Incidence and clinicobiologic characteristics of leukemic B-cell chronic lymphoproliferative disorders with more than one B-cell clone

Abstract

Leukemic B-chronic lymphoproliferative disorders (B-CLPDs) are generally believed to derive from a monoclonal B cell; biclonality has only occasionally been reported. In this study, we have explored the incidence of B-CLPD cases with 2 or more B-cell clones and established both the phenotypic differences between the coexisting clones and the clinicobiologic features of these patients. In total, 53 B-CLPD cases with 2 or more B-cell clones were studied. Presence of 2 or more Bcell clones was suspected by immunophenotype and confirmed by molecular/ genetic techniques in leukemic samples (n ‫؍‬ 42) and purified B-cell subpopulations (n ‫؍‬ 10). Overall, 4.8% of 477 consecutive B-CLPDs had 2 or more B-cell clones, their incidence being especially higher among hairy cell leukemia (3 of 13), large cell lymphoma (2 of 10), and atypical chronic lymphocytic leukemia (CLL) (4 of 29). In most cases the 2 B-cell subsets displayed either different surface immunoglobulin (sIg) light chain (n ‫؍‬ 37 of 53) or different levels of the same sIg (n ‫؍‬ 9 of 53), usually associated with other phenotypic differences. Compared with monoclonal cases, B-CLL patients with 2 or more clones had lower white blood cell (WBC) and lymphocyte counts, more frequently displayed splenomegaly, and required early treatment. Among these, the cases in which a CLL clone coexisted with a non-CLL clone were older and more often displayed B symptoms, a monoclonal component, and diffuse infiltration of bone marrow and required early treatment more frequently than cases with monoclonal CLL or 2 CLL clones. (Blood. 2003;102:2994-3002)

Double productive immunoglobulin sequence rearrangements in patients with chronic lymphocytic leukemia

“…However, the development of new B-cell subclones resulting from the occurrence of additional genetic mutations in the neoplastic cells during the evolution of the disease has been described [35][36][37], with studies reporting CLL cases with two unrelated B-cell clones [9,[36][37][38][39]. In order to minimize the risk of including such cases in our series of patients with double productive IGHV rearrangements, we checked blood smear morphology and we run a four marker phenotypical panel as a requisite for inclusion in the study in all 60 patients.…”

“…The expression of a single Ig light chain by CLL B-cells (j or k) was required ( Fig. 1) based on previous studies reporting that biclonality in CLL can be reliably ascertained by flow cytometry, with distinct B-cell populations usually expressing different sIg light chains isotypes [9,36,40,41]. To confirm this assumption in our series, we studied two cases with double IGHV rearrangement where flow cytometry had revealed expression of distinct surface Ig light chain (j and k).…”

“…It has been speculated that cases with B-cell clones expressing double IGHV might undergo the second rearrangement to masquerade the binding reactivity of the original B-cell receptor, thus allowing escape from clonal deletion [8]. These cases should be distinguished from those characterized by the presence of two or more phenotypically or morphologically distinct leukemic populations (biclonal), where the double IGHV rearrangements represent either two concomitant underlying diseases or CLL subclones that generate during the course of the disease [9]. The prevalence of double IGHV expression in patients with apparently monoclonal CLL is not negligible, since it has been reported in up to 5% of the cases [7,8].…”

Immunoglobulin sequence analysis and prognostication in CLL: guidelines from the ERIC review board for reliable interpretation of problematic cases

“…Along these lines, it has been reported that up to 5% of patients with B-cell chronic lymphoproliferative malignancies may display two or more clonal populations. 14 In such cases, if two separate tumor populations are indicated by flow cytometry, biclonality can be conclusively proven only after identification of the light chain sequence(s) at the molecular level.…”

Comprehensive translocation and clonality detection in lymphoproliferative disorders by next-generation sequencing

“…In two CLL cases, a total of three IGK locus gene rearrangements were detected by NGS in each case, raising the possibility of more than one clonal population being present, as previously described in chronic B-cell LPD. 13 Additionally, aberrant clonal rearrangements were seen that were not detected with conventional PCRbased approaches (e.g. IGKV to IGK intron), which warrant further analysis.…”