Page 129 - Haematologica July

with either a potentially protective or activating effect of these cellular components of the immune system (microenvironment) on the expanded clonal B-cells.40,41 Therefore, on one hand, increased numbers of (functional- ly impaired) T cells have been described in CLL38,42,43 while on the other hand, we have recently shown increased titers of plasma antibodies against CMV and EBV in MBLhi and CLL patients vs. MBLlo and non-MBL controls, despite their antibody (immune)deficient state.37 Taken together, these latter findings might further support the existence of additional signals coming from immune cells other than clonal B cells, that could already contribute to the expan- sion of (cyto)genetically altered CLL-like clones at the ear- liest stages of disease, by promoting activation, prolifera- tion and/or survival of specific B-cell clones.
A major goal of our study was to investigate the medi- um-term rate of progression of MBLlo to MBLhi and (poten- tially also) CLL. Overall, only one subject evolved from MBLlo to MBLhi, and none transformed to CLL, which would translate into a progression rate from MBLlo to MBLhi of 1.8% after seven years of follow-up. Despite the fact that the rate of progression of MBLlo to MBLhi and CLL appears to be extremely low, one of the most astonishing findings of our follow-up study was the significantly high- er frequency of deaths among MBLlo subjects, associated with a significant adverse impact on OS vs. both non-MBL controls, particularly among females, and the general pop- ulation (of similar age and sex distribution) living in the same region in Spain. However, comparisons with the general population must be considered with care, since the conditions of this population might differ from that of non-MBL individuals recruited at the Primary Health Services. Multivariate analysis showed a borderline signif- icant association between the presence of MBLlo clones and a shorter survival. Despite this, the specific mechanisms responsible for the higher frequency of infections and deaths observed, particularly among women, are unknown, and further studies are required to validate and clarify these results. In this regard, controversial results have been reported on MBLhi subjects in the literature. Thus, while Shanafelt et al. showed no differences in OS of MBLhi vs. the general population,33 Shim et al. pointed out a higher frequency of deaths in their MBLlo cohort (4/11; 36%), albeit no statistically significant differences were found vs. non-MBL controls in the latter study, prob- ably due to the small sample size.22 In addition, Fazi et al. also reported that 16/137 (12%) CLL-like MBLlo subjects died before re-evaluation after a median time of three years, which is a high proportion of their whole cohort.10 However, in the aforementioned report no information about the age of the deceased subjects is provided, and therefore, if it is the case they were older (than those sub- jects remaining alive) such high mortality rates might have been expected. Even more strikingly is the overrepresenta-
tion of infections as causes of death in MBLlo compared to that of our non-MBL cohort. Impaired immune responses and higher frequencies of infection have been recurrently reported in both MBLhi and CLL,44–47 but so far very little information exists in MBLlo, and such an association deserves further investigations. Several groups pointed out that the frequency of clonal hematopoiesis dramatically increases with age in the general population, especially among the elderly, in a similar way to the increased fre- quency of MBLlo, reflecting a clear relationship between clonal hematopoiesis and a higher risk of death.48,49 Whether or not both phenomena are related to MBLlo deserves future investigations.
In summary, we show herein that although MBLlo is a persistent and dynamic condition with a progressive acquisition of cytogenetic alterations, usually associated with an increased clone size and higher T- and NK-cell numbers in PB over time, progression of MBLlo to MBLhi and CLL is extremely rare in the medium-term. Despite this, the MBLlo subjects analyzed herein, particularly women, showed a shortened OS associated with an increased risk of death, particularly due to infections, fur- ther supporting the notion that MBLlo could be a marker of an impaired immune system, indirectly associated with a poorer outcome. Additional studies are necessary to con- firm these findings and shed light onto the specific immune defects and microenvironmental factors involved in MBLlo.
Funding
This work was supported by the RD06/0020/0035 and RD12/0036/0048 grants from Red Temática de Investigación Cooperativa en Cáncer (RTICC), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, (Madrid, Spain and FONDOS FEDER); CB16/12/00400 grant (CIBERONC, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, (Madrid, Spain and FONDOS FEDER); the FIS PI06/0824-FEDER, PS09/02430-FEDER, PI12/00905- FEDER, DTS15/00119-FEDER, PI16/00787-FEDER and PI17/00399-FEDER grants, from the Fondo de Investigación Sanitaria of Instituto de Salud Carlos III; the GRS206/A/08 grant, (Ayuda al Grupo GR37 de Excelencia, SAN/1778/2009) from the Gerencia Regional de Salud (Consejería de Educación and Consejería de Sanidad of Castilla y León, Valladolid, Spain) and the SA079U14 grant (Consejería de Educación and Consejería de Sanidad of Castilla y León, Valladolid, Spain). ML Gutiérrez is supported by grant PTA2014-09963-I from the Instituto de Salud Carlos III.
Acknowledgments
The authors would like to thank “The Primary Health Care Group of Salamanca for the Study of MBL” for their contribution to the study; a complete list of members is included in the Online Supplementary Information.
References
from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute – Working Group 1996 guidelines. Blood. 2008;111(12):5446–5456.
3. Scarfo L, Ferreri AJM, Ghia P. Chronic lym- phocytic leukaemia. Crit Rev Oncol Hematol. 2016;104:169–182.
4. Bachow SH, Lamanna N. Evolving strate-
gies for the treatment of chronic lympho- cytic leukemia in the upfront setting. Curr Hematol Malig Rep. 2016;11(1):61–70.
5. Chiorazzi N. Implications of new prognos- tic markers in chronic lymphocytic leukemia. Hematol Am Soc Hematol Educ Progr. 2012;2012:76–87.
6. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of
:
1.
2.
Rai KR, Jain P. Chronic lymphocytic leukemia (CLL)-Then and now. Am J Hematol. 2016;91(3):330–340.
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia : a report
haematologica | 2018; 103(7)
7y follow-up of monoclonal B-cell lymphocytosis
1207