Kahl Highlights Frontline Considerations in Changing CLL Landscape

Brad S. Kahl, MD

Age, disease-characteristics, and comorbidities are factors physicians need to consider before administering ibrutinib (Imbruvica) or chemoimmunotherapy to patients with chronic lymphocytic leukemia (CLL), said Brad Kahl, MD.

“CLL is a rapidly changing area with lots of new drugs being developed and new indications,” said Kahl, professor in the Department of Medicine, Washington University School of Medicine in St. Louis, Siteman Cancer Center. “It's become fairly complicated in a relatively short period of time figuring out the optimal choices and strategies that one needs to make when managing a patient with CLL right now.”

Ibrutinib has held a frontline indication for patients with CLL since 2016. In October, the FDA granted the BTK inhibitor a priority review designation for use in combination with obinutuzumab (Gazyva). The application was based on data from the phase III iLLUMINATE (PCYC-1130) trial, updates of which are likely to be presented at the 2018 ASH Annual Meeting.

Moreover, venetoclax (Venclexta) received a full approval in June 2018 following its accelerated approval in 2016 for patients with or without 17p deletion who received at least 1 prior therapy. The BCL-2 inhibitor also holds an indication in combination with rituximab (Rituxan) in the same patient subset based on data from the phase III MURANO trial, which boasted a 92% overall response rate.

Though these novel therapies have demonstrated high response rates, Kahl noted that the ongoing CAPTIVATE trial of ibrutinib combined with venetoclax may shift the landscape once again.

OncLive: What are the available frontline options for patients with CLL?

In an interview with OncLive^® during the 2018 State of the Science Summit™ on Hematologic Malignancies, Kahl discussed the rapidly evolving therapeutic landscape of CLL and the novel combinations on the horizon.Kahl: The first big decision that clinicians will be faced with when starting a patient on frontline treatment is whether to give them traditional chemoimmunotherapy. For younger patients, this was the fludarabine-cyclophosphamide-rituximab (FCR) regimen. For older patients, bendamustine/rituximab is typically a very good choice and commonly used. For much older patients, chlorambucil with obinutuzumab is a very reasonable choice.

A couple of years ago, ibrutinib was approved for frontline use. Now, any patient can be offered that option, and it creates some interesting choices for the clinician and the patient. Ibrutinib is incredibly active in CLL with high response rates and durable remissions. On the other hand, ibrutinib is meant to be administered as chronic daily therapy, whereas these other choices I mentioned all have finite durations of administration. Patients can look forward to being done with their treatment in about 6 months, which isn't true with ibrutinib.

Have you found that most patients opt for ibrutinib as opposed to chemotherapy?

Is ibrutinib being compared with any of these regimens?

The tradeoff is more toxicity in the short-run and a treatment-free interval or chronic daily therapy. We lack the comparative data to say you should choose one over the other. We're operating in a world where we are making educated guesses on behalf of our patients and then having this discussion with them to make a decision jointly.Most patients are aware of the option for novel targeted agents. Most patients have a pretty horrific view of chemotherapy and what that might be like. You normally have to educate them a bit that the chemotherapy plan isn't perhaps quite as horrible as they would imagine. It's very doable for most patients, but we're definitely seeing more patients interested in avoiding chemotherapy. There’s no question about it. Yes, and some of those trials have completed; we're just waiting for data. The US cooperative groups have conducted 2 important trials. One trial compared ibrutinib with BR for older, less fit patients. A letter from the Data Safety Monitoring Board wrote that ibrutinib is superior to BR in terms of progression-free survival (PFS). There's no overall survival difference to date.

What other aspects do you consider in selecting therapy for patients?

I'll often tell patients that ibrutinib will keep them in remission longer, but choosing the chemotherapy option now is still OK. When their disease comes out of remission in 2 to 6 years, they can do ibrutinib at that time. That's a perfectly acceptable strategy. The other trial is single-agent ibrutinib or ibrutinib/rituximab versus the FCR regimen. That trial is fully enrolled, but we don't have any results yet. Besides age, comorbidities are very important. You can see a 72-year-old patient who is extremely healthy and a 62-year-old patient who is extremely unhealthy. Age is an important factor when weighing these considerations because bone marrow health and bone marrow reserve diminishes with age. Certain regimens become quite difficult as you get older. You could be a very healthy, fit, 72-year-old; you're just not appropriate for FCR in my opinion. BR would be a better choice.

