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ASH 2021: Dr. John Seymour on Acquired Mutations in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) After Fixed-Duration Venetoclax-Rituximab Treatment

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Venetoclax was approved for treating relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) in 2018. This decision was based on results from the MURANO trial, a phase 3 clinical trial comparing venetoclax + rituximab with bendamustine + rituximab (a standard chemoimmunotherapy at the time the trial was conducted). Patients treated with venetoclax + rituximab lived longer without their cancer progressing than those treated with bendamustine + rituximab. After 5 years of follow-up, the progression-free survival was 54 months in the venetoclax + rituximab group compared with 17 months in the bendamustine + rituximab group. This study showed that targeted therapies are much more effective for treating relapsed/refractory CLL/SLL than chemoimmunotherapy.

At the American Society of Hematology (ASH) 2021, our own Dr. Brian Koffman interviewed Dr. John Seymour, Director of the Department of Hematology at Peter McCallum Cancer Center in Melbourne, Australia. They discussed an analysis of acquired mutations in patients from the MURANO trial whose disease had progressed.

Takeaways:

  • When we treat cancer, cancer doesn’t just sit still; it tries to find ways to survive and work around drugs through a clonal evolution process.
  • Chemoimmunotherapy is generally not used repeatedly because it tends to produce mutations in TP53, often rendering cancer resistant to further chemoimmunotherapy.
  • When venetoclax was being developed, patients were given continuous therapy, and about half of them developed resistance to venetoclax through mutations in BCL2 (the protein venetoclax targets). This tended to happen after 3 years of exposure to the drug.
  • For this study, researchers wanted to see if patients would develop resistance mutations at the same rate when venetoclax was given as a fixed-duration treatment rather than a continuous treatment.
  • In the MURANO trial, venetoclax was a fixed-duration treatment, which patients received for 2 years and then stopped. Rituximab was administered for 6 months in both the venetoclax and bendamustine groups.
  • Among patients who progressed after bendamustine + rituximab treatment, approximately 1 out of 3 had a newly-acquired TP53 mutation.
  • Among patients who progressed after venetoclax + rituximab treatment, approximately 1 out of 5 had a newly-acquired TP53 mutation.
  • None of the 42 patients who progressed after venetoclax + rituximab treatment had any BCL2 mutations.

Conclusions:

Even though the sample size for this study is small, these results are encouraging and suggest that fixed-duration venetoclax can be used for treatment more than once. This is largely because fixed-duration treatment reduces the likelihood of developing BCL2 resistance mutations. However, we don’t yet know whether retreatment with venetoclax might cause further mutations to arise. Thus far, it appears that using venetoclax as a fixed-duration treatment preserves its potential for reuse in the future.

Towards the end of the interview, Drs. Seymour and Koffman share a few minutes of an interesting discussion on the present and future management of CLL in the era of targeted therapies.

Please enjoy this interview with Dr. Seymour from the ASH meeting, held in December 2021 in Atlanta, GA, and virtually.

You can read the actual abstract here: Assessment of the Clonal Dynamics of Acquired Mutations in Patients (Pts) with Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Treated in the Randomized Phase 3 Murano Trial Supports Venetoclax-Rituximab (VenR) Fixed-Duration Combination Treatment (Tx)

Take care of yourself first.

Ann Liu, PhD