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Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. However, it is much less frequent in Asians including in Asians living in Western countries. At present, it is well-established that virtually every CLL case is preceded by an indolent stage known as monoclonal B-cell lymphocytosis (MBL) of CLL phenotype (CLL-like MBL). MBL is categorized as high-count (MBL) or low-count MBL (MBL), based on the presence of more versus less than 500 CLL-like clonal B cells/mL in peripheral blood (PB), respectively. MBL cases have a probability of progression to CLL requiring therapy of ~1–2% patients/year. In contrast, the clinical significance of MBL remains to be determined, with rare progression to MBL and CLL in the medium-term (5–7 years). CLL-like MBL is present in 7-14% individuals from Western adult (>40 years) populations with an overall median (range) MBL clone size of ~1 cell/mL (0.1-10 cells/mL), based on high-sensitive multiparameter flowcytometry (MFC). In turn, the only study performed in Asian populations reported a lower prevalence of MBL of 1.3% in Taiwan, after analyzing 500,000 PB cells/case. Even though the precise mechanisms (e.g. genetic, environmental or both) that lead to such ethnical differences on the prevalence of CLL still remain unknown, they might be related either to a significantly lower frequency of MBL and/or to a lower rate of malignant transformation of CLL-like MBL to CLL. Therefore, the investigation of the prevalence of CLL-like MBL in Asian populations might contribute to better understand such ethnical differences and to shed light on the pathogenesis of CLL. Here, we investigated the frequency and characteristics of CLL-like MBL clones among Japanese descendants living in a Western environment through high-sensitive MFC. Overall, 258 healthy adult (≥40 years) Japanese descendants living in Sao Paulo (Brazil), without race miscegenation –108 males (42%) and 150 females (58%), with a median (range) age of 66 years (40-96 years) and no differences in the sex-distribution per age ranges, were randomly invited to participate in the study at the outpatient laboratory sample collection facility of two general hospitals (Hospital Santa Cruz and Hospital S. Paulo/UNIFESP) in Sao Paulo (Brazil) (Online Supplementary Materials and Methods and Online Supplementary Table S1), and sequentially followed for between 1-5 years after the study had been approved by the corresponding local Ethics Committees. Detection of MBL cells and enumeration of the main normal residual PB lymphocyte populations were based on high-sensitivity 8-color MFC analysis of ≥5x10 leukocytes/sample (Online Supplementary Materials and Methods and Online Supplementary Table S2). Whenever enough sample was available, clonal B cells were sorted to investigate CLLassociated cytogenetic abnormalities by interphase fluorescence in situ hybridization (iFISH) and the mutational status of their immunoglobulin heavy chain (IGVH) sequences. In total, 27 of 258 (10.5%) individuals showed MBL clones, including a greater frequency of males (16 of 108, 15%) versus females (11 of 150, 7%) (P=0.05) (Table 1). The frequency of MBL cases progressively increased with age from 4% in subjects aged 40–59 years to 22% among older (≥80 years) adults (P=0.02). Of note, such an increase was significantly higher in males than females (10x vs. 3x, P=0.002) (Figure 1; Table 1). Interestingly, the MBL clone size was systematically <500 cells/mL (<0.5 cells/mL in 92% cases) with median (range) counts of 0.12 cells/mL (0.03-20 cells/mL) (Table 1; Online Supplementary Table S3). Of note, MBL clones were significantly larger in men versus women, both in absolute (P=0.04) and in relative numbers (P=0.02), and they progressively increased with age (P=0.04 and P=0.05, respectively) in parallel to the greater frequency of MBL (Figure 1). None of the eight CLL-like MBL clones studied carried any CLL-associated cytogenetic abnormality, while 4 of 6 cases in which enough purified MBL cells were available displayed mutated IGHV gene sequences (Online Supplementary Table S4). Altogether, these results show that, despite the similarly high prevalence of MBL here reported for the Japanese population living in Sao Paulo and other series of healthy MBL Caucasians, Japanese presenting with MBL displayed unique features. These included: i) greater predominance of MBL in men versus women (men/women ratio of 2 vs. 0.71-1.7); ii) almost four-fold smaller MBL clone sizes (median of 0.12 cells/mL vs. 1 cell/mL; range: 0.1-34 cells/mL), even when high-sensitive MFC methods had been used; and iii) greater predominance of CLL-like versus non-CLL-like MBL pheno-

High frequency of chronic lymphocytic leukemia-like low-count monoclonal B-cell lymphocytosis in Japanese descendants living in Brazil