scholarly journals Rituximab use in Warm and Cold Autoimmune Hemolytic Anemia

2020 ◽  
Author(s):  
Irina Murakhovskaya
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Blood Cells ◽  
Rare Condition ◽  
Cold Agglutinin ◽  
Toxicity Profile ◽  
Cold Agglutinin Disease ◽  
First Line ◽  
Hematologic Disorder

Autoimmune hemolytic anemia is a rare condition characterized by destruction of red blood cells with and without involvement of complement. It is associated with significant morbidity and mortality. In warm autoimmune hemolytic anemia less than 50% of patients remain in a long-term remission following initial steroid therapy and subsequent therapies are required. Cold agglutinin disease is a clonal hematologic disorder which requires therapy in majority of patients and responds poorly to steroids and alkylators. Rituximab has a favorable toxicity profile and has demonstrated efficacy in autoimmune hemolytic anemia in first line as well as relapsed setting. Rituximab is the preferred therapy for steroid refractory wAIHA and as part of the first- and second-line treatment of cold agglutinin disease. This article reviews the mechanism of action of the rituximab and current literature its role in management of primary and secondary warm autoimmune hemolytic anemia and cold agglutinin disease.

scholarly journals Rituximab Use in Warm and Cold Autoimmune Hemolytic Anemia

2020 ◽  
Vol 9 (12) ◽  
pp. 4034
Author(s):  
Irina Murakhovskaya
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Blood Cells ◽  
Rare Condition ◽  
Cold Agglutinin ◽  
Toxicity Profile ◽  
Cold Agglutinin Disease ◽  
First Line ◽  
Hematologic Disorder

Autoimmune hemolytic anemia is a rare condition characterized by destruction of red blood cells with and without involvement of complement. It is associated with significant morbidity and mortality. In warm autoimmune hemolytic anemia, less than 50% of patients remain in long-term remission following initial steroid therapy and subsequent therapies are required. Cold agglutinin disease is a clonal hematologic disorder that requires therapy in the majority of patients and responds poorly to steroids and alkylators. Rituximab has a favorable toxicity profile and has demonstrated efficacy in autoimmune hemolytic anemia in first-line as well as relapsed settings. Rituximab is the preferred therapy for steroid refractory warm autoimmune hemolytic anemia (wAIHA) and as part of the first- and second-line treatment of cold agglutinin disease. This article reviews the mechanism of action of rituximab and the current literature on its role in the management of primary and secondary warm autoimmune hemolytic anemia and cold agglutinin disease.

scholarly journals Autoimmune hemolytic anemia

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 382-389 ◽  
Author(s):  
Anita Hill ◽  
Quentin A. Hill
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Clinical Evidence ◽  
Line Treatment ◽  
Future Prospects ◽  
Cold Agglutinin Disease ◽  
First Line ◽  
Phase 3 ◽  
Complement Inhibitors ◽  
First Line Treatment

Abstract The diagnosis of autoimmune hemolytic anemia (AIHA) can be made with a stepwise approach that aims to identify laboratory and clinical evidence of hemolysis and then determine the immune nature of hemolysis with the direct anti-globulin test. Once alternative causes for these findings have been excluded, AIHA is established, and the clinician must search for secondary causes, as well as identify the type of AIHA. Rituximab is now the preferred second-line treatment for primary warm AIHA and first-line treatment for primary cold agglutinin disease (CAD), either as monotherapy or combined with bendamustine. Complement inhibitors have shown utility in stabilizing AIHA patients with acute severe hemolysis. Future prospects are discussed and include the C1s inhibitor BIVV009 (sutimlimab) that is now entering phase 3 studies for CAD.

scholarly journals Cold Agglutinin Disease Transfusion Practices in the United States: An Electronic Medical Record-Based Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3690-3690
Author(s):  
Jun Su ◽  
Rajeshwari Punekar ◽  
Jaime Morales Arias ◽  
Nisha Jain
Keyword(s):  
Medical Record ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Index Date ◽  
Cold Agglutinin ◽  
Cold Agglutinin Disease ◽  
Employment Equity ◽  
Medical Activity ◽  
Equity Ownership ◽  
Rbc Transfusion

