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Editorials
based on: (i) the percentage of bone marrow blasts, includ- ing promonocytes, and (ii) the white blood cell count in the circulation. The latter criterion, though, is artificial, since most CMML cases present with a white blood cell count of 8-14x109/L, often oscillating around the cut-off value of 13x109/L.
All types of CMML show similarities with certain types of MDS. The paper by Valent et al. refers to a close relation- ship between MDS with multilineage dysplasia and dys- plastic CMML-0, MDS with excess blasts-1 and dysplastic CMML-1, as well as MDS with excess blasts-2 and dysplas- tic CMML-2. In Figure 1, we try to illustrate the relation- ships within the large family of monocytoses.
Valent et al. propose the term “oligomonocytic CMML” in order to emphasize, as also pointed out by others, that it may be appropriate to diagnose CMML based on bone marrow monocytosis and CMML-typical somatic muta- tions, even if marked monocytosis is missing in the periph- eral blood.12,13
The group also points out that CMML can display two different types of acceleration and progression. On the one hand, dysplastic CMML can adopt typical features of MPN by showing accelerated proliferation with organomegaly and constitutional symptoms, without necessarily produc- ing an excess of blasts. This evolution from a dysplastic to a proliferative type may be heralded by increasing white cell counts, often accompanied by splenic enlargement. On the other hand, progression of CMML in terms of increas- ing blast percentage, i.e. from CMML-0 to CMML-1 or CMML-2, often occurs without a marked increase in white cell count or development of organomegaly. To complicate matters, both types of evolution can occur simultaneously or sequentially, and can be caused (or at least accompanied) by clonal evolution in terms of new somatic mutations, increased variant allele frequencies, or acquisition of chro- mosomal aberrations. As disease evolution may be more prominent in the bone marrow or peripheral blood, the authors recommend classifying the disease according to the highest blast count detectable.
Finally, the authors recommend complementing the group of CMML entities by including rare MPN-MDS vari- ants, namely CMML with KITD816V+ systemic mastocyto- sis, and MDS-MPN with PDGFRA/B, FGFR1, or PCM-JAK2 rearrangements, because these rare entities are often associ- ated with pronounced monocytosis.
The paper by Valent et al. provides a comprehensive description of all the diagnostic tools needed to assign patients to the appropriate category within the heteroge- neous group of non-clonal and clonal monocytoses. It sum- marizes our current knowledge and represents a starting point for future refinements of the classification of bone marrow disorders characterized by monocytosis.
References
1. Valent P, Orazi A, Savona MR, et al. PProposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions. Haematologica. 2019;10410):1935-1949.
2. BennettJM,CatovskyD,DanielMT,etal.Proposalsfortheclassifica- tion of the myelodysplastic syndromes. Br J Haematol. 1982;51(2):189- 199.
3. Brunning RD, Bennett JM, Flandrin G, et al. Myelodysplastic syn- dromes: introduction. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 3rd ed. Lyon: IARC; 2001.
4. Orazi A, Bennett JM, Germing U, Brunning RD, Bain BJ, Thiele J. Chronic myelomonocytic leukemia. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC; 2008.
5. Orazi A, Bennett JM, Germing U, et al. Chronic myelomonocytic leukemia. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC; 2017.
6. Bowen DT. Chronic myelomonocytic leukemia: lost in classification? Hematol Oncol. 2005;23(1):26-33.
7. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488-2498.
8. Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeter- minate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126(1):9-16.
9. ValentP,KernW,HoermannG,etal.Clonalhematopoiesiswithonco- genic potential (CHOP): separation from CHIP and roads to AML. Int J Mol Sci. 2019;20(3).
10. CargoC,CullenM,TaylorJ,etal.Theuseoftargetedsequencingand flow cytometry to identify patients with a clinically significant mono- cytosis. Blood. 2019;133(12):1325-1334.
11. Cazzola M. Clonal monocytosis of clinical significance. Blood. 2019;133(12):1271-1272.
12. GeyerJT,TamW,LiuYC,etal.Oligomonocyticchronicmyelomono- cytic leukemia (chronic myelomonocytic leukemia without absolute monocytosis) displays a similar clinicopathologic and mutational pro- file to classical chronic myelomonocytic leukemia. Mod Pathol. 2017;30(9):1213-1222.
13. Schuler E, Frank F, Hildebrandt B, et al. Myelodysplastic syndromes without peripheral monocytosis but with evidence of marrow mono- cytosis share clinical and molecular characteristics with CMML. Leuk Res. 2018;65:1-4.
p66Shc deficiency sets the scene for clinically aggressive chronic lymphocytic leukemia
Richard Rosenquist
Dept. of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden E-mail: RICHARD ROSENQUIST - richard.rosenquist@ki.se
doi:10.3324/haematol.2019.225904
Chronic lymphocytic leukemia (CLL) is a paradig- matic malignancy in which both cell-extrinsic (microenvironmental) and cell-intrinsic (genetic) factors contribute not only to the pathogenesis of the dis- ease but also to disease evolution and outcome.1,2 In more recent years, the genomic landscape of CLL has been unraveled with the identification of “driver” gene muta-
tions associated with clinical aggressiveness and chemo-
refractory disease, such as ATM, BIRC3, NOTCH1, NFK- 3-5
BIE, SF3B1 and TP53. In addition to genetic aberrations, we also know that the B-cell receptor (BCR) immunoglobulin plays a pivotal role in driving the dis- ease onset and evolution. The somatic hypermutation status of IGHV genes divides patients into two major
haematologica | 2019; 104(10)