Time-limited, Combined Regimen in Chronic Lymphocytic Leukemia: A Promising Strategy to Achieve a Drug Holiday

Abstract

Chemoimmunotherapy (CIT) is defined as standard first line treatment for chronic lymphocytic leukemia (CLL) patients while patients with unfavorable biological characteristics such as unmutated immunoglobulin heavy chain (UM-IGHV) and TP53 aberration failed to benefit from it. The emergency of the small molecular targeted agents including Bruton’s tyrosine kinase (BTK) inhibitor (BTKi) leads to a brand-new era, from a CIT to a chemo-free era in CLL. However, the treatment of target agents is not enough to attain a deep remission and high rate of complete remission (CR), especially in patients with high risks. The long duration brought about problems, such as cost, drug resistance and toxicity. To benefit CLL in progression free survival (PFS) and long-term remission, exploration of time-limited therapies, mainly with BTKi plus CIT and BCL2i based combination therapy has become a mainstream in clinical trials. The time-limited combination therapy shed light on the promising potentiality to attain sustainable deep remission and partly overcame the risk factors, although long term follow-up is required to consolidate the conclusion. In this review, we intend to introduce key results of clinical trials with combination therapy, discuss the achievements and limitations and put forward future direction for clinical trial design in this field.

Keywords

small molecular targeted agents / Bruton’s tyrosine kinase inhibitor / chronic lymphocytic leukemia / chemoimmunotherapy / combination

References

[1] An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol, 2016,17(6):779–790

[2] ThompsonPA, TamCF, O’BrienSM, et al.. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood, 2016, 127(3): 303-309

[3] FischerK, BahloJ, FinkAM, et al.. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood, 2016, 127(2): 208-215

[4] EichhorstB, FinkAM, BahloJ, 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): 928-942

[5] BurgerJA, BarrPM, RobakT, et al.. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia, 2020, 34(3): 787-798

[6] SharmanJP, EgyedM, JurczakW, et al.. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet, 2020, 395(10232): 1278-1291

[7] FlinnIW, HillmenP, MontilloM, et al.. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood, 2018, 132(23): 2446-2455

[8] RobertsW, DavidsMS, PagelJM, et al.. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic Leukemia. N Engl J Med, 2016, 374(4): 311-322

[9] KeatingMJ, BrienSO, AlbitarM, et al.. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol, 2005, 23(18): 4079-4088

[10] HallekM, FischerK, Fingerle-RowsonG, et al.. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet, 2010, 376(9747): 1164-1174

[11] RossiD, Terzi-di-BergamoL, De PaoliL, et al.. Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia. Blood, 2015, 126(16): 1921-1924

[12] GoedeV, FischerK, BuschR, et al.. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med, 2014, 370(12): 1101-1110

[13] BrownJR, O’BrienS, KingsleyCD, et al.. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial. Blood, 2015, 125(18): 2779-2785

[14] StilgenbauerS, BoschF, LeblondV, et al.. Obinutuzumab alone or combined with chemotherapy in previously untreated (fit or unfit) or relapsed/refractory chronic lymphocytic leukemia (CLL) patients: final results from the phase IIIb GREEN safety study with a focus on efficacy. Blood, 2019, 134(supplement 1): 3035

[15] LeblondV, AktanM, FerraCC, et al.. Safety of obinutuzumab alone or combined with chemotherapy for previously untreated or relapsed/refractory chronic lymphocytic leukemia in the phase IIIb GREEN study. Haematologica, 2018, 103(11): 1889-1898

[16] Al-SawafO, ZhangC, RobrechtS, et al.. Severe infections in patients with chronic lymphocytic leukemia treated with (immuno-)chemotherapy: a pooled analysis of Gcllsg trials. Blood, 2020, 136(supplement 1): 18-19

[17] BenjaminiO, JainP, TrinhL, 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): 1643-1650

[18] ChengS, MaJ, GuoA, et al.. BTK inhibition targets in vivo CLL proliferation through its effects on B-cell receptor signaling activity. Leukemia, 2014, 28(3): 649-657

[19] HermanSE, MustafaRZ, GyamfiJA, et al.. Ibrutinib inhibits BCR and NF-kappaB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood, 2014, 123(21): 3286-3295

[20] HermanSE, GordonAL, HertleinE, et al.. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood, 2011, 117(23): 6287-6296

