Cold Agglutinin Research Articles

Classical Complement Inhibition By SAR445088 (BIVV020) in Adults with Cold Agglutinin Disease: Safety, Tolerability and Activity Results from the Open-Label, Non-Randomized, Single-Dose Phase 1b Study

Background:Cold agglutinin disease (CAD) is a rare, chronic autoimmune hemolytic anemia characterized by complement-mediated hemolysis. The classical complement inhibitor sutimlimab, is the first approved pharmacotherapy for treating patients with CAD. The second-generation complement inhibitor SAR445088 (BIVV020) is a humanized monoclonal antibody that selectively inhibits the activated form of C1s (sutimlimab inhibits total C1s). Furthermore, SAR445088 contains mutations that increase FcRn binding, preventing its degradation and allowing it to be recycled back into the system, resulting in reduced drug clearance and a prolonged half-life, which may allow a longer dosing interval than that of sutimlimab. Aims:This Phase 1b open-label study evaluated the safety, tolerability, effect on hemolysis, and pharmacodynamics (PD)/pharmacokinetics (PK) of a single intravenous (IV) dose of SAR445088. The study aimed to assess the impact of SAR445088 on complement-mediated hemolysis to support proof of concept for SAR445088 as a treatment for patients with CAD. Methods:The study design included up to three single-dose cohorts with a maximum of six patients per cohort. SAR445088 was administered on Day 1 with follow-up visits from Day 2 to Day 71; end of study (EOS) visit was on Day 106. The first cohort received a dose of 30 mg/kg IV with decisions about the selection of the dose for the next cohort being based on safety, biomarker activity, and PD. In the second cohort, patients received a lower dose of 15 mg/kg IV; a third, higher-dose cohort was not enrolled. To be enrolled in the study, participants needed to be aged ≥18 years with a confirmed diagnosis of CAD and a hemoglobin level ≤11.0 g/dL at time of screening. The primary endpoint was assessment of safety, with secondary endpoints of hematologic biomarkers and PD/PK. Results:Twelve patients received a single IV dose of SAR445088 (n=6, 30 mg/kg; n=6, 15 mg/kg). Patients enrolled in the study were mainly female (91.7%, n=11) with a median age (range) of 69 (54-80) years, and median (range) hemoglobin at baseline was 9.60 (4.8-10.9) g/dL. There were no treatment-emergent serious adverse events (AEs), discontinuations or deaths reported in the study. Fifty-eight treatment-emergent AEs (TEAEs) were reported in 11 patients (91.7%). There was one reported pre-treatment severe AE (Grade 3) of hemolytic anemia in a patient in the 15 mg/kg IV cohort which began prior to treatment and continued during the treatment period; the remainder of TEAEs were mild or moderate in severity (Grade 1 or 2). The most frequently reported AE was hematuria. No serious infections, meningococcal infections, hypersensitivity, or thromboembolic events were reported. Nine patients (n=4, 30 mg/kg IV cohort; n=5, 15 mg/kg IV cohort) reached an increase of hemoglobin ≥1.5 g/dL from baseline to Day 106 (EOS visit); eight patients (n=4 for both cohorts) reached an increase in hemoglobin >1.0 g/dL from baseline to Day 15 (Figure A). Total mean bilirubin decreased by Day 1 and this was sustained to Day 106 (EOS visit; Figure B).The decrease was more pronounced in the 30 mg/kg IV cohort. Improvements in clinical markers correlated with sustained reductions in CH50 in both treatment cohorts. Reductions in mean percent classical complement pathway (CP) activity were noted 1 hour after a single dose of 30 or 15 mg/kg IV, followed by gradual rebound of CP activity over the 15-week study period. Conclusion:SAR445088 was generally well tolerated; no safety concerns were identified in patients with CAD. A single IV dose of SAR445088 led to classical complement inhibition, control of hemolysis, and improvement in anemia, which was sustained for 15 weeks.

