Highlighting Developments and Informing Treatment Planning in CLL Care

In an interview with CancerNetwork®, Deborah Stephens, DO, an associate professor of Medicine, director of the CLL and Richter’s Program, and physician leader of the CLL and Lymphoma Research Program at the University of North Carolina School of Medicine; and Jacob D. Soumerai, MD, a clinical investigator in Lymphoma and assistant professor in Medicine at Massachusetts General Hospital, highlighted emergent advancements in clinical practice for patients with chronic lymphocytic leukemia (CLL) following a Lymphoma Research Foundation (LRF)–endorsed CLL working group.

Initially, challenges related to CLL were discussed, with Stephens highlighting the multiplicity of viable targeted treatment options and Soumerai describing that the subtle differences in these treatment options inspired the establishment of the CLL workshop to inform therapeutic decision-making. Furthermore, Soumerai discussed frontline treatment options for patients with asymptomatic CLL, particularly those seeking time-limited therapies. Stephens further identified treatment options in the second-line setting and beyond, touching upon BTK inhibition as well as bispecific use in this patient population.

Furthermore, Stephens and Soumerai disclosed points that resonated with them at the CLL workshop, with the former highlighting the use of minimal residual disease (MRD) and BTK resistance mutations in informing clinical practice and the latter emphasizing the importance of engaging patients in shared decision-making processes. Then, Soumerai discussed the establishment of a clinical guide intended to inform practice for clinicians managing CLL and educate patients regarding the implications of their treatment options. Stephens further expressed that the establishment of the guide was intended to provide a more comprehensive source to inform clinicians as well as give patients a sense of agency in advocating for their treatment decisions.

CancerNetwork: What are some challenges related to CLL that health care professionals are currently facing?

Stephens: There are many great things that are happening for physicians in the management of CLL because there are many [effective] targeted treatments that are available. Challenges result around trying to figure out how to sequence the therapy and pick the best treatment that comes first in line so we can still [treat] the patients in the second or third line. A part of that comes because the challenge is not having a cure for CLL yet. We are talking about sequencing treatments because there is not one treatment that the patients can receive and then complete.

Another challenge I would say that faces clinicians is that unlike a lot of other lymphoid malignancies, CAR T and transplant have been successful in helping patients, whereas with CLL, there’s a lot of morbidity associated with it. Due to the age of patients, it’s hard to get patients well enough and in remission [to be] in a good spot to go to transplant or CAR T. Those are some of the main features that are affecting physicians right now.

Soumerai: We are in a space where there are so many options that one of the most difficult things about treating patients with CLL is keeping up with the subtle differences in some of these therapies and the effects on the patients we are caring for. That has served as the foundation for the [CLL working group]. How do we meet that problem by giving clinicians all the information about the differences in these treatments, the differences in patients that help guide whether we should be recommending one treatment approach vs another and [making] all the different decisions that spiral after that initial treatment decision is made?

What ongoing clinical trials are currently evaluating treatments for patients with CLL?

Soumerai: There are many ongoing clinical trial efforts, some of which have been completed, and we are simply awaiting the data to inform clinical practice. One way to [review these trials] would be to start from diagnosis. There’s an important intergroup study, the phase 3 SWOG 1925 study [NCT04269902], which is evaluating whether we can take patients with asymptomatic CLL who do not meet current accepted standard criteria for the initiation of therapy, and identify those patients who have a higher risk for an unfavorable CLL outcome using something called the CLL-International Prognostic Index [CLL-IPI] risk tool.1 It is also testing whether, in this select group of patients, early treatment with time-limited therapy with venetoclax [Venclexta] and obinutuzumab [Gazyva] might improve their outcomes.

This is an effort that Stephens is playing a major role in leading, and it does have the potential, in the future, to inform the care of patients. Right now, the clear standard of care is to observe, without treatment, patients who are asymptomatic and do not meet these criteria. But this is an important study.

