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Initial Therapy of Chronic Lymphocytic Leukemia

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Chronic Lymphocytic Leukemia

Part of the book series: Hematologic Malignancies ((HEMATOLOGIC))

Abstract

For treatment decisions in CLL consideration should be given to the clinical stage, the patient’s prognostic profile as well as comorbidities. For patients without very high-risk genomic alterations first-line treatment with chemoimmunotherapy is a well-examined and established standard of care. FCR is the preferred treatment in physically fit patients with mild or no comorbidities. Depending on the burden of comorbidities, less intense chemoimmunotherapy regimens based on bendamustine or chlorambucil in combination with CD20 antibodies should be used upfront in patients with relevant concomitant diseases. Patients with high-risk genomic alterations, such as TP53 mutation/deletion, should be treated with the new targeted drugs. The BTK-inhibitor ibrutinib is approved not only for frontline therapy of high-risk CLL but also for CLL with all other genetic findings. In patients with unmutated IGHV status the disadvantages of chemoimmunotherapy, such as secondary malignancies or the development of chemo-resistant clones, have to be weighed against its possible benefits, such as the short period of treatment with chemoimmunotherapy compared with the continuous therapy required with novel drugs. The fact that several novel agents are available in relapsed CLL after kinase inhibitor frontline therapy, without evidence of cross resistance between classes of agents, supports the use of novel therapeutics in frontline of CLL with unfavorable genetic results.

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References

  1. Altman SJ, Haut A, Cartwright GE, Wintrobe MM. Early experience with p-(N, N-di-2-chloroethyl)-aminophenylbutyric acid (CB 1348), a new chemotherapeutic agent effective in the treatment of chronic lymphocytic leukemia. Cancer. 1956;9(3):512–7.

    Article  CAS  PubMed  Google Scholar 

  2. Hansen MM, Andersen E, Christensen BE, Christiansen I, Geisler C, Kristensen D, et al. CHOP versus prednisolone + chlorambucil in chronic lymphocytic leukemia (CLL): preliminary results of a randomized multicenter study. Nouv Rev Fr Hematol. 1988;30(5–6):433–6.

    CAS  PubMed  Google Scholar 

  3. Montserrat E, Alcala A, Parody R, Domingo A, Garcia-Conde J, Bueno J, et al. Treatment of chronic lymphocytic leukemia in advanced stages. A randomized trial comparing chlorambucil plus prednisone versus cyclophosphamide, vincristine, and prednisone. Cancer. 1985;56(10):2369–75.

    Article  CAS  PubMed  Google Scholar 

  4. Raphael B, Andersen JW, Silber R, Oken M, Moore D, Bennett J, et al. Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial treatment for chronic lymphocytic leukemia: long-term follow-up of an Eastern Cooperative Oncology Group randomized clinical trial. J Clin Oncol. 1991;9(5):770–6.

    Article  CAS  PubMed  Google Scholar 

  5. Keating MJ, Kantarjian H, O’Brien S, Koller C, Talpaz M, Schachner J, et al. Fludarabine: a new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia. J Clin Oncol. 1991;9(1):44–9.

    Article  CAS  PubMed  Google Scholar 

  6. Keating MJ, O’Brien S, Kantarjian H, Plunkett W, Estey E, Koller C, et al. Long-term follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as a single agent. Blood. 1993;81(11):2878–84.

    CAS  PubMed  Google Scholar 

  7. Robak T, Blonski JZ, Kasznicki M, Blasinska-Morawiec M, Krykowski E, Dmoszynska A, et al. Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial. Blood. 2000;96(8):2723–9.

    CAS  PubMed  Google Scholar 

  8. Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000;343(24):1750–7.

    Article  CAS  PubMed  Google Scholar 

  9. Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood. 2006;107(3):885–91.

    Article  CAS  PubMed  Google Scholar 

  10. Flinn IW, Neuberg DS, Grever MR, Dewald GW, Bennett JM, Paietta EM, et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol. 2007;25(7):793–8.

    Article  CAS  PubMed  Google Scholar 

  11. Catovsky D, Richards S, Matutes E, Oscier D, Dyer MJ, Bezares RF, 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.

    Article  CAS  PubMed  Google Scholar 

  12. Robak T, Blonski JZ, Gora-Tybor J, Jamroziak K, Dwilewicz-Trojaczek J, Tomaszewska A, et al. Cladribine alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone in the treatment of progressive chronic lymphocytic leukemia: report of a prospective, multicenter, randomized trial of the Polish Adult Leukemia Group (PALG CLL2). Blood. 2006;108(2):473–9.

