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REVIEW

Taking the Next Step in Double Refractory Disease: Current and Future Treatment Strategies for Chronic Lymphocytic Leukemia

& ORCID Icon
Pages 181-198 | Received 01 Nov 2023, Accepted 28 Feb 2024, Published online: 08 Mar 2024

References

  • Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745–2760. doi:10.1182/blood-2017-09-806398
  • Santos FP, O’Brien S. Small lymphocytic lymphoma and chronic lymphocytic leukemia: are they the same disease? Cancer J. 2012;18(5):396–403. doi:10.1097/PPO.0b013e31826cda2d
  • Yao Y, Lin X, Li F, Jin J, Wang H. The global burden and attributable risk factors of chronic lymphocytic leukemia in 204 countries and territories from 1990 to 2019: analysis based on the global burden of disease study 2019. Biomed Eng Online. 2022;21(1):4. doi:10.1186/s12938-021-00973-6
  • Fischer K, Bahlo J, Fink AM, 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. doi:10.1182/blood-2015-06-651125
  • Eichhorst B, Fink AM, Bahlo J, 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. doi:10.1016/s1470-2045(16)30051-1
  • Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101–1110. doi:10.1056/NEJMoa1313984
  • Burger JA, Wiestner A. Targeting B cell receptor signalling in cancer: preclinical and clinical advances. Nat Rev Cancer. 2018;18(3):148–167. doi:10.1038/nrc.2017.121
  • de Claro RA, McGinn KM, Verdun N, et al. FDA approval: ibrutinib for patients with previously treated mantle cell lymphoma and previously treated chronic lymphocytic leukemia. Clin Cancer Res. 2015;21(16):3586–3590. doi:10.1158/1078-0432.ccr-14-2225
  • Eyre TA, Riches JC. The evolution of therapies targeting Bruton tyrosine kinase for the treatment of chronic lymphocytic leukaemia: future perspectives. Cancers. 2023;15(9):2596. doi:10.3390/cancers15092596
  • Ghia P, Pluta A, Wach M, et al. Acalabrutinib versus investigator’s choice in relapsed/refractory chronic lymphocytic leukemia: final ASCEND trial results. Hemasphere. 2022;6(12):e801. doi:10.1097/hs9.0000000000000801
  • Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278–1291. doi:10.1016/s0140-6736(20)30262-2
  • Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2023;388(4):319–332. doi:10.1056/NEJMoa2211582
  • Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(8):1031–1043. doi:10.1016/s1470-2045(22)00293-5
  • Robertson LE, Plunkett W, McConnell K, Keating MJ, McDonnell TJ. Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome. Leukemia. 1996;10(3):456–459.
  • Kater AP, Wu JQ, Kipps T, et al. Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations from the MURANO Phase III study. J Clin Oncol. 2020;38(34):4042–4054. doi:10.1200/jco.20.00948
  • Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225–2236. doi:10.1056/NEJMoa1815281
  • Mato AR, Hess LM, Chen Y, et al. Outcomes for Patients With Chronic Lymphocytic Leukemia (CLL) previously treated with both a covalent BTK and BCL2 Inhibitor in the United States: a Real-World Database Study. Clin Lymphoma Myeloma Leuk. 2023;23(1):57–67. doi:10.1016/j.clml.2022.09.007
  • Rolli V, Gallwitz M, Wossning T, et al. Amplification of B cell antigen receptor signaling by a Syk/ITAM positive feedback loop. Mol Cell. 2002;10(5):1057–1069. doi:10.1016/s1097-2765(02)00739-6
  • Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012;120(6):1175–1184. doi:10.1182/blood-2012-02-362624
  • Burger JA, Chiorazzi N. B cell receptor signaling in chronic lymphocytic leukemia. Trends Immunol. 2013;34(12):592–601. doi:10.1016/j.it.2013.07.002
  • Stamatopoulos K, Agathangelidis A, Rosenquist R, Ghia P. Antigen receptor stereotypy in chronic lymphocytic leukemia. Leukemia. 2017;31(2):282–291. doi:10.1038/leu.2016.322
  • Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer. 2002;2(9):647–656. doi:10.1038/nrc883
