Data Registry of Auto Immune Hemolytic Anemia (DRAIHA)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Autoimmune Hemolytic Anemia

• Study Type: Observational
• Enrollment (Anticipated): 720

Contacts and Locations

• Study Contact: Name: M. Jalink, MD; Phone Number: +31205123373; Email: m.jalink@sanquin.nl
• Study Contact Backup: Name: Masja De Haas, Prof. MD PhD; Phone Number: +31205123373; Email: m.dehaas@sanquin.nl

Study Locations

• Netherlands
  • Amsterdam-Zuidoost, Netherlands
    • Not yet recruiting
    • AMC
  • Nijmegen, Netherlands
    • Recruiting
    • UMC Radboud

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients, from the age of 3 months, with a positive DAT a positive eluate and signs of hemolysis and patients with a positive DAT for complement only with a negative eluate but with signs of hemolysis, and blood donors with a positive DAT and a positive eluate and/or clinically relevant cold autoantibodies.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Patients; 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; Blood donors with a positive direct antiglobulin test and a positive eluate and/or clinically relevant cold auto-antibodies

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Sanquin Research & Blood Bank Divisions
• Collaborators: Radboud University Medical Center; Maastricht University Medical Center; UMC Utrecht; Erasmus Medical Center; Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); St. Antonius Hospital; Leiden University Medical Center; Onze Lieve Vrouwe Gasthuis; Haga Hospital; Spaarne Gasthuis; Jeroen Bosch Ziekenhuis; Isala; Prothya Biosolutions
• Investigators: Principal Investigator: M. De Haas, Prof. MD PhD, Center for Clinical Transfusion Research (CCTR), Sanquin, The Netherlands; Principal Investigator: S.S Zeerleder, Prof. MD PhD, University Hospital, University of Bern, Switzerland and Department for BioMedical Research, University of Bern, Switzerland

Publications and helpful links

General Publications

• Garratty G. Immune hemolytic anemia associated with negative routine serology. Semin Hematol. 2005 Jul;42(3):156-64. doi: 10.1053/j.seminhematol.2005.04.005.
• Freedman J. False-positive antiglobulin tests in healthy subjects and in hospital patients. J Clin Pathol. 1979 Oct;32(10):1014-8. doi: 10.1136/jcp.32.10.1014.
• Barcellini W, Fattizzo B, Zaninoni A, Radice T, Nichele I, Di Bona E, Lunghi M, Tassinari C, Alfinito F, Ferrari A, Leporace AP, Niscola P, Carpenedo M, Boschetti C, Revelli N, Villa MA, Consonni D, Scaramucci L, De Fabritiis P, Tagariello G, Gaidano G, Rodeghiero F, Cortelezzi A, Zanella A. Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients. Blood. 2014 Nov 6;124(19):2930-6. doi: 10.1182/blood-2014-06-583021. Epub 2014 Sep 16.
• Rottenberg Y, Yahalom V, Shinar E, Barchana M, Adler B, Paltiel O. Blood donors with positive direct antiglobulin tests are at increased risk for cancer. Transfusion. 2009 May;49(5):838-42. doi: 10.1111/j.1537-2995.2008.02054.x. Epub 2009 Jan 2.
• Meulenbroek EM, de Haas M, Brouwer C, Folman C, Zeerleder SS, Wouters D. Complement deposition in autoimmune hemolytic anemia is a footprint for difficult-to-detect IgM autoantibodies. Haematologica. 2015 Nov;100(11):1407-14. doi: 10.3324/haematol.2015.128991. Epub 2015 Sep 9.
• Zanella A, Barcellini W. Treatment of autoimmune hemolytic anemias. Haematologica. 2014 Oct;99(10):1547-54. doi: 10.3324/haematol.2014.114561.
• Reynaud Q, Durieu I, Dutertre M, Ledochowski S, Durupt S, Michallet AS, Vital-Durand D, Lega JC. Efficacy and safety of rituximab in auto-immune hemolytic anemia: A meta-analysis of 21 studies. Autoimmun Rev. 2015 Apr;14(4):304-13. doi: 10.1016/j.autrev.2014.11.014. Epub 2014 Dec 9.
• Shi J, Rose EL, Singh A, Hussain S, Stagliano NE, Parry GC, Panicker S. TNT003, an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinins. Blood. 2014 Jun 26;123(26):4015-22. doi: 10.1182/blood-2014-02-556027. Epub 2014 Apr 2.
• Wouters D, Stephan F, Strengers P, de Haas M, Brouwer C, Hagenbeek A, van Oers MH, Zeerleder S. C1-esterase inhibitor concentrate rescues erythrocytes from complement-mediated destruction in autoimmune hemolytic anemia. Blood. 2013 Feb 14;121(7):1242-4. doi: 10.1182/blood-2012-11-467209. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2019
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: May 31, 2019
• First Submitted That Met QC Criteria: July 17, 2019
• First Posted (Actual): July 18, 2019

Study Record Updates

• Last Update Posted (Actual): July 19, 2019
• Last Update Submitted That Met QC Criteria: July 17, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Hematologic Diseases; Anemia; Hemolysis; Anemia, Hemolytic; Anemia, Hemolytic, Autoimmune
• Other Study ID Numbers: PPOC 15-27

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No