Promises and pitfalls of targeted agents in chronic lymphocytic leukemia

Abstract

Targeted agents have significantly improved outcomes for patients with chronic lymphocytic leukemia, particularly high-risk subgroups for whom chemoimmunotherapy previously offered limited efficacy. Two classes of agent in particular, the Bruton tyrosine kinase inhibitors (e.g., ibrutinib) and the B-cell lymphoma 2 inhibitor, venetoclax, induce high response rates and durable remissions in the relapsed/refractory and frontline settings. However, maturing clinical data have revealed promises and pitfalls for both agents. These drugs induce remissions and disease control in the majority of patients, often in situations where modest efficacy would be expected with traditional chemoimmunotherapy approaches. Unfortunately, in the relapsed and refractory setting, both agents appear to be associated with an inevitable risk of disease relapse and progression. Emerging patterns of resistance are being described for both agents but a common theme appears to be multiple sub-clonal drivers of disease progression. Understanding these mechanisms and developing effective and safe methods to circumvent the emergence of resistance will determine the longer-term utility of these agents to improve patients’ quality and length of life. Rational drug combinations, optimised scheduling and sequencing of therapy will likely hold the key to achieving these important goals.

Keywords

Chronic lymphocytic leukemia / drug resistance / venetoclax / B-cell lymphoma 2 / ibrutinib / bruton tyrosine kinase / idelalisib / phosphatidylinositol 3-kinase

References

[1] Siegel RL,Jemal A.Cancer statistics, 2019..CA Cancer J Clin2019;69:7-34

[2] 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

[3] 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

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

[5] Goede V,Dyer MJ,Smolej L.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..23rd Congress of the European Haematology Association;2018;

[6] Goede V,Engelke A,Lepretre S.Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study..Leukemia2015;29:1602

[7] Strati P,O’Brien SM,Burger J.Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion..Haematologica2014;99:1350-5 PMCID:PMC4116834

[8] Balducci L.ESH-SIOG international conference on haematological malignancies in the elderly..Expert Rev Hematol2010;3:675-7

[9] 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

[10] Laurenti L,Autore F,Mauro FR.Chlorambucil plus rituximab as front-line therapy for elderly and/or unfit chronic lymphocytic leukemia patients: Correlation with biologically-based risk stratification..Haematologica2017;102:e352-e5 PMCID:PMC5685238

[11] Lin KI,Keating MJ,O’Brien S.Relevance of the immunoglobulin VH somatic mutation status in patients with chronic lymphocytic leukemia treated with fludarabine, cyclophosphamide, and rituximab (FCR) or related chemoimmunotherapy regimens..Blood2009;113:3168-71 PMCID:PMC4916943

[12] Hamblin TJ,Gardiner A,Stevenson FK.Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia..Blood1999;94:1848-54

[13] Krober A,Benner A,Bruckle E.V(D) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia..Blood2002;100:1410-6

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

[15] Roberts AW,Pagel JM,Puvvada SD.Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia..N Engl J Med2016;374:311-22 PMCID:PMC7107002

[16] Furman RR,Coutre SE,Pagel JM.Idelalisib and rituximab in relapsed chronic lymphocytic leukemia..N Engl J Med2014;370:997-1007 PMCID:PMC4161365

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

[18] Moreno C,Demirkan F,Anz B.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 Oncol2019;20:43-56

[19] Woyach JA,Heerema NA,Booth AM.Ibrutinib regimens versus chemoimmunotherapy in older patients wituntreated CLL..N Engl J Med2018;379:2517-28 PMCID:PMC6325637

[20] Fischer K,Bahlo J,Tandon M.Effect of fixed-duration venetoclax plus obinutuzumab on progression-free survival, and rates and duration of minimal residual disease negativity in previously untreated patients with chronic lymphocytic leukemia and comorbidities..J Clin Oncol2019;37:7502

[21] Fischer K,Bahlo J,Tandon M.Venetoclax and obinutuzumab in patients with cll and coexisting conditions..N Engl J Med2019;380:2225-36

[22] Seymour JF,Eichhorst B,D’Rozario J.Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia..N Engl J Med2018;378:1107-20

[23] 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

[24] Seymour EK.Rapid transitions in the standard of care for chronic lymphocytic leukemia (CLL)..Oncotarget2019;10:2484-5 PMCID:PMC6493463

[25] 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

[26] Chen Q,Ayer T,Flowers CR.Economic burden of chronic lymphocytic leukemia in the era of oral targeted therapies in the United States..J Clin Oncol2017;35:166-74 PMCID:PMC5559889

[27] 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

[28] 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

[29] Rossi D,Gaidano G.Biology and treatment of Richter syndrome..Blood2018;131:2761-72

[30] Anderson MA,Lew TE,Juneja M.Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax..Blood2017;129:3362-70

[31] Maddocks KJ,Lozanski G,Zhao W.Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia..JAMA Oncol2015;1:80-7 PMCID:PMC4520535

[32] Souers AJ,Boghaert ER,Catron ND.ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets..Nat Med2013;19:202-8

[33] Moore VDG,Certo M,Novina CD.Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737..J Clin Invest2007;117:112-21 PMCID:PMC1716201