  • Bennett R, Thompson E, Tam C; SOHO State of the Art Updates and Next Questions. Mechanisms of resistance to BCL2 inhibitor therapy in chronic lymphocytic leukemia and potential future therapeutic directions. Clin Lymphoma Myeloma Leuk. 2022;22(11):795–804. doi:10.1016/j.clml.2022.07.013
  • Hallek M, Al-Sawaf O. Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures. Am J Hematol. 2021;96(12):1679–1705. doi:10.1002/ajh.26367
  • Stephens DM. NCCN guidelines update: chronic lymphocytic leukemia/small lymphocytic lymphoma. J Natl Compr Canc Netw. 2023;21(5.5):563–566. doi:10.6004/jnccn.2023.5007
  • Honigberg LA, Smith AM, Sirisawad M, et al. 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 U S A. 2010;107(29):13075–13080. doi:10.1073/pnas.1004594107
  • Herman SE, Gordon AL, Hertlein E, 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. doi:10.1182/blood-2011-01-328484
  • Ponader S, Chen SS, Buggy JJ, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012;119(5):1182–1189. doi:10.1182/blood-2011-10-386417
  • de Rooij MF, Kuil A, Geest CR, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119(11):2590–2594. doi:10.1182/blood-2011-11-390989
  • Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42. doi:10.1056/NEJMoa1215637
  • Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213–223. doi:10.1056/NEJMoa1400376
  • Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015;373(25):2425–2437. doi:10.1056/NEJMoa1509388
  • Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib–rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432–443. doi:10.1056/NEJMoa1817073
  • Moreno C, Greil R, Demirkan F, et al. First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase III iLLUMINATE trial. Haematologica. 2022;107(9):2108–2120. doi:10.3324/haematol.2021.279012
  • Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517–2528. doi:10.1056/NEJMoa1812836
  • Hillmen P, Pitchford A, Bloor A, et al. Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24(5):535–552. doi:10.1016/s1470-2045(23)00144-4
  • Shanafelt TD, Wang XV, Hanson CA, et al. Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood. 2022;140(2):112–120. doi:10.1182/blood.2021014960
  • Xiao L, Salem J-E, Clauss S, et al. Ibrutinib-mediated atrial fibrillation attributable to inhibition of C-terminal src kinase. Circulation. 2020;142(25):2443–2455. doi:10.1161/CIRCULATIONAHA.120.049210
  • Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323–332. doi:10.1056/NEJMoa1509981
  • Herman SEM, Montraveta A, Niemann CU, et al. The Bruton Tyrosine Kinase (BTK) inhibitor acalabrutinib demonstrates potent on-target effects and efficacy in two mouse models of chronic lymphocytic leukemia. Clin Cancer Res. 2017;23(11):2831–2841. doi:10.1158/1078-0432.ccr-16-0463
  • Sharma S, Pepin X, Burri H, et al. Bioequivalence and relative bioavailability studies to assess a new acalabrutinib formulation that enables coadministration with proton-pump inhibitors. Clin Pharmacol Drug Dev. 2022;11(11):1294–1307. doi:10.1002/cpdd.1153
  • Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized Phase III trial. J Clin Oncol. 2021;39(31):3441–3452. doi:10.1200/jco.21.01210
  • Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naive chronic lymphocytic leukemia: 6-year follow-up of elevate-TN. Blood. 2023;142(Suppl 1):636. doi:10.1182/blood-2023-174750
  • Molica S, Giannarelli D, Montserrat E. Comparison between venetoclax-based and Bruton tyrosine kinase inhibitor-based therapy as upfront treatment of Chronic Lymphocytic Leukemia (CLL): a systematic review and network meta-analysis. Clin Lymphoma Myeloma Leuk. 2021;21(4):216–223. doi:10.1016/j.clml.2020.10.012
  • Davids MS, Telford C, Abhyankar S, Waweru C, Ringshausen I. Matching-adjusted indirect comparisons of safety and efficacy of acalabrutinib versus other targeted therapies in patients with treatment-naïve chronic lymphocytic leukemia. Leuk Lymphoma. 2021;62(10):2342–2351. doi:10.1080/10428194.2021.1913144
