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ASH 2021: Targeting Venetoclax-Resistant CLL By Bcl-XL Degradation

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Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL / SLL) can develop resistance to targeted cancer treatments such as venetoclax. Advances are being developed exploring exciting natural biologic processes to address the resistant variations of CLL / SLL.

We know that for most with CLL / SLL targeted therapies like venetoclax usually work better than chemoimmunotherapy, but resistance can develop.

In this study presented at the American Society of Hematology Annual Meeting and Exhibition (ASH 2021), researchers are doing pre-clinical studies on CLL cells to develop alternative approaches to prevent or overcome resistance.


  • Chronic lymphocytic leukemia is the most prevalent leukemia in the western world and is associated with resistance to apoptosis, another word for programmed cell death or cell suicide. This leads to too many cancer cells living too long and accumulating in the blood, bone marrow and lymphatic system.
  • The anti-apoptotic or pro-survival protein Bcl-2 protects cancer cells from apoptosis or death and is overexpressed in CLL.
  • Venetoclax is a targeted therapy that blocks Bcl-2, an important protein that prevents cancer cells from dying. Usually blocking Bcl-2 leads to rapid cancer cell death.
  • Most patients respond very well to venetoclax.
  • This research is complex stuff for the scientists to sort out, but here is a brief overview for us patients:
    • When Bcl-2 is blocked by venetoclax, CLL cancer cells can respond by producing excessive Bcl-xL that also enhances pro-survival signaling. This in turn blocks venetoclax function and leads to resistance.
    • Mutations in p53, augmented by Bcl-xL, also increase the risk of resistance.
    • Developing agents that target the Bcl-xL pathway is a promising way to overcome venetoclax resistance.
    • Degraders, as the name implies, degrade, or chew up the pro-cancer protein rather than blocking it.
    • PROTAC or Proteolysis Targeting Chimeric technology harnesses the body’s own natural protein disposal system to degrade and remove disease-causing proteins selectively and efficiently.
    • A side effect of blocking Bcl-xL is toxicity to platelets, the cell that controls bleeding.
    • Fortunately, the new Bcl-xL PROTAC degrader addresses the venetoclax resistance at concentrations or levels that are not toxic to platelet function.


We now have great targeted treatments available for CLL / SLL that do not include chemotherapy. However, in many cases, resistance eventually develops. The good news is talented researchers are developing new strategies to address these resistant cases. PROTAC degraders are experimental medications that do not simply block the problem protein, but actually destroy it. Though early in development, they are a promising novel approach for difficult to treat CLL / SLL.

Hope is on the horizon.


SMART PATIENTS GET SMART CARE™. You will most likely never need chemotherapy but may need a targeted treatment like venetoclax, ibrutinib, or acalabrutinib. Be sure your doctor offers you the choice of one of these targeted agents when it is time to start treatment.

If your CLL / SLL develops resistance to venetoclax or another targeted agent, there are options such as experimental PROTAC or Proteolysis Targeting Chimeric that do not simply block the problem protein, but actually destroy it. Ask your doctor about or get a second opinion on the latest research and best treatment options including clinical trials with PROTAC degraders.

You can read the original ASH 2021 abstract by the team of researchers at

You can read more about Venetoclax at

Stay positive and safe. We are all part of an excellent organization for hope, help, and education.

Michael Green MD and CLL patient