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Aktuelle Therapiestrategien zur chronischen lymphatischen Leukämie

Current treatment strategies for chronic lymphocytic leukemia

  • Leitthema
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Der Onkologe Aims and scope

Zusammenfassung

Durch die Erforschung der Signalwege von B‑Lymphozyten und die Identifizierung von beteiligten Kinasen konnten viele neue, zielgerichtete Therapien entwickelt werden. Am weitesten und besten erforscht sind die Kinaseinhibitoren Ibrutinib und Idelalisib sowie der BCL2-Inhibitor Venetoclax. Zahlreiche prognostische und prädiktive Biomarker stehen zur Verfügung. Die Auswahl der Erstlinientherapie orientiert sich am TP53-Status, dem IGHV-Status und der Patientenfitness. Aktuelle klinische Daten unterstreichen die gute Wirksamkeit der neuen Substanzen sowohl in der Rezidiv- als auch in der Erstlinientherapie. Erworbene Bruton-Tyrosinkinase(BTK)-Resistenzen, medikamentenspezifische Nebenwirkungen und mangelnde Patienten-Compliance sind klinisch ein zunehmendes Problem der neuen Substanzen. Zudem gibt es nur wenige Daten zu Langzeittoxizitäten. Patienten sollten deswegen, wenn immer es geht, innerhalb klinischer Studien behandelt werden. In diesem Übersichtsartikel sollen auf die neuesten Entwicklungen der Diagnostik und Therapie der chronischen lymphatischen Leukämie (CLL) eingegangen und die wichtigsten Aspekte für die Praxis heraus gearbeitet werden.

Abstract

Due to an increasing molecular understanding of the signal pathways of B‑lymphocytes and identification of the kinases involved, many new targeted treatments could be developed. The most and best researched are the kinase inhibitors ibrutinib and idelalisib as well as the BCL2 inhibitor venetoclax. A variety of prognostic and predictive biomarkers have been identified. Currently the selection of first-line treatment is oriented to the TP53 status, immunoglobulin heavy chain gene (IGHV) mutational status and patient fitness. Recent clinical studies underline the effectiveness of the novel substances as first-line treatment and in recurrence situations. Acquired Bruton tyrosine kinase (BTK) resistance, medication-specific side effects and a lack of patient compliance are an increasing clinical problem of the new substances. Additionally, little is known about the long-term toxicity. Therefore, patients should be treated within clinical trials whenever possible. This review article summarizes the most recent developments in the diagnostics and treatment of chronic lymphocytic leukemia (CLL) and the most important aspects for the practice are worked out.

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Literatur

  1. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H et al (2018) iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 131(25):2745–2760

    Article  CAS  Google Scholar 

  2. The International CLL-IPI working group (2016) An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol 17(6):779–790

    Article  Google Scholar 

  3. Soumerai JD, Ni A, Xing G, Huang J, Furman RR, Jones J et al (2018) Evaluation of the CLL-IPI in relapsed and refractory chronic lymphocytic leukemia in idelalisib phase‑3 trials. Leuk Lymphoma. https://doi.org/10.1080/10428194.2018.1540782

    Article  PubMed  Google Scholar 

  4. Nadeu F, Delgado J, Royo C, Baumann T, Stankovic T, Pinyol M et al (2016) Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood 127(17):2122–2130

    Article  CAS  Google Scholar 

  5. Rawstron AC, Fazi C, Agathangelidis A, Villamor N, Letestu R, Nomdedeu J et al (2016) A complementary role of multiparameter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study. Leukemia 30(4):929–936

    Article  CAS  Google Scholar 

  6. Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J et al (2010) Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 376(9747):1164–1174

    Article  CAS  Google Scholar 

  7. Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P et al (2016) Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood 127(2):208–215

    Article  CAS  Google Scholar 

  8. Thompson PA, Tam CS, O’Brien SM, Wierda WG, Stingo F, Plunkett W et al (2016) Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 127(3):303–309

