Atypical case of B-cell Chronic Lymphocytic Leukemia presenting with extreme hyperleukocytosis / Hiperleucocitoză extremă într-un caz atipic de leucemie limfatică cronică cu celulă B

Open access


Very few cases of chronic lymphocytic leukemia (CLL) presenting with extreme hyperleukocytosis are reported in the literature. We describe the case of a 66 years old woman, with newly diagnosed CLL presenting with extreme hyperleukocytosis of 774.2 x 109/liter, Rai stage III and Binet stage C. The patient has no comorbidities and the CIRS score (cumulative illness rating scale) is well below 6, with normal creatinine clearance. Some other interesting aspects related with this case are the atypical immunophenotype, the expression of Cyclin D1, and the B hepatitis viral infection, which made her diagnosis and treatment challenging. The patient was tested for NOTCH1 mutation and it was positive. There is important evidence that NOTCH1 mutations are associated with rapidly progressive disease and resistance to treatment. The distinction of CLL from mantle cell lymphoma (MCL) is not always easy because some MCLs may mimic CLL clinically, histologically, and/or phenotypically. The hepatitis B prophylaxis for viral reactivation was not available an in the end the patient was treated only with fludarabine and cyclophosphamide, without rituximab. CD200 should be introduced in the routine panel for flow cytometry to distinguish CLL from mantle cell lymphoma and NOTCH1 mutation is associated with poor prognosis and should be evaluated at diagnosis. CLL with extreme hyperleukocytosis presentation is very rare and sometimes an atypical CLL may represent a diagnostic pitfall.

1. van Dongen JJM, Orfao A, on behalf of the EuroFlow Consortium. EuroFlow: Resetting leukemia and lymphoma immunophenotyping. Basis for companion diagnostics and personalized medicine. Leukemia. Sep 2012; 26(9): 1899-907. DOI: 10.1038/leu.2012.121

2. Rossi D, Rasi S, Fabbri G, Spina V, Fangazio M, Forconi F, et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood. Jan 12, 2012; 119(2): 521-9. DOI: 10.1182/blood-2011-09-379966

3. Gianfelici V. Activation of the NOTCH1 pathway in chronic lymphocytic leukemia. Haematologica March 2012; 97:328-30. DOI: 10.3324/haematol.2012.061721


5. Alcalay D, Deleplanque P, Maubras MA, Guilhot F.Therapeutic leukapheresis in a leukostasis syndrome complicating chronic lymphoid leukemia. Ann Med Interne (Paris). 1988;139 Suppl 1:53-4.

6. de Fijter CW, Schuur J, Potter van Loon BJ, Kingma WP, Schweitzer MJ. Acute cardiorespiratory failure as presenting symptom of chronic lymphocytic leukemia. Neth J Med. 1996 Jul;49(1):33-7. DOI: 10.1016/0300-2977(96)00008-3

7. Durzyński T, Konopka L, Traczyk Z. Leukostasis syndrome in a case of chronic lymphocytic leukemia. Pol Merkur Lekarski. 1999 Jan;6(31):30-1.

8. Beaubien ER, Wilson TW, Satkunam N. Sudden death in a patient with chronic lymphocytic leukemia. CMAJ. 1998 Nov 3;159(9):1123-5.

9. Cukierman T, Gatt ME, Libster D, Goldschmidt N, Matzner Y. Chronic lymphocytic leukemia presenting with extreme hyperleukocytosis and thrombosis of the common femoral vein. Leuk Lymphoma. 2002 Sep;43(9):1865-8. DOI: 10.1080/1042819021000006367

10. Bumbea H, Vladareanu AM, Vintilescu A, Radesi S, Ciufu C, Onisai M, et al. The lymphocyte immunophenotypical pattern in chronic lymphocytic leukemia associated with hepatitis viral infections. J Med Life. 2011 Aug 15;4(3):256-63.

11. Gradowski JF, Sargent RL, Craig FE, Cieply K, Fuhrer K, Sherer C, Swerdlow SH. Chronic lymphocytic leukemia/ small lymphocytic lymphoma with cyclin D1 positive proliferation centers do not have CCND1 translocations or gains and lack SOX11 expression. Am J Clin Pathol. 2012 Jul;138(1):132-9. DOI: 10.1309/ AJCPIVKZRMPF93ET

12. Swerdlow SH, Campo E, Seto M, et al. Mantle cell lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al, editors. WHO Classification of Tumours of Haematopoietic and LymphoidTissues. Lyon, France: IARC; 2008. p. 229-2323.

13. Gao J, Peterson L, Nelson B, et al. Immunophenotypic variations in mantle cell lymphoma. Am JClin Pathol. 2009; 132:699-706. DOI: 10.1309/AJCPV8LN5ENMZOVY

14. O’Malley DP, Vance GH, Orazi A. Chronic lymphocytic leukemia/small lymphocytic lymphoma with trisomy 12 and focal cyclin D1 expression: a potential diagnostic pitfall. Arch Pathol LabMed. 2005; 129:92-5.

