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ASH 2018: Kipps on Venetoclax Outcomes Including Resistance—The “Whack a Mole” Challenge

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By Larry Marion

Part one of two. Part two will be continued next week.

Resistance is the scariest word in the English language for chronic lymphocytic leukemia patients.  Novel agents such as ibrutinib and venetoclax are breakthrough drugs to control and perhaps eliminate CLL, but not for everyone.  Between a fifth and a third of CLL patients using these novel agents develop resistance—the drugs fail to control the disease after a period of time.

In this video, Dr. Brian Koffman, a CLL patient, family doctor and chief medical officer and EVP of the CLL Society and Thomas j. Kipps, M.D. of the Moores Cancer Center at the University of California at San Diego, review new research on positive and negative venetoclax outcomes, including techniques on how to overcome resistance.  Drs. Koffman and Kipps met at the American Society of Hematology (ASH) annual meeting in San Diego in December 2018.

Dr. Kipps is a world-renowned cancer researcher. He is a Professor of Medicine and holds the Evelyn and Edwin Tasch Chair in Cancer Research, and Deputy Director of Research Operations at Moores. He also is the Director of the Blood Cancer Research Fund at Moores. The Blood Cancer Research Fund concentrates on developing cures for all types of blood related cancers, specifically CLL.

Key Take Aways

  • “At least two thirds of the patients using venetoxclax may get into deep undetectable MRD,” Dr. Kipps notes. “We have to worry about the third that does not. We’re trying to understand the mechanisms of that resistance.” Resistance typically occurs between the 30 and 60th month of treatment.
  • In a study done by the University of Melbourne in Australia and presented at the ASH 2018 meeting, half of the patients with identified venetoclax resistance (8 of 15) acquired a mutation within the gene that encodes the BCL-2 protein targeted by venetoclax. That mutation precludes the venetoclax from binding very well to the tumor cells. “Essentially, the tumor cells escape from the venetoclax,” Dr. Kipps explains.
  • The presence of a similar type of mutation disrupting the binding and therefore the anti CLL activity also occurs in ibrutinib resistance, notes Dr. Koffman.
  • “Cancer sometimes is like whack a mole,” explains Dr. Kipps. “It keeps coming up when you hit it down.”
  • There are theoretical advantages in stopping drugs after a deep remission has been achieved as it may remove pressure on the cancerous CLL cells to mutate around the drug. That lack of therapeutic pressure on the cells may make it less likely that the CLL will become resistance to the therapy.
  • During a clinical trial comparing venetoclax plus rituximab vs. bendamustine plus rituximab, as reported at ASH 2018, it appears that stopping the venetoclax treatment after 24 months led to what may be a durable long-term response for most patients. Unlike the rapid progression that sometimes follows discontinuing ibrutinib treatment, most patients who were not MRD negative continued to do well after stopping treatment at the two year point. “And those who were MRD negative did spectacularly well,” Dr. Kipps added. “Over 95% still without any evidence of recurrent disease.”
  • Another benefit of venetoclax and rituximab vs. bendamustine and rituximab is the speed of relapse—patients using V+R who relapsed had a slower rate of relapse. And those patients who had a relapse after stopping treatment went into complete remission after being re-treated with venetoclax. “It is very important to know that it is possible to revisit treatments with venetoclax.”
  • In the laboratory with cell grown outside the body in cultures, Dr. Kipps found that leukemic cells continuously exposed to venetoclax for long periods of time developed a mutation that provided a selective survival advantage. “So there is something to be said that continuing therapy poses a risk—it would bring out resistance,” Dr. Kipps explains.

Author commentary

It is heartening to see how CLL researchers remain focused on helping patients despite the proliferation of breakthrough drugs including ibrutinib and venetoclax. To hear Dr. Kipps worry about what happens next in CLL treatments should provide survivors with hope that even as the blood cancer adapts to treatment—I love the “whack a mole” analogy—researchers and clinicians will be ready with a counter attack.

Thanks for reading

Larry Marion

Larry Marion is a CLL survivor who has been using ibrutinib for more than five years. He begins venetoclax treatment in May, in the hope that he may be able to terminate anti-CLL drug treatment one of these days. Marion is a former science writer and editor for various business and technology publications.

For more information about the Australian report on venetoclax resistance–

https://cllsociety.org/2018/12/ash-2018-professor-hillmen-on-venetoclax-resistance-in-cll/

https://www.cancertherapyadvisor.com/home/news/conference-coverage/american-society-of-hematology-ash/ash-2018/gly101val-mutation-directly-causes-resistance-to-venetoclax/