[34] Robertson LE,McConnell K,McDonnell TJ.Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome..Leukemia1996;10:456-9

[35] 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

[36] 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

[37] Roberts AW,Brown JR,Kipps TJ.Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: Results of a phase I study of navitoclax in patients with relapsed or refractory disease..J Clin Oncol2012;30:488-96 PMCID:PMC4979082

[38] Stilgenbauer S,Schetelig J,Seymour JF.Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: A multicentre, open-label, phase 2 study..Lancet Oncol2016;17:768-78

[39] Rawstron AC,Letestu R,Fazi C.Improving efficiency and sensitivity: European Research Initiative in CLL (ERIC) update on the international harmonised approach for flow cytometric residual disease monitoring in CLL..Leukemia2013;27:142-9

[40] Rawstron AC,Agathangelidis A,Letestu R.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..Leukemia2016;30:929-36 PMCID:PMC4832072

[41] Rawstron AC,Ritgen M,Ghia P.International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia..Leukemia2007;21:956-64

[42] Stilgenbauer S,Schetelig J,Seymour JF.Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: Results from the full population of a phase II pivotal trial..J Clin Oncol2018;36:1973-80

[43] Brander DM,Ma S,Choi MY.Durability of responses on continuous therapy and following drug cessation in deep responders with venetoclax and rituximab: long-term follow-up analysis of a Phase 1b study in patients with relapsed CLL..Blood2019;134:3036

[44] Seymour JF,Brander DM,Barrientos J.Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: A phase 1b study..Lancet Oncol2017;18:230-40 PMCID:PMC5316338

[45] Coutre S,Furman RR,Heffner L.Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy..Blood2018;131:1704-11 PMCID:PMC5922273

[46] 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

[47] Flinn IW,Dyer MJS,Maris MB.Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia..Blood2019;133:2765-75 PMCID:PMC6706803

[48] Seymour JF,Eichhorst B,D’Rozario J.Four-year analysis of MURANO study confirms sustained benefit of time-limited venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia..Blood2019;134:355

[49] 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

[50] Fischer K,Al-Sawaf O,Tandon M.Quantitative analysis of minimal residual disease (MRD) shows high rates of undetectable MRD after fixed-duration chemotherapy-free treatment and serves as surrogate marker for progression-free survival: a prospective analysis of the randomized CLL14 Trial..Blood2019;134:36

[51] Kipps TJ,Grosicki S,Cosolo W.A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia..Leuk Lymphoma2015;56:2826-33 PMCID:PMC4643417

[52] Roberts AW,Kahl BS,Sweetenham JW.Phase 1 study of the safety, pharmacokinetics, and antitumour activity of the BCL 2 inhibitor navitoclax in combination with rituximab in patients with relapsed or refractory CD 20+ lymphoid malignancies..Br J Haematol2015;170:669-78 PMCID:PMC4534314

[53] Böttcher S,Fischer K,Busch RM.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 Oncol2012;30:980-8

[54] Kovacs G,Fink AM,Cramer P.Minimal residual disease assessment improves prediction of outcome in patients with chronic lymphocytic leukemia (CLL) who achieve partial response: Comprehensive analysis of two phase III studies of the german CLL study group..J Clin Oncol2016;34:3758-65

[55] Kwok M,Varghese A,O’Connor SJ.Minimal residual disease is an independent predictor for 10-year survival in CLL..Blood2016;128:2770-3

[56] Lew TE,Lin VS,Came NA.Undetectable peripheral blood mrd should be the goal of venetoclax in CLL, but attainment plateaus after 24 months..Blood Adv2020;4:165-73 PMCID:PMC6960473

[57] Davids MS,Wierda W,Stilgenbauer S.Comprehensive safety analysis of venetoclax monotherapy for patients with relapsed/refractory chronic lymphocytic leukemia..Clin Cancer Res2018;24:4371-9

[58] AbbVieVenclexta (venetoclax) tablets full prescribing information.2016;

[59] Howard SC,Pui CH.The tumor lysis syndrome..N Engl J Med2011;364:1844-54 PMCID:PMC3437249

[60] Davids MS,Seymour JF,Kahl BS.Safety, efficacy and immune effects of venetoclax 400 mg daily in patients with relapsed chronic lymphocytic leukemia (CLL)..J Clin Oncol2017;34:7527

[61] Roberts AW,Kipps TJ,Davids MS.Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables..Blood2019;134:111-22 PMCID:PMC6624969

[62] Del Poeta G,Chiarenza A,Pozzo F.Impaired nodal shrinkage and apoptosis lacking define the adverse independent clinical outcome of NOTCH1 mutated chronic lymphocytic leukemia patients in the age of targeted agents..Blood2019;134:1744

[63] Blombery P.Mechanisms of intrinsic and acquired resistance to venetoclax in B-cell lymphoproliferative disease..Leuk Lymphoma2019;1-6

[64] Adams JM.The BCL-2 arbiters of apoptosis and their growing role as cancer targets..Cell Death Differ2018;25:27-36 PMCID:PMC5729526

[65] Bojarczuk K,Gobessi S,Pozzato G.BCR signaling inhibitors differ in their ability to overcome Mcl-1–mediated resistance of CLL B cells to ABT-199..Blood2016;127:3192-201

