Venetoclax Data Prompt Rethink of CLL Therapy

Five years ago, the only treatment for chronic lymphocytic leukemia (CLL) was intravenous chemo-immunotherapy. Since then, however, several agents have been approved, including venetoclax (Venclexta; AbbVie), which blocks the antiapoptotic protein BCL2.

The question now is which targeted drug to prescribe to which patient and in what order. Emerging data from phase III studies should help inform that decision.

Venetoclax was granted accelerated approval in 2016 for patients with relapsed or refractory disease and a chromosome 17p deletion. The FDA decision was based on data from single-arm phase I and II studies. The first phase III trial, the 389-patient MURANO study, reached its primary completion date only last year—and an early analysis was presented last month at the American Society of Hematology (ASH) 2017 Annual Meeting in Atlanta, GA.

That study compared venetoclax plus the anti-CD20 drug rituximab (Rituxan; Genentech) with bendamustine plus rituximab for relapsed or refractory CLL. As John Seymour, MD, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia, reported, the overall response rate, as assessed by trial investigators, was 93% for those on the venetoclax–rituximab combination, compared with 68% among those taking bendamustine and rituximab. Complete responses were achieved by 27% and 8% of patients, respectively, and the percentage of patients in remission 2 years after treatment initiation was 85% versus 36%, with a statistically significant benefit in overall survival.

Notably, responses to the venetoclax-containing regimen were consistent across patients, regardless of age, p53 mutations, or chromosome 17p deletions. “In every clinical and biologic subset, this clearly beat the conventional, standard chemo-immunotherapy,” Seymour says. Many experts say it's now only a matter of time before venetoclax earns FDA approval as a second-line treatment for patients without the 17p deletion, as it is already in Europe, Australia, and other parts of the world.

Ibrutinib or another BTK inhibitor, not chemo-immunotherapy, will likely then become the first drug most patients try, as there's growing evidence that the standard chemotherapy-based regimen—fludarabine, cyclophosphamide, and rituximab—produces long-term remissions only in the minority of patients with mutant IGHV and no high-risk chromosomal aberrations. Patients whose disease progresses on ibrutinib, or who can't tolerate its side effects, can then confidently start on venetoclax—as evidenced by recently published data showing a response rate of 65%.

“It's a very active drug,” says Anthony Mato, MD, of the University of Pennsylvania in Philadelphia, “and the more access we have to it, especially in the relapsed–refractory setting, the better.” Mato presented data at the ASH meeting showing that the response rate seen in venetoclax trials held up in clinical practice.

Eventually, venetoclax will probably gain approval as a first-line agent, regardless of cytogenetic biomarker status. When that happens, clinicians will have to choose whether to use venetoclax or ibrutinib first.

“In some ways it's a Coke versus Pepsi argument,” says Seymour. Venetoclax requires more monitoring when therapy begins, owing to the risk of tumor lysis syndrome, which can be fatal. However, some patients can discontinue the therapy after 1 to 2 years because it often leads to negative minimal residual disease (MRD) in the bone marrow—a measure of cancer burden—something not generally seen with ibrutinib, which generally must be taken for life. As such, Seymour says, venetoclax may be a more attractive option for younger, fitter patients who can tolerate the added risk, whereas ibrutinib may be preferable for older, frailer patients.

An alternative strategy: combination therapy. In the CLARITY study, for example, 38 patients who had relapsed on chemo-immunotherapy received both ibrutinib and venetoclax for 6 months. All 38 responded, and the combination was well tolerated. Nearly half had a complete response and 32% achieved MRD clearance. (This sign of deep remission typically occurs in only about 15% of patients on venetoclax monotherapy and almost never with ibrutinib alone.) “It does seem like there's synergy between the two drugs,” says Peter Hillmen, MD, PhD, of the University of Leeds, UK, who presented the data at ASH.

Some researchers are also adding obinutuzumab (Gazyva; Genentech) to the mix, testing a three-drug regimen in untreated patients. For example, Kerry Rogers, MD, of Ohio State University in Columbus, reported that 76% of 24 evaluable patients who had received venetoclax, ibrutinib, and obinutuzumab achieved MRD negativity in their marrow and experienced less toxicity than with chemo-immunotherapy.

“Right now we're obsessing over which [drug] we start with and which one comes next, and eventually we'll probably just give them all together so that question goes away,” says Matthew Davids, MD, MMSc, of Dana-Farber Cancer Institute in Boston, MA.

However, another study involving venetoclax and obinutuzumab, but not ibrutinib, yielded about the same rate of bone-marrow MRD negativity: 75% of 32 treatment-naïve individuals. That's led trial investigator Ian Flinn, MD, PhD, of the Sarah Cannon Research Institute in Nashville, TN, to question whether triplet therapy is overkill. “I'm not so sure that you need all three,” he says. A better understanding should come next year when researchers report the results of the 445-person CLL14 trial of the venetoclax–obinutuzumab combination versus chlorambucil plus obinutuzumab as a first-line treatment.

Given the opportunity to eliminate disease in most patients, “episodic time-limited therapy with some sort of combination is hopefully what we're going to do,” Rogers says. –Elie Dolgin