Therapeutic approaches and drug-resistance in chronic lymphocytic leukaemia

Abstract

The treatment of chronic lymphocytic leukaemia has been revolutionised in recent years, first by the introduction of chemoimmunotherapy regimens and subsequently by the development of drugs, including ibrutinib, idelalisib and venetoclax, that target components of the B-cell receptor signalling pathway or B-cell lymphoma 2 family of proteins. Despite high initial response rates in patients treated with chemoimmunotherapy or targeted agents, a significant proportion of patients relapse with progressive and refractory disease. In a subset of these patients, drug resistance has been associated with specific genetic lesions or activation of alternate pro-survival pathways. However, the mechanisms that confer drug resistance in the remainder of the patients with refractory disease have yet to be fully elucidated. In this review, we discuss our current understanding of the mechanics of drug resistance in chronic lymphocytic leukaemia and describe how this knowledge may aid in rationalising future treatment strategies to prevent the development of refractory or aggressive transformation of the disease.

Keywords

Chronic lymphocytic leukaemia / drug resistance / targeted cancer therapy

References

[1] Chiorazzi N,Ferrarini M.Chronic lymphocytic leukemia..N Engl J Med2005;352:804-15

[2] Rossi D.The clinical implications of gene mutations in chronic lymphocytic leukaemia..Br J Cancer2016;114:849-54 PMCID:PMC4984803

[3] Rossi D,De Paoli L,Ghilardi G.Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia..Blood2015;126:1921-4 PMCID:PMC4743433

[4] Condoluci A.Clonal evolution in chronic lymphocytic leukemia..Clinical Lymphoma Myeloma Leukemia2019;19:S16-9

[5] Tsimberidou AM,Abruzzo LV,Wierda WG.Chemoimmunotherapy may overcome the adverse prognostic significance of 11q deletion in previously untreated patients with chronic lymphocytic leukemia..Cancer2009;115:373-80 PMCID:PMC4404627

[6] Stilgenbauer S,Paschka P,Rossi M.Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial..Blood2014;123:3247-54

[7] Spunarova M,Pavlova S,Brychtova Y.Impact of gene mutations and chromosomal aberrations on progression-free survival in chronic lymphocytic leukemia patients treated with front-line chemoimmunotherapy: clinical practice experience..Leuk Res2019;81:75-81

[8] Landau DA,Taylor-Weiner AN,Reiter JG.Mutations driving CLL and their evolution in progression and relapse..Nature2015;526:525-30 PMCID:PMC4815041

[9] Badoux XC,Wang X,Ferrajoli A.Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL..Blood2011;117:3016-24 PMCID:PMC4123386

[10] Hallek M,Fingerle-Rowson G,Busch R.Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial..Lancet2010;376:1164-74

[11] Keating MJ,Albitar M,Plunkett W.Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia..J Clin Oncol2005;23:4079-88

[12] Wierda W,Wen S,Garcia-Manero G.Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia..J Clin Oncol2005;23:4070-8

[13] Thompson PA,O’Brien SM,Stingo F.Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia..Blood2016;127:303-9 PMCID:PMC4760129

[14] Benjamini O,Trinh L,Strom SS.Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: distribution and clinical outcomes..Leuk Lymphoma2015;56:1643-50 PMCID:PMC4437921

[15] Deans JP,Polyak MJ.CD20-mediated apoptosis: signalling through lipid rafts..Immunology2002;107:176-82 PMCID:PMC1782791

[16] Alomari M,Kaufman KL,Mulligan SP.Profiling the lipid raft proteome from human MEC1 chronic lymphocytic leukemia cells..J Proteom Bioinform2014;S7:005

[17] Hammadi M,Tempescul A,Berthou C.Membrane microdomain sphingolipids are required for anti-CD20-induced death of chronic lymphocytic leukemia B cells..Haematologica2012;97:288-96 PMCID:PMC3269491

[18] Fischer K,Fink AM,Herling CD.Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial..Blood2016;127:208-15

[19] Brieghel C,Yde CW,Jønson L.Deep targeted sequencing of TP53 in chronic lymphocytic leukemia: clinical impact at diagnosis and at time of treatment..Haematologica2019;104:789-96 PMCID:PMC6442964

[20] Ferracin M,Rizzotto L,Veronese A.MicroRNAs involvement in fludarabine refractory chronic lymphocytic leukemia..Mol Cancer2010;9:123 PMCID:PMC2892453

[21] Gagez AL,Leprêtre S,Letestu R.miR-125b and miR-532-3p predict the efficiency of rituximab-mediated lymphodepletion in chronic lymphocytic leukemia patients. A French Innovative Leukemia Organization study..Haematologica2017;102:746-54 PMCID:PMC5395115