Insights into Large Granular Lymphocytic Leukemia-Associated Hemolytic Anemia: Clinical Associations, Therapeutic Responses, and Optimal Management Strategies from a Large Institutional Study

Introduction Large granular lymphocytic leukemia (LGLL) is characterized by a clonal proliferation of cytotoxic CD8+ T or CD3− natural killer (NK) cells. The disease typically presents with neutropenia in about 39-62% of patients, and anemia in up to 50% 1. While most cases of anemia in LGLL resemble pure red cell aplasia and present as reticulocytopenic and malproductive, we have also observed rare instances of hemolytic anemia (HA) with a high reticulocyte count. This unique and atypical presentation has prompted us to investigate the clinical features of LGLL with HA, aiming to gain insights into the pathogenesis of both conditions. In light of this, we conducted a comprehensive and systematic study of hemolysis within the context of LGLL. Methods We retrospectively examined clinical and molecular features of a large series of LGLL cases (n=262) diagnosed and managed at the Cleveland Clinic Foundation from 1998 to 2023 to identify those experiencing hemolysis. LGLL diagnosis was based on the presence of i) elevated LGL count (>0.5 × 10^9/L), ii) clonal TCR rearrangement, iii) VB expansion, iv) flow cytometric detection of aberrant CTL or NK cell proliferation and v) STAT3/5 mutation and vi) LGLL infiltration of the marrow. A diagnosis was established with >4/6 criteria fulfilled. HA diagnosis was based on evidence at any time during clinical course of laboratory signs of hemolysis. Results Overall, the median age at diagnosis was 63 years (IQR: 55-72) with a M:F ratio of 0.5. Majority of patients had been diagnosed with T-LGLL (n=225), whereas 22 had NK-LGLL. In 32/262 cases (12%), clinical and laboratory features were asserted to establish the diagnosis of HA. Of these, 22 (68%) had T-LGLL and 8 (25%) had NK-LGLL (Table 1). When comparing HA patients to the rest of the cohort, we observed a higher proportion of NK-LGLL cases with HA (25% vs 8%, p < 0.001). HA presented as the initial sign of the disease in majority of patients (88%), and 40% of them required transfusion support based on the degree of anemia and hemodynamics. The direct anti-globin test was positive in 30% of cases. Warm autoimmune HA (AIHA) was observed in 23% of patients, cold agglutinin disease in 7%, and one patient had both. Among 7 patients with IgG AIHA, 5 were also positive for anti-C3b, C3d antibodies. Two-thirds of the patients had multilineage cytopenia. Coexisting B-cell dyscrasia was identified in 13 cases, more frequently in HA than in those without (40% vs 26%, p=0.048), and autoimmune disorders in 8 cases (25%). HA in LGLL was also more likely to be associated with presence of splenomegaly (59% vs 21%, p<0.00001) and polyclonal hypergammaglobulinemia (22% vs 8%, p=0.02). Notably, STAT3 mutations were present in a higher proportion of HA patients (38% vs 22%, p=0.02), whereas median LGLL clone size (%) was similar between groups (68% vs 53%, p=0.5). Overall, 77% of HA patients received treatment, and 16% had still evidence of hemolysis at a median follow-up of 82 months. The majority (47%) were treated with steroids with a positive, albeit transient response (7 out of 15 treated). Other first-line treatments and their corresponding median duration of response (months) included cyclosporine (n=7, 72 months), cyclophosphamide (n=5, 72 months), IVIG (n=1, 16 months), and methotrexate (n=11, 21 months). Subsequent lines of therapy included campath (n=9), cyclosporine (CSA) (n=4), cyclophosphamide (n=9), intravenous immunoglobulin (IVIG) (n=2), MTX (n=4), rituximab (n=1), sirolimus (n=1), tacrolimus (n=2), and tofacitinib (n=2). Splenectomy was performed as definitive treatment for refractory cytopenia in 9 patients, with a durable response in 5 patients at last follow-up ( Fig.1). Conclusions Based on this large series, our study illustrates that LGLL represents a clonal lymphoproliferative disorder that is closely linked to HA. Notably, NK-LGLL cases exhibited a stronger association with HA. Our observations indicate that treatment with steroids and other therapeutic agents resulted in positive responses in a fraction of patients, while splenectomy demonstrated the most enduring response. These significant findings contribute substantially to advancing our comprehension of LGLL-associated HA and its optimal management strategies. AIHA in patients with LGLL points towards a global immune dysfunction in this disease beyond clonal cytotoxic T/NK cell expansion.

