Cold Agglutinin Research Articles

Monoclonal Gammopathy of Undetermined Cardiovascular Significance; Current Evidence and Novel Insights.

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition characterized by the presence of low levels of a monoclonal protein in the serum and a low percentage of clonal plasma cells in the bone marrow. MGUS may progress to multiple myeloma or other plasma cell disorders at a rate of 1% annually. However, MGUS may also have adverse effects on the cardiovascular system independent of its malignant potential. Emerging data have shown that MGUS is associated with cardiovascular disease. The mechanisms underlying this association are not fully understood but may involve genetic abnormalities, vascular calcification, cryoglobulinemia, cold agglutinin disease, autoantibodies and the direct or indirect effects of the monoclonal protein on the vascular endothelium. Herein, we review current evidence in this field and we suggest that patients with MGUS may benefit from regular cardiovascular risk assessment to prevent severe cardiovascular complications, in parallel with close hematological follow-up to monitor potential disease progression.

Recombinant erythropoietin in autoimmune hemolytic anemia with inadequate bone marrow response: a prospective analysis

AbstractUp to 30% of patients with autoimmune hemolytic anemia (AIHA) show inadequate bone marrow (BM) compensatory response with inappropriately low levels of reticulocytes and endogenous erythropoietin. Ineffective BM compensation is associated with more severe anemia, transfusion need, and hospital admission, and treatment with recombinant erythropoietin (rEPO) may be beneficial. Here, we prospectively analyzed the efficacy and safety of rEPO in a single-center cohort of 47 patients with AIHA with inadequate reticulocytosis and endogenous erythropoietin at baseline. Epoetin alpha 40 000 international units per week were administered subcutaneously until hemoglobin (Hb) >11 g/dL and then tapered off. Overall response was 55% at 15 days, 74% at 1 month, 74% at 3 months, 80% at 6 months, and 91% at 12 months. Consistently, Hb values significantly increased from baseline to each subsequent time point (P<.001) with a median increase of +1.4, +2.4, +3.4, +3.8, and +4.4 g/dL, respectively. Transfusion needs reduced from 30% to <10% at 15 days and thereafter (P < .001). Concomitant medications included prednisone or methylprednisolone (N = 40, stable since >2 weeks from enrollment), mycophenolate mofetil (N = 1, ongoing since >3 months from enrollment), and rituximab (N = 7 patients with cold agglutinin disease from day 8). No association between concomitant medications and response to rEPO was found. Treatment was generally safe without rEPO-related severe adverse events. The comparison with an AIHA population not treated with rEPO showed a significant benefit of rEPO at 15 days and 1 month on response and Hb increase. These data support the use of rEPO as an add on to standard immunosuppression in AIHA with inadequate BM compensation. This trial was registered at www.clinicaltrials.gov as #NCT05931718.

Targeting Complement Inhibition in Cold Hemolysis; A Multifaceted Approach Using Sutimlimab and Washed Red Cell Transfusions

Introduction: Cold agglutinin syndrome (CAS) is a transient disorder mediated by autoantibodies that cause red cell agglutination at cold temperatures. CAS is often associated with infections rather than malignant or autoimmune conditions. Sutimlimab, a monoclonal antibody directed against the complement component C1s, was previously shown to improve anemia and fatigue in cold agglutinin disease (CAD) in single-arm studies. However, its use in CAS has not yet been elucidated. Here, we describe a case where complement inhibition using the novel C1s inhibitor, as well as washed and warmed red cell transfusions, were used to treat CAS in the setting of a rare autoantibody directed toward the Pr antigen Case report: A healthy 46-year-old woman presented with severe acute hemolytic anemia: with nadir hemoglobin of 4.7, hematocrit of 13.4%, 0.2% of reticulocytes, total bilirubin of 9.8 mg/dL, and unconjugated bilirubin of 8.4 mg/dL. A peripheral blood smear review revealed severe anemia with agglutination of red blood cells. An extensive infectious workup was negative including COVID-19, Parvovirus B19, CMV, EBV, CMV, and HIV. Over a period of two weeks, she received three doses of IVIG, prednisone, and 17 transfusions units of warmed red blood cells in the setting of persistent hemolytic anemia. Despite the evidence of severe hemolysis, her reticulocyte count remained very low (&amp;lt;0.5%). A bone marrow biopsy showed trilineage hematopoiesis with erythroid hypoplasia and maturation arrest. A direct Coombs test was intermittently positive but probably confused by IgG infusions, with anti-I and anti-i titers of 1:64, and positive for C3. Thermal amplitude studies showed agglutination at 30°C, 37°C, and room temperature. Red blood cell antibodies were not identified in the eluate. The indirect antiglobulin test was negative for ficin-treated RBCs showing no agglutination. This led the reference laboratory to report that the cold agglutination was directed against the anti-pr antigen and that this patient had clinically significant anti-Pr antibodies. The patient was kept warm and started on Danazol and Sutimlimab. However, the patient continued to have hemolysis after transfusions. After receiving her second dose of Sutimlimab and in the context of persistent hemolytic anemia, she underwent another bone marrow biopsy on day 34 after presentation. The biopsy showed hypercellular bone marrow with erythroid hyperplasia and complete maturation. However, this was not reflected in reticulocytosis until day 44. The patient received her third dose of Sutimlimab, and red blood cell transfusions were washed in addition to being warmed, which resolved hemolysis after transfusion reactions. She received a total of 30 red blood cell transfusions since presentation. The patient's anemia improved, with a hemoglobin level of 8.8 mg/dL and a reticulocyte count of 13%, and she was discharged on Day 51 after presentation (figure 1). She received one more dose of Sutimlimab (total of four doses) with complete resolution of her anemia, a normal reticulocyte count, normal LDH, negative Coombs study, and negative cold agglutinin titers. Conclusion: Here, we describe a challenging case of CAS caused by a rare Pr autoantibody, with a failure of first-line treatments for CAS. This report is the first to describe the use of Sutimlimab as a treatment for CAS. After initiating Sutimlimab, the patient continued to experience significant hemolysis shortly after transfusions, exhibiting hemoglobinuria and an inadequate increase in hematocrit. Only when the red blood cell transfusions were washed to remove complement, the hemolytic reactions ceased and significant increases in hematocrit occurred. This finding may be a consideration in other cases of cold agglutinin anemia. As CAS is a transient disorder, Sutimlimab could ultimately be discontinued once the hemolysis resolved. This case illustrates the role of complement inhibition in CAS and the potential need to warm and wash red blood cells in severe cases of CAS.

Cold Agglutinin Disease (CAD) Real-World Evidence (CADENCE) Registry: Update to the Study Design of the First International, Prospective CAD Registry

