Form Of Autoimmune Hemolytic Anemia Research Articles

Artemis deficiency: A large cohort including a novel variant with increased radiosensitivity.

Artemis deficiency is an autosomal recessive disorder characterized by a combined immunodeficiency with increased cellular radiosensitivity. In this review, the clinical and genetic characteristics of 15 patients with DCLRE1C variants are presented. The demographic, clinical, immunologic, and genetic characteristics of patients with confirmed DCLRE1C variants diagnosed between 2013 and 2023 were collected retrospectively. Three patients were evaluated for radiosensitivity by the Comet assay, compared with age- and sex-matched healthy control. Seven patients who had severe infections in the first 6 months of life were diagnosed with T-B-NK+ SCID (severe combined immunodeficiency). Among them, four individuals underwent transplantation, and one of those died due to post-transplant complications in early life. Eight patients had hypomorphic variants. Half of them were awaiting a suitable donor, while the other half had already undergone transplantation. The majority of patients were born into a consanguineous family (93.3%). Most patients had recurrent sinopulmonary infections (73.3%), and one patient had no other infection than an acute respiratory infection before diagnosis. Two patients (13.3%) had autoimmunity in the form of autoimmune hemolytic anemia. Growth retardation was observed in only one patient (6.6%), and no malignancy was detected in the surviving 11 patients during the median (IQR) of 21.5 (12-45) months of follow-up. Three patients who had novel variants exhibited increased radiosensitivity and compromised DNA repair, providing a potential vulnerability to malignant transformation. Early diagnosis, radiation avoidance, and careful preparation for transplantation contribute to minimizing complications, enhancing life expectancy, and improving the patient's quality of life.

Autoimmune Hemolytic Anemia: A Review

Autoimmune hemolytic anemia (AIHA) is defined as an anemia caused by the destruction of red blood cells by antibodies directed against the patient's own red blood cell surface antigens. Different forms of AIHA are distinguished based on the characteristics of the antibody responsible for the disease. The most common form (70% of cases) is warm antibody autoimmune hemolytic anemia. These antibodies become active at temperatures between 35°C and 40°C. This type of hemolysis occurs mainly within tissues, particularly in the spleen. The diagnosis of AIHA relies on rigorous interpretation of immunohematological parameters, as well as additional tests to exclude associated diseases. In "idiopathic" cases, it is recommended to continue monitoring elderly patients beyond remission to detect the possible occurrence of lymphoma or myelodysplastic syndrome. Corticosteroid therapy is the standard treatment, but it can lead to numerous side effects. The efficacy of rituximab appears particularly promising in "refractory" forms of AIHA, and its use in the early phase of management to spare corticosteroid therapy should be evaluated in a prospective and randomized study.

A Single Center Experience for Clinical Evaluation of Paroxysmal Cold Hemoglobinuria and Donath-Landsteiner Testing

Introduction: Paroxysmal cold hemoglobinuria (PCH) is a rare form of autoimmune hemolytic anemia (AIHA), mainly affecting children. The diagnosis and management is challenging due to similarities to other causes for AIHA and limited availability to Donath-Landsteiner (DL) testing. Methods: In this single-center retrospective study, we aimed to characterize the clinical presentation and outcomes of PCH patients, defined as having positive Donath-Landsteiner antibodies, compared to a cohort of AIHA patients. Results: DL-positive patients were observed to have higher lactose dehydrogenase levels and lower reticulocyte counts compared to DL-negative patients, although this was not statistically significant. We also observed that using steroids in DL-positive patients did not significantly impact their recovery. Conclusions: Our findings support the limited published data on PCH patients and further prompt prompting larger multicenter studies to further characterize these patients so that they are more readily identified, especially in centers where DL antibody testing is not readily available.

A single center experience for clinical evaluation of paroxysmal cold hemoglobinuria and Donath-Landsteiner testing.

Paroxysmal cold hemoglobinuria (PCH) is a rare form of autoimmune hemolytic anemia (AIHA), mainly affecting children. The diagnosis and management are challenging due to similarities to other causes for AIHA and limited availability to Donath-Landsteiner (DL) testing. In this single-center retrospective study, we aimed to characterize the clinical presentation and outcomes of PCH patients, defined as having positive Donath-Landsteiner antibodies, compared to a cohort of AIHA patients. DL-positive patients were observed to have higher lactate dehydrogenase levels and lower reticulocyte counts compared to DL-negative patients, although this was not statistically significant. We also observed that using steroids in DL-positive patients did not significantly impact their recovery. Our findings support the limited published data on PCH patients and further prompt larger multicenter studies to further characterize these patients so that they are more readily identified, especially in centers where DL antibody testing is not readily available.

