Frontline Therapy of CLL: Evolving Treatment Paradigm
Purpose of Review
Chronic lymphocytic leukemia (CLL) has multiple current frontline therapy options, including chemoimmunotherapy (CIT) and most recently, ibrutinib. Here, we review the most recent updates in the frontline treatment of CLL, including updates in CIT, updates in targeted therapies, and ongoing clinical trials.
Ibrutinib was FDA-approved for the upfront treatment of CLL in 2016 after being studied in older patients and those with 17p deletions or TP53 mutations. The introduction of ibrutinib has dramatically changed the treatment paradigm of CLL.
Recent updates in CIT include that immunoglobulin heavy chain variable (IGHV) gene mutation status is strongly predictive of response to CIT. Regarding targeted therapy, next-generation BTK and PI3K inhibitors are currently being studied in the upfront treatment of CLL, which may have less toxicity than their first-generation counterparts. Other novel targeted therapies are being studied in the frontline setting, most notably venetoclax including in combinations, with hopes to achieve chemotherapy-free, time-limited treatment options. Multiple key ongoing phase 3 clinical trials will be answering these important clinical questions.
KeywordsCLL Chronic lymphocytic leukemia Frontline First-line Upfront Treatment
Compliance with Ethical Standards
Conflict of Interest
Craig S. Boddy declares no potential conflicts of interest.
Shuo Ma reports personal fees from Pharmacyclics, Genetech, Abbvie, Gilead, and AstraZeneca and grants from Pharmacyclics, Abbvie, Gilead, AstraZeneca, Celgene, Xeme, and NCCN.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.SEER Cancer Stat Facts Chronic lymphocytic leukemia, MD http://seer.cancer.gov/statfacts/html/clyl.html. Accessed 27 Nov 2017.
- 2.Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. 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. 2008;111(12):5446–56. https://doi.org/10.1182/blood-2007-06-093906.CrossRefPubMedPubMedCentralGoogle Scholar
- 3.•• 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. https://doi.org/10.1056/NEJMoa1509388. This is a very important reference since it led to the FDA approval of ibrutinib as a frontline therapy in all patients with CLL—the first and only FDA-approved targeted frontline therapy in CLL. CrossRefPubMedPubMedCentralGoogle Scholar
- 4.• Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015;16(2):169–76. https://doi.org/10.1016/S1470-2045(14)71182-9. This is also a very important reference for ibrutnib, showing its efficacy in 17p- or TP53-mutated patients patients that are very difficult to otherwise treat. CrossRefPubMedGoogle Scholar
- 7.Herishanu Y, Perez-Galan P, Liu D, Biancotto A, Pittaluga S, Vire B, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011;117(2):563–74. https://doi.org/10.1182/blood-2010-05-284984.CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Quiroga MP, Balakrishnan K, Kurtova AV, Sivina M, Keating MJ, Wierda WG, et al. B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406. Blood. 2009;114(5):1029–37. https://doi.org/10.1182/blood-2009-03-212837.CrossRefPubMedPubMedCentralGoogle Scholar
- 12.O’Brien S, Jones JA, Coutre SE, Mato AR, Hillmen P, Tam C, et al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 2016;17(10):1409–18. https://doi.org/10.1016/s1470-2045(16)30212-1.CrossRefPubMedGoogle Scholar
- 13.Tam CS, Quach H, Nicol A, Badoux X, Rose H, Prince H, et al. Safety and activity of the highly specific BTK inhibitor, BGB-3111 plus obinutuzumab in patients (PTS) with follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). Hematol Oncol. 2017;35:113. https://doi.org/10.1002/hon.2437_102.CrossRefGoogle Scholar
- 14.Flinn IW, O’Brien S, Kahl B, Patel M, Oki Y, Foss FF, et al. Duvelisib, a novel oral dual inhibitor of PI3K-delta,gamma, is clinically active in advanced hematologic malignancies. Blood. 2017:blood-2017-05-786566. https://doi.org/10.1182/blood-2017-05-786566.
