Recommendations for the diagnosis and treatment of chronic lymphocytic leukaemia (CLL) – 2018
Authors:
M. Doubek 1; M. Špaček 2; Š. Pospíšilová 1; M. Jarošová 1; T. Papajík 3; R. Urbanová 3; M. Šimkovič 4; D. Lysák 5; M. Brejcha 6; L. Smolej 4
Authors‘ workplace:
Interní hematologická a onkologická klinika, Fakultní nemocnice a Lékařská fakulta Masarykovy Univerzity Brno
1; I. interní klinika – klinika hematologie, 1. lékařská fakulta Univerzity Karlovy a Všeobecná fakultní nemocnice Praha
2; Hemato-onkologická klinika, Fakultní nemocnice a Lékařská fakulta Univerzity Palackého Olomouc
3; IV. interní hematologická klinika, Fakultní nemocnice Hradec Králové a Lékařská fakulta Univerzity Karlovy v Hradci Králové
4; Hematologicko-onkologické oddělení, Fakultní nemocnice Plzeň
5; Hematologické oddělení, Onkologické centrum Nový Jičín
6
Published in:
Transfuze Hematol. dnes,24, 2018, No. 3, p. 208-220.
Category:
Overview
Chronic lymphocytic leukaemia has a remarkably heterogeneous clinical course. The diagnostic procedures and therapeutic interventions need to be individually tailored according to patient age, comorbidities and therapeutic aims. There have been crucial developments in prognostication and therapy in recent years (e.g., significance of TP53 mutations, introduction of novel monoclonal antibodies, B-cell receptor signalling and Bcl-2 inhibitors). Therefore, the Czech CLL Study Group, the working group of the Czech Haematological Society, has developed these updated guidelines to facilitate the decision-making process for diagnosis and treatment in clinical practice. The guidelines are based on a comprehensive analysis of current literature and the principles of evidence-based medicine.
Key words:
chronic lymphocytic leukemia – diagnostics – treatment
Czech Group for Chronic Lymphocytic Leukaemia, section of the Czech Society of Haematology of the Czech medical Society of Jan Evangelista Purkyně
Sources
1. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for diagnosis, indications for treatment, response assessment and supportive management of chronic lymphocytic leukemia. Blood 2018; doi: 10.1182/blood-2017-09-806398.
2. Dearden C. B- and T-cell prolymphocytic leukemia: antibody approaches. Hematology Am Soc Hematol Educ Program 2012:645–651.
3. Moreau EJ, Matutes E, A‘Hern RP, et al. Improvement of the chronic lymphocytic leukemia scoring system with the monoclonal antibody SN8 (CD79b). Am J Clin Pathol 1997;108:378–382.
4. Rawstron AC, Kreuzer KA, Soosapilla A, et al. Reproducible diagnosis of chronic lymphocytic leukemia by flow cytometry: An European Research Initiative on CLL (ERIC) & European Society for Clinical Cell Analysis (ESCCA) Harmonisation project. Cytometry B Clin Cytom 2018;94:121–128.
5. Strati P, Shanafelt TD. Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification. Blood 2015;126:454–462.
6. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood 1975;46:219–234.
7. Binet JL, Auquier A, Dighiero G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981;48:198–206.
8. Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015;26(Suppl 5):v78–v84.
9. Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000;343:1910–1916.
10. Ghia P, Stamatopoulos K, Belessi C, et al. ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia. Leukemia 2007;21:1–3.
11. Malcikova J, Pavlova S, Kozubik KS, Pospisilova S. TP53 mutation analysis in clinical practice: lessons from chronic lymphocytic leukemia. Hum Mutat 2014;35:663–671.
12. Malcikova J, Tausch E, Rossi D, et al. ERIC recommendations for TP53 mutation analysis in chronic lymphocytic leukemia-update on methodological approaches and results interpretation. Leukemia 2018;32(5):1070–1080.
13. Pospisilova S, Gonzalez D, Malcikova J, et al. ERIC recommendations on TP53 mutation analysis in chronic lymphocytic leukemia. Leukemia 2012;26:1458–1461.
14. Brejcha M, Stoklasova M, Brychtova Y, et al. Clonal evolution in chronic lymphocytic leukemia detected by fluorescence in situ hybridization and conventional cytogenetics after stimulation with CpG oligonucleotides and interleukin-2: a prospective analysis. Leuk Res 2014;38:170–175.
15. Baliakas P, Iskas M, Gardiner A, et al. Chromosomal translocations and karyotype complexity in chronic lymphocytic leukemia: a systematic reappraisal of classic cytogenetic data. Am J Hematol 2014;89:249–255.