[66] Davids MS,Wiestner A,Wang L.Decreased mitochondrial apoptotic priming underlies stroma-mediated treatment resistance in chronic lymphocytic leukemia..Blood2012;120:3501-9 PMCID:PMC3482860

[67] 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 PMCID:PMC5004430

[68] 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

[69] Jain N,Thompson P,Burger J.Ibrutinib and venetoclax for first-line treatment of CLL..N Engl J Med2019;380:2095-103

[70] Tausch E,Dolnik A,Chyla B.Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia..Haematologica2019;104:e434-e7 PMCID:PMC6717583

[71] Birkinshaw RW,Luo CS,White CA.Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations..Nat Commun2019;10:2385 PMCID:PMC6547681

[72] Blombery P,Nguyen T,McBean M.Detection of multiple recurrent novel BCL2 mutations co-occurring with BCL2 Gly101Val in patients with chronic lymphocytic leukemia on long term venetoclax..Blood2019;134:171

[73] Blombery P,Nguyen T,Thompson ER.Characterization of a novel venetoclax resistance mutation (BCL2 Phe104Ile) observed in follicular lymphoma..Br J Haematol2019;186:e188-91

[74] Guieze R,Rosebrock D,Hernandez-Sanchez M.Mitochondrial reprogramming underlies resistance to BCL-2 inhibition in lymphoid malignancies..Cancer Cell2019;36:369-84 e13 PMCID:PMC6801112

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

[76] Brown JR,Chang J,Biondo J.Outcomes of ibrutinib therapy in ibr-naïve patients with chronic lymphocytic leukemia progressing after venetoclax..Blood2019;134:4320

[77] Greil R,Leber B,Quaresmini G.Efficacy and safety of ibrutinib after venetoclax treatment in ibr-naïve patients with relapsed/refractory chronic lymphocytic leukemia : follow-up of patients from the MURANO study..Blood2018;132:5548

[78] Mato A,Eyre T,Hill B.Efficacy of therapies following venetoclax discontinuation in CLL: focus on B-cell receptor signal transduction inhibitors and cellular therapies..Blood2019;134:502

[79] Mato AR,Allan JN,Pagel JM.Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the united states..Haematologica2018;103:1511-7 PMCID:PMC6119152

[80] Lin VS,Handunnetti SM,Nguyen T.BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax..Blood2020;[Epub ahead of print]

[81] Roeker L,Dreger P,Eyre T.Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents..Blood2019;134:3321

[82] Honigberg LA,Sirisawad M,Loury D.The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy..Proc Natl Acad Sci USA2010;107:13075-80 PMCID:PMC2919935

[83] Craxton A,Kurosaki T.Syk and Bruton’s tyrosine kinase are required for B cell antigen receptor-mediated activation of the kinase Akt..J Biol Chem1999;274:30644-50

[84] Herman SE,Hertlein E,Zhang X.Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765..Blood2011;117:6287-96 PMCID:PMC3122947

[85] Petro JB.Phospholipase C-γ2 couples Bruton’s tyrosine kinase to the NF-κB signaling pathway in B lymphocytes..J Biol Chem2001;276:1715-9

[86] Petro JB,Ballard DW.Bruton’s tyrosine kinase is required for activation of IκB kinase and nuclear factor κB in response to B cell receptor engagement..J Exp Med2000;191:1745-54 PMCID:PMC2193161

[87] de Gorter DJ,Kersseboom R,van Gils JM.Bruton’s tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing..Immunity2007;26:93-104

[88] Niemann CU,Maric I,Biancotto A.Disruption of in vivo chronic lymphocytic leukemia tumor–microenvironment interactions by ibrutinib–findings from an investigator-initiated phase II study..Clin Cancer Res2016;22:1572-82 PMCID:PMC4818677

[89] Byrd JC,Coutre SE,Burger JA.Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia..N Engl J Med2013;369:32-42 PMCID:PMC3772525

[90] Ahn IE,Tian X,Sun C.Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study..Blood2018;131:2357-66 PMCID:PMC5969380

[91] Farooqui MZ,Martyr S,Saba N.Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: A phase 2, single-arm trial..Lancet Oncol2015;16:169-76 PMCID:PMC4342187

[92] O’Brien S,Coutre SE,Burger JA.Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial..Lancet Oncol2014;15:48-58 PMCID:PMC4134524

[93] 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

[94] Jones J,Coutre S,Furman RR.Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials..Br J Haematol2018;182:504-12 PMCID:PMC6120509

[95] Brown JR,O’Brien S,Reddy NM.Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL..Leukemia2018;32:83-91 PMCID:PMC5770586

[96] Munir T,O’Brien S,Barr PM.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 Hematol2019; PMCID:PMC6899718

[97] Barr PM,Owen C,Bairey O.Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: Extended phase 3 results from RESONATE-2..Haematologica2018;103:1502-10 PMCID:PMC6119145

[98] 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

[99] O’Brien S,Coutre SE,Hillmen P.Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): A phase 2, open-label, multicentre study..Lancet Oncol2016;17:1409-18

