On June 8, 2018, the U.S. Food and Drug Administration (FDA) expanded a targeted drug, venetoclax venetoclax (trade name: Venclexta, manufactured by Abbott) for indication.
Venetoclax was originally approved by the FDA in 2016 for the treatment of chronic lymphocytic leukemia (CLL) in the presence of 17p deficiency. At the same time, the FDA approved a companion diagnostic to venetoclax, the Vysis CLL FISH probe kit (manufactured by Abbott Molecular), to detect 17p deletion in patients with CLL.
With this expanded indication, patients with relapsed/refractory chronic lymphocytic leukemia who have received at least one prior therapy, with or without 17p deletion, can be treated with venetoclax. venetoclax in combination with rituximab has the potential to replace the current standard regimen as the first choice for patients with relapsed or refractory CLL patients as the treatment of choice.
To date, venetoclax is the first approved drug to target the BCL2 protein in cancer cells (17p deficiency leads to BCL2 protein overexpression), with FDA Breakthrough Therapy designation, priority approval, and expedited review status, as well as orphan drug designation.
What is CLL?
CLL is a clonal proliferative tumor of mature B lymphocytes with specific immunophenotypic features, characterized by aggregation of lymphocytes in the peripheral blood, bone marrow, spleen, and lymph nodes, primarily in middle-aged and older adults.
The incidence of 17p deletion is about 10% in patients with untreated CLL and about 20% in patients who relapse after treatment. 17p deletion refers to cancer cells that have lost a portion of chromosome 17, and patients with CLL with 17p deletion are at high risk with median survival of less than 24 months.
For CLL patients who are young, in good physical status, and without 17p deletion, the first-line regimen is fludarabine + cyclophosphamide + rituximab (FCR regimen). However, in patients with 17p deficiency, the FCR regimen is not as effective, and the BR regimen of bendamustine in combination with rituximab is another first-line treatment option in the clinic and is not superior to the FCR regimen.
How does Venetoclax work?
The part of chromosome 17 that is missing contains p53, and BCL2 is part of the p53 signaling pathway. It can help cancer cells “live forever”. Therefore, when BCL2 is overexpressed, not only do the cancer cells not die, but they are also easily resistant to the drug.
BCL2 overexpression has been found in many CLL patients, and BCL2 represents a plausible therapeutic target.
Figure Illustration of how venetoclax works
Source: Why bother doing fancy tests in patients with CLL?
Evidence of efficacy: 80% remission with rituximab alone, significant improvement in PFS with rituximab
In 2016, venetoclax was approved primarily based on a single-arm dose-escalation trial. The 106 patients in the study with 17p deficiency had previously undergone multiple treatments with poor outcomes. After monotherapy with venetoclax, nearly 80% of patients in the study achieved remission (both complete and partial remission), and 85% of patients had remission lasting longer than 1 year. Moreover, venetoclax was particularly effective in patients with a poor prognosis, including those who had failed to respond to fludarabine, a chemotherapy agent.
This indication expansion is based on the results of a large clinical trial (the MURANO study). The study included 389 patients with relapsed or refractory CLL, and progression-free survival (PFS) after venetoclax combined with rituximab was significantly better than the standard bendamustine combined with rituximab in the BR regimen (2-year PFS: 84.9% vs 36.3%). Moreover, patients benefited from this regimen regardless of whether they had 17p deletion or not. Further analysis suggested that venetoclax in combination with rituximab was effective in removing small residual lesions, a major cause of cancer recurrence and metastasis, resulting in a significant improvement in PFS.
Serious adverse reactions: watch for differentiation syndrome
Common adverse reactions to Venetoclax include low white blood cell count (neutropenia), diarrhea, nausea, anemia, upper respiratory tract infection, low platelet count (thrombocytopenia), and fatigue.
A serious adverse reaction to Venetoclax is tumor lysis syndrome. When tumor lysis syndrome occurs, tumor cells lyse spontaneously or rapidly in response to chemotherapeutic agents for a short period of time, causing rapid release of intracellular material and its metabolites into the bloodstream, resulting in severe metabolic disturbances with clinical manifestations such as hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, cardiac arrhythmias, and acute renal failure.
In that 2016 dose-escalation phase I trial, three patients developed clinical tumor lysis syndrome, which led to one patient death. The investigators subsequently changed the dosing regimen in the trial, and venetoclax was titrated upward, which reduced the risk of tumor lysis syndrome.
How to use venetoclax?
According to the approved product insert, the recommended use and dosage of venetoclax is as follows:
- The recommended dose of Venetoclax monotherapy is 400 mg orally daily after completing 5 weeks of dose escalation.
- The recommended dose of Venetoclax monotherapy is 400 mg orally daily after completing 5 weeks of dose escalation.
- The recommended dose of Venetoclax in combination with rituximab is 400 mg orally daily (week 5 and beyond); rituximab is started after receiving 400 mg of venetoclax daily for 7 days.
- No live attenuated vaccines should be given while taking the drug.
In addition to CLL, researchers have also tried venetoclax as a treatment for other B-cell cancers, including diffuse large B-cell lymphoma, follicular lymphoma, and condylomatous lymphoma, with no definitive results published yet, and hopefully all with similarly good outcomes as CLL.
Venetoclax has not yet been approved by the State Food and Drug Administration, but an application has been submitted, and it is believed that it will soon be available for the treatment of CLL patients in China.