Vol 12, No 2 (2021)
Guidelines / Expert consensus
Published online: 2021-11-30

open access

Page views 3359
Article views/downloads 396
Get Citation

Connect on Social Media

Connect on Social Media

Diagnostic and therapeutic recommendations of the Polish Society of Haematologists and Transfusiologists and Polish Adult Leukemia Group-CLL for chronic lymphocytic leukemia in 2021

Iwona Hus12, Krzysztof Giannopoulos34, Krzysztof Jamroziak5, Jerzy Błoński6, Dariusz Wołowiec7, Jacek Roliński89, Piotr Smolewski10, Tadeusz Robak6
Hematology in Clinical Practice 2021;12(2):37-66.

Abstract

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, with a median age at diagnosis of approximately 70 years. The natural course of the disease varies greatly, and patients with nonprogressive and asymptomatic leukemia do not require treatment. The results of CLL treatment have improved significantly in recent years, mainly due to the introduction of new, more effective drugs, including BCR inhibitors and BCL2 inhibitors. The new drugs are used continuously, while venetoclax in combination with anti-CD20 antibodies is used for 24 (rituximab) or 12 (obinutuzumab) months, depending on the type of antibody and line of therapy. The choice of treatment protocol should largely depend on the assessment of 17p deletion/TP53 mutation and immunoglobulin variable heavy chain (IGVH) mutation status, which correlate with a worse response to immunochemotherapy.

The role of immunochemotherapy, which until recently was the mainstay of CLL treatment, has now significantly decreased. In the first-line, it is recommended only in patients without 17p deletion/TP53 mutation, with mutated IGVH. Other patients should receive novel targeted therapies. However, at the time of the preparation of these recommendations, these therapies are not available in the firs-line of treatment in Poland. Novel targeted therapies play a major role in the treatment of refractory/relapsed CLL, and immunochemotherapy is recommended primarily in patients with a long-term response to first-line therapy.

In this article, we present an update of the guidelines for the diagnosis and treatment of CLL, including the treatment of autoimmune complications, as well as the prophylaxis and treatment of infections, developed by the Polish Society of Haematologists and Transfusiologists and PALG-CLL Working Group.