Povetacicept (ALPN-303), a Potent Dual BAFF/APRIL Antagonist in Development for the Treatment of Autoimmune Cytopenias, Suppresses Disease in a Mouse Model of Autoimmune Hemolytic Anemia

Introduction: B cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) play key roles in B cell development, survival, and differentiation into antibody-secreting cells (ASC). Given their importance in ASC survival and antibody production, inhibition of BAFF and/or APRIL (particularly in combination) is a promising approach for the treatment of a variety of autoimmune or autoantibody-related diseases including autoimmune cytopenias like warm autoimmune hemolytic anemia (wAIHA), immune thrombocytopenia (ITP), and cold agglutinin disease (CAD). Significantly higher levels of both BAFF and APRIL have been observed in the serum of patients with AIHA and ITP compared to healthy subjects, and polymorphisms in BAFF and TACI have been associated with ITP [Abdel-Hamid et al., Am J Med, 2011; Xu et al., Int J Hematol., 2015; Emmerich, et al., Br J Haematol, 2007; Peng, et al., J Thromb Haemost, 2017; Yu, et al., Blood Adv, 2021]. Belimumab, an anti-BAFF antibody, has demonstrated encouraging efficacy in the treatment of ITP associated with systemic lupus erythematosus [De Marchi, et al., Clin Exp Rheumatol, 2017] and in combination with rituximab in patients with ITP [Mahévas, et al., Haematologica, 2021]. Currently, there are no BAFF and/or APRIL inhibitors approved to treat AIHA or ITP. Povetacicept (ALPN-303) is an engineered, potent dual BAFF/APRIL antagonist. We previously evaluated the impact of BAFF/APRIL co-inhibition preclinically in the accelerated HODxOTII transgenic mouse model of AIHA, in which povetacicept treatment significantly suppressed plasma cells in the spleen and bone marrow, reduced pathogenic anti-RBC autoantibodies, and significantly increased hematocrit [Dillon et al., ASH 2022 abstract #3763]. Here, we have evaluated povetacicept in a second preclinical model of AIHA, a rat red blood cell (RRBC)-to-mouse model of erythrocyte autoimmunity. Methods: In the RRBC model, C57BL/6NJ mice were immunized weekly with 2 x 10 8 Wistar rat RBC for 10 weeks, leading to development of anti-mouse RBC autoantibodies. Groups of mice were treated twice weekly via intraperitoneal injection with povetacicept or a matched Fc isotype control. Analyses included anti-RRBC alloantibodies and autoantibodies bound to mouse erythrocytes (measured via direct anti-globulin test [DAT]). While significant anemia does not occur in this model, serum lactate dehydrogenase (LDH) was also measured as an index measure of subclinical hemolysis. Immune cell subset analysis of splenocytes by flow cytometry was also performed. Results: As compared to Fc control, povetacicept treatment significantly reduced levels of anti-RRBC and DAT of IgM and IgG isotypes and significantly limited serum LDH elevations at various timepoints during the study ( Figure 1). Furthermore, at 10 weeks, numbers of T follicular helper (Tfh) cells, total B cells, germinal center (GC) B cells, and plasma cells were significantly lower in spleens of povetacicept-treated mice ( Figure 2). Conclusions: Povetacicept effectively reduced pathogenic autoantibodies and key B cell populations (e.g., ASC) and limited serum LDH elevations in this mouse model of erythrocyte autoimmunity. These data suggest that povetacicept may reduce multiple pathogenic inflammatory processes including autoantibody production and may be an effective treatment for AIHA and other autoimmune cytopenias. Povetacicept is currently being evaluated in an open-label study (RUBY-4; NCT05757570) of adults with autoimmune cytopenias (ITP, AIHA, and CAD).

Clinical Breakthrough Hemolysis (BTH) during Monotherapy with the Oral Factor B Inhibitor Iptacopan Is Generally Not Severe and Managed without Treatment Discontinuation: 48-Week Data from the Phase III Apply-PNH and Appoint-PNH Trials in Paroxysmal Nocturnal Hemoglobinuria (PNH)

