Monoclonal B-Cell Lymphocytosis (MBL) Is Closely Related to Chronic Lymphocytic Leukemia (CLL) and May Be Better Classified as Early-Stage CLL.
Authors: Kern Wolfgang , Haferlach Claudia , Dicker Frank , Schnittger Susanne , Haferlach Torsten 
Published: October 2019

Abstract
Abstract 2349
Poster Board II-326
Monoclonal B-cell lymphocytosis (MBL) is separated from chronic lymphocytic leukemia (CLL) mainly by the somewhat arbitrary cut-off of 5000/μl CLL-phenotype cells in peripheral blood. While MBL in general shows an indolent clinical course this is also true for early-stage CLL. This may call into question the adequateness of separating MBL from CLL. Therefore, we prospectively analyzed a series of 298 cases with MBL by immunophenotyping, fluorescence in situ hybridization (FISH; probes for detection of del(6q21), del(11q22.3) (ATM), +12, del(13q14) (D13S25, D13S319), del(17p13) (TP53), and t(11;14)(q13;q32) (IGH-CCND1)), chromosome banding analysis (CBA) and molecular genetics (analysis of IgVH mutation status) for parameters which are established as prognostically relevant in CLL. Data was compared to a previously published series of 356 cases with CLL (Cytometry B Clin Cytom 2009;Epub.). Male:female ratio was similar for MBL and CLL (2.1:1 vs. 1.8:1, n.s.) as was mean±SD age (66.5±10.5 vs. 65.7±10.2 years, n.s.). Mean±SD cells with CLL phenotype in peripheral blood amounted to 2,417±1,497/μl in MBL and to 27,771±39,607/μl in CLL (p<0.001). ZAP-70 expression (mean±SD MFI ratio T-cells:B-cells 4.3±3.0 vs. 5.1±3.3, p=0.011) and CD38 expression (mean±SD % positive cells 33.5±28.9 vs. 26.5±31.5, p=0.004) were stronger in MBL. FISH analysis revealed similar frequencies of del(11q22.3) (8.1% vs. 11.7%, n.s.). In contrast, +12 (22.8% vs. 13.7%, p=0.003) and t(11;14) (2.1% vs. 0.0%, p=0.008) were observed more frequently in MBL while del(6q21) (1.8% vs. 6.1%, p=0.008), del(13q14) (45.1% vs. 64.3%, p<0.001), del(13q14) as sole abnormality (35.0% vs. 47.7%, p=0.002), and del(17q13) (1.4% vs. 8.0%, p<0.001) were more frequent in CLL. CBA demonstrated a normal karyotype (31.5% vs. 21.6%, p=0.004) and trisomies (10.7% vs. 6.2%, p=0.045) more often in MBL while deletions were observed less often (30.5% vs. 39.3%, p=0.021). Analysis of IgVH revealed a mutated status more frequently in MBL (76.3% vs. 60.6%, p<0.001). Thus, while some good risk parameters have been encountered more frequently in MBL compared to CLL there was no clear predominance of all good risk parameters but rather a mixed distribution between MBL and CLL. We next analyzed the prognostic impact of the above parameters in cases with MBL. Time to therapy (TTT) was negatively affected by a higher CD38 expression (p=0.007), del(11q22.3) (p=0.01), the presence of independent clones as identified by CBA, and an unmutated IgVH status (p=0.001). Multivariate analysis revealed a higher CD38 expression (p=0.026) as the only independent parameter affecting TTT. Overall survival (OS) was negatively affect by del(6q21) (p=0.001) and by the presence of independent clones as identified by CBA (p=0.056) while a normal karyotype by CBA was associated with a better OS (p=0.031). When analyzing both MBL and CLL cohorts together, +12 (p=0.011) was found to be related to shorter TTT and del(13q14) as sole abnormality (p=0.038) and a higher ZAP-70 ratio T-cells:B-cells (p=0.007) were related to longer TTT. Neither the amount of cells with CLL phenotype in peripheral blood nor the presence of MBL were significantly related to TTT. The only parameters independently related to TTT were del(11q22.3) (p=0.007) and +12 (p=0.037). Parameters negatively affecting OS were MBL (p=0.006), the presence of independent clones as identified by CBA (p=0.038) and a female gender (p=0.047). Multivariate analysis demonstrated MBL (p=0.021) and the presence of independent clones as identified by CBA (p=0.046) as independently related to OS. The present data indicates that biologic characteristics of CLL are found in MBL and that there is no general predominance of good risk parameters in MBL as compared to CLL. Thus, MBL may not be considered a distinct disease but rather an early stage of CLL. This is further supported by the lack of impact of MBL as compared to CLL on the TTT. Furthermore, it is suggested that cases classified as MBL should undergo assessment of prognostic parameters including CBA as one prognostic parameter as shown for CLL cases.

Disclosures:
Kern: MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Dicker:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.