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Novel Therapies in Chronic Lymphocytic Leukemia: A Rapidly Changing Landscape

  • Leukemia (PH Wiernik, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Treatment landscape of chronic lymphocytic leukemia (CLL) has changed since 2014 after the introduction of inhibitors of B-cell receptor signaling pathway (ibrutinib, acalabrutinib, idelalisib and duvelisib) and the inhibitor of the anti-apoptotic protein BCL-2 (venetoclax). In 2019, novel agents were upgraded from being a “great treatment option” to the “preferred choice” for all lines of treatment after number of randomized clinical trials proved their superiority compared to conventional chemoimmunotherapy (CIT) regimens. A growing number of next-generation molecules are in clinical trials with a promise of improved efficacy and less toxicity. This includes agents with expected better safety profile (zanubrutinib, umbralisib, etc.) or more importantly with a potential to overcome the resistance mechanism to early generation agents (ARQ-531, LOXO-305, or vecabrutinib). Early intervention has once again become an active topic of research and, if proven to provide an overall survival benefit, will eliminate the “watch and wait” strategy for asymptomatic CLL patients. Until then, treatment should only be offered to patients who meet the standard treatment indication in standard practice. With our upgraded therapeutic toolbox, there are and will be many unanswered questions. CLL field will need to define the optimal treatment sequence and most effective combinations with a goal of having a time-limited and chemotherapy-free regimen that provides longest remissions and potentially cure. Cellular immunotherapy with chimeric antigen receptor T-cell (CAR-T) may become available for high-risk CLL along with allogeneic stem cell transplant (allo-SCT). Financial toxicity of novel agents especially when used in combination will need to be an important aspect of research in coming years to avoid unnecessary overtreatment of patients. As current prognostic models (CLL-IPI, etc.) were developed and validated in the CIT era, there is ongoing effort to develop new models using clinical and molecular characteristics to accurately define high-risk CLL in the era of novel agents. We all need to keep in mind that access to the novel agents is currently limited to certain developed countries and every effort should be made to make sure patients around the world also benefit from these outstanding drugs.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.

    PubMed  Google Scholar 

  2. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Rawstron AC, Kreuzer KA, Soosapilla A, Spacek M, Stehlikova O, Gambell P, et al. Reproducible diagnosis of chronic lymphocytic leukemia by flow cytometry: an European research initiative on CLL (ERIC) & European Society for Clinical Cell Analysis (ESCCA) harmonisation project. Cytometry B Clin Cytom. 2018;94(1):121–8.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  5. Landgren O, Albitar M, Ma W, Abbasi F, Hayes RB, Ghia P, et al. B-cell clones as early markers for chronic lymphocytic leukemia. N Engl J Med. 2009;360(7):659–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Morabito F, Mosca L, Cutrona G, Agnelli L, Tuana G, Ferracin M, et al. Clinical monoclonal B lymphocytosis versus Rai 0 chronic lymphocytic leukemia: a comparison of cellular, cytogenetic, molecular, and clinical features. Clin Cancer Res. 2013;19(21):5890–900.

    CAS  PubMed  Google Scholar 

  7. Vardi A, Dagklis A, Scarfo L, Jelinek D, Newton D, Bennett F, et al. Immunogenetics shows that not all MBL are equal: the larger the clone, the more similar to CLL. Blood. 2013;121(22):4521–8.

    CAS  PubMed  Google Scholar 

  8. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46(2):219–34.

    CAS  PubMed  Google Scholar 

  9. Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981;48(1):198–206.

    CAS  PubMed  Google Scholar 

  10. Hallek M, Wanders L, Ostwald M, Busch R, Senekowitsch R, Stern S, et al. Serum beta(2)-microglobulin and serum thymidine kinase are independent predictors of progression-free survival in chronic lymphocytic leukemia and immunocytoma. Leuk Lymphoma. 1996;22(5–6):439–47.

    CAS  PubMed  Google Scholar 

  11. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94(6):1848–54.

    CAS  PubMed  Google Scholar 

  12. Dohner 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.

    CAS  PubMed  Google Scholar 

  13. Brown JR, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre SE, et al. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018;32(1):83–91.