Background: In PNH, BTH is characterized by the re-emergence of intravascular hemolysis (IVH) despite ongoing complement inhibition and is recognized by the reappearance of IVH/PNH signs/symptoms, coupled with a marked increase in lactate dehydrogenase (LDH) and sharp decrease in hemoglobin (Hb). Iptacopan is the first oral proximal complement inhibitor targeting factor B in the alternative pathway and has shown efficacy and safety in complement inhibitor-naïve PNH patients (pts; APPOINT-PNH; NCT04820530) and pts with persistent anemia despite anti-C5 treatment (APPLY-PNH; NCT04558918). In the APPLY-PNH 24-week (wk) analysis, iptacopan monotherapy showed superiority in the adjusted annualized rate of clinical BTH vs C5 inhibitors. Aim: We report the proportion of pts with clinical BTH, exposure-adjusted occurrence rates and BTH characteristics during iptacopan monotherapy in the Phase III APPLY-PNH and APPOINT-PNH trials (study completion [48-wk data]: 6 March and 18 April 2023, respectively). Methods: The prespecified protocol criteria for clinical BTH were LDH >1.5 × upper limit of normal (ULN) and increased vs the last 2 assessments, plus a ≥2 g/dL Hb decrease (vs the last assessment or within 15 days) or significant PNH signs/symptoms. All BTH was classed as an adverse event and evaluated for severity (investigator assessment) and seriousness (per protocol). In APPLY-PNH, adults who had received anti-C5 therapy for ≥6 months and had mean Hb <10 g/dL were randomized to receive oral iptacopan 200 mg twice daily or continue their anti-C5 regimen for 24 wks (randomized treatment period [RTP]). In APPOINT-PNH, adult complement inhibitor-naïve pts with mean Hb <10 g/dL and mean LDH >1.5 × ULN received iptacopan 200 mg twice daily for 24 wks. Both trials then had extension periods in which all pts could receive iptacopan monotherapy for another 24 wks. Results: In APPLY-PNH, 61/62 pts in the iptacopan arm continued iptacopan in the extension period and 34/35 in the anti-C5 arm switched to iptacopan. All 40 pts in APPOINT-PNH entered the extension period. When these 48-wk trials completed, 136 pts had received iptacopan with varying exposure (total exposure ~111 pt-years), of whom 9 had clinical BTH (10 events, Table). Two pts were in APPOINT-PNH (2/40, 2 events) and 7 in APPLY-PNH (7/96, 8 events). Of the iptacopan-treated pts in APPLY-PNH, 2 had BTH in the RTP; 1 of these pts plus 5 others had BTH in the extension period (including 1 who switched from anti-C5 to iptacopan at Wk 24). The exposure-adjusted occurrence rate of clinical BTH on iptacopan was 11.0 events per 100 pt-years in APPLY-PNH (95% confidence interval [CI] 5.2‒23.3) and 5.2 events per 100 pt-years in APPOINT-PNH (95% CI 1.3‒20.5). In the 24-wk APPLY-PNH RTP, 6/35 pts in the anti-C5 arm had clinical BTH (11 events); the exposure-adjusted occurrence rate was 66.9 events per 100 pt-years (95% CI 25.0‒178.9), which is >6 times higher than the rates on iptacopan. Of the 10 clinical BTH events reported on iptacopan, all were mild or moderate except 1 severe (and serious) event despite large PNH RBC clone sizes of >90% reported before 5/8 events with available clone size data. The impact of BTH on Hb was generally transient (Figure). Potential complement-amplifying conditions (CACs) were identified for 8 clinical BTH events during iptacopan treatment; the severe event was associated with COVID-19 and the temporal appearance of cold agglutinins. No pts discontinued iptacopan because of clinical BTH. RBC transfusions were the most common intervention; 1 pt received a 900 mg dose of eculizumab. In the anti-C5 arm in the APPLY-PNH RTP, 1/11 BTH events was severe and 2/11 were associated with potential CACs. Conclusions: In Phase III trials, 136 PNH pts received iptacopan monotherapy and few pts had clinical BTH, with severity being comparable to that with anti-C5 despite PNH RBC clone sizes >90%. Most clinical BTH events on iptacopan were associated with potential CACs; BTH was manageable with no intervention or RBC transfusion and without iptacopan discontinuation. The exposure-adjusted occurrence rates support our prior finding of a significantly lower adjusted annualized rate of clinical BTH with iptacopan vs anti-C5. BTH must be monitored with any complement inhibitor, but these data show that BTH was infrequent on iptacopan and support the positive safety profile of proximal complement inhibition with oral iptacopan monotherapy in hemolytic PNH.