Article available in PDF format

View PDF Download PDF file

References

  1. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016; 127(20): 2375–2390.
  2. Cancer Stat Facts: NHL — Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). https://seer.cancer.gov/statfacts/html/cllsll.html (April 23, 2021).
  3. Hallek M. Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment. Am J Hematol. 2019; 94(11): 1266–1287.
  4. Goldin LR, Slager SL, Caporaso NE. Familial chronic lymphocytic leukemia. Curr Opin Hematol. 2010; 17(4): 350–355.
  5. Sud A, Chattopadhyay S, Thomsen H, et al. Analysis of 153 115 patients with hematological malignancies refines the spectrum of familial risk. Blood. 2019; 134(12): 960–969.
  6. Robak T. Second malignancies and Richter's syndrome in patients with chronic lymphocytic leukemia. Hematology. 2004; 9(5–6): 387–400.
  7. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018; 131(25): 2745–2760.
  8. Eichhorst B, Robak T, Montserrat E, et al. ESMO Guidelines Committee. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021; 32(1): 23–33.
  9. Rawstron AC, Bennett FL, O'Connor SJM, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med. 2008; 359(6): 575–583.
  10. Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood. 1975; 46(2): 219–234.
  11. 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(1): 198–206, doi: 10.1002/1097-0142(19810701)48:1<198::aid-cncr2820480131>3.0.co;2-v.
  12. Rai KR. A critical analysis of staging in CLL. In: Gale RP, Rai KR. ed. Chronic lymphocytic leukemia: recent progress and future directions. Liss, New York 1987: 253–264.
  13. Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000; 343(26): 1910–1916.
  14. Zenz T, Eichhorst B, Busch R, et al. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010; 28(29): 4473–4479.
  15. Hallek M, Fischer K, Fingerle-Rowson G, et al. International Group of Investigators, German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010; 376(9747): 1164–1174.
  16. O'Brien S, Furman RR, Coutre S, et al. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018; 131(17): 1910–1919.
  17. Jones J, Mato A, Coutre S, et al. Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials. Br J Haematol. 2018; 182(4): 504–512.
  18. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial. J Clin Oncol. 2018; 36(19): 1973–1980.
  19. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019; 380(23): 2225–2236.
  20. 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): 1848–1854.
  21. Lin K, Sherrington PD, Dennis M, et al. Relationship between p53 dysfunction, CD38 expression, and IgV(H) mutation in chronic lymphocytic leukemia. Blood. 2002; 100(4): 1404–1409.
  22. Stilgenbauer S, Bullinger L, Lichter P, et al. German CLL Study Group (GCLLSG). Genetic and chronic lymphocytic leukemia: genomic aberrations and V(H) gene mutation status in pathogenesis and clinical course. Leukemia. 2002; 16(6): 993–1007.
  23. Kröber A, Bloehdorn J, Hafner S, et al. Additional genetic high-risk features such as 11q deletion, 17p deletion, and V3-21 usage characterize discordance of ZAP-70 and VH mutation status in chronic lymphocytic leukemia. J Clin Oncol. 2006; 24(6): 969–975.
  24. Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016; 127(2): 208–215.
  25. Burger JA, Tedeschi A, Barr PM, et al. RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015; 373(25): 2425–2437.
  26. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019; 381(5): 432–443.
  27. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018; 379(26): 2517–2528.
  28. Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019; 20(1): 43–56.
  29. Ghia P, Rawstron A. Minimal residual disease analysis in chronic lymphocytic leukemia: a way for achieving more personalized treatments. Leukemia. 2018; 32(6): 1307–1316.
  30. Böttcher 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(9): 980–988.
  31. Kwok M, Rawstron AC, Varghese A, et al. Minimal residual disease is an independent predictor for 10-year survival in CLL. Blood. 2016; 128(24): 2770–2773.
  32. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018; 378(12): 1107–1120.
  33. Kater AP, Kipps T, Eichhorst B, et al. Five-year analysis of Murano study demonstrates enduring undetectable minimal residual disease (uMRD) in a subset of relapsed/refractory chronic lymphocytic leukemia (R/R CLL) patients (pts) following fixed-duration venetoclax-rituximab (VenR) therapy (tx). Blood. 2020; 136(Suppl 1): 19–21.