Cold agglutinin disease (CAD) is a rare chronic autoimmune hemolytic anemia (AIHA) characterized by classical complement pathway (CP)-mediated hemolysis. CAD is associated with a substantial disease burden negatively impacting quality of life (QoL), including severe fatigue, and increased risk of both thromboembolic events and early mortality. Due to the rarity of CAD, there is scarce information regarding its natural history, long-term impacts, and complications. Sutimlimab, a humanized monoclonal antibody that selectively inhibits the CP, is the first approved treatment for CAD. In the CARDINAL and CADENZA Phase 3 trials, sutimlimab reduced hemolysis, anemia, was generally well tolerated, and meaningfully improved QoL. The CADENCE Registry (NCT05791708) is a large international database of patients with CAD or cold agglutinin syndrome (CAS, a cold antibody-driven hemolytic anemia associated with an underlying condition). First launched in 2019, the first study patient was enrolled in 2022 following a COVID-19 pandemic-related hiatus. Presented here is an update on the current CADENCE protocol and study design. CADENCE is a multinational, multicenter, observational, prospective, longitudinal registry study enrolling patients ≥18 years of age diagnosed with CAD (diagnostic criteria: a monospecific direct antiglobulin test strongly positive for C3d and negative or weakly positive for immunoglobulin G and a cold agglutinin titer ≥1:64) or CAS (CAD diagnostic criteria, with causative infection, autoimmune disorder or overt malignancy). Exclusion criteria include patients with a diagnosis of warm or mixed AIHA and those actively participating in a CAD/CAS interventional trial. The main study objective is to better understand patient demographics, clinical characteristics, treatment patterns, healthcare resource utilization (HRU), natural history of disease, long-term clinical outcomes, and impact on patient QoL. A sutimlimab-treated cohort sub-study is ongoing to assess the real-world safety and effectiveness of sutimlimab in patients with CAD, fulfilling the regulatory commitment for a post-authorization safety study. The enrollment period is expected to last ~3 years and patients will be followed for 3 years after the last patient enrolled. Data collection will include both clinical assessments as per standard of care and patient-reported outcome (PRO) data collected at enrollment and at ~6-month interval follow-ups. Additional safety data will be collected for the sutimlimab cohort. The CADENCE Registry's first patient enrolled (after study restart) was in Q2 2022, with last patient's first visit expected in Q2 2025 and last patient's last visit expected in 2028 ( Figure). The registry will collect data on ~400 patients with CAD/CAS across ~90 sites in 8 countries: Austria, France, Germany, Italy, Japan, Spain, the UK, and the US. Among them, ≥30 patients with CAD treated with sutimlimab are expected to take part in the cohort study. Key data to be collected include clinical characteristics, disease complications, comorbidities, mortality, treatment regimens, HRU, and PROs. Biomarkers for hemolysis will be assessed, including lactate dehydrogenase, haptoglobin, total and indirect bilirubin. In the sutimlimab cohort, data will also be collected on adverse events (AEs), serious AEs, and AEs of special interest (serious infections, Raynaud's, arterial hypertension, autoimmune disorders, hypersensitivity/anaphylaxis, exposure in pregnancy, overdose). PRO measures include the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, the 36-item Short Form Health Survey (SF-36), and the CAD symptoms and impact questionnaire (CAD-SIQ), a novel 11-item questionnaire specifically designed for CAD. Interim analyses will occur annually. Final analyses will be performed at study end both at regional and global levels. As of July 13, 2023, 47 of 82 targeted sites have been activated, and 113 of 405 targeted patients (CAD/CAS) have been enrolled, including 13 sutimlimab-treated patients. CADENCE is the first global registry for patients with CAD and will help advance understanding of the natural history and disease process of this rare condition. This registry will also assess the long-term safety and effectiveness of sutimlimab in patients with CAD in a real-world setting, providing clinicians with data that may help improve treatment practices.

C3+ and C3- Warm Autoimmune Hemolytic Anemias: A Comparison of Clinical Characteristics and Treatment Outcomes

Background: Warm autoimmune hemolytic anemia (WAIHA) is mostly IgG mediated (IgG+C3-), which may at times fix complement (IgG+C3+). Whether the clinical outcome of complement-fixing (C3+) WAIHA is different from that of non-complement fixing (C3-) WAIHA remains unclear. The goal of this retrospective study was to describe and compare the clinical characteristics and treatment outcomes of patients with C3+ and C3- WAIHA. Methods: We included adult WAIHA patients seen at our institution from 2001-2023 who met all of the following criteria: A) age &amp;gt;18 years; B) direct antiglobulin test [DAT] IgG+ + C3+ with no cold agglutinin; and C) biochemical evidence of hemolysis. Response to treatment was based on the international consensus criteria: complete (CR; normal Hb or Hb ≥12 g/dL, with resolution of hemolysis); partial (PR; Hb &amp;gt;10 but &amp;lt;12 g/dL or Hgb &amp;gt;12 g/dL without resolution of hemolysis); or no response (neither CR nor PR). 223 WAIHA patients were found, and 132 patients were ultimately included. The most common reason for exclusion was a lack of complete DAT that included C3 testing. Results: There were 59 patients with C3- WAIHA and 73 patients with C3+ WAIHA, reflecting 44.7% and 55.3% of total patients respectively. Pertinent demographic, clinical, and treatment information are shown in Table 1. Slightly over half (52.3%) were males and the mean age (SD) was 63.9 years (18.1). Concomitant lymphoproliferative disease was present in 34.1% of the patients. The 3 most common treatments were steroids (97%), rituximab (66.7%), and splenectomy (18.2%). The median follow-up from diagnosis was 20.0 months (range, 1.0-251.8 months), and 14.4% of patients had died at the time of this analysis with no difference between the groups (P=0.82). There was no significant difference in the demographic composition, clinical findings, and treatment received in both groups. The number of treatments received were similar between C3- and C3+ WAIHA groups (Table 1). After first line of treatment, response was achieved in 86.4% and 94.4% of the C3- and C3+ groups (P=0.12), respectively. Additionally, 62.7% of the C3- group and 80.8% of the C3+ group were in PR or CR by their most recent CBC (P=0.02). 33.9% and 43.8% of the C3- and C3+ groups relapsed at least once (P=0.25). In those who relapsed, there was an average of 2.6 relapse events in the C3- WAIHA group compared to 1.8 relapse events in the C3+ WAIHA group (P=0.03). However, there was no difference in time to first relapse between the groups (P=0.51), shown in Figure 1. Conclusion: There have been retrospective descriptions of multiple AIHA subtypes and response rates to different therapies; however, this is one of the first studies to our knowledge to focus specifically on outcomes between complement subgroups. In our large group of patients with C3- and C3+ WAIHA, the clinical presentation, treatments utilized, and response to treatment were similar. Our data suggest that C3- and C3+ WAIHA can be approached and treated similarly.

Ethnic Diversity in Presentation of Waldenström Macroglobulinaemia and IgM Mgcs in the United Kingdom- a Real-World Data Analysis

Introduction: Waldenström Macroglobulinaemia (WM) is a low-grade B-cell lymphoma characterised by lymphoplasmacytic marrow infiltration with a circulating IgM protein with an incidence of approximately 0.55 cases per 100,000 in the United Kingdom (UK). WM may be asymptomatic, symptomatic and/or associated with IgM-related entities (monoclonal gammopathies) of clinical significance (MGCS). A central aim of the WMUK Charity and Clinical Forum is to systematically upload demographic, clinical data and treatment outcomes from a significant proportion of the UK's WM population. Such data provide important insights on the epidemiology and clinical features of this distinct uncommon disorder. Clinical correlates with ethnicity are important but sparsely characterised. This analysis focusses on baseline demographics and outcomes across different ethnic groups in the UK. Methods: We retrospectively reviewed data from the Rory Morrison WMUK Registry, collating descriptive data of WM, non-IgM lymphoplasmacytic lymphoma and IgM MGCS from 24 centres across the UK, diagnosed between June 1978 and June 2023. Research ethics approval was obtained. Baseline characteristics were compared using χ 2 or Fisher's exact tests (categorical variables) or Wilcoxon Mann-Whitney/Kruskal-Wallis tests (continuous variables). Differences were considered significant at p-values &amp;lt;0.05. Statistical analyses were performed using STATA v17.0 (StataCorp, Texas, USA). Results: 1073 patients with documented self-reported ethnicity and a diagnosis of WM (n=985), non-IgM LPL (n=32) or IgM MGCS (n=88) were included. Those with asymptomatic IgM MGUS were excluded. Of 982 with a diagnosis of WM, 12% (114/985) had concurrent MGCS. Across the entire cohort, IgM MGCS comprised peripheral neuropathy including anti-MAG neuropathy (n=114), cold agglutinin disease/syndrome (n=43), AL amyloidosis (n=20), mixed autoimmune haemolytic anaemia (n=13), cryoglobulinaemia (n=8), Schnitzler syndrome (n=8) and C1 esterase deficiency (n=2). Non-IgM LPL had similar baseline characteristics to WM although a trend towards a lower presenting M-protein (7g/l vs 18g/l, p=0.07). Ethnicity was categorised in accordance with the UK National Census (ethnicity-facts-figures.service.gov.uk). The majority was white (90%; 968/1073: English/Welsh/Scottish/Irish) including 35 patients identified as ‘other’ white. The remaining 105 (10%) were from the following ethnic groups (collectively ‘ethnic minorities’, EM): 54 Asian (22 Indian, 4 Pakistani, 1 Bangladeshi, 7 Chinese, 20 other), 19 Black (5 African, 11 Caribbean, 3 other), 6 Mixed/multiple, 26 Other ethnic group. EM presented at a younger age compared to the white cohort (60 vs 65 years, p&amp;lt;0.001) with a lower presenting M-protein at WM diagnosis (11g/l vs 18g/l, p=0.028). A similar proportion of patients had IgM MGCS in white vs EM cohorts (11% vs 8%, p=0.69). In those with IgM MGCS alone, presenting M-protein was similar across both ethnic categories (5g/l vs 3g/l, p=0.36). MYD88 L265P mutation was assessed in 387 WM patients (36%), of which MYD88 L265P was identified in 88% (322/364) and CXCR4 mutation tested in 91 patients and mutated in 29% (26/91). MYD88-mutated WM was observed less frequently in the EM versus white cohorts (79% vs 90%, p=0.05). A similar proportion presented with symptomatic WM across ethnic groups (56% vs 53%, p=0.56). In those with WM diagnosed since 2010 (n=956), median follow up was 8 years (95% CI 7-8), median overall survival was not reached. International Prognostic Scoring System for WM (IPSSWM) was predictive of overall survival. Overall survival estimates did not differ when comparing ethnic groups. Conclusions: Analysis of the national registry for WM shows that ethnic minorities comprise 10% of WM/IgM MGCS, present with WM at a younger age, a lower M-protein and with a higher proportion of MYD88-wild type cases which may suggest different disease biology. There was no difference in overall survival in our cohort. Limitations include the retrospective analysis of real-world data and incomplete documentation of baseline data. Further analysis of molecular signatures across ethnicities, treatment and outcome is warranted and ongoing.