Introduction Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia (AIHA) accounting for 20% of all cases, with no approved therapies and limited management options for patients. CAD is characterized by immunoglobulin M-mediated erythrocyte agglutination, which triggers activation of the classical complement pathway leading to hemolysis and subsequent anemia. Red blood cell (RBC) transfusions are used as a supportive treatment in CAD to temporarily alleviate anemia, although the transfusion practices are variable among providers treating patients with CAD. Recent RBC transfusion guidelines from the AABB (formerly the American Association of Blood Banks) recommend that transfusions be administered with a restrictive threshold in most clinical scenarios (ie, transfusion is not indicated until hemoglobin [Hb] reaches 7-8 g/dL and/or patients exhibit anemia-related symptoms) to avoid associated complications such as acute reactions, alloantibody development, and hemochromatosis (Carson et al, JAMA, 2016; Carson et al, N Engl J Med, 2017). Because of the dearth of information available regarding trends in RBC transfusion practices among US hematologists, the objective of this longitudinal, retrospective, observational assessment of an electronic medical record database was to evaluate transfusion practices applied to patients with CAD in the US. Methods Patients were retrospectively identified from Optum® de-identified Electronic Health Record (EHR) dataset. Adult patients with ≥1 AIHA-related medical encounter between January 2007 and September 2018 (study period) and ≥3 mentions of CAD-related terms from physician notes ("cold agglutinin disease," "cold autoimmune hemolytic anemia," or "cold agglutinin hemoglobinuria") were included (Broome et al, Blood, 2017). The index date for each patient was the date of first mention of CAD during the study period. The baseline period was defined as the interval from the start of medical activity in the EHR database or study period (whichever occurred 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, end of medical activity, or death (whichever occurred earlier). The study sample was categorized into 2 study groups, the transfusion group (patients with CAD with ≥1 RBC transfusion after the index date) and the non-transfusion group (patients with CAD without any transfusions during the study period). Patients were further grouped based on the following Hb levels (g/dL): <8, ≥8 to ≤10, and >10 to ≤12. The closest Hb level prior to the most recent transfusion (within the prior 15 days and the lowest level) was used for the transfusion group and the lowest Hb level during the study period was used for the non-transfusion group. Descriptive statistics included mean, standard deviation, and median values for continuous variables and frequency (n and percent) for categorical variables. No adjustment was made for this descriptive analysis. Results A total of 903 patients with CAD were identified from the Optum EHR database; most patients were white (n=760 [84%]) and female (n=560 [62%]). Baseline demographics and clinical characteristics of each group can be found in the Table. Of the patients with CAD, 548 (61%) did not receive transfusions and 355 (39%) received ≥1 RBC transfusion. Among patients with CAD who received transfusions, 84% (n=297) had ≥2 RBC transfusions. Out of the 903 patients with CAD, 864 had Hb levels reported and 752 had Hb levels ≤12 g/dL. Forty-four percent (n=329/752) of those CAD patients received ≥1 RBC transfusion. When separated by Hb levels, 18% of patients with Hb >10 to ≤12 g/dL (n=19/108); 41% (n=88/216) of patients with Hb ≥8 to ≤10 g/dL; and 52% (n=222/428) of patients with Hb <8 g/dL received ≥1 RBC transfusion. Of the 423 (56%) patients with CAD and Hb levels ≤12 g/dL who did not receive RBC transfusions, 21% (n=89/423) had Hb levels >10 to ≤12 g/dL; 30% (n=128/423) had Hb levels ≥8 to ≤10 g/dL; and 49% (n=206/423) had Hb levels <8 g/dL. Conclusions Overall, patients with CAD are not a heavily transfused population. Even in those with a significantly decreased Hb (<8 g/dL), approximately half of them (49%) did not receive RBC transfusions. This suggests that the use of transfusions in patients with CAD may not reflect disease severity. Further prospective studies are needed to fully understand the impact of transfusions on patients with CAD. Disclosures Su: Sanofi Genzyme: Employment, Equity Ownership. Punekar:Sanofi: Employment, Equity Ownership. Morales Arias:Sanofi: Employment, Equity Ownership. Jain:Sanofi Genzyme: Employment, Equity Ownership.

