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I. Criado et al.
del(13q14)(RB1) Baseline follow-up Trisomy 12 Baseline follow-up del(11q)(ATM) Baseline follow-up del(17p)(TP53) Baseline follow-up
t(14q32) Baseline follow-up
0/2 (0%) NA
0/3 (0%) 0/9(0%)
0/2 (0%) 0/9 (0%)
0/2 (0%) 0/9 (0%)
NA 0/3 (0%)
3/13 (23%); 14±3.2% NS 1/7 (14%); 47% NA
1/11 (9%); 59% NS 1/40 (3%); 70% NS
0/6 (0%) NS 0/39 (0%) NS
0/5 (0%) NS 1/39 (3%); 10% NS
NA NA 5/20 (25%); 31±33% NS
1206
#2/56 individuals carried a clonal MBLlo CLL-like population along with at least one MBLlo non CLL-like clone. Results expressed as median (range) or as *number of cases (per- centage). Cytogenetic alterations are expressed as percentage of cases and mean percentage of cells affected ± SD. P-values shown in the right column refer to comparisons between MBLlo subjects who showed decreased/stable vs. increase clone sizes,while P-values shown in rows represent differences among subjects within each group at baseline and after seven years of follow-up. CLL: chronic lymphocytic leukemia; MBLlo: low-count monoclonal B-cell lymphocytosis; N.: number; NA: not applicable; NK: natural killer; NS: not statistically significantly different (P>0.05).
in which a single clone had not yet emerged as dominant vs. the others, as might occur at the latter, e.g., CLL stage. Most importantly, over two thirds of all CLL-like MBLlo clones showed a significantly increased size in PB after seven years, while for non CLL-like clones more variable kinetics were observed, depending on the specific pheno- type of clonal B-cells. Interestingly, we also observed a sig- nificant increase in the frequency of cytogenetic alter- ations over time, evidencing that B-cell clones are not only dynamic in terms of clone size, but also regarding their capacity to acquire new cytogenetic alterations. Of note, del(13q14), which has been found to be a common mosaicism in the general population,28,29 was absent in non-clonal B cells from 5/5 cases investigated in which CLL-like clonal cells did carry this alteration, indicating that the emergence of this alteration in MBLlo is specific for the clonal population. Altogether, these findings suggest that cytogenetic alterations are a relatively early, but not primary, event in the natural history of MBL/CLL, and might have a potential role in the progression of MBLlo to
MBLhi and CLL.
The presence and type of cytogenetic lesions, the IGHV
mutational status, or the presence of stereotyped recep- tors are some of the most important prognostic factors in CLL, which also define the outcome of MBLhi individuals; furthermore, it might identify a subset of cases in whom the presence of the B-cell clonal population influences OS.30–33 Unfortunately, in the present study, the mutational status and VDJ rearrangements were only assessed (both baseline and follow-up) in 8/65 MBLlo individuals (data not shown), making it impossible to validate solid conclusions regarding the potential association with the risk for pro- gression into MBLhi and CLL. To the best of our knowl- edge, the frequency and impact on disease progression of recurrent mutations (i.e., NOTCH1, SF3B1, MYD88, etc.) found in CLL, and also in MBLhi, to a lesser extent, has not been elucidated for MBLlo.34–36 Therefore, analysis of these CLL-related mutations in MBLlo cases might further con- tribute to an improvement in better delineating intrinsic tumor cell factors associated to disease progression.
In addition, the environment in which CLL-like MBLlo
Table 5. Variables studied in the Cox regression multivariate analysis showing an independent impact (P<0.1) on OS for the whole MBLlo plus non-MBL cohort.
Variables
Whole cohort Cardiovascular disease Age (<65y vs. ≥65y) Solid tumor
MBLlo clones
HR (95%CI) P
2.65 (1.30 - 5.41)
5.08 (1.48 - 17.49) 0.01
2.86 (1.26 - 6.46) 0.01 2.14 (0.97 - 4.72) 0.06
haematologica | 2018; 103(7)
0.007
CI: confidence interval; HR: hazard ratio; MBLlo: low-count monoclonal B-cell lympho- cytosis; N: number; OS: overall survival; PB: peripheral blood.The complete list of vari- ables analyzed in the Cox regression model is provided in Online Supplementary Table S6.
clones develop might be influenced by chronic immune responses against e.g., host viruses, that might play a crit- ical role in the expansion of clonal B cells, as recently sug- gested.37 In line with this hypothesis, herein we also show that the expansion of CLL-like MBLlo clones after seven years of follow-up (vs. baseline) is accompanied by a sig- nificant increase of all T-cell (but CD4+CD8+cytotoxic T- cells) and NK-cell populations in PB.
Controversial results have been reported regarding PB T- cell numbers in MBLlo. Hence, while te Raa et al. found normal CD4+ and CD8+ T-cell counts in PB of MBLhi,38 other studies have demonstrated that around half of the MBLlo individuals show ≥1 clonal/oligoclonal CD4+CD8+ T-cell population, with an overall increased frequency of clonal T-cell populations vs. age-matched individuals from the general population.10,39 However, the presence of clonal (CD4+CD8+ and other) T-cell expansions has also been described as a common event in older individuals, and has been associated with the ageing of the immune system.39 In this respect, we demonstrate herein that changes in the number of circulating PB T-cell and NK-cell populations among our CLL-like MBLlo subjects were not age-related, via a parallel analysis of a large group of 250 age- and sex- matched non-MBL controls (Online Supplementary Table S5). From a pathophysiological point of view, the increase in most PB T- and NK-cell populations could be associated