Total arch replacement for an aortic arch aneurysm with cold agglutinin disease after rituximab and plasmapheresis

BackgroundCold agglutinin disease can lead to significant complications, especially for patients undergoing arch repair requiring hypothermic circulatory arrest. Rituximab and plasmapheresis are treatments for cold agglutinin disease. However, its use in patients with Stanford type A dissection has not been reported. Therefore, after consultation with hematologists, we used rituximab and plasmapheresis before mild hypothermic aortic arch surgery to maintain the body temperature above the thermal altitude.Case presentationThis report describes an 86-year-old male patient with acute type A aortic dissection who received outpatient treatment for rheumatoid arthritis and a 55-mm thoracic aortic aneurysm. The patient was scheduled to undergo urgent surgery for a type A intramural hematoma and progressive aortic aneurysm; however, laboratory test results indicated blood clotting and cold agglutinin. Consequently, urgent surgery was rescheduled. After consulting with hematologists, rituximab was initiated 3 months before surgery, and plasmapheresis was performed 2 days before surgery for cold agglutinin disease. Under mild hypothermia conditions, total arch replacement using the frozen elephant trunk technique was performed while maintaining cerebral and lower body perfusion. The postoperative course was uneventful. On postoperative day 42, the patient was discharged without any neurological deficits.ConclusionsThis case involving total arch replacement with mild hypothermia for an aortic arch aneurysm with cold agglutinin disease after rituximab treatment and plasmapheresis resulted in a successful outcome.

PB1458 Thromboembolic (TE) Events in Cold Agglutinin Disease (CAD): Post-Hoc Analysis PRE- and ON-Sutimlimab Treatment in the Phase 3 CARDINAL and CADENZA Studies

PB1458 Thromboembolic (TE) Events in Cold Agglutinin Disease (CAD): Post-Hoc Analysis PRE- and ON-Sutimlimab Treatment in the Phase 3 CARDINAL and CADENZA Studies

Clinical and clonal characteristics of monoclonal immunoglobulin M-associated type I cryoglobulinaemia.

Monoclonal immunoglobulin M-associated type I cryoglobulinaemia is poorly characterised. We screened 534 patients with monoclonal IgM disorders over a 9-year period and identified 134 patients with IgM type I cryoglobulins. Of these, 76% had Waldenström macroglobulinaemia (WM), 5% had other non-Hodgkin lymphoma (NHL) and 19% had IgM monoclonal gammopathy of undetermined significance (MGUS). Clinically relevant IgM-associated disorders (including cold agglutinin disease [CAD], anti-MAG antibodies, amyloidosis and Schnitzler syndrome) coexisted in 31%, more frequently in MGUS versus WM/NHL (72% vs. 22%/29%, p < 0.001). The majority of those with cryoglobulins and coexistent CAD/syndrome had the molecular characteristics of a CAD clone (wild-type MYD88 in 80%). A half of all patients had active manifestations at cryoglobulin detection: vasomotor (22%), cutaneous (16%), peripheral neuropathy (22%) and hyperviscosity (9%). 16/134 required treatment for cryoglobulin-related symptoms alone at a median of 38 days (range: 6-239) from cryoglobulin detection. At a median follow-up of 3 years (range: 0-10), 3-year cryoglobulinaemia-treatment-free survival was 77% (95% CI: 68%-84%). Age was the only predictor of overall survival. Predictors of cryoglobulinaemia-related treatment/death were hyperviscosity (HR: 73.01; 95% CI: 15.62-341.36, p < 0.0001) and cutaneous involvement (HR: 2.95; 95% CI: 1.13-7.71, p = 0.028). Type I IgM cryoglobulinaemia is more prevalent than previously described in IgM gammopathy and should be actively sought.

Cold autoimmune hemolytic anemia

Cold agglutinins are antibodies that recognize antigens on erythrocytes at temperatures below normal body temperature. Antibodies are of IgM nature and bind to “I” or “i” antigens on red blood cells, causing agglutination in red blood cells. This situation results in anemia by creating extravascular hemolysis. If there is no underlying disease, it is called primary or idiopathic cold agglutinin disease (CAD), and if there is, it is called secondary cold agglutinin syndrome (CAS). Primary CAD is an extremely rare disease, with an incidence and prevalence of 1 per million and 16 per million, respectively. It is seen twice more in women than in men, and the median age of diagnosis is 67 (between 30-92 years). The etiology of CAS includes infections, autoimmune and lymphoproliferative diseases. There are cold-related symptoms and symptoms of anemia in the clinic. In treatment, it is necessary to avoid cold in order to reduce cold-induced symptoms and hemolysis. Currently, the most effective treatment for reducing antibody production is rituximab. It can be given alone or in combination with bendamustine, interferon alfa, fludarabine and prednisolone. bortezomib is used when rituximab is ineffective or contraindicated. Plasmapheresis or intravenous immunoglobulin can be given when there is critical hemolysis or when the effectiveness of immunosuppressive therapy may start late. Treatment in CAS is the treatment of the underlying disease.

