Venetoclax (Venclexta)

An oral oncology medication for the treatment of patients with chronic lymphocytic leukemia (CLL) with or without a 17p deletion and have been treated with at least one prior therapy.

Approved for both treatment naïve and relapse/refractory patients with CLL.

BH 3 mimetic class.

A Bcl2 inhibitor.

A BCL2 homologous domain 3 mimetic compound that disrupts anti-apoptotic signaling through BCL 2 inducing programmed cell death of CLL cells.

Has high avidity to protein B-cell lymphoma 2, within the family of proteins inside a cell that regulates apoptosis.

Approved based on MURANO—a randomized (1:1), multicenter, open-label trial:  enetoclax and Rituximab.

Probably best used in CLL in combination with an antibody.

In refractory/relapsed CLL  single agent venetoclax leads to a partial response or better in approximately 75% of patients and 20% having a complete remission.

The use of antibody therapy with venetoclax lowers the apoptotic threshold of the cancer cells which makes venetoclax work better and mitigates some of the compensatory rise in othe BCL2 family members.

Researchers compared Venclexta with rituximab (VEN+R) versus bendamustine with rituximab (B+R) in 389 patients with CLL who had received at least one prior line of therapy.

Patients receiving VEN+R completed a 5-week ramp up of Venclexta followed by Venclexta 400 mg once daily for 24 months measured from the rituximab start date.

Rituximab was initiated after the ramp-up period, and it was given for 6 cycles—375 mg/m2 intravenously on cycle 1 day 1 and 500 mg/m2intravenously on day 1 of cycles 2-6, with a 28-day cycle length.

The researchers then compared the first study arm to patients who received 6 cycles of B+R—bendamustine 70 mg/m2 on days 1 and 2 of each 28-day cycle and rituximab.

The median follow-up of 23 months, the median progression free. survival was not reached in the VEN+R arm and was 18.1 months in the B+R arm.

There was an overall response rate of 92% in the VEN+R arm compared to 72% for those treated with B+R.

Associated with increased risk of death in myeloma. Venetoclax is efficacious in the 11; 14 translocation or high BCL-2-expressing myeloma subset.

Has its greatest clinical activity in CLL where BCL2 has near universal finding in that disease.

As a BCL2 inhibitor approved as a monotherapy or in combination with rituximab or obinutuzumab for CLL—has previously demonstrated complete response rates of up to 50% in patients with this disease.

Secondary resistance is the most frequent cause of treatment failure in CLL

One of them resistance mechanisms in patients with CLL treated with venetoclax is acquisition of BCL2 mutation (Gly101Val) that reduces venetoclax binding to BCL2.

Among the patients harboring the Gly101Val mutation, additional BCL2 mutations were found in 91% (n = 10), with a median of three mutation detected per patient. 

The most common adverse reactions reported included, neutropenia, diarrhea, upper respiratory tract infection, fatigue, cough, and nausea.

The first treatment that targets the B-cell lymphoma 2 (BCL-2) protein, which supports cancer cell growth and is overexpressed in many patients with CLL.

Inhibits the B-cell lymphoma protein that makes cancer cells resistant to therapy.

Patients with CLL who have a 17p deletion lack a portion of the chromosome that acts to suppress cancer growth.

17p deletion chromosomal abnormality occurs in approximately 10 percent of patients with untreated CLL and in approximately 20 percent of patients with relapsed CLL.

A targeted therapy that inhibits a protein involved in keeping tumor cells alive,

A small molecule inhibitor which works through the inhibition of a protein in the B cell lymphoma family by binding to the anti-apoptotic protein BCL-2 and increases apoptosis in CLL cells.

The efficacy was tested in a single-arm clinical trial of 106 patients with CLL who have a 17p deletion and who had received at least one prior therapy.

In this trial l participants took this agent orally every day, beginning with 20 mg and increasing over a five-week period to 400 mg.

Results showed that 80 percent of trial participants experienced a complete or partial remission of their cancer.

It is safe in these patients as a long-term continuous therapy.

About 10% of all patients stopped venetoclax treatment due to side effects.

Most common side effects include: neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia and fatigue.

Serious complications can include pneumonia, neutropenia with fever, fever, autoimmune hemolytic anemia, anemia and metabolic tumor lysis syndrome.

Live attenuated vaccines should not be given.

Routes ofadministration as oral tablets.

Protein binding >99.9%.

Metabolism by hepatic mechanisms CYP3A4, and CYP3A5.

Onset of action Tmax = 5–8 hours.

Biological half-life~26 hours.

Excretion feces >99.9% and 20.8% as unchanged venetoclax

A small molecule oral drug that treats chronic lymphocytic leukemia (CLL) in those with a specific chromosomal abnormality.

For patients with CLL who have relapsed or have been refractory to previous treatment and have the 17p deletion genetic mutation.

Used a second line treatment for chronic lymphocytic leukemia, only if there is a 17p deletion as determined by an approved test.

Side effects include.: neutropenia, nausea, anemia, diarrhea, upper respiratory tract infection, fatigue, and thrombocytopenia.

Major side effects include tumor lysis syndrome and severe neutropenia.

Additionally, this drug may cause fertility problems in males.

A BH3-mimetic and acts as a Bcl-2 inhibitor.

It blocks this anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein, leading to programmed cell death of CLL cells.

Overexpression of Bcl-2 in some lymphoid malignancies has sometimes shown to be linked with increased resistance to chemotherapy.

Maximum plasma concentration achieved after oral administration occurred 5-8 hours after dose.

It is recommended that Venetoclax be administered with a meal.

Highly bound to human plasma protein, the fraction unbound in plasma is less than 0.01.

Is metabolized by CYP3A4/5.

Individuals using the drug should not consume grapefruit products because they contain CYP3A inhibitors.

While using venetoclax it is not recommended to use other drugs which contain CYP3A inhibitors including:erythromycin, ciprofloxacin, diltiazem, dronedarone, fluconazole, verapamil.

Venetoclax is excreted from the body via the fecal route.

Approved for use in those with CLL who have 17p deletion (deletion located on the chromosome 17 short arm) and who have been treated with at least one prior therapy.

The combination of ventoclax (Venclexta) and rituximab significantly improved progression free survival compared with rituximab and bendamustine in patients with relapsed or refractory CLL (MURANO study).

The combination of ibrutinib plus venetoclax yielded a high rate of undetectable minimal residual disease (MRD) when used as first-line treatment for chronic lymphocytic leukemia (CLL), according to the CAPTIVATE trial.

77% of patients in the CAPTIVATE trial had undetectable blood MRD after just six cycles of combined treatment.

In the above study 14 patients completing 12 cycles of the combination, 86% had undetectable bone marrow MRD, including all complete responders and most of the partial responders.

Approved for use in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of adult patients with newly-diagnosed acute myeloid leukemia who are aged 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

Among patients with untreated CLL and coexisting morbidity venetocax-obinutuzumab was associated with longer progression free survival tha chlorambucil-obiutuzuab.

Recommended dose is 400 mg a day, after initiation at 20 mg a day with weekly stepwise increases to reaching 400 mg.

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