[21] ByrdJC, BrownJR, O’BrienS, et al.. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med, 2014, 371(3): 213-223

[22] ByrdJC, FurmanRR, CoutreSE, et al.. Ibrutinib treatment for first-Line and relapsed/refractory chronic lymphocytic leukemia: final analysis of the pivotal phase Ib/II PCYC-1102 Study. Clin Cancer Res, 2020, 26(15): 3918-3927

[23] O’BrienS, FurmanRR, CoutreS, et al.. Single-agent ibrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood, 2018, 131(17): 1910-1919

[24] XuW, YangS, ZhouK, et al.. Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with the BTK inhibitor zanubrutinib: phase 2, single-arm, multicenter study. J Hematol Oncol, 2020, 13(1): 48

[25] BrownJR, RobakT, GhiaP, et al.. Efficacy and safety of zanubrutinib in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with del(17p): follow-up results from arm C of the SEQUOIA (BGB-3111-304) trial. Blood, 2020, 136(supplement 1): 11-12

[26] XuW, SongY, WangT, et al.. Updated results from the phase II study of orelabrutinib monotherapy in chinese patients with relapsed or refractory chronic lymphocytic leukemia/small cell leukemia. Blood, 2020, 136(supplement 1): 26-27

[27] WoyachJA, RuppertAS, HeeremaNA, et al.. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med, 2018, 379(26): 2517-2528

[28] BurgerJA, SivinaM, FerrajoliA, et al.. Randomized trial of ibrutinib versus ibrutinib plus rituximab (Ib plus R) in patients with chronic lymphocytic leukemia (CLL). Blood, 2017, 130(supplement 1): 427

[29] ShanafeltTD, WangXV, KayNE, et al.. Ibrutinibrituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med, 2019, 381(5): 432-443

[30] ShanafeltTD, WangV, KayNE, et al.. Ibrutinib and rituximab provides superior clinical outcome compared to FCR in younger patients with chronic lymphocytic leukemia (CLL): extended follow-up from the E1912 Trial. Blood, 2019, 134(supplement _1): 33

[31] MorenoC, GreilR, DemirkanF, et al.. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol, 2019, 20(1): 43-56

[32] LampsonBL, DavidsMS. The development and current use of BCL-2 inhibitors for the treatment of chronic lymphocytic leukemia. Curr Hematol Malig Rep, 2017, 12(1): 11-19

[33] StilgenbauerS, EichhorstB, ScheteligJ, et al.. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase h pivotal trial. J Clin Oncol, 2018, 36(19): 1973-1980

[34] JonesJA, MatoAR, WierdaWG, et al.. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol, 2018, 19(1): 65-75

[35] CoutreS, ChoiM, FurmanRR, et al.. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood, 2018, 131(15): 1704-1711

[36] FlinnIW, O’BrienS, KahlB, et al.. Duvelisib, a novel oral dual inhibitor of PI3K-delta, gamma, is clinically active in advanced hematologic malignancies. Blood, 2018, 131(8): 877-887

[37] BurrisHR, FlinnIW, PatelMR, et al.. Umbralisib, a novel PI3Kdelta and casein kinase-1epsilon inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol, 2018, 19(4): 486-496

[38] MatoAR, NabhanC, ThompsonMC, et al.. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica, 2018, 103(5): 874-879

[39] MatoAR, ThompsonM, AllanJN, et al.. Real-world outcomes and management strategies for venetoclaxtreated chronic lymphocytic leukemia patients in the United States. Haematologica, 2018, 103(9): 1511-1517

[40] AhnIE, TianX, IpeD, et al.. Prediction of outcome in patients with chronic lymphocytic leukemia treated with ibrutinib: development and validation of a four-factor prognostic model. J Clin Oncol, 2021, 39(6): 576-585

[41] WoyachJA, RuppertAS, GuinnD, et al.. BTK(C481S)-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol, 2017, 35(13): 1437-1443

[42] BlomberyP, AndersonMA, GongJN, et al.. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov, 2019, 9(3): 342-353

[43] MuraliI, KasarS, McWilliamsEM, et al.. Activating MAPK pathway mutations mediate primary resistance to PI3K inhibitors in chronic lymphocytic leukemia (CLL). Blood, 2018, 132(supplement 1): 587

