Chronische lymphatische Leukämie beim alten und geriatrischen Patienten

  • Valentin Goede
  • Michael Hallek
  • Barbara Eichhorst
Chapter
Part of the Springer Reference Medizin book series (SRM)

Zusammenfassung

Betroffene mit CLL sind häufig alt. Bei Vorliegen einer Behandlungspflichtigkeit sollte im Rahmen der Therapieplanung neben der molekularen Charakterisierung der CLL (17p-Deletion und TP53-Mutation) auch die gesundheitliche Fitness des Betroffenen sorgfältig beurteilt werden. Neben einer umfassenden Anamnese und körperlichen Untersuchung sind dabei Komorbiditäts-Scores und geriatrische Assessments informativ. Therapiestandard für die unvorbehandelte CLL ohne 17p-Deletion bzw. TP53-Mutation ist bei älteren Patienten die Immunchemotherapie, wobei sich die Auswahl der Chemokomponente (Fludarabin, Bendamustin, Chlorambucil) und des Antikörpers (Rituximab, Ofatumumab, Obinutuzumab) nach der gesundheitlichen Fitness richtet. Die unvorbehandelte CLL mit 17p-Deletion oder TP53-Mutation wird bevorzugt mit dem Kinaseinhibitor Ibrutinib behandelt. Ältere Patienten mit Frührezidiv erhalten Ibrutinib, Idelalisib plus Rituximab oder Venetoclax. Spätrezidive können erneut immunchemotherapiert werden.