  • Tam CS, Trotman J, Opat S, et al. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019;134(11):851–859. doi:10.1182/blood.2019001160
  • Brown JR, Eichhorst BF, Lamanna N, et al. Extended follow-up of ALPINE randomized Phase 3 study confirms sustained superior progression-free survival of zanubrutinib versus ibrutinib for treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL). Blood. 2023;142(Suppl 1):202. doi:10.1182/blood-2023-174289
  • Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768–778. doi:10.1016/s1470-2045(16)30019-5
  • Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2015;374(4):311–322. doi:10.1056/NEJMoa1513257
  • Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107–1120. doi:10.1056/NEJMoa1713976
  • Al-Sawaf O, Robrecht S, Zhang C, et al. S145: venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized CLL14 Study. Hemasphere. 2023;7(Suppl):e064430a. doi:10.1097/01.HS9.0000967492.06443.0a
  • Eichhorst B, Niemann CU, Kater AP, et al. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388(19):1739–1754. doi:10.1056/NEJMoa2213093
  • Hallek M. First line therapy of CLL. Hematol Oncol. 2023;41(Supple 1):129–135. doi:10.1002/hon.3145
  • Jones JA, Mato AR, Wierda WG, 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. doi:10.1016/s1470-2045(17)30909-9
  • Greil R, Fraser G, Leber B, et al. Efficacy and Safety of Ibrutinib (IBR) after Venetoclax (VEN) Treatment in IBR-Naïve Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL): follow-up of patients from the MURANO study. Blood. 2018;132(Suppl 1):5548. doi:10.1182/blood-2018-99-118148
  • Lin VS, Lew TE, Handunnetti SM, et al. BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax. Blood. 2020;135(25):2266–2270. doi:10.1182/blood.2020004782
  • Thompson MC, Harrup RA, Coombs CC, et al. Venetoclax retreatment of patients with chronic lymphocytic leukemia after a previous venetoclax-based regimen. Blood Adv. 2022;6(15):4553–4557. doi:10.1182/bloodadvances.2022007812
  • Skarbnik A, Miranda M, Yong AS, et al. A matching-adjusted indirect comparison (MAIC) of the efficacy and safety of acalabrutinib (acala) versus zanubrutinib (zanu) in relapsed or refractory chronic lymphocytic leukemia (RR CLL). J Clin Oncol. 2023;41(16 Suppl):7540. doi:10.1200/JCO.2023.41.16_suppl.7540
  • Mato AR, Roeker LE, Jacobs R, et al. Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy. Clin Cancer Res. 2020;26(14):3589–3596. doi:10.1158/1078-0432.ccr-19-3815
  • Mato AR, Davids MS, Sharman J, et al. Recognizing unmet need in the era of targeted therapy for CLL/SLL: “What’s Past Is Prologue” (Shakespeare). Clin Cancer Res. 2022;28(4):603–608. doi:10.1158/1078-0432.ccr-21-1237
  • Aronson JH, Skånland SS, Roeker LE, Thompson MC, Mato AR. Approach to a patient with “double refractory” chronic lymphocytic leukemia: “Double, double toil and trouble” (Shakespeare). Am J Hematol. 2022;97(Suppl 2):S19–S25. doi:10.1002/ajh.26682
  • Lew TE, Lin VS, Cliff ER, et al. Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition. Blood Adv. 2021;5(20):4054–4058. doi:10.1182/bloodadvances.2021005083
  • Thompson MC, Roeker LE, Coombs CC, et al. Addressing a new challenge in chronic lymphocytic leukemia: outcomes of therapies after exposure to both a covalent Bruton’s tyrosine kinase inhibitor and venetoclax. Blood. 2021;138(Suppl 1):2628. doi:10.1182/blood-2021-150751
  • Furman RR, Cheng S, Lu P, et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med. 2014;370(24):2352–2354. doi:10.1056/NEJMc1402716
  • Nakhoda S, Vistarop A, Wang YL. Resistance to Bruton tyrosine kinase inhibition in chronic lymphocytic leukaemia and non-Hodgkin lymphoma. Br J Haematol. 2023;200(2):137–149. doi:10.1111/bjh.18418