[44] RhodesJM, BarrientosJC. Chemotherapy-free frontline therapy for CLL: is it worth it?. Hematology Am Soc Hematol Educ Program, 2020, 2020(1): 24-32

[45] HallekM, ChesonBD, CatovskyD, et al.. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood, 2018, 131(25): 2745-2760

[46] FurstenauM, SilvaND, EichhorstB, et al.. Minimal residual disease assessment in CLL: ready for use in clinical routine?. Hemasphere, 2019, 3(5): e287

[47] KwokM, RawstronAC, VargheseA, et al.. Minimal residual disease is an independent predictor for 10-year survival in CLL. Blood, 2016, 128(24): 2770-2773

[48] KovacsG, RobrechtS, FinkAM, et al.. 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 Oncol, 2016, 34(31): 3758-3765

[49] DimierN, DelmarP, WardC, et al.. A model for predicting effect of treatment on progression-free survival using MRD as a surrogate end point in CLL. Blood, 2018, 131(9): 955-962

[50] LetestuR, DahmaniA, BoubayaM, et al.. Prognostic value of high-sensitivity measurable residual disease assessment after front-line chemoimmunotherapy in chronic lymphocytic leukemia. Leukemia, 2020, 35(6): 1597-1609

[51] ThompsonPA, PetersonCB, StratiP, et al.. Serial minimal residual disease (MRD) monitoring during firstline FCR treatment for CLL may direct individualized therapeutic strategies. Leukemia, 2018, 32(11): 2388-2398

[52] DavidsMS, BranderDM, KimHT, et al.. Ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial treatment for younger patients with chronic lymphocytic leukaemia: a single-arm, multicentre, phase 2 trial. Lancet Haematol, 2019, 6(8): e419-e428

[53] JainN, ThompsonPA, BurgerJA, et al.. Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for first-line treatment of IGHV-mutated CLL and without del(17p)/mutated TP53. Blood, 2019, 134(supplement 1): 357

[54] MichalletAS, LetestuR, Garff-TavernierML, et al.. A fixed-duration, measurable residual disease-guided approach in CLL: follow-up data from the phase 2 ICLL-07 FILO trial. Blood, 2021, 137(8): 1019-1023

[55] EichhorstB, FinkAN, BuschR, et al.. Frontline chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) shows superior efficacy in comparison to bendamustine (B) and rituximab (BR) in previously untreated and physically fit patients (pts) with advanced chronic lymphocytic leukemia (CLL): final analysis of an international, randomized study of the German CLL Study Group (GCLLSG) (CLL10 study). Blood, 2014, 124(21): 19

[56] FischerK, CramerP, BuschR, et al.. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase IIIb trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol, 2011, 29(26): 3559-3566

[57] BrownJR, BarrientosJC, BarrPM, et al.. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood, 2015, 125(19): 2915-2922

[58] FraserG, CramerP, DemirkanF, et al.. Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Leukemia, 2019, 33(4): 969-980

[59] Chanan-KhanA, CramerP, DemirkanF, et al.. 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 Oncol, 2016, 17(2): 200-211

[60] SeymourJF, KippsTJ, EichhorstB, et al.. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med, 2018, 378(12): 1107-1120

[61] KaterAP, KippsTJ, EichhorstB, et al.. Five-year analysis of Murano study demonstrates enduring undetectable minimal residual disease (uMRD) in a subset of relapsed/refractory chronic lymphocytic leukemia (R/R CLL) patients (Pts) following fixed-duration venetoclax-rituximab (VenR) therapy (Tx). Blood, 2020, 136(supplement 1): 19-21

[62] KaterAP, SeymourJF, HillmenP, et al.. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase IIIb study. J Clin Oncol, 2019, 37(4): 269-277

[63] KaterAP, WuJQ, KippsT, et al.. Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations drom the MURANO phase III study. J Clin Oncol, 2020, 38(34): 4042-4054

[64] Al-SawafO, ZhangC, RobrechtS, et al.. Clonal dynamics after venetoclax-obinutuzumab therapy: novel insights from the randomized, phase 3 CLL14 trial. Blood, 2020, 136(supplement 1): 22-23

[65] FischerK, Othman Al-SawafO, BahloJ, et al.. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med, 2019, 380(23): 2225-2236