Literatur

  1. Abrisqueta P, Pereira A, Rozman C, Aymerich M, Gine E, Moreno C, Muntanola A, Rozman M, Villamor N, Hodgson K, Campo E, Bosch F, Montserrat E (2009) Improving survival in patients with chronic lymphocytic leukemia (1980–2008): the Hospital Clinic of Barcelona experience. Blood 114:2044–2050CrossRefPubMedGoogle Scholar
  2. Bachow SH, Lamanna N (2016) Evolving strategies for the treatment of chronic lymphocytic leukemia in the upfront setting. Curr Hematol Malig Rep 11:61–70CrossRefPubMedGoogle Scholar
  3. Baumann T, Delgado J, Santacruz R, Martinez-Trillos A, Royo C, Navarro A, Pinyol M, Rozman M, Pereira A, Villamor N, Aymerich M, Lopez C, Carrio A, Montserrat E (2014) Chronic lymphocytic leukemia in the elderly: clinico-biological features, outcomes, and proposal of a prognostic model. Haematologica 99:1599–1604CrossRefPubMedPubMedCentralGoogle Scholar
  4. Binet JL, Leporrier M, Dighiero G, Charron D, D’Athis P, Vaugier G, Beral HM, Natali JC, Raphael M, Nizet B, Follezou JY (1977) A clinical staging system for chronic lymphocytic leukemia: prognostic significance. Cancer 40:855–864CrossRefPubMedGoogle Scholar
  5. Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, O’Dwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ (2015) Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med 373:2425–2437CrossRefPubMedPubMedCentralGoogle Scholar
  6. Byrd JC, Brown JR, O’Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P (2014) Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 371:213–223CrossRefPubMedPubMedCentralGoogle Scholar
  7. Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M, Kranzhofer N, Rohrberg R, Soling U, Burkhard O, Westermann A, Goede V, Schweighofer CD, Fischer K, Fink AM, Wendtner CM, Brittinger G, Dohner H, Emmerich B, Hallek M (2009) First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 114:3382–3391CrossRefPubMedGoogle Scholar
  8. Eichhorst B, Robak T, Montserrat E, Ghia P, Hillmen P, Hallek M, Buske C (2015) Chronic lymphocytic leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 26(Suppl 5):v78–v84CrossRefPubMedGoogle Scholar
  9. Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, Lange E, Koppler H, Kiehl M, Sokler M, Schlag R, Vehling-Kaiser U, Kochling G, Ploger C, Gregor M, Plesner T, Trneny M, Fischer K, Dohner H, Kneba M, Wendtner CM, Klapper W, Kreuzer KA, Stilgenbauer S, Bottcher S, Hallek M (2016) 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 17:928–942CrossRefPubMedGoogle Scholar
  10. Ferrajoli A, O’Brien S, Wierda W, Lerner S, Faderl S, Kantarjian H, Keating MJ (2005) Treatment of patients with CLL 70 years old and older: a single center experience of 142 patients. Leuk Lymphoma 46:S87CrossRefGoogle Scholar
  11. Finnes HD, Chaffee KG, Call TG, Ding W, Bowen DA, Conte M, McCullough KB, Merten JA, Bartoo GT, Smith MD, Schwager SM, Slager SL, Kay NE, Shanafelt TD, Parikh SA (2015) The importance of pharmacovigilance during ibrutinib therapy for chronic lymphocytic leukemia (CLL) in routine clinical practice. Blood 126:717Google Scholar
  12. Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, Langerbeins P, von Tresckow J, Engelke A, Maurer C, Kovacs G, Herling M, Tausch E, Kreuzer KA, Eichhorst B, Bottcher S, Seymour JF, Ghia P, Marlton P, Kneba M, Wendtner CM, Dohner H, Stilgenbauer S, Hallek M (2016) Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood 127:208–215CrossRefPubMedGoogle Scholar
  13. Flinn IW, Panayiotidis P, Afanasyev B, Janssens A, Grosicki S, Homenda W, Smolej L, Kuliczkowski K, Doubek M, Domnikova N, West SL, Chang CN, Barker AM, Gupta IV, Wright OJ, Offner F (2016) A phase 2, multicenter study investigating ofatumumab and bendamustine combination in patients with untreated or relapsed CLL. Am J Hematol 91:900–906CrossRefPubMedGoogle Scholar
  14. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O’Brien SM (2014) Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370:997–1007CrossRefPubMedPubMedCentralGoogle Scholar
  15. Goede V, Raymonde B, Stilgenbauer S, Winter E, Fink A-M, Fischer K, Hallek M (2012) Cumulative Illness Rating Scale (CIRS) is a valuable tool to assess and weigh comorbidity in patients with chronic lymphocytic leukemia: results from the CLL8 trial of the German CLL study group. Haematologica 97:0154Google Scholar
  16. Goede V, Cramer P, Busch R, Bergmann M, Stauch M, Hopfinger G, Stilgenbauer S, Dohner H, Westermann A, Wendtner CM, Eichhorst B, Hallek M (2014a) Interactions between comorbidity and treatment of chronic lymphocytic leukemia: results of German chronic lymphocytic leukemia study group trials. Haematologica 99:1095–1100CrossRefPubMedPubMedCentralGoogle Scholar
