Data Registry of Auto Immune Hemolytic Anemia

Study Overview
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Brief Summary
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In autoimmune hemolytic anemia (AIHA) auto-antibodies directed against red blood cells (RBCs) lead to increased RBC clearance (hemolysis). This can result in a potentially life-threatening anemia. AIHA is a rare disease with an incidence of 1-3 per 100,000 individuals. An unsolved difficulty in diagnosis of AIHA is the laboratory test accuracy. The current 'golden standard' for AIHA is the direct antiglobulin test (DAT). The DAT detects autoantibody- and/or complement-opsonized RBCs. The DAT has insufficient test characteristics since it remains falsely negative in approximate 5-10% of patients with AIHA, whereas a falsely positive DAT can be found in 8% of hospitalized individuals. Also apparently healthy blood donors can have a positive DAT. The consequences of DAT positivity are not well known and may point to early, asymptomatic disease, or to another disease associated with formation of RBC autoantibodies, such as a malignancy or (systemic) autoimmune disease. Currently, there are no guidelines to follow-up DAT positive donors. A second unsolved difficulty is the choice of treatment in AIHA. Hemolysis can be stopped or at least attenuated with corticosteroids, aiming to inhibit autoantibody production and/or RBC destruction. Many patients do not respond adequately to corticosteroid treatment or develop severe side effects. Currently, it is advised to avoid RBC transfusions since these may lead to aggravation of hemolysis and RBC alloantibody formation. But in case symptomatic anemia occurs, RBC transfusions need to be given. An evidence-based transfusion strategy for AIHA patients is needed to warrant safe transfusion in this complex patient group. To design optimal diagnostic testing and (supportive) treatment algorithms, the investigators will study a group well-characterized patients with AIHA and blood donors without AIHA, via a prospective centralized clinical data collection and evaluation of new laboratory tests. With this data the knowledge of the AIHA pathophysiology and to evaluate diagnostic testing in correlation with clinical features and treatment outcome can be improved.

Official Title
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The DRAIHA Study: Data Registry of AutoImmune Hemolytic Anemia, to Improve Diagnostic Testing for the Development of Personalized Treatment Protocols in AIHA Patients

Conditions
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Autoimmune Hemolytic Anemia

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sufficient comprehension of the Dutch language Signed informed consent by patient and/or parent/caretaker or donor Patients older than 3 months Patients with a positive DAT, a positive eluate and signs of hemolysis* Patients with a positive DAT with complement only, negative eluate, but with signs of hemolysis Donors with a (repeatedly) positive DAT and a positive eluate and/or clinically relevant cold auto-antibodies Exclusion Criteria: Prior inclusion in the DRAIHA study

Ages Eligible for Study
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Minimum Age: 3 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients<br>Patients with a positive DAT, a positive eluate and signs of hemolysis Patients with a positive DAT with complement only, negative eluate, but with hemolysis | |
| Blood donors<br>Blood donors with a positive direct antiglobulin test and a positive eluate and/or clinically relevant cold auto-antibodies | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunological characteristics of autoantibodies in autoimmune hemolytic anemia (AIHA) patients - laboratory tests. | Documentation of characteristics of autoantibodies (e.g. isotype, subtype, titer, thermal amplitude). | 12-18 months | 
| Assessment of hemolysis before and after therapy, reported per class of auto-immune hemolytic anemia. - laboratory tests | Documentation of hemolysis parameters (hemoglobin level (g/dL), reticulocytes (%), haptoglobin (mg/dL), bilirubin (μmol/L) and LDH(U/L)) before and after each type of therapy. AIHA classification as IgG/IgA only, IgG/IgA with complement activation or complement activation only. | 12-18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of underlying disease that causes or is associated with AIHA. | Documentation of physician-reported underlying disease that caused AIHA (e.g. autoimmune and/or lymphoproliferative disease, infection, medication). | 12-18 months | 
| Type of treatment prescribed as first-line, second-line or further-line treatment for AIHA. | The percentage of patients receiving first, second or further-line treatment for AIHA will be calculated. | 12-18 months | 
| Hematological response after each treatment line (CR, CR-u, PR and NR) | Percentage of patients with CR, CR-u, PR and NR after each treatment line. Hematological response will be classified as CR (complete remission), CR-u (CR- undetermined), PR (partial response) and NR (no response). CR: normal hemoglobin, no signs of hemolysis (normal haptoglobin, normal amount of reticulocytes, bilirubin, LDH), no treatment and transfusion independence during the last 4 weeks. CR-u: as CR, but hemoglobin, reticulocytes, LDH and/or bilirubin are deviating through another reason (e.g. underlying malignant disease). PR: 1. Hemoglobin > 10g/dL, no signs of hemolysis, transfusion independent, but a continuous treatment with low dose prednisone (< 10 mg/day) or other immunosuppressive therapy is necessary. 2. Compensated hemolytic anemia with an stable hemoglobin >10g/dL, transfusion independent, maximal dose of prednisone < 10mg/day or other continuous immunosuppressive therapy or EPO. NR: no PR reached | 12-18 months | 
| Relapse-free survival, defined as the time since the achievement of complete or partial remission until relapse of AIHA or dead from any cause. | Relapse-free survival will be calculated as the time since the achievement of complete or partial remission until relapse of AIHA or dead from any cause. Median RFS and 95% CI will be calculated. | 12-18 month | 
| Documentation of adverse events during the treatment of AIHA. | Documentation of adverse events during the treatment of AIHA indicated according to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) Publish Date: May 28, 2009 | 12-18 month | 
| Assessment of hemolysis parameters after red blood cell transfusion. | Documentation of hemolysis parameters (hemoglobin level (g/dL), reticulocytes (%), haptoglobin (mg/dL), bilirubin (μmol/L) and LDH (U/L)) before red blood cell transfusion. | 1 and 7 days after transfusion | 
| Change in the incidence of auto- and alloantibodies after red blood cell transfusion. | Compare the incidence of auto- and alloantibodies before and after red blood cell transfusion. | 12-18 months | 
| Characteristics of autoantibodies of DAT positive blood donors. | Documentation of characteristics of autoantibodies (e.g. isotype, subtype, titer, thermal amplitude) of DAT positive blood donors. | 12-18 months |