Using a Quality Improvement Activity to Enhance the Knowledge, Competence and Confidence of Clinicians Managing Patients with Cold Agglutinin Disease

Introduction Cold agglutinin disease (CAD) is an autoimmune hemolytic anemia that is rare and poorly understood. This means that clinicians can find understanding the immunopathogenesis of CAD and individualizing therapy challenging, and may struggle to maintain their knowledge of current and emerging therapies, so patients may not receive optimal care. Therefore, we designed an easily accessible, online, continuing medical education activity for hematologists and hematologist-oncologists, using quality improvement principles together with other change approaches, to improve the care clinicians provide to patients with CAD. Methods The online activity included 3 short videos presented by faculty who shared their expertise in managing patients with CAD. We set learning objectives based on key topics we identified as being challenging for clinicians. This allowed us to measure the impact of the education on knowledge, competence (based on Moore's outcomes framework Levels 3 and 4), intention to change practice and clinical confidence. We also measured participation and satisfaction (Moore's Levels 1 and 2), and changes by region (EU5, Latin America and USA) and clinician experience. Questionnaires were fielded by an independent third party (Nuaxia Limited [Richmond, UK]) at baseline (n=100) and within 3 months (n=100) and 6 months (n=50) after participation in the activity to assess knowledge, competence, satisfaction, intention to change practice and confidence. Additionally, these assessments allowed us to identify the need for further educational activities and the topics they should cover. Participation was measured using Google Analytics. Questionnaire responses were analyzed by touchIME statisticians and data from 3 and 6 months were pooled for combined analysis. The margin of error was calculated as ~3% based on a standard confidence interval of 95%. Results At 6 months, the combined analysis showed an increase from baseline in declarative and procedural knowledge, and competence of 12%, 25% and 20%, respectively (Figure 1). These improvements did not show any significant variation by geography (p=0.432) or by years in practice (p=0.923). Analysis by question topic showed that the significant improvements were achieved consistently (p=0.003) for immunopathogenesis, p&amp;lt;0.001 for current and emerging therapies, and p&amp;lt;0.001 for individualizing treatments; Figure 2). The total number of questions answered correctly also increased significantly (p&amp;lt;0.001) from baseline (64.3%; SD 1.808) at the 6-month combined follow-up (82.0%; SD 1.808). The combined analysis showed clinician confidence in managing CAD improved from 44%, being moderately or extremely confident at baseline, to 72% at 6 months; a median of 57% of learners said they would make a change in their clinical practice. At 6 months post-launch, 6,754 participants had engaged with the education and the overall satisfaction was 88%. Conclusion This educational activity led to significant improvements in the knowledge and competence of hematologists and hematologist-oncologists in the understanding and management of CAD. Further, the majority of participants stated they were more confident and would change their clinical practice, which may improve the quality and effectiveness of patient care. The short, accessible format of this activity meant clinicians could participate whenever convenient and the use of expert-led videos made it engaging and applicable, which may have contributed to the success of the activity. Feedback from learners and our analysis indicate that further quality improvement initiatives on this topic would be beneficial and should cover integrating novel therapies into the clinic, as well as improving diagnostic accuracy in the non-speciality clinic.

Autoimmune Cytopenia Associated with Indolent B-Cell Clones: A Large Multicentric Cohort Study

Introduction Autoimmune cytopenias (AIC) are a group of rare diseases sharing immune-induced accelerated destruction and/or impaired production of blood cells. AIC can be associated with overt B-cell lymphoid neoplasia. In that case, the management is based on the treatment of the hematological malignancy. However, AIC can be associated with indolent B-cell clones (IBC). In that case, the treatment of the AIC is not consensual. We aimed to describe the treatments used in France for IBC-associated AIC, and to compare their effectiveness, safety, and impact on IBC progression. Methods We conducted a multicenter, retrospective observational study including adults treated between 2000 and 2022 for a definite AIC (immune thrombocytopenia, ITP; autoimmune hemolytic anemia, AIHA; or Evans syndrome, ES) associated with an IBC, namely: chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma, monoclonal B lymphocytosis, and mantle cell lymphoma. Patients who required a specific treatment of the underlying IBC for one or several of the following reason(s) were excluded: extensive marrow infiltration leading to impaired megacaryopoiesis and/or erythropoiesis, massive organ infiltration and/or compressive lymphadenopathies, lymphocytosis doubling within 6 months (with a lymphocytes count &amp;gt;30 x 10 9/L), doubling of lymphadenopathy size within 2 months, hyperviscosity, and any other IBC-related condition requiring treatment (amyloidosis, neuropathy...). Patients were classified according first-line treatment for AIC: group 1 for those treated without chemotherapy (corticosteroids, intravenous immunoglobulin, rituximab...); group 2 for those treated with chemotherapy (cyclophosphamide, ibrutinib...). Only the first-line treatment was assessed. Response to treatment was defined according to standard international criteria. An infection was defined as serious if graded &amp;gt;2, according to the Common Terminology Criteria for Adverse Events. The progression was defined as the need to urge lymphoma-specific therapy. Subgroup analyses were performed by type of AIC (ITP, warm/mixed AIHA, cold agglutinin disease, and ES). Overall survival was estimated using the Kaplan-Meier method and comparison was performed using Log-rank test. Results In total, 187 patients were included throughout 30 French university and general hospitals using the French reference center network for immune cytopenias in adults. The median age at diagnosis of AIC was 75 years (range 43 to 97 years) with a male/female ratio of 1.47 (Table 1). We observed 105 (56.1%) patients with AIHA, 80 (42.8%) with CLL and 44 (23.5%) with MZL. In most cases (58.8%), the time elapsed between IBC and AIC diagnosis was £6 months. We included 132 (72.2%) patients in group 1. Among them, 75 (55.6%) patients were treated with only corticosteroids +/- intravenous immunoglobulin, 52 (38.5%) with rituximab, 2 with splenectomy, and 1 with dapsone. We included 52 (27.8%) patients in group 2. Among them, 46 (88.5%) patients were treated as first-line with a rituximab-cyclophosphamide-dexamethasone combined regimen, 2 with rituximab-bendamustine, 2 with chloraminophen, 1 with fludarabine-cyclophosphamide-dexamethasone, and 1 with ibrutinib. Both overall response and relapse rates were similar between groups: 86.6% versus 86.5% and 45.5% versus 41.5%, respectively. We did not find any difference in subgroup analyses by type of AIC. Serious infections were observed in 17.6% patients: 17.8% in group 1, 17.3% in group 2. With a median of follow-up of 39.8 months (95% IC 30.0 to 51.3), the overall survival did not differ between group 1 (84.0% at 4 years, 95% IC 73.7 to 90.5) and group 2 (81.8% at 4 years, 95% IC 66.1 to 90.7), nor the progression rate of IBC was similar in both groups (9.6% and 7.7%, respectively). Conclusion We report the largest cohort of AIC associated with IBC. So far, very few patients with lymphomas such as MZL have been described in this situation. We observed that treatments were heterogeneous. Whatever the strategy used (treating AIC only or also using chemotherapy for the IBC), the effectiveness and safety profiles of first-line treatments were not different. Additional analyses are ongoing to better clarify the impact of rituximab alone versus rituximab and chemotherapy, and IBC' characteristics on the overall progression-free survival.

