Expanding the Utility of Novel Combination Regimens in CLL

Caroline Seymour

Danielle Brander, MD

Danielle Brander, MD

Although potent in and of themselves, ibrutinib (Imbruvica) and venetoclax (Venclexta), are showing enhanced safety profiles, time-limited administration, and patient scope when used in combination for the treatment of patients with newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL), explained Danielle M. Brander, MD.

“At the end of the day, we have these novel drugs that are very effective for patients with historically high-risk markers and older patients with comorbidities who couldn’t tolerate any therapy,” said Brander. “Now, these patients are having a good quality of life with treatment-free intervals.”

In an interview during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies, Brander, assistant professor of medicine, Duke Cancer Institute, discussed the investigational combination treatments that are bringing patients with CLL one step closer to well-tolerated, time-limited therapy.

OncLive: Could you discuss the most exciting therapeutic advances made in CLL?

Brander: It's been an exciting year of caring for patients with CLL. Within the past year, there have been 2 frontline studies that looked at chemotherapy versus ibrutinib and showed a superior progression-free survival (PFS) with ibrutinib. This was particularly true for the patients with higher-risk disease. It’s important to remember to test for these high-risk markers, such as IGHV [with] fluorescence in situ hybridization. Even if they are, these are some patients at risk for progression.

Now, we're looking at the use of these drugs in combination; [there is a] trial looking at the combination of ibrutinib and venetoclax in the frontline setting. Several other trials were presented at the 2018 ASH Annual Meeting that looked at other novel agents in the frontline setting, such as the treatment-naïve cohort of a study with acalabrutinib (Calquence). That study showed very good efficacy and potentially some different safety profiles than [what we’ve seen historically] with BTK inhibitors.

For patients with previously treated CLL, we’ve seen the follow-up data from the MURANO trial with the combination of venetoclax and rituximab (Rituxan) versus the combination of bendamustine and rituximab. When [the trial] was presented at the 2018 ASH Annual Meeting, patients were off therapy for about 1 year. We’re still seeing very good rates of PFS and patients are able to achieve deep responses with time-limited therapy. There are also ongoing trials for patients who are intolerant to or have progressed on these drugs.

What are the clinical implications of the phase II CLARITY trial?

There are 2 ways to look at the results [from this trial]: one is the safety of combining the 2 drugs, and the second is the efficacy. When we talk about the safety of a combination, we don't want to see any toxicities that are greater than either drug alone; that’s certainly true with the combination of ibrutinib and venetoclax. You don't see any toxicity that's different from what we would expect from each agent alone. Interestingly, patients were treated with ibrutinib first for 3 months before they received the combination. From a safety perspective, it helps because patients have a reduction in the risk of tumor lysis and disease bulk before they start venetoclax, after which their risk of tumor lysis went down. We'll need longer follow-up, as the goal of the study was to stop therapy for patients who had undetectable levels of minimal residual disease (MRD). From a safety perspective, you may be able to eliminate some toxicities if you either reduce the combination or stop the drugs altogether.

At the 2018 ASCO Annual Meeting, a preplanned analysis was presented on the first 30 patients [with regard to] MRD [negativity]. Overall response rates were extremely high, near 100% and MRD negativity was confirmed in 75% to 77% of patients. This suggests that, with longer follow-up, patients who would be appropriate for the combination might have lower toxicity and time-limited therapy after achieving MRD [negativity], which we know in CLL is a very important marker for long-term remissions.

Could you discuss other investigational combination regimens with ibrutinib?

CAR T-cell therapy is a growing area in CLL. Some of the first promising trials with CAR T-cell therapy were in CLL. Combinations [with CAR T-cell therapy] and ibrutinib are promising for 2 reasons. Many of our high-risk patients are already on ibrutinib, so you wouldn’t be stopping a drug that's potentially still controlling some of the disease.

Preclinically and in some of the initial trials, ibrutinib not only helps keep the disease in check, but it can also potentially help the efficacy [and safety profile of CAR T-cell therapy]. For example, you might see less adverse events, such as cytokine release syndrome. Certainly, it's a promising area.

What are some other targets worth exploring?

When we talk about targeted inhibitors in CLL and other B-cell lymphomas, there are 2 main categories. There are those that target important proteins along the B-cell receptor signaling pathway, such as ibrutinib or acalabrutinib; these target BTK, which is one component of that pathway. Other important components in that signaling pathway are PI3K inhibitors. Approved PI3K inhibitors include idelalisib (Zydelig) and duvelisib (Copiktra). I use the broad category, but there are different isoforms of PI3K. Some of these are PI3K-delta inhibitors and some are PI3K–gamma-delta; that'll be the difference between whether they’re tested in CLL versus other lymphomas.

Apart from the B-cell receptor pathway, I mentioned trials with venetoclax, which is a BCL-2 inhibitor. This is an important antiapoptotic protein. In CLL, there is a defect in programmed cell death. The idea of an anti-apoptosis inhibitor is to tip the balance towards apoptosis. There are also combination therapy trials that may offer a complimentary approach in targeting the B-cell receptor signaling pathway.

Lastly, we think of intracellular targets when we say targets, but some of our oldest immunotherapies and targeted agents are anti-CD20 inhibitors. These CD20 monoclonal antibodies reside on the surface of CLL and other B-cell malignancies. For a long time, we only had rituximab. Then, we had ofatumumab (Arzerra). Now, we have these next-generation antibodies with enhanced killing, such as obinutuzumab (Gazyva).
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