[22] Cerna K,Chochola V,Seda V.MicroRNA miR-34a downregulates FOXP1 during DNA damage response to limit BCR signalling in chronic lymphocytic leukaemia B cells..Leukemia2019;33:403-14

[23] Pozzo F,Arruga F,Macor P.NOTCH1 mutations associate with low CD20 level in chronic lymphocytic leukemia: evidence for a NOTCH1 mutation-driven epigenetic dysregulation..Leukemia2016;30:182-9

[24] Tausch E,Schlenk RF,Dolnik A.Prognostic and predictive role of gene mutations in chronic lymphocytic leukemia: results from the pivotal phase III study COMPLEMENT1..Haematologica2020;Epub ahead of print. doi: 10.3324/haematol.2019.229161

[25] Edelmann J,Landau DA,Bahlo J.Frequent evolution of copy number alterations in CLL following first-line treatment with FC(R) is enriched with TP53 alterations: results from the CLL8 trial..Leukemia2017;31:734-8 PMCID:PMC5332302

[26] Baliakas P,Iskas M,Plevova K.Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact..Blood2019;133:1205-16 PMCID:PMC6509568

[27] Guièze R,Clifford R,Pereira B.Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL..Blood2015;126:2110-7

[28] Fischer K,Busch R,Bahlo J.Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group..J Clin Oncol2011;29:3559-66

[29] Teeling JL,Cragg MS,Pluyter M.Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas..Blood2004;104:1793-800

[30] Bologna L,Da Roit F,Rambaldi A.Ofatumumab is more efficient than rituximab in lysing B chronic lymphocytic leukemia cells in whole blood and in combination with chemotherapy..J Immunol2013;190:231-9

[31] Cartron G,Dilhuydy MS,Leblond V.Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study..Blood2014;124:2196-202

[32] Goede V,Busch R,Eichhorst B.Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions..N Engl J Med2014;370:1101-10

[33] Ysebaert L,Klein C.Obinutuzumab (GA101) is highly effective against chronic lymphocytic leukemia cells in ex vivo B-cell depletion irrespective of high-risk prognostic markers..Blood Cancer J2015;5:e367 PMCID:PMC4670946

[34] Burger JA.B cell receptor signaling in chronic lymphocytic leukemia..Trends Immunol2013;34:592-601 PMCID:PMC3898793

[35] Burger JA.The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: insight into disease biology and new targeted therapies..Semin Cancer Biol2014;24:71-81

[36] Chen SS,Chang S,Ham S.BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia..Leukemia2016;30:833-43 PMCID:PMC4832074

[37] Pavlasova G,Seda V,Osickova J.Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis..Blood2016;128:1609-13 PMCID:PMC5291297

[38] Herman SEM,Jones J,Farooqui M.Treatment with ibrutinib inhibits BTK- and VLA-4-dependent adhesion of chronic lymphocytic leukemia cells in vivo..Clin Cancer Res2015;21:4642-51 PMCID:PMC4609275

[39] Kapoor I,Sharma A,Bodo J.Resistance to BTK inhibition by ibrutinib can be overcome by preventing FOXO3a nuclear export and PI3K/AKT activation in B-cell lymphoid malignancies..Cell Death Dis2019;10:924 PMCID:PMC6892912

[40] Pan Z,Li SJ,Sprengeler PA.Discovery of selective irreversible inhibitors for Bruton’s tyrosine kinase..Chem Med Chem2007;2:58-61

[41] Burger JA,Barr PM,Owen C.Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia..N Engl J Med2015;373:2425-37 PMCID:PMC4722809

[42] Byrd JC,O’Brien S,Kay NE.Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia..N Engl J Med2014;371:213-23 PMCID:PMC4134521

[43] Stephens DM.How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia..Blood2019;133:1298-307 PMCID:PMC6428663

[44] Mato AR,Thompson MC,Brander DM.Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis..Haematologica2018;103:874-9 PMCID:PMC5927982

[45] Furman RR,Lu P,Perez AR.Ibrutinib resistance in chronic lymphocytic leukemia..N Engl J Med2014;370:2352-4 PMCID:PMC4512173

[46] Woyach JA,Liu TM,Zapatka M.Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib..N Engl J Med2014;370:2286-94 PMCID:PMC4144824

[47] Kanagal-Shamanna R,Patel KP,Bueso-Ramos C.Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor-resistant chronic lymphocytic leukemia with disease progression and Richter transformation..Cancer2019;125:559-74