  17. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Dohner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M (2014b) Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 370:1101–1110CrossRefPubMedGoogle Scholar
  18. Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Montero LF, Montillo M, Fegan C, Asikanius E, Humphrey K, Fingerle-Rowson G, Hallek M (2015a) Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia 29:1602–1604CrossRefPubMedGoogle Scholar
  19. Goede V, Fischer K, Bosch F, Follows G, Frederiksen H, Cuneo A, Ludwig H, Crompton N, Maurer J, Uguen M, Fingerle-Rowson G, Hallek M (2015b) Updated survival analysis from the CLL11 study: obinutuzumab versus rituximab in chemoimmunotherapy-treated patients with chronic lymphocytic leukemia. Blood 126:1733CrossRefGoogle Scholar
  20. Goede V, Bahlo J, Chataline V, Eichhorst B, Durig J, Stilgenbauer S, Kolb G, Honecker F, Wedding U, Hallek M (2016) Evaluation of geriatric assessment in patients with chronic lymphocytic leukemia: results of the CLL9 trial of the German CLL study group. Leuk Lymphoma 57:789–796CrossRefPubMedGoogle Scholar
  21. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ (2008) Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 111:5446–5456CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grunhagen U, Bergmann M, Catalano J, Zinzani PL, Caligaris-Cappio F, Seymour JF, Berrebi A, Jager U, Cazin B, Trneny M, Westermann A, Wendtner CM, Eichhorst BF, Staib P, Buhler A, Winkler D, Zenz T, Bottcher S, Ritgen M, Mendila M, Kneba M, Dohner H, Stilgenbauer S (2010) Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 376:1164–1174CrossRefPubMedGoogle Scholar
  23. Hamaker ME, Prins MC, Stauder R (2014a) The relevance of a geriatric assessment for elderly patients with a haematological malignancy – a systematic review. Leuk Res 38:275–283CrossRefPubMedGoogle Scholar
  24. Hamaker ME, Mitrovic M, Stauder R (2014b) The G8 screening tool detects relevant geriatric impairments and predicts survival in elderly patients with a haematological malignancy. Ann Hematol 93:1031–1040CrossRefPubMedGoogle Scholar
  25. Hamaker ME, Schiphorst AH, ten Bokkel HD, Schaar C, van Munster BC (2014c) The effect of a geriatric evaluation on treatment decisions for older cancer patients – a systematic review. Acta Oncol 53:289–296CrossRefPubMedGoogle Scholar
  26. Hillmen P, Robak T, Janssens A, Babu KG, Kloczko J, Grosicki S, Doubek M, Panagiotidis P, Kimby E, Schuh A, Pettitt AR, Boyd T, Montillo M, Gupta IV, Wright O, Dixon I, Carey JL, Chang CN, Lisby S, McKeown A, Offner F (2015) 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 385:1873–1883CrossRefPubMedGoogle Scholar
  27. Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (2016) SEER cancer statistics review, 1975–2013. National Cancer Institute, Bethesda. http://seer.cancer.gov/csr/1975_2013/, based on November 2015 SEER data submission, posted to the SEER web site, April 2016
  28. International CLL-IPI Working Group (2016) An international progrnostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol 17:779–790CrossRefGoogle Scholar
  29. Knauf WU, Lissichkov T, Aldaoud A, Liberati A, Loscertales J, Herbrecht R, Juliusson G, Postner G, Gercheva L, Goranov S, Becker M, Fricke HJ, Huguet F, Del Giudice I, Klein P, Tremmel L, Merkle K, Montillo M (2009) Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 27:4378–4384CrossRefPubMedGoogle Scholar
  30. Knauf W, Abenhardt W, Dorfel S, Meyer D, Grugel R, Munz M, Hartmann H, Marschner N (2015) Routine treatment of patients with chronic lymphocytic leukaemia by office-based haematologists in Germany-data from the prospective tumour registry lymphatic neoplasms. Hematol Oncol 33:15–22CrossRefPubMedGoogle Scholar
  31. Kovacs G, Bahlo J, Kluth S, Cramer P, Fink A-M, Fischer K, Gross-Ophoff-Mueller C, Langerbeins P, Maurer C, von Tresckow J, Wendtner C-M, Stilgenbauer S, Hallek M, Eichhorst B, Goede V (2015) Prognostic impact and risk factors of reducing prescribed doses of fludarabine, cyclophosphamide and rituximab (FCR) during frontline treatment of chronic lymphocytic leukemia (CLL). Blood 126:4156Google Scholar
  32. Lampson B, Matos T, Haesook K, Kassar S, Morgan E, Hirakawa M, Fein J, Fernandes S, Ritz J, Brown JR (2015) Idelalisib given front-line for the treatment of chronic lymphocytic leukemia results in frequent and severe immune-mediated toxicities. Blood 126:497Google Scholar
