Venetoclax, Next Generation BTK Inhibitors Show Promise in CLL


Following the success of ibrutinib, second-generation BTK inhibitors have shown even better outcomes with fewer toxicities.

Although they may be effective in different sub-populations of patients with chronic lymphocytic leukemia (CLL), venetoclax and next-generation Bruton tyrosine kinase (BTK) inhibitors have shown significant promise in this disease space, according to a presentation at the American Society of Hematology 2021 Annual Meeting and Exposition.

As a first-generation BTK inhibitor, ibrutinib showed remarkable response rates across patients with relapsed CLL, according to presenter Constantine Tam, MBBS, from the Royal Melbourne Hospital in Australia. At 7 years of follow up, progression-free survival (PFS) rates reached 34% for patients with relapsed disease and 83% for patients treated in the frontline setting, Tam said.

“In an age where chemotherapy was really starting to not work, ibrutinib represented the first major breakthrough in the treatment of chemo-refractory CLL,” Tam said in the presentation.

Frontline ibrutinib was compared with chemotherapy in several studies. In the RESONATE 2 study, treatment with ibrutinib outperformed standard-of-care chemotherapy in both PFS and overall survival.

PFS was also superior with ibrutinib in the Alliance trial, which Tam noted was the second randomized trial to show that ibrutinib plus rituximab essentially produced the same result as ibrutinib monotherapy. Based on these findings, ibrutinib monotherapy became a standard of care. Despite these encouraging results, Tam noted that ibrutinib has some significant drawbacks, including toxicities and adverse events (AEs).

Following the success of ibrutinib, second-generation BTK inhibitors have shown even better outcomes with fewer toxicities, Tam said. Researchers have found improved PFS with acalabrutinib, which is associated with many reduced AEs, including atrial fibrillation, hypertension, and what Tam called “nuisance” AEs (muscle aches, joint pain, rash, etc.).

Zanubrutinib is a more specific inhibitor of BTK compared with ibrutinib, and the ALPINE study found that zanubrutinib had improved PFS versus ibrutinib. Furthermore, investigators found reduced AEs similar to those with acalabrutinib.

Tam said that there are now 3 head-to-head studies comparing ibrutinib with next-generation BTK inhibitors, all of which have found significantly reduced AEs. Despite these encouraging findings, however, BTK inhibitors cannot clear minimal residual disease (MRD), and therefore require indefinite therapy.

To handle this limitation, Tam said venetoclax has shown significant promise as a fixed-duration dose. The CLL14 study evaluated venetoclax and obinutuzumab compared to chlorambucil and obinutuzumab, assigning patients to receive 12 months of therapy. Remarkably, after this period, patients were able to remain drug-free. Tam noted that the main power of this regimen is that it is highly efficient in MRD clearance, with researchers finding 74% clearance in the venetoclax and obinutuzumab arm.

Furthermore, MRD clearance was distinctly associated with the PFS outcome in the CLL14 trial, Tam said. Patients with MRD negativity did exceedingly well with a very long PFS, according to Tam.

There are some exceptions to these findings, including patients with TP53 aberrant CLL or those with IgHV-unmutated CLL. The CLL14 study found that patients with TP53 aberrant disease who received ventoclax did fairly well but had a less robust PFS curve than other patients.

Furthermore, those with 17p deletions had a lower undetectable MRD (uMRD) clearance. Based on these findings, BTK inhibitor therapy may remain more effective in this patient population.

Similarly, patients with IgHV-unmutated CLL do fairly well overall with venetoclax treatment, but still tend to have an inferior outcome compared to patients with IgHV-mutated disease. Because of this, Tam said BTK inhibitor therapy probably provides better disease control for this patient population.

Finally, Tam reviewed the re-dosing findings from the MURANO study, in which 25 patients who had previously received venetoclax were re-challenged after 12 to 38 months off therapy. At the time of retreatment, 14 of these patients carried a 17p deletion, 3 of which were newly acquired and 4 with increased clone size. No patients with 17p deletion achieved uMRD clearance with retreatment.

“Therefore, although a short intermittent therapy may, theoretically, reduce the risk of adverse prognostic features emerging and disease resistance, the data in MURANO does not support this contention so far,” Tam concluded.


Tam, C. Up-Front Therapy: The Case for Continuous Treatment. Presented at: American Society of Hematology 2021 Annual Meeting and Exposition. December 12, 2021. Accessed December 10, 2021.

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