Mutations in Histone Lysine Methyltransferase Genes Are Associated with Autoimmune Cytopenias

Introduction Epigenetic mechanisms are important in regulation of gene expression by modifying chromatin structure to facilitate DNA accessibility (Lau et al Nat Immunol. 2018). DNA methylation and histone modifications are critical for the pathogenesis of hematologic malignancies and autoimmune diseases (Surace et al Front Immunol. 2019) Alterations in enzymes involved in histone modification are associated with immunodeficiencies, including Kabuki syndrome (KS), a rare genetic disorder associated with autoimmune cytopenias, such as immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) (Margot et al J Am Coll Med Genet 2020) caused by loss-of-function KMT2D and KDM6A mutations. Somatic mutations in the KMT2D gene have also been observed in patients with Cold Agglutinin Disease. (Małecka et al Br J Haematol. 2018). Aims: The aims of this study are: 1) to identify the frequency of mutations in histone methyltransferase genes (MT) KMT2D, KMT2A, KMT2C and KDM6A in patients with autoimmune cytopenias, and 2) to compare clinical, laboratory and immunological characteristics, and response to therapy in patients with or without mutation in MT and autoimmune cytopenias (AIC). Methods Data mining software from the electronic medical record was used to identify patients ≥ 18 years with a diagnosis of AIC, including ITP, warm and cold AIHA, autoimmune neutropenia, and Evans Syndrome (ES), who had Next Generation Sequencing (NGS) performed. Cytopenias due to malignancy, nutritional deficiency, medications, pregnancy, or infection were excluded. Patients were categorized into two groups based on the presence or absence of mutation in the MT genes (MT+, MT-) with variant allelic frequency (VAF) &amp;gt; 2%. Demographic, laboratory, and clinical characteristics, treatment outcomes, and NGS sequencing data were collected and compared between groups. Next, KMT2 mutations seen in patients with AIC were cross-referenced against the 1000 Genome Project (1000GP) population database to evaluate the frequency of polymorphisms in the general population (Auton et al Nature 2015). CADD in silico prediction algorithm was used to score the potential deleterious effect of MT mutations (Kirchner Nat Genet. 2014). Chi-Square test was used for categorical variables. Statistical analysis was completed in R software. Results Among 495 patients who underwent NGS, 79 (16%) had a mutation in MT genes. These mutations were present in 36% of patients with AIC as compared to 13% in those without AIC (p=0.0005). Among 55 patients with AIC, mutations in the MT genes were present in 20 patients (MT+), 35 patients did not have these mutations (MT-). KMT2C mutations were seen in 10 (50%) patients, KMT2D mutations in 9 patients (45%, one patient had two KMT2D mutations), 1 patient (5%) had both KMT2C &amp; KMT2D variants (Figure 1). The median VAF was 39.5% (IQR, 15.45 - 49.80). The MT+ group had a significantly higher proportion of Hispanic (60% vs 31%) and non-Hispanic White patients (25% vs 14%), p=0.038, Table 1. The median age at diagnosis for the MT+ cohort was younger compared to MT- (45.5 vs 58 years old, respectively), though not statistically significant. AIC diagnoses in both groups were ITP (44%) wAIHA (22%) cAIHA (9%) Autoimmune Neutropenia (2%), and ES (24%). Compared to the MT- group, the MT+ group had lower IgG levels (p=0.0041) and absolute lymphocyte count (p=0.041). MT+ patients with AIHA were more likely to have positive Direct Coombs and complement involvement. No significant differences were found in median nadir hemoglobin and platelet counts, need for therapy, or median number of lines of therapy. Best overall response to therapy was similar in the two groups (93%), with more complete responses in MT- group (55% vs 33%) though not statistically significant. Next, we assessed KMT2 polymorphisms in the general population. Most of the polymorphisms were not present in the 1000GP database and none had a frequency &amp;gt; 0.001. The average Phred score was 19.8; 12/20 patients had Phred score &amp;gt; 20, suggesting that most mutations are in the top 1% of the deleterious variants. Conclusion We report for the first time that patients with autoimmune cytopenias have a high frequency of variants in MT genes. Median allelic frequency close to 50% suggests potential germline predisposition to immune dysregulation and autoimmunity however further studies are needed to better understand the impact of these observations.

Combined Safety Data for Sutimlimab in Cold Agglutinin Disease: A Post-Hoc Analysis of the Phase 3 Cardinal and Cadenza Studies

Background: Cold agglutinin disease (CAD) is a rare, chronic, autoimmune hemolytic anemia mediated by the classical complement pathway (CP).Sutimlimab is a first-in-class, humanized, monoclonal antibody that selectively inhibits C1s of the C1 complex, preventing CP activation and CP-mediated hemolysis. CARDINAL (NCT03347396) was an open-label, single-arm, Phase 3 study of sutimlimab in patients with CAD and recent history of transfusion; CADENZA (NCT03347422) was a randomized, double-blind, placebo-controlled, Phase 3 study of sutimlimab in patients with CAD and no recent history of transfusion. Both studies had a 26-week treatment period (Part A) followed by a long-term extension (Part B), reporting data up to 2 years after the last patient finished Part A of CARDINAL and up to 1 year after the last patient finished Part A of CADENZA. With long-term treatment in both studies, sutimlimab demonstrated sustained efficacy with improvements in hemolysis and anemia, sustained clinically meaningful improvements in quality of life, and it had a favorable safety profile. Aims: To report combined safety data from Part A and B of the Phase 3 CARDINAL and CADENZA studies in sutimlimab-treated patients with CAD. Methods: In CARDINAL Part A, patients received sutimlimab on Days 0 &amp; 7, then biweekly until the end of Part B. In CADENZA Part A, patients received sutimlimab or placebo on Days 0 &amp; 7, then biweekly; in Part B, patients continued to receive biweekly sutimlimab or switched from placebo to receive sutimlimab on Days 0 &amp; 7, then biweekly. Data fromall enrolled patients who received at least 1 dose of sutimlimab in CARDINAL (N=24) and CADENZA (N=42), including a post-treatment follow-up 9 weeks after the last dose, were combined into the Safety Analysis Set. Endpoints for this analysis included the incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), and adverse events of special interest (AESIs). AESIs were selected based on a list of important identified risks and important potential risks for sutimlimab. Results: The Safety Analysis Set included 66 patients. At baseline, the median age was 69.5 years (range 46-88) and the majority (72.7%) were female, with a median duration since CAD diagnosis of 5.7 years (range 0-33). The median patient follow-up was 129.1 weeks (range 5-175). Sixty-four (97.0%) patients experienced ≥1 TEAE ( Table 1). Eighty-six TEAEs assessed as related to sutimlimab by the investigator occurred in 30 (45.5%) patients. Fifty-three TESAEs were reported in 22 (33.3%) patients. Three (4.6%) patients each experienced one TESAE assessed as related or possibly related to sutimlimab by the investigator (related vitreous hemorrhage, related viral infection, and possibly related severe cerebral venous thrombosis). Seven patients discontinued sutimlimab treatment and/or the studies due to ≥1 TEAE, 4 in CARDINAL and 3 in CADENZA. Four patients died during the studies: 1 in CADENZA with a TESAE of lung squamous cell carcinoma and sutimlimab was withdrawn due to this TESAE prior to the patient's death; 3 in CARDINAL, 1 patient died after premature discontinuation of sutimlimab due to AEs (fatal infection of Klebsiella pneumoniae, acrocyanosis), 1 patient died due to a newly diagnosed hepatic cancer in the first month of the study, and 1 patient died due to exacerbation of CAD during the 9-week washout period approximately 1.5 months after the last dose of sutimlimab. No deaths were assessed as related to sutimlimab by the investigator. Treatment-emergent AESIs (selected based on a list of important identified risks and important potential risks for sutimlimab) are presented in Table 1. Fourteen TEAEs of serious infection were reported in 9 patients (13.6%; one assessed as related to sutimlimab by the investigator), 31 TEAEs of hypertension were reported in 17 patients (25.8%), 28 TEAEs of acrocyanosis and/or Raynaud's phenomenon were reported in 13 patients (19.7%), and 4 TEAEs of thromboembolic events were reported in 4 patients (6.1%). No TEAEs of serious hypersensitivity reaction and/or anaphylaxis, meningococcal infection or development of systemic lupus erythematosus were reported. Conclusion: The combined safety analysis of the Phase 3 CARDINAL and CADENZA studies (Part A and B) demonstrated that sutimlimab was generally well tolerated, with the type and frequency of TEAE consistent with an older and medically complex population.

