BTKi Improves Disease Control in CLL After Progression on Venetoclax

Treatment with a Bruton tyrosine kinase inhibitor (BTKi) showed efficacy in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) that progressed on venetoclax, according to a study published in Blood. Duration of remission to venetoclax was associated with progression-free survival (PFS) following BTKi therapy in these patients, but according to lead study author Mary Anderson, MD, of the Royal Melbourne Hospital in Australia, this finding should be interpreted with caution because of the small sample size and lack of a multivariate adjusted analysis.

Dr. Anderson and colleagues retrospectively evaluated the medical records of 23 consecutive patients with relapsed/refractory CLL who received BTKi therapy after their disease progressed on venetoclax during participation in one of four clinical trials. In these trials, participants received venetoclax 100 to 600 mg/day. The majority of patients received venetoclax 400 mg/day.

Treatment for progressive CLL after venetoclax included ibrutinib 420 mg per day (n = 21) or zanubrutinib 160 mg twice per day (n = 2).

At the time of BTKi initiation, the median age of the overall cohort was 72 years (range = 50-89). In 19 patients, the median time from CLL diagnosis to the start of venetoclax was 8 years (range = 3-19). The median time from CLL diagnosis to the start of BTKi therapy was 11 years (range = 5-22).

Participants received a median of 4 prior therapies (range = 2-9). Most patients (91%) had received fludarabine, cyclophosphamide, and rituximab. Prior to BTKi therapy, approximately 76% of patients had disease-harboring TP53 abnormalities, while 68% had complex karyotype. The majority of patients (91%) had achieved an objective response to venetoclax.

The median duration between discontinuation of venetoclax and start of BTKi therapy was 1 month (range = <1-11). Out of 23 enrolled patients, 20 (91%) achieved objective responses to BTKi therapy, including 16 who achieved partial response (PR)/PR with treatment-induced lymphocytosis and 4 patients who achieved complete remission (CR).

In addition, the median PFS following the start of BTKi therapy was 34 months (95% CI 10.4-undefined). A total of 11 patients (48%) remained on BTKi therapy at a median survivor follow-up of 33 months (range = 2-53). Approximately 52% of patients (n=12) stopped BTKi therapy because of progressive disease (n=8) or toxicity (n=4).

The median overall survival after the start of BTKi therapy was 42 months (95% CI 34.2-undefined). A total of 8 deaths were recorded, 4 attributed to progressive disease and 4 to drug toxicity.

In univariate analysis, duration of remission during venetoclax therapy for ≥24 months was associated with significantly longer PFS on subsequent BTKi therapy compared with remission for <24 months (34 vs. 23 months, respectively; hazard ratio = 0.31; 95% CI 0.09-1.03; p=0.044).

A total of 8 patients had the BCL2 Gly101Val mutation, which is associated with resistance to venetoclax. In this subpopulation, the median PFS was not reached at a median follow-up of 33 months.

“Our data validate that the patients [with the Gly101Val mutation] are very sensitive to BTKi therapy,” said Dr. Anderson. “Given the paucity of other good options to date, BTKi therapy is likely to remain a good option for most patients who progress on venetoclax,” she added.

In addition, patients who achieved CR/undetectable measurable residual disease (uMRD) and had prolonged remission to venetoclax also had significantly longer PFS on BTKi therapy (p=0.029). Among 4 patients with previous uMRD on venetoclax, all were still receiving BTKi therapy at a median of 21 months (range = 2-46).

Dr. Anderson concluded that these findings, together with previous research showing venetoclax may salvage ibrutinib failure, suggest that clinicians may be able to sequence BTKi and venetoclax interchangeably, depending on the circumstances.

The authors report to relevant conflicts of interest.


Lin VS, Lew TE, Handunnetti SM, et al. BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax. Blood. 2020 Apr 3. [Epub ahead of print]

BCL2 G101V mutations are found in up to half of patients receiving venetoclax continuously who relapse, according to data from Cancer Discovery1 and Haematologica.2 We don’t yet know the frequency of these mutations in patients exposed to venetoclax intermittently, since the mutations tend to arise later in the course of treatment.

These findings, combined with other reports showing similar data, are very helpful in presenting treatment options to patients. While it has been suspected that BTKi would be effective in patients after receiving venetoclax based on the different mechanism of action and disparate resistance mechanisms of these drugs, it is useful to have data showing this to be true.

This is a retrospective study on a relatively small group of patients, which limits the ability to make conclusive statements. Prospective data would help, but one problem we have with these highly effective agents is that the length of remission durations mean that a prospective study would take too long to be feasible. There are ongoing trials attempting to answer the question of how the efficacy of sequential therapies (BTKi followed by BCL2 inhibitor, or BCL2 followed by BTKi) compares with combination therapies (BTKi plus BCL2).

Jennifer Woyach, MD
The Ohio State University
Columbus, OH


  1. Blombery P, Anderson MA, Gong J, et al. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov. 2019 Mar;9:342-353.Tausch E, Close W, Dolnik A, et al.
  2. Venetoclax resistance and acquired BCL2 mutations In chronic lymphocytic leukemia. Haematologica. 2019 Sep;104:e434-e437.