    CAS  PubMed  Google Scholar 

  14. Rossi D, Rasi S, Fabbri G, Spina V, Fangazio M, Forconi F, et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood. 2012;119(2):521–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Sportoletti P, Baldoni S, Cavalli L, Del Papa B, Bonifacio E, Ciurnelli R, et al. NOTCH1 PEST domain mutation is an adverse prognostic factor in B-CLL. Br J Haematol. 2010;151(4):404–6.

    PubMed  Google Scholar 

  16. Oscier DG, Rose-Zerilli MJ, Winkelmann N. Gonzalez de Castro D, Gomez B, Forster J, et al. the clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial. Blood. 2013;121(3):468–75.

    CAS  PubMed  Google Scholar 

  17. Rossi D, Gaidano G. The clinical implications of gene mutations in chronic lymphocytic leukaemia. Br J Cancer. 2016;114(8):849–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Rossi D, Khiabanian H, Spina V, Ciardullo C, Bruscaggin A, Fama R, et al. Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia. Blood. 2014;123(14):2139–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Rossi D, Gerber B, Stussi G. Predictive and prognostic biomarkers in the era of new targeted therapies for chronic lymphocytic leukemia. Leuk Lymphoma. 2017;58(7):1548–60.

    CAS  PubMed  Google Scholar 

  20. International CLLIPIwg. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;17(6):779–90.

    Google Scholar 

  21. Ahn IE, Tian X, Albitar M, Herman SEM, Cook EM, Soto S, et al. Validation of clinical prognostic models and integration of genetic biomarkers of drug resistance in CLL patients treated with ibrutinib. Blood. 2018;132(Suppl 1):186-.

  22. Thompson PA, O'Brien SM, Wierda WG, Ferrajoli A, Stingo F, Smith SC, et al. Complex karyotype is a stronger predictor than del(17p) for an inferior outcome in relapsed or refractory chronic lymphocytic leukemia patients treated with ibrutinib-based regimens. Cancer. 2015;121(20):3612–21.

    CAS  PubMed  Google Scholar 

  23. 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.

    PubMed  Google Scholar 

  24. Stehlikova O, Chovancova J, Tichy B, Krejci M, Brychtova Y, Panovska A, et al. Detecting minimal residual disease in patients with chronic lymphocytic leukemia using 8-color flow cytometry protocol in routine hematological practice. Int J Lab Hematol. 2014;36(2):165–71.

    CAS  PubMed  Google Scholar 

  25. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. • Kater AP, Seymour JF, Hillmen P, Eichhorst B, Langerak AW, Owen C, et al. 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. 2019;37(4):269–77. Follow-up of MURANO patients after finishing 2-years of treatment, shows importance of MRD eradication as a predictor of long-term remission.

    CAS  PubMed  Google Scholar 

  27. 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.

    CAS  PubMed  Google Scholar 

  28. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists' Collaborative Group. J Natl Cancer Inst. 1999;91(10):861–8.

  29. Langerbeins P, Bahlo J, Rhein C, Cramer P, Pflug N, Fischer K, et al. The CLL12 trial protocol: a placebo-controlled double-blind phase III study of ibrutinib in the treatment of early-stage chronic lymphocytic leukemia patients with risk of early disease progression. Future Oncol. 2015;11(13):1895–903.

    CAS  PubMed  Google Scholar 

  30. Langerbeins P, Bahlo J, Rhein C, Gerwin H, Cramer P, Fürstenau M, et al. IBRUTINIB versus placebo in patients with asymptomatic, treatment-NAÏVE early stage CLL: primary endpoint results of the phase 3 double-blind randomized CLL12 trial. Hematol Oncol. 2019;37(S2):38–40.

    Google Scholar 

  31. 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.

    CAS  PubMed  Google Scholar 

  32. 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.

    CAS  PubMed  Google Scholar 

  33. Brown JR, Porter DL, O'Brien SM. Novel treatments for chronic lymphocytic leukemia and moving forward. American Society of Clinical Oncology educational book / ASCO American Society of Clinical Oncology Meeting. 2014;34:e317–25.

    Google Scholar 

  34. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. • Ahn IE, Farooqui MZH, Tian X, Valdez J, Sun C, Soto S, et al. Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase II study. Blood. 2018. Most important prospective data in regards to efficacy of ibrutinib in TN CLL patients with del17p.