[100] Jain P,Wierda WG,Thompson PA.Long-term follow-up of treatment with ibrutinib and rituximab in patients with high-risk chronic lymphocytic leukemia..Clin Cancer Res2017;23:2154-8 PMCID:PMC5397369

[101] 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

[102] 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

[103] Abrisqueta P,Ferra CM,Fernandez M.Preliminary results of ibrutinib followed by ofatumumab consolidation in previously untreated patients with chronic lymphocytic leukemia: GELLC7 trials from the spanish group of CLL (GELLC)..Blood2019;134:4296

[104] Shanafelt TD,Kay NE,O’Brien SM.ibrutinib and rituximab provides superior clinical outcome compared to FCR in younger patients with chronic lymphocytic leukemia : extended follow-up from the E1912 trial..Blood2019;134:33

[105] Burger JA,Jain N,Kadia T.Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia..Blood2019;133:1011-9 PMCID:PMC6405333

[106] Borge M,Podaza E,Fernandez Grecco H.Ibrutinib impairs the phagocytosis of rituximab-coated leukemic cells from chronic lymphocytic leukemia patients by human macrophages..Haematologica2015;100:e140-2 PMCID:PMC4380736

[107] Da Roit F,Taylor RP,Gritti G.Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: Implications for combination therapy..Haematologica2015;100:77-86 PMCID:PMC4281316

[108] Kohrt HE,Rafiq S,Butchar JP.Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity..Blood2014;123:1957-60 PMCID:PMC3962169

[109] 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

[110] Golay J,Introna M.The specific Bruton tyrosine kinase inhibitor acalabrutinib (ACP-196) shows favorable in vitro activity against chronic lymphocytic leukemia B cells with CD20 antibodies..Haematologica2017;102:e400-3 PMCID:PMC5622871

[111] Woyach JA,Bhat SA,Jianfar M.Acalabrutinib with obinutuzumab (Ob) in treatment-naive (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): three-year follow-up..J Clin Oncol2019;37:7500

[112] Byrd JC,Schuh A,Chaves JM.Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated results from the phase 1/2 ACE-CL-001 study..Blood2017;130:498

[113] Sharman JP,Fogliatto LM,Munir T.ELEVATE TN: Phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil in patients with treatment-naive chronic lymphocytic leukemia (CLL)..Blood2019;134:31

[114] Alduaij W,Honeychurch J,Potluri S.Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies..Blood2011;117:4519-29 PMCID:PMC3099571

[115] Dalle S,Besseyre de Horts T,Herting F.Preclinical studies on the mechanism of action and the anti-lymphoma activity of the novel anti-CD20 antibody GA101..Mol Cancer Ther2011;10:178-85

[116] Herter S,Mundigl O,Weinzierl T.Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models..Mol Cancer Ther2013;12:2031-42

[117] Mössner E,Moser S,Schmidt C.Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell–mediated B-cell cytotoxicity..Blood2010;115:4393-402 PMCID:PMC2881503

[118] Patz M,Forcob N,Frenzel LP.Comparison of the in vitro effects of the anti-CD20 antibodies rituximab and GA101 on chronic lymphocytic leukaemia cells..Br J Haematol2011;152:295-306

[119] Cramer P,Bahlo J,Langerbeins P.Bendamustine followed by obinutuzumab and venetoclax in chronic lymphocytic leukaemia (CLL2-BAG): Primary endpoint analysis of a multicentre, open-label, phase 2 trial..Lancet Oncol2018;19:1215-28

[120] von Tresckow J,Bahlo J,Langerbeins P.CLL2-BIG: Sequential treatment with bendamustine, ibrutinib and obinutuzumab (GA101) in chronic lymphocytic leukemia..Leukemia2019;33:1161-72

[121] Sun C,Lee YS,Lipsky A.Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib..Blood2015;126:2213-9 PMCID:PMC4635117

[122] Long M,Do P,Gordon A.Ibrutinib treatment improves T cell number and function in CLL patients..J Clin Invest2017;127:3052-64 PMCID:PMC5531425

[123] Dubovsky JA,Natarajan G,Jaglowski S.Ibrutinib is an irreversible molecular inhibitor of ITK driving a TH1-selective pressure in T lymphocytes..Blood2013;122:2539-49 PMCID:PMC3795457

[124] Fraietta JA,Patel PR,Zheng Z.Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia..Blood2016;127:1117-27 PMCID:PMC4778162

[125] Gauthier J,Hay KA,Lymp J.Efficacy and toxicity of CD19-specific chimeric antigen receptor T-cells alone or in combination with ibrutinib for relapsed and/or refractory CLL..Biol Blood Marrow Transplant2019;25:S9-10

[126] Gill SI,Frey NV,O’Brien M.Prospective clinical trial of anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia shows a high response rate..Blood2018;132:298

[127] Baptista MJ,Keyvanfar K,Ahn IE.Patients with chronic lymphocytic leukemia treated with ibrutinib show expansion of T-cell clonotypes composed of antitumor cytotoxic CD8+ T-cells..Blood2019;134:3030

[128] Bercusson A,Shah A,Armstrong-James D.Ibrutinib blocks Btk-dependent NF-kB and NFAT responses in human macrophages during Aspergillus fumigatus phagocytosis..Blood2018;132:1985-8 PMCID:PMC6450054