[48] Sharma S,Guo A,Kadri S.Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL..Oncotarget2016;7:68833-41 PMCID:PMC5356593

[49] Quinquenel A,Letestu R,Fleury C.Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study..Blood2019;134:641-4

[50] Sinha S,Tian S,Wu X.PD-1 Overexpression in richter’s transformation (RT) and aggressive chronic lymphocytic leukemia (CLL) after progression on ibrutinib increases Bcl-2 expression via Akt/mTOR pathway..Am Soc Hematology2018;

[51] Jain N,Singh RK,Shirazi F.Overcoming ibrutinib resistance by targeting phosphatidylinositol-3-kinase signaling in diffuse large B-cell lymphoma..bioRxiv2019;523761

[52] Del Poeta G,Pozzo F,Santinelli E.The amount of apoptosis predicts outcome in ibrutinib-treated chronic lymphocytic leukemia (CLL)..Blood2018;132 (Supplement 1):4397

[53] Tissino E,Herman SEM,Ahn IE.Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia..J Exp Med2018;215:681-97 PMCID:PMC5789417

[54] Hillmen P,Brock K,Yates F.Ibrutinib plus venetoclax in relapsed/refractory CLL: results of the bloodwise TAP clarity study..Blood2018;132 (Supplement 1):182

[55] Davids MS,Nicotra A,Francoeur K.Umbralisib in combination with ibrutinib in patients with relapsed or refractory chronic lymphocytic leukaemia or mantle cell lymphoma: a multicentre phase 1-1b study..Lancet Haematol2019;6:e38-47 PMCID:PMC7132223

[56] Wang M,Zinzani PL,Casasnovas O.Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial..Lancet2018;391:659-67

[57] Tam C,Opat S,Gilbertson M.The BTK inhibitor, Bgb-3111, is safe, tolerable, and highly active in patients with relapsed/refractory B-cell malignancies: initial report of a phase 1 first-in-human trial..Blood2015;126:

[58] Walter HS,Dyer MJ,Jones C.A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies..Blood2016;127:411-9 PMCID:PMC4731845

[59] Montalban X,Weber MS,Piasecka-Stryczynska K.Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis..N Engl J Med2019;380:2406-17

[60] Goess C,Murdock S,Sampson E.ABBV-105, a selective and irreversible inhibitor of Bruton’s tyrosine kinase, is efficacious in multiple preclinical models of inflammation..Mod Rheumatol2019;29:510-22

[61] Park JK,Park JA,Lee YJ.HM71224, a novel Bruton’s tyrosine kinase inhibitor, suppresses B cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritis..Arthritis Res Ther2016;18:91 PMCID:PMC4835877

[62] Liclican A,Xing W,Steiner B.Biochemical characterization of tirabrutinib and other irreversible inhibitors of Bruton’s tyrosine kinase reveals differences in on - and off - target inhibition..Biochim Biophys Acta Gen Subj2020;1864:129531

[63] Brown JR,Barr PM,Burger JA.The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia..Blood2015;125:2915-22 PMCID:PMC4424415

[64] Lampson BL.Are BTK and PLCG2 mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?.Expert Rev Hematol2018;11:185-94 PMCID:PMC6082118

[65] Brown JR,Coutre SE,Flinn IW.Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia..Blood2014;123:3390-7 PMCID:PMC4123414

[66] Lampson BL,Matos TR,Rassenti L.Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity..Blood2016;128:195-203 PMCID:PMC4946200

[67] Woyach JA.Targeted therapies in CLL: mechanisms of resistance and strategies for management..Blood2015;126:471-7 PMCID:PMC4513250

[68] Scheffold A,Tausch E,Ghia P.IGF1R as druggable target mediating PI3K-δ inhibitor resistance in a murine model of chronic lymphocytic leukemia..Blood2019;134:534-47

[69] Murali I,McWilliams EM,Tyekucheva S.Activating MAPK pathway mutations mediate primary resistance to PI3K inhibitors in chronic lymphocytic leukemia (CLL)..Am Soc Hematology2018;

[70] Crassini K,Stevenson WS,Ward C.MEK1/2 inhibition by binimetinib is effective as a single agent and potentiates the actions of Venetoclax and ABT-737 under conditions that mimic the chronic lymphocytic leukaemia (CLL) tumour microenvironment..Br J Haematol2018;182:360-72

[71] Flinn IW,Montillo M,Illés Á.The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL..Blood2018;132:2446-55 PMCID:PMC6284216