  34. Catovsky D, Else M, Richards S. Chlorambucil — still not bad: a reappraisal. Clin Lymphoma Myeloma Leuk. 2011; 11(Suppl 1): S2–S6.
  35. Robak T, Blonski JZ, Jamroziak K, et al. A randomized, multicenter study (PALG CLL4/ML 21283) of maintenance treatment with rituximab versus observation after induction treatment with rituximab, cladribine, and cyclophosphamide (RCC) regimen in patients with progressive chronic lymphocytic leukemia: interim analysis. Blood. 2013; 122(21): 1640.
  36. Dearden C, Wade R, Else M, et al. UK National Cancer Research Institute (NCRI), Haematological Oncology Clinical Studies Group, NCRI CLL Working Group. The prognostic significance of a positive direct antiglobulin test in chronic lymphocytic leukemia: a beneficial effect of the combination of fludarabine and cyclophosphamide on the incidence of hemolytic anemia. Blood. 2008; 111(4): 1820–1826.
  37. Aapro MS, Bohlius J, Cameron DA, et al. European Organisation for Research and Treatment of Cancer. 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(1): 8–32.
  38. Lukenbill J, Kalaycio M. Fludarabine: a review of the clear benefits and potential harms. Leuk Res. 2013; 37(9): 986–994.
  39. Robak T, Błoński J, Skotnicki AB, et al. Rituximab, cladribine, and cyclophosphamide (RCC) induction with rituximab maintenance in chronic lymphocytic leukemia: PALG-CLL4 (ML21283) trial. Eur J Haematol. 2018; 100(5): 465–474.
  40. Robak T, Jamroziak K, Gora-Tybor J, et al. Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study). J Clin Oncol. 2010; 28(11): 1863–1869.
  41. Robak T, Dmoszynska A, Solal-Céligny 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(10): 1756–1765.
  42. Robak T, Smolewski P, Cebula B, et al. Rituximab combined with cladribine or with cladribine and cyclophosphamide in heavily pretreated patients with indolent lymphoproliferative disorders and mantle cell lymphoma. Cancer. 2006; 107(7): 1542–1550.
  43. Fisher K, Kramer P, Busch R, et al. German CLL Study Group. 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(26): 3559–3566.
  44. Fischer K, Cramer P, Busch R, et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2012; 30(26): 3209–3216.
  45. Eichhorst B, Fink AM, Bahlo J, et al. international group of investigators, German CLL Study Group (GCLLSG). 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(7): 928–942.
  46. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014; 370(12): 1101–1110.
  47. 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(7): 1602–1604.
  48. Goede V, Fischer K, Dyer M, et al. Overall survival benefit of obinutuzumab over rituximab when combined with chlorambucil in patients with chronic lymphocytic leukemia and comorbidities: final survival analysis of the CLL11 study Study EHA Congress, 2018. Abstract S151.
  49. 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(9980): 1873–1883.
  50. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013; 369(1): 32–42.
  51. Byrd JC, Brown JR, O'Brien S, et al. RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014; 371(3): 213–223.
  52. Byrd JC, Furman RR, Coutre SE, et al. Ibrutinib treatment for first-line and relapsed/refractory chronic lymphocytic leukemia: final analysis of the pivotal phase Ib/II PCYC-1102 study. Clin Cancer Res. 2020; 26(15): 3918–3927.
  53. Munir T, Brown JR, O'Brien S, et al. Final analysis from RESONATE: up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019; 94(12): 1353–1363.
  54. Lin VS, Lew TE, Handunnetti SM, et al. BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax. Blood. 2020; 135(25): 2266–2270.
  55. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020; 34(3): 787–798.
  56. Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020; 38(25): 2849–2861.
  57. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020; 395(10232): 1278–1291.
  58. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014; 370: 997–1007.
  59. Zinzani PL, Rambaldi A, Gaidano G, et al. Infection control in patients treated for chronic lymphocytic leukemia with ibrutinib or idelalisib: recommendations from Italian society of hematology. Leuk Res. 2019; 81: 88–94.
  60. Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018; 132(23): 2446–2455.
  61. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016; 374(4): 311–322.
  62. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial. J Clin Oncol. 2018; 36(19): 1973–1980.
