FCR Retains Curative Potential in Young Patients With Favorable CLL Biology

John Seymour, AM, MBBS, FRACP, FAHMS, PhD

FCR (fludarabine, cyclophosphamide, and rituximab [Rituxan]) plays a crucial role in the curative treatment of a subgroup of patients with chronic lymphocytic leukemia (CLL) and should still be considered for these patients despite the emergence of newer standards of care, such as BTK inhibitors and venetoclax (Venclexta), according to John Seymour, AM, MBBS, FRACP, FAHMS, PhD.

“The preclinical science, understanding the mechanism of how these drugs work, how they interact, and their synergies, was critical to building the FCR regimen,” Seymour said in an interview with OncLive® during the 2023 SOHO Annual Meeting in Houston, Texas. “Those lessons are important for all of us as we try and build these targeted agents into combination regimens that hopefully in the future will have similar curative potential.”

In the interview, Seymour discussed the characteristics of patients with CLL who may benefit from FCR, how genetic testing can provide key insights into individual patient disease patterns, and treatment sequencing options after progression on FCR.

Seymour is the director of the Hematology Department at the Peter MacCallum Cancer Centre and the Royal Melbourne Hospital in Australia.

OncLive: Could you provide a brief overview of your SOHO presentation entitled, "How We Developed a Curative Therapy for CLL and Stopped Using It?"

Seymour: There were 3 goals of the presentation. There was a historical goal. People in the field may not understand some of the work and particularly the mechanistic work, understanding combinations. There was a personal element, given that particularly with [SOHO] being in Houston, several of the people who made huge contributions to the development of FCR are based in Houston, particularly Michael Keating, MB, BS, and William Plunkett, PhD, [both of The University of Texas MD Anderson Cancer Center].

The third goal was [to relay] that I still see, in a small subgroup of patients, a clinical role for FCR. Perhaps the pendulum had swung a little too far or the baby might have been thrown out with the bathwater to some extent. [I wanted] to emphasize that niche clinical role [for FCR] to be considered for that patient subset.

What patient subset may still benefit from a curative treatment option with FCR?

It is a small subset, and it’s selected by disease biology. The subset of patients that FCR has curative potential in is those with mutated IGVH status or the absence of TP53 aberrancies, so favorable biology. Some other rarer mutations may come into consideration.

Also [important are] age and renal function [because] that will also allow tolerance. [These are] patients under the age of 65 years with adequate renal function, creatinine clearance above 60 [CrCl], and favorable disease biology, which ultimately ends up being only about 15% of all the patients who may need treatment for CLL. However, approximately half of that 15% is cured with FCR and never requires therapy for the remainder of their natural life. Although targeted agents are well tolerated in the short term, [patients can receive] continuous [treatment with] BTK inhibitors with cumulative toxicity risks, including cardiac arrhythmias, or time-limited, venetoclax-based treatments [that] at this point [have no] proof of curative potential.

How does the variety of targeted therapies available for CLL emphasize the need for genetic testing and determining personalized treatment approaches for each patient?

Thinking of the potential application of these therapies should trigger in clinicians [that it is] important to understand the individual biologic profile of the patients [we treat]. One [risk is], because targeted agents, particularly the BTK inhibitors, are generally good against all subsets [of CLL], there is perhaps the dumbing-down potential to say, ‘well, I’m going to use this drug anyway; I won’t bother testing.’ [This] hides the nuance for the individual patient and removes some of that forewarning and expectation around how a patient’s disease might behave in the longer term, and what potentially more intensive therapies, [including] immunotherapies, bone marrow transplant, and CAR T-cell therapy, might need to be considered in the future.

How do you sequence these treatment options?

[The population that will benefit from FCR is] a small minority, but if you are using FCR, for half of those patients, it will be the only treatment they ever need for their natural life; hence, sequencing is not required. If you use FCR and the disease recurs, I do not see any role for further use of any DNA-damaging chemotherapy. If this will be used, it’s once only and done.

Probably one of the most feared risks of FCR in the past has been its cumulative [risk of] myelodysplasia or acute myeloid leukemia that can be as high as approximately 10%. However, that is a cumulative risk from repeated exposure to DNA-damaging agents. If you’re using it as a single exposure, that risk is approximately 2%.

[Most patients will receive a] sequence of BTK inhibitors and [BCL-2 inhibition with] venetoclax, the current classes of therapy. My preferred approach in younger patients, especially those with mutated IGVH is time-limited therapy, because for their time horizon, the proportion of their remaining life, you would want to have as much time off drug as possible.

For most patients, you will need to use both classes of drugs. If a patient’s tolerance of venetoclax, for example, may not be as good in 5 or 7 years, you may prefer to get that in now, knowing that you can deliver a BTK inhibitor subsequently. Regarding efficacy, we have good data now going in both directions. We have those options, and we can discuss [preferences] with the patient, because ultimately both tools will need to be used at some point.

What is your main message for colleagues?

For those niche, uncommon patients, still consider FCR. Have that discussion. The patient may not wish to go down that path but have the discussion.

What other presentations at SOHO stood out to you?

The presentation by Tanya Siddiqi, MD, [of City of Hope in Duarte, California] about the [phase 1/2] TRANSCEND CLL 004 trial [NCT03331198] indicates that there is a role for CAR T-cell therapy in CLL. Defining that role, considering how we protect T-cell function, and identifying the [optimal] patient group are the challenges, but the proof of principle that CAR T-cell therapy has a role in CLL is now established.

One of the strengths of the SOHO meeting is there are no parallel sessions. People are not drawn in multiple directions. And there’s a strong, young faculty here. The availability of all the speakers [created] a wonderful interchange between attendees and speakers that I haven’t seen at many other meetings. It’s a dynamic and collegial meeting.