  • Quinquenel A, Fornecker L-M, Letestu R, et al. Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study. Blood. 2019;134(7):641–644. doi:10.1182/blood.2019000854
  • Woyach J, Huang Y, Rogers K, et al. Resistance to acalabrutinib in CLL is mediated primarily By BTK mutations. Blood. 2019;134(Suppl 1):504. doi:10.1182/blood-2019-127674
  • Handunnetti SM, Tang CPS, Nguyen T, et al. BTK Leu528Trp - a potential secondary resistance mechanism specific for patients with chronic lymphocytic leukemia treated with the next generation BTK inhibitor zanubrutinib. Blood. 2019;134(Suppl 1):170. doi:10.1182/blood-2019-125488
  • Blombery P, Thompson ER, Lew TE, et al. Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: potential for pirtobrutinib cross-resistance. Blood Adv. 2022;6(20):5589–5592. doi:10.1182/bloodadvances.2022008325
  • Wang E, Mi X, Thompson MC, et al. Mechanisms of resistance to noncovalent Bruton’s tyrosine kinase inhibitors. N Engl J Med. 2022;386(8):735–743. doi:10.1056/NEJMoa2114110
  • Blombery P, Anderson MA, Gong J-N, 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. doi:10.1158/2159-8290.cd-18-1119
  • Tausch E, Close W, Dolnik A, et al. Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia. Haematologica. 2019;104(9):e434–e437. doi:10.3324/haematol.2019.222588
  • Blombery P, Thompson ER, Nguyen T, et al. Multiple BCL2 mutations cooccurring with Gly101Val emerge in chronic lymphocytic leukemia progression on venetoclax. Blood. 2020;135(10):773–777.
  • Lucas F, Larkin K, Gregory CT, et al. Novel BCL2 mutations in venetoclax-resistant, ibrutinib-resistant CLL patients with BTK/PLCG2 mutations. Blood. 2020;135(24):2192–2195.
  • Deng J, Isik E, Fernandes SM, Brown JR, Letai A, Davids MS. Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia. 2017;31(10):2075–2084. doi:10.1038/leu.2017.32
  • Kater AP, Slinger E, Cretenet G, et al. Combined ibrutinib and venetoclax treatment vs single agents in the TCL1 mouse model of chronic lymphocytic leukemia. Blood Adv. 2021;5(23):5410–5414. doi:10.1182/bloodadvances.2021004861
  • Wierda WG, Allan JN, Siddiqi T, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia: primary analysis results from the minimal residual disease cohort of the randomized Phase II CAPTIVATE study. J Clin Oncol. 2021;39(34):3853–3865. doi:10.1200/JCO.21.00807
  • Ghia P, Wierda WG, Barr PM, et al. Relapse after first-line fixed duration ibrutinib + venetoclax: high response rates to ibrutinib retreatment and absence of BTK mutations in patients with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) with up to 5 years of follow-up in the Phase 2 Captivate Study. Blood. 2023;142(Suppl 1):633. doi:10.1182/blood-2023-187128
  • Soumerai JD, Mato AR, Dogan A, et al. Zanubrutinib, obinutuzumab, and venetoclax with minimal residual disease-driven discontinuation in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2021;8(12):e879–e890. doi:10.1016/S2352-3026(21)00307-0
  • Kater AP, Owen C, Moreno C, et al. Fixed-duration ibrutinib-venetoclax in patients with chronic lymphocytic leukemia and comorbidities. NEJM Evid. 2022;1(7):EVIDoa2200006. doi:10.1056/EVIDoa2200006
  • Moreno C, Munir T, Owen C, et al. First-line fixed-duration Ibrutinib Plus Venetoclax (Ibr+Ven) versus Chlorambucil Plus Obinutuzumab (Clb+O): 55-month follow-up from the Glow Study. Blood. 2023;142(Suppl 1):634. doi:10.1182/blood-2023-177713
  • Janssen. European Commission Approves IMBRUVICA® (ibrutinib) in a fixed-duration combination regimen for adult patients with previously untreated Chronic Lymphocytic Leukaemia (CLL) [press release]; 2022 [August 4]. Available from: https://www.jnj.com/european-commission-approves-imbruvica-ibrutinib-in-a-fixed-duration-combination-regimen-for-adult-patients-with-previously-untreated-chronic-lymphocytic-leukaemia-cll. Accessed October 4, 2023.