Other factors to consider are disease characteristics. We look at fluorescence in situ hybridization testing for chromosomal abnormalities. Any patient with a 17p abnormality or a p53 mutation probably shouldn't get chemoimmunotherapy. Ibrutinib would be a much better choice for them. The other thing to factor in is the immunoglobulin heavy chain gene mutational status. It's pretty clear that patients who have the unmutated version have less favorable disease. They don't respond as well to chemoimmunotherapy as patients with mutated disease.

What are the sequencing considerations?

The data we have on ibrutinib suggest that the drug works equally well in mutated and unmutated disease. If I have a patient with unmutated disease, I might lean toward ibrutinib for them, whereas if I have a patient with mutated disease, I might lean toward the chemoimmunotherapy regimen for them, given that we lack the comparative data right now. Ibrutinib is basically chronic daily therapy, so patients can be on that for years. If the patient is 56 years old, particularly if they have mutated disease, I might favor doing their 6-month course of therapy and save ibrutinib for later. Patients only get older and less healthy, which is true of everybody.

How has venetoclax impacted the landscape?

I had this conversation with a patient recently as we weighed these considerations. She was 75 years old, and we were trying to decide between BR and ibrutinib for her. She could tolerate BR quite well right now, but it definitely gets harder as you get older. If you think in terms of sequencing, there might be some advantages for her to have BR now and the ibrutinib for later when she is older and less fit. Having said that, not all CLL physicians subscribe to this philosophy. I don't mean to imply that there's a right or a wrong answer here.Venetoclax is a BCL-2 inhibitor that is incredibly active in CLL with potency comparable to that of ibrutinib. They’ve not yet been compared in a head-to-head trial. There was an important trial published this past year in the New England Journal of Medicine, which looked at the combination of venetoclax and rituximab versus BR in relapsed CLL. Venetoclax was given for a fixed duration of 2 years. Historically, all of the novel, oral, targeted agents are given indefinitely. That can become a drag for a patient from a financial and toxicity standpoint.

Even with these novel agents, what is the biggest challenge?

What trials are you looking forward to reading out?

Rituximab was given for 6 months and then venetoclax was given for 2 years. Bendamustine was dosed at 70 mg/m2. The results showed very strong superiority for the venetoclax/ rituximab regimen over the BR regimen. The PFS curve was very impressive; about 84% of patients were progression free at 2 years. It’s a very potent regimen, and an excellent second-line therapy for any patient with CLL. Those results were equally good whether the patients were mutated or unmutated, and virtually as good whether they had 17p deletion or not. Venetoclax works very well even in the unfavorable subtypes. The challenge right now is the decision making. You have all of these outstanding choices. The decision making can get a little complicated, but that's a good problem to have. Financial considerations end up being a real challenge for some patients. The drugs are expensive, especially because they're chronic therapy. That has to be looked into right away when you're considering one of these novel targeted strategies for a patient. We heard about iLLUMINATE in a press release a few months ago. That is the frontline treatment of ibrutinib and obinutuzumab versus chlorambucil and obinutuzumab. According to the press release, the ibrutinib arm was superior for PFS. I suspect we might see that data at the 2018 ASH Annual Meeting. It'll be interesting to see if that combination of ibrutinib and obinutuzumab gets a frontline indication and whether that becomes a preferred choice over ibrutinib alone.

Presented at the 2018 ASCO Annual Meeting were early results from a trial called CAPTIVATE, which combined ibrutinib and venetoclax—the 2 most potent and active agents. Patients started on ibrutinib for 3 months, which debulks the patient's disease and then makes the initiation of venetoclax simpler as there's less risk for tumor lysis syndrome. After a few months of the combination, the response rates in the small group of patients they were able to report on looked outstanding. The minimal residual disease—negative rates looked outstanding. This combination should be very potent and will be a very interesting combination to keep our eyes on as we get more data.

Seymour JF, Kippes TJ, Eichhorst B, et al. Venetoclax—rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018; 378:1107-1120. doi: 10.1056/NEJMoa1713976.