[72] Kim JH,Park C.Interleukin-6 mediates resistance to PI3K-pathway-targeted therapy in lymphoma..BMC Cancer2019;19:936 PMCID:PMC6785854

[73] Burris HA,Patel MR,Deng C.Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study..Lancet Oncol2018;19:486-96

[74] Friedberg JW,Sweetenham J,Vose JM.Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia..Blood2010;115:2578-85 PMCID:PMC2852362

[75] Coffey GP,Betz A,Birrell M.Cerdulatinib Pharmacodynamics and Relationships to Tumor Response Following Oral Dosing in Patients with Relapsed/Refractory B-cell Malignancies..Clin Cancer Res2019;25:1174-84

[76] Guo A,Coffey G,Pandey A.Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia: Cerdulatinib, but not ibrutinib, induces apoptosis of tumor cells protected by the microenvironment..Oncotarget2017;8:12953-67 PMCID:PMC5355069

[77] Hamlin PA,Fenske TS,Miller CB.The dual SYK/JAK inhibitor cerdulatinib demonstrates rapid tumor responses in a phase 2 study in patients with relapsed/refractory B-and T-cell non-Hodgkin lymphoma (NHL)..Hematological Oncol2017;35:74

[78] Abrams ST,Lin K,Treweeke AT.B-cell receptor signaling in chronic lymphocytic leukemia cells is regulated by overexpressed active protein kinase CbetaII..Blood2007;109:1193-201

[79] Nakagawa R,Tarafdar A,Dunn K.Generation of a poor prognostic chronic lymphocytic leukemia-like disease model: PKCα subversion induces up-regulation of PKCβII expression in B lymphocytes..Haematologica2015;100:499-510 PMCID:PMC4380723

[80] Burlacu A.Regulation of apoptosis by Bcl-2 family proteins..J Cell Mol Med2003;7:249-57 PMCID:PMC6741335

[81] Cimmino A,Fabbri M,Ferracin M.miR-15 and miR-16 induce apoptosis by targeting BCL2..Proc Natl Acad Sci U S A2005;102:13944-9 PMCID:PMC1236577

[82] van Delft MF,Mason KD,Chen L.The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized..Cancer Cell2006;10:389-99 PMCID:PMC2953559

[83] Gandhi L,Ribeiro de Oliveira M,Gandara D.Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors..J Clin Oncol2011;29:909-16 PMCID:PMC4668282

[84] Delbridge AR.The BCL-2 protein family, BH3-mimetics and cancer therapy..Cell Death Differ2015;22:1071-80 PMCID:PMC4572872

[85] de Weerdt I,Dobber J,Eldering E.First Evidence of Restoration of T and NK Cell Compartment after Venetoclax Treatment..Blood2018;132 (Supplement 1):1860

[86] Anderson MA,Seymour JF,Kim SY.The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism..Blood2016;127:3215-24 PMCID:PMC4920022

[87] Kater AP,Hillmen P,Langerak AW.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 Oncol2019;37:269-77

[88] Roberts AW,Pagel JM,Puvvada SD.Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia..N Engl J Med2016;374:311-22 PMCID:PMC7107002

[89] Herling CD,Weiss J,Jachimowicz RD.Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia..Nat Commun2018;9:727 PMCID:PMC5820258

[90] Blombery P,Gong JN,Birkinshaw RW.Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia..Cancer Discov2019;9:342-53

[91] Tausch E,Dolnik A,Chyla B.Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia..Haematologica2019;104:e434-7 PMCID:PMC6717583

[92] Choudhary GS,Mazumder S,Smith MR.MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies..Cell Death Dis2015;6:e1593 PMCID:PMC4669737

[93] Guièze R,Rosebrock D,Hernández-Sánchez M.Mitochondrial reprogramming underlies resistance to BCL-2 inhibition in lymphoid malignancies..Cancer Cell2019;36:369-84.e13 PMCID:PMC6801112

[94] Vogler M,Majid A,Sun XM.Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia..Blood2009;113:4403-13

[95] Punnoose EA,Peale F,Belmont LD.Expression profile of BCL-2, BCL-XL, and MCL-1 predicts pharmacological response to the BCL-2 selective antagonist venetoclax in multiple myeloma models..Mol Cancer Ther2016;15:1132-44

[96] Touzeau C,Le Gouill S,Leverson JD.The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma..Leukemia2014;28:210-2 PMCID:PMC3887407

[97] Burger JA,Wierda WG,Hoellenriegel J.Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study..Lancet Oncol2014;15:1090-9 PMCID:PMC4174348