There is an important study that was presented at the 2024 American Society of Hematology [ASH] Annual Meeting called the phase 3 AMPLIFY trial [NCT03836261].2 This was a trial that compared the combination of acalabrutinib [Calquence] and venetoclax with or without obinutuzumab [vs] chemotherapy. This was a positive study––the combination of acalabrutinib/venetoclax ± obinutuzumab was superior to chemotherapy and is likely to lead to this being approved in the frontline setting for patients with CLL.

This is an interesting regimen. Patients like time-limited therapy, but there is also an interest in not receiving the infusional therapy: the obinutuzumab antibody therapy. For a patient who is more inclined towards time-limited treatment and does not want the infusion but may be a good candidate for a BTK inhibitor on the basis of their medical history and other factors, this is likely to be a compelling option.

There are other data that are ongoing. There is a regimen of a newer BCL2 inhibitor called sonrotoclax [BGB-11417], which is being combined with zanubrutinib [Brukinsa]. We saw some exciting data showing that this [combination] is associated with favorable safety outcomes but also high rates of undetectable MRD. There is an ongoing randomized trial that has completed accrual we are awaiting the results of called [the phase 3] CELESTIAL-TNCLL [NCT06073821] study, which compares this regimen against venetoclax/obinutuzumab.3 This is also an exciting study.

This is just the beginning. There are many other trials that are ongoing and are potentially poised to change the standard of care for CLL.

Stephens: Another exciting trial, along the same lines in the frontline setting, is the phase 3 CLL17 study [NCT04608318]. That is looking at [whether we can] do time-limited therapy with venetoclax and obinutuzumab, or potentially therapy with ibrutinib [Imbruvica] and venetoclax, compared to continuous therapy with ibrutinib.4 It’s the first study that has compared this continuous therapy with the other novel targeted agents.

The study is going to be a bit of a challenge to interpret once it’s completed because when it was designed, ibrutinib was the standard BTK inhibitor that most people used. Now, with acalabrutinib and zanubrutinib, most people use these next-generation inhibitors. It’s going to be an important study because it looks at all targeted, time-limited therapies vs indefinite therapy. There are some weak spots because ibrutinib is the BTK inhibitor that was used, but it will still provide important data.

In the second-line setting, important recent studies that were presented included the phase 3 BRUIN CLL-321 study [NCT04666038], which looked at the third-generation BTK inhibitor pirtobrutinib [Jaypirca], which is currently approved in the third-line setting for patients with CLL after treatment failure of [prior] BTK inhibition and venetoclax.5,6 This clinical trial looked at the second-line setting. There were a fair number of patients who [had recently received] BTK inhibition, and the thought was that they will use that to apply for getting pirtobrutinib in earlier lines of therapy.

[Regarding] later lines of therapy, there are still many great novel agents that we do not quite know how to use yet but are showing great activity––things like BTK-degrading agents. Those are exciting because they work even when BTK inhibitors do not work anymore. [Investigators are] taking a different approach with the bispecific antibodies like epcoritamab-bysp [Epkinly], glofitamab-gxbm [Columvi] and mosunetuzumab-axgb [Lunsumio] by looking at their effects. Those are still fairly early studies.

Were there any points brought up while attending the CLL working group that resonated with you?

Stephens: This was a nice group of physicians from across the country that all agreed to work with the LRF to come up with some practical guidelines. It was a great collaborative group. We spent a lot of time workshopping and trying to get complete agreement and consensus between all of the experts. There were a couple of key pieces that I felt still took a lot of discussion, and there was not a clear consensus on them. That [includes] the use of MRD and how to use it in clinic. Should we be guiding therapy by it? Another piece was, should we be using BTK resistance mutations in clinical practice? Because there was not a consensus, we decided that it’s not quite ready for mainstream [practice], but there is a lot of clinical trials ongoing that hope to help address how to best use this in clinical practice.

Soumerai: For most patients with CLL, the primary decision-making is that choice of initial therapy. One thing that really resonated for me was the fact that we have so many factors that drive the decision-making. But at the end of the day, probably for a majority of patients, there are multiple reasonable treatment approaches. One of the key things is the importance of engaging patients. There are some interesting data that we cited in that most patients want to participate in these discussions. They want to be engaged in a shared decision-making discussion regarding their treatment decisions, yet less than half of patients actually report having this opportunity.