[66] HillmenP, BoucherRH, WebsterN, et al.. Continued long term responses to ibrutinib + venetoclax treatment for relapsed/refractory CLL in the Blood Cancer UK TAP Clarity trial. Blood, 2020, 136(supplement 1): 17-18

[67] HillmenP, RawstronAC, BrockK, et al.. Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: the CLARITY study. J Clin Oncol, 2019, 37(30): 2722-2729

[68] WierdaWG, TamCS, AllanJN, et al.. Ibrutinib (Ibr) plus venetoclax (Ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): 1-year disease-free survival (DFS) results from the MRD cohort of the phase 2 CAPTIVATE study. Blood, 2020, 136(supplement 1): 16-17

[69] TamCS, SiddiqiT, AllanJN, et al.. Ibrutinib (Ibr) plus venetoclax (Ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): results from the MRD cohort of the phase 2 CAPTIVATE study. Blood, 2019, 134(supplement 1): 35

[70] JainN, KeatingMJ, ThompsonPA, et al.. Combinedibrutinib and venetoclax for first-line treatment for patients with chronic lymphocytic leukemia (CLL): focus on MRD results. Blood, 2020, 136(supplement 1): 42-43

[71] JainN, KeatingM, ThompsonP, et al.. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med, 2019, 380(22): 2095-2103

[72] RogersKA, HuangY, RuppertAS, et al.. Three-year follow-up from a phase 2 study of combination obinutuzumab, ibrutinib, and venetoclax in chronic lymphocytic leukemia. Blood, 2020, 136(supplement 1): 9-10

[73] Huber H, Edenhofer S, Tresckow JV, et al. CLL2-GIVE, a prospective, open-label, multicenter phase-II trial of obinutuzumab (GA101, G), ibrutinib (I), plus venetoclax (VE) in untreated patients with CLL with 17p deletion/TP53 mutation. EHA Abstract, 2020,S157

[74] SoumeraiJD, MatoAR, CarterJ, et al.. Initial results of a multicenter, investigator initiated study of MRD driven time limited therapy with zanubrutinib, obinutuzumab, and venetoclax. J Clin Oncol, 2020, 38: 8006 15 suppl

[75] Soumerai JD, Mato AR, Carter J, et al. MRD-Driven Time Limited Therapy with Zanubrutinib, Obinutuzumab, and Venetoclax (BOVen) in Previously Untreated Chronic Lymphocytic Leukemia. Blood, 2020,1307

[76] DavidsMS, LampsonBL, TyekuchevaS, et al.. Updated safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab (AVO) for frontline treatment of chronic lymphocytic leukemia (CLL). Blood, 2020, 136(supplement 1): 200-221

[77] SharmanJP, CoutreSE, FurmanRR, et al.. Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol, 2019, 37(16): 1391-1402

[78] FurmanRR, SharmanJP, CoutreSE, et al.. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med, 2014, 370(11): 997-1007

[79] CramerP, Von TresckowJ, FinkA, et al.. Bendamustine followed by obinutuzumab and idelalisib in patients with chronic lymphocytic leukemia (CLL): CLL2-BCG Trial of the German CLL Study Group (GCLLSG). Blood, 2020, 136(supplement 1): 21-23

[80] GribbenJG, JurczakW, JacobsRW, et al.. Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O plus Chl) in patients with treatment naive (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 Unity-CLL study. Blood, 2020, 136(supplement 1): 37-39

[81] MatoAR, SvobodaJ, Luning PrakET, et al.. Phase I/II study of umbralisib (TGR-1202) in combination with ublituximab (TG-1101) and pembrolizumab in patients with relapsed/refractory CLL and Richter’s transformation. Blood, 2018, 132(supplement 1): 297

[82] McClanahanF, HannaB, MillerS, et al.. PD-L1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia. Blood, 2015, 126(2): 203-211

[83] DingW, LaPlantBR, CallTG, et al.. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood, 2017, 129(26): 3419-3427

[84] JainN, BasuS, ThompsonPA, et al.. Nivolumab combined with ibrutinib for CLL and Richter transformation: a phase II trial. Blood, 2016, 128(22): 59

[85] YounesA, BrodyJ, CarpioC, et al.. Safety and efficacy of the combination of ibrutinib and nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukemia. Blood, 2017, 130(supplement 1): 833