Keeping up with the Cartashians - Classical Hematology Drug Approvals over Past 5 Years

Classical hematological disorders encompass a broad array of congenital and acquired blood conditions, ranging from thrombotic and hemorrhagic disorders, hemoglobinopathies such as sickle cell disease/thalassemia, abnormalities in blood counts, disorders of iron metabolism, obstetric hematologic conditions, and rare genetic hematologic diseases. The past decade has seen a revolution in research and therapeutic development for these disorders. It has led to FDA approval of novel therapies such as gene therapies for hemophilia and hemoglobinopathies, targeted therapies for coagulation and complement disorders, factor VIII mimetics, new immunotherapeutic targets for cytopenia and genomic-directed diagnosis and therapy for a wide range of blood disorders. Between January 2018 and July 2023, 34 new drugs have been approved for different classical hematological disorders, and several more have received approval for new or expanded indications. This is changing how we treat patients with classical hematological conditions. Most classical hematological disorders have an impact on patients' quality of life as well as life span, and for decades, many of these disorders were managed with limited therapy options with variable efficacy. Rare hemolytic disorders such as cold agglutinin disease, paroxysmal nocturnal hemoglobinuria, thrombotic thrombocytopenic purpura, atypical hemolytic uremic syndrome, sickle cell disease, thalassemia, porphyria all have expanded options. Newer agents for the management of anemia, thrombocytopenia and leukopenia in different clinical settings are available. Lastly, management of hemophilia is being revolutionized by extended half-life products, non-factor options and gene therapy. Hemophilia care has always been deemed to be costly, but gene therapy is getting additional attention due to the high price tag. We have compiled the list of all new drugs that got FDA approval for classical hematological disorders over past 5 years and plan to present this in the form of an infographic providing details on the drug along with its indication, trial leading to approval and cost implications of each therapy. Our intention is to summarize the drug development for classical hematology and highlight “not so benign” nature of these disorders and related therapy particularly in terms of financial toxicity for the patients.

Prevalence and Incidence of Primary Autoimmune Hemolytic Anemia and Cold Agglutinin Disease in the United States, 2016-2022: A Retrospective Study in Administrative Claims

Background Autoimmune hemolytic anemia (AIHA) is a decompensated acquired hemolysis caused by autoantibodies that act against red blood cells leading to anemia. Cold agglutinin disease (CAD) is a rare subtype of AIHA mediated by classical complement pathway activation, characterized by chronic hemolysis, severe anemia, fatigue, weakness, dizziness, and circulatory problems. The aim of this study was to update the epidemiology of AIHA and CAD in the United States using administrative claims data that includes commercially insured patients, as well as those with Medicare Advantage, Medicare Fee for Service (FFS) and Managed Medicaid plans. Methods Administrative closed claims from Optum CDM database (commercially insured single-payer and Medicare Advantage), Inovalon MORE 2 Registry (commercially insured multi-payer, Medicare Advantage, and Managed Medicaid), and 100% Medicare FFS (Part A/B services) data were used for this analysis. AIHA cases were defined as patients with at least 2 claims with ICD-9/10 diagnosis codes for AIHA (283.0, D59.1, D59.10, D59.11, D59.12, D59.13, D59.19) at least 30 days apart. CAD cases were defined as patients with at least 2 claims with ICD-10 diagnosis codes for CAD (D59.12) or at least 1 claim with diagnosis code for AIHA followed by 1 claim with diagnosis code for CAD (D59.12) at least 30 days apart. Index date was assigned to the first observed claims with the AIHA/CAD diagnosis. Analyses included patients 18 years of age and above with at least 180 days of continuous enrollment in their health plan prior to index for the assessment of the exclusion criteria. Patients with secondary causes of AIHA/CAD (e.g., lymphoma, leukemia, myeloma, cytomegalovirus, or Epstein-Barr virus) were excluded. US census data from years 2016-2021 was used to standardize the incidence and prevalence estimates by age and sex. Point prevalence was calculated as of January 1 st of each year using an all-data lookback. Period prevalence was calculated using a one calendar year assessment period. Incidence estimated new cases in a given year among patients with no prior evidence of AIHA in all data lookback. For CAD, estimates were presented for years 2022/23 due to the recency of the ICD-10 code specific to CAD (active as of 1 October 2020). Results Age and sex standardized point prevalence of AIHA per 1,000,000 persons was approximately 210 in the Medicare FFS across years 2016-2021, 160 in the Optum claims across years 2016-2022, and 50 in the MORE 2 database across years 2016-2022. One-year prevalence per 1,000,000 persons was approximately 190 in the Medicare FFS, 70 in the Optum claims, and 50 in the MORE 2 database across study years. Incidence per 1,000,000 was 50-60 in the Medicare FFS, 20-30 in the Optum claims, and 15 in the MORE 2 database. While overall standardized estimates differed across databases, incidence and prevalence estimates were similar when stratified by age group, indicating that standardization did not fully account for the underlying differences in the composition and representativeness of the overall US population in the three databases. Incidence and prevalence were higher among females than males and increased with age as expected. Incidence per 1,000,000 for year 2021 ranged from roughly 10-80 among those under the age of 45 years to 30-80 among those over the age of 65 years across the three databases. Point prevalence per 1,000,000 for year 2021 had a broader range from 30 to 220 among those under the age of 45 years and from 120 to 360 among those over the age of 65 years. The standardized point prevalence per 1,000,000 for CAD was 31 in Optum claims (year 2023), 33 in Medicare FFS (year 2021), and 14 in MORE 2 (year 2021). Prevalence of CAD was higher among females and increased with age. Conclusion This multi-database analysis provides updated epidemiology estimates for AIHA and CAD in the US. Age and sex standardized point prevalence for AIHA ranged from 60 to 210 per 1,000,000 across the 3 databases, with higher prevalence in the Medicare FFS database which primarily captures population over the age of 65 and was lower in the two databases that capture younger age groups, such as Managed Medicaid and commercially insured populations. Similarly, incidence of AIHA ranged from 15 to 60 per 1,000,000. Point prevalence of CAD ranged from 14 to 33 per 1,000,000. These estimates are in line with those previously reported for North America and Western Europe.