    Article  CAS  PubMed  Google Scholar 

  13. Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R, et al. Chlorambucil in indolent chronic lymphocytic leukemia. French Cooperative Group on Chronic Lymphocytic Leukemia. N Engl J Med. 1998;338(21):1506–14.

    Article  CAS  PubMed  Google Scholar 

  14. Montserrat E, Villamor N, Urbano-Ispizua A, Ribera JM, Lozano M, Vives-Corrons JL, et al. Treatment of early stage-B chronic lymphocytic leukemia with alpha-2b interferon after chlorambucil reduction of the tumoral mass. Ann Hematol. 1991;63(1):15–9.

    Article  CAS  PubMed  Google Scholar 

  15. Schweighofer C, Levy V, MĂ¼ller C, Busch R, Porcher R, Ibach S, et al. Early versus deferred treatment with combined fludarabine, cyclophosphamide and rituximab (FCR) improves event-free survival in patients with high-risk Binet stage a chronic lymphocytic leukemia – first results of a randomized German-French cooperative phase III trial. Blood. 2013;122:524.

    Google Scholar 

  16. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. Guidelines for diagnosis, indications for treatment, response assessment and supportive management of chronic lymphocytic leukemia. Blood. 2018;131(25):2745–60.

    Article  CAS  PubMed  Google Scholar 

  17. Howlader N. Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA, editors. SEER cancer statistics review, 1975–2011. Bethesda: National Cancer Institute. http://seercancergov/csr/1975_2011/, based on November 2013 SEER data submission, posted to the SEER web site, April 2014. 2014.

    Google Scholar 

  18. Linn BS, Linn MW, Gurel L. Cumulative illness rating scale. J Am Geriatr Soc. 1968;16(5):622–6.

    Article  CAS  PubMed  Google Scholar 

  19. Miller MD, Paradis CF, Houck PR, Mazumdar S, Stack JA, Rifai AH, et al. Rating chronic medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating Scale. Psychiatry Res. 1992;41(3):237–48.

    Article  CAS  PubMed  Google Scholar 

  20. Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994;47(11):1245–51.

    Article  CAS  PubMed  Google Scholar 

  21. Yancik R, Wesley MN, Ries LA, Havlik RJ, Long S, Edwards BK, et al. Comorbidity and age as predictors of risk for early mortality of male and female colon carcinoma patients: a population-based study. Cancer. 1998;82(11):2123–34.

    Article  CAS  PubMed  Google Scholar 

  22. Hamaker ME, Jonker JM, de Rooij SE, Vos AG, Smorenburg CH, van Munster BC. Frailty screening methods for predicting outcome of a comprehensive geriatric assessment in elderly patients with cancer: a systematic review. Lancet Oncol. 2012;13(10):e437–44.

    Article  PubMed  Google Scholar 

  23. Hamaker ME, Prins MC, Stauder R. The relevance of a geriatric assessment for elderly patients with a haematological malignancy--a systematic review. Leuk Res. 2014;38(3):275–83.

    Article  CAS  PubMed  Google Scholar 

  24. 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(4):1582–7.

    Article  CAS  PubMed  Google Scholar 

  25. Extermann M. Measurement and impact of comorbidity in older cancer patients. Crit Rev Oncol Hematol. 2000;35(3):181–200.

    Article  CAS  PubMed  Google Scholar 

  26. Balducci L, Extermann M. Management of cancer in the older person: a practical approach. Oncologist. 2000;5(3):224–37.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  28. Rossi D, Cerri M, Deambrogi C, Sozzi E, Cresta S, Rasi S, et al. The prognostic value of TP53 mutations in chronic lymphocytic leukemia is independent of Del17p13: implications for overall survival and chemorefractoriness. Clin Cancer Res. 2009;15(3):995–1004.

    Article  CAS  PubMed  Google Scholar 

  29. Zenz T, Eichhorst B, Busch R, Denzel T, Habe S, Winkler D, et al. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010;28(29):4473–9.

    Article  PubMed  Google Scholar 

  30. Pospisilova S, Gonzalez D, Malcikova J, Trbusek M, Rossi D, Kater AP, et al. ERIC recommendations on TP53 mutation analysis in Chronic Lymphocytic Leukemia. Leukemia. 2012;26(7):1458–61.

