Patients with CLL who relapse after or become refractory to treatments like ibrutinib or idelalisib have poor outcomes. Venetoclax (also known as ABT-199) is an oral inhibitor of the BCL-2 (B-cell lymphoma 2) protein. The BCL-2 protein plays a critical role in preventing cells from undergoing apoptosis (cell death), in healthy cells and in CLL cells. In a recent study presented at the 2016 annual ASH meeting, we evaluated the effectiveness of venetoclax in treating people who relapsed after or were refractory to ibrutinib or idelalisib.
During this phase 2 trial 64 people with CLL were divided into two arms. The first arm consisted of those who were relapsed or refractory to ibrutinib, while the second arm included those who were relapsed or refractory to idelalisib. 43 patients were enrolled in the first arm and were on ibrutinib for a median of 17 months, receiving venetoclax for a median of 13 months, while 21 patients in the second arm were on idelalisib for a median of 8 months and received venetoclax for a median of 9 months. Thirty-nine patients in the ibrutinib arm and 21 patients in idelalisib arm completed the full course of treatment. The objective response rate as determined by investigators was 69% (27/39) for people who were ibrutinib resistant, and 57% (12/21) for the idelalisib resistant. At the time of analysis no median progression free survival or overall survival has been reached. Overall the progression free survival was 72% and overall survival was 90% for all participants.
The results from this trial demonstrate that venetoclax has displayed robust activity and is tolerable for people whose CLL has progressed after treatment with ibrutinib and idelalisib. Although there have been few complete responses, patients will continue to be monitored to chart any further improvements. Additional follow up will be required to assess how long lasting venetoclax responses will be.
Dan Landau, M.D., Ph.D. recently sat down to speak with The Video Journal of Hematology Oncology about how technology with drive future advances in the treatment of CLL. Currently we understand that a malignant population such as a population of CLL cells in any patient, is actually not uniform but composed of multiple sub-populations, which continuously compete, evolve and create diversity. The therapeutic challenge is that in each patient, we are not dealing with one disease but with a collection of many diseases.
Therefore, it is not surprising that therapies can fail. With new genomic technologies, it is now possible to survey this genetic complexity for large cohorts of patients in order to understand the processes underlying the complexity. By taking an evolutionary perspective and combining it with genomic methods, we can infer the past history of disease and use this information to predict its future.
Dr Landau points out how today data science approaches are already being used to predict real world outcomes in advertising or on the stock market for example. However, data science approaches are not really being applied in cancer research. Further, he discusses non-genetic sources of diversity, such as epigenetics and spatial location. All of these layers of information need to be considered in order to understand the evolutionary process.
Finally, he discusses the idea of measuring clonal kinetics directly in patients, i.e. measuring the rate of growth of each clone with each therapy and come up with an optimized therapeutic approach through the use of algorithms; he considers this approach to be a radical extension of the precision medicine paradigm.
Recently the director of the CLL Research Center at Weill Cornell Medicine, Dr. Richard Furman sat down with Targeted Oncology to discuss how he treats patients with CLL. Although he emphasized the importance of physician autonomy in the selection of treatments they should be willing to use the latest treatments approved by the FDA. Referring to venetoclax, which received FDA approval earlier this year for CLL patients with del 17p CLL he said,
“If you have a patient with CLL of any type and you believe venetoclax is best for [that patient], you absolutely should use it. There’s nothing about the specificity of the FDA approval that should prevent you. Insurance coverage may be another matter, but clinically speaking, you’re on solid ground.”
Additionally he noted the importance of progression free survival (PFS), which refers to the length of time during and after a treatment in which a disease has not gotten worse. He said,
“Hands down, PFS is the single most important thing to patients. As oncologists who must balance many clinical concerns, it can be easy for us to forget that fact.”
You can continue reading about Dr. Furman’s treatment options in the article.