Hospitalization for Infection in Patients with Primary Autoimmune Hemolytic Anemia Treated with Rituximab. a Prospective, Nationwide Cohort Study in France

Introduction Autoimmune hemolytic anemia (AIHA) is a rare disease caused by the production of autoantibodies directed against red blood cells. Infections are frequent and severe in patients with primary AIHA. Rituximab is the reference second-line treatment for warm AIHA and the basis of the treatment of symptomatic cold agglutinin disease. However, the risk of infection after rituximab is not known in these patients with primary AIHA the real-world. Opportunistic infections had been described and the use of specific prophylaxis is debated. Consequently, this cohort study aimed to: (i) measure the incidence of hospitalization for infection after the exposure to rituximab in adult patients with primary AIHA; (ii) describe the types of these infections; (iii) measure the 30-day overall mortality after the first hospitalization for infection; (iv) determine the factors associated with hospitalization for infection; and (v) assess the effectiveness of pneumocystis prophylaxis. Methods Patients were selected from the AHEAD cohort (Autoimmune HEmolytic Anemia: a population-baseD study) between January 2012 and July 2018. This cohort consists in all adult patients with incident AIHA, selected in the French National Health Database. This database covers virtually the entire French population (67 million individuals). It links socio-demographic, outpatient, and hospitalization data. Patients with AIHA were identified using the International Classification of Diseases, tenth version (ICD-10) D59.1 code as hospital discharge or long-term disease diagnosis (the latter being coded by general practitioners). Incident cases were selected using a prior observation period of at least 2 years without the D59.1 diagnosis code. This code yielded a positive predictive value of 90.0% (95% CI: 79.5 to 96.2) in a previous validation study. We restricted the study population to adult patients exposed to rituximab. The first infusion of rituximab defined the index date. Patients with causes of secondary AIHA before the index date were excluded. We assessed the cumulative incidence of hospitalizations with a discharge diagnosis of infection during the six months after the index date (median duration of B-cell depletion). The overall mortality was measured during the 30 days after hospitalization for infection. We assessed the association of age, sex, comorbidities, red blood cell transfusions before the index date (as indicator of AIHA severity), exposure to corticosteroids, to other immunosuppressive drugs, splenectomy (time-varying exposures) as well as pneumococcal and influenza vaccinations before the index date on the occurrence of hospitalization for infection using Cox regression models. A sensitivity analysis was performed using Fine and Gray's models with death as competitive risk. Pneumocystis pneumonia was identified using the B48.5 and B59 discharge diagnosis codes. The association with specific prophylaxis was assessed. Results Between 2012 and 2018, we identified 959 adult patients with incident primary AIHA who received rituximab. The mean age was 67 years and 61% of the patients were women. The 6-month cumulative incidence of hospitalization with a discharge diagnosis of infection was 18.3% (95% CI: 15.9 to 20.9). The most frequently characterized infections were pulmonary, urogenital, and gastrointestinal. Opportunistic infections were observed in 28 (16.6%) patients. The 30-day overall mortality after the first hospitalization for infection was 12.5% (95% CI: 8.0 to 18.0). The risk factors associated with hospitalization for infection in multivariable analysis were an age ≥70 years (HR: 2.7; 95% CI: 1.6-4.6) and current exposure to corticosteroids (HR: 1.6; IC 95%: 1.2-2.2). The results of the sensitivity analysis were concordant. In total, 189 (19.7%) patients were exposed to pneumocystis prophylaxis and 14 pneumocystis pneumonia occurred. All cases occurred during the exposure to corticosteroids and in patients with no specific prophylaxis. All but 2 were aged ≥70 years. Conclusion The incidence of hospitalizations for infection and mortality after hospitalization for infection were high in adult patients with primary AIHA treated with rituximab. Opportunistic infections were not uncommon. Concomitant exposure to corticosteroids and an older age are the main risk factors for infection. Pneumocystis prophylaxis should be discussed for these patients.

Efficacy of Sutimlimab in Improving FACIT-Fatigue Scores in Patients with Cold Agglutinin Disease: A Post-Hoc Analysis of the Phase 3 Cadenza (Part A) Study

Background Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia characterized by chronic hemolysis mediated by classical complement pathway activation. Chronic inflammation and anemia associated with CAD can lead to profound fatigue and general weakness, impacting the patients' quality of life. Sutimlimab is a first-in-class humanized monoclonal antibody approved for the treatment of CAD. To assess the effect of sutimlimab on patients' self-reported fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-Fatigue] scores) in CAD, a post-hoc analysis of the CADENZA Part A study was carried out. Objective To assess the effect of sutimlimab vs placebo on FACIT-Fatigue total score, and individual items of the FACIT-fatigue scale in patients with CAD. Methods CADENZA (NCT03347422) Part A was a phase 3, double-blind, 26-Week study where patients were randomized (1:1) to receive intravenous sutimlimab or placebo. The 13-item FACIT-Fatigue questionnaire comprising 11 fatigue items and 2 energy items (‘I have energy’ or 'I am able to do my usual activities') was scored on a 0 (“not at all”) to 4 (“very much”) response scale, and the total scores ranged from 0 to 52; higher scores indicated less fatigue. Least square (LS) mean difference (sutimlimab vs placebo) in change from the baseline (BL) in FACIT-Fatigue total score were estimated at all visits using mixed model for repeated measures. Treatment assessment timepoint (TAT) was the average of values from Week 23, 25, and 26 visits. Patients were considered responders if they achieved a change from BL in FACIT-Fatigue total score of ≥5, did not receive blood transfusions from Week 5 through TAT, and did not take any protocol prohibited CAD medications. Patients with missing data at a given visit were considered non-responders. Time to first response to treatment was assessed using the Kaplan-Meier product limit method. For the item level analysis of the FACIT-Fatigue scale, the proportion of patients reporting the two worst response options 'Quite a bit' or ‘Very much’ for fatigue items and ‘Not at all’ or ‘A little bit’ for energy items was calculated at BL and Week 26. Results A total of 42 patients were included in the study (sutimlimab group: n=22; placebo group: n=20). The median (range) age of patients was 66.0 (46-88) years and 78.6% (n=33) were female. The mean (SD) FACIT-Fatigue total score for the pooled population at BL was 32.30 (11.83). About 79% of patients (n=33) had a total score below the general healthy population mean of 43. The LS mean (95% CI) difference (sutimlimab vs placebo) in change from BL in the FACIT-Fatigue total score was 4.97 (0.35─9.60) at Week 1 and 8.93 (4.00─13.85) at TAT. The nominal significant difference that started at Week 1 (rapid treatment effect) was sustained throughout Part A ( Figure 1). Overall, the fatigue response rate was higher in the sutimlimab group than placebo group throughout the study. The median time (95% CI) to first FACIT-Fatigue response in the sutimlimab and placebo groups were 3.1 (1.1─3.1) and 9.1 (3.3─22.4) weeks (log-rank test p&amp;lt;0.05), respectively. At BL, ~25-30% of the patients had reported the two worst response options (‘Quite a bit’ or 'Very much') for most of the FACIT-fatigue items. Around 40.5% (17/42) of the patients responded with one of the two worst options for item 'I feel tired', and more than half of the patients (22/42; 52.4%) reported one of the two worst options (‘Not at all’ or 'A little bit') for item 'I have energy'. At Week 26, lower proportion of patients in sutimlimab group reported one of the two worst options for fatigue and energy items compared with the placebo group ( Figure 2). Conclusion Sutimlimab treatment led to rapid and sustainable improvement in FACIT-Fatigue scores and higher response rates as compared to placebo. Number needed to treat to observe a sutimlimab-related FACIT-Fatigue benefit was 4. The proportion of severe FACIT-Fatigue answers for fatigue and energy items was noticeably lower in sutimlimab-treated patients at Week 26 compared to placebo, highlighting the effect of sutimlimab in improving almost all dimensions of FACIT-Fatigue scale.