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.

Cold Agglutinin Disease – Diagnostic and Therapeutic Challenges in the Clinical Setting

Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA), in which IgM specific antibodies cause the agglutination of red blood cells (RBCs) at temperatures < 37°C and activate the classical pathway of complement leading to extravascular hemolysis, C3b-coated RBCs are phagocytosed by the macrophages of the reticuloendothelial system (predominantly in the liver). Up to date there are two clinical-pathologic entities recognized as distinct with different therapeutic implications: cold agglutinin disease and cold agglutinin syndrome (CAS). Primary CAD is recognised as clonal B-cell lymphoproliferative disorder of the bone marrow, clinical and imagistic evidence of associated malignancy. CAS arises in the setting of an underlying disorder such as infection, autoimmune disease or malignancy (non Hodgkin lymphoma or other malignant process). The diagnosis of CAD is often delayed due to the unpredictable clinical course. In spite of the current therapeutic options which are directed at the pathogenic B cells or the complement system, the low response rates and frequent relapses lead to challenges regarding the management of this disease.

Novel therapeutic agents for hemolytic anemia

In recent years, it has become clear that various diseases are caused by complement (related molecule) abnormalities (complementopathies) or are exacerbated by complement (complement-related diseases), and novel therapeutic agents targeting complement (anti-complement agents) are now being developed. Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disorder characterized by complement-mediated intravascular hemolysis due to a deficiency of complement regulatory factors, making it a perfect candidate for anti-complement agents. In 2007, the anti-C5 monoclonal antibody eculizumab was approved for PNH, as the first anti-complement agent. The indications for eculizumab are expanding, and aggressive development is underway for new anti-complement agents, not only for PNH but also a variety of other diseases. In addition, the anti-C1s antibody sutimlimab was approved last year for the treatment of cold agglutinin disease, a form of autoimmune hemolytic anemia. This presentation overviews novel anti-complement agents for these hemolytic anemias.

Medically-attended anxiety and depression is increased among newly diagnosed patients with cold agglutinin disease: Analysis of an integrated claim-clinical cohort in the United States.

Cold agglutinin disease (CAD) is a rare, chronic form of autoimmune hemolytic anemia. Clinical manifestations can include classical complement pathway-mediated chronic hemolysis, anemia, and profound fatigue. Research has shown that patients with other anemias may develop anxiety and depression, but this has not been studied previously in patients with CAD. CAD patients were identified in the Optum Claims-Clinical dataset (between January 1, 2006-June 30, 2016) and matched to comparison patients without CAD by patient factors. Adjusted Cox regression models estimated time to anxiety and depression, defined by three different outcomes: medication use, hospitalization, and therapy related to anxiety and depression. Subset analyses were performed for primary CAD. Patients were followed until they had anxiety and depression, they left the Optum system, death, or the study period ended (June 30, 2016). Patients with CAD (n = 384) were more likely to have medically attended anxiety and depression (adjusted hazard ratio [aHR]: 1.6; 95% confidence interval [CI]: 1.3-2.1), to be prescribed antidepressants or psychotherapy after their CAD diagnosis (aHR: 1.8; 95% CI: 1.2-2.9), or to be hospitalized for an anxiety and depression-related event along with medication or psychotherapy (aHR: 2.0; 95% CI: 1.4-2.9) relative to matched comparisons (n = 2789), during the follow-up period. Patients with primary CAD were at increased risk for medically attended anxiety and depression (aHR: 1.8; 95% CI: 1.4-2.4), with the highest risk for prescription medication or therapy (aHR: 2.7; 95% CI: 1.6-4.6). Our study indicates that medically attended anxiety and depression manifest at a higher rate in CAD patients than in a matched non-CAD cohort. Study findings suggest that CAD patients may experience a greater burden on mental health that may negatively contribute to their overall quality of life. Further investigation on this topic is warranted.