    Article  CAS  PubMed  Google Scholar 

  31. Stilgenbauer S, Schnaiter A, Paschka P, Zenz T, Rossi M, Dohner K, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014;123(21):3247–54.

    Article  CAS  PubMed  Google Scholar 

  32. Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K, et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med. 2011;365(26):2497–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS, et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell. 2013;152(4):714–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Baliakas P, Hadzidimitriou A, Sutton LA, Rossi D, Minga E, Villamor N, et al. Recurrent mutations refine prognosis in chronic lymphocytic leukemia. Leukemia. 2014;29:329–36.

    Article  CAS  PubMed  Google Scholar 

  35. Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood. 2003;101(1):6–14.

    Article  CAS  PubMed  Google Scholar 

  36. Woyach JA, Ruppert AS, Heerema NA, Peterson BL, Gribben JG, Morrison VA, et al. Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. J Clin Oncol. 2011;29(10):1349–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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;23:4079–88.

    Article  CAS  PubMed  Google Scholar 

  38. Thompson PA, Tam CS, O’Brien SM, Wierda WG, Stingo F, Plunkett W, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127(3):303–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hallek M, Fischer K, Fingerle-Rowson G, Fink A, Busch R, Mayer J, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia: a randomised, open-label, phase III trial. Lancet. 2010;376:1164–74.

    Article  CAS  PubMed  Google Scholar 

  40. Bottcher S, Ritgen M, Fischer K, Stilgenbauer S, Busch RM, Fingerle-Rowson G, 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):980–8.

    Article  PubMed  Google Scholar 

  41. Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127(2):208–15.

    Article  CAS  PubMed  Google Scholar 

  42. Kay NE, Geyer SM, Call TG, Shanafelt TD, Zent CS, Jelinek DF, et al. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood. 2007;109(2):405–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Reynolds C, Di Bella N, Lyons RM, Hyman W, Richards DA, Robbins GJ, et al. A phase III trial of fludarabine, cyclophosphamide, and rituximab vs. pentostatin, cyclophosphamide, and rituximab in B-cell chronic lymphocytic leukemia. Investig New Drugs. 2012;30(3):1232–40.

    Article  CAS  Google Scholar 

  44. Wierda WG, Kipps TJ, Durig J, Griskevicius L, Stilgenbauer S, Mayer J, et al. Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood. 2011;117(24):6450–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shanafelt T, Lanasa MC, Call TG, Beaven AW, Leis JF, LaPlant B, et al. Ofatumumab-based chemoimmunotherapy is effective and well tolerated in patients with previously untreated chronic lymphocytic leukemia (CLL). Cancer. 2013;119(21):3788–96.

    Article  CAS  PubMed  Google Scholar 

  46. Fischer K, Cramer P, Busch R, Bottcher S, Bahlo J, Schubert J, 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):3209–16.

    Article  CAS  PubMed  Google Scholar 

  47. Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, 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(7):928–42.

    Article  CAS  PubMed  Google Scholar 

  48. Flinn IW, Panayiotidis P, Afanasyev B, Janssens A, Grosicki S, Homenda W, et al. A phase 2, multicenter study investigating ofatumumab and bendamustine combination in patients with untreated or relapsed CLL. Am J Hematol. 2016;91(9):900–6.

    Article  CAS  PubMed  Google Scholar 

  49. Di Gaetano N, Xiao Y, Erba E, Bassan R, Rambaldi A, Golay J, et al. Synergism between fludarabine and rituximab revealed in a follicular lymphoma cell line resistant to the cytotoxic activity of either drug alone. Br J Haematol. 2001;114(4):800–9.

    Article  PubMed  Google Scholar 

  50. Schulz H, Klein SK, Rehwald U, Reiser M, Hinke A, Knauf WU, et al. Phase 2 study of a combined immunochemotherapy using rituximab and fludarabine in patients with chronic lymphocytic leukemia. Blood. 2002;100(9):3115–20.

    Article  CAS  PubMed  Google Scholar 

  51. Bosch F, Ferrer A, Villamor N, Gonzalez M, Briones J, Gonzalez-Barca E, et al. Fludarabine, cyclophosphamide, and mitoxantrone as initial therapy of chronic lymphocytic leukemia: high response rate and disease eradication. Clin Cancer Res. 2008;14(1):155–61.