16. Stevens-Kroef M, Simons A, Rack K, Hastings RJ. Cytogenetic nomenclature and reporting. Methods Mol Biol 2017;1541:303–309.
17. Hastings RJ, Cavani S, Bricarelli FD, Patsalis PC, Kristoffersson U, Co-ordinators EP. Cytogenetic guidelines and quality assurance: a common European framework for quality assessment for constitutional and acquired cytogenetic investigations. Eur J Hum Genet 2007;15:525–527.
18. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41.
19. Hallek M. Chronic lymphocytic leukemia: 2015 Update on diagnosis, risk stratification, and treatment. Am J Hematol 2015;90:446–460.
20. Thurmes P, Call T, Slager S, et al. Comorbid conditions and survival in unselected, newly diagnosed patients with chronic lymphocytic leukemia. Leuk Lymphoma 2008;49:49–56.
21. Extermann M, Overcash J, Lyman GH, Parr J, Balducci L. Comorbidity and functional status are independent in older cancer patients. J Clin Oncol 1998;16:1582–1587.
22. Goede V, Cramer P, Busch R, et al. Interactions between comorbidity and treatment of chronic lymphocytic leukemia: results of German Chronic Lymphocytic Leukemia Study Group trials. Haematologica 2014;99:1095–1100.
23. Parmelee PA, Thuras PD, Katz IR, Lawton MP. Validation of the Cumulative Illness Rating Scale in a geriatric residential population. J Am Geriatr Soc 1995;43:130–137.
24. Salvi F, Miller MD, Grilli A, et al. A manual of guidelines to score the modified cumulative illness rating scale and its validation in acute hospitalized elderly patients. J Am Geriatr Soc 2008;56:1926–1931.
25. Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol 2012;30:2820–2822.
26. Cramer P, Langerbeins P, Eichhorst B, Hallek M. Advances in first-line treatment of chronic lymphocytic leukemia current recommendations on management and first-line treatment by the German CLL Study Group (GCLLSG). Eur J Haematol 2016;96:9–18.
27. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010;376:1164–1174.
28. Zelenetz AD, Gordon LI, Wierda WG, et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2015. J Natl Compr Canc Netw 2015;13:326–362.
29. Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol 2015;16:169–176.
30. Singh M, Mealing S, Baculea S, Cote S, Whelan J. Impact of novel agents on patient-relevant outcomes in patients with previously untreated chronic lymphocytic leukemia who are not eligible for fludarabine-based therapy. J Med Econ 2017;20:1066–1073.
31. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol 2007;25:5616–5623.
32. Eichhorst B, Fink AM, Bahlo J, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 2016;17:928–942.
33. Michallet AS, Rossignol J, Cazin B, Ysebaert L. Rituximab-cyclophosphamide-dexamethasone combination in management of autoimmune cytopenias associated with chronic lymphocytic leukemia. Leuk Lymphoma 2011;52:1401–1403.
34. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014;370:1101–1110.
35. Goede V, Fischer K, Engelke A, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia 2015;29:1602–1604.
36. Hillmen P, Robak T, Janssens A, et al. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet 2015;385:1873–1883.
37. Michallet AS, Aktan M, Hiddemann W, et al. Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. Haematologica 2018;103:698–706.
38. Hillmen P, Gribben JG, Follows GA, et al. Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia: Final analysis of an open-label phase II study. J Clin Oncol 2014;32:1236–1241.
39. Sinha R, Redekop WK. Cost-effectiveness of ibrutinib compared with obinutuzumab with chlorambucil in untreated chronic lymphocytic leukemia patients with comorbidities in the United Kingdom. Clin Lymphoma Myeloma Leuk 2018;18:e131–e142.
40. Flinn IW, Panayiotidis P, Afanasyev B, et al. A phase 2, multicenter study investigating ofatumumab and bendamustine combination in patients with untreated or relapsed CLL. Am J Hematol 2016;91:900–906.
41. Smolej L, Brychtova Y, Doubek M, et al. Low-dose FCR is a safeand effective treatment option for elderly/comorbid patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Updated results of project Q-Lite by Czech CLL Study Group. Blood 2014;124:4670.
42. Simkovic M, Motyckova M, Belada D, et al. Five years of experience with rituximab plus high-dose dexamethasone for relapsed/refractory chronic lymphocytic leukemia. Arch Med Sci 2016;12:421–427.
43. Smolej L, Doubek M, Panovska A, et al. Rituximab in combination with high-dose dexamethasone for the treatment of relapsed/refractory chronic lymphocytic leukemia. Leuk Res 2012;36:1278–1282.
44. Byrd JC, Brown JR, O‘Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014;371:213–223.
45. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014;370:997–1007.