Primary Epithelioid Pulmonary Angiosarcoma with WAIHA and Thrombocytopenia: A Rare Association

Abstract Introduction/Objective Angiosarcomas accounts for approximately 1%-2% of sarcomas, particularly involving the deep soft tissue. As a subtype, primary epithelioid angiosarcoma is an extremely rare neoplasm. Herein, we present an unusual primary epithelioid angiosarcoma of the right upper lung lobe with multiple nodal and bony metastases and associated severe form of autoimmune hemolytic anemia (WAIHA) and thrombocytopenia. Methods/Case Report Our case is a 79-year-old female with a recent onset of warm type autoimmune hemolytic anemia with positive coombs test and thrombocytopenia. The patient serum was also positive for EBV (IgG and IgM). On chest CT scan, a right upper lobe, metabolically active lung mass with mediastinal lymphadenopathy was found. Metabolically active bilateral osseous lesions identified within thoracic spine, ribs, bilateral humeri and femurs. A transbronchial core biopsy of the lung mass revealed poorly differentiated epithelioid hemorrhagic neoplasm with extensive necrosis and vascular background. The tumor cells are positive for AE1/AE3, CK7, FLI-1, BRG1 (SMARCA4, retained), and vimentin; and faint weak focal membranous staining for CD31, Factor VIII, and ERG. They are negative for CK20, TTF-1, Napsin-A, p63, p40, SMA, Melan-A, HMB45, GATA3, PAX-8, CDX-2, HepPar, synaptophysin, calretinin, CAMTA1, EBER (EBV) and S100 (Figure-1-A-D, H&E, 10X, CK AE2/AE3, FLI-1, CD31). This immunoprofile and histologic features favor epithelioid angiosarcoma. Results (if a Case Study enter NA) NA. Conclusion Comprehensive morphological and immunohistochemical findings supported the diagnosis of epithelioid angiosarcoma. The importance of reporting this case was the unusual pulmonary primary presentation, associated nodal and osseous secondary involvement, together with the unique systemic presentation with warm autoimmune hemolytic anemia and thrombocytopenia in a patient with active EBV infection.

Autoimmune Hemolytic Anemia in Children: Laboratory Investigation, Disease Associations, and Treatment Strategies.

Autoimmune hemolytic anemia is a relatively uncommon pediatric clinical condition. As such, the evaluation and management of these cases can be challenging for even the most seasoned pediatrician. In this review, the 3 major forms of autoimmune hemolytic anemia in children will be discussed: warm autoimmune hemolytic anemia, cold agglutinin disease, and paroxysmal cold hemoglobinuria. After a general description of the laboratory approach to these entities, the pathophysiology of these disease processes, including important disease associations, will be described, and treatment strategies will be discussed. This will provide the reader with a rational approach to identifying and managing pediatric patients with these uncommon autoimmune conditions.

Healthcare resource utilization among patients with cold agglutinin disease in Denmark

Objectives Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia that may manifest in complement-mediated chronic hemolytic anemia, profound fatigue, and transient agglutination-mediated circulatory symptoms. This study compared the healthcare resource utilization (HRU) of patients with CAD with a matched non-CAD comparison cohort using national Danish health registry data. Methods All cases of CAD were identified from 1 January 1999 to 30 June 2016, in the Danish National Patient Registry using the International Classification of Diseases, Tenth Revision, discharge diagnosis codes. A subcohort of patients with primary CAD was identified based on the absence of secondary predisposing concomitant diseases. CAD cases were matched to individuals without CAD from the general population based on birth year, sex, and 19 disease categories of the Charlson Comorbidity Index. Comparative analyses assessed inpatient hospitalizations, outpatient clinic visits, emergency room visits, transfusion use, and expensive drug use between cohorts 6 months before and 12 months after the admission date of the first hospital visit with CAD diagnosis (index date). Results A total of 104 patients with CAD were matched to 1003 comparison cohort members. Throughout the 12 months after the index date, patients with CAD were more likely to have at least one inpatient hospitalization (odds ratio [OR], 3.9; 95% confidence interval [CI], 2.5–6.0), outpatient clinic visit (OR, 17.2; 95% CI, 6.8–43.1), and blood transfusion (OR, 93.0; 95% CI, 33.3–259.8) than matched comparisons. HRU was similarly higher among patients with CAD than matched comparisons during the 6 months before the index date. Findings were similar among patients with primary CAD. Conclusions Characterization of HRU among European patients with CAD has not previously been conducted. This study shows that patients with CAD utilize significant resources in Denmark. Increased HRU uses among patients with CAD before diagnosis presents opportunities for earlier diagnosis and management.

