Venetoclax Promising in the Treatment of CLL

New York – In a presentation at the 2018 Lymphoma & Myeloma congress, Richard R. Furman, MD, Weill Cornell Medicine, discussed venetoclax in the treatment of patients with chronic lymphocytic leukemia (CLL).

“What I really want to emphasize is that venetoclax is a BH3 mimetic, so it works just like a BH3-only protein and it sequesters BCL-2 and it prevents BCL-2 from sequestering the pro-apoptotic proteins enabling them to actually induce apoptosis,” said Dr Furman.

“This is a threshold that cells actually have to cross before undergoing apoptosis. So by sequestering these proteins, the question is do we move the cells closer to the threshold or do we push them further from the threshold, and this is going to have inadvertent important implications when we start talking about ideas like combination therapy,” he added.

Venetoclax is approved for safe use with a weekly dosing schedule starting at an initial dose of 20mg daily for 1 week. If the patient has no evidence of tumor lysis, the dose increases weekly to 50mg daily for a week, 100mg daily for a week, 200mg daily for a week, up to 400mg indefinitely until disease progression or unacceptable toxicity.

Dr Furman explained that a key component to prevent tumor lysis is to stratify the patients as low, medium, and high risk based upon lymph node size and lymphocyte count.

“Based upon these characteristics, we actually have a very nice prescriptive means for preventing tumor lysis in these patients, which is very successful. Since the advent of this, there actually hasn’t been any evidence of clinical tumor lysis in a patient,” said Dr Furman.

He discussed the M13-982 trial, which studied venetoclax monotherapy in patients with relapsed CLL and 17p deletion. This study lead to the accelerated approval of venetoclax, showing an overall response rate of 79%, 8% complete response (CR), 3% nodular partial response (PR), and 69% PR. 64% of PRs met CR or CR incomplete criteria except for some persistent lymphadenopathy. A total of 25 of 48 patients had no CLL in the bone marrow and 18 of 45 patients were MRD-negative in the peripheral blood.

“This is proof that even though there were a large number of PRs, this is successful treatment for patients,” said Dr Furman.

He also discussed the MURANO trial comparing venetoclax plus rituximab versus bendamustine and rituximab, which is lead to the full approval of venetoclax in relapsed/refractory CLL.

Dr Furman emphasized that the rate of MRD-negativity is going to be helpful in determining the fixed duration of therapy in the future, and how much is enough. The MURANO trial started showing MRD-negativity around 4 months, which then starts to plateau by 9 months.

“it really gets to the idea that maybe anything beyond this isn’t necessarily going to be helpful. At that point in time we can start to identify those patients who might need something else,” said Dr Furman.

When looking toward the future, Dr Furman highlighted the CAPTIVATE study that is looking at ibrutinib plus venetoclax in previously untreated CLL. This study has two cohorts, an MRD negative cohort and MRD positive cohort.

The MRD positive cohort receives 3 months of ibrutinib to try and diminish the tumor lysis risk and then 12 months of ibrutinib plus venetoclax. Patients are then assessed for MRD in the blood and bone marrow. If they are MRD-negative, they are then randomized to start ibrutinib plus venetoclax discontinued or placebo. Those who are MRD-positive are then randomized to go on ibrutinib or ibrutinib plus venetoclax.

The second cohort receives 3 months of ibrutinib followed by 12 months of ibrutinib plus venetoclax.

“What I think is important from this is it gives us the interesting opportunity to investigate what happens when we discontinue therapy,” said Dr Furman.

The second part of the CAPTIVATE trial is a progression/reintroduction phase, which tests whether or not if venetoclax is discontinued and the patient starts to progress, will the reintroduction of venetoclax be able to rescue them.

The ibrutinib lead in dramatically reduces tumor lysis risk. Initial results showed that 90% of patients with high risk for tumor lysis shifted to medium or low risk. After 6 cycles of ibrutinib plus venetoclax, 77% of the patients are MRD-negative in the peripheral blood, after 12 cycles 93% are negative in the peripheral blood and 86% in the bone marrow.—Janelle Bradley