    Article  CAS  PubMed  Google Scholar 

  52. Munir T, Howard DR, McParland L, Pocock C, Rawstron AC, Hockaday A, et al. Results of the randomized phase IIB ADMIRE trial of FCR with or without mitoxantrone in previously untreated CLL. Leukemia. 2017;31(10):2085–93.

    Article  CAS  PubMed  Google Scholar 

  53. Brown JR, Abramson J, Hochberg E, Mikler E, Dalton V, Werner L, et al. A phase I study of lenalidomide in combination with fludarabine and rituximab in previously untreated CLL/SLL. Leukemia. 2010;24(11):1972–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Egle A, Steurer M, Gassner F, Geisberger R, Melchardt T, Pleyer L, Weiss L, Fridrik M, Thaler J, Lang A, Greil R. Lenalidomide/rituximab maintenance after induction with fludarabine/rituximab in combination with escalating doses of Lenalidomide in previously untreated chronic lymphocytic leukemia (CLL): the revlirit CLL5 AGMT phase I/II study, final results. Blood. 2013;122(21):4164.

    Google Scholar 

  55. Mato AR, Foon KA, Feldman T, Schuster SJ, Svoboda J, Chow KF, et al. Reduced-dose fludarabine, cyclophosphamide and rituximab (FCR-lite) plus lenalidomide, followed by lenalidomide consolidation/maintenance, in previously untreated chronic lymphocytic leukemia. Am J Hematol. 2015;90:487–92.

    Article  CAS  PubMed  Google Scholar 

  56. Robak T, Blonski J, Skotnicki AB, Piotrowska M, Wrobel T, Rybka J, 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):465–74.

    Article  CAS  PubMed  Google Scholar 

  57. Kay NE, Wu W, Kabat B, LaPlant B, Lin TS, Byrd JC, et al. Pentostatin and rituximab therapy for previously untreated patients with B-cell chronic lymphocytic leukemia. Cancer. 2010;116(9):2180–7.

    CAS  PubMed  Google Scholar 

  58. Zhou Y, Tang G, Medeiros LJ, McDonnell TJ, Keating MJ, Wierda WG, et al. Therapy-related myeloid neoplasms following fludarabine, cyclophosphamide, and rituximab (FCR) treatment in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Mod Pathol. 2012;25(2):237–45.

    Article  CAS  PubMed  Google Scholar 

  59. Gerrie AS, Toze CL, Ramadan KM, Li CH, Sutherland J, Yee A, et al. Oral fludarabine and rituximab as initial therapy for chronic lymphocytic leukemia or small lymphocytic lymphoma: population-based experience matches clinical trials. Leuk Lymphoma. 2012;53(1):77–82.

    Article  CAS  PubMed  Google Scholar 

  60. Elter T, Gercheva-Kyuchukova L, Pylylpenko H, Robak T, Jaksic B, Rekhtman G, et al. Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. Lancet Oncol. 2011;12(13):1204–13.

    Article  CAS  PubMed  Google Scholar 

  61. Elter T, James R, Busch R, Winkler D, Ritgen M, Bottcher S, et al. Fludarabine and cyclophosphamide in combination with alemtuzumab in patients with primary high-risk, relapsed or refractory chronic lymphocytic leukemia. Leukemia. 2012;26(12):2549–52.

    Article  CAS  PubMed  Google Scholar 

  62. Lepretre S, Aurran T, Mahe B, Cazin B, Tournilhac O, Maisonneuve H, et al. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood. 2012;119(22):5104–10.

    Article  CAS  PubMed  Google Scholar 

  63. Geisler CH, van T’ Veer MB, Jurlander J, Walewski J, Tjonnfjord G, Itala Remes M, et al. Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL. Blood. 2014;123(21):3255–62.

    Article  CAS  PubMed  Google Scholar 

  64. Parikh SA, Keating MJ, O’Brien S, Wang X, Ferrajoli A, Faderl S, et al. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia. Blood. 2011;118(8):2062–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood. 2009;114(16):3382–91.

    Article  CAS  PubMed  Google Scholar 

  66. Catovsky D, Else M, Richards S. Chlorambucil--still not bad: a reappraisal. Clin Lymphoma Myeloma Leuk. 2011;11(Suppl 1):S2–6.

    Article  PubMed  Google Scholar 

  67. Woyach JA, Ruppert AS, Rai K, Lin TS, Geyer S, Kolitz J, et al. Impact of age on outcomes after initial therapy with chemotherapy and different chemoimmunotherapy regimens in patients with chronic lymphocytic leukemia: results of sequential cancer and leukemia group B studies. J Clin Oncol. 2013;31(4):440–7.