[129] Ahn IE,Farooqui M,Wiestner A.Atypical pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib..Blood2016;128:1940-3 PMCID:PMC5064717

[130] Baron M,Challan Belval T,Denis B.Fungal infections in patients treated with ibrutinib: Two unusual cases of invasive aspergillosis and cryptococcal meningoencephalitis..Leuk Lymphoma2017;58:2981-2

[131] Chan TS,Chim CS,Kwong YL.Disseminated fusarium infection after ibrutinib therapy in chronic lymphocytic leukaemia..Ann Hematol2017;96:871-2

[132] Messina JA,Spec A,Perfect JR.Disseminated cryptococcosis with brain involvement in patients with chronic lymphoid malignancies on ibrutinib..Open Forum Infect Dis2017;4:ofw261 PMCID:PMC5413986

[133] Grommes C,Palaskas N,Campos C.Ibrutinib unmasks critical role of Bruton tyrosine kinase in primary CNS lymphoma..Cancer Discov2017;7:1018-29 PMCID:PMC5581705

[134] Lionakis MS,Roschewski M,Butman JA.Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma..Cancer Cell2017;31:833-43 e5 PMCID:PMC5571650

[135] Ghez D,Protin C,Ledoux MP.Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib..Blood2018;131:1955-9

[136] Varughese T,Cohen N,Seo SK.Serious infections in patients receiving ibrutinib for treatment of lymphoid cancer..Clin Infect Dis2018;67:687-92 PMCID:PMC6093991

[137] Rogers KA,Zhao Q,Byrd JC.Incidence of opportunistic infections during ibrutinib treatment for B-cell malignancies..Leukemia2019;33:2527-30

[138] Byrd JC,O’Brien S,Schuh A.Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia..N Engl J Med2016;374:323-32 PMCID:PMC4862586

[139] Tam CS,Opat S,Cull G.Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL..Blood2019;134:851-9 PMCID:PMC6742923

[140] Aarup K,Pedersen RS,Bergmann OJ.Real-world outcomes for 205 Danish patients with chronic lymphocytic leukemia treated with ibrutinib..Blood2019;134:1767

[141] Woyach JA,Guinn D,Blachly JS.BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia..J Clin Oncol2017;35:1437-43 PMCID:PMC5455463

[142] Kamel S,Ysebaert L,Burbury K.Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation..Leukemia2015;29:783

[143] Levade M,Garcia C,Cadot S.Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions..Blood2014;124:3991-5

[144] Shatzel JJ,Tao DL,Danilov AV.Ibrutinib-associated bleeding: Pathogenesis, management and risk reduction strategies..J Thromb Haemost2017;15:835-47 PMCID:PMC6152914

[145] Brown JR,O’Brien S,Hillmen P.Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials..Haematologica2017;102:1796-805 PMCID:PMC5622864

[146] McMullen JR,Ooi JY,Keating MJ.Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-AKT signaling..Blood2014;124:3829-30

[147] Guha A,Zhao Q,Woyach JA.Ventricular arrhythmias following ibrutinib initiation for lymphoid malignancies..J Am Coll Cardiol2018;72:697-8

[148] Lampson BL,Glynn RJ,Jacobsen ED.Ventricular arrhythmias and sudden death in patients taking ibrutinib..Blood2017;129:2581-4 PMCID:PMC7219062

[149] Chanan-Khan A,Demirkan F,Silva RS.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 Oncol2016;17:200-11

[150] Byrd JC,Furman RR,Devereux S.Acalabrutinib, a second-generation Bruton tyrosine kinase (BTK) inhibitor, in previously untreated chronic lymphocytic leukemia..J Clin Oncol2016;34:15

[151] Byrd JC,Furman RR,O’Brien SM.Acalabrutinib in treatment-naive chronic lymphocytic leukemia: updated results from the phase 1/2 ACE-CL-001 study..Blood2018;132:692

[152] Rogers KA,Allan JN,Sharman JP.Phase 2 study of acalabrutinib in ibrutinib intolerant patients with relapsed/refractory chronic lymphocytic leukemia..J Clin Oncol2019;37:15

[153] 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

[154] Walter HS,Rule SA,Morschhauser F.Long-term follow-up of patients with CLL treated with the selective Bruton’s tyrosine kinase inhibitor ONO/GS-4059..Blood2017;129:2808-10 PMCID:PMC5437828

[155] Cull G,Opat S,Trotman J.Treatment with the Bruton tyrosine kinase inhibitor zanubrutinib (BGB-3111) demonstrates high overall response rate and durable responses in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma: updated results from a phase 1/2 trial..Blood2019;134:500

[156] Forum UC.Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: A uk and ireland analysis of outcomes in 315 patients..Haematologica2016;101:1563-72 PMCID:PMC5479600

[157] Iskierka-Jazdzewska E,Giannopoulos K,Holojda J.Efficacy and toxicity of compassionate ibrutinib use in relapsed/refractory chronic lymphocytic leukemia in poland: Analysis of the polish adult leukemia group (PALG)..Leuk Lymphoma2017;58:2485-8