Medically Attended Anxiety or Depression Is Increased Among Newly Diagnosed Patients with Cold Agglutinin Disease (CAD)

CAD is a rare form of autoimmune hemolytic anemia (AIHA) that accounts for approximately 20% of all AIHA and is characterized by classical complement pathway-activated hemolysis. Clinical manifestations of CAD can include complement-mediated chronic hemolytic anemia, profound fatigue, as well as transient agglutination-mediated circulatory symptoms (Berentsen et al. Hematol Oncol Clin North Am. 2015; Swiecicki et al. Blood. 2013). Recent research has shown that patients with anemia are more likely to develop depression and anxiety (Shafi et al. J Coll Physicians Surg Pak. 2018; Vulser et al. Acta Psychiatr Scand. 2016), but this has not been previously studied in patients with CAD. We conducted a matched-cohort comparison study evaluating the risk of medically attended anxiety or depression in patients with and without CAD. All patients with CAD were identified in the Optum Claims-Clinical dataset by reviewing clinical notes for CAD terms. Patients with CAD were matched (1:10) to non-CAD patients by age (±3 years), sex, race, region of residence, and active time and season and year of entry date in the Optum health plan. Inclusion criteria included 25 years of age or older with no history of anxiety or depression. Medically attended anxiety or depression was defined using International Classification of Diseases (ICD-9 and ICD-10) codes for inpatient stays and outpatient hospital visits, medication class, and procedure codes for psychotherapy. Cox regression models were built to estimate time to hospitalizations without medications or psychotherapy, medications or psychotherapy without hospitalization, hospitalization with medication or psychotherapy, or any of these outcomes adjusted for age, sex, race, region, comorbidity score, and cluster (matched CAD and non-CAD cohorts). As patients with both primary CAD (not due to secondary causes) and secondary cold agglutinin syndrome (coexisting diagnosis of malignancy or infection) were included in the primary analysis, subset analyses also were performed for patients with primary CAD. A total of 384 patients with CAD (mean [standard deviation {SD}] age: 70.0 [13.0] years) and 2789 patients without CAD (comparisons; mean [SD] age: 69.6 [12.7] years) were identified between 2006 and 2016. The mean (SD) time to event for any hospitalization, medication use, or psychotherapy was 27.7 (24.4) months for patients with CAD and 38.2 (25.6) months for comparisons with patients with CAD being 60% more likely to have medically attended anxiety or depression (adjusted hazard ratio [aHR]: 1.6; 95% confidence interval [CI]: 1.3-2.1). Patients with CAD were almost twice as likely to be prescribed medication or psychotherapy for anxiety and depression after their CAD diagnosis (aHR: 1.8; 95% CI: 1.2-2.9) or to be hospitalized for a depression or anxiety-related event along with medication or psychotherapy (aHR: 2.0; 95% CI: 1.4-2.9). There was also a nonsignificant risk for patients with CAD being hospitalized for anxiety and depression without medication or psychotherapy (aHR: 1.2; 95% CI: 0.8-1.9). Subanalysis of patients with primary CAD also were at a statistically significant increased risk for medically attended anxiety or depression (aHR: 1.8; 95% CI: 1.4-2.4) with the largest risk for prescription medication or psychotherapy (aHR: 2.7; 95% CI: 1.6-4.6). To our knowledge, this is the first study to evaluate anxiety or depression among patients with CAD. Our study indicates that medically attended depression and anxiety manifest at a higher rate in patients with CAD compared with a matched non-CAD cohort. These findings suggest that patients with CAD may experience extra-hematologic manifestations of the disease that potentially have a broader impact on their overall mental health, physical health, and quality of life. Further investigation on this topic is warranted. Disclosures Patel: Sanofi: Current Employment. Jiang:EpidStrategies: Current Employment. Nicholson:EpidStrategies: Current Employment. Frankenfeld:EpidStrategies: Current Employment. Iglesias-Rodriguez:Sanofi: Current Employment. Fryzek:EpidStrategies: Current Employment. Su:Sanofi: Current Employment.

Rituximab-containing therapy for cold agglutinin disease: a retrospective study of 16 patients

Cold agglutinin disease (CAD) is a rare form of autoimmune haemolytic anaemia, and because of its rareness, there is no standard treatment for CAD patients. We retrospectively analysed the response to rituximab-containing therapy in CAD patients at our hospital. All patients received rituximab-containing therapy for at least 1 month. A total of 16 patients (11 males and 5 females) were included. The median age at the onset of the disease was 63.5 years (range 41–79). Most patients had manifestations including anaemia (81.3%) or cold-induced circulatory symptoms (75.0%). The median haemoglobin level was 72 g/L (range 29–101), and the median cold agglutinin titre was 1,024 (range 64–2,048). Thirteen of 16 patients (81%) responded to the therapy. Responders achieved a median increase in haemoglobin levels of 45 g/L. Grade 3–4 neutropenia occurred in 3 patients (19%), but only 1 (6%) of them experienced infection. Anaphylaxis related to rituximab occurred in 1 patient. During follow-up, five patients experienced relapse, and two patients died. The estimated median progression-free survival was 36 months, and median overall survival was not yet reached. In conclusion, A rituximab-based therapy in accordance with individual patient characteristics may be a reasonable choice for CAD patients.