  • Hillmen P, Cairns DA, Bloor A, et al. Ibrutinib Plus Venetoclax with MRD-directed duration of treatment is superior to FCR and is a new standard of care for previously untreated CLL: report of the Phase III UK NCRI FLAIR Study. Blood. 2023;142(Suppl 1):631. doi:10.1182/blood-2023-178298
  • Aslan B, Kismali G, Iles LR, et al. Pirtobrutinib inhibits wild-type and mutant Bruton’s tyrosine kinase-mediated signaling in chronic lymphocytic leukemia. Blood Cancer J. 2022;12(5):80. doi:10.1038/s41408-022-00675-9
  • Woyach JA, Brown JR, Ghia P, et al. Pirtobrutinib in Post-cBTKi CLL/SLL: ~30 months follow-up and subgroup analysis with/without prior BCL2i from the Phase 1/2 BRUIN Study. Blood. 2023;142(Suppl 1):325. doi:10.1182/blood-2023-185852
  • Eli Lilly and Company. Jaypirca® (pirtobrutinib) Now Approved by U.S. FDA for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who have received at least two lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor [press release]. 2023 [December 1]. Available from: https://investor.lilly.com/news-releases/news-release-details/jaypircar-pirtobrutinib-now-approved-us-fda-treatment-adult. Accessed January 27, 2024.
  • Woyach JA, Flinn IW, Awan FT, et al. Efficacy and safety of nemtabrutinib, a wild-type and C481S-mutated Bruton tyrosine kinase inhibitor for B-cell malignancies: updated analysis of the open-label Phase 1/2 Dose-Expansion Bellwave-001 Study. Blood. 2022;140(Suppl 1):7004–7006. doi:10.1182/blood-2022-163596
  • Linton K, Forconi F, Lewis D, et al. Robust Bruton’s tyrosine kinase (BTK) degradation with NX-5948, an oral BTK degrader, in a first-in-human phase 1a trial in relapsed/refractory B cell malignancies. Hematol Oncol. 2023;41(Suppl 2):573–574. doi:10.1002/hon.3164_428
  • Portelinha A, Wendel HG. The cat-and-mouse game of BTK inhibition. Blood. 2023;141(13):1502–1503. doi:10.1182/blood.2022018936
  • Mihalic JT, Brathaban N, Bravo B, et al. Abstract 3423: NX-2127: a first-in-class clinical stage degrader of BTK and IKZF1/3 for the treatment of patients with B cell malignancies. Cancer Res. 2023;83(7 Suppl):3423. doi:10.1158/1538-7445.am2023-3423
  • Mato AR, Wierda WG, Ai WZ, et al. NX-2127-001, a First-in-Human Trial of NX-2127, a Bruton’s Tyrosine Kinase-Targeted Protein Degrader, in patients with relapsed or refractory chronic lymphocytic leukemia and B-cell malignancies. Blood. 2022;140(Suppl 1):2329–2332. doi:10.1182/blood-2022-164772
  • Robbins D, Noviski M, Tan M, et al. POS0006 NX-5948, a selective degrader of btk, significantly reduces inflammation in a model of autoimmune disease. Ann Rheum Dis. 2021;80(Suppl 1):204. doi:10.1136/annrheumdis-2021-eular.1675
  • Davids MS, Chanan-Khan A, Mudenda B, et al. Lisaftoclax (APG-2575) safety and activity as monotherapy or combined with acalabrutinib or rituximab in patients (pts) with treatment-naïve, relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (R/R CLL/SLL): initial data from a Phase 2 Global Study. Blood. 2022;140(Suppl 1):2326–2328. doi:10.1182/blood-2022-160386
  • Soumerai JD, Lasica M, Opat S, et al. A Phase 1 Study with the Novel B-Cell Lymphoma 2 (Bcl-2) Inhibitor Bgb-11417 As Monotherapy or in Combination with Zanubrutinib (ZANU) in Patients (Pts) with Non-Hodgkin Lymphoma (NHL) or Waldenström Macroglobulinemia (WM): preliminary data. Blood. 2022;140(Suppl 1):9325–9327. doi:10.1182/blood-2022-169664