[158] Mato AR,Ujjani C,Howlett C.Comparable outcomes in chronic lymphocytic leukaemia (CLL) patients treated with reduced-dose ibrutinib: Results from a multi-centre study..Br J Haematol2018;181:259-61

[159] Chen LS,Cruz ND,Wu Q.A pilot study of lower doses of ibrutinib in patients with chronic lymphocytic leukemia..Blood2018;132:2249-59 PMCID:PMC6251009

[160] O’Brien SM,Byrd JC,Blum KA.Prognostic factors for complete response to ibrutinib in patients with chronic lymphocytic leukemia: A pooled analysis of 2 clinical trials..JAMA Oncol2018;4:712-6 PMCID:PMC5885180

[161] Chiodin G,Martino EA,Tracy I.High surface IgM levels associate with shorter response duration and bypass of the BTK blockade during ibrutinib therapy in CLL patients..Blood2019;134:1752

[162] Ahn IE,Albitar M,Cook EM.Validation of clinical prognostic models and integration of genetic biomarkers of drug resistance in CLL patients treated with ibrutinib..Blood2018;132:186

[163] Miller CR,Heerema NA,Labanowska J.Near-tetraploidy is associated with richter transformation in chronic lymphocytic leukemia patients receiving ibrutinib..Blood advances2017;1:1584-8 PMCID:PMC5728464

[164] Thompson PA,Wierda WG,Stingo F.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..Cancer2015;121:3612-21 PMCID:PMC4866653

[165] Jones D,Zhao W,Tu H.PLCG2 C2 domain mutations co-occur with BTK and PLCG2 resistance mutations in chronic lymphocytic leukemia undergoing ibrutinib treatment..Leukemia2017;31:1645-7

[166] Ahn IE,Albitar A,Tian X.Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia..Blood2017;129:1469-79 PMCID:PMC5356450

[167] 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

[168] Kadri S,Fitzpatrick C,Sukhanova M.Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL..Blood Adv2017;1:715-27 PMCID:PMC5728051

[169] 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

[170] Landau DA,Rosebrock D,Fein J.The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy..Nat Commun2017;8:2185 PMCID:PMC5736707

[171] 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

[172] Woyach J,Rogers KA,Grever MR.Resistance to acalabrutinib in CLL is mediated primarily by BTK mutations..Blood2019;134:504

[173] Handunnetti S,Nguyen T,Thompson ER.BTK Leu528Trp - a potential secondary resistance mechanism specific for patients with chronic lymphocytic leukemia treated with the next generation BTK inhibitor zanubrutinib..Blood2019;134:170

[174] Fama R,Rasi S,Ciardullo C.Ibrutinib-naive chronic lymphocytic leukemia lacks Bruton tyrosine kinase mutations associated with treatment resistance..Blood2014;124:3831-3

[175] Mato AR,Lamanna N,Ujjani CS.Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: Results from a multicenter study of 683 patients..Ann Oncol2017;28:1050-6

[176] Staber PB,Brugger W,Greil R.Primary analysis of anti-CD19 tafasitamab (MOR208) treatment in combination with idelalisib or venetoclax in R/R CLL patients who failed prior BTK inhibitor therapy (COSMOS Trial)..Blood2019;134:1754

[177] Porcu P,Kahl BS,Oki Y.Clinical activity of duvelisib (IPI-145), a phosphoinositide-3-kinase-δ, γ inhibitor, in patients previously treated with ibrutinib..Blood2014;124:3335

[178] Awan FT,Patel-Donnelly D,Rao AV.Entospletinib monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia previously treated with b-cell receptor inhibitors: Results of a phase 2 study..Leuk Lymphoma2019;60:1972-7

[179] Aslan B,Peoples MD,Vellano CP.Vecabrutinib inhibits C481 mutated Bruton’s tyrosine kinase and its downstream signaling in vitro..Cancer Res2019;79:

[180] Fabian CA,Guinn D,Fox JA.SNS-062 demonstrates efficacy in chronic lymphocytic leukemia in vitro and inhibits C481S mutated bruton tyrosine kinase..Cancer Res2017;77:1207

[181] Allan JN,Patel K,Mato AR.Preliminary safety, pharmacokinetic, and pharmacodynamic results from a phase 1b/2 dose-escalation and cohort-expansion study of the noncovalent, reversible Bruton’s tyrosine kinase inhibitor, Vecabrutinib, in B-lymphoid malignancies..Blood2018;132:3141

[182] Brandhuber B,Smith S,Spencer S.LOXO-305, a next generation reversible BTK inhibitor, for overcoming acquired resistance to irreversible BTK inhibitors..Clin Lymphoma Myeloma Leuk2018;18:S216

[183] Mato A,Pagel JM,Cheah CY.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..Blood2019;134:501

[184] Naeem AS,Tyekucheva S,Rai V.LOXO-305: Targeting C481S Bruton tyrosine kinase in patients with ibrutinib-resistant CLL..Blood2019;134:478

[185] Johnson AR,Katewa A,Belmont LD.Battling BTK mutants with noncovalent inhibitors that overcome Cys481 and Thr474 mutations..ACS Chem Biol2016;11:2897-907

