In a Phase III trial, treatment with the targeted cancer drug venetoclax in combination with rituximab more than doubled the likelihood that patients with chronic lymphocytic leukaemia (CLL) would survive for two years without cancer progression compared to treatment with the standard chemo-immunotherapy drug bendamustine with rituximab.

The study is the first randomised trial to show venetoclax is superior to a standard chemo-immunotherapy regimen and the first randomised study to evaluate the survival benefit of venetoclax in combination with rituximab, according to researchers.

The trial focused on patients who experienced continuing or recurrent CLL after initial cancer treatment.

CLL is one of the main types of leukaemia (cancers of the white blood cells) and accounts for about a quarter of new cases of leukaemia each year.

Leukaemia cells survive an abnormally long time by producing proteins that interfere with the normal process of cell death.

Venetoclax is designed to hasten the death of leukaemia cells by binding to and blocking the activity of one such protein, known as BCL-2.

By contrast, bendamustine works by interfering with cancer cells’ DNA.

Rituximab is a monoclonal antibody designed to help the body’s immune system recognise and attack leukaemia cells.

Venetoclax is approved for use against CLL in the United States and several other countries, but approvals are limited to small subgroups of patients, such as those with a specific genetic abnormality.

The present trial, carried out at 109 sites globally, sought to assess the safety and efficacy of venetoclax in a broad patient population.

The trial enrolled 389 patients whose CLL had persisted or recurred after at least one previous course of treatment including chemotherapy.

Half of the patients were randomly assigned to a regimen of six monthly doses of venetoclax plus rituximab and half received six cycles of bendamustine plus rituximab.

Patients assigned to the venetoclax arm continued to use venetoclax alone for two years or until leukaemia returned.

To date, researchers have tracked patients for a median of about two years.

The vast majority (84.9%) of patients receiving venetoclax survived for two years without showing evidence of disease progression, compared to just 36.3 percent of those who received bendamustine.

Venetoclax also outperformed bendamustine for the trial’s secondary endpoints, which included overall survival and markers of cancer remission.

In particular, those on venetoclax were far more likely to achieve MRD clearance, which was achieved in 83.5 percent of those taking venetoclax and 23.1 percent of those taking bendamustine.

These results suggest venetoclax could be discontinued after two years with a low risk of recurrence in those patients with a deep remission, researchers said.

“This is the first randomized trial comparing any of the new agents targeted to treat CLL against a standard chemoimmunotherapy program, and it has proved the superiority of the chemotherapy-free approach,” said lead study author John Seymour, MBBS, PhD, director of the Haematology Department at the Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.

“It suggests that venetoclax should replace chemotherapy for relapsed/refractory CLL and is suggestive that the combination with rituximab is the preferred manner to use the drug. There is also evidence of eradication of detectable disease that opens the prospect of time-limited therapy in this setting.”

While venetoclax was associated with a greater risk of abnormally low white blood cell counts, there was no increase in severe infections or deaths related to this side effect, said Seymour.

The researchers continue to monitor participants to assess long-term survival and disease progression.

Source: ASH 2017