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CLL Updates
CLL Updates: Experts Offer Guidance on the Latest Evidence From ASH 2025 and Address Commonly Asked Questions

Released: December 31, 2025

Sameh Gaballa
Sameh Gaballa, MD
Nitin Jain
Nitin Jain, MD
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Key Takeaways
  • The CLL17 trial offered evidence that fixed-duration therapy with venetoclax combinations is not inferior to continuous ibrutinib in patients with treatment-naive CLL.
  • The BRUIN CLL-313 and BRUIN CLL-314 trials showed that pirtobrutinib is more effective than bendamustine/rituximab and noninferior to ibrutinib as therapy for both first-line and BTK-naive relapsed/refractory CLL.
  • For patients with progressive CLL following covalent BTKi and BCL2-targeted therapies, pirtobrutinib, lisocabtagene maraleucel, and allogeneic transplant (for eligible patients) are options to consider.

Several studies on initial therapy for chronic lymphocytic leukemia (CLL) that have the potential to affect clinical practice were reported at the 2025 American Society of Hematology (ASH) annual meeting and published concurrently. Experts Sameh Gaballa, MD, and Nitin Jain, MD, offer their insights on these new data and how they will affect clinical practice. Then, they address questions from a healthcare professional audience during a recent live webinar. 

Key Studies on First-line Therapy for CLL Presented at ASH 2025 

CLL17: Fixed Duration vs Continuous Therapy for Treatment-Naive CLL
The phase III CLL17 trial compared fixed-duration therapy with either venetoclax plus obinutuzumab or venetoclax plus ibrutinib vs continuous ibrutinib in patients with treatment-naive CLL (n = 909). The trial found that fixed-duration therapies were not inferior to continuous ibrutinib regarding progression-free survival (PFS), meeting the primary endpoint of the trial. The rate of undetectable measurable residual disease (<10-4) in the peripheral blood was highest with venetoclax/obinutuzumab (73.3%), followed by venetoclax/ibrutinib (47.2%), and 0% with continuous ibrutinib. The overall survival rate at 3 years was similar among the 3 treatments. The rate of neutropenia was higher with the combination approaches. 

Nitin Jain, MD:
This trial confirms the current practice of moving away from continuous ibrutinib therapy and increasing use of time-limited approaches. However, median follow-up is relatively short at 3 years. Longer follow-up of this trial will be very important.

BRUIN CLL-313: Pirtobrutinib as First-line Therapy for CLL/SLL
Pirtobrutinib is a noncovalent BTK inhibitor approved for patients with relapsed/refractory CLL/small lymphocytic lymphoma (SLL) after treatment with a covalent BTK inhibitor. The phase III BRUIN CLL-313 trial compared pirtobrutinib with bendamustine/rituximab as initial therapy (n = 282). Patients with 17p deletions (del[17p]) were excluded. Cross over from bendamustine/rituximab was allowed. The primary endpoint of improved PFS was met with an HR of 0.20 (95% CI: 0.11-0.37). Overall survival data are immature but favor pirtobrutinib despite a crossover rate of 52.9%. Discontinuations and dose reductions were lower with pirtobrutinib and the median treatment time was longer. There was a low rate of atrial fibrillation and atrial flutter with pirtobrutinib.

BRUIN CLL-314: Pirtobrutinib vs Ibrutinib for BTKi Treatment-Naive CLL/SLL
The phase III BRUIN CLL-314 trial compared the noncovalent BTK inhibitor pirtobrutinib with the covalent BTK inhibitor ibrutinib in patients with CLL/SLL who had not received previous BTK inhibitor therapy (n = 662). The primary endpoint was noninferiority of overall response rate (ORR) with a key secondary endpoint of superiority of PFS. The ORR was higher with pirtobrutinib in the intention-to-treat population as well as in both treatment-naive and relapsed/refractory patient populations. The HR for PFS by investigator was 0.569 (95% CI: 0.399-0.834) and 0.755 by blinded independent review (95% CI: 0.531-1.075), although data are still immature. Efficacy was highest among the previously untreated patient population both in terms of ORR and PFS. As in the BRUIN-313 trial, there were fewer dose reductions and discontinuations with pirtobrutinib, and the rate of atrial fibrillation and atrial flutter was lower with pirtobrutinib.

Nitin Jain, MD:
The BRUIN CLL-313 and BRUIN CLL-314 trials report the first prospective data with pirtobrutinib monotherapy in first-line therapy for CLL and should lead to frontline approval of pirtobrutinib. Given the lack of data so far on the use of a covalent BTK inhibitor after pirtobrutinib, I would think that frontline pirtobrutinib use will be most likely in older adults who prefer the ease of a once-daily oral therapy over venetoclax-based combinations and who are likely going to need just 1 line of therapy, such as patients older than 80 years of age.

