The Paradox of Progress: Personalizing First-Line Therapy in CLL

The treatment landscape for chronic lymphocytic leukemia (CLL) has undergone a seismic shift, moving from the era of nonspecific chemo-immunotherapy to highly targeted molecular inhibition. While the introduction of Bruton tyrosine kinase (BTK) inhibitors and BCL2 antagonists has significantly improved progression-free survival across all risk groups, it has also introduced a paradox of choice for the community clinician.

Today, the central debate in frontline management revolves around 2 distinct philosophies: the convenience of continuous oral monotherapy vs the potency of time-limited, fixed-duration combinations. Both approaches offer high efficacy, yet they demand vastly different commitments regarding laboratory monitoring, infusion center resources, and long-term toxicity management.

In an interview with Targeted Oncology, Marc S. Hoffmann, MD, associate professor and director of the Lymphoma Program at the University of Kansas Cancer Center, explores the nuanced decision-making process required to navigate this choice. From the evolving data of the CLL17 (NCT04608318)¹ and CLL14 (NCT02242942)² trials to the critical role of IGHV mutation status and p53 aberrations, he discusses how to balance clinical evidence with patient-specific factors to optimize long-term outcomes and functional cures.

Targeted Oncology: With the shift from chemo-immunotherapy to targeted agents, community oncologists often face a paradox of choice. How do you personally navigate the choice between a continuous BTK inhibitort vs time-limited venetoclax (Venclexta)-based therapy?

Marc S. Hoffmann, MD: I think it's a really important question. There are a couple of factors that I generally use. First of all, I would say that we do not have randomized data [to support either choice], and particularly now with CLL17 getting published, [which showed] that basically all of these arms are equivalent, at least at 3 years.  While this is not a long follow-up period, it does suggest that the regimens are potentially more similar than they are different, at least in terms of efficacy.

Since the clinical efficacy appears comparable in the short term, how much weight do you give to the patient’s lifestyle and their ability to adhere to specific monitoring protocols?

Patient preference plays a critical role here. What the patient wants to do ends up being a really important component of what we decide. If patients have a really strong feeling that they don't want to do something intravenous, or if they have really a strong feeling that they're not able to do the more intensive laboratory monitoring that is required in order to do venetoclax, then often those patients end up on long-term single-agent BTK inhibition.

You mentioned the convenience of BTK inhibitors, but you’ve also spoken about the appeal of treatment-free intervals. Do you find yourself leaning toward one approach when looking for deeper molecular responses?

I personally have a bias towards time-limited, highly effective therapy that leads to deep and durable remissions, so I tend to prefer to do combination therapy. That being said, I have a lot of patients who are on single-agent BTK inhibitors, mainly driven by patient preferences. The longer-term data from CLL14 that suggest that we may see some really durable, long-term remissions with obinutuzumab [Gazvya] and venetoclax in IGHV-mutated patients. So I tend to steer IGHV-mutated patients to [obinitizumab plus venetoclax]; sometimes they don't want to do it for whatever reason, or it's not practical, but I will often bring up the fact that we believe that there seem to be some patients who might even be functionally cured of their disease with that regimen.

While IGHV status helps guide you toward time-limited therapy, how do you adjust your strategy for high-risk patients, specifically those with p53 mutations or 17p deletions?

This is a big question and unmet need in our field:  What do we do with people that have loss of p53 function, either via p53 mutation or 17p deletion? Abberant p53 leads to loss of function in the p53 system, which leads to increased mutation burden and genomic instability.  There is at least a long-term theoretical rationale that those patients should be on continuous therapy, predominantly due to genomic instability and consequent generation of resistance mutations. Historically, there has been a bias towards longer-term continuous therapy in these patients for those reasons, but we continue to lack high-quality randomized data to inform this.  At the end of the day, I try to get the majority of these patients on clinical trials.

Has the latest data from the CLL17 trial provided any clarity on whether these high-risk patients truly fare better on continuous treatment vs the time-limited approach?

In CLL17, the number of patients with p53 mutations was quite small, with fewer than 30 patients in each arm, and the number of progression events even smaller. So, it's a little hard to parse this out, but it looked like there might be a little bit of early signal that the continuous ibrutinib [Imbruvica] arm may outperform the time-limited arms.  However, as mentioned, I nearly universally try and get them on clinical trials. From a community practice standpoint, if your patient has the ability to travel to a larger volume referral center for CLL, I recommend referring them for an opinion. These patients have higher rates of complications like Richter transformation, shorter remission durations, and sometimes more explosive disease kinetics, so having them networked in with a high-volume CLL center will be of benefit. There are some biological differences, and some patients do worse than others, but it's really that one population of p53-aberrant patients that keeps us up at night.

REFERENCES

1.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 February 10, 2026. https://clinicaltrials.gov/study/NCT04608318

2.Comparison of the treatments of obinutuzumab + venetoclax versus obinutuzumab + chlorambucil in patients with chronic lymphocytic leukemia. ClinicalTrials.gov. Updated November 6, 2025. Accessed February 10, 2026. https://clinicaltrials.gov/study/NCT02242942