Hemolytic Anemia as Presentation of T-Cell Large Granular Lymphocytic Leukemia After Kidney Transplantation: A Case Report

T-cell large granular lymphocytic (T-LGL) leukemia is a rare clonal proliferation presenting with cytopenia, splenomegaly, and autoimmune manifestations. It has rarely been described in recipients of solid organ transplants.We report the clinical case of a young kidney transplant recipient that developed T-LGL leukemia 3 years after kidney transplantation. The disorder manifested with a severe form of autoimmune hemolytic anemia in the absence of other laboratory abnormalities. The anemia was successfully treated with an intense course of corticosteroids ands witch of immunosuppressive therapy from a calcineurin inhibitor to sirolimus, a mammalian target of rapamycin inhibitor.Our case shows that autoimmune hemolytic anemia can be a life-threatening manifestation of T-LGL disease. The antiproliferative effects of sirolimus may be useful in the treatment of symptoms of T-LGL leukemia in kidney transplantation.

Intestinal diffuse large B-cell lymphoma preceding cold agglutinin disease

Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia, which shows IgM antibodies in the serum of the patient against red blood cell antigens, showing maximal reactivity at 4°C. CAD can be idiopathic or secondary to infections such as mycoplasma, Epstein–Barr virus, cytomegalovirus, lymphoma, and plasma cell dyscrasia. It can present either as hemolytic anemia or acrocyanosis. We are reporting a case of CAD presenting with acrocyanosis, which initially did not show any secondary etiology despite extensive work-up. However, after a gap of 1½ years, the patient presented with intestinal obstruction, which was diagnosed to be due to malignant stricture secondary to intestinal diffuse large B-cell lymphoma. This association makes it important to follow-up cases of CAD without secondary etiology for the development of lymphoma in future.

Mortality Among Patients with Cold Agglutinin Disease in the United States: An Electronic Health Record (EHR)-Based Analysis

Introduction Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA). It is characterized by both IgM-mediated agglutination of erythrocytes and hemolysis mediated by activation of the classical complement pathway. Recent studies have shown an increased risk of thromboembolic events (TE) in CAD patients. In addition, a recent analysis using the Danish National Patient Registry demonstrated a significant increase in mortality for CAD patients compared with matched individuals from the general population in Denmark (Bylsma et al, HemaSphere, 2018). Mortality among CAD patients has not been assessed in a US population. This study evaluated mortality risk in the largest cohort of CAD patients in the US. Methods Patients were retrospectively identified from the Optum® de-identified EHR dataset. Between January 2007 and September 2018 (study period), patients with ≥1 AIHA-related medical encounter and ≥3 mentions from physician notes of CAD-related terms ("cold agglutinin disease," "cold autoimmune hemolytic anemia," or "cold agglutinin hemoglobinuria") were included in the CAD cohort ("case"). For this cohort, the first mention of CAD terms was set as the index date. Patients without an AIHA-related medical encounter were included in the non-CAD cohort ("control"). For the control cohort, the index date was assigned based on the average occurrence of index date in the CAD population for the duration in the EHR database. For both cohorts, the baseline period was defined as the interval from the start of the medical activity in the EHR database or study period (whichever occurs later) to the index date, and the follow-up period was defined as the interval from the index date to the end of the study period, the end of medical activity, or death (whichever occurs earlier). The case and control cohorts were matched by age, gender, race, region, index year, and follow-up period using 1:5 nearest neighbor matching. Both cohorts were stratified according to the presence or absence of ≥1 TE during the study period. Mortality rate per 100,000 patients was calculated as the number of patients who died in each cohort divided by the number of patients in each cohort, from 2007 to 2018, multiplied by 100,000. Mortality rate was compared between matched cohorts using a Poisson test. An independent t-test was used to compare age at death between matched CAD and control groups; and time to death (starting from the index date) was analyzed using Kaplan-Meier curves and compared between matched cohorts using log-rank P test. Results In total, 651 CAD patients and 3,255 matched non-CAD controls were identified. Of these, 35% (n=228) of CAD patients and 20% (n=641) of non-CAD patients experienced ≥1 TE (P<0.001). Median age at index date for both cohorts was 72 years. Most patients were female (CAD 64%; non-CAD 65%) and Caucasian (CAD 85%; non-CAD 85%). Median follow-up duration was 42 months for the CAD cohort and 51 months for the control cohort. Mean (standard deviation [SD]) Elixhauser Comorbidity Index Score was 8.0 (4.9) for CAD patients and 4.5 (4.1) for matched controls. The overall mortality rate was significantly higher for the CAD cohort than the matched-control cohort (CAD: 17,512 vs non-CAD: 11,306; P<0.001). For patients that experienced ≥1 TE during the study period, the mortality rate in the CAD cohort was 23,684 compared with 15,913 in the matched-control cohort (P<0.001; Table 1). During the study period, 114 CAD patients and 368 matched non-CAD patients died. The mean (SD) age at death in the CAD cohort (77 [12] years) was lower compared with the matched controls (82 [8] years; P<0.001). For patients with ≥1 TE, mean (SD) age at death was 77 (13) years vs 82 (7) years for the CAD and control cohorts, respectively (P<0.001; Table 1). A Kaplan-Meier analysis demonstrated a significantly decreased survival probability among CAD patients compared with matched controls (P<0.001; Figure 1). In addition, CAD patients with ≥1 TE also had a significant decrease in survival when compared with matched controls with ≥1 TE (P<0.001). Conclusions CAD patients in the US have an increased mortality risk compared with a matched non-CAD population. The associated increased TE risk observed among CAD patients may be a contributing factor to this mortality. Further studies are needed to better define this association and elucidate other potential contributors to mortality in these patients. Disclosures Hill: Apellis: Honoraria; Novartis: Speakers Bureau; Bioverativ, a Sanofi company: Honoraria; Alexion: Research Funding. Punekar:Sanofi: Employment, Equity Ownership. Morales Arias:Sanofi: Employment, Equity Ownership. Broome:Cellphire: Research Funding; Alexion: Honoraria, Research Funding; Sanofi Genzyme: Honoraria, Research Funding; Incyte: Research Funding; Rigel: Research Funding. Su:Sanofi Genzyme: Employment, Equity Ownership.