15. Abboudi Z, Patel K, Naresh KN. Cyclin D1 expression in typical chronic lymphocytic leukaemia.Eur J Haematol. 2009; 83:203-7. DOI: 10.1111/j.1600-0609.2009.01276.x

16. Craig FE, Foon KA. Flow cytometric immunophenotyping for hematologic neoplasms. Blood. 2008;111:3941-67. DOI: 10.1182/blood-2007-11-120535

17. Ho AK, Hill S, Preobrazhensky SN, Miller ME, Chen Z, Bahler DW. Small B-cell neoplasms with typical mantle cell lymphoma immunophenotypes often include chronic lymphocytic leukemias. Am J Clin Pathol. 2009 Jan;131(1):27-32. DOI: 10.1309/AJCPPAG4VR4IPGHZ

18. Grigore GE, Ivanov IC, Zlei M, Dăscălescu A, Popescu R, Petreuș T, et al. Specific Associations Between Clinical Signs, Immune Cells, Disease Genetic Background and Burden in a Group of Patients with B-Cell Chronic Lymphocytic Leukemia. Rev Romana Med Lab. 2014;22(1):79-92. DOI: 10.2478/rrlm 2014-0004

19. te Raa GD, van Oers MH, Kater AP; HOVON CLL working party. Monoclonal B-cell lymphocytosis: recommendations from the Dutch Working Group on CLL for daily practice. Neth J Med. 2012 Jun;70(5):236-41.

20. Sandes AF, de Lourdes Chauffaille M, Oliveira CR, Maekawa Y, Tamashiro N, Takao TT, et al. CD200 has an important role in the differential diagnosis of mature B-cell neoplasms by multiparameter flow cytometry. Cytometry B Clin Cytom. 2014 Mar;86(2):98-105. DOI: 10.1002/cyto.b.21128

21. Alapat D, Coviello-Malle J, Owens R, Qu P, Barlogie B, Shaughnessy JD, et al. Diagnostic usefulness and prognostic impact of CD200 expression in lymphoid malignancies and plasma cell myeloma. Am J Clin Pathol. 2012 Jan;137(1):93-100. DOI: 10.1309/ AJCP59UORCYZEVQO

22. El Desoukey NA, Afify RA, Amin DG, Mohammed RF. CD200 expression in B-cell chronic lymphoproliferative disorders. J Investig Med. 2012 Jan;60(1):56-61. DOI: 10.231/JIM.0b013e31823908f9

23. Palumbo GA, Parrinello N, Fargione G, Cardillo K, Chiarenza A, Berretta S, et al. CD200 expression may help in differential diagnosis between mantle cell lymphoma and B-cell chronic lymphocytic leukemia. Leuk Res. 2009 Sep;33(9):1212-6. DOI: 10.1016/j.leukres.


24. Ghia P, Hallek M. Management of chronic lymphocytic leukemia. Haematologica. Jun 2014; 99(6):965-72. DOI: 10.3324/haematol.2013.096107

25. Del Giudice I, Rossi D, Chiaretti S, Marinelli M, Tavolaro S, Gabrielli S, et al. NOTCH1 mutations in +12 chronic lymphocytic leukemia (CLL) confer an unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL. Haematologica. 2012 Mar;97(3):437-41. DOI: 10.3324/haematol.2011.060129

26. Sportoletti P, Baldoni S, Del Papa B, Aureli P, Dorillo E, Ruggeri L, et al. A revised NOTCH1 mutation frequency still impacts survival while the allele burden predicts early progression in chronic lymphocytic leukemia. Leukemia. 2014 Feb;28(2):436-9. DOI: 10.1038/leu.2013.289

27. Stilgenbauer S, Schnaiter A, Paschka P, Zenz T, Rossi M, Döhner K, et al.Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014 May 22;123(21):3247-54. DOI: 10.1182/blood-2014-01-546150

28. Strati P, Keating MJ, O’Brien SM, Ferrajoli A, Burger J, Faderl S et al. Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion. Haematologica. Aug 2014; 99(8):1350-5. DOI: 10.3324/ haematol.2014.104661

29. Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010 Oct 2; 376(9747):1164-74. DOI: 10.1016/S0140-6736(10)61381-5

30. Keating MJ, O’Brien S, Albitar M, Lerner S, Plunkett W, Giles F et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20; 23(18):4079-88. DOI: 10.1200/JCO.2005.12.051

31. Tam CS, O’Brien S, Wierda W, Kantarjian H, Wen S, Do KA et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008 Aug 15;112(4):975-80. DOI: 10.1182/ blood-2008-02-140582

32. Jeromin S, Weissmann S, Haferlach C, Dicker F, Bayer K, Grossmann V, et al. SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients. Leukemia. 2014 Jan;28(1):108-17. DOI: 10.1038/leu.2013.263

33. Tosello V, Ferrando AA. The NOTCH signaling pathway: role in the pathogenesis of T-cell acute lymphoblastic leukemia and implication for therapy. Ther Adv Hematol. Jun 2013; 4(3): 199-210. DOI: 10.1177/2040620712471368

Revista Romana de Medicina de Laborator

Romanian Journal of Laboratory Medicine

Journal Information

IMPACT FACTOR 2018: 0,800
5-year IMPACT FACTOR: 0,655

CiteScore 2017: 0.31

SCImago Journal Rank (SJR) 2018: 0.194
Source Normalized Impact per Paper (SNIP) 2018: 0.306


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 174 130 16
PDF Downloads 73 63 7