CLL Paradigm Prepares to Expand With Novel Therapies as Chemo Is Phased Out

James Gerson, MD

Treatment considerations for patients with chronic lymphocytic leukemia (CLL) have changed significantly compared with historic parameters, said James Gerson, MD. However, as Bruton tyrosine kinase (BTK) inhibitors have largely replaced the use of chemotherapy, selecting the optimal treatment for patients is ultimately less challenging.

“It’s actually interesting because [treatment selection] has gotten a bit easier,” said Gerson. “Now that we are using more targeted therapies, it is interesting that [disease features, such as mutational status,] are less relevant.”

Additionally, options are poised to expand even further with chimeric antigen receptor (CAR) T-cell therapy and novel BTK inhibitors, such as LOXO-305.

In an interview with OncLive^® during a 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Gerson, an assistant professor of clinical medicine at Penn Medicine, discussed how he navigates treatment selection for patients with CLL and exciting developments in the pipeline.

OncLive®: What factors do you consider when selecting a treatment for patients. How has it changed compared with historic considerations?

Gerson: A couple of years ago, when we were still using a lot of chemotherapy in the frontline setting, it was critical to think about risk factors, such as IGHV status and common deletions in 17p, 11q, and 17b that we saw on karyotyping or next-generation sequencing. These [factors] were important to avoid chemotherapy in high-risk patients who would have worse or suboptimal outcomes with chemotherapy, according to pretty clear data.

There is still potentially some importance of 17p deletions and TP53 mutations, mostly because the data are not as mature for [agents] such as venetoclax [Venclexta] and obinutuzumab [Gazyva]. The data are much more mature for ibrutinib [Imbruvica]. A clinician might say that somebody with one of those features should potentially get the treatment that has the most robust data. However, apart from that, we can offer BTK inhibitors versus BCL-2 inhibitors with a CD20[-directed antibody] to really any patient.

The only exception to that now is the one population that still could be considered for chemotherapy: young patients with very good risk features who are highly motivated for short-duration therapy and are OK with the effects of chemotherapy. Those patients could certainly be considered for chemotherapy, even in today’s world.

Arguably and not necessarily for the FDA or treating oncologist to worry about, cost is definitely a factor. [A recent] article published in Blood looked at the cost-effectiveness of ibrutinib. To no one’s real surprise, [ibrutinib] is not cost-effective at all at the current pricing. Therefore, from a systems perspective, we probably should still offer chemotherapy, because otherwise we are going to [be met with financial toxicities], but it is hard to tell that to the patients sitting in front of us. It’s hard for us to tell a patient who says that they do not want chemotherapy that we are spending too much money and that they cannot get the new [options]. It is relevant that the system is untenable in the way we currently have it, but it is hard to know whether that comes from the patient, the physician, or a society that is not willing to pay for these very expensive medications. That’s important, but it is not coming into the clinic very often.

What options are available for patients who develop resistance to BTK inhibitors?

A longer-term update from the MURANO trial [NCT02005471] showed [that patients who received] venetoclax and rituximab [Rituxan] had very good outcomes, even at longer follow-up, compared with bendamustine and rituximab. That remains my go-to for a patient who is treated with ibrutinib or any BTK inhibitor in the frontline setting. 

What do we do for patients who have already been exposed to venetoclax? This is something that hasn’t happened yet but is going to start happening more and more. Patients will have gotten frontline venetoclax and obinutuzumab, relapsed, received a BTK inhibitor, and relapsed again. At that point, what do we do?

Some data presented by Anthony Mato, MD, MSCE [of Memorial Sloan Kettering Cancer Center] at the 2019 American Society of Hematology Annual Meeting and Exposition [showed] that PI3K [inhibitors] are not very efficacious [in the] scenario [of patients previously exposed to venetoclax]. Whether or not those patients should be considered for clinical trials, allogeneic stem cell transplant, or CAR T-cell therapy trials [is yet to be determined]. Now, PI3K [inhibitors] are the FDA-approved options for such patients. Although I would try to steer patients toward a clinical trial in an academic setting, many patients in the community setting will go on PI3K inhibitors in the third-line setting.

What ongoing efforts are in development that have the potential to address current challenges?

The biggest challenge now is that CLL is an incurable malignancy. The real hope is that with some of these trends, such as triplets being introduced to the frontline setting or cellular therapy, we may start curing a lot of these patients. 

The cost issue I mentioned earlier with ibrutinib in the frontline setting is really predicated on the fact that ibrutinib and acalabrutinib [Calquence] [are given indefinitely]. Patients are on those medications for the long run. Obviously, the months and years of cost are associated with the lack of cost-effectiveness. If we can come up with schemas that are [time limited], such as venetoclax, ibrutinib, and obinutuzumab given in the frontline setting for 6 months, that [would be beneficial]. Yes, they are expensive, but it will not be a long-term cost. That is the most exciting part of the CLL field coming up; we may actually start curing some of these patients with triplet or alternative therapies.

Are there specific research efforts underway that you’d like to highlight?

Being at Penn Medicine, I can speak to our own [research] first. We have 2 clinical trials open for patients with CLL. One is using a novel BTK inhibitor called LOXO-305. That medication was specifically designed to [overcome] BTK inhibitor resistance, and it appears to be effective in patients who have previously been exposed to and progressed on a BTK inhibitor. That is definitely an exciting option. We are actively accruing for that. 

We also have a trial that is coming very soon to evaluate ibrutinib as a lead-in to CAR T-cell therapy. I don’t think it is yet open because things have obviously been put on hold because of the novel coronavirus disease 2019.

CAR T-cell therapy is obviously very exciting across the board as a very effective and potentially curative strategy. The [toxicity] can be somewhat concerning at times, but it is something that we are very excited about. [CAR T-cell therapy] is likely going to be coming for CLL in the next couple of years. 

Other trials around the country are using various strategies [beyond] combinations. One of our satellite centers has a trial [open] looking at a novel triplet regimen in the up-front setting. That’s also very exciting because it is another potentially curative therapy, although we don’t really know yet. Other combinations around the country are also being looked at pretty seriously.