglutinin-producing abnormal cells in the bone marrow. Sutimlimab, a new drug for treatment of CAD, is an artificially produced antibody that binds to a protein called C1s. This binding results in inhibition of complement, a system of active proteins that is part of the immune system and promotes red blood cell destruction in CAD. Clinical trials have shown that most patients with CAD respond well to treatment with sutimlimab, with rapid improvement in anemia and fatigue. The risk of serious side effects is very low provided the patient is vaccinated against certain types of bacteria. Sutimlimab, which is administered by intravenous infusion, was recently approved in the USA. This drug appears to be particularly useful in CAD patients with severe anemia, in those who cannot tolerate other treatment options and in those in whom other therapies have failed. The choice of treatment in CAD should be individualized.

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

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.