СУЧАСНІ ПІДХОДИ ДО ДІАГНОСТИКИ ТА ПРОГНОЗУВАННЯ ПЕРЕБІГУ ХРОНІЧНОГО ЛІМФОЛЕЙКОЗУ
DOI:
https://doi.org/10.15407/oncology.2025.03.172Ключові слова:
хронічний лімфолейкоз, В-лімфоцити, прогностичні факториАнотація
Однією з ключових проблем сучасної гематології є своєчасна та високоточна діагностика лімфопроліферативних захворювань. Серед лейкемій найпоширенішим є хронічний лімфолейкоз (ХЛЛ), який зазвичай зустрічається серед пацієнтів старшого віку та має дуже варіабельний перебіг пухлинного процесу. Специфічні генетичні та епігенетичні зміни призводять до порушень регуляції проліферації та апоптозу у В-клітинах при ХЛЛ. Клінічна гетерогенність ХЛЛ, а також майже безсимптомний в більшості випадків перебіг ускладнює діагностику на ранніх стадіях захворювання. У зв’язку з цим, особливого значення набуває комплексний підхід до діагностики цієї нозологічної форми раку, що включає морфологічний аналіз клітин крові, їх імунофенотипування та молекулярно-генетичні дослідження, що дозволяє своєчасно ідентифікувати патологічний клон В-лімфоцитів і визначити прогностично важливі характеристики перебігу захворювання.
Посилання
Puckrin R, Owen C, Peters A. Underrepresentation of small lymphocytic lymphoma in clinical trials for chronic lym- phocytic leukemia. Eur J Haematol 2025; 114 (4): 636–40. https://doi.org/ 10.1111/ejh.14376.
Fabbri G, Dalla-Favera R. The molecular pathogenesis of chronic lymphocytic leukaemia. Nat Rev Cancer 2016; 16 (3): 145–62. https://doi.org/10.1038/nrc.2016.8
Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin 2024; 74 (1): 12–49. https://doi.org/10. 3322/caac.21830.
Unifi ovanyy klinichnyy protokol pervynnoyi ta spetsiali- zovanoyi medychnoyi dopomohy “Khronichnyy limfol- eykoz” nakaz Ministerstva okhorony zdorovʺya Ukrayiny vid 09.09.2022. https://www.dec.gov.ua/mtd/hronichnyj- limfoyidnyj-lejkoz/. (in Ukrainian).
Philchenkov AA, Zavelevich MP, Abramenko IV, et al. Current state of laboratory diagnosis of mature B-cell lymphoid neo- plasms in Ukraine. Oncology 2022; 24 (3): 184–96. https:// doi.org/10.32471/oncology.2663-7928.t-24-3-2022-g.10753 (in Ukrainian).
Wierda W, Brown J, Abramson J, et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma, Version 2.2024, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2024; 22 (3): 175–204. https://doi. org/10.6004/jnccn.2024.0018.
Matutes E, Owusu-Ankomah K, Morilla R, et al. The im- munological profi of B-cell disorders and proposal of a scoring system for the diagnosis of CLL.Leukemia 1994; 8 (10): 1640–5.
Niyonizeye Е, Wang Х, YanD, et al. Building a new score system for the diagnosis and diff rential diagnosis of typi- cal CLL/SLL, atypical CLL/SLL, and MCL based on the flow cytometry immunophenotyping. Ann Hematol 2025; 104: 1807–19. https://doi.org/10.1007/s00277-025- 06231-2.
Rawstron AC, Kreuzer KA, Soosapilla A, et al. Reproducible diagnosis of chronic lymphocytic leukemia by fl w cytom- etry: An European Research Initiative on CLL (ERIC)
& European Society for Clinical Cell Analysis (ESCCA) Harmonisation project. Cytometry B Clin Cytom 2018; 94: 121–8. https://doi.org/10.1002/cyto.b.21595.
Robak T, Krawczyńska A, Cebula-Obrzut B, et al. Atypical chronic lymphocytic leukemia-the current status. Cancers (Basel) 2023; 15 (18): 4427. https://doi.org/10.3390/can- cers15184427.
Porakishvili N, Memon A, Vispute K, et al. CD180 functions in activation, survival and cycling of B chronic lymphocytic leukaemia cells. Br J Haematol 2011; 153 (4): 486–98. https://doi.org/10.1111/j.1365-2141.2011.08605.
Gordiienko I, Shlapatska L, Kholodniuk VM, et al. CD150 and CD180 are involved in regulation of transcription fac- tors expression in chronic lymphocytic leukemia cells. Exp Oncol 2017; 39 (4): 291–8.
