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Autoimmune hemolytic anemias and IgG antierythrocyte autoantibodies in Waldenström's macroglobulinemia: association with FcγRIIa polymorphism

Leukemia volume 20, pages 1179–1181 (2006)Cite this article

Autoimmune hemolytic anemia (AIHA) and cryoglobulinemia, occur at diagnosis or later both in 10–20% of patients with Waldenström's Macroglobulinemia (WM).1, 2 Immunoglobulin G fragment C (Fcγ)-mediated erythrophagocytosis has been recognized as the major pathogenic mechanism responsible for AIHA.3, 4 The clearance of immune complexes and the efficacy of their phagocytosis by splenic macrophages depend on the interactions between Fcγ receptors (FcγR) and immunoglobulin G (IgG).3 Therefore, genetic polymorphisms that modulate the affinity of FcγRIIa and FcγRIIIa for IgG may influence these processes. The phenotypic expression of valine (V) or phenylalanine (F) at amino acid 158 of FcγRIIIa receptor (FcγRIIIa-158V/F polymorphism) is associated with higher or lower affinity for IgG1 and IgG3.3 Consequently, the homozygous FcγRIIIa-158F genotype is associated with a lower response rate to rituximab therapy.2 Similarly, FcγRIIa gene displays a G to A point mutation in the ligand binding domain, causing an arginine (R) to histidine (H) amino-acid substitution at position 131.3 Both alleles bind IgG1 and IgG3. The FcγRIIa-131H allele has a higher affinity for IgG2 than FcγRIIa-131R allele,3 whereas FcγRIIa-131R is more efficient than FcγRIIa-131H for mediating C-reactive protein (CRP)-dependent phagocytosis.5 C-reactive protein is an acute phase serum protein involved in the recognition of products of damaged autologous cells, and elevated serum concentrations have been described in lymphoproliferative disorders, especially WM. In addition, the FcγRIIa is involved in immune complex and cryoglobulin-induced production of cytokines, such as interleukin (IL)-6 and IL-10, two cytokines of importance for B-cell malignant disorders.6 The FcγRIIa-R/H131 polymorphism influences the development of several autoimmune disorders such as systemic lupus erythematosus.3 Therefore, we evaluated the relationships between the FcγRIIa-131R/H and FcγRIIIa-158V/F polymorphisms, and clinical characteristics including AIHA and cryoglobulinemia in 74 WM patients.

Seventy-four patients, with WM diagnosed and treated according to the recommendations established during the second International Workshop on WM,2 were included in the study. Median age was 64 years (range 39–98 years, M/F=2) and informed consent was obtained from all patients according to local institutions guidelines. Autoimmune hemolytic anemia was defined by the combination of an anemia (hemoglobin <12 g/dl), one or more laboratory signs of hemolysis (reticulocytosis, decreased haptoglobin, increased bilirubin, or lactic dehydrogenase) and the presence of antierythrocyte autoantibody detected by the direct antiglobulin test (DAT). Treatment initiation criteria2 and all AIHA diagnostic criteria, including positive DAT were assessed every 6 months. Twenty-two patients (29%) with asymptomatic WM remained untreated at the date of the analysis. First-line therapy included chlorambucil (39 patients), combination chemotherapy (2), fludarabine alone (6) or in combination with other chemotherapy (3), and rituximab alone (2). Rituximab and fludarabine were delivered later in 10 and 14 additional patients, respectively. There was no difference in the number of treatments, the use of fludarabine and rituximab between the genotypic groups. Genomic DNA was extracted from peripheral blood using standard phenol–chloroform method. Genotyping for FcγRIIa-131R/H and FcγRIIIa-158V/F polymorphisms were performed with a PCR-based restriction fragment length polymorphism assay. The clinical and laboratory characteristics in the different genotypic groups were compared using the Yates modified χ2-test or the Fisher exact test. Cumulative incidences of competing risks were computed as previously described, estimates in each group of patients were compared with the test proposed by Gray. Survival after first treatment initiation and overall survival were calculated from the date of the first-line therapy initiation and the date of diagnosis, respectively, to the date of death or last follow-up evaluation, in the 59 patients diagnosed before 1 December 2003. The stopping date was 31 January 2005 and median follow-up of alive patients was 55 months (14–253). Survival curves were compared using the log-rank test with bootstrap resampling (1000 replicates). All analyses were carried out using Splus 6.2 (MathSoft, Cambridge, MA, USA) software and the R1.8.1 language, especially the cmprsk package (2.1–3 version) developed by Gray (Cambridge, MA, USA).

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Acknowledgements

We thank Audrey Gravey, Valérie Grandières and Catherine Vanicatte for their excellent technical assistance and Marc Daeron (U255, Institut Pasteur, Paris) for his thoughtful comment.

This work was supported by the Comité de la Somme de la Ligue contre le Cancer.

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  1. Service d’Hématologie -Immunologie-Cytogénétique, Centre Hospitalier, Valenciennes, France

    S Poulain & P Duthilleul

  2. Service d’Hématologie Clinique, Centre Hospitalier Schaffner, Lens, France

    I Dervite, L Stalnikiewicz & P Morel

  3. Service des Maladies du Sang, Centre Hospitalier Regional Universitaire, Lille, France

    X Leleu, A-S Moreau, V Coiteux & S de Botton

  4. Service d’Hématologie Clinique, Centre Hospitalier, Valenciennes, France

    J Fernandes

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Poulain, S., Dervite, I., Leleu, X. et al. Autoimmune hemolytic anemias and IgG antierythrocyte autoantibodies in Waldenström's macroglobulinemia: association with FcγRIIa polymorphism. Leukemia 20, 1179–1181 (2006). https://doi.org/10.1038/sj.leu.2404199

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