- 20.• Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311–22. https://doi.org/10.1056/NEJMoa1513257. An important reference demonstrating venteoclax’s impact in CLL, which may revolutionize how CLL is treated in the future. CrossRefPubMedGoogle Scholar
- 21.• 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. https://doi.org/10.1016/s1470-2045(16)30019-5. An important reference demonstrating venteoclax’s impact in CLL, which may revolutionize how CLL is treated in the future. CrossRefPubMedGoogle Scholar
- 22.Chronic lymphocytic leukemia/small lymphocytic lymphoma. National Comprehensive Cancer Network (NCCN). https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Accessed 1 Dec 2017.
- 23.• 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. https://doi.org/10.1182/blood-2014-01-546150. Important reference showing FCR’s efficacy based on IGHV mutation status. CrossRefPubMedGoogle Scholar
- 24.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 (London, England). 2010;376(9747):1164–74. https://doi.org/10.1016/s0140-6736(10)61381-5.CrossRefGoogle Scholar
- 25.• 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. https://doi.org/10.1200/jco.2011.36.9348. This sudy shows the correlation with attaining MRD negativity and long-term outcomes when treated with FCR. CrossRefPubMedGoogle Scholar
- 26.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. https://doi.org/10.1016/S1470-2045(16)30051-1.CrossRefPubMedGoogle Scholar
- 28.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(12):1236–41. https://doi.org/10.1200/jco.2013.49.6547.CrossRefPubMedPubMedCentralGoogle Scholar
- 29.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. https://doi.org/10.1002/ajh.23668.CrossRefPubMedGoogle Scholar
- 31.Rossi D, Terzi-di-Bergamo L, De Paoli L, Cerri M, Ghilardi G, Chiarenza A, et al. Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia. Blood. 2015;126(16):1921–4. https://doi.org/10.1182/blood-2015-05-647925.CrossRefPubMedPubMedCentralGoogle Scholar
- 32.• 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. https://doi.org/10.1182/blood-2015-09-667675. This study shows a tail on the Kaplan-Meier curve of possible cures in young, IGHV-mutated CLL patients treated with FCR. CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Benjamini O, Jain P, Trinh L, Qiao W, Strom SS, Lerner S, et al. Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: distribution and clinical outcomes. Leuk Lymphoma. 2015;56(6):1643–50. https://doi.org/10.3109/10428194.2014.957203.CrossRefPubMedGoogle Scholar
- 34.Eichhorst BF BJ, Maurer C, Lange E, Köppler H, 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 Abstracts: 58th Annual Meeting Abstracts. 2016;128(22):abstr 4382.Google Scholar
- 36.Brown JR, O’Brien S, Kingsley CD, Eradat H, Pagel JM, Lymp J, et al. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial. Blood. 2015;125(18):2779–85. https://doi.org/10.1182/blood-2014-12-613570.CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Sharman JPYH, Boxer M, DiBella N, Babu S, Li J, Mun YJ, et al. Results of a phase II multicenter study of obinutuzumab plus bendamustine in pts with previously untreated chronic lymphocytic leukemia (CLL). J Clin Oncol. 2017;35(suppl):abstr 7523.Google Scholar
- 38.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. https://doi.org/10.1002/ajh.24430.CrossRefPubMedGoogle Scholar
- 40.Byrd JC, Flynn JM, Kipps TJ, Boxer M, Kolibaba KS, Carlile DJ, et al. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia. Blood. 2016;127(1):79–86. https://doi.org/10.1182/blood-2015-03-634394.CrossRefPubMedPubMedCentralGoogle Scholar
