Clinical trial NCT04024202: Data Registry of Auto Immune Hemolytic Anemia
Official title: The DRAIHA Study: Data Registry of AutoImmune Hemolytic Anemia, to Improve Diagnostic Testing for the Development of Personalized Treatment Protocols in AIHA Patients
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Autoimmune Hemolytic Anemia
Lead sponsor: Sanquin Research & Blood Bank Divisions
Sponsor class: OTHER
Collaborators: name: Leiden University Medical Center
name: Radboud University Medical Center
name: UMC Utrecht
name: Maastricht University Medical Center
name: Erasmus Medical Center
name: Haga Hospital
name: Isala
name: Jeroen Bosch Ziekenhuis
name: St. Antonius Hospital
name: Onze Lieve Vrouwe Gasthuis
name: Spaarne Gasthuis
name: Amsterdam University Medical Center
name: Prothya Biosolutions
First posted: 2019-07-18
Enrollment: 720
Sex: ALL
Minimum age (years): 3
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Immunological characteristics of autoantibodies in autoimmune hemolytic anemia (AIHA) patients - laboratory tests.
timeFrame: 12-18 months
measure: Assessment of hemolysis before and after therapy, reported per class of auto-immune hemolytic anemia. - laboratory tests
timeFrame: 12-18 months
Secondary outcomes:
measure: Incidence of underlying disease that causes or is associated with AIHA.
timeFrame: 12-18 months
measure: Type of treatment prescribed as first-line, second-line or further-line treatment for AIHA.
timeFrame: 12-18 months
measure: Hematological response after each treatment line (CR, CR-u, PR and NR)
timeFrame: 12-18 months
measure: Relapse-free survival, defined as the time since the achievement of complete or partial remission until relapse of AIHA or dead from any cause.
timeFrame: 12-18 month
measure: Documentation of adverse events during the treatment of AIHA.
timeFrame: 12-18 month
measure: Assessment of hemolysis parameters after red blood cell transfusion.
timeFrame: 1 and 7 days after transfusion
measure: Change in the incidence of auto- and alloantibodies after red blood cell transfusion.
timeFrame: 12-18 months
measure: Characteristics of autoantibodies of DAT positive blood donors.
timeFrame: 12-18 months
Other outcomes:
Locations:
city: Amsterdam-Zuidoost
country: Netherlands
facility: AMC
city: Nijmegen
country: Netherlands
facility: UMC Radboud
Study officials:
affiliation: Center for Clinical Transfusion Research (CCTR), Sanquin, The Netherlands
name: M. De Haas, Prof. MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, University of Bern, Switzerland and Department for BioMedical Research, University of Bern, Switzerland
name: S.S Zeerleder, Prof. MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Zanella A, Barcellini W. Treatment of autoimmune hemolytic anemias. Haematologica. 2014 Oct;99(10):1547-54. doi: 10.3324/haematol.2014.114561.
citation: 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.
citation: 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.
citation: 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.