What material is contained within the clinical guide inspired by the CLL working group?

Soumerai: There are 3 main outputs of this effort. The first is a clinical guide that’s directed at clinicians. This is now published in Blood Advances and includes information on, [for example], what is the standard workup?7 How do we approach the workup of a patient with newly diagnosed CLL or prior to any line of therapy subsequent to that? How do we make the decision to initiate therapy once we make this decision? What are the factors that influence treatment selection? Once we go down an initial line of therapy and a patient requires a change in therapy, how do we make that decision from the beginning at diagnosis all the way through a patient’s life with CLL? All that information is in this primary clinical guideline, but there are 2 additional pieces here.

The LRF is an outstanding organization that supports patients. One of the things we wanted to do was provide all the same data [and] guideline information to patients in parallel. Along with the LRF, we helped to develop a lay summary version of the guidelines. This is something that should be available soon on the LRF website and will provide patients with the same information. There are, again, 2 outputs here. One is an English version, and the other is a Spanish version. The hope is that all of this [work] will form the basis for future educational efforts targeting both clinicians and patients.

How will the integration of the guide into clinical practice enhance treatment for patients?

Stephens: As a part of this workshop, we focused on trying to make these timely and intuitive guidelines for physicians. [We tried] to get beyond what is provided by other guidelines, like the NCCN guidelines, [to offer] a more candid discussion of why we would do one thing or another. If a clinician reads that, they have a good idea on what’s recommended by a large panel of experts––they have some rationale behind it. I hope that leads to better patient care over time in addition to the patient-directed materials. Patients can come into their clinic visits prepared. If they have read the guidelines, they could be prepared with intuitive questions and can help to guide their own care.

References

1. Stephens DM, Moseley A, Hill BT, et al. Randomized, phase III study of early intervention with venetoclax and obinutuzumab versus delayed therapy with venetoclax and obinutuzumab in newly diagnosed asymptomatic high-risk patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): EVOLVE CLL/SLL study (SWOG S1925, NCT#04269902). J Clin Oncol. 2021;39(suppl 15):TPS7567. doi:10.1200/JCO.2021.39.15_suppl.TPS7567
2. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab versus chemoimmunotherapy for first-line treatment of chronic lymphocytic leukemia: interim analysis of the multicenter, open-label, randomized, phase 3 AMPLIFY trial. Blood. 2024;144(suppl 1):1009. doi:10.1182/blood-2024-200701
3. Shadman M, Kater AP, Woyach JA, et al. CELESTIAL-TNCLL: An ongoing, open-label, multiregional, phase 3 study of sonrotoclax (BGB-11417) + zanubrutinib vs venetoclax + obinutuzumab for treatment-naïve (TN) CLL. J Clin Oncol. 2024;42(16):TPS7087. doi:10.1200/JCO.2024.42.16_suppl.TPS7087
4. Ibrutinib monotherapy versus fixed-duration venetoclax plus obinutuzumab versus fixed-duration ibrutinib plus venetoclax in patients with previously untreated chronic lymphocytic leukaemia (CLL) (CLL17). ClinicalTrials.gov. Updated December 31, 2024. Accessed March 7, 2025. https://tinyurl.com/bdf4dsn3
5. Sharman JP, Munir T, Grosicki S, et al. BRUIN CLL-321: randomized phase III trial of pirtobrutinib versus idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in btk inhibitor pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma. Blood. 2024;144(suppl 1):886. doi:10.1182/blood-2024-198147
6. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. News release. FDA. December 1, 2023. Accessed March 7, 2025. https://bit.ly/48011OO
7. Soumerai JD, Barrientos JC, Ahn IE, et al. Consensus recommendations from the 2024 Lymphoma Research Foundation Workshop on treatment selection and sequencing in CLL or SLL. Blood Adv. Published online November 19, 2024. doi:10.1182/bloodadvances.2024014474