The Evolving Role of Prognostic Markers for CLL in the Era of Novel Agents

Partner | Cancer Centers | <b>Huntsman Cancer Institute at the University of Utah </b>

Deborah M. Stephens, DO, discusses her approach to treating a patients with chronic lymphocytic leukemia, how CAR T-cell therapy may fit into the treatment paradigm, and the numerous trials that have shown promise in this space.

Although the treatment armamentarium has expanded significantly for the treatment of patients with chronic lymphocytic leukemia (CLL), it remains essential for prognostic markers to be checked at diagnosis in order to help inform decisions when it comes to choosing the optimal therapy, according to Deborah M. Stephens, DO.

“We don't have a cure for CLL yet, so doing further research on clinical trials is the way that we are going to get there,” Stephens said. “This is a good time for patients with CLL, because there are a lot of options to choose from and you can't go wrong with a lot of them.”

In an interview with OncLive, Stephens, director of the CLL and Lymphoma Program at Huntsman Cancer Institute, discussed her approach to treating a patients with CLL, how CAR T-cell therapy may fit into the treatment paradigm, and the numerous trials that have shown promise in this space.

OncLive: Could you discuss the evolving role of prognostic markers for CLL?

Stephens: The role of prognostic factors in patients with CLL is evolving because the [overall] treatment landscape of [the disease] has mostly transitioned from standard chemoimmunotherapy drugs to targeted agents. Risk factors that were important with chemoimmunotherapy can be slightly different with targeted therapies. [There are] key prognostic factors and data comparing these factors when patients are treated with standard chemotherapies, like regimens containing fludarabine, cyclophosphamide, and rituximab vs ibrutinib [Imbruvica] vs venetoclax [Venclexta]. It is important to check these at diagnosis. Data from real-world [analyses] show how frequently, or infrequently, as it turns out, these factors are checked at [that time point].

What pivotal trials are looking at prognostic markers with novel agents in CLL?

I am the principal investigator on a clinical trial that specifically uses these prognostic factors, when checked at diagnosis, to enroll patients with high-risk CLL. This is the phase 3 EVOLVE CLL study [NCT04269902], which is specifically for patients who were diagnosed with CLL within the last year and have high-risk disease, [defined as a] CLL International Prognostic Index score of 4 or higher, or a complex karyotype.

When these patients are enrolled, they are randomized 2:1 to early vs delayed therapy with venetoclax and obinutuzumab [Gazyva]. Notably, these are typically patients who would be observed, so they need to be asymptomatic from a CLL standpoint when enrolling. The goal of this study is to determine whether we can improve the overall survival of patients by giving early intervention with these targeted agents. This study is currently open and it is enrolling at many centers across the country.

What is the optimal use or sequence of the available therapies in the paradigm?

One thing to highlight is that we have so many great options for patients with CLL right now, that many of the choices are not wrong choices. [Treatment for these patients] depends on what adverse effects they are willing to tolerate, and the length of therapy. [In my practice], I spend a lot of time talking about the different options when patients begin therapy. I no longer use standard chemoimmunotherapy in patients with IGHV-unmutated disease or those with deletion 17p or TP53 mutations. [However, chemoimmunotherapy] is an option in patients with low-risk disease, and it is worth discussing.

Some of the patients who are younger and high-risk prefer to do time-limited therapy. The venetoclax plus obinutuzumab combination is time limited to 1 year, so a lot of people like that. We [also] have a BTK inhibitor selection, and a lot of older individuals or people who do not want to come in for any IV infusions can benefit from these agents.

We have [recently] heard several head-to-head trials comparing ibrutinib vs acalabrutinib and ibrutinib vs zanubrutinib. All of these [agents] likely have similar efficacy, but the second-generation drugs, such as acalabrutinib [Calquence] and zanubrutinib [Brukinsa], are less toxic than ibrutinib. At the current time, zanubrutinib is not approved for [patients with] CLL, so a less toxic BTK inhibitor option that is currently approved would be acalabrutinib.

Where do you envision CAR T-cell therapy best fitting for your patients with CLL?

We do not fully know the answer to [this question] yet. However, patients who are high-risk [could potentially] benefit the most [from this modality]. [This includes] patients with deletion 17p, TP53 mutations, and patients who have already relapsed on a BTK inhibitor and venetoclax.

[CAR T-cell therapy] is a good alternative because it fits into this space that allogeneic stem cell transplant [ASCT] used to fit for patients with CLL. However, [CAR T-cell therapy is] much more tolerable for the older population, which is important since the average age of diagnosis for CLL is 70 years old. By the time these patients have gone through several treatments, they are [older] than 70 years. Although there are toxicities [associated with CAR T-cell therapy], they are significantly less than what is seen with ASCT. If I had to pick an ideal patient for a CAR T-cell therapy trial, it would be a young patient who has already relapsed on ibrutinib or another BTK inhibitor, as well as venetoclax therapy.

What recent trials have pushed the needle forward in this space?

We saw the first results of the phase 3 ELEVATE-RR trial [NCT02477696], which was the randomized study that compared ibrutinib with acalabrutinib in patients with relapsed or refractory CLL. This was particularly notable because it showed no difference in efficacy between acalabrutinib and ibrutinib in terms of progression-free survival. [The study] also showed a favorable toxicity profile with acalabrutinib. [The trial] has shifted the field to more prescription of acalabrutinib to limit toxicities.

A similar study was presented at the 2021 EHA Congress. The [phase 3] ALPINE study [NCT03734016] compared ibrutinib vs zanubrutinib in relapsed or refractory CLL. The primary end point in this study was overall response rate [ORR] and zanubrutinib did have an improved ORR vs ibrutinib. There was [also] a benefit in terms of a favorable toxicity profile. These data were early, [with] a short follow-up of only 1 year, which is a short follow-up for patients with CLL. Hopefully, we will be seeing more and more of these data throughout the year as they submit updates to different conferences.

The third-generation BTK inhibitor, pirtobrutinib [LOXO-305], looked at response rates in patients with Richter's transformation. This is a super high-risk patient group with an average survival of only 6 to 9 months from diagnosis. It was promising to see that this new drug, pirtobrutinib, has some efficacy in this population. Longer follow-up data on this study [would be nice], but they are promising results.

What are some other anticipated trends for research in CLL as we head into 2022? Is there anything you're looking forward to seeing at the 2021 ASH Annual Meeting?

I would love to see some further updates and more prolonged data of the ALPINE study comparing ibrutinib vs zanubrutinib. We [might] see a lot more cellular therapy variations and clinical trials with CAR T-cell therapy. Most of them now are directed at CD19, but there are several other ongoing studies with different targets such as ROR1. For a long time, venetoclax was the only BCL-2 inhibitor around and we saw the first data presented at the 2021 ASCO Annual Meeting of the next-generation BCL-2 inhibitor, lisaftoclax (APG-2575).

I suspect that we will be seeing more of these next-generation BCL-2 inhibitors. My hope is to figure out a way around the prolonged ramp up, as that sometimes is difficult to manage for patients and practitioners, depending on practice location.