46. Coutre SE, Barrientos JC, Brown JR, et al. Management of adverse events associated with idelalisib treatment: expert panel opinion. Leuk Lymphoma 2015;56:2779–2786.
47. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 2016;374:311–322.
48. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol 2016;17:768–778.
49. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 2018;378:1107–1120.
50. Chanan-Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol 2016;17:200–211.
51. Zelenetz AD, Barrientos JC, Brown JR, et al. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol 2017;18:297–311.
52. Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 2002;99:3554–3561.
53. Stilgenbauer S, Zenz T, Winkler D, et al. Subcutaneous alemtuzumab in fludarabine-refractory 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;27:3994–4001.
54. Fischer K, Cramer P, Busch R, et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2011;29:3559–3566.
55. Cuneo A, Follows G, Rigolin GM, et al. Efficacy of bendamustine and rituximab as first salvage treatment in chronic lymphocytic leukemia and indirect comparison with ibrutinib: a GIMEMA, ERIC and UK CLL FORUM study. Haematologica 2018; doi: 10.3324/haematol.2018.189837.
56. Robak T, Dmoszynska A, Solal-Celigny P, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 2010;28:1756–1765.
57. Badoux XC, Keating MJ, Wang X, et al. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood 2011;117:3016–3024.
58. Awan FT, Hillmen P, Hellmann A, et al. A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia. Br J Haematol 2014;167:466–477.
59. Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 2010;28:1749–1755.
60. Durot E, Michallet AS, Lepretre S, Le QH, Leblond V, Delmer A. Platinum and high-dose cytarabine-based regimens are efficient in ultra high/high-risk chronic lymphocytic leukemia and Richter‘s syndrome: results of a French retrospective multicenter study. Eur J Haematol 2015;95:160–167.
61. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013;369:32–42.
62. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 2015;125:2497–2506.
63. Bottcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol 2012;30:980–988.
64. Logan AC, Zhang B, Narasimhan B, et al. Minimal residual disease quantification using consensus primers and high-throughput IGH sequencing predicts post-transplant relapse in chronic lymphocytic leukemia. Leukemia 2013;27:1659–1665.
65. Dreger P, Corradini P, Kimby E, et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia 2007;21:12–17.
66. Dreger P, Schetelig J, Andersen N, et al. Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents? Blood 2014;124:3841–3849.
67. Rossi D, Gaidano G. Richter syndrome: molecular insights and clinical perspectives. Hematol Oncol 2009;27:1–10.
68. Parikh SA, Kay NE, Shanafelt TD. How we treat Richter syndrome. Blood 2014;123:1647–1657.
69. Parikh SA, Shanafelt TD. Risk factors for Richter syndrome in chronic lymphocytic leukemia. Curr Hematol Malig Rep 2014;9:294–299.
70. Osterborg A, Foa R, Bezares RF, et al. Management guidelines for the use of alemtuzumab in chronic lymphocytic leukemia. Leukemia 2009;23:1980–1988.
71. Smolej L, Prochazka V, Spacek M, et al. Doporučení pro léčbu alemtuzumabem u chronické lymfocytární leukemie. Vnitr Lek 2012;58:232–236.
72. Moia R, Diop F, Favini C, Kodipad AA, Gaidano G. Potential of BCL2 as a target for chronic lymphocytic leukemia treatment. Expert Rev Hematol 2018;11:391–402.
73. Oscier D, Dearden C, Eren E, et al. Guidelines on the diagnosis, investigation and management of chronic lymphocytic leukaemia. Br J Haematol 2012;159:541–564.
74. Dhalla F, Lucas M, Schuh A, et al. Antibody deficiency secondary to chronic lymphocytic leukemia: should patients be treated with prophylactic replacement immunoglobulin? J Clin Immunol 2014;34:277–282.
75. Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers. Hematology Am Soc Hematol Educ Program 2013;158–167.
76. Bokemeyer C, Aapro MS, Courdi A, et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update. Eur J Cancer 2007;43:258–270.
77. Aapro MS, Bohlius J, Cameron DA, et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer 2011;47:8–32.
78. Tsimberidou AM, Wen S, McLaughlin P, et al. Other malignancies in chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol 2009;27:904–910.
Labels
Haematology Internal medicine Clinical oncologyArticle was published in
Transfusion and Haematology Today
2018 Issue 3
Most read in this issue
- Non-infectious non-malignant lymphadenopathy – sinus histiocytosis with massive lymphadenopathy, Rosai-Dorfman disease
- Next generation sequencing: basic bioinformatic terms and analytic protocols for DNA analysis
- Recommendations for the diagnosis and treatment of chronic lymphocytic leukaemia (CLL) – 2018
- Non-infectious and non-malignant lymphadenopathy – idiopathic (HHV-8 negative) Castleman disease