  63. Jones JA, Mato A, Wierda W, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018; 19(1): 65–75.
  64. Al-Sawaf O, Zhang C, Robecht S, et al. Clonal dynamics after venetoclax-obinutuzumab therapy: novel insights from the randomized, phase 3 CLL14 trial. ASH, 2020. Abstract 127.
  65. Fischer K, Al-Sawaf O, Hallek M. Preventing and monitoring for tumor lysis syndrome and other toxicities of venetoclax during treatment of chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2020; 2020(1): 357–362.
  66. Dreger P, Schetelig J, Andersen N, et al. European Research Initiative on CLL (ERIC) and the European Society for Blood and Marrow Transplantation (EBMT). Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents? Blood. 2014; 124(26): 3841–3849.
  67. Dreger P, Michallet M, Bosman P, et al. Ibrutinib for bridging to allogeneic hematopoietic cell transplantation in patients with chronic lymphocytic leukemia or mantle cell lymphoma: a study by the EBMT Chronic Malignancies and Lymphoma Working Parties. Bone Marrow Transplant. 2019; 54(1): 44–52.
  68. Dreger P, Döhner H, Ritgen M, et al. German CLL Study Group. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. 2010; 116(14): 2438–2447.
  69. Shea T, Johnson J, Westervelt P, et al. Cancer and Leukemia Group B. Reduced-intensity allogeneic transplantation provides high event-free and overall survival in patients with advanced indolent B cell malignancies: CALGB 109901. Biol Blood Marrow Transplant. 2011; 17(9): 1395–1403.
  70. van Gelder M, de Wreede LC, Bornhäuser M, et al. Long-term survival of patients with CLL after allogeneic transplantation: a report from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2017; 52(3): 372–380.
  71. Frey NV, Gill S, Hexner EO, et al. Long-term outcomes from a randomized dose optimization study of chimeric antigen receptor modified t cells in relapsed chronic lymphocytic leukemia. J Clin Oncol. 2020; 38(25): 2862–2871.
  72. Linn BS, Linn MW, Gurel L. Cumulative illness rating scale. J Am Geriatr Soc. 1968; 16(5): 622–626.
  73. 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(10): 1926–1931.
  74. Hallek M. Therapy of chronic lymphocytic leukaemia. Best Pract Res Clin Haematol. 2010; 23(1): 85–96.
  75. Wierda WG, Byrd JC, Abramson JS, et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 4.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2020; 18(2): 185–217.
  76. Cuneo A, Follows G, Rigolin GM, et al. GIMEMA, European Research Initiative on CLL (ERIC) and UK CLL forum. 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; 103(7): 1209–1217.
  77. Langerbeins P, Busch R, Anheier N, et al. Poor efficacy and tolerability of R-CHOP in relapsed/refractory chronic lymphocytic leukemia and Richter transformation. Am J Hematol. 2014; 89(12): E239–E243.
  78. Richter MN. Generalized reticular cell sarcoma of lymph nodes associated with lymphatic leukemia. Am J Pathol. 1928; 4(4): 285–292.7.
  79. Tsimberidou AM, Keating MJ. Richter syndrome: biology, incidence, and therapeutic strategies. Cancer. 2005; 103(2): 216–228.
  80. Bockorny B, Codreanu I, Dasanu CA. Hodgkin lymphoma as Richter transformation in chronic lymphocytic leukaemia: a retrospective analysis of world literature. Br J Haematol. 2012; 156(1): 50–66.
  81. Jamroziak K, Grzybowska-Izydorczyk O, Jesionek-Kupnicka D, et al. Poor prognosis of Hodgkin variant of Richter transformation in chronic lymphocytic leukemia treated with cladribine. Br J Haematol. 2012; 158(2): 286–288.
  82. Chigrinova E, Rinaldi A, Kwee I, et al. Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome. Blood. 2013; 122(15): 2673–2682.
  83. Fabbri G, Khiabanian H, Holmes AB, et al. Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome. J Exp Med. 2013; 210(11): 2273–2288.
  84. Rossi D, Spina V, Forconi F, et al. Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis. Int J Cancer. 2012; 130(12): 3006–3010.
  85. Tsimberidou AM, O'Brien S, Khouri I, et al. Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol. 2006; 24(15): 2343–2351.
  86. Papajík T, Mysliveček M, Urbanová R, et al. 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography examination in patients with chronic lymphocytic leukemia may reveal Richter transformation. Leuk Lymphoma. 2014; 55(2): 314–319.
  87. Tsimberidou AM, O'Brien SM, Cortes JE, et al. Phase II study of fludarabine, cytarabine (Ara-C), cyclophosphamide, cisplatin and GM-CSF (FACPGM) in patients with Richter's syndrome or refractory lymphoproliferative disorders. Leuk Lymphoma. 2002; 43(4): 767–772.
