Venetoclax for the Treatment of CLL Patients who have Relapsed after or are Refractory to Ibrutinib/Idelalisib


By Richard Furman, M.D.

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.

Venetoclax Approved by FDA for the Treatment of CLL Patients with 17p Deletion

The Backstory

On April 11, 2016 the FDA approved venetoclax (Venclexta) for the treatment of patients with chronic lymphocytic leukemia (CLL) with the 17p deletion who have been treated with at least one prior therapy. This is the first FDA approval for venetoclax.

In addition to this recent FDA approval, venetoclax has been granted priority review for its new drug application (NDA) of venetoclax as a single agent in CLL, as well as FDA breakthrough therapy designation for use in combination with rituximab (Rituxan) to treat patients with relapsed/refractory chronic lymphocytic leukemia (CLL).

What is venetoclax?

Venetoclax, previously known as ABT-199 is the first FDA-approved treatment that targets the B-cell lymphoma 2 (BCL-2) protein. The BCL-2 protein plays an important role in enabling CLL cells to survive. CLL cells and other lymphomas overexpress 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.

What is the 17p deletion and how does it affect CLL?

17p deletion occurs  when part of chromosome 17 in the CLL cells is deleted in the CLL cells. This abnormality only occurs in the CLL cells, and not normal cells, and results in losing the p53 protein. The p53 protein plays an important role in enabling a cell to undergo suicide, and prevent itself from growing out of control. In CLL cells with a 17p deletion, the second genetic copy is often mutated, and as a result, these cells can grow more aggressively and are less responsive to chemotherapy. This results in worse clinical outcomes. Agents like venetoclax work independent of p53, and therefore are still effective in these cases. The 17p deletion is found in approximately 3-7% of newly diagnosed CLL patients, but increases to 30-40% in relapsed and refractory cases.

Why was venetoclax granted FDA approval?

Venetoclax was granted FDA approval based on the results from the M13-982 trial investigating venetoclax in patients with 17p deletion who had received at least one prior therapy. Venetoclax demonstrated an overall response rate of 80%, which included 8% complete response rates. Almost three quarters of patients were free from progression at one year.

Were there any side effects?

The most worrisome side effect of venetoclax is life-threatening tumor lysis syndrome. In the initial studies, when a full dose was administered on day one, two patients died as a result of tumor lysis. Since a modified weekly ramp-up starting at 20 mg and increasing weekly to 50 mg, 100 mg, 200 mg, and finally 400 mg once daily, no cases of clinically significant tumor lysis were seen. Common, less serious side effects included low white blood cell count, diarrhea, nausea, anemia, upper respiratory tract infection, low platelet count, and fatigue. More serious side effects included pneumonia, fever, autoimmune hemolytic anemia, anemia, and tumor lysis syndrome.

How can you access venetoclax now?

Venetoclax is commercially available. Clinical trials investigating the use of venetoclax in patients who are progressed after B-cell receptor (BCR) inhibitors, namely ibrutinib and idelalisib, are ongoing.

FDA Expedites Review of New CLL Treatment

The Backstory

DRFurman_5284In May 2015, the Federal Drug Administration (FDA) granted venetoclax a breakthrough therapy designation for treating patients with relapsed or refractory chronic lymphocytic leukemia (CLL) with a specific genetic alteration – the 17p deletion. A second FDA breakthrough therapy designation was granted to venetoclax earlier this month for use in combination with rituximab (Rituxan) to treat patients with relapsed/refractory CLL. Last week, the FDA announced that they are granting “Priority Review” to venetoclax. This means that the treatment has been shown to be so effective compared to standard treatment options that the FDA is committed to allocating significant resources to further evaluate it. The label of Priority Review can be of great help in getting new, promising treatment options to more people as quickly as possible.

What is venetoclax?

Venetoclax (also known as ABT-199) is an oral inhibitor of the bcl-2 (B-cell lymphoma 2) protein. BCL-2 protein plays a critical role in preventing cells from undergoing apoptosis (cell death), including CLL cells.

Why did the FDA decide to grant Priority Review to venetoclax?

This Priority Review status is based upon results presented by investigators at the 2015 annual meeting of the American Society of Hematology (ASH) that took place in early December.

In this study, they found that of the 107 patients treated, 85 patients (79.4%) responded to treatment with venetoclax.

Of these patients who responded, eight patients (7.5%) experienced a complete response, meaning that no detectable levels of cancer remained. Three patients (2.8%) experienced nodular partial response (nPR), while 74 patients (69.2%) experienced partial response. Unlike a complete response a nPR includes some persistent remaining modules of lymphocytes. In the past it was difficult to differentiate these CLL cells from normal cells. However, we now know that patients with nPR do better than patients with partial responses, but not as well as complete responses.

Were there any side effects?

The side effect of primary concern based upon earlier studies was tumor lysis syndrome, which occurs when the CLL cells breakdown too rapidly and release too many of their breakdown products at one time, potentially causing kidney failure and death. Researchers sought to implement strategies to minimize the risk of tumor lysis.  Other side effects were comparable or less prevalent than those experienced by people who received current standard chemotherapy treatment for CLL.

How can you access venetoclax now?

At Weill Cornell Medicine, we have a clinical trial with venetoclax already underway for relapsed/refractory CLL patients who have previously been treated with an inhibitor of the BCR signaling pathway, including idelalisib or ibrutinib. If you are interested in enrolling in or learning more about this clinical trial, please contact Amelyn Rodriguez RN, by email or phone (212) 746-1362.

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