Differentiation on Biological Basis of Monoclonal B-Cell Lymphocytosis (MBL) From Chronic Lymphocytic Leukemia (CLL): Results of a Prospective GISL (Gruppo Italiano Studio Linfomi) Trial

The arbitrary cut-off of 5000/\ub5L chronic lymphocytic leukemia (CLL)-phenotype cells in peripheral blood is generally used to separate monoclonal B-cell lymphocytosis (MBL) from CLL. However, a major concern is the biological differentiation, if any, between MBL and CLL. We tried to address the issue therefore analyzing 261 Rai stage 0 patients enrolled in a Gruppo Italiano Studio Linfomi (GISL) prospective multicentre trial designed to validate biological parameters in early CLL as well as to assess the impact on clinical outcome of an early versus delayed policy of treatment with subcutaneous alemtuzumab in the high biological risk. In this cohort, biological characteristics of 105 (40.2%) patients who would be reclassified as MBL using the 2008 CLL diagnostic criteria were compared with those of the remaining 156 patients who had more than 5000/\ub5L CLL-phenotype cells in peripheral blood and fulfilled diagnostic criteria of CLL. Male to female ratio was similar for MBL and CLL (54/53 vs. 92/66, P=0.21) as was median age (58.18 vs 58.18, P=0.98). Median absolute number of cells with CLL phenotype in peripheral blood was 3120/\ub5L (range,400-4959) in MBL and 9925/\ub5L (range, 5020-110000) in CLL (P<0.0001). No difference in the CD38 status (P=0.48),ZAP-70 expression (P=0.29) or cytogenetic abnormalities as detected by FISH [trisomy 12 (P=0.24); deletion 11q (P=0.68); del17p (P=0.09)] was found between patients with MBL and CLL. The only feature differentiating CLL from MBL was represented by an excess of patients with unmutated IgVH disease in the former group (CLL,69.2% vs. MBL, 30.8%: P=0.04). In addition, patients with CLL had an about 2-fold risk of having IgVH germline status in comparison to patients with MBL (OR,1.80; 95% CI, 1.02-3.13; P=0.04). Since the arbitrary cut-off of 5000/\ub5L CLL-phenotype cells in peripheral blood failed to identify a peculiar biological profile for either MBL or CLL, we wondered whether a different B-cell threshold based on disease clinical outcome better stratified patients according to biological risk. In an independent cohort including 818 Rai stage 0 patients registered in a GIMEMA (Gruppo Italiano Malattie EMatologiche Maligne dell\u2019Adulto) database, we demonstrated that a count of 10000/ \ub5L B-cells is the best lymphocyte threshold to predict time to first therapy (TFT). When this cut-off was applied to the GISL series we found that the distribution of main high-risk features [CD38, P=0.83; trisomy 12,P=0.36; del11q,P=0.85; del17,P=0.37) was similar between patients with B-cell lymphocytes higher and lower than 10000/ \ub5L. Only an excess of cases with unmutated IgVH (P=0.04) and slightly increase of ZAP-70 (P=0.06) characterized patients B-cell higher than 10000 \ub5L. In conclusion, present data obtained from a prospective multicentre study indicate that biological characteristics of CLL are found also in MBL and there is no general predominance of good risk variables in MBL in comparison to CLL. This implies that MBL may not be considered a distinct disease but as an early stage of CLL