Though venetoclax-based regimens can produce high response rates in patients with chronic lymphocytic leukemia (CLL), disease progression during or after treatment is common, according to a review recently published in Blood. 1

While intrinsic venetoclax resistance is rare, various mechanisms of acquired resistance have been identified, the review authors noted.

“So far, we have seen acquired resistance primarily associated with the acquisition of specific mutations in BCL2, most commonly G101V, although other point mutations near this amino acid have been implicated as well, and there are also cases where these mutations are not present,” explained Jennifer A. Woyach, MD, a hematologist-oncologist at The Ohio State University Comprehensive Cancer Center in Columbus, who was not involved in the new review but coauthored a March 2020 review on the topic.2

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“Preclinical work3 has suggested upregulation of BCL2 family members such as BCL-XL and MCL-1 in venetoclax-resistant models, but this has not been as clearly seen clinically,” Dr Woyach said.  

In light of the preliminary evidence, the use of BCL-XL and MCL-1 inhibitors to target residual disease should be explored in future research, according to Thomas Lew, MBBS, of Peter MacCallum Cancer Centre in Melbourne, Australia, and colleagues, who wrote the review published in Blood.1

Predicting Progression on Venetoclax

A range of factors have been found to predict disease progression on venetoclax treatment, according to Meghan C. Thompson, MD, a fellow in hematology and medical oncology at Memorial Sloan Kettering Cancer Center in New York, New York.

“The traditional high-risk features that tend to predict resistance to other CLL-directed therapies also are emerging as important predictors of patients who will have progressive disease on venetoclax-based therapies,” Dr Thompson said.

As described in a December 2020 review Dr Thompson coauthored4, features linked to less durable responses include heavily pretreated disease, bulky lymphadenopathy, and high-risk cytogenetic and molecular features, including TP53 aberrations and unmutated IGHV.  

“Minimal residual disease at the end of fixed-duration venetoclax treatment has also been associated with a shorter progression-free survival,” Dr Thompson added. “However, this is an evolving area, given that the initial trials of venetoclax included heavily pretreated patients, including patients with prior chemoimmunotherapy exposure, and now venetoclax in combination with obinutuzumab is increasingly being used in the first-line setting.”

Treatment Considerations for Progressive CLL

Treatment recommendations for patients with progressive CLL after venetoclax-based regimens are based primarily on retrospective data.

When deciding on alternate treatment strategies, one must consider the reasons for venetoclax discontinuation and the patient’s history of exposure to previous therapies, according to Dr Lew and colleagues.

“Firstly, if the patient discontinues venetoclax for a reason other than progressive disease, it is important that the patient meets the International Workshop on CLL (iwCLL) criteria5 for initiation of CLL-directed therapy,” Dr Thompson noted. “If the patient does not meet iwCLL criteria, then the patient may be observed until CLL progression.”

It is also important to consider the timing of relapse, according to Dr Woyach.

“For someone who progresses after venetoclax therapy where there was a long remission duration off-treatment, re-treatment with a venetoclax-based regimen would be appropriate,” Dr Woyach said. “For someone who progresses while on venetoclax or shortly after discontinuation, an alternative therapy should be considered.”

BTK, PI3K Inhibitors and Venetoclax Re-treatment

In their review, Dr Lew and colleagues recommended BTK inhibitor therapy for patients who have not previously shown resistance to it.1 The authors cited results of 2 retrospective studies showing an objective response rate of 84% to 91% and a median progression-free survival (PFS) of 32 to 34 months in patients receiving a BTK inhibitor after venetoclax, including those with BLC2-mutated disease.

Patients with previous intolerance to ibrutinib may achieve durable remissions with a more selective agent such as acalabrutinib or zanubrutinib, according to Dr Lew and colleagues.

The authors also noted that adding rituximab to venetoclax monotherapy has been shown to deepen responses in select cases of progressive CLL.

“For those dual-refractory patients who have progressed on both a covalent BTK inhibitor and venetoclax, the only standard therapy available would be a PI3K inhibitor,” Dr Woyach said.

However, PI3K inhibitors have been linked to poor outcomes (median PFS, 5 months) when used after venetoclax.1 Enrollment in a clinical trial represents the best option for this type of patient, and reversible BTK inhibitors are currently showing promise in these cases, according to Dr Lew and colleagues.

The potential role of venetoclax re-treatment after a previous course of completed therapy is an emerging topic for investigation.

Dr Thompson and colleagues have presented data demonstrating an overall response rate of 72.2% in a small number of CLL patients re-treated with a venetoclax-based regimen, with a median time of 8.7 months between the first and second course of venetoclax.6 Similar results were presented by another group.7

“However, venetoclax re-treatment is not standard of care at this time, and larger retrospective studies and prospective validation of this strategy are needed to see whether patients can be re-treated with venetoclax prior to switching to another class of agents,” Dr Thompson said.

For cases in which no BCL2 mutations are detected, Dr Lew and colleagues would consider venetoclax re-treatment with a concomitant anti-CD20 antibody.1 Although more evidence is needed to guide timing considerations, the authors think the ideal candidates for this approach are patients with treatment-free remissions lasting more than 24 months.

The authors “do not favor re-treatment for patients who have ceased venetoclax for [less than] 12 months prior to developing PD [progressive disease], unless no other feasible therapeutic options exist,” as stated in their review.

Future Directions

Researchers are currently aiming to address multiple remaining gaps in CLL therapy.

In the quest for additional therapies to treat progressive CLL after treatment with both venetoclax and a BTK inhibitor, ongoing clinical trials are exploring the use of noncovalent BTK inhibitors, including pirtobrutinib, as well as cellular therapies that include CD19-directed chimeric antigen receptor T-cell therapy.1

Dr Woyach noted the need to clarify the optimal frontline agent — venetoclax, a BTK inhibitor, or a combination of both — and the influence of factors such as genomic features, patient age, and fitness on these treatment recommendations.

Other important questions pertain to the “best therapy for Richter’s transformation and whether there are ways to modify or eliminate the risk of Richter’s transformation,” Dr Woyach pointed out. “All of these questions are the subject of multiple clinical trials right now, so hopefully we will soon find some answers.” 

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


  1. Lew TE, Tam CS, Seymour JF. How I treat chronic lymphocytic leukemia after venetoclax. Blood. Published online April 19, 2021. doi:10.1182/blood.2020008502
  2. Awan FT, Al-Sawaf O, Fischer K, Woyach JA. Current perspectives on therapy for chronic lymphocytic leukemia. Am Soc Clin Oncol Educ Book. 2020;40:1-10. doi:10.1200/EDBK_279099
  3. Bose P, Gandhi V, Konopleva M. Pathways and mechanisms of venetoclax resistance. Leuk Lymphoma. 2017;58(9):1-17. doi:10.1080/10428194.2017.1283032
  4. Thompson MC, Mato AR. Treatment of relapsed chronic lymphocytic leukemia after venetoclax. Hematology Am Soc Hematol Educ Program. 2020(1):18-23. doi:10.1182/hematology.2020000160
  5. 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
  6. Thompson MC, Allan JN, Sail K, et al. Venetoclax re-treatment of chronic lymphocytic leukemia (CLL) patients after a previous venetoclax-based regimen Blood. 2020;136(suppl 1):39-41. doi:10.1182/blood-2020-138725
  7. Harrup RA, Owen C, D’Rozario J, et al. Efficacy of subsequent novel targeted therapies, including repeated venetoclax-rituximab (VenR), in patients (pts) with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) previously treated with fixed-duration VenR in the Murano study. Blood. 2020;136(suppl 1):44-45.