[98] Skarzynski M,Lee YS,Maric I.Interactions between ibrutinib and anti-CD20 antibodies: competing effects on the outcome of combination therapy..Clin Cancer Res2016;22:86-95 PMCID:PMC4703510

[99] Jaglowski SM,Nagar V,Andritsos LA.Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study..Blood2015;126:842-50 PMCID:PMC4536539

[100] Shanafelt TD,Kay NE,O’Brien S.Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia..N Engl J Med2019;381:432-43 PMCID:PMC6908306

[101] Jones JA,Wierda WG,Choi M.Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial..Lancet Oncol2018;19:65-75 PMCID:PMC6027999

[102] Hillmen P,Brock K,Yates FJ.Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: the CLARITY study..J Clin Oncol2019;37:2722-9 PMCID:PMC6879312

[103] Jain N,Thompson P,Burger J.Ibrutinib and Venetoclax for First-Line Treatment of CLL..N Engl J Med2019;380:2095-103

[104] O’Brien S,Coutre S,Burger JA.Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience..Blood2018;131:1910-9 PMCID:PMC5921964

[105] Fruman DA.Idelalisib--a PI3Kδ inhibitor for B-cell cancers..N Engl J Med2014;370:1061-2 PMCID:PMC4088325

[106] Lunning M,Nastoupil L,Burger JA.Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia..Blood2019;134:1811-20 PMCID:PMC7042665

[107] Mato AR,Eyre TA,Lamanna N.A retrospective comparison of venetoclax alone or in combination with an anti-CD20 monoclonal antibody in R/R CLL..Blood Adv2019;3:1568-73 PMCID:PMC6538868

[108] Thijssen R,Weller K,Beaumont T.Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors..Haematologica2015;100:e302-6 PMCID:PMC5004430

[109] Jak M,van Lier RA,van Oers MH.CD40 stimulation sensitizes CLL cells to rituximab-induced cell death..Leukemia2011;25:968-78

[110] Dobrovolsky D,Morrow S,Faust T.Bruton tyrosine kinase degradation as a therapeutic strategy for cancer..Blood2019;133:952-61 PMCID:PMC6396177

[111] Shen Y,Sandhu S,Christopherson RI.Dual inhibition of MEK1/2 and AKT by binimetinib and MK2206 induces apoptosis of chronic lymphocytic leukemia cells under conditions that mimic the tumor microenvironment..Leuk Lymphoma2019;60:1632-43

[112] Shen Y,O’Dwyer ME,Christopherson R.The dual PI3/PIM-kinase inhibitor, Ibl-202, is highly synergistic with venetoclax against CLL cells, and TP53-knock-out cells, and under conditions that mimic the tumor microenvironment..Blood2018;132(Supplement 1):1870

[113] Tahir SK,Hessler P,Idler KB.Potential mechanisms of resistance to venetoclax and strategies to circumvent it..BMC Cancer2017;17:399 PMCID:PMC5457565

[114] Ramsey HE,Lee T,Arrate MP.A novel MCL1 inhibitor combined with venetoclax rescues venetoclax-resistant acute myelogenous leukemia..Cancer Discov2018;8:1566-81 PMCID:PMC6279595

[115] Ding W,Call TG,Leis JF.Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL..Blood2017;129:3419-27 PMCID:PMC5492091

[116] Herrera AF,Mehta A,Pagel JM.Safety and activity of ibrutinib in combination with durvalumab in patients with relapsed or refractory follicular lymphoma or diffuse large B-cell lymphoma..Am J Hematol2020;95:18-27 PMCID:PMC6904508

[117] Gao C,Wang HZ,Zhang M.Inhibition of heat shock protein 90 as a novel platform for the treatment of cancer..Curr Pharm Des2019;25:849-55

[118] Crassini K,O’Dwyer M,Christopherson R.The dual inhibitor of the phosphoinositol-3 and PIM kinases, IBL-202, is effective against chronic lymphocytic leukaemia cells under conditions that mimic the hypoxic tumour microenvironment..Br J Haematol2018;182:654-69

[119] Ljungström V,Young E,Mansouri L.Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations..Blood2016;127:1007-16 PMCID:PMC4768426

[120] Chai-Adisaksopha C.FCR achieves long-term durable remissions in patients with IGHV-mutated CLL..Blood2017;130:2278-82

[121] Fischer K,Busch R,Bahlo J.Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group..J Clin Oncol2012;30:3209-16

[122] Eichhorst B,Bahlo J,Kovacs G.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 Oncol2016;17:928-42

[123] Burger JA,Taylor-Weiner A,Zhang H.Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition..Nat Commun2016;7:11589 PMCID:PMC4876453