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Chronic lymphocytic leukemia

Chronic lymphocytic leukemia in 2020: a surfeit of riches?

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Fig. 1: Timeline of US Food and Drug Administration approvals for chronic lymphocytic leukemia.

References

  1. 1.

    Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376:1164–74.

    CAS  Article  Google Scholar 

  2. 2.

    Burger JA, Montserrat E. Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling. Blood. 2013;121:1501–9.

    CAS  Article  Google Scholar 

  3. 3.

    Galletti G, Caligaris-Cappio F, Bertilaccio MT. B cells and macrophages pursue a common path toward the development and progression of chronic lymphocytic leukemia. Leukemia. 2016;30:2293–301.

    CAS  Article  Google Scholar 

  4. 4.

    Nguyen PH, Niesen E, Hallek M. New roles for B cell receptor associated kinases: when the B cell is not the target. Leukemia. 2019;33:576–87.

    CAS  Article  Google Scholar 

  5. 5.

    Chen SS, Chang BY, Chang S, Tong T, Ham S, Sherry B, et al. BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia. Leukemia. 2016;30:833–43.

    CAS  Article  Google Scholar 

  6. 6.

    Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425–37.

    CAS  Article  Google Scholar 

  7. 7.

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

    CAS  Article  Google Scholar 

  8. 8.

    Byrd JC, Brown JR, O’Brien S, Barrientos JC, Kay NE, Reddy NM, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213–23.

    Article  Google Scholar 

  9. 9.

    Shanafelt TD, Wang XV, Kay NE, Hanson CA, O’Brien S, Barrientos J, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381:432–43.

    CAS  Article  Google Scholar 

  10. 10.

    Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379:2517–28.

    CAS  Article  Google Scholar 

  11. 11.

    Mato AR, Nabhan C, Thompson MC, Lamanna N, Brander DM, Hill B, et al. Toxicities and outcomes of 621 ibrutinib-treated chronic lymphocytic leukemia patients in the United States: a real-world analysis. Haematologica. 2018;103:874–9.

    CAS  Article  Google Scholar 

  12. 12.

    Woyach JA, Furman RR, Liu T-M, Ozer HG, Zapatka M, Ruppert AS, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286–94.

    Article  Google Scholar 

  13. 13.

    Brown JR. Phosphatidylinositol 3 kinase delta inhibitors: present and future. Cancer J. 2019;25:394–400.

    CAS  Article  Google Scholar 

  14. 14.

    Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, et al. Venetoclax and OBinutuzumab in Patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225–36.

    CAS  Article  Google Scholar 

  15. 15.

    Jain N, Keating M, Thompson P, Ferrajoli A, Burger J, Borthakur G, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019;380:2095–103.

    CAS  Article  Google Scholar 

  16. 16.

    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;127:303–9.

    CAS  Article  Google Scholar 

  17. 17.

    Ghia P, Rawstron A. Minimal residual disease analysis in chronic lymphocytic leukemia: a way for achieving more personalized treatments. Leukemia. 2018;32:1307–16.

    Article  Google Scholar 

  18. 18.

    Blombery P, Anderson MA, Gong J-N, Thijssen R, Birkinshaw RW, Thompson ER, et al. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov. 2019;9:342–53.

    CAS  Article  Google Scholar 

  19. 19.

    Hoechstetter MA, Busch R, Eichhorst B, Bühler A, Winkler D, Bahlo J, et al. Prognostic model for newly diagnosed CLL patients in Binet stage A: results of the multicenter, prospective CLL1 trial of the German CLL study group. Leukemia. 2020;34:1038–51.

    CAS  Article  Google Scholar 

  20. 20.

    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;31:2745–60.

    Article  Google Scholar 

  21. 21.

    Moreira J, Rabe KG, Cerhan JR, Kay NE, Wilson JW, Call TG, et al. Infectious complications among individuals with clinical monoclonal B-cell lymphocytosis (MBL): a cohort study of newly diagnosed cases compared to controls. Leukemia. 2013;27:136–41.

    CAS  Article  Google Scholar 

  22. 22.

    Agius R, Brieghel C, Andersen MA, Pearson AT, Ledergerber B, Cozzi-Lepri A, et al. Machine learning can identify newly diagnosed patients with CLL at high risk of infection. Nat Commun. 2020;11:363.

    CAS  Article  Google Scholar 

  23. 23.

    Andersen MA, Moser CE, Lundgren J, Niemann CU. Epidemiology of bloodstream infections in patients with chronic lymphocytic leukemia: a longitudinal nation-wide cohort study. Leukemia. 2019;33:662–70.

    Article  Google Scholar 

  24. 24.

    Manso BA, Zhang H, Mikkelson MG, Gwin KA, Secreto CR, Ding W, et al. Bone marrow hematopoietic dysfunction in untreated chronic lymphocytic leukemia patients. Leukemia. 2018;33:638–52.

    Article  Google Scholar 

  25. 25.

    Kleinstern G, Rishi A, Achenbach SJ, Chaffee KG, Kay NE, Shanafelt TD, et al. Factors associated with non-melanoma skin cancer (NMSC) among chronic lymphocytic leukemia (CLL) patients. Blood. 2017;130(Suppl 1):2158.

    Google Scholar 

  26. 26.

    Shanafelt TD, Bowen D, Venkat C, Slager SL, Zent CS, Kay NE, et al. Quality of life in chronic lymphocytic leukemia: an international survey of 1482 patients. Br J Haematol. 2007;139:255–64.

    Article  Google Scholar 

  27. 27.

    Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature. 2001;411:355–65.

