New Study Offers First Direct Comparison Between Venetoclax, Ibrutinib in CLL

Patients with relapsing/remitting chronic lymphocytic leukemia (CLL) have a range of new therapeutic options. A new study is the first to directly compare 2 of the more prominent new therapies.

Venetoclax has increasingly become a prominent therapeutic option for patients with chronic lymphocytic leukemia (CLL). Now, a new study evaluates its effectiveness against another well-known therapy, ibrutinib.

Writing in the journal Haematologica, investigators from the United States and United Kingdom note that no such comparison has previously been made between the 2 therapies.

The study comes as treatment of the relapsing/remitting form of CLL (R/R CLL) has been dramatically reshaped by the development and approval of novel agents.

Ibtrutinib is a Bruton tyrosine kinase inhibitor (BTKi) targeting B-cell receptor pathway signalling. First author Toby A. Eyre, MBChB, MD, of Oxford University Hospitals, in the United Kingdom, notes that the drug has shown significant benefit as a monotherapy for patients with relapsing CLL. Another drug, idelalisib, targets the same pathway and has been approved for use in combination with rituximab. However, despite improvements in progression-free survival among patients, Eyre and colleagues say toxicity concerns have limited its use.

Venetoclax is a B-cell lymphoma 2 inhibitor (BCL2i), approved for use with or without rituximab.

“Venetoclax is increasingly utilized at first relax in combination with rituximab for a 2-year fixed duration,” the investigators write. “However, to date, no prospective trials have directly compared ibrutinib to venetoclax as NA1 in R/R CLL.”

Eyre and his team sought to change that by creating a large-scale, international, multicenter study using data from previous studies into each novel agent. They found 433 patients who received ibrutinib or venetoclax with or without CD20 as NA1. Of those progression-free survival (PFS) data were available for 417 patients. Median follow-up was 14 months for the patients on ibrutinib (the majority), and 13.5 months for the patients receiving venetoclax. The primary endpoints of the study were overall response rate (ORR) and PFS.

The investigators found ibrutinib had an ORR of 71% and a PFS rate of 12%. Patients on venetoclax saw an ORR of 96% and a PFS rate of 56%. Dose interruptions were reported in about one-third of patients in each cohort, and dose reductions were reported in roughly one-quarter of patients for both ibrutinib (22%) and venetoclax (26%).

Discontinuation rates for 41% for ibrutinib and 25% for venetoclax. In the case of ibrutinib, the most common reasons given for discontinuation were adverse events (22%), CLL progression (8%), and Richter’s transformation (2%),” Tyre and colleagues write. Allogeneic stem-cell transplantation was the most common reason for discontinuation in the venetoclax cohort (10%), followed by CLL progression (4%), and unrelated death event (4%).

Venetoclax also had a superior complete response rate, which Eyre and colleagues say likely contributed to its PFS advantage over ibrutinib, but the advantage did not carry over to overall survival.

“In light of this, and in the absence of randomized data comparing these approaches, our data provides reassurance that either option remains a reasonable approach as NA1 in R/R CLL,” the authors write.

Therefore, they conclude, the choice of an NA1 ought to be based on factors such as “individual patient factors, drug access, deliverability and patient preference.”


Eyre TA, Lamanna N, Roeker LE, et al. Comparative analysis of targeted novel therapies in relapsed, refractory chronic lymphocytic leukaemia. Haematologica. 2020. doi:10.3324/haematol.2019.241539.

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