Is Splenectomy still the best treatment for Autoimmune hemolytic anemia

Introduction:&#x0D; Autoimmune hemolytic anemia (AIHA) is an acquired, heterogeneous group of diseases that includes AIHA with warm type antibodies, cold agglutinin disease (CAD), mixed type AIHA, paroxysmal cold hemoglobinuria, and atypical AIHA.&#x0D; Currently CAD is defined as chronic, clonal lymphoproliferative disease, while presence of cold agglutinin in gastrointestinal tract is known as cold agglutinin syndrome. AIHA is mediated by autoantibodies against red blood cells (RBCs), these antibodies cause premature destruction of erythrocytes. The pathogenesis of AIHA is complex and still not yet fully understood.&#x0D; Aim of study:&#x0D; The purpose of the study was to review the literature on the treatment options for Autoimmune Hemolytic Anemia&#x0D; Materials and methods: A systemic review was conducted using PubMed, ScienceDirect, Google Scholar databases. The search strategy was based on following terms: Aiha, splenectomy autoimmune anemia, aiha treatment,&#x0D; Results and Conclusions:&#x0D; Based on the review of the medical literature, we believe that Splenectomy is no longer the most effective method of treating any type of AIHA and the Rituximab treatment presented by us seems to be safer and definitely less burdensome for the patient.&#x0D; Of course, splenectomy is still used in AIHA - but nowadays it is more limited due to the very high effectiveness of the described non-surgical treatment

Unusual case of cold agglutination induced hemolysis in a child with systemic lupus erythematosus

Autoimmune hemolytic anemia (AIHA) is a common symptom of systemic lupus erythematosus (SLE), but cold agglutinin disease is uncommon. We describe a rare instance of cold agglutinin causing hemolytic anemia in an eight-year-old girl who had a history of maternal antiphospholipid antibody syndrome. The girl had hemolytic anemia, and the Coombs test revealed both warm and cold antibodies with a significant titer of cold agglutinin. Whole exon sequencing revealed a heterozygous mutation in the GPI gene, which was previously described for non-spherocytic hemolytic anemia, but its significance in SLE is unknown. Patient responded to corticosteroids and azathioprine. The purpose of this article is to highlight this extremely rare SLE manifestation and compare it to previously reported cases.

26 Sustained complement C1s inhibition with sutimlimab in patients with cold agglutinin disease results in continued efficacy during part B of the randomized placebo-controlled phase 3 CADENZA study (NCT03347422)

26 Sustained complement C1s inhibition with sutimlimab in patients with cold agglutinin disease results in continued efficacy during part B of the randomized placebo-controlled phase 3 CADENZA study (NCT03347422)

Long-term sutimlimab improves quality of life for patients with cold agglutinin disease: CARDINAL 2-year follow-up

AbstractCold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia with a substantial burden on patient’s quality of life. CARDINAL was a 2-part, open-label, single-arm, multicenter phase 3 study evaluating the C1s inhibitor, sutimlimab, for treatment of CAD. Part A consisted of the pivotal study phase, with the part B extension phase assessing long-term safety and durability of response including patient-reported outcomes, which is the focus of this report. Altogether, 22 patients continued from part A to part B, majority female (68.2%) with a median age of 71.5 years (range, 55-85). Throughout treatment, score improvement on the Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue scale exceeded a predefined, group-level clinically important change of ≥5 points vs baseline, with a mean (standard error [SE]) change of 11.7 (3.7) points at week 135. The 12-Item Short Form Health Survey physical and mental component scores remained above baseline, with week 123 mean change (SE) exceeding clinically important changes of 3.9 for physical and 2.8 for mental component scores at 4.7 (2.8) and 3.8 (5.7) points, respectively. EuroQol Visual Analogue Scale, scoring patients’ self-rated health, also remained above baseline with a change of 17.1 (5.6) points at week 135. Patient Global Impression of (fatigue) Severity improved vs baseline, corroborating FACIT-Fatigue scores. Patient Global Impression of Change indicated a reduction in perceived disease burden. Data from CARDINAL part B support sustained alleviation of CAD disease burden after long-term treatment with sutimlimab over 2 years, returning toward baseline upon treatment cessation. This trial was registered at www.clinicaltrials.gov as #NCT03347396.