scholarly journals The Immunomodulatory Effect and Clinical Efficacy of Daratumumab in a Patient With Cold Agglutinin Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Anna Zaninoni ◽  
Juri A. Giannotta ◽  
Anna Gallì ◽  
Rosangela Artuso ◽  
Paola Bianchi ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Plasma Cell ◽  
Clinical Efficacy ◽  
Lupus Erythematosus ◽  
Autoimmune Hemolytic Anemia ◽  
Plasma Cells ◽  
Proteasome Inhibitors ◽  
Immunomodulatory Effect ◽  
Cold Agglutinin ◽  
Cold Agglutinin Disease

Daratumumab is a monoclonal antibody directed against the transmembrane glycoprotein CD38 expressed on plasma cells and lymphoplasmocytes, with a proven efficacy in multiple myeloma. Here we show its clinical efficacy in a patient with cold agglutinin disease (CAD) relapsed after multiple lines of therapy. CAD is caused by cold reactive autoantibodies that induce complement mediated hemolysis and peripheral circulatory symptoms. The disease is also characterized by the presence of monoclonal IgM gammopathy and of a lymphoid bone marrow infiltration that benefits from B-cell targeting therapies (i.e., rituximab) but also from plasma cell directed therapies, such as proteasome inhibitors. In the patient described, we also show that daratumumab therapy influenced the dynamics of several immunoregulatory cytokine levels (IL-6, IL-10, IL-17, IFN-γ, TNF-α, TGF-β) indicating an immunomodulatory effect of the drug beyond plasma cell depletion. In addition, we provide a literature review on the use of daratumumab in autoimmune conditions, including multi-treated and refractory patients with autoimmune hemolytic anemia (both CAD and warm forms), Evans syndrome (association of autoimmune hemolytic anemia and immune thrombocytopenia) and non-hematologic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis.

The Natural History of Cold Agglutinin Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5152-5152
Author(s):  
Paul L Swiecicki ◽  
Livia Hegerova ◽  
Morie A Gertz
Keyword(s):  
Drug Therapy ◽  
Hemolytic Anemia ◽  
Age At Onset ◽  
Disease Diagnosis ◽  
Cold Agglutinin ◽  
Common Symptom ◽  
Cold Agglutinin Disease ◽  
Treatment Regimens ◽  
Hematologic Disorder ◽  
Initial Symptoms