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

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

PF431 CLINICAL CHARACTERISTICS, TREATMENT PATTERNS, AND THROMBOEMBOLIC RISK OF PATIENTS WITH COLD AGGLUTININ DISEASE (CAD) IN JAPAN

Background:CAD is a rare form of autoimmune hemolytic anemia with a prevalence in Northern Europe of 16 cases per 1 million inhabitants (Berentsen S. Semin Hematol 2018). Ig M autoantibodies bind to red blood cells and trigger hemolysis via activation of the classical complement pathway. Although clinical and epidemiological studies are limited, recent evidence indicates that CAD patients in Europe and North America have an increased risk of thromboembolic events (TE) (Bylsma LC, et al. EHA 2018; Broome C, et al. Blood 2017). The 1‐year case‐fatality of TE has been reported as 23% (Tagalakis V, et al. Am J Med 2013). There are no studies evaluating the clinical course and risk of TE in CAD patients in Japan or other Asian populations.Aims:To describe clinical characteristics, treatment patterns, and risk of TE in CAD patients in Japan.Methods:Patients were retrospectively identified from 2008 to 2017 using a hospital‐based administrative claims database (Medical Data Vision), representing approximately 300 hospitals and 20 million patients in Japan. CAD cohort inclusion required age ≥18 years and CAD diagnosis (Japanese Disease Code 2830009) entry on ≥3 separate occasions within the study period. The first CAD diagnostic code entry was used as the index date. Patients in the comparison cohort had no history of CAD and were matched 10:1 to patients in the CAD group by age, sex, year and season of diagnosis, follow‐up time, and comorbidities using the Charlson Comorbidity Index. Conditional logistic regression was used to adjust for these variables when comparing cohorts.Results:344 CAD patients were identified with a slight female preponderance (53.2%), mean age of 66.8 years and 18.9‐month mean duration of follow‐up. The most frequently used treatment was steroids (34.2%). Other treatments included cytotoxic chemotherapy (6.9%), rituximab (5.9%), and immunosuppressants (5.9%). A total of 3440 patients with matching characteristics were included in the control group to compare the risk of TE among cohorts. Overall, CAD patients had an increased rate of TE versus patients without CAD (34.8% vs 17.9%, respectively; P < 0.0001) (Figure). The rate of arterial and venous TE was also higher in CAD versus non‐CAD cohorts (25.0% vs 4.6% and 8.4% vs 4.0%, respectively; P < 0.0001 for both analyses). Most cases of arterial TE in CAD patients corresponded to myocardial infarctions (87.2%). There was no difference in cerebral TE among the CAD and non‐CAD groups (10.4% vs 11.9%, respectively). The overall odds ratio (OR [95% confidence interval]) for development of TE in the CAD cohort versus non‐CAD cohort was 2.81 (2.18–3.61). Corresponding ORs for arterial and venous TE were 8.59 (6.16–11.98) and 2.37 (1.56–3.62), respectively.Summary/Conclusion:This study is the first to evaluate the clinical characteristics, treatment practices, and TE risk of CAD patients in Japan. Our results indicate that the CAD treatment approach used in Japan (ie, predominantly with steroids) differs from that reported for other countries. However, in accordance with recent reports from non‐Asian populations, this study demonstrates an increased risk of TE in the Japanese population. Interestingly, the rate of arterial TE was higher in Japan, which was mostly attributed to the high prevalence of myocardial infarctions in our CAD cohort. Japanese healthcare providers should be aware of these risks to properly monitor their CAD patients. Prospective studies are needed to further evaluate these findings.image