  36. Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, 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.

    CAS  PubMed  Google Scholar 

  37. Cory S, Roberts AW, Colman PM, Adams JM. Targeting BCL-2-like proteins to kill cancer cells. Trends Cancer. 2016;2(8):443–60.

    PubMed  Google Scholar 

  38. •• 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(23):2225–36. The CLL14 study was critical and led to the FDA approval of venetoclax in combination with obinutzumab for frontline CLL.

    CAS  PubMed  Google Scholar 

  39. van Oers MH, Kuliczkowski K, Smolej L, Petrini M, Offner F, Grosicki S, et al. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2015;16(13):1370–9.

    PubMed  Google Scholar 

  40. Byrd JC, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre S, et al. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019;133(19):2031–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Munir T, Brown JR, O'Brien S, Barrientos JC, Barr PM, Reddy NM, 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):1353–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 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(3):213–23.

    PubMed  PubMed Central  Google Scholar 

  43. 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.

    CAS  PubMed  Google Scholar 

  44. Byrd JC, Woyach JA, Furman RR, Martin P, O'Brien SM, Brown JR, et al. Acalabrutinib in treatment-naive (TN) chronic lymphocytic leukemia (CLL): updated results from the Phase 1/2 ACE-CL-001 Study. Blood. 2018;132(Suppl 1):692.

    Google Scholar 

  45. Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768–78.

    CAS  PubMed  Google Scholar 

  46. 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:JCO2017766840.

  47. • 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. MURANO study showed superiority of venetoclax and rituximab over BR (both PFS and OS) and led the approval of the combination for previously treated CLL patients.

    CAS  PubMed  Google Scholar 

  48. Flinn IW, Hillmen P, Montillo M, Nagy Z, Illes A, Etienne G, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018;132(23):2446–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 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(11):997–1007.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. • 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. Prospective trial showing efficacy of venetoclax in patients who progress on ibrutinib.

    CAS  PubMed  Google Scholar 

  51. Awan FT, Schuh A, Brown JR, Furman RR, Pagel JM, Hillmen P, et al. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv. 2019;3(9):1553–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Rogers KA, Thompson PA, Allan JN, Coleman M, Sharman JP, Cheson BD, et al. Phase 2 study of acalabrutinib in ibrutinib -intolerant patients with relapsed/refractory chronic lymphocytic leukemia. Hematol Oncol. 2019;37(S2):60–1.

    Google Scholar 

  53. •• Dreger P, Ghia P, Schetelig J, van Gelder M, Kimby E, Michallet M, et al. High-risk chronic lymphocytic leukemia in the era of pathway inhibitors: integrating molecular and cellular therapies. Blood. 2018;132(9):892–902. Important recommendations from the EBMT and ERIC for treatment of high-risk CLL.

    CAS  PubMed  Google Scholar 

  54. •• Mato ARRL, Eyre TA, Jacobs R, Hill BT, Lamanna N, Brander DM, et al. Efficacy of therapies following venetoclax discontinuation in CLL: focus on B-cell receptor signal transduction inhibitors and cellular therapies. Blood. 2019;134(supplement 1). This multi-center retrospective study is important as it provides evidence for efficacy of ibrutinib after progrssion on venetoclax.

  55. Eichhorst BF, Bahlo J, Maurer C, Lange E, Köppler H, Kiehl MG, et al. Favorable toxicity profile and long term outcome of elderly, but physically fit CLL patients (pts) receiving first line bendamustine and rituximab (BR) frontline chemoimmunotherapy in comparison to fludarabine, cyclophosphamide, and rituximab (FCR) in advanced chronic lymphocytic leukemia (CLL): update analysis of an international, randomized study of the German CLL Study Group (GCLLSG) (CLL10 Study). Blood. 2016;128(22):4382.

    Google Scholar 

  56. 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.

    CAS  PubMed  Google Scholar 

  57. 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(25):2425–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. •• 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(5):432–43. First study showing OS benefit in favor of ibrutinib and rituximab compared to FCR.