[186] Lee SK,Catlett IM,Griffies A.Safety, pharmacokinetics, and pharmacodynamics of BMS-986142, a novel reversible BTK inhibitor, in healthy participants..Eur J Clin Pharmacol2017;73:689-98 PMCID:PMC5423977

[187] Reiff SD,Smith LL,Muhowski EM.The BTK inhibitor ARQ 531 targets ibrutinib-resistant CLL and Richter transformation..Cancer Discov2018;8:1300-15 PMCID:PMC6261467

[188] Smith PF,Nunn PA,Karr D.A Phase I trial of PRN1008, a novel reversible covalent inhibitor of Bruton’s tyrosine kinase, in healthy volunteers..Br J Clin Pharmacol2017;83:2367-76 PMCID:PMC5651318

[189] Woyach J,Flinn IW,Savage R.Final results of phase 1, dose escalation study evaluating ARQ 531 in patients with relapsed or refractory B-cell lymphoid malignancies..Blood2019;134:4298

[190] Lannutti BJ,Herman SE,Steiner B.CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability..Blood2011;117:591-4 PMCID:PMC3694505

[191] Brown JR,Coutre SE,Flinn IW.Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia..Blood2014;123:3390-7 PMCID:PMC4123414

[192] Herman SE,Wagner AJ,Zhao W.Phosphatidylinositol 3-kinase-δ inhibitor cal-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals..Blood2010;116:2078-88 PMCID:PMC2951855

[193] Zelenetz AD,Kipps TJ,O’Brien S.A phase 2 study of idelalisib monotherapy in previously untreated patients ≥ 65 years with chronic lymphocytic leukemia or small lymphocytic lymphoma..Blood2014;124:1986

[194] De Vos S,Barrientos JC,Flinn IW.A phase 1 study of the selective PI3Kδ inhibitor idelalisib (GS-1101) in combination with therapeutic anti-CD20 antibodies (rituximab or ofatumumab) in patients with relapsed or refractory chronic lymphocytic leukemia..Blood2013;122:4180

[195] Furman RR,Barrientos JC,Flinn IW.Long-term follow-up of a phase 1 study of idelalisib (ZYDELIG®) in combination with anti-CD20 antibodies (rituximab or ofatumumab) in patients with relapsed or refractory chronic lymphocytic leukemia..Blood2014;124:5653

[196] Ghia P,Wach M,Kozak T.Acalabrutinib versus investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory CLL: the randomised, controlled, phase 3 ASCEND trial..SSRN2019;

[197] Ali K,Pineiro R,Pearce W.Inactivation of PI3K p110delta breaks regulatory T-cell-mediated immune tolerance to cancer..Nature2014;510:407-11 PMCID:PMC4501086

[198] Patton DT,Pearce WP,Monk CR.Cutting edge: The phosphoinositide 3-kinase p110δ is critical for the function of CD4+ CD25+ FOXP3+ regulatory T cells..J Immunol2006;177:6598-602

[199] Gadi D,Griffith A,Tyekucheva S.Imbalance in T cell subsets triggers the autoimmune toxicity of PI3K inhibitors in CLL..Blood2019;134:1745

[200] O’Brien S,Kipps TJ,Zelenetz AD.Update on a phase 2 study of idelalisib in combination with rituximab in treatment-naïve patients ≥ 65 years with chronic lymphocytic leukemia or small lymphocytic lymphoma..Blood2014;124:1994

[201] Lampson BL,Davids MS,Freedman AS.Efficacy results of a phase 2 trial of first-line idelalisib plus ofatumumab in chronic lymphocytic leukemia..Blood Adv2019;3:1167-74 PMCID:PMC6457234

[202] Coutre SE,de Vos S,Schreeder MT.Idelalisib in combination with rituximab or bendamustine or both in patients with relapsed/refractory chronic lymphocytic leukemia..HemaSphere2018;2:e39 PMCID:PMC6745995

[203] Sharman JP,Furman RR,Pagel JM.Second interim analysis of a phase 3 study of idelalisib (ZYDELIG®) plus rituximab for relapsed chronic lymphocytic leukemia: efficacy analysis in patient subpopulations with del (17p) and other adverse prognostic factors..Blood2014;124:330

[204] Jones JA,Brown JR,Badoux X.Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: An open-label, randomised phase 3 trial..Lancet Haematol2017;4:e114-e26

[205] Jones JA,Wach M,Menter AR.Updated results of a Phase III randomized, controlled study of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukemia..J Clin Oncol2016;34:7515

[206] 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

[207] Coutre S,Brown JR,Furman RR.Safety of idelalisib in B-cell malignancies: Integrated analysis of eight clinical trials..J Clin Oncol2015;33:e18030

[208] Cheah CY,Neelapu SS,Oki Y.Lenalidomide, idelalisib, and rituximab are unacceptably toxic in patients with relapsed/refractory indolent lymphoma..Blood2015;125:3357-9 PMCID:PMC5161005

[209] Barr PM,Spurgeon SE,Greenwald DR.Phase 2 study of idelalisib and entospletinib: Pneumonitis limits combination therapy in relapsed refractory CLL and NHL..Blood2016;127:2411-5 PMCID:PMC4874222