Clinical Features of Immune Checkpoint Inhibitor-Associated Autoimmune Hemolytic Anemia: A Series of 14 Cases

Introduction: The development of immune checkpoint inhibitors (ICPis) has ushered in a new paradigm for the treatment of both solid and liquid malignancies. However, these therapies, which promote an activated T cell phenotype, can cause a unique spectrum of autoimmune toxicities known as immune-related adverse events (IRAEs), which can affect a variety of organ systems. Autoimmune hemolytic anemia (AIHA) has been described as a rare complication of ICPis, but existing data are mostly limited to isolated case reports. Further, guidelines for the diagnosis and treatment of these patients are lacking. We describe the clinical and laboratory features of 14 patients who developed ICPi-associated AIHA.Methods: We contacted hematology departments at 18 academic medical centers across the U.S. to inquire about potential cases of ICPi-associated AIHA. Nine centers contributed a total of 14 cases to the current series. We defined AIHA as an abrupt decrease in hemoglobin ≥2g/dL, the presence of at least two laboratory features of hemolysis (elevated serum lactate dehydrogenase [LDH], elevated reticulocyte percentage, low or absent serum haptoglobin, and spherocytes), and the exclusion of other causes of anemia. We collected data on demographics and comorbidities, features of AIHA, and response to treatment. We defined complete recovery (CR) and partial recovery (PR) of hemoglobin as an increase from the nadir hemoglobin to within 1 and 2 g/dL of the baseline value, respectively, in the absence of recent transfusion.Results: The clinical features of the 14 patients in our cohort with ICPi-associated AIHA are summarized in the Figure (panel A). Underlying malignancies included melanoma (n = 9), non-small cell lung cancer (n = 3), colorectal cancer (n = 1), and acute myelogenous leukemia (n = 1). Four patients had a pre-existing diagnosis of a lymphoproliferative disorder, and two of these patients were known to have a positive direct antiglobulin test (DAT) prior to initiation of ICPi. ICPis used included ipilimumab, nivolumab, a combination of ipilimumab and nivolumab, and pembrolizumab.Representative hemoglobin and LDH trends are shown in the Figure (panels B and C). The median (interquartile range [IQR]) interval from initiation of ICPis to AIHA was 55 (22-110) days. Eight patients (57%) were DAT positive: 3 were positive for both IgG and C3; 3 were positive for IgG alone; 2 were positive for C3 alone; and 1 was weakly positive on polyspecific testing. Five patients (36%) were DAT negative, and in one patient a DAT was not performed. The median (IQR) hemoglobin nadir was 6.3 (6.1-8.0) g/dL,and 11 patients (79%) required red blood cell transfusion. All patients were treated with glucocorticoids, with 3 requiring additional immunosuppressive therapy.All patients achieved a CR or PR of hemoglobin in response to treatment (CR, n = 11; PR, n =3). The median (IQR) time from the hemoglobin nadir to CR or PR was 47 (30-62) days. Seven patients (50%) experienced at least one other IRAE. Seven patients (50%) were re-challenged with ICPis, and one patient developed recurrent AIHA with re-challenge.Conclusion: ICPi-associated AIHA is a recently-described phenomenon, which will be encountered more frequently with the widespread use of ICPis. ICPi-associated AIHA shares many clinical features with other forms of AIHA; however, a unique aspect of ICPi-associated AIHA appears to be a relatively high incidence of DAT negativity (36% in our series, compared with 3-11% in other forms of AIHA). It is possible that more advanced DAT testing - i.e., “super-Coombs” - which was not performed in any of the patients in this series, would have yielded different results.Glucocorticoids appear to be an effective first-line regimen in most patients with ICPi-associated AIHA. Furthermore, we found that AIHA does not necessarily recur with ICPi re-challenge. Additional studies are needed to better understand the mechanisms underlying ICPi-associated AIHA and optimal treatment strategies. [Display omitted] DisclosuresAnagnostou:ASH Research Training Award for Fellows 2018: Research Funding; Mayo Clinic SPORE: Research Funding; Mayo Clinic Immune Monitoring Core: Research Funding; Mayo Clinic Hematology Research Division: Research Funding. Salama:BMS: Research Funding; Celldex: Research Funding; Dynavax: Research Funding; Genentech: Research Funding; Merck: Research Funding; Reata: Research Funding; Incyte: Research Funding; Immunocore: Research Funding; Array: Consultancy; Merck: Consultancy; Biocryst: Consultancy; BMS: Speakers Bureau.