Abstract Abstract 5152 Introduction: Cold agglutinin disease (CAD) is a rare and poorly understood disorder accounting for 15% of patients with autoimmune hemolytic anemia. Treatment has been largely controversial with few studies addressing safety and efficacy of various treatment regimens. This study reports a single institution's experience with cold agglutinin disease, defines the clinical features, prognosis and management. Methods: A retrospective analysis of Mayo Clinic medical records since 1960 was performed to identify all cases of CAD. Initial appraisal identified 89 patients after which an in depth review of clinical notes, laboratory evaluations, and treatment regimens was performed. Statistical analysis was performed via descriptive statistics and Kaplan-Meier survival. Results: The median age at onset of symptoms was 65 years (range: 40, 82), while the median age at diagnosis was 72 (42, 91). The most common sign at presentation was anemia (38. 4%). The most common symptom during the course of disease was similarly finger discoloration (43. 8%). Over half of patients had symptoms that were triggered by a cold environment (52. 8%) and a minority (22. 5%) had exacerbations precipitated by other factors. The median time from onset of symptoms to time of disease diagnosis was 37 months (0, 374). The majority of patients had an underlying hematologic disorder (48. 3%) of which the most common was monoclonal gammopathy of undetermined significance. At diagnosis the average hemoglobin was 10. 2 (6. 2, 17. 7) with positive coombs testing in 75% of patients. All patients had documented positive cold agglutinin titers. Approximately 40% of patients received transfusions at some point during their disease course and 83% needed drug therapy at some point. The most common reason to initiate drug treatment was progressive anemia (44. 9%). In 15% of patients, CAD was able to be managed with watchful waiting. The median duration between initial symptoms to initiation of treatment was 60 months. 56. 2% and 33. 7% of patients required second and third line therapy respectively. Treatment characteristics and responses are displayed in Table 1. Rituximab showed the longest duration of response and had the lowest percentage of patients needing further treatment, while 4 out of 5 patients on prednisone required additional therapies. Median survival in all patients with CAD was 127. 5 months and 76. 9% of patients were alive at 5-years after diagnosis (Figure 1). Conclusions: This is the largest study of patients with cold agglutinin disease to date. Symptoms were frequently ill-defined resulting in delay of diagnosis. Although drug therapy was frequently indicated, many patients were successfully observed. New treatment agents including Rituximab demonstrate promising response rates compared to traditional regimens, especially in patients with underlying hematologic abnormalities. These results support consideration of CAD as part of the differential diagnosis in the setting of new onset anemia and re-enforces the importance of evaluation for underlying B Cell abnormality in this patient population. Disclosures: Off Label Use: Rituximab, Cyclophosphomide, Chlorambucil, and Prednisone will be discussed as therapy modalatities for the treatment of cold agglutinin hemolytic anemia.

scholarly journals Effective Treatment of Cold Agglutinin Disease/Cold Agglutinin Syndrome with Ibrutinib: An International Case Series

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Marit Jalink ◽  
Sigbjørn Berentsen ◽  
Jorge J. Castillo ◽  
Steven Treon ◽  
Bruno Fattizzo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Hemolytic Anemia ◽  
Median Duration ◽  
Autoimmune Hemolytic Anemia ◽  
Research Funding ◽  
Cold Agglutinin ◽  
Cold Agglutinin Disease ◽  
Btk Inhibitor

