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.
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.
CLL patients who relapse after or are refractory to ibrutinib or idelalisib often have few treatment options and poor outcomes. In an ongoing phase II study, presented at the 2016 annual ASCO meeting, researchers investigated the activity of venetoclax in patients with CLL who have relapsed or become refractory to ibrutinib or idelalisib. Venetoclax (Venclexta, ABT-199), is the first FDA-approves treatment that inhibits the BCL-2 (B-cell lymphoma 2) protein. The BCL-2 protein plays an important role in enabling CLL cells to survive. CLL cells and other lymphomas over express and are more dependent upon BCL-2 protein than normal cells. Therefore, when venetoclax inhibits the protein, the CLL cells die, while the normal cells continue unharmed.
54 patients were enrolled into the two arms of the trial based upon whether they were relapsed or refractory to ibrutinib (Arm A, 38 patients) or idelalisib (Arm B, 10 patients). 48 patients were evaluable for responses. The overall response rate for ibrutinib treated patients was 61% (CR=8%; PR=53%) and for idelalisib was 50% (CR=0%; PR=50%). Side effects were found in less than 20% of patients with the most common including neutropenia, diarrhea, nausea, anemia, fatigue, and hypophosphatemia. These results show that venetoclax displays promising activity for CLL patients who have relapsed or are refractory to both ibrutinib and idelalisib and can be safely administered.
Further research is required to demonstrate the depth and duration of response, but these initial results are positive.