Seasonal Patterns of Anemia, Hemolytic Markers and Healthcare Resource Utilization Among Patients with Cold Agglutinin Disease in the United States: A Retrospective Analysis

Introduction: Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia in which circulating immunoglobulin M autoantibodies bind to the “I” antigen on red blood cells (RBCs), preferentially at lower temperatures (Berentsen et al. Hematol Oncol Clin North Am, 2015). This results in both agglutination of RBCs and complement-mediated hemolysis. “Cold” typically refers to the immune biology (thermal amplitude) of the antibody and not to clinical features of the disease. Although exposure to cold temperatures may precipitate both the circulatory symptoms of CAD and hemolysis (Berentsen. Br J Haematol, 2018), seasonal variation of CAD manifestations is poorly understood (Lyckholm et al. N Engl J Med, 1996; Berentsen et al. Hematology, 2007). There are no clinical trials to support the efficacy of nonpharmacologic management of CAD by cold avoidance or relocation to warm regions (Berentsen. Br J Haematol, 2018; Swiecicki et al. Blood, 2013). Given the lack of data on clinical and laboratory effects of seasonality on the manifestations of CAD, we compared hemoglobin (Hgb) as well as markers of hemolysis and healthcare resource utilization (HRU) for patients with CAD between seasons.Methods: Patients were identified from the Optum-Humedica database, containing de-identified information on medications, laboratory results, diagnoses, procedures, and clinical notes for more than 14 million people annually from all 50 states. Individuals with “cold agglutinin disease” in their clinical notes on at least 3 separate dates were considered patients with CAD. If “cold agglutinin disease” was documented on just 1 or 2 dates, patients were included only after an independent review and agreement by 2 hematologists. The laboratory parameters related to hemolysis, median minimum Hgb, median maximum bilirubin, and median maximum lactate dehydrogenase (LDH), were evaluated, as well as inpatient days, outpatient visits, emergency room visits, and transfusion days. Multivariate regression models were built to explore variation by season comparing the values in fall, winter, and spring to the values in the summer. Data were adjusted for age at baseline, gender, race, region, year, and Charlson Comorbidity Index prior to baseline and accounted for clustering of correlated observations.Results: A total of 808 patients with CAD were identified from the Optum-Humedica database for analysis from 2009 to 2016. Most patients were ≥65 years of age (66%), female (63%), white (84%), and from the Midwest (43%). The median minimum Hgb value for winter as compared with summer was decreased by 0.54 g/dL (P<0.001). The median maximum bilirubin and LDH increased by 0.12 mg/dL (P=0.005) and 42.1 U/L (P<0.001) in winter versus summer, respectively. There were no differences in inpatient days, outpatient visits, emergency room visits, or transfusion days between winter and summer (Table). No significant seasonal disease pattern in HRU was noted in these patients.Conclusions: Patients with CAD in this cohort had evidence of persistent hemolysis independent of the season. Disease manifestations as evaluated by HRU measures were fairly consistent all year long. The variations in median Hgb, bilirubin, and LDH between winter and summer were not associated with differences in clinical outcomes, as there were no significant changes in HRU or transfusion days. These data suggest that perceptions of CAD as a seasonal disorder may not be accurate and recommendations such as moving to regions with warmer climates likely provide no meaningful clinical benefit. The lack of seasonal variability in this cohort suggests that treatment considerations for patients with CAD should be season-independent. DisclosuresRöth:Pfizer: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Bioverativ: Consultancy, Honoraria; Amgen: Research Funding. Fryzek:Sanofi: Research Funding. Jiang:Epidstat: Employment. Morales:Bioverativ: Employment. Broome:Bioverativ: Honoraria, Research Funding; Alexion: Honoraria.