Background In cold agglutinin mediated autoimmune hemolytic anemia (cAIHA), anti-red blood cell autoantibodies lead to complement-mediated hemolysis with or without symptoms of acrocyanosis after exposure at low temperatures. cAIHA can be divided into cold agglutinin disease (primary CAD) and cold agglutinin syndrome (CAS). The latter is secondary to diseases such as B-cell malignancies including CLL, infections or autoimmune disorders. In primary CAD, more than 90% of patients have a monoclonal IgM (mostly low level) and often a small bone marrow B-cell clone. There is no approved treatment. For patients with significant hemolytic anemia or acrocyanosis despite thermal protection, rituximab is the most accepted first line treatment with an overall response rate of 50% and median duration of response <1 year. Cytotoxic combinations such as rituximab-bendamustine produce more sustained remissions, although with concerns for long-term adverse effects and stem cell toxicity. Studies involving complement inhibitors are showing promising results on hemolysis, although cold induced peripheral symptoms (IgM mediated rather than complement-mediated) will not improve. Recent international guidelines on cAIHA suggest treatment with the Bruton tyrosine kinase (BTK)-inhibitor ibrutinib in refractory patients with cAIHA (Jäger et al Blood Rev 2020). Indeed, the underlying pathophysiology of cAIHA suggest that BTK inhibition could be effective. Aims To evaluate the efficacy of ibrutinib on anemia, hemolysis and acrocyanosis in patients with cold agglutinin-mediated AIHA (CAD/CAS). Methods An international retrospective study was undertaken of cAIHA patients (CAD/CAS) treated with BTK inhibition using a preformed questionnaire. For eligible patients, laboratory and clinical data regarding underlying disease, bone marrow pathology, hemolytic parameters and patient-reported acrocyanosis were collected at diagnosis, 30 days, 3 months, 6 months and 12 months and last date of follow up. Hemoglobin (Hb) response was considered none (NR), partial (PR, >2 g/dL Hb increase or >10g/dL) or complete (CR, >12g/dL). Adverse events were graded according to the Common Terminology Criteria, version-5.0 (2017). Results So far, 10 patients with cAIHA treated with a BTK-inhibitor (all involving ibrutinib) could be included in the study. Patients were followed from April 2014 until June 2020 at 5 centers (Italy (2), Norway, The United Kingdom and The United States). Median duration of follow up was 20 months (1-74 months). The main findings are summarized in table 1. The indication to start treatment was cAIHA based in all but 1 case (CLL). Median previous number of therapies was 2. All patients had a complement-mediated hemolytic anemia, 7 were transfusion-dependent, and 7 reported symptoms of acrocyanosis at the initiation of ibrutinib. After initiation of ibrutinib, all patients showed an improvement in hemoglobin (Median rise: 4.4 g/dL) resulting in 1 PR and 9 CR. All 7 transfusion-dependent patients became transfusion independent (5 within 30 days). In all but 1 patient, markers of hemolysis (LDH, bilirubin) improved after initiation of ibrutinib (see Figure 1). All 7 patients with acrocyanosis reported clear clinical improvement, with complete resolution of symptoms in 5. There was 1 adverse event (grade 1 bleeding). Data collection is still ongoing and future updates are expected. Conclusion Data show that ibrutinib is effective in the treatment of cAIHA with a notable and brisk improvement of both the hemolytic anemia as well as the cold induced peripheral symptoms. Although preliminary, these promising data support further research of BTK-inhibitor based treatment of cAIHA (CAD/CAS) in a prospective study. Disclosures Berentsen: Alexion, Apellis, Bioverativ and Janssen-Cilag: Other: Travel grants ; Alexion, Apellis, Bioverativ, Janssen-Cilag, True North Therapeutics: Honoraria; Apellis, Bioverativ, Momenta Pharmaceuticals and True North Therapeutics: Consultancy; Mundipharma: Research Funding. Castillo:TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Kymera: Consultancy; Abbvie: Research Funding; Janssen: Consultancy, Research Funding. Treon:Bristol-Meyer-Squibb: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding. D'Sa:Sanofi: Honoraria; BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. OffLabel Disclosure: BTK-inhibitors (ibrutinib/acalabrutinib) are not yet indicated for the use in (primairy) cold autoimmune hemolytic anemia (cAIHA). However it is indicated for use in Waldenstrom macroglobulinemia (WM) and chronic lymphatic leukemia (CLL). Here we report retrospective data on a cohort of cases treated with ibrutinib for cAIHA mostly secondary to WM or CLL.

scholarly journals Cold agglutinin disease related mismatch between hematocrit and hemoglobin values

2020 ◽  
Vol 7 (2) ◽  
pp. 770
Author(s):  
Emre Hoca ◽  
Fatma Pınar Ziyadanoğlu ◽  
Atay Can Kula ◽  
Hayriye Esra Ataoğlu
Keyword(s):  
Autoimmune Diseases ◽  
Autoimmune Hemolytic Anemia ◽  
Blood Cells ◽  
Epstein Barr Virus ◽  
Cold Agglutinin ◽  
Cold Agglutinin Disease ◽  
Cold Agglutinins ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

Autoimmune hemolytic anemia is a disease characterized by destruction of red blood cells (RBC) and anemia, caused by production of antibodies released against the body’s own RBCs. While this condition is more commonly idiopathic, it may accompany autoimmune diseases as well. Cold agglutinin disease (CAD) is a rare subtype of acquired autoimmune hemoliytic anemia, however, is an idiosyncratic clinical and pathological terminology, usually seen in older ages. This condition is caused by IgM antibodies called “cold agglutinins” formed against I antigens on RBC membranes which cause agglutination of RBCs at lower temperatures. In this case, a 56 year old male patient who was diagnosed with CAD secondary to Epstein-Barr virus (EBV) infection is being presented.

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