    CAS  Article  Google Scholar 

  28. 28.

    Langerbeins PBJ, Rhein C, Gerwin H, Cramer P, Furstenau M, Al-Sawaf O, et al. Ibrutinib versus placebo in patients with asymptomatic, treatment-naive early stage chronic lymphocytic leukemia (CLL): primary endpoint results of the phase 3 double-blind randomized CLL12 trial. In: Proceedings of the 24th Congress of the European Hematology Association. 2019. Abstract: LB2602.

  29. 29.

    Shanafelt TD, Ghia P, Lanasa MC, Landgren O, Rawstron AC. Monoclonal B-cell lymphocytosis (MBL): biology, natural history and clinical management. Leukemia. 2010;24:512–20.

    CAS  Article  Google Scholar 

  30. 30.

    Rawstron AC, Bennett FL, O’Connor SJ, Kwok M, Fenton JA, Plummer M, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med. 2008;359:575–83.

    CAS  Article  Google Scholar 

  31. 31.

    Shanafelt TD, Kay NE, Parikh SA, Achenbach SJ, Lesnick CE, Hanson CA, et al. Risk of serious infection among individuals with and without low count monoclonal B-cell lymphocytosis (MBL). Leukemia. 2020. https://doi.org/10.1038/s41375-020-0799-8. Online ahead of print.

  32. 32.

    Solomon BM, Chaffee KG, Moreira J, Schwager SM, Cerhan JR, Call TG, et al. Risk of non-hematologic cancer in individuals with high count monoclonal B-cell lymphocytosis (MBL). Leukemia. 2015;30:331–6.

    Article  Google Scholar 

  33. 33.

    Cheng S, Guo A, Lu P, Ma J, Coleman M, Wang YL. Functional characterization of BTK(C481S) mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors. Leukemia. 2015;29:895–900.

    CAS  Article  Google Scholar 

  34. 34.

    Mato AR, Flinn IW, Pagel JM, Brown JR, Cheah CY, Coombs CC, et al. Results from a First-in-Human, Proof-of-Concept Phase 1 Trial in pretreated B-cell malignancies for Loxo-305, a next-generation, highly selective, non-covalent BTK inhibitor. Blood. 2019;134(Suppl 1):501.

    Article  Google Scholar 

  35. 35.

    Woyach J, Stephens DM, Flinn IW, Bhat SA, Savage RE, Chai F, et al. Final results of phase 1, dose escalation study evaluating ARQ 531 in patients with relapsed or refractory B-cell lymphoid malignancies. Blood. 2019;134(Suppl 1):4298.

    Article  Google Scholar 

  36. 36.

    Al-Sawaf O, Robrecht S, Bahlo J, Fink AM, Cramer P, Tresckow J, et al. Richter transformation in chronic lymphocytic leukemia (CLL)—a pooled analysis of German CLL Study Group (GCLLSG) front line treatment trials. Leukemia. 2020. https://doi.org/10.1038/s41375-020-0797-x. Online ahead of print.

  37. 37.

    Ding W, LaPlant BR, Call TG, Parikh SA, Leis JF, He R, et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood. 2017;129:3419–27.

    CAS  Article  Google Scholar 

  38. 38.

    Jain N, Basu S, Thompson PA, Ohanian M, Ferrajoli A, Pemmaraju N, et al. Nivolumab combined with ibrutinib for CLL and richter transformation: A Phase II Trial. Blood. 2016;128:59.

    Article  Google Scholar 

  39. 39.

    Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725–33.

    CAS  Article  Google Scholar 

  40. 40.

    Melenhorst JJ, Porter DL, Tian L, Lacey SF, Nobles CL, Fraietta JA, et al. Long-term remission of CLL sustained by pauciclonal anti-CD19 chimeric antigen receptor T (CTL019) cell clones. Blood. 2018;132(Suppl 1):699.

    Article  Google Scholar 

  41. 41.

    Porter DL, Hwang W-T, Frey NV, Lacey SF, Shaw PA, Loren AW. et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7:303ra139

    Article  Google Scholar 

  42. 42.

    Turtle CJ, Hay KA, Hanafi L-A, Li D, Cherian S, Chen X, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor–modified T cells after failure of ibrutinib. J Clin Oncol. 2017;35:3010–20.

    CAS  Article  Google Scholar 

  43. 43.

    Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med. 2020;382:545–53.

    CAS  Article  Google Scholar 

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Acknowledgements

RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme. NEK acknowledges support from the National Institutes of Health RO1 AG58266 and RO1 CA 193541.

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Correspondence to Sameer A. Parikh.

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SAP: research funding to the institution from Pharmacyclics, MorphoSys, Janssen, Astra Zeneca, TG Therapeutics, Bristol Myers Squibb, AbbVie, and Ascentage Pharma. Advisory Board compensation to the institution from: Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie. NEK: research funding to the institution from Acerta Pharma, Bristol Myers Squibb, Pharmacyclics, Tolero Pharmaceuticals, MEI Pharma Abbvie and Sunesis. Data Safety Monitoring Committee (DSMC) for Agios Pharm, AstraZeneca, Cytomyx Therapeutics, and Rigel. Advisory Board for Cytomx Therapy, Pharmacyclics, Juno Therapeutics, Astra Zeneca, and Oncotracker. The other author declare that he has no conflict of interest.

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Parikh, S.A., Gale, R.P. & Kay, N.E. Chronic lymphocytic leukemia in 2020: a surfeit of riches?. Leukemia 34, 1979–1983 (2020). https://doi.org/10.1038/s41375-020-0852-7

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