ASH 2016: Professor John Seymour on Using Venetoclax in Combination to Treat CLL

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Dr. Seymour from the Peter MacCallum Cancer Centre in Melbourne, Australia was one of the pioneers in the development of venetoclax for treating chronic lymphocytic leukemia (CLL).

While it is a potent drug on its own, its real strength may be when used in combinations with other agents.

We at the CLL Society have long argued that in order to cure our CLL, or to at least offer very long-term control, we need to use drug cocktails. Dr. Byrd discusses that in this short article and video on baking a cake of cure.

That is where the research is heading and Dr. Seymour brings us up to pace on some of the promising early data on the combinations that include venetoclax (Venclexta) presented at the 2016 American Society of Hematology (ASH) Annual Meeting.

Key Take Away Points:

• Over half the patients who took venetoclax with rituximab reached a complete remission (CR) compared to the 20% with CR when used as a single agent.
• Obinutuzumab is a more powerful antibody when combined with chemotherapy, but can have severe infusion reactions.
• There is now data that it is safe to use obinutuzumab first and then to add venetoclax.
• Tumor lysis syndrome is still a concern with venetoclax and may be different when it is used in combination therapies.
• Because ibrutinib pushes cells out from their protective niches, there is reason to be optimistic and also exciting early data about its use in combination with both obinutuzumab and venetoclax.
• It is a realistic and reasonable goal to pursue a cure of CLL with these types of combinations.
• Limited duration therapy may also be possible in the future.

Studies with links to the abstracts referenced by Dr. Seymour from ASH 2016 are listed below:

1. Detailed Safety Analysis of Venetoclax Combined with Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia where 57% of the patients reached MRD-.
2. Safety and Efficacy of Venetoclax and Obinutuzumab in Patients with Previously Untreated Chronic Lymphocytic Leukemia (CLL) and Coexisting Medical Conditions: Final Results of the Run-in Phase of the Randomized CLL14 Trial where 7 out of 12 patients had a complete response (CR) and 10 of 12 where MRD- in the blood.
3. Phase 1b Results of a Phase 1b/2 Study of Obinutuzumab, Ibrutinib, and Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) in early assessments with 12 patients, all had responded to the combination, and two reached CR. Four patients achieved MRD negativity by flow assessment in both their peripheral blood and bone marrow.

Please note that all of these studies were in difficult to treat relapsed and refractory CLL patients.

Here is my interview with Dr. Seymour who carefully explains our early foray into these powerful and potentially, dare I say, curative combinations. You can also read the transcript here.

Exciting times indeed

Brian Koffman, MD  6/6/17