    Article  CAS  Google Scholar 

  9. Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C et al (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(7):928–942

    Article  CAS  Google Scholar 

  10. Shanafelt TD, Wang V, Kay NE, Hanson CA, O’Brien SM, Barrientos JC et al (2018) A randomized phase III study of Ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN Cancer Research Group (E1912). Blood 132(Suppl 1):LBA‑4

    Article  Google Scholar 

  11. Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W et al (2018) Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL. N Engl J Med 379(26):2517–2528

    Article  CAS  Google Scholar 

  12. Lampson BL, Yu L, Glynn RJ, Barrientos JC, Jacobsen ED, Banerji V et al (2017) Ventricular arrhythmias and sudden death in patients taking ibrutinib. Blood 129(18):2581–2584

    Article  CAS  Google Scholar 

  13. O’Brien S, Jones JA, Coutre SE, Mato AR, Hillmen P, Tam C et al (2016) Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol 17(10):109–1418

    Google Scholar 

  14. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM et al (2014) Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 370(12):1101–1110

    Article  CAS  Google Scholar 

  15. Goede V (2018) 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. EHA Learning Center, S 215923

    Google Scholar 

  16. Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P et al (2015) Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med 373(25):2425–2437

    Article  CAS  Google Scholar 

  17. Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L et al (2019) 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 20(1):43–56

    Article  CAS  Google Scholar 

  18. Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M et al (2019) Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. N Engl J Med 380(23):2225–2236

    Article  CAS  Google Scholar 

  19. Byrd JC, Brown JR, O’Brien S, Barrientos JC, Kay NE, Reddy NM et al (2014) Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 371(3):213–223

    Article  Google Scholar 

  20. Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S et al (2016) 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 17(2):200–211

    Article  CAS  Google Scholar 

  21. Fraser G, Cramer P, Demirkan F, Silva RS, Grosicki S, Pristupa A et al (2018) Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Leukemia. https://doi.org/10.1038/s41375-018-0276-9

    Article  PubMed  PubMed Central  Google Scholar 

  22. Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D’Rozario J, Assouline S et al (2018) Venetoclax-Rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 378(12):1107–1120

    Article  CAS  Google Scholar 

  23. Kater AP, Seymour JF, Hillmen P, Eichhorst B, Langerak AW, Owen C et al (2018) Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study. J Clin Oncol. https://doi.org/10.1200/jco.18.01580

    Article  PubMed  Google Scholar 

  24. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P et al (2014) Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370(11):997–1007

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Klinik I für Innere Medizin und CIO Köln Bonn, Universität Köln, Kerpener Str. 62, 50937, Köln, Deutschland

    Petra Langerbeins, Barbara Eichhorst & Michael Hallek

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  1. Petra Langerbeins
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  2. Barbara Eichhorst
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  3. Michael Hallek
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Correspondence to Petra Langerbeins.

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Interessenkonflikt

P. Langerbeins: Research & travel support by Janssen. Honoraria by Janssen, Abbvie. Advisory Board: Sunesis, Janssen. B. Eichhorst: Research support: Roche, Janssen, Abbvie, Gilead. Advisory Board: Janssen, Gilead, Roche, Abbvie, Novartis, Celgene. Honoraria: Roche, Novartis, Gilead, Janssen, Abbvie, Celgene. M. Hallek: Research support for Roche, Gilead, Mundipharma, Janssen, Celgene, Pharmacyclics, Abbvie. Speakers bureau and Advisory Board: Roche Gilead, Mundipharma, Janssen, Celgene, Pharmacyclics, Boehringer.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

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Langerbeins, P., Eichhorst, B. & Hallek, M. Aktuelle Therapiestrategien zur chronischen lymphatischen Leukämie. Onkologe 25, 1004–1008 (2019). https://doi.org/10.1007/s00761-019-00655-y

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