  • Cheah CY, Tam CS, Lasica M, et al. A Phase 1 Study with the Novel B-Cell Lymphoma 2 (Bcl-2) Inhibitor Bgb-11417 as monotherapy or in Combination with Zanubrutinib (ZANU) in Patients (Pts) with CLL/SLL: preliminary data. Blood. 2022;140(Suppl 1):2321–2323. doi:10.1182/blood-2022-169662
  • Brandhuber B, Ku K, Lallena MJ, et al. Abstract 1258: preclinical characterization of LOXO-338, a novel, oral and selective BCL2 inhibitor. Cancer Res. 2021;81(13 Suppl):1258. doi:10.1158/1538-7445.am2021-1258
  • Liu C, Yang M, Zhang D, Chen M, Zhu D. Clinical cancer immunotherapy: current progress and prospects. Front Immunol. 2022;13:961805. doi:10.3389/fimmu.2022.961805
  • Perutelli F, Jones R, Griggio V, Vitale C, Coscia M. Immunotherapeutic strategies in chronic lymphocytic leukemia: advances and challenges. Front Oncol. 2022;12:837531. doi:10.3389/fonc.2022.837531
  • Beers SA, Chan CH, French RR, Cragg MS, Glennie MJ. CD20 as a target for therapeutic type I and II monoclonal antibodies. Semin Hematol. 2010;47(2):107–114. doi:10.1053/j.seminhematol.2010.01.001
  • Hillmen P, Robak T, Janssens A, et al. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015;385(9980):1873–1883. doi:10.1016/S0140-6736(15)60027-7
  • Cortelezzi A, Sciumè M, Liberati AM, et al. Bendamustine in combination with Ofatumumab in relapsed or refractory chronic lymphocytic leukemia: a GIMEMA Multicenter Phase II Trial. Leukemia. 2014;28(3):642–648. doi:10.1038/leu.2013.334
  • Jones JA, Robak T, Brown JR, et al. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol. 2017;4(3):e114–e126. doi:10.1016/S2352-3026(17)30019-4
  • Wang K, Wei G, Liu D. CD19: a biomarker for B cell development, lymphoma diagnosis and therapy. Exp Hematol Oncol. 2012;1(1):36. doi:10.1186/2162-3619-1-36
  • Staber PB, Jurczak W, Greil R, et al. Tafasitamab combined with idelalisib or venetoclax in patients with CLL previously treated with a BTK inhibitor. Leuk Lymphoma. 2021;62(14):3440–3451. doi:10.1080/10428194.2021.1964020
  • Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin’s Lymphoma. N Engl J Med. 2014;372(4):311–319. doi:10.1056/NEJMoa1411087
  • Xu-Monette ZY, Zhou J, Young KH. PD-1 expression and clinical PD-1 blockade in B-cell lymphomas. Blood. 2018;131(1):68–83. doi:10.1182/blood-2017-07-740993
  • Riches JC, Davies JK, McClanahan F, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood. 2013;121(9):1612–1621. doi:10.1182/blood-2012-09-457531
  • Ding W, LaPlant BR, Call TG, et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood. 2017;129(26):3419–3427. doi:10.1182/blood-2017-02-765685
  • Jain N, Senapati J, Thakral B, et al. A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL. Blood Adv. 2023;7(10):1958–1966. doi:10.1182/bloodadvances.2022008790
  • Jain N, Ferrajoli A, Thompson PA, et al. Venetoclax, obinutuzumab and atezolizumab (PD-L1 Checkpoint Inhibitor) for treatment for patients with Richter transformation. Blood. 2021;138(Suppl 1):1550. doi:10.1182/blood-2021-154279
  • Wei J, Yang Y, Wang G, Liu M. Current landscape and future directions of bispecific antibodies in cancer immunotherapy. Front Immunol. 2022;13:1035276. doi:10.3389/fimmu.2022.1035276
  • Thompson PA, Jiang X, Banerjee P, et al. A phase two study of high dose blinatumomab in Richter’s syndrome. Leukemia. 2022;36(9):2228–2232. doi:10.1038/s41375-022-01649-3
  • Eichhorst B, Eradat H, Niemann CU, et al. Epcoritamab monotherapy and combinations in relapsed or refractory chronic lymphocytic leukemia or Richter’s Syndrome: new escalation and expansion cohorts in epcore Cll-1. Hematol Oncol. 2023;41(Suppl 2):828–829. doi:10.1002/hon.3166_OT10