    PubMed  PubMed Central  Google Scholar 

  59. Shanafelt TD, Wang V, Kay NE, Hanson CA, O'Brien SM, Barrientos JC, et al. 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. 2018;132(Suppl 1):LBA-4-LBA-.

  60. 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.

  61. • Sharman JPM, Banerji V, Fogliatto LM, Herishanu Y, Munir T, Walewska R, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients (Pts) with treatment-naive chronic lymphocytic leukemia (CLL). Blood. 2019;134(supplement 1). This study led to approval of acalabrutinib for CLL in the first-line setting.

  62. O'Brien SM, Furman RR, Coutre SE, Flinn IW, Burger J, Blum K, et al. Five-year experience with single-agent ibrutinib in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia. Blood. 2016;128(22):233.

    Google Scholar 

  63. Mato AR, Nabhan C, Thompson MC, Lamanna N, Brander DM, Hill B, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103(5):874–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Wang M, Rule S, Zinzani PL, Goy A, Casasnovas O, Smith SD, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659–67.

    CAS  PubMed  Google Scholar 

  65. • Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M, et al. Acalabrutinib vs rituximab plus idelalisib (IdR) or bendamustine (BR) by investigator choice in relapsed/refractory (RR) chronic lymphocytic leukemia: phase 3 ASCEND study. Hematol Oncol. 2019;37(S2):86–7. This study led to the approval of acalabrutinib for CLL in the relapsed setting.

    Google Scholar 

  66. Wierda WG, Byrd JC, Abramson JS, Bilgrami SF, Bociek G, Brander D, et al. NCCN guidelines insights: chronic lymphocytic leukemia/small lymphocytic lymphoma, version 2.2019. J Natl Compr Cancer Netw. 2019;17(1):12–20.

    CAS  Google Scholar 

  67. Cheson BD, Heitner Enschede S, Cerri E, Desai M, Potluri J, Lamanna N, et al. Tumor Lysis syndrome in chronic lymphocytic leukemia with novel targeted agents. Oncologist. 2017;22(11):1283–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Roeker LE, Fox CP, Eyre TA, Brander DM, Allan JN, Schuster SJ, et al. Tumor Lysis, adverse events, and dose adjustments in 297 venetoclax-treated CLL patients in routine clinical practice. Clin Cancer Res. 2019;25(14):4264–70.

    PubMed  PubMed Central  Google Scholar 

  69. Jeyakumar D, O'Brien S. B cell receptor inhibition as a target for CLL therapy. Best Pract Res Clin Haematol. 2016;29(1):2–14.

    PubMed  Google Scholar 

  70. Lannutti BJ, Meadows SA, Herman SE, Kashishian A, Steiner B, Johnson AJ, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117(2):591–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Coutre SE, Barrientos JC, Brown JR, de Vos S, Furman RR, Keating MJ, et al. Management of adverse events associated with idelalisib treatment: expert panel opinion. Leuk Lymphoma. 2015;56(10):2779–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Lampson BL, Kasar SN, Matos TR, Morgan EA, Rassenti L, Davids MS, et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood. 2016;128(2):195–203.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Yeung CC, Hockenbery DM, Westerhoff M, Coutre SE, Sedlak RH, Dubowy RL, et al. Pathological assessment of gastrointestinal biopsies from patients with idelalisib-associated diarrhea and colitis. Future Oncol. 2018;14(22):2265–77.

    CAS  PubMed  Google Scholar 

  74. Coutre SE, Burger JA, Pagel JM. Discussion: managing risk when using idelalisib. Clin Adv Hematol Oncol. 2016;14(5 Suppl 8):13.

    PubMed  Google Scholar 

  75. Khouri IF, Wei W, Korbling M, Turturro F, Ahmed S, Alousi A, et al. BFR (bendamustine, fludarabine, and rituximab) allogeneic conditioning for chronic lymphocytic leukemia/lymphoma: reduced myelosuppression and GVHD. Blood. 2014;124(14):2306–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Sorror ML, Storer BE, Sandmaier BM, Maris M, Shizuru J, Maziarz R, et al. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol. 2008;26(30):4912–20.