  33. Maddocks KJ, Ruppert AS, Lozanski G, Heerema NA, Zhao W, Abruzzo L, Lozanski A, Davis M, Gordon A, Smith LL, Mantel R, Jones JA, Flynn JM, Jaglowski SM, Andritsos LA, Awan F, Blum KA, Grever MR, Johnson AJ, Byrd JC, Woyach JA (2015) Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol 1:80–87CrossRefPubMedPubMedCentralGoogle Scholar
  34. Martell RE, Peterson BL, Cohen HJ, Petros WP, Rai KR, Morrison VA, Elias L, Shepherd L, Hines J, Larson RA, Schiffer CA, Hurwitz HI (2002) Analysis of age, estimated creatinine clearance and pretreatment hematologic parameters as predictors of fludarabine toxicity in patients treated for chronic lymphocytic leukemia: a CALGB (9011) coordinated intergroup study. Cancer Chemother Pharmacol 50:37–45CrossRefPubMedGoogle Scholar
  35. Michallet AS, Aktan M, Schuh A, Widenius T, Johansson P, Raposo J, Meddeb B, Moreno C, Hiddemann W, Bernhardt A, Kellershohn K, Messeri D, Osborne S, Leblond V (2015) Rituximab in combination with bendamustine or chlorambucil for the treatment of chronic lymphocytic leukaemia: primary results from the randomised phase IIIb MABLE study. Leuk Lymphoma 56S:88Google Scholar
  36. Mulligan SP, Gill D, Turner P, Renwick WEP, Latimer M, Mackinlay N, Berkahn L, Simpson D, Campbell P, Forsyth CJ, Cull G, Harrup R, Sulda M, Best G, Bressel M, Di Iulio J, Kuss BJ (2014) 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 124:3325Google Scholar
  37. Nikitin E, Kisilichina D, Zakharov O, Lugovskaya S, Varlamova E, Obukhova T, Biderman B, Kaplanskaya I, Naumova E, Pochtar M, Sudarikov A, Domracheva E, Ivanova V, Kovaleva L, Ptushkin V (2013) Randomised comparison of FCR-lite and CLR (chlorambucil plus rituximab) regimens in elderly patients with chronic lymphocytic leukemia. Haematologica 98:1147CrossRefGoogle Scholar
  38. O’Brien SM, Lamanna N, Kipps TJ, Flinn I, Zelenetz AD, Burger JA, Keating M, Mitra S, Holes L, Yu AS, Johnson DM, Miller LL, Kim Y, Dansey RD, Dubowy RL, Coutre SE (2015) A phase 2 study of idelalisib plus rituximab in treatment-naive older patients with chronic lymphocytic leukemia. Blood 126:2686–2694CrossRefPubMedPubMedCentralGoogle Scholar
  39. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS (1975) Clinical staging of chronic lymphocytic leukemia. Blood 46:219–234PubMedGoogle Scholar
  40. Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF (2016) Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 374:311–322CrossRefPubMedGoogle Scholar
  41. Schiphorst AH, Ten Bokkel HD, Breumelhof R, Burgmans JP, Pronk A, Hamaker ME (2016) Geriatric consultation can aid in complex treatment decisions for elderly cancer patients. Eur J Cancer Care (Engl) 25:365–370CrossRefGoogle Scholar
  42. Shanafelt TD, Rabe KG, Kay NE, Zent CS, Jelinek DF, Reinalda MS, Schwager SM, Bowen DA, Slager SL, Hanson CA, Call TG (2010) Age at diagnosis and the utility of prognostic testing in patients with chronic lymphocytic leukemia. Cancer 116:4777–4787CrossRefPubMedPubMedCentralGoogle Scholar
  43. Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, Puvvada SD, Wendtner CM, Roberts AW, Jurczak W, Mulligan SP, Bottcher S, Mobasher M, Zhu M, Desai M, Chyla B, Verdugo M, Enschede SH, Cerri E, Humerickhouse R, Gordon G, Hallek M, Wierda WG (2016) Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol 17:768–778CrossRefPubMedGoogle Scholar
  44. Thurmes P, Call T, Slager S, Zent C, Jenkins G, Schwager S, Bowen D, Kay N, Shanafelt T (2008) Comorbid conditions and survival in unselected, newly diagnosed patients with chronic lymphocytic leukemia. Leuk Lymphoma 49:49–56CrossRefPubMedGoogle Scholar
  45. Truger MS, Jeromin S, Weissmann S, Dicker F, Kern W, Schnittger S, Haferlach T, Haferlach C (2015) Accumulation of adverse prognostic markers worsens prognosis in chronic lymphocytic leukaemia. Br J Haematol 168:153–156CrossRefPubMedGoogle Scholar
  46. Zent CS, Burack WR (2014) Mutations in chronic lymphocytic leukemia and how they affect therapy choice: focus on NOTCH1, SF3B1, and TP53. Hematology Am Soc Hematol Educ Program 2014:119–124PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Deutschland, ein Teil von Springer Nature 2018

Authors and Affiliations

  • Valentin Goede
    • 1
  • Michael Hallek
    • 2
  • Barbara Eichhorst
    • 2
  1. 1.Klinik I für Innere MedizinUniklinik Köln und Sektion für Onkologische Geriatrie, Klinik für Geriatrie, St. Marien-HospitalKölnDeutschland
  2. 2.Klinik I für Innere MedizinUniklinik KölnKölnDeutschland

Section editors and affiliations

  • Ulrich Wedding
    • 1
  1. 1.Abteilung für PalliativmedizinUniversitätsklinikum Jena, Klinik für Innere Medizin IIJenaDeutschland

Personalised recommendations