  88. Rogers KA, Huang Y, Ruppert AS, et al. A single-institution retrospective cohort study of first-line R-EPOCH chemoimmunotherapy for Richter syndrome demonstrating complex chronic lymphocytic leukaemia karyotype as an adverse prognostic factor. Br J Haematol. 2018; 180(2): 259–266.
  89. Jain N, Ferrajoli A, Basu S, et al. et al.. A phase II trial of nivolumab combined with ibrutinib for patients with Richter transformation [abstract]. Blood. 2018; 132(Suppl 1): 296.
  90. Younes A, Brody J, Carpio C, et al. Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study. Lancet Haematol. 2019; 6(2): e67–e78.
  91. Ding W, LaPlant BR, Call TG, et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood. 2017; 129(26): 3419–3427.
  92. Cwynarski K, van Biezen A, de Wreede L, et al. Autologous and allogeneic stem-cell transplantation for transformed chronic lymphocytic leukemia (Richter's syndrome): a retrospective analysis from the chronic lymphocytic leukemia subcommittee of the chronic leukemia working party and lymphoma working party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012; 30(18): 2211–2217.
  93. Wang Y, Tschautscher MA, Rabe KG, et al. Clinical characteristics and outcomes of Richter transformation: experience of 204 patients from a single center. Haematologica. 2020; 105(3): 765–773.
  94. Tsimberidou AM, O'Brien S, Kantarjian HM, et al. Hodgkin transformation of chronic lymphocytic leukemia: the M. D. Anderson Cancer Center experience. Cancer. 2006; 107(6): 1294–1302.
  95. Barcellini W, Capalbo S, Agostinelli RM, et al. GIMEMA Chronic Lymphocytic Leukemia Group. Relationship between autoimmune phenomena and disease stage and therapy in B-cell chronic lymphocytic leukemia. Haematologica. 2006; 91(12): 1689–1692.
  96. Zent CS, Kay N. Autoimmune complications in chronic lymphocytic leukaemia (CLL). Best Pract Res Clin Haematol. 2010; 23(1): 47–59.
  97. Dearden C, Wade R, Else M, et al. UK National Cancer Research Institute (NCRI), Haematological Oncology Clinical Studies Group, NCRI CLL Working Group. The prognostic significance of a positive direct antiglobulin test in chronic lymphocytic leukemia: a beneficial effect of the combination of fludarabine and cyclophosphamide on the incidence of hemolytic anemia. Blood. 2008; 111(4): 1820–1826.
  98. Lewis FB, Schwartz RS, Dameshek W. X-radiation and alkylating agents as possible "trigger" mechanisms in the autoimmune complications of malignant lymphophroliferative disease. Clin Exp Immunol. 1966; 1(1): 3–11.
  99. Montillo M, Tedeschi A, Leoni P. Recurrence of autoimmune thrombocytopenia after treatment with fludarabine in a patient with chronic lymphocytic leukemia. Leuk Lymphoma. 1994; 15(1–2): 187–188.
  100. Weiss RB, Freiman J, Kweder SL, et al. Hemolytic anemia after fludarabine therapy for chronic lymphocytic leukemia. J Clin Oncol. 1998; 16(5): 1885–1889.
  101. Myint H, Copplestone JA, Orchard J, et al. Fludarabine-related autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia. Br J Haematol. 1995; 91(2): 341–344.
  102. Rogers KA, Ruppert AS, Bingman A, et al. Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia. Leukemia. 2016; 30(2): 346–350.
  103. Montillo M, O'Brien S, Tedeschi A, et al. Ibrutinib in previously treated chronic lymphocytic leukemia patients with autoimmune cytopenias in the RESONATE study. Blood Cancer J. 2017; 7(2): e524.
  104. Hampel PJ, Larson MC, Kabat B, et al. Autoimmune cytopenias in patients with chronic lymphocytic leukaemia treated with ibrutinib in routine clinical practice at an academic medical centre. Br J Haematol. 2018; 183(3): 421–427.
  105. Davids MS, Hallek M, Wierda W, et al. Comprehensive safety analysis of venetoclax monotherapy for patients with relapsed/refractory chronic lymphocytic leukemia. Clin Cancer Res. 2018; 24(18): 4371–4379.
  106. Dearden C. Disease-specific complications of chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2008: 450–456.
  107. Cortes J, O'Brien S, Loscertales J, et al. Cyclosporin A for the treatment of cytopenia associated with chronic lymphocytic leukemia. Cancer. 2001; 92(8): 2016–2022, doi: 10.1002/1097-0142(20011015)92:8<2016::aid-cncr1539>3.0.co;2-e.
  108. D'Arena G, Laurenti L, Capalbo S, et al. Rituximab therapy for chronic lymphocytic leukemia-associated autoimmune hemolytic anemia. Am J Hematol. 2006; 81(8): 598–602.
