CLL Treatment Individualization Prompts Changes in Patient Evaluation and Care

The assortment of approved options and regimens in chronic lymphocytic leukemia (CLL), while positive, complicate both the treatment selection and sequencing process, and require nuanced decision-making for individualization according to Mary Ann Anderson, MBBS, FRACP, FRCPA, PhD.

“Whatever you choose, your patients are likely to do well, because these are all wonderful options for managing CLL, but we can tailor treatment and make nuanced decisions for the individual patient in front of us,” Anderson said in an exclusive interview with OncLive^®.

In the interview, conducted at the 2026 SOHO Annual Meeting, Anderson discussed the range of CLL treatment regimens that contain agents like pirtobrutinib (Jayprica), acalabrutinib (Calquence), zanubrutinib (Brukinsa), obinutuzumab (Gazyva), and venetoclax (Venclexta), in addition to highlighting the importance of individualizing frontline therapy choices.^1,2

Anderson is an associate professor at Royal Melbourne Hospital and Peter MacCallum Cancer Centre and a clinician scientist at the Walter and Eliza Hall Institute in Australia.

OncLive: What are the currently approved CLL treatment regimens?

Anderson: We’re extremely fortunate that in last decade, [CLL] has seen an explosion of effective and safe treatments. One of the challenges with this rapid evolution is that we now have a variety of different treatment choices, but little head-to-head data to tell us which choice is superior for which patient group. Those of us who do this all the time refer to these combinations of therapies as a bunch of different acronyms. For those who are not as immersed in the field, it can feel like an alphabet soup of options, and working out which of this group of potential options is right for your patients can sometimes feel overwhelming.

There are a variety of new options coming forward. Most recently, [pirtobrutinib] has become available, and we have zanubrutinib, which became available before that, and soon hopefully treatments like sonrotoclax [Beqalzi] will become available as well. There’s a constantly moving pipeline of new options. While that’s wonderful, it also creates greater complexity around deciding what to do [in practice]. Just because [a certain treatment] is the newest kid on the block doesn’t necessarily make it the best option for all patients. We need to be mindful of how we approach these decisions, particularly when a patient’s treatment journey may go over a 10- to 20-year horizon. It’s not just about first-line treatment, it’s thinking about how we sequence therapies going forward for the patient.

How do you approach selecting between the approved CLL regimens?

[Evaluating data between approved CLL regimens] can be confusing and, at times, overwhelming. One of the key things we need to keep in mind at all times is the patient in front of us. As we have a greater array of options for patients, we can move into a world where we individualize treatment choices. [Therefore, we need to] look at our patients [and ask]: What do they want? Do they want simply 1 tablet a day, or 1 tablet twice a day? Do they want a time-limited approach to treatment, or indefinite treatment? How do their comorbidities play into these decisions? What about their concurrent medications? The other layer [to individualizing CLL treatments] is a patient’s genetic risk factors. There are a number of factors that play into [determining] the best treatment for the patient in front of us. The takeaway from all of these emerging data is that there’s no one-size-fits-all [treatment]; you’ve got to individualize it and have a discussion with your patient to get the right treatment for them.

I try to put the patient front and center, and I explain to them what the options are and why I’ve come to a particular recommendation in their case. [Additionally,] I [point out that] there are a variety of approved options for that are all equally good. The first treatment decision we need to make when having these discussions is whether to go for a continuous approach to therapy or a time-limited approach. In the frontline CLL setting, that is the key question, and there are pros and cons to each.

A continuous BTK inhibitor-based approach is easy to start. You write a prescription, and the patient starts taking their tablets. A time-limited approach requires BCL-2 inhibitors and carries a risk of tumor lysis syndrome, which by necessity means slower ramp-ups, closer monitoring of blood tests, and is more complex and demanding on the patient and the physician’s time.

A continuous approach has advantages and disadvantages, and is associated with a clear, known set of adverse effects [AEs]. BTK inhibitors as a class are associated with hypertension, atrial fibrillation, and increased bleeding risk. [Thus] for patients receiving concurrent blood thinners or with known cardiac disease or coexisting cardiovascular comorbidities, that may be a less attractive approach. BCL-2 inhibitors also have known [AEs] and need to be partnered with other agents, and if partnered with monoclonal antibodies, there’s a risk of viral infections, which can be challenging. [When BCL-2 inhibitors are] partnered with a BTK inhibitor, [both] carry the same AEs. I go through carefully how those AEs and concurrent medications interplay into the discussion.

One of the things we know about BTK inhibitors is that they are given indefinitely until patients develop either toxicity or progressive disease. One challenge is that if a patient develops progressive disease on a BTK inhibitor, it is often associated with on-target mutations that confer resistance to subsequent BTK inhibitor therapy. Pirtobrutinib is one of the new kids on the block, and the data suggest that it is an effective treatment in frontline CLL. The challenge is that while we have good data for pirtobrutinib rescuing failure of covalent BTK inhibitors, such as acalabrutinib and zanubrutinib, we don’t have data [showing] we can rescue pirtobrutinib failure with the first-generation BTK inhibitors. [This dynamic with BTK inhibitors] circles back to [the idea that] just because [a treatment] looks effective doesn’t mean that, when looking at a sequencing horizon, it’s necessarily the best choice.

One of the things I like about time-limited therapy is that patients typically respond to treatment, and therapy then stops at some point in the future. Many of these patients go on to relapse; however, because they relapse off treatment, they are less likely to relapse with on-target mutations, and there are emerging data to tell us that we can salvage these relapses with retreatment using BCL-2 inhibitors and BTK inhibitors. The traditional paradigm of measuring success, like progression-free survival [PFS], starts to become more complex, because we’re not just comparing the PFS [between] continuous BTK inhibitors. Comparing PFS from a continuous BTK inhibitor with PFS from a BCL-2 inhibitor isn’t a fair comparison; perhaps the better comparison is the total PFS from a line of therapy. For example, PFS with a first venetoclax-based therapy, and then PFS2 with a second venetoclax-based therapy. Some of the old paradigms [for measuring efficacy with CLL regimens] are starting to fall by the wayside.

It is a key philosophical and complex medical decision as to whether you go with a continuous BTK inhibitor or a BCL-2 inhibitor–based approach. [There are] pros and cons to each. While these regimens are associated with AEs, we know what they are and that they can be used safely.

Editor's Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.

References

1. Nanda R, Jones D, Larson C, et al. Pirtobrutinib following covalent BTK inhibitor exposure in relapsed/refractory chronic lymphocytic leukemia: a systematic review and pooled analysis. Clin Lymphoma Myeloma Leukemia. 2026;26(suppl 1):S633-S634. doi:10.1016/S2152-2650(26)02089-6
2. Al-Sawaf O, Stumpf J, Zhang C, et al. Fixed-duration versus continuous treatment for chronic lymphocytic leukemia. N Engl J Med. 2026;394(suppl 11):1084-1096. doi:10.1056/NEJMoa2515458