- 41.Flinn IW, Ruppert AS, Harwin W, Waterhouse D, Papish S, Jones JA, et al. A phase II study of two dose levels of ofatumumab induction followed by maintenance therapy in symptomatic, previously untreated chronic lymphocytic leukemia. Am J Hematol. 2016;91(10):1020–5. https://doi.org/10.1002/ajh.24468.CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Frankfurt O, Ma S, Gordon L, Winter JN, Horowitz JM, Rademaker A, et al. Phase II study of alemtuzumab-rituximab therapy in previously untreated patients with chronic lymphocytic leukemia: short- and long-term outcomes. Leuk Lymphoma. 2015;56(2):315–23. https://doi.org/10.3109/10428194.2014.910654.CrossRefPubMedGoogle Scholar
- 43.Fink AM BJ, Sandra R, Al-Sawaf O, Aldaoud A et al. Lenalidomide maintenance after front line therapy substantially prolongs progression free survival in high risk cll: interim results of a phase 3 study (CLL M1 study of the German CLL Study Group). Blood Abstracts: 58th Annual Meeting Abstracts. 2016;128(22):abstr 229.Google Scholar
- 44.Ruppert ASBJ, Heerema NA, Smith MR, Godwin JE, Couban S, Fehniger TA, et al. A genetic risk-stratified, randomized phase 2 intergroup study of fludarabine/antibody combinations in symptomatic, untreated chronic lymphocytic leukemia (CLL): results from cancer and leukemia group B (CALGB) 10404 (Alliance). J Clin Oncol. 2017;35(suppl):abstr 7503.Google Scholar
- 45.Greil R, Obrtlikova P, Smolej L, Kozak T, Steurer M, Andel J, et al. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016;3(7):e317–29. https://doi.org/10.1016/S2352-3026(16)30045-X.CrossRefPubMedGoogle Scholar
- 46.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(6):487–92. https://doi.org/10.1002/ajh.23983.CrossRefPubMedGoogle Scholar
- 47.O’Brien SM FR, Coutre SE, Flinn IW, et al. Five-year experience with single-agent ibrutinib in patients with previously untreated and relapsed/refractory chronic lymphocytic Leukemia/Small Lymphocytic Leukemia. Blood Abstracts: 58th Annual Meeting Abstracts. 2016;128(22):abstr 233.Google Scholar
- 48.Barr P RT, Owen CJ, Tedeschi A, et al. Updated Efficacy and Safety from the Phase 3 Resonate-2 Study: Ibrutinib As First-Line Treatment Option in Patients 65 Years and Older with Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia. Blood Abstracts: 58th Annual Meeting Abstracts. 2016;128(22):abstr 234.Google Scholar
- 50.Sese L, Rivaud E, Bron C, Leblond V, Raffoux E, Longchampt E, et al. Unexpected pneumocystis jirovecii pneumonia in patients with untreated chronic lymphocytic leukemia. Leuk Lymphoma. 2017:1–4. https://doi.org/10.1080/10428194.2017.1357170.
- 51.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. https://doi.org/10.1182/blood-2016-03-707133.CrossRefPubMedPubMedCentralGoogle Scholar
- 52.O’Brien SM, Lamanna N, Kipps TJ, Flinn I, Zelenetz AD, Burger JA, et al. A phase 2 study of idelalisib plus rituximab in treatment-naive older patients with chronic lymphocytic leukemia. Blood. 2015;126(25):2686–94. https://doi.org/10.1182/blood-2015-03-630947.CrossRefPubMedPubMedCentralGoogle Scholar
- 53.Thompson PA, Stingo F, Keating MJ, Ferrajoli A, Burger JA, Wierda WG, et al. Outcomes of patients with chronic lymphocytic leukemia treated with first-line idelalisib plus rituximab after cessation of treatment for toxicity. Cancer. 2016;122(16):2505–11. https://doi.org/10.1002/cncr.30069.CrossRefPubMedGoogle Scholar
- 54.Gilead Sciences. Direct Healthcare Professional Communication. Restrictions on the use of Zydelig® (idelalisib) for the treatment of chronic lymphocytic leukaemia (CLL) and relapsed follicular lymphoma (FL) following new clinical trial results. March 23, 2016.Google Scholar