Afacan-Öztürk HB, Falay M, Albayrak M, et al. CD81 ex- pression in the diff rential diagnosis of chronic lympho- cytic leukemia. Clin Lab 2019; 65 (3): 313–7. https://doi. org/10.7754/Clin.Lab.2018.180802.
Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberra- tions and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343 (26): 1910–6. https://doi.org/10.1056/ NEJM200012283432602.
Buccheri V, Barreto WG, Fogliatto LM, et al. Prognostic and therapeutic stratifi ation in CLL: Focus on 17p deletion and p53 mutation. Ann Hematol 2018; 97 (12): 2269–78. https://doi.org/ 10.1007/s00277-018-3503-6.
Isin M, Yenerel M, Aktan M, et al. Analysis of p53 tumor suppressor pathway genes in chronic lymphocytic leuke- mia. DNA Cell Biol 2012; 31 (5): 777–82. https://doi.org/ 10.1089/dna.2011.1314.
Hallek M. Chronic lymphocytic leukemia: 2025 update on the epidemiology, pathogenesis, diagnosis, and therapy. Am J Hematol 2025; 100 (3): 450–80. https://doi.org/10.1002/ ajh.27546.
Guiyedi K, Parquet M, Aoufouchi S, et al. Increased c-MYC expression associated with active IGH locus rearrangement: An emerging role for c-MYC in chronic lymphocytic leu- kemia. Cancers (Basel) 2024; 16 (22): 3749. https://doi. org/10.3390/cancers16223749.
Kulis M, Martin-Subero JI. Integrative epigenomics in chronic lymphocytic leukaemia: Biological in sights and clinical applications. Br J Haematol 2023; 200 (3): 280–90. https://doi.org/10.1111/bjh.18465.
Arruga F, Gyau BB, Iannello A, et al. Immune response dysfunction in chronic lymphocytic leukemia: Dissecting molecular mechanisms and microenvironmental conditions. Int J MolSci 2020; 21 (5): 1825. https://doi.org/10.3390/ ij 1051825.
Rossi D, Gaidano G. Richter syndrome. Adv Exp Med Biol 2013; 792: 173–91. https://doi.org/10.1007/978-1-4614- 8051-8_8.
Ehrmann AS, Zadro A, Tausch E, et al. The NOTCH1 and miR-34a signaling network is aff ed by TP53 alterations in CLL. Leuk Lymphoma 2024; (13): 1941–53. https://doi. org/10.1080/10428194.2024.2392839.
Kolijn PM, Hosnijeh FS, Späth F, et al. High-risk subtypes of chronic lymphocytic leukemia are detectable as early as 16 years prior to diagnosis. Blood 2021; 139 (10): 1557–63. https://doi.org/10.1182/blood.2021012890.
Claus R, Lucas DM, Ruppert AS, et al. Validation of ZAP- 70 methylation and its relative significance in predicting outcome in chronic lymphocytic leukemia. Blood 2014; 124 (1): 42–8. https://doi.org/10.1182/blood-2014-02- 555722.
Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46 (2): 219– 34.
Binet JL, Auquier A, Dighiero G, et al. A new prognostic clas- sifi ation of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981; 48: 198–206.
Braish J, Cerchione C, Ferrajoli A. An overview of prognostic markers in patients with CLL. Front Oncol 2024; 14 (5): 1371057. doi.org/10.3389/fonc.2024.1371057.
Kohlhaas V, Blakemore SJ, Al-Maarri M, et al. Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1. Blood 2021; 137 (5): 646–60. https://doi.org/10.1182/blood.2020005734.
Timár B, Fülöp Z, Csernus B, et al. Relationship between the mutational status of VH genes and pathogenesis of diffuse large B-cell lymphoma in Richter’s syndrome. Leu- kemia 2004; 18 (2): 326–30. https://doi.org/10.1038/sj. leu.2403249.
Chen J, Sathiaseelan V, Chilamakuri CS, et al. ZAP-70 augments tonic B-cell receptor and CCR7 signaling in IGHV-unmutated chronic lymphocytic leukemia. Blood Adv 2024; 8 (5): 1167–78. https://doi.org/10.1182/blood advances.2022009557.
Bosch F, Dalla-Favera R. Chronic lymphocytic leukaemia: from genetics to treatment. Nat Rev Clin Oncol 2019; 16 (11): 684–701. https://doi.org/10.1038/s41571-019- 0239-8.
Montserrat E. New prognostic markers in CLL. Hematology Am Soc Hematol Educ Program 2006: 279–84. https://doi. org/10.1182/asheducation-2006.1.279.
Molica S. The evolving role of time-limited targeted therapy in chronic lymphocytic leukemia. Expert Rev Anticancer Ther 2020; 20 (12): 1015–19. https://doi.org/10.1080/147 37140.2020.1829482.
