Molecular cytogenetic follow-up of chronic lymphocytic leukemia patients with unfavorable prognosis

In this pilot study results of prolonged (up to 74 month) follow-up of 16 CLL patients with del17p13 or del11q22 in the first I-FISH analysis have been presented. It was shown that the presences of del17p13 or del11q22 as well as the rate of the aberrant cells having those abnormalities are significant for the prognosis and clinical course of CLL. The high rate (more than 70 %) of cells with 17p13 deletion means very unfavorable cytogenetic marker and indicates the short survival. On the other hand the low rate of cells with 17p13 deletion may predict disease progression but in case of effective treatment there are no effects on the patient’s survival. The high rate (more than 70 %) of cells with del11q22 indicates the early requiring for treatment. It was revealed the frequency of cells with marker aberrations may change in the same patient including decreasing to the control level as result of treatment and without it too. The frequency of aberrant cells decreases significantly after the finishing of appropriated treatments program and usually returns to its previous level in case of relapse and/or progression of disease. The subclones’ ratio between different marker abnormalities could vary during treatment and after its ending. It’s also possible the occurrence of new leukemic cells subclones. Taking in consideration the wide range of clinical CLL course and the possibility of the clonal evolution, the FISH-analysis should be as integral part of clinical practice both during the CLL staging and the next patient’s follow-up.

1. Eichhorst B., Dreyling M., Robak T. et al. Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011;22(Suppl 6):vi50–4. DOI: 10.1093/annonc/mdr377.

2. Состояние онкологической помощи населению России в 2014 году. Под ред. А. Д. Каприна, В. В. Старинского, Г. В. Петровой. М., 2015. 236 с. ПЕРЕВОД

3. Döhner H., Stilgenbauer S., Benner A. et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000;343(26):1910–6.

4. Davids M. S., Vartanov A., Werner L. et al. Controversial fluorescence in situ hybridization cytogenetic abnormalities in chronic lymphocytic leukaemia: new insights from a large cohort. Br J Haematol 2015;170(5):694–703. DOI: 10.1111/bjh. 13498.

5. Delgado J., Espinet B., Olivera A. C. et al. Chronic lymphocytic leukaemia with 17p deletion: a retrospective analysis of prognostic factors and therapy results. Br J Haematol 2012;157(1):67–74. DOI: 10.1111/j. 1365–2141.2011.09000. x.

6. Stilgenbauer S., Zenz T., Winkler D. et al. Subcutaneous alemtuzumab in fludarabinerefractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2009;27(24):3994– 4001. DOI: 10.1200/JCO. 2008.21.1128.

7. Catovsky D., Richards S., Matutes E. et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 2007;370(9583):230–9.

8. Oscier D., Wade R., Davis Z. et al. Prognostic factors identified three risk groups in the LRF CLL4 trial, independent of treatment allocation. Haematologica 2010;95(10):1705–12. DOI: 10.3324/ haematol. 2010.025338.

9. Tam C. S., Shanafelt T. D., Wierda W. G. et al. De novo deletion 17p13.1 chronic lymphocytic leukemia shows significant clinical heterogeneity: the M. D. Anderson and Mayo Clinic experience. Blood 2009;114(5):957–64. DOI: 10.1182/ blood-2009‑03‑210591.

10. El-Ghammaz A. M., Abdelwahed E., Mostafa N. N., Mansour D. A. De novo deletion 17p13.1 as a predictor for disease progression in chronic lymphocytic leukemia. Clin Exp Med 2015;15(4):493–9. DOI: 10.1007/s10238‑014‑0317‑2.

11. Müller-Hermelink H. K., Montserrat E., Catovsky D. et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma. In: WHO classification of tumour of haematopoietic and lymphoid tissues. Lyon: IARC, 2008. P. 179–82.

12. Janssens A., Van Roy N., Poppe B. et al. High-risk clonal evolution in chronic B- lymphocytic leukemia: single-center interphase fluorescence in situ hybridization study and review of the literature. Br J Haematol 2012;89(1):72–80. DOI: 10.1111/j. 1600–0609.2012.01790. x.

13. Ojha J., Secreto C., Rabe K. et al. Monoclonal B-cell lymphocytosis is characterized by mutations in CLL putative driver genes and clonal heterogeneity many years before disease progression. Leukemia 2014;28(12):2395–8. DOI: 10.1038/leu. 2014.226.

14. Lai Y. Y., Huang X. J. Cytogenetic characteristics of B cell chronic lymphocytic leukemia in 275 Chinese patients by fluorescence in situ hybridization: a multicenter study. Chin Med J (Engl) 2011;124(16):2417–22.

15. Yang S. M., Li J. Yo., Gale R. P., Huang X. J. The mystery of chronic lymphocytic leukemia (CLL): Why is it absent in Asians and what does this tell us about etiology, pathogenesis and biology. Blood Rev 2015;29(3):205–13. DOI: 10.1016/j. blre. 2014.12.001.

16. Marasca R., Maffei R., Martinelli S. et al. Clinical heterogeneity of de novo 11q deletion chronic lymphocytic leukemia: prognostic relevance of extent of 11q deleted nuclei inside leukemic clone. Hematol Oncol 2013;31(2):88–95. DOI: 10.1002/hon. 2028.

17. Jain P., Keating M., Thompson P. A. et al. High fluorescence in situ hybridization percentage of deletion 11q in patients with chronic lymphocytic leukemia is an independent predictor of adverse outcome. Am J Hematol 2015;90(6):471–7. DOI: 10.1002/ajh. 23978.