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Un-mutated IgVH in chronic lymphocytic leukemia is associated with a higher risk of immune thrombocytopenia

Leukemia volume 21, pages 1092–1093 (2007)Cite this article

The prevalence of immune thrombocytopenia (IT) in chronic lymphocytic leukemia (CLL) is around 2%. This makes IT the most frequent autoimmune disorder during CLL, second only to hemolytic anemia.1 Autoreactive antibodies are not usually produced by the neoplastic clone.2 So far it is unknown if mutational status of immunoglobulin heavy-chain variable-region (IgVH) gene has any influence on the risk of developing autoimmune phenomena during the course of the disease. IgVH DNA sequence analysis, introduced since 2000 in the diagnostic work-up of our patients with CLL, revealed an apparent higher risk for un-mutated CLL to develop IT during the course of the disease. To verify this observation we performed a case–control study in the entire cohort of 680 CLL patients consecutively referred to our Department from 1st January 1995 to 1st January 2005. We evaluated IgVH status and VH gene repertoire in all the 20 CLL patients who developed IT at presentation or during the course of the disease, and in 20 CLL controls without IT. Cases fulfilled all the following criteria: rapid (<2 weeks) and severe fall (at least half of the initial level and below 100 × 103/μl) of the platelet count; normal or augmented number of megakariocytes in bone marrow in the absence of extensive (>90%) lymphoid infiltration; no or limited splenomegaly; no recent (<1 month) cytotoxic treatment. Controls were matched for gender, age and RAI stage at diagnosis, year of diagnosis, and length of follow-up to adjust for the time at risk of developing thrombocytopenia. Cases and controls met the diagnostic criteria for CLL of the National Cancer Institute. DNA was obtained from peripheral blood or bone marrow specimens at diagnosis or at the time of matching. Sequences were aligned to IMGT and V-BASE directories and analyzed using DNAPLOT and IMGT/VQUEST software. Sequences differing more than 2% from the corresponding germ-line gene were considered mutated. Median follow-up time from diagnosis of CLL was 64 months. All cases, except one, presented with RAI stage 0 or 1, median time to thrombocytopenia was 13 months (range 0–147), median platelet count at nadir was 12 × 103/μl (range 1–70), with all patients except one requiring specific therapy for thrombocytopenia. An exceedingly high prevalence of un-mutated IgVH was found in patients with IT (16 out of 20, 80%). For comparison only six out of 20 (30%) of controls showed un-mutated IgVH, a figure consistent with their early RAI stage.3 The odds ratio of developing IT in un-mutated CLL could be estimated as 9.33 (95% CI 1.82–52.6, P=0.001). In addition, in patients who developed IT we found an excess of VH1 and VH3 families without any case of VH4, usually reported as one of the most frequent gene assortment in CLL4, 5 (P=0.0004, by χ2 test, see Table 1).

Table 1 IgVH mutational status in cases and controls
Full size table

Although the results of this study warrant further confirmation from multicenter investigations because of the low incidence of IT in CLL, for the first time they strongly correlate the development of IT to IgVH un-mutated status in CLL patients. One could speculate that in the un-mutated CLL group, which is characterized by a peculiar antibody reactivity and by a more aggressive clinical course,6 there would be a major failure in controlling the emergence of auto-antibodies from normal B cells.

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  1. Department of Hematology, Ospedale S Bortolo, Vicenza, Italy

    C Visco, I Giaretta, M Ruggeri, D Madeo, A Tosetto & F Rodeghiero

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  1. C Visco
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  2. I Giaretta
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Correspondence to F Rodeghiero.

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Visco, C., Giaretta, I., Ruggeri, M. et al. Un-mutated IgVH in chronic lymphocytic leukemia is associated with a higher risk of immune thrombocytopenia. Leukemia 21, 1092–1093 (2007). https://doi.org/10.1038/sj.leu.2404592

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