Cost-Effectiveness of Sutimlimab Versus Standard-of-Care in Transfusion Dependent Patients with Primary Cold Agglutinin Disease in the United States

Introduction: Primary cold agglutinin disease (CAD) is an autoimmune hemolytic anemia characterized by the presence of cold-reactive antibodies that lead to red blood cell destruction at low temperatures. Patients with CAD who are transfusion-dependent experience the burden of increased health resource utilization and reduced quality-of-life. The standard-of-care (SOC) in patients with primary CAD has included chemoimmunotherapy, transfusion support, and cold avoidance. Sutimlimab is a humanized monoclonal antibody that selectively inhibits C1-mediated hemolysis. It is the only FDA-approved therapeutic for patients with cold agglutinin disease regardless of history of transfusion, with approval based on two phase 3 clinical studies. The cost-effectiveness of this expensive therapeutic in the care of patients with either transfusion-independent or transfusion-dependent primary CAD is not known. We sought to fill this gap by determining the cost-effectiveness of sutimlimab versus standard-of-care for the transfusion-dependent patient population with primary CAD. Methods: For this independent analysis free of industry influence, we built a Markov state transition model of adult patients with transfusion-dependent primary CAD to determine the cost-effectiveness of sutimlimab versus SOC, over a lifetime time-horizon and across accepted willingness-to-pay thresholds in US dollars per quality-adjusted life-year (QALY). For transition probabilities, we employed phase 3 study data (NCT03347396) with descriptive statistics informing the documented pre- versus on-sutimlimab clinical benefit, including the decrement in hemolytic anemia severity and transfusion burden. For SOC, we assumed that all patients undergo the costs and risks of chemoimmunotherapy with bendamustine-rituximab, followed by rituximab monotherapy and subsequent treatment with mycophenolate mofetil, with all patients remaining dependent on transfusion care. Health resource utilization costs for SOC were further supplemented with country- and disease-specific real-world costs over a median of 42.8 and 33.0 months of follow-up after incident primary CAD diagnosis across two claims databases. These costs were assessed from the highest of 1) annualized cost quartile and 2) the worst ordinal category of hemolytic anemia severity (defined as hemoglobin &amp;lt;8 g/dL) across all of 1) hospitalizations, 2) emergency visits, 3) outpatient services, and 4) blood transfusions. We assumed no loss of sutimlimab efficacy and no discontinuation off sutimlimab due to adverse events. Age- and sex-adjusted, disease-specific mortality was employed. Effectiveness was calculated in QALYs and was informed directly from trial-specific utilities. The primary outcome was the incremental cost-effectiveness ratio (ICER) or the incremental net monetary benefit (iNMB), if the intervention was found to be cost-saving. The secondary outcome was a scenario analysis for patients with a body weight of &amp;lt;75 kilograms that mandate lower dosing per-kilogram sutimlimab dosing, as per the FDA package insert. We concluded by conducting deterministic and probabilistic sensitivity analyses, capturing uncertainty in all parameters simultaneously over 10,000 Monte Carlo simulations. Results: In the base-case analysis, treatment with sutimlimab versus SOC accrued 5.60 and 4.79 QALYs at costs of $9.52 and $7.67 million, respectively, with the ICER for sutimlimab treatment being $2,280,000/QALY [95% credible interval 960,000-13,900,000]. In the scenario analysis for patients with lower body weight (i.e., lower sutimlimab dosing), the ICER was $1,910,000/QALY. Model results were sensitive to sutimlimab cost. In a probabilistic sensitivity analysis, SOC was favored over sutimlimab in 100% of 10,000 iterations. An exploratory threshold analysis showed that the mortality hazard with sutimlimab would need to decrease by 201% for sutimlimab to become cost-effective. Conclusion: Sutimlimab is conventionally cost-ineffective compared to SOC in transfusion-dependent patients with CAD. Distributional cost-effectiveness analysis (DCEA) to potentially justify sutimlimab as an equitable therapeutic option despite cost-ineffectiveness in the United States context is needed.

Cold Agglutinin Disease: Challenges in the Serological Workup and Management

Abstract Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia associated with autoantibodies that react mainly in the cold. CAD can interfere with immunohematology tests. We report two cases of CAD presented initially as blood grouping discrepancy leading us to further workup. Case I was a 61-year-old female with symptoms of weakness, bone pain, and difficulty breathing with laboratory findings of high cold agglutinin titers of 1:1024. Bone marrow aspirate revealed a mixture of &gt;30% plasma cell and plasma blast. Bone marrow biopsy revealed an interstitial, focal, and nodular pattern of involvement by plasma cells, leading to the diagnosis of plasma cell dyscrasias. Case II analyzed was benign CAD with cold agglutinin titers of 1:64, with no other abnormality. Both patients were managed successfully. We report serological and clinical findings of two CAD cases with similar serological findings but different clinical outcomes.

Cytokine polymorphisms in patients with autoimmune hemolytic anemia.

Autoimmune hemolytic anemia (AIHA) is due to autoantibodies with or without complement activation and involves cellular and cytokine dysregulation. Here, we investigated cytokine single-nucleotide polymorphisms (SNPs) of TNF-α, TGF-β1, IL-10, IL-6, and IFN-γ, along with their serum levels. The former were related to hematological parameters, therapy, and clinical outcome. The study included 123 consecutive patients with primary AIHA [77 warm AIHA and 46 cold agglutinin disease (CAD)], followed up for a median of 49 months. Results show that the allelic frequency of TNF-α -308 G/A polymorphisms was significantly lower in patients versus controls. Moreover, the genotypic frequency of TNF-α -308G/A and TGF-β gene codon 25 G/C genotypes was significantly lower in patients versus controls. Considering cytokine SNP genotypes associated with different gene expression levels, TNF-α high gene expression was significantly more frequent in patients, TGF-β and IL-10 high gene expression was higher in patients with more severe anemia, and TGF-β high gene expression was higher in patients with active disease. Considering treatment, TNF-α and TGF-β high gene expression was more frequent in multitreated patients and particularly in CAD. It may be speculated that this genetic predisposition to a stronger inflammatory response may result in a greater immune dysregulation and in a relapsed/refractory disease. Regarding cytokine serum levels, TNF-α and TGF-β were significantly lower, and IL-10 and IL-6 were significantly higher in patients versus controls, underlying the complex interplay between genetic background and disease features.

A US Retrospective Observational Study of Rituximab Use in Cold Agglutinin Disease

Background Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia (AIHA). Rituximab is approved for treatment of B-cell lymphoma and severe rheumatoid arthritis and used off-label as a treatment for AIHA, including CAD. There is limited real-world evidence on patterns of rituximab use, safety, response rate and duration of response among patients with CAD. Objectives The key objectives were: 1) to characterize patients who initiated rituximab and examine their treatment patterns; 2) to describe the incidence of serious infections (SIs) prior and post rituximab treatment; 3) to assess the rate and duration of response to rituximab using hemolytic markers. Methods This retrospective, cohort study included adult (aged ≥18 years) patients with CAD from Optum's de-identified Market Clarity Data (2007-2021). Patients with CAD (Cohort 1) were indexed on their CAD diagnosis date. Cohort 1 patients who had ≥1 rituximab infusion (Cohort 2) were indexed on their 1 st rituximab infusion date ( Figure 1). Patients with cold agglutinin syndrome associated comorbidities on or before their index date were excluded. For each cohort, demographics, and clinical characteristics at index date, and for Cohort 2, clinical characteristics during 1 year before index date were described. Data for rituximab treatment patterns included number of courses, treatment type (monotherapy or combination therapy), complete or incomplete course, and the use of blood transfusion (BT) as rescue therapy. In Cohort 2, the incidence rates of SIs per 1000 patient-years before and after treatment (within 6 months of 1 st infusion) were assessed. Response to treatment was assessed using hemolytic markers (hemoglobin [Hb], bilirubin, and lactate dehydrogenase [LDH]). From baseline, a change of ≥2 g/dL was considered a Hb response, while a decrease of 50% was assessed as proxy for a bilirubin or LDH response. Relapse was defined as the reversal of biomarker levels below the minimum response threshold. Response duration was the period from the date of response to that of relapse. Results A total of 611 CAD patients were identified (Cohort 1); 94 of them received rituximab (Cohort 2). Median time from CAD diagnosis to rituximab initiation was 43.5 (Interquartile range [IQR]: 13.0-308.3) days. Overall, Cohort 2 had a more severe disease status at treatment initiation than all patients with CAD (Cohort 1) at diagnosis (higher comorbidity scores, rates of health care resource utilization, lower Hb, and more severely elevated hemolytic markers; Table 1). In Cohort 2, the mean (SD) number of rituximab courses per patient was 1.45 (1.16); 24 (25.5%) of patients had ≥1 incomplete course; 37 (39.4%) required BT rescue therapy, and the median time from rituximab initiation to 1 st BT was 31 (IQR: 1.5-110.5) days. Combination therapy was rarely used (3/94; 0.03%); only 1 patient completed. The incidence rate (95% CI) of SIs (per 1000 patient-years) post CAD diagnosis in Cohort 2 was ~3 times higher in the 4 to 6 months after rituximab initiation (637.1 [242.2-1032.0]) than before (245.4 [125.1-365.6]). Proportion of corticosteroid use was the same during 1 year prior to rituximab initiation and concomitantly with rituximab (54/94; 57.4%, both). For patients in Cohort 2 with available data, 69.5% (41/59) had a Hb response, 59.6% (28/47) had a bilirubin response, and 31.3% (10/32) had a LDH response to the 1 st course of rituximab (median [IQR] time to response: 48.0 [33.5-85.0], 68.0 [33.3-199.8], and 67.5 [45.3-211.3] days, respectively). Among patients who responded to the 1 st course, Hb relapse occurred in 68.3% (28/41), bilirubin relapse in 53.6% (15/28), and LDH relapse in 80.0% (8/10) of patients (median [IQR] time from response to relapse: 44.0 [13.3-90.8], 98.00 [29.0-257.0], and 93.00 [21.3-161.8] days, respectively). Conclusions The findings highlight outcomes of rituximab use for treatment of CAD in a real-world setting. Patients who initiated rituximab had more severe disease compared to all patients with CAD. Rituximab was predominantly given as monotherapy, with an average of 1.45 courses per patient. About 25% of patients had ≥1 incomplete rituximab course, and rescue therapy with BTs was often required. Patients receiving rituximab experienced 3 times more SIs after initiating rituximab than before treatment. Although responses to rituximab were commonly observed, duration of response was short, and the rate of relapse was high.