  109. Bowen DA, Call TG, Shanafelt TD, et al. Treatment of autoimmune cytopenia complicating progressive chronic lymphocytic leukemia/small lymphocytic lymphoma with rituximab, cyclophosphamide, vincristine, and prednisone. Leuk Lymphoma. 2010; 51(4): 620–627.
  110. Kaufman M, Limaye SA, Driscoll N, et al. A combination of rituximab, cyclophosphamide and dexamethasone effectively treats immune cytopenias of chronic lymphocytic leukemia. Leuk Lymphoma. 2009; 50(6): 892–899.
  111. Robak T, Błasińska-Morawiec M, Krykowski E, et al. Autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia treated with 2-chlorodeoxyadenosine (cladribine). Eur J Haematol. 1997; 58(2): 109–113.
  112. Quinquenel A, Willekens C, Dupuis J, et al. Bendamustine and rituximab combination in the management of chronic lymphocytic leukemia-associated autoimmune hemolytic anemia: a multicentric retrospective study of the French CLL intergroup (GCFLLC/MW and GOELAMS). Am J Hematol. 2015; 90(3): 204–207.
  113. Quinquenel A, Godet S, Dartigeas C, et al. Ibrutinib and idelalisib in the management of CLL-associated autoimmune cytopenias: a study from the FILO group. Am J Hematol. 2019; 94(7): E183–E185.
  114. Lacerda MP, Guedes NR, Yamakawa PE, et al. Treatment of refractory autoimmune hemolytic anemia with venetoclax in relapsed chronic lymphocytic leukemia with del(17p). Ann Hematol. 2017; 96(9): 1577–1578.
  115. Zent CS, Ding W, Schwager SM, et al. The prognostic significance of cytopenia in chronic lymphocytic leukaemia/small lymphocytic lymphoma. Br J Haematol. 2008; 141(5): 615–621.
  116. Visco C, Ruggeri M, Laura Evangelista M, et al. Impact of immune thrombocytopenia on the clinical course of chronic lymphocytic leukemia. Blood. 2008; 111(3): 1110–1116.
  117. Kyasa MJ, Parrish RS, Schichman SA, et al. Autoimmune cytopenia does not predict poor prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma. Am J Hematol. 2003; 74(1): 1–8.
  118. Hamblin TJ, Oscier DG, Young BJ. Autoimmunity in chronic lymphocytic leukaemia. J Clin Pathol. 1986; 39(7): 713–716.
  119. D'Arena G, Capalbo S, Laurenti L, et al. Chronic lymphocytic leukemia-associated immune thrombocytopenia treated with rituximab: a retrospective study of 21 patients. Eur J Haematol. 2010; 85(6): 502–507.
  120. Rossignol J, Michallet AS, Oberic L, et al. Rituximab–cyclophosphamide–dexamethasone combination in the management of autoimmune cytopenias associated with chronic lymphocytic leukemia. Leukemia. 2011; 25(3): 473–478.
  121. Cesana C, Carlo-Stella C, Mangoni L, et al. Response to cyclosporin A and recombinant human erythropoietin in a case of B cell chronic lymphocytic leukemia and pure red cell aplasia. Leukemia. 1996; 10(8): 1400–1401.
  122. Koehrer S, Keating MJ, Wierda WG. Eltrombopag, a second-generation thrombopoietin receptor agonist, for chronic lymphocytic leukemia-associated ITP. Leukemia. 2010; 24(5): 1096–1098.
  123. Visco C, Rodeghiero F, Romano A, et al. Eltrombopag for immune thrombocytopenia secondary to chronic lymphoproliferative disorders: a phase 2 multicenter study. Blood. 2019; 134(20): 1708–1711.
  124. Paul S, Jain N, Ferrajoli A, et al. A phase II trial of eltrombopag for patients with chronic lymphocytic leukaemia (CLL) and thrombocytopenia. Br J Haematol. 2019; 185(3): 606–608.
  125. Chikkappa G, Pasquale D, Zarrabi MH, et al. Cyclosporine and prednisone therapy for pure red cell aplasia in patients with chronic lymphocytic leukemia. Am J Hematol. 1992; 41(1): 5–12.
  126. Ghazal H. Successful treatment of pure red cell aplasia with rituximab in patients with chronic lymphocytic leukemia. Blood. 2002; 99(3): 1092–1094.
  127. Abbott BL. Chronic lymphocytic leukemia: recent advances in diagnosis and treatment. Oncologist. 2006; 11(1): 21–30.
  128. Oscier D, Dearden C, Eren E, et al. British Committee for Standards in Haematology. Guidelines on the diagnosis, investigation and management of chronic lymphocytic leukaemia. Br J Haematol. 2012; 159(5): 541–564.
  129. Molica S. Infections in chronic lymphocytic leukemia: risk factors, and impact on survival, and treatment. Leuk Lymphoma. 1994; 13(3-4): 203–214.
  130. Quinquenel A, Aurran-Schleinitz T, Clavert A, et al. Diagnosis and Treatment of Chronic Lymphocytic Leukemia: Recommendations of the French CLL Study Group (FILO). Hemasphere. 2020; 4(5): e473.
  131. Molteni A, Nosari A, Montillo M, et al. Multiple lines of chemotherapy are the main risk factor for severe infections in patients with chronic lymphocytic leukemia with febrile episodes. Haematologica. 2005; 90(8): 1145–1147.