    PubMed  PubMed Central  Google Scholar 

  77. Shadman M, Maloney DG, Storer B, Sandmaier BM, Chauncey TR, Smedegaard Andersen N, et al. Rituximab-based allogeneic transplant for chronic lymphocytic leukemia with comparison to historical experience. Bone Marrow Transplant. 2019.

  78. Shadman M, Gauthier J, Hay KA, Voutsinas JM, Milano F, Li A, et al. Safety of allogeneic hematopoietic cell transplant in adults after CD19-targeted CAR T-cell therapy. Blood Adv. 2019;3(20):3062–9.

    PubMed  PubMed Central  Google Scholar 

  79. • Turtle CJ, Hay KA, Hanafi LA, 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(26):3010–20. This study shows efficacy of CAR-T for CLL with acceptable toxicity profile.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Ruella M, Kenderian SS, Shestova O, Fraietta JA, Qayyum S, Zhang Q, et al. The addition of the BTK inhibitor ibrutinib to anti-CD19 chimeric antigen receptor T cells (CART19) improves responses against mantle cell lymphoma. Clin Cancer Res. 2016;22(11):2684–96.

    CAS  PubMed  Google Scholar 

  81. Gauthier J, Hirayama AV, Hay KA, Li D, Lymp J, Sheih A, et al. Comparison of efficacy and toxicity of CD19-specific chimeric antigen receptor T-cells alone or in combination with ibrutinib for relapsed and/or refractory CLL. Blood. 2018;132(Suppl 1):299.

    Google Scholar 

  82. Tam CS, Trotman J, Opat S, Burger JA, Cull G, Gottlieb D, et al. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019;134(11):851–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Zou YX, Zhu HY, Li XT, Xia Y, Miao KR, Zhao SS, et al. The impacts of zanubrutinib on immune cells in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Hematol Oncol. 2019;37(4):392–400.

    CAS  PubMed  Google Scholar 

  84. Tam CSRT, Ghia P, Kahl BS, Walker P, Janowski W, Simpson D, et al. Efficacy and safety of zanubrutinib in patients with treatment-naive chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with Del(17p): initial results from Arm C of the Sequoia (BGB-3111-304) Trial. Blood. 2019;134(Supplement 1):499.

    Google Scholar 

  85. Bond DA, Woyach JA. Targeting BTK in CLL: beyond Ibrutinib. Curr Hematol Malig Rep. 2019;14(3):197–205.

    PubMed  Google Scholar 

  86. Umbralisib inhibits PI3Kdelta with less toxicity than previous inhibitors. Cancer discovery. 2018;8(4):382.

  87. Jain N, Keating MJ, Thompson PA, Ferrajoli A, Burger JA, Borthakur G, et al. Combined ibrutinib and venetoclax in patients with treatment-naïve high-risk chronic lymphocytic leukemia (CLL). Blood. 2018;132(Suppl 1):696.

    Google Scholar 

  88. 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(22):2095–103.

    CAS  PubMed  Google Scholar 

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Funding

Mazyar Shadman has received research funding from AbbVie, Genentech, Pharmacyclics, Acerta Pharma, Verastem Oncology, Gilead, TG Therapeutics, BeiGene, Sunesis, Celgene, Mustang Bio, and Merck and has received compensation from AbbVie, Genentech, Pharmacyclics, AstraZeneca, Verastem Oncology, Gilead, Sound Biologics, Atara Biotherapeutics, Cellectar Biosciences, and ADC Therapeutics.

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Authors and Affiliations

  1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Lorenzo Iovino MD, PhD & Mazyar Shadman MD, MPH

  2. UO Ematologia, Università degli Studi di Pisa, Pisa, Italy

    Lorenzo Iovino MD, PhD

  3. Department of Medicine, Medical Oncology Division, University of Washington, Seattle, WA, USA

    Mazyar Shadman MD, MPH

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  1. Lorenzo Iovino MD, PhD
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  2. Mazyar Shadman MD, MPH
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Correspondence to Mazyar Shadman MD, MPH.

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Lorenzo Iovino declares that he has no conflict of interest.

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Iovino, L., Shadman, M. Novel Therapies in Chronic Lymphocytic Leukemia: A Rapidly Changing Landscape. Curr. Treat. Options in Oncol. 21, 24 (2020). https://doi.org/10.1007/s11864-020-0715-5

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