- 55.Amaya-Chanaga CI CM, Nguyen N, DeVore E, MacCarthy C, et al. A Phase Ib/II Study of Ibrutinib in Combination with Obinutuzumab-Gazyva As First-Line Treatment for Patients with Chronic Lymphocytic Leukemia > 65 Years Old or with Coexisting Conditions. Blood Abstracts: 58th Annual Meeting Abstracts. 2016;128(22):abstr 2048.Google Scholar
- 56.Rawstron AC MT, Muñoz-Vicente S, Brock K, Yates FJ, et al. Addition of Obinutuzumab to Ibrutinib Enhances Depletion of CLL Cells in the Peripheral Blood and Bone Marrow after 1 Month of Combination Therapy: Initial Results from the Bloodwise TAP Iciclle Extension Study. Blood Abstracts: 58th Annual Meeting Abstracts. 2016;128(22):abstr 2049.Google Scholar
- 57.von Tresckow J CP, Bahlo J, Robrecht S, Engelke A, et al. CLL2-BIG - a Novel Treatment Regimen of Bendamustine Followed By GA101 and Ibrutinib Followed By Ibrutinib and GA101 Maintenance in Patients with Chronic Lymphocytic Leukemia (CLL): Results of a Phase II-Trial. Blood Abstracts: 58th Annual Meeting Abstracts. 2016;128(22):abstr 640.Google Scholar
- 58.Davids MS KH, Brander DM, Bsat J, Savell A, et al. Initial Results of a Multicenter, Phase II Study of Ibrutinib Plus FCR (iFCR) As Frontline Therapy for Younger CLL Patients. Blood Abstracts: 58th Annual Meeting Abstracts. 2016;128(22):abstr 3243.Google Scholar
- 59.Jain NTP, Burger JA, Borthakur G, Bose P, Estrov Z, et al. Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (GA101) (iFCG) for previously untreated patients with chronic lymphocytic leukemia (CLL) with mutated IGHV and non-del (17p). J Clin Oncol. 2017;35(suppl):abstr 7522.Google Scholar
- 60.• Seymour JF, Ma S, Brander DM, Choi MY, Barrientos J, Davids MS, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 2017;18(2):230–40. https://doi.org/10.1016/s1470-2045(17)30012-8. This study shows very signficant rates of MRD negativity in relapsed CLL patients treated with this novel combination, which questions how it fare would if incorporated as a frontline therapy. CrossRefPubMedPubMedCentralGoogle Scholar
- 61.Fischer K A-SO, Fink AM, Dixon M, Bahlo J, et al. Safety and efficacy of venetoclax and obinutuzumab in patients with previously untreated chronic Lymphocytic leukemia (CLL) and coexisting medical conditions: final results of the run-in phase of the randomized CLL14 trial (BO25323). Blood Abstracts: 58th Annual Meeting Abstracts. 2016;128(22):abstr 2054.Google Scholar
- 64.Stilgenbauer S MF, Wendtner CM, Cartron G, Hallek M, et al. Phase Ib Study (GO28440) of venetoclax with bendamustine/rituximab or bendamustine/obinutuzumab in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia. Blood Abstracts: 58th Annual Meeting Abstracts. 2016;128(22):abstr 4393.Google Scholar
- 65.Cramer P, von Tresckow J, Bahlo J, Robrecht S, Al-Sawaf O, Langerbeins P, et al. Bendamustine (b), followed by obinutuzumab (g) and venetoclax (a) in patients with chronic lymphocytic leukemia (CLL): CLL2-bag trial of the German CLL Study Group (GCLLSG). Hematol Oncol. 2017;35:25–7. https://doi.org/10.1002/hon.2437_5.CrossRefGoogle Scholar
- 66.Cramer P vTJ, Bahlo J, Robrecht S, Engelke A, et al. Low incidence of tumor lysis syndromes (TLS) and infusion related reactions (IRR) in the CLL2-bag trial evaluating a sequential treatment of bendamustine (B), obinutuzumab (GA101, G) and venetoclax (ABT-199, A) in patients with chronic lymphocytic leukemia (CLL): interim safety results of a phase-II-trial of the German CLL Study Group (GCLLSG). Blood Abstracts: 58th Annual Meeting Abstracts. 2016;128(22):abstr 2044.Google Scholar
- 67.Strati P TP, Keating M, Hinojosa C, Rodriguez D, et al. A phase II study of the combination of lenalidomide and rituximab in patients with treatment-naïve and relapsed chronic lymphocytic leukemia. Blood Abstracts: 58th Annual Meeting Abstracts. 2016;128(22):abstr 4389.Google Scholar