Investigators Searching for Best Path Forward Amid Abundance of Advancements in CLL

Danielle Brander, MD

Danielle Brander, MD

While new, unanswered questions have come to the surface along with recent developments in the treatment paradigm of chronic lymphocytic leukemia (CLL), this is a good problem for physicians to have, said Danielle Brander, MD.

“For patients who I have sitting in front of me to talk about their options for [the] frontline or relapsed/refractory setting, first I tell them, in a good way, ‘It's now a long discussion because we have a lot of different agents,’” she explained. “But there are also a lot of areas of unmet need in terms of research.”

Brander, assistant professor at Duke University and the Duke Cancer Institute, took part in the 2nd Annual Live Medical Crossfire^®: Hematologic Malignancies, discussing some of the most relevant clinical issues in the management of hematologic malignancies.

In an interview withTargeted Oncology, she highlighted how recent advances are changing the field of CLL and what it means for physicians and their patients.

TARGETED ONCOLOGY:Can you provide an overview on the current treatment landscape for CLL?

Brander:There have been a lot of changes in the treatment options available for patients with CLL. For frontline treated patients, what has changed the most in the past 5 years is that we're trying to identify both the patients who may still be both eligible for and benefit from long-term chemoimmunotherapy. [These are] young, favorable-risk patients—IGHVmutated, no high-risk deletion 11q or deletion 17p. [These patients] can sometimes get very long-term, 10- or 12-year plus, remissions from frontline chemotherapy with fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR).

There are also patients with favorable-risk disease who might be older, who, for a host of other comorbid reasons, may get meaningful remission from a fixed duration of frontline chemotherapy, even bendamustine/rituximab (BR). However, I don't use BR for younger patients.

In the frontline setting, the only targeted agent currently approved outside of clinical trials is ibrutinib (Imbruvica). More recently, there was a publication that looked at 5-year follow-up of a cohort of patients in the mostly frontline setting. What we learned is that patients who were not high risk, so did not have 17p deletions orTP53mutations, and particularly some of the older patients who tolerated ibrutinib had extremely low progression-free survival (PFS) over the 5 years.

Most of the other agents have been approved or studied in the relapsed/refractory setting. There's a little bit of a debate about a subset of patients who might benefit from chemotherapy or reasons you might use chemoimmunotherapy. If patients are relapsed/refractory, by and large, a lot of these patients are being transitioned to the novel therapies.

Right now, the agents that are approved for CLL in the relapsed/refractory setting are ibrutinib for patients who didn't get it in the frontline setting, idelalisib (Zydelig) if they had more than 2 prior lines or are not eligible for other treatments, and venetoclax (Venclexta) is the most recent. Venetoclax was just approved [by the FDA] in the past month for all relapsed/refractory patients with CLL based on a clinical trial called MURANO, where patients were randomized to either BR or venetoclax/rituximab.

There are about one-quarter of patients in both arms who had high-risk 17p deletion, but part of that is understanding […] why those patients didn't go directly to targeted agents. They were treated in countries or places that didn't yet have the novel agents available. At the end, there was a significant difference in PFS between BR and venetoclax/rituximab, and that was a fixed duration of venetoclax.

Then, we have what I say are the "next-generation” targeted inhibitors. Even with all those agents that are approved, there are clinical trials, appropriately and excitingly, that are looking at next-generation BTK inhibitors. We have acalabrutinib (Calquence), which is going to be randomized in high-risk patients versus ibrutinib in a phase III trial looking at differences in toxicity. There are several other agents being looked at in the relapsed/refractory setting that are also BTK inhibitors.

The same is true for PI3K inhibitors, either PI3K-delta or PI3K-gamma and -delta, that are being evaluated either in comparison with idelalisib or in general for relapsed/refractory patients. Then, as I mentioned, [there is] venetoclax across different lines of therapy. There are also a lot of combinations being looked at in the relapsed/refractory setting.