Molica S, Levato D, Cascavilla N, et al. Clinico-prognostic implications of simultaneous increased serum levels of so- luble CD23 and beta2-microglobulin in B-cell chronic lym- phocytic leukemia. Eur J Haematol 1999; 62 (2): 117–22. https://doi.org/10.1111/j.1600-0609.1999.tb01731.x.
Hallek M, Langenmayer I, Nerl C, et al. Elevated serum thymidine kinase levels identify a subgroup pathigh risk of disease progression in early, nonsmoldering chronic lymphocytic leukemia. Blood 1999; 93 (5): 1732–7.
AlJabban A, Azevedo RS, Antel K, et al. Mutational signa- ture analysis of chronic lymphocytic leukemia uncovering genomic patterns and prognostic implications. Am J Clin Pathol 2025; 164 (4): 530–44. https://doi.org/10.1093/ ajcp/aqaf059.
Hamblin TJ, Davis Z, Gardiner A, et al. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94 (6): 1848–54.
Rassenti LZ, Huynh L, Toy TL, et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med 2004; 351 (9): 893–901. https:// doi.org/10.1056/NEJMoa040857.
Damle RN, Wasil T, Fais F, et al. Ig V gene mutation sta- tus and CD38 expression as novel prognostic in dicators in chronic lymphocytic leukemia. Blood 1999; 94 (6): 1840–7.
Brachtl G, Hofbauer J, Greil R. The pathogenic relevance of the prognostic markers CD38 and CD49d in chronic lymphocytic leukemia. Ann Hematol 2014; 93: 361–74. https://doi.org/10.1007/s00277-013-1967-y.
Tissino E, Pozzo F, Benedetti D, et al. CD49d promotes di- sease progression in chronic lymphocytic leukemia: new in sights from CD49d bimodalexpression. Blood 2020; 135 (15): 1244–54. https://doi.org/10.1182/blood.2019003179.
Catherwood MA, Gonzalez D, Donaldson D, et al. Relevance of TP53 for CLL diagnostics. J ClinPathol 2019; 72 (5): 343–46. https://doi.org/10.1136/jclinpath-2018-205622.
Tzeng HE, Lee YW, Lin CT, et al. Multicolour and lineage- specifi interphase chromosome Flow-FISH: method de- velopment and clinical validation. Pathology 2024; 56 (5): 671–80. https://doi.org/10.1016/j.pathol.2024.04.001.
Austen B, Skowronska A, Baker C, et al. Mutation status of the residual ATM allele is an important determinant to the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q de- letion. J Clin Oncol 2007; 25 (34): 5448–57. https://doi. org/10.1200/JCO.2007.11.2649.
Chigrinova E, Rinaldi A, Kwee I, et al. Two main genetic pathways lead to the transformation of chronic lympho- cytic leukemia to Richter syndrome. Blood 2013; 122 (15): 2673–82. https://doi.org/10.1182/blood-2013-03-489518.
Isik S, Gunden G, Gunduz E, et al. An anomaly with potential as a new prognostic marker in CLL with del(13q): Gain of 16p13.3. Cytogenet Genome Res 2021; 161 (10–11): 479–87. https://doi.org/10.1159/000520242.
Lin K, Farahani M, Yang Y, et al. Loss of MIR15A and MIR16-1 at 13q14 is associated with increased TP53 mRNA, de-repression of BCL2 and adverse outcome in chronic lymphocytic leukaemia. Br J Haematol 2014; 167 (3): 346–55. https://doi.org/10.1111/bjh.13043.
Garding A, Bhattacharya N, Claus R, et al. Epigenetic up- regulation of lncRNAs at 13q14.3 in leukemia is linked to the In Cis downregulation of a gene cluster that targets NF-kB. PLoS Genet 2013; 9 (4): e1003373. https://doi. org/10.1371/journal.pgen.1003373.
Hammarsund M, Corcoran MM, Wilson W, et al. Characte- rization of a novel B-CLL candidate gene — DLEU7 — located in the 13q14 tumor suppressor locus. FEBS Lett 2004; 556 (1–3): 75–80. https://doi.org/10.1016/s0014- 5793(03)01371-1.
Kalla C, Scheuermann MO, Kube I, et al. Analysis of 11q22- q23 deletion target genes in B-cell chronic lymphocytic leukaemia: evidence for a pathogenic role of NPAT, CUL5, and PPP2R1B. Eur J Cancer 2007; 43 (8): 1328–35. https:// doi.org/10.1016/j.ejca.2007.02.005.
Balatti V, Bottoni A, Palamarchuk A, et al. NOTCH1 mu- tations in CLL associated with trisomy 12. Blood 2012; 119 (2): 329–31. https://doi.org/10.1182/blood-2011-10-386144.