  • Kater AP, Ye JC, Sandoval-Sus J, et al. Subcutaneous epcoritamab in patients with Richter’s syndrome: early results from Phase 1b/2 Trial (EPCORE CLL-1). Blood. 2022;140(Suppl 1):850–851. doi:10.1182/blood-2022-158298
  • Abbvie. EPKINLY™ (epcoritamab-bysp) Approved by U.S. FDA as the first and only bispecific antibody to treat adult patients with relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL) [press release]; 2023 [May 19]. Available from: https://news.abbvie.com/news/press-releases/epkinly-epcoritamab-bysp-approved-by-us-fda-as-first-and-only-bispecific-antibody-to-treat-adult-patients-with-relapsed-or-refractory-diffuse-large-b-cell-lymphoma-dlbcl.htm. Accessed October 4, 2023.
  • Carlo-Stella C, Hutchings M, Offner F, et al. Glofitamab monotherapy induces durable complete remissions and has a manageable safety profile in patients with Richter’s transformation. Hematol Oncol. 2023;41(Suppl 2):63–65. doi:10.1002/hon.3163_28
  • Genentech. FDA Approves Genentech’s Columvi, the first and only bispecific antibody with a fixed-duration treatment for people with relapsed or refractory diffuse large B-cell lymphoma [press release]; 2023 [June 15]. Available from: https://www.gene.com/media/press-releases/14994/2023-06-15/fda-approves-genentechs-columvi-The-firs. Accessed October 4, 2023.
  • Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–2544. doi:10.1056/NEJMoa1707447
  • Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2018;380(1):45–56. doi:10.1056/NEJMoa1804980
  • Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–448. doi:10.1056/NEJMoa1709866
  • Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3(95):95ra73. doi:10.1126/scitranslmed.3002842
  • Todorovic Z, Todorovic D, Markovic V, et al. CAR T cell therapy for chronic lymphocytic leukemia: successes and shortcomings. Curr Oncol. 2022;29(5):3647–3657. doi:10.3390/curroncol29050293
  • Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene Maraleucel (liso-cel) in R/R CLL/SLL: 24-month median follow-up of TRANSCEND CLL 004. Blood. 2023;142(Suppl 1):330. doi:10.1182/blood-2023-179529
  • Ruella M, Maus MV. Catch me if you can: leukemia escape after CD19-directed T cell immunotherapies. Comput Struct Biotechnol J. 2016;14:357–362. doi:10.1016/j.csbj.2016.09.003
  • Shadman M, Yeung C, Redman M, et al. Safety and efficacy of third generation CD20 targeted CAR-T (MB-106) for treatment of relapsed/refractory B-NHL and CLL. Blood. 2021;138(Suppl 1):3872. doi:10.1182/blood-2021-149181
  • Hudecek M, Schmitt TM, Baskar S, et al. The B-cell tumor–associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor. Blood. 2010;116(22):4532–4541. doi:10.1182/blood-2010-05-283309
  • Faitschuk E, Hombach AA, Frenzel LP, Wendtner CM, Abken H. Chimeric antigen receptor T cells targeting Fc μ receptor selectively eliminate CLL cells while sparing healthy B cells. Blood. 2016;128(13):1711–1722. doi:10.1182/blood-2016-01-692046
  • Fraietta JA, Beckwith KA, Patel PR, et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood. 2016;127(9):1117–1127. doi:10.1182/blood-2015-11-679134
  • Wierda WG, Dorritie KA, Munoz J, et al. Transcend CLL 004: Phase 1 cohort of lisocabtagene maraleucel (liso-cel) in combination with ibrutinib for patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). Blood. 2020;136:39–40. doi:10.1182/blood-2020-140622