Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by mature monoclonal B lymphocytes. The chronic activation of the B-cell receptor in CLL allows for survival of malignant B cells. Bruton tyrosine kinase (BTK) inhibitors can block the phosphorylation of the B-cell receptor downstream kinases and stop signaling, therefore halting proliferation.

 Ibrutinib (Imbruvica) was approved in 2016 by the FDA for patients with untreated CLL based on findings from the phase 3 RESONATE-2 trial (NCT01722487).

 In RESONATE-2, ibrutinib 420 mg once daily (n = 136) was compared with oral chlorambucil (n = 133). An overall response rate (ORR) of 92% was noted and a progression-free survival (PFS) benefit was seen in all subgroups, including patients with 

 mutations. At 8 years follow-up, median PFS and overall survival had not yet been reached for patients in the ibrutinib arm, with 59% of patients still alive and progression free.

Ibrutinib is typically given until progression or intolerable toxicity. However, a fixed-duration regimen is possible with the addition of venetoclax (Venclexta). In the phase 2 CAPTIVATE-FD trial (NCT02910583), 3 cycles of ibrutinib followed by 12 cycles of ibrutinib plus venetoclax were given (n = 159). The ORR was 96% (95% CI, 93%-99%), with a complete remission rate of 55% (95% CI, 48%-63%). Minimal residual disease (MRD) evaluation with flow cytometry from peripheral blood and bone marrow demonstrated high MRD negativity rates of approximately 60% and 77%, respectively. Notable adverse events (AEs) included neutropenia; the rate of atrial fibrillation and major hemorrhage were similar to those observed in prior ibrutinib trials.

Ibrutinib’s off-target inhibition can result in AEs such as rash, diarrhea, atrial fibrillation, and bleeding.

 To address this issue, a new generation of BTK inhibitors restricting off-target inhibition was developed. The phase 3 ELEVATE-TN trial (NCT02475681) evaluated first-line acalabrutinib (Calquence) 100 mg twice a day alone (n = 179) or in combination with obinutuzumab (Gazyva; n = 179) vs chlorambucil and obinutuzumab (n = 177). The ORRs in the acalabrutinib monotherapy arm and the acalabrutinib combination arm were 86% (95% CI, 80%-90%) and 94% (95% CI, 89%-97%), respectively. The median PFS was not yet reached in patients treated with acalabrutinib (alone or as part of the combination) vs 22.6 months (95% CI, 20.2-27.6) months among patients treated with chemoimmunotherapy. AEs such as atrial fibrillation and hemorrhage were lower in comparison with previously reported AEs with ibrutinib. A 5-year follow-up continued to show the benefit of this regimen, with PFS rates up to 84%.

Finally, findings from the phase 3 ALPINE trial (NCT03734016) of patients with relapsed/refractory CLL showed encouraging results with zanubrutinib (Brukinsa). Patients were randomly assigned to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily. The ORR for zanubrutinib was 78%, compared with 62% for ibrutinib. Twelve-month PFS was also superior with zanubrutinib at 95% vs 84% with ibrutinib. The AE rate leading to treatment discontinuation as well as rates of reported atrial fibrillation and hemorrhage were lower with zanubrutinib.

 Furthermore, frontline zanubrutinib had similar favorable outcomes in the phase 3 SEQUOIA trial (NCT03336333), including improvement in PFS compared with rituximab (Rituxan) and bendamustine (Bendeka).

Overall, BTK inhibitors are an excellent treatment option for patients with CLL. The response rates achieved with this agent class are high and survival benefits are clear compared with chemoimmunotherapy. The choice of BTK inhibitor regimen must be tailored to the patient, taking into consideration their preferences and comorbidities, as well as potential treatment-related AEs.

Cesar Gentille Sanchez, MD, is a hematologist/ oncologist at the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences (UAMS) in Little Rock. He is an assistant professor in the Department of Internal Medicine at UAMS College of Medicine.

Ahn IE, Brown JR. Targeting Bruton’s tyrosine kinase in CLL. 

. 2021;12:687458. doi:10.3389/fimmu.2021.687458

Hallek M, Al-Sawaf O. Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures. 

. 2021;96(12):1679-1705. doi:10.1002/ajh.26367

Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. 

. 2022;6(11):3440-3450. doi:10.1182/ bloodadvances.2021006434

Tam CS, Allan JN, Siddiqi T, et al. Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort. 

. 2022;139(22):3278-3289. doi:10.1182/ blood.2021014488

Estupiñán HY, Berglöf A, Zain R, Smith CIE. Comparative analysis of BTK inhibitors and mechanisms underlying adverse effects. 

. 2021;9:630942. doi:10.3389/fcell.2021.630942

Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab versus obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: five-year follow-up of ELEVATE-TN. 

. 2022;40(suppl 16):7539. doi:10.1200/JCO.2022.40.16_suppl.7539

Brown JR, Hillmen P, Eichhorst B, et al. CLL-115 First interim analysis of ALPINE study: results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). 

. 2022;22(suppl 2):S266. doi:10.1016/ S2152-2650(22)01324-6

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