Autoantibodies in Chronic Immune-Mediated Demyelinating Polyneuropathy

Autoantibodies against nodal and paranodal proteins, such as neurofascin 140/186, neurofascin 155, contactin 1, and contactin-associated protein 1, have been identified in subsets of patients with chronic inflammatory demyelinating polyneuropathy. Their distinctive characteristics including poor response to immunoglobulin led to the establishment of a new disease entity called "autoimmune nodopathies." IgM monoclonal antibodies against myelin-associated glycoproteins cause intractable sensory-dominant demyelinating polyneuropathy. IgM anti-GM1 and IgG anti-LM1 antibodies are associated with multifocal motor neuropathy and chronic inflammatory demyelinating polyneuropathy, respectively. Monoclonal IgM against disialosyl ganglioside epitopes induces chronic ataxic neuropathy with ophthalmoplegia and cold agglutinin.

Cold agglutinin syndrome in a patient with human immunodeficiency virus infection

Abstract A 44-year-old female with no prior comorbidities presented with a history of easy fatiguability and yellowish discolouration of eyes of 3 months duration. On examination, she had pallor and icterus. Jugular venous pressure was elevated. Earlier, the patient was diagnosed to have autoimmune haemolytic anaemia and was started on steroids 2 weeks ago elsewhere. Laboratory investigations showed severe anaemia, elevated mean corpuscular volume and lactate dehydrogenase levels. Corrected reticulocyte count was 2.5%. Unconjugated hyperbilirubinaemia was evident. Coomb’s test was positive. In view of suspicion for cold agglutinin syndrome (CAS), monospecific agglutinin test with cold agglutinin titres was done, which tested positive. Serological testing was positive for human immunodeficiency virus (HIV) 1. The patient was diagnosed to have CAS secondary to HIV infection.

Utility of Dithiothreitol in a Case of Spontaneous Autoagglutination Due to Mixed Autoimmune Hemolytic Anemia in a Child – A Rare Scenario

Mixed autoimmune hemolytic anemia (AIHA) represents &lt;5% of pediatric AIHA cases. Spontaneous agglutination is known in patients with cold agglutinins reacting at room temperature. They often interfere with serological tests; generally, they can be dispersed by simple warming techniques. Rarely, in severe cases, as seen in the index case, dithiothreitol treatment of the red cells is needed to eliminate autoagglutination.

A patient with the highly suspected B cell lymphoma accompanied by the erythrocytes cold agglutination: Case report.

Cold agglutinins are related with B cell lymphoproliferative disorder and lymphoma, and can agglutinate red blood cells (RBCs) at an optimum temperature of 3-4°C, which is the undergoing cause of RBCs cold agglutination. RBC cold agglutination may lead to an extreme abnormality of RBC parameters of complete blood count (CBC). The present study reports a case of an old patient with severe infectious fever and anemia presenting extremely abnormal levels of RBC parameters in CBC and a sand-like appearance of blood on tube wall. The validating tests indicated the presence of the RBCs cold agglutination and the highly suspected B cell lymphoma. The 37°C-incubation corrected the CBC results of the patient, and the microscopic observation and flow cytometry analysis of blood and marrow indicated many abnormal B lymphocytes. Subsequently, the patient was diagnosed with a highly suspected B-cell lymphoma. The blood with a sand-like appearance was reanalyzed to validate the cold agglutination by 37°C-water incubation. The smears of peripheral blood and marrow were made for morphological observation by using optical microscopy. Moreover, the clusters of differentiation of the white blood cells were analyzed to confirm the type of abnormal white blood cells with a flow cytometer. The RBCs cold agglutination was validated, and the highly suspected B cell lymphoma was proved as the undergoing cause. This case focuses on the discovery and solutions of RBCs cold agglutination, and emphasizes the importance of microscopic observation in the exploration of undergoing causes of cold agglutination.

Molecular pharmacology in complement-mediated hemolytic disorders.

In the last decade, a deeper understanding of the pathogenesis of complement mediated hemolytic disorders, such as paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD), warm type autoimmune hemolytic anemia (AIHA) with complement activation (wAIHA), and atypical hemolytic uremic syndrome (aHUS), paved the way to the therapeutic shift from purely supportive approaches to complement-targeted therapies. This resulted in a significant improvement in disease management, survival, and quality of life. In this review, we will provide a snapshot of novel therapies for complement-mediated hemolytic anemias with a focus on those ready to use in clinical practice. C5 inhibitors eculizumab and the long-acting ravulizumab, are the established gold standard for untreated PNH patients, whilst the C3 inhibitor pegcetacoplan should be considered for suboptimal responders to anti-C5 drugs. Several additional compounds targeting the complement cascade at different levels (other C5 inhibitors, factor B and D inhibitors) are under active investigation with promising results. In CAD, immunosuppression with rituximab remains the first-line. However, recently FDA and EMA approved the anti-C1s monoclonal antibody, sutimlimab, that showed dramatic responses and whose regulatory approval is soon awaited in many countries. Other drugs under investigation in AIHA include the C3 inhibitor pegcetacoplan, and the anti-C1q ANX005 for warm AIHA with complement activation. Finally, aHUS is an indication for complement inhibitors. Eculizumab and ravulizumab have been approved, whilst other C5 inhibitors, and novel lectin pathway inhibitors are under active investigation in this disease.