How do you sequence the agents? Who does better with combining several agents versus [who will] do well with monotherapy for time-abbreviated courses? That is why I still strongly believe that nearly all patients should consider clinical trials, importantly for their own benefit. Also, it is because there are so many gaps where we're trying to find the best, most cohesive treatment options for patients.

TARGETED ONCOLOGY:What is the biggest challenge in the field right now?

Brander:[The biggest challenge is] trying to help patients navigate areas where there is no mature research in terms of: how do the novel agents in the frontline setting do long term for those favorable-risk patients? Can we replace chemotherapy for those favorable-risk patients? Is it the same for relapsed/refractory patients on phase II trials or trials that are randomizing [agents] to chemotherapy? And, how do you compare the novel agents? For example, now that venetoclax/rituximab is approved for all patients with relapsed/refractory disease, do patients go from chemotherapy to the venetoclax/rituximab or ibrutinib? We have longer data with ibrutinib, and [we have data] sequencing from ibrutinib to venetoclax and not yet from venetoclax to ibrutinib.

For younger patients with higher-risk changes, what is the best frontline therapy? We know it's not chemotherapy, but is it these single agents or are we going to find combination agents?

Finally, the patients I'm most concerned about are the patients who are high risk. They greatly benefit from these novel agents. Honestly, they are grateful to have nonchemotherapy opportunities, particularly if they're TP53 dysfunctional where we knew chemotherapy didn't work. While many will do well on these agents, some patients are either intolerant or they develop resistance.

In one of the studies where patients stopped or progressed on ibrutinib and went to venetoclax, there was an above 60% response rate, but we know that patients who never get a deep response eventually relapse. How do you make recommendations for patients who have acquired resistance to more than 1 novel agent? That's very difficult and is what we're looking at—maybe not even in the next line of targeted inhibitors, but other consolidation options through the few patients where we might consider allogeneic transplant if a clinical trial is not available. I also think it's an area of need where maybe CAR T-cell therapies or other immunotherapies could provide benefit.

TARGETED ONCOLOGY:Where do you see the field heading in the next decade?

Brander:I felt better to hear Dr. Neil Kay, who for several decades has been 1 of the experts to help carry the field forward—along with all the patients who have participated in trials and other investigators—say that his head is spinning from some of the developments from the past 2 years or even the past year. But most of that spinning, for us trying to make recommendations to patients, is all in a positive way. Patients have options and we're trying to find the best path forward.

What I hope will come out of longer-term follow-up in the frontline setting is whether some of those favorable-risk patients with long-term remissions from chemoimmunotherapy might also have very favorable long remissions with novel agents or a combination of novel agents. [This could be] a time-limited approach, potentially nonchemotherapy in the frontline setting. Five [or 10] years might give us a little more window, but we're going to need a sufficient portion of patients to know what that benefit is on overall survival. Hopefully, in that interval, we'll be getting next-line agents that will cloud the picture a bit because they'll be sequenced to those agents.

A lot of these clinical trials have had important laboratory correlatives that have been looked at in terms of looking at next-generation sequencing.NOTCH1mutations are 10% to 14% of patients in the frontline setting, and we know that can impact patients' risk for transformation, as well as their short- and longer-term responses to some of the therapies. In general, I'm hoping the science will also help us delineate which markers we test for in a cohesive way and how to follow those.

That gets back to the question of greatest areas of unmet need. Patients who transform from CLL into another lymphoma—and we call that Richter's transformation—their median survivals can be at 1 year or less. Therefore, [we are] recognizing those patients and intervening before it happens; maybe better disease control earlier on is better.

Lastly, one of our paradigms so far, which is included in the International Workshop on CLL 2018 guidelines, is when to treat patients in the first place. That still has not changed even with these novel agents, but there are important clinical trials looking at the novel agents in the highest-risk patients, so probably patients with deletion 17p orTP53