Thrombophilia Screening in Autoimmune Hemolytic Anemia: A Single-Center Cross-Sectional Study

Background Autoimmune hemolytic anemia (AIHA) is characterized by an increased rate of thrombosis, whose predictors are not completely clarified, although an association with active hemolysis (i.e., LDH &amp;gt;1.5 x ULN), anemia severity and previous splenectomy has been reported. Moreover, antithrombotic prophylaxis and its duration are not standardized in this patient-population. The value of thrombophilia screening, including congenital and acquired abnormalities, has not been established yet. Aim To investigate the prevalence of inherited and acquired thrombophilia abnormalities in a cohort of AIHA patients with or without thrombosis. Methods AIHA patients followed from January 2019 until September 2022 at a tertiary hematologic center in Milan, have been systematically tested for Factor V Leiden (FVL) and prothrombin (FII) G20210A mutation, protein C (PC), protein S (PS), antithrombin (AT) levels, and the presence of antiphospholipid antibodies (APLA, i.e., lupus anticoagulant, LAC, anti-cardiolipin and anti-b2-glycoprotein-1). Patients' hematological characteristics, additional thrombotic risk factors, history of venous/arterial thrombosis before and after AIHA diagnosis, and anticoagulant and/or antiplatelet therapies were retrospectively recorded. Results As shown in table 1, 59% of 92 enrolled patients were female with a median age at diagnosis of 70.5 years (range 24-89), and were classified as warm AIHA (50%), cold agglutinin disease (31.5%), mixed/atypical AIHA (9.8%), and Evans syndrome (association of AIHA and other immune cytopenia, 8.7%). Thrombophilia screening resulted positive in 19 patients (20.7%) including FVL (1.1%), F II (1.1%), APLA (10.8%), PC deficiency (1.1%), PS deficiency (2.2%), AT deficiency (2.2%), and more than one abnormality (2.2%). Additional risk factors considered were thrombosis prior to AIHA diagnosis, reported in 6 patients (7%, 3 venous and 3 arterial), and associated conditions (29%), including autoimmune disease (N=17), lymphoproliferative disease (N=7), myeloproliferative neoplasm (N=1), and paroxysmal nocturnal hemoglobinuria (N=1). Furthermore, 97% of subjects presented at least one risk factor (i.e., diabetes, obesity, bed rest, etc.) in addition to AIHA. Twenty-seven patients (28%) received anticoagulant prophylaxis after AIHA diagnosis, mainly short-term for hemolysis (42%) or surgery of lower limb fractures (37%), and long-term for atrial fibrillation in 24%; 22% of patients were on antiplatelet prophylaxis, and 4 patients had been splenectomized. Since AIHA diagnosis, 26 patients (28%) experienced thrombosis (77% venous, 23% arterial), with 33 total events (3 patients had &amp;gt; 1 event). Median hemoglobin and LDH at thrombosis were 8.6 g/dL (2-11.7), and 374 U/L (129-1873) respectively, indicating active hemolysis. No relationship was found with inherited thrombophilia abnormalities (3 patients, 8% experienced thrombosis vs 7, 10.5% who did not), whilst a significant association was noted with APLA positivity (p&amp;lt;0.05). Two patients with APLA experienced more than 1 event, one had 1 venous and 1 arterial event. Conclusions Along with disease activity and Evans syndrome, positivity for APLA appears the main predictor of thrombosis in AIHA and is therefore worth of testing, whilst extensive thrombophilia screening encompassing inherited abnormalities appears less useful.

Clinical Utility of Monoclonal Gammopathy Screening in the Evaluation of Anemia

Background Screening for monoclonal gammopathy (MG) is often performed in the evaluation of anemia. While certain MGs may be associated with anemia, these are rare conditions. Monoclonal gammopathy of undetermined significance (MGUS; prevalence of 8% among age &amp;gt;50 years) is common, but rarely causes anemia in isolation. Therefore, abnormal results from MG screening may be unrelated to patient symptoms and result in both financial and psychological harm. Limited data exist to guide clinicians regarding the utility of MG testing for anemia. Aims This study aims to describe both the clinical utility of MG screening during the evaluation of anemia and the most common etiologies for anemia in patients whose workup included MG screening. Methods We reviewed medical records of patients who received MG screening to evaluate anemia at Mayo Clinic in 2021. Patients with a previously diagnosed MG were excluded. MG testing included serum protein electrophoresis and free light chain assessments. The following data were extracted: hemoglobin, hematocrit, mean corpuscular volume (MCV), calcium, creatinine, eGFR, and the final hematologic diagnosis related to the monoclonal protein. Clinician documentation was evaluated to determine the attributed etiology of anemia. Results Among the 271 patients with anemia who were screened for MG, 33 (12.2%) were found to have a newly diagnosed MG. Only 2 patients screened for MG were ultimately found to have anemia caused by MG. These included a case of multiple myeloma and one patient with cold agglutinin disease and secondary hemolysis. In all patients screened, their anemia was ultimately thought to be due to iron deficiency (31.7%), B12 deficiency (3.0%), anemia of chronic disease (ACD)/inflammatory anemia (14.4%), chronic kidney disease (CKD) (3.7%), hemolysis (1.5%), hypogonadism (1.9%), idiopathic (21.0%), multifactorial: iron deficiency + ACD/inflammatory (3.0%), multifactorial: nutritional; iron deficiency + B12 deficiency (3.0%), multifactorial: ACD + CKD (5.2%), multifactorial: iron deficiency + CKD (1.8%), multifactorial: not otherwise specified (NOS) (6.6%), medications (0.4%), and other (2.6%). Both patients with newly diagnosed MG associated anemia presented with peripheral neuropathy as their primary symptom. Among these 2 patients diagnosed with dysproteinemia associated anemia, only one (0.4%) was placed on therapy for their MG. Summary/Conclusions In the evaluation of anemia, routine MG screening has low clinical utility. Less than 1 in 100 patients were found to have anemia attributable to MG. Furthermore, only 0.4 in 100 patients received MG-directed therapy. Most patients screened with SPEP for undifferentiated anemia were found to have anemia attributable to common causes including iron/nutritional deficiency, inflammatory processes, and CKD. Most patients with undifferentiated anemia would benefit from an anemia evaluation that focuses on the most common causes up front. Given the cost to healthcare and potential psychological harm to the patient of incidental MG diagnosis, further study is warranted to guide clinicians and limit the ordering of MG testing to individuals who are most likely to derive benefit.