Puente XS, Pinyol M, Quesada V, et al. Whole-genome se- quencing identifies recurrent mutations in chronic lympho- cytic leukaemia. Nature 2011; 475 (7354): 101–5. https:// doi.org/10.1038/nature10113.
Asslaber D, Wacht N, Leisch M, et al. BIRC3 expression predicts CLL progression and defines treatment sensitivity via enhanced NF-κB nuclear translocation. Clin Cancer Res 2019; 25 (6): 1901–12. https://doi.org/10.1158/1078- 0432.CCR-18-1548.
Pacholewska A, Grimm C, Herling CD, et al. Altered DNA methylation profiles in SF3B1 mutated CLL patients. Int J Mol Sci 2021; 22 (17): 9337. https://doi.org/10.3390/ ij 179337.
Sun C. The SF3b complex: splicing and beyond. Cell Mol Life Sci 2020; 77 (18): 3583–95. https://doi.org/10.1007/ s00018-020-03493-z.
Wang L, Brooks AN, Fan J et al. Transcriptomic character- ization of SF3B1 mutation reveals its pleiotropic eff in chronic lymphocytic leukemia. Cancer Cell 2016; 30 (5): 750–63. https://doi.org/10.1016/j.ccell.2016.10.005.
Martínez-Trillos A, Pinyol M, Navarro A, et al. Mutations in TLR/MYD88 pathway identify a subset of young chronic lymphocytic leukemia patients with favorabl eoutcome. Blood 2014; 123 (24): 3790–6. https://doi.org/10.1182/ blood-2013-12-543306.
Calin GA, Cimmino A, Fabbri M, et al. MiR-15a and miR- 16-1 cluster functions in human leukemia. Proc Natl Acad Sci USA 2008; 105 (13): 5166–71. https://doi.org/10.1073/ pnas.0800121105.
Cimmino A, Calin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 2005; 102 (39): 13944–9. https://doi.org/10.1073/ pnas.0506654102.
Zenz T, Häbe S, Denzel T, et al. miR-34a as part of the re- sistance network in chronic lymphocytic leukemia. Blood 2009; 113 (16): 3801–8. https://doi.org/10.1182/blood- 2009-05-224071.
Cui B, Chen L, Zhang S, et al. MicroRNA-155 infl ences B-cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia. Blood 2014; 124 (4): 546–54.
Santanam U, Zanesi N, Efanov A, et al. Chronic lymphocytic leukemia modeled in mouse by targeted miR-29 expression. Proc Natl Acad Sci USA 2010; 107 (27): 12210–5.
Wong KY, Yim RL, Kwong YL, et al. Epigenetic inactivation of the MIR129-2 in hematological malignancies. J Hematol Oncol 2013; 6: 16. https://doi.org/10.1186/1756-8722-6-16.
Al-Harbi S, Hill BT, Mazumder S, et al. Anantiapoptotic BCL-2 family expression index predicts the response of chronic lymphocytic leukemia to ABT-737. Blood 2011; 118 (13): 3579–90. https://doi.org/10.1182/blood-2011- 03-340364.
Nückel H, Hüttmann A, Klein-Hitpass L, et al. Lipoprotein li- pase expression is a novel prognostic factor in B-cell chron- ic lymphocytic leukemia. Leuk Lymphoma 2006; 47 (6): 1053–61. https://doi.org/10.1080/10428190500464161.
Maloum K, Settegrana C, Chapiro E, et al. IGHV gene mu- tational statusand LPL/ADAM29 gene expression as clinical outcome predictors in CLL patients in remission following treatment with oral fludarabin epluscyclophosphamide. Ann Hematol 2009; 88 (12): 1215–21. https://doi.org/10.1007/ s00277-009-0742-6.
Josefsson P, Geisler CH, Leff H, et al. CLLU1 expres- sion analysis adds prognostic information to risk prediction in chronic lymphocytic leukemia. Blood 2007; 109 (11): 4973–9. https://doi.org/10.1182/blood-2006-11-054916.
Ghosh AK, Secreto CR, Knox TR, et al. Circulating microve- sicles in B-cell chronic lymphocytic leukemia canstimulate marrow stromal cells: implications for disease progression. Blood 2010; 115 (9): 1755–64. https://doi.org/10.1182/ blood-2009-09-242719.
Fayad L, Keating MJ, Reuben JM, et al. Interleukin-6 and interleukin-10 levels in chronic lymphocytic leukemia: correlation with phenotypic characteristics and outcome. Blood 2001; 97 (1): 256–63. https://doi.org/10.1182/blood. v97.1.256.
