Abstract
To assess biologic features related to the development of immune thrombocytopenia (ITP) in patients with chronic lymphocytic leukemia (CLL). We retrospectively analyzed 463 patients with CLL with available immunoglobulin heavy-chain variable (IGHV) gene status and B-cell receptor (BCR) configuration [heavy-chain complementary-determining region 3 (HCDR3)], of whom thirty-six developed ITP, according to previously defined criteria. Most of them had available cytogenetic analysis. We observed a significant association between ITP occurrence and IGHV unmutated gene status (P < 0.0001), unfavorable cytogenetic lesions (P = 0.005), and stereotyped HCDR3 (P = 0.006). The more frequent stereotyped HCDR3 subsets were #1 (IGHV1-5-7/IGHD6-19/IGHJ4; 16 of 16 unmutated) and #7 (IGHV1-69 or IGHV3-30/IGHD3-3/IGHJ6; 13 of 13 unmutated), both being significantly more represented among patients developing ITP (P = 0.003 and P = 0.001, respectively). Moreover, restricting the analysis to unmutated patients, subset #7 confirmed its independent significant association with the occurrence of ITP (P = 0.013). Both unmutated IGHV mutational status, del(11)(q23) and stereotyped BCR were significantly associated with shorter time to ITP development (P < 0.0001, P = 0.02, and P = 0.005, respectively) than other patients. Our data suggest that patients with CLL and peculiar BCR conformations are at higher risk of developing secondary ITP and that stereotyped BCR may be involved in the pathogenesis of this complication.
Highlights
Chronic lymphocytic leukemia (CLL) is characterized by the progressive accumulation of monoclonal B lymphocyte with a distinct phenotype (CD5+, CD23+, CD22- and low level of surface Ig) in peripheral lymphoid organs, bone marrow and peripheral blood [1, 2].The clinical outcome of chronic lymphocytic leukemia (CLL) patients is widely heterogeneous and frequently associated with cellular and molecular markers and/or specific genomic alterations
Our data suggest that patients with CLL and peculiar B-cell receptor (BCR) conformations are at higher risk of developing secondary immune thrombocytopenia (ITP), and that stereotyped BCR may be involved in the pathogenesis of this complication
We analyzed the immunoglobulin heavy-chain variable (IGHV) repertoire of a large series of CLL patients with secondary ITP, and we evaluated the occurrence of BCR stereotyped profiles
Summary
Chronic lymphocytic leukemia (CLL) is characterized by the progressive accumulation of monoclonal B lymphocyte with a distinct phenotype (CD5+, CD23+, CD22- and low level of surface Ig) in peripheral lymphoid organs, bone marrow and peripheral blood [1, 2].The clinical outcome of CLL patients is widely heterogeneous and frequently associated with cellular and molecular markers and/or specific genomic alterations. It has been reported that more than 20% of CLL patients exhibit closely homologous (“stereotyped”) heavy chain complementary-determining region 3 (HCDR3) sequences. This finding has suggested that clones sharing stereotyped BCRs may expand due to the stimulation by a restricted set of epitopes, and that antigenic driving may play an important role in the pathogenesis of the disease [2,3,4,5,6]. The risk of AIC occurrence in the course of CLL has been reported to be higher for patients with poor prognostic variables (ie, high blood lymphocyte count, rapid blood lymphocyte doubling time, increased serum β-2 microglobulin level, high expression of ZAP-associated protein 70 and CD38, and unmutated IGHV) [10, 13,14,15,16,17]. Neoplastic B-cells with UM configuration are characterized by polyreactive receptors that can bind multiple antigens and are more prone to interactions with surrounding T- and B-cells, like antibody producing non-neoplastic B-cells [15, 17, 22,23,24,25,26]
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