  132. Morrison VA. Management of infectious complications in patients with chronic lymphocytic leukemia. Hematology. 2007; 2007(1): 332–338.
  133. Rai KR, Keating MJ. Overview of the complications of chronic lymphocytic leukemia. https://www.uptodate.com/contents/overview-of-the-complications-of-chronic-lymphocytic-leukemia (March 30, 2021).
  134. Ye X, Xiao X, Li B, et al. Low humoral immune response and ineffective clearance of SARS-CoV-2 in a COVID-19 patient with CLL during a 69-day follow-up. Front Oncol. 2020; 10: 1272.
  135. Kos I, Balensiefer B, Roth S, et al. Prolonged course of COVID-19-associated pneumonia in a B-cell depleted patient after rituximab. Front Oncol. 2020; 10: 1578.
  136. Hammond SP, Chen K, Pandit A, et al. Risk of hepatitis B virus reactivation in patients treated with ibrutinib. Blood. 2018; 131(17): 1987–1989.
  137. Pawłowska M, Flisiak R, Gil L, et al. Prophylaxis of hepatitis B virus (HBV) infection reactivation - recommendations of the Working Group for prevention of HBV reactivation. Clin Exp Hepatol. 2019; 5(3): 195–202.
  138. Ryan CE, Cheng MP, Issa NC, et al. Pneumocystis jirovecii pneumonia and institutional prophylaxis practices in CLL patients treated with BTK inhibitors. Blood Adv. 2020; 4(7): 1458–1463.
  139. Ghez D, Calleja A, Protin C, et al. Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib. Blood. 2018; 131(17): 1955–1959.
  140. Besa EC. Use of intravenous immunoglobulin in chronic lymphocytic leukemia. Am J Med. 1984; 76(3A): 209–218.
  141. Griffiths H, Brennan V, Lea J, et al. Crossover study of immunoglobulin replacement therapy in patients with low-grade B-cell tumors. Blood. 1989; 73(2): 366–368.
  142. Wasserman RL, Church JA, Peter HH, et al. IgPro10 in PID Study group. Pharmacokinetics of a new 10% intravenous immunoglobulin in patients receiving replacement therapy for primary immunodeficiency. Eur J Pharm Sci. 2009; 37(3–4): 272–278.
  143. Lucas M, Hugh-Jones K, Welby A, et al. Immunomodulatory therapy to achieve maximum efficacy: doses, monitoring, compliance, and self-infusion at home. J Clin Immunol. 2010; 30(Suppl 1): S84–S89.
  144. Maarschalk-Ellerbroek LJ, Hoepelman IM, Ellerbroek PM. Immunoglobulin treatment in primary antibody deficiency. Int J Antimicrob Agents. 2011; 37(5): 396–404.
  145. Provan D, Chapel HM, Sewell WA, et al. UK Immunoglobulin Expert Working Group. Prescribing intravenous immunoglobulin: summary of Department of Health guidelines. BMJ. 2008; 337: a1831.
  146. Scarfò L, Chatzikonstantinou T, Rigolin GM, et al. COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus. Leukemia. 2020; 34(9): 2354–2363.
  147. Hosoda T, Harada S, Okamoto K, et al. COVID-19 and fatal sepsis caused by hypervirulent klebsiella pneumoniae, Japan, 2020. Emerg Infect Dis. 2021; 27(2): 556–559.
  148. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020; 395(10229): 1054–1062.
  149. Griffiths H, Lea J, Bunch C, et al. Predictors of infection in chronic lymphocytic leukaemia (CLL). Clin Exp Immunol. 1992; 89(3): 374–377.
  150. Sinisalo M, Aittoniemi J, Käyhty H, et al. Vaccination against infections in chronic lymphocytic leukemia. Leuk Lymphoma. 2003; 44(4): 649–652.
  151. Sinisalo M, Vilpo J, Itälä M, et al. Antibody response to 7-valent conjugated pneumococcal vaccine in patients with chronic lymphocytic leukaemia. Vaccine. 2007; 26(1): 82–87.
  152. Pollyea DA, Brown JMY, Horning SJ. Utility of influenza vaccination for oncology patients. J Clin Oncol. 2010; 28(14): 2481–2490.
  153. Hartkamp A, Mulder AH, Rijkers GT, et al. Antibody responses to pneumococcal and haemophilus vaccinations in patients with B-cell chronic lymphocytic leukaemia. Vaccine. 2001; 19(13–14): 1671–1677.
  154. de Lavallade H, Garland P, Sekine T, et al. Repeated vaccination is required to optimize seroprotection against H1N1 in the immunocompromised host. Haematologica. 2011; 96(2): 307–314.
  155. Yri OE, Torfoss D, Hungnes O, et al. Rituximab blocks protective serologic response to influenza A (H1N1) 2009 vaccination in lymphoma patients during or within 6 months after treatment. Blood. 2011; 118(26): 6769–6771.
  156. Garassino MC, Vyas M, de Vries EGE, et al. European Society for Medical Oncology. The ESMO call to action on COVID-19 vaccinations and patients with cancer: Vaccinate. Monitor. Educate. Ann Oncol. 2021; 32(5): 579–581.



Hematology in Clinical Practice