    Article  CAS  PubMed  Google Scholar 

  68. Hillmen P, Gribben JG, Follows GA, Milligan D, Sayala HA, Moreton P, 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;32:1236–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Foa R, Del Giudice I, Cuneo A, Del Poeta G, Ciolli S, Di Raimondo F, et al. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014;89(5):480–6.

    Article  CAS  PubMed  Google Scholar 

  70. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101–10.

    Article  CAS  PubMed  Google Scholar 

  71. Hillmen P, Robak T, Janssens A, Babu KG, Kloczko J, Grosicki S, 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):1873–83.

    Article  CAS  PubMed  Google Scholar 

  72. Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, et al. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27(4):498–503.

    Article  CAS  PubMed  Google Scholar 

  73. Foon KA, Mehta D, Lentzsch S, Kropf P, Marks S, Lenzner D, et al. Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia. Blood. 2012;119(13):3184–5.

    Article  CAS  PubMed  Google Scholar 

  74. Mulligan SG, Gill DS, Turner P, Renwick WEP, Latimer M, Mackinlay N, Berkahn L, Simpson D, Campbell P, Forsyth C, Cull G, Harrup R, Sulda M, Best G, Bressel M, Di Iulio J, Kuss B. A randomised dose de-escalation study of oral fludarabine, ±oral cyclophosphamide and intravenous rituximab as first-line therapy of fit patients with chronic lymphocytic leukaemia (CLL) aged ≥65 years: final analysis of response and toxicity. Blood. 2014;124:3325.

    Google Scholar 

  75. Dartigeas C, Van Den Neste E, Berthou C, Maisonneuve H, Lepretre S, Dilhuydy MS, et al. Evaluating abbreviated induction with fludarabine, cyclophosphamide, and dose-dense rituximab in elderly patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2015;28:1–7.

    Google Scholar 

  76. Michallet AS, Aktan M, Hiddemann W, Ilhan O, Johansson P, Laribi K, et al. Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. Haematologica. 2018;103(4):698–706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Mossner E, Brunker P, Moser S, Puntener U, Schmidt C, Herter S, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010;115(22):4393–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Patz M, Isaeva P, Forcob N, Muller B, Frenzel LP, Wendtner CM, et al. Comparison of the in vitro effects of the anti-CD20 antibodies rituximab and GA101 on chronic lymphocytic leukaemia cells. Br J Haematol. 2011;152(3):295–306.

    Article  CAS  PubMed  Google Scholar 

  79. Dalle S, Reslan L, Besseyre de Horts T, Herveau S, Herting F, Plesa A, et al. Preclinical studies on the mechanism of action and the anti-lymphoma activity of the novel anti-CD20 antibody GA101. Mol Cancer Ther. 2011;10(1):178–85.

    Article  CAS  PubMed  Google Scholar 

  80. Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Montero LF, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015;29:1602–4.

    Article  CAS  PubMed  Google Scholar 

  81. Smolej L, Brychtova Y, Doubek M, Cmunt E, Spacek M, Belada D, Motyckova M, Zygulova I, Adamova D, Prochazka V, Simkovic M, Klaskova K, Kozak T. Low-dose FCR is a safe and 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(21):4670.

    Google Scholar 

  82. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. O’Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48–58.

    Article  CAS  PubMed  Google Scholar 

  84. Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M, et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125:2497–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. O’Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, et al. Single-agent ibrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018;131(17):1910–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Leong DP, Caron F, Hillis C, Duan A, Healey JS, Fraser G, et al. The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis. Blood. 2016;128(1):138–40.

    Article  CAS  PubMed  Google Scholar 

  87. Byrd JC, Harrington B, O’Brien S, Jones JA, Schuh A, Devereux S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323–32.

    Article  CAS  PubMed  Google Scholar 

  88. 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.