[210] Ghia P,Tausch E,Scheffold A.Whole-exome sequencing revealed no recurrent mutations within the PI3K pathway in relapsed chronic lymphocytic leukemia patients progressing under idelalisib treatment..Blood2016;128:2770

[211] Scheffold A,Tausch E,Dolnik A.In vivo modeling of resistance to PI3Kδ inhibitor treatment using EµTCL1-Tg tumor transfer model..Blood2016;128:190

[212] Flinn IW,Kahl B,Oki Y.Duvelisib, a novel oral dual inhibitor of PI3K-δ, γ, is clinically active in advanced hematologic malignancies..Blood2018;131:877-87 PMCID:PMC6033052

[213] De Henau O,Winkler D,Liu C.Overcoming resistance to checkpoint blockade therapy by targeting PI3K gamma in myeloid cells..Nature2016;539:443-7 PMCID:PMC5634331

[214] Kaneda MM,Ralainirina N,Leem CJ.PI3Kγ is a molecular switch that controls immune suppression..Nature2016;539:437

[215] Reif K,Sasaki T,Vanhaesebroeck B.Cutting edge: Differential roles for phosphoinositide 3-kinases, p110gamma and p110delta, in lymphocyte chemotaxis and homing..J Immunol2004;173:2236-40

[216] Balakrishnan K,Fu M,Burger JA.The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL..Leukemia2015;29:1811-22 PMCID:PMC4558374

[217] Flinn IW,Montillo M,Illes A.The phase 3 DUO trial: Duvelisib vs ofatumumab in relapsed and refractory CLL/sll..Blood2018;132:2446-55 PMCID:PMC6284216

[218] Burris HAIII,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

[219] Barr PM,Ma S,Bui A.A phase 1/2 study of umbralisib ublituximab and venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia..Blood2019;134:360

[220] Mato AR,Lamanna N,Barrientos JC.A phase 2 study to assess the safety and efficacy of umbralisib (TGR 1202) in pts with CLL who are intolerant to prior BTK or PI3Kδ inhibitor therapy..J Clin Oncol2018;36:7530

[221] Nastoupil LJ,Vose JM,Siddiqi T.Tolerability and activity of ublituximab, umbralisib, and ibrutinib in patients with chronic lymphocytic leukaemia and non-hodgkin lymphoma: A phase 1 dose escalation and expansion trial..Lancet Haematol2019;6:e100-e9

[222] Zelenetz AD,Brown JR,Delgado J.Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: Interim results from a phase 3, randomised, double-blind, placebo-controlled trial..Lancet Oncol2017;18:297-311 PMCID:PMC5589180

[223] Fraser G,Demirkan F,Grosicki S.Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma..Leukemia2019;33:969-80 PMCID:PMC6484712

[224] Davids MS,Tyekucheva S,McDonough M. A Phase Ib/II study of duvelisib in combination with FCR for front-line therapy of younger CLL patients. EHA Annual Meeting 2018

[225] Davids MS,Kim HT,Bsat J.Ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial treatment for younger patients with chronic lymphocytic leukaemia: a single-arm, multicentre, phase 2 trial..Lancet Haematol2019;6:e419-28 PMCID:PMC7036668

[226] Thompson PA,Strati P,Keating MJ.Serial minimal residual disease (MRD) monitoring during first-line FCR treatment for CLL may direct individualized therapeutic strategies..Leukemia2018;32:2388-98 PMCID:PMC6192870

[227] Hilal T,Leis JF.Economic impact of oral therapies for chronic lymphocytic leukemia-the burden of novelty..Curr Hematol Malig Rep2018;13:237-43

[228] Tam CS,Allan JN,Flinn IW.Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma: results from the MRD cohort of the phase 2 CAPTIVATE study..Blood2019;134:

[229] Lampson BL,Crombie JL,Merryman RW.Preliminary safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia..Blood2019;134:32

[230] Jain N,Thompson P,Burger J.Combined ibrutinib and venetoclax for first-line treatment for patients with chronic lymphocytic leukemia..Blood2019;134:34

[231] Jain N,Thompson P,Ferrajoli A.Combined ibrutinib and venetoclax in patients with relapsed/refractory chronic lymphocytic leukemia..Blood2019;134:359

[232] Rogers KA,Ruppert AS,Heerema NA.Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia..Blood2018;132:1568-72 PMCID:PMC6182267

[233] Rogers KA,Ruppert AS,Hoffman C.Phase 2 study of combination obinutuzumab, ibrutinib, and venetoclax in treatment-naive and relapsed/refractory chronic lymphocytic leukemia..Blood2018;132:693

[234] Niemann C,Kersting S,Veldhuis GJ.Venetoclax and ibrutinib for patients with relapsed/refractory chronic lymphocytic leukemia - 15-month safety, response and MRD evaluation: third interim analysis from the Phase II Vision HO141 trial..Blood2019;134:4292

[235] Thompson P,Jain N,Kadia T.Venetoclax added to ibrutinib in high-risk CLL achieves a high rate of undetectable minimal residual disease..Blood2019;134:358

[236] Crombie J,Savell A,Choiniere M.A Phase I study of duvelisib and venetoclax in patients with relapsed or refractory CLL/SLL..Blood2019;134:1763