Complement-directed therapy for cold agglutinin disease: sutimlimab

ABSTRACT Introduction Cold agglutinin disease (CAD) is a rare subtype of autoimmune hemolytic anemia defined as a distinct, low-grade lymphoproliferative disorder and characterized by the presence of immunoglobulin M (IgM) antibodies that recognize the ‘I’ antigen on red blood cell membranes. Hemolysis in CAD is mediated by activation of the classical complement pathway by IgM–antigen complexes. Sutimlimab directly targets classical complement pathway activation and has been shown to be generally well tolerated with rapid and sustained effects on hemoglobin levels, hemolytic markers, and fatigue in patients with CAD. Areas covered This review will outline the drug profile of sutimlimab and summarize the key efficacy and safety data focusing on the Phase 3 studies that formed the basis of the approval of sutimlimab in patients with CAD in the US, the EU, and Japan. Expert opinion Sutimlimab provides patients with an approved therapeutic option that can be used as part of a holistic approach to CAD management. The beneficial effects of sutimlimab go beyond rapid inhibition of hemolysis and include sustained meaningful improvements in fatigue and quality-of-life measures. Further, real-world evidence of the effectiveness and safety of sutimlimab in CAD and cold agglutinin syndrome will be assessed via the CADENCE registry.

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.

Efficacy of Rituximab in CANOMAD: A Systematic Review.

CANOMAD, characterized by chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M (IgM) paraprotein, cold agglutinins, and disialosyl antibodies, encompasses a clinical, radiological, and laboratory diagnosis. CANOMAD is a rare condition, with fewer than 100 cases reported in the literature. The understanding and diagnosis of the disease have improved in the last few years, but the treatment of CANOMAD is mainly unknown, and there is not a clear consensus about it. We conducted a systematic review regarding the efficacy of rituximab in CANOMAD's treatment to investigate the clinical and biological response of CANOMAD in patients treated with rituximab. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analyses of Observational Studies in Epidemiology (MOOSE) reporting guidelines for this systematic review. To analyze the bias of the study, we used the Joanna Briggs Institute's (JBI) Critical Appraisal Checklist to analyze the bias of the case reports, and we used the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool for the observational studies. We only included case reports, case series, and observational studies written in English with patients formally diagnosed with CANOMAD and treated with rituximab. We excluded systematic reviews, literature reviews, and meta-analyses. We investigated the clinical and biological responses of the patients to rituximab. The clinical response was classified as complete recovery (CR), partial response (PR), stable disease (SD), and non-response (NR). We gathered 34 patients. The literature uses a modified Rankin score to define complete improvement (CR), partial response (PR), stable disease (SD), and progression. Clinically, there were three patients with CR, five with PR, 15 with SD, and 11 with progression. The biological response was assessed by measuring the decrease in antibody titers in 27 patients. Among those, six patients had CR, 12 had PR, eight had SD, and one had progression. Among 15 patients with neurological evaluation, 10 had ocular symptoms, and two presented with bulbar symptoms. Seven of the ten patients with ocular symptoms had SD, two had PR, and one had progression. Only 14 patients had a report of demyelinating features. Three had an axonal pattern, six had a demyelinating pattern, and five had a mixed pattern. Among patients with an axonal pattern, three had an SD. Among patients with a demyelinating pattern, three had a PR, two had an SD, and one had progression. Among patients with a mixed pattern, four had SD, and one had progression. We concluded that patients with CR have a shorter disease duration than patients with PR, SD, or progression. In addition, patients with CR had longer follow-ups than the other groups, suggesting that being treated early with rituximab improves the clinical outcome and has a sustained effect. There were no differences in the frequency of ocular and bulbar symptoms among patients with CANOMAD. The axonal pattern is more common in patients with SD, suggesting that axonal and mixed patterns could be markers of a bad prognosis.