    Article  CAS  PubMed  Google Scholar 

  89. 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):2517–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Satram-Hoang S, Reyes C, Hoang KQ, Momin F, Skettino S. Treatment practice in the elderly patient with chronic lymphocytic leukemia-analysis of the combined SEER and medicare database. Ann Hematol. 2014;93(8):1335–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Castro JE, James DF, Sandoval-Sus JD, Jain S, Bole J, Rassenti L, et al. Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia. Leukemia. 2009;23(10):1779–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Badoux XC, Keating MJ, Wen S, Lee BN, Sivina M, Reuben J, et al. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood. 2011;118(13):3489–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Strati P, Keating MJ, Wierda WG, Badoux XC, Calin S, Reuben JM, et al. Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. Blood. 2013;122(5):734–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chanan-Khan A, Egyed M, Robak T, Martinelli de Oliveira FA, Echeveste MA, Dolan S, et al. Randomized phase 3 study of lenalidomide versus chlorambucil as first-line therapy for older patients with chronic lymphocytic leukemia (the ORIGIN trial). Leukemia. 2017;31(5):1240–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Stilgenbauer S, Eichhorst B, Schetelig J, Hillmen P, Seymour JF, Coutre S, 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):1973–80. https://doi.org/10.1200/JCO.2017.76.6840.

    Article  CAS  PubMed  Google Scholar 

  96. Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D’Rozario J, Assouline S, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107–20.

    Article  CAS  PubMed  Google Scholar 

  97. Fischer K, Al-Sawaf O, Fink AM, Dixon M, Bahlo J, Warburton S, et al. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood. 2017;129(19):2702–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Cramer P, von Tresckow J, Bahlo J, Robrecht S, Al-Sawaf O, Langerbeins P, et al. Bendamustine (B), followed by obinutuzumab (G, GA101) and venetoclax (A, abt-199) in patients with chronic lymphocytic leukemia (CLL): CLLl2-BAG phase-II-trial of the German CLL Study Group (GCLLSG). EHA learning center 2017. Abstract S464.

    Google Scholar 

  99. Hillmen P, Munir T, Rawstron A, Brock K, Monoz Vicente S, Yates F, et al. Initial results of ibrutinib plus venetoclax in relapsed, refractory CLL (Bloodwise TAP CLARITY study): high rates of overall response, complete remission and MRD eradication after 6 months of combination therapy. Blood. 2017;130:428.

    Google Scholar 

  100. Burger JA, Sivina M, Ferrajoli A, Jain N, Kim E, Kadia Z, et al. Randomized trial of Ibrutinib versus ibrutinib plus rituximab (Ib+R) in patients with chronic lymphocytic leukemia (CLL). Blood. 2017;130:427.

    Google Scholar 

  101. Dimier N, Delmar P, Ward C, Morariu-Zamfir R, Fingerle-Rowson G, Bahlo J, et al. A model for predicting effect of treatment on progression-free survival using MRD as a surrogate end point in CLL. Blood. 2018;131(9):955–62.

    Article  CAS  PubMed  Google Scholar 

  102. Maurer C, Langerbeins P, Bahlo J, Cramer P, Fink AM, Pflug N, et al. Effect of first-line treatment on second primary malignancies and Richter’s transformation in patients with CLL. Leukemia. 2016;30(10):2019–25.

    Article  CAS  PubMed  Google Scholar 

  103. Jones JA, Mato AR, Wierda WG, Davids MS, Choi M, Cheson BD, 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.

    Article  CAS  PubMed  Google Scholar 

  104. Coutre S, Choi M, Furman RR, Eradat H, Heffner L, Jones JA, et al. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018;131(15):1704–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Bosch F, Hallek M. Venetoclax after idelalisib: relevant progress for CLL. Blood. 2018;131(15):1632–3.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department I of Internal Medicine, Center of Integrated Oncology, University of Cologne, Cologne, Germany

    Barbara Eichhorst, Othman Al-Sawaf & Michael Hallek

  2. CECAD - Cologne Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases, Cologne, Germany

    Michael Hallek

Authors
  1. Barbara Eichhorst
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  2. Othman Al-Sawaf
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  3. Michael Hallek
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Correspondence to Barbara Eichhorst .

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Editors and Affiliations

  1. Department I of Internal Medicine, University of Cologne, Cologne, Nordrhein-Westfalen, Germany

    Michael Hallek

  2. Department I of Internal Medicine, University of Cologne, Cologne, Nordrhein-Westfalen, Germany

    Barbara Eichhorst

  3. Division of Molecular Pathology, The Institute of Cancer Research, London, UK

    Daniel Catovsky

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Eichhorst, B., Al-Sawaf, O., Hallek, M. (2019). Initial Therapy of Chronic Lymphocytic Leukemia. In: Hallek, M., Eichhorst, B., Catovsky, D. (eds) Chronic Lymphocytic Leukemia. Hematologic Malignancies. Springer, Cham. https://doi.org/10.1007/978-3-030-11392-6_6

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