Frequently Asked Questions 

The number of patients with TP53 mutations or del(17p) was quite small in both the CAPTIVATE and CLL14 studies of fixed-duration therapy. Would you treat these high-risk patients only with continuous therapy?

Sameh Gaballa, MD:
Typically, for patients with high-risk disease, we would favor a continuous therapy with BTK therapy. But for some patients with high-risk disease, including del(17p), you could use fixed-duration therapy, like venetoclax/obinutuzumab from the CLL14 study, the median PFS for those patients was more than 4 years. One must remember that not all patients with del(17p) or TP53 mutations are the same, and some tend to progress sooner.

Nitin Jain, MD:
The CAPTIVATE trial of 1 year of venetoclax plus ibrutinib included patients with TP53 or del(17p) mutations. The PFS at 5.5 years for patients with del(17p) was 36% vs 66% for the entire fixed-duration therapy cohort from CAPTIVATE. In CLL17, the 3-year PFS rates were 62.0% (n = 23), 69.0% (n = 25), and 79.4% (n = 21) for venetoclax/obinutuzumab, venetoclax/ibrutinib, and ibrutinib, respectively, as presented at ASH 2025. 

I will say that in a clinical practice outside of a clinical trial setting for patients with del(17p) or TP53 mutations, my recommendation still would be continuous second-generation BTK inhibitor, either acalabrutinib or zanubrutinib. In the CLL17 trial mentioned above, patients with del(17p) appear to do better with continuous ibrutinib compared with the venetoclax-based time-limited combinations.

Is it important to try to prioritize combination therapies that are less susceptible to resistance mutations?

Nitin Jain, MD:
Resistance mutations typically develop during long-term BTK inhibitor treatment. Combinations, whether it is a BTK inhibitor plus venetoclax combination or venetoclax/obinutuzumab combination, are given for a fixed duration of 1-2 years, in either the frontline or relapsed/refractory setting. Generally, if patients do not relapse when they are on the therapy, they relapse once they are off therapy 1-5 years later. 

When patients relapse during the off-therapy phase, many of the studies, especially the CAPTIVATE data, show that none of these patients has BTK, BCL, or PLC gamma 2 mutations at relapse. If you treat those patients with the same drugs they had in the first-line setting, whether it is ibrutinib or a venetoclax combination or something else, they remain sensitive to that previous therapy in relapsed/refractory setting. 

By using combination, fixed-duration approaches, we expect to see fewer resistance mutations developing in patients with CLL. Also combining 2 different classes of drugs—a BCL2 inhibitor and a BTK inhibitor—helps because if patients are developing or about to develop a resistance to one, hopefully the other drug will take care of those resistance clones.

A 50-year-old patient diagnosed at 45 years of age with CLL and receiving ibrutinib has severe myalgias and arthralgias. Can he be switched to a different drug?

Sameh Gaballa, MD:
Yes. It is reasonable to try a second-generation BTK inhibitor like zanubrutinib or acalabrutinib, which are more specific with fewer off-target adverse effects for a patient who is not tolerating a first-generation BTK inhibitor but not progressing. If patients are progressing while receiving a covalent BTK inhibitor, then switching to another covalent BTK inhibitor is not recommended because they are not likely to respond. In that situation, if you want to continue with a BTK inhibitor, you would want to use a noncovalent BTK inhibitor like pirtobrutinib.

After covalent or noncovalent BTK inhibitor and BCL2 inhibitor, is CAR T-cell therapy worthwhile for a low complete response (CR) outcome, or is allogeneic transplant better?

Nitin Jain, MD:
If you use lisocabtagene maraleucel CAR T-cell therapy, which is the only CAR T-cell therapy approved for CLL, the CR rate is approximately 18%. However, the ORR is approximately 43%. When you add a BTK inhibitor together with CAR T-cell therapy, we see improvements in the CR rate (45%) and the ORR (86%).

I think both are appropriate options. Allogeneic transplant has a much longer track record. Historically, many more patients have been treated with allogeneic transplant, but it is also associated with more toxicities and graft-vs-host disease. In general, the CLL field is moving away from allogeneic transplant. My personal preference would be to go with CAR T-cell therapy. 

However, if the patient meets transplant requirements for age and comorbidities, then I would recommend having a consult with a transplant physician and identifying a donor. Then you can potentially move forward with the transplant, if that is the patient’s preference or if the CAR T-cell therapy does not work for that patient.

Sameh Gaballa, MD:
I completely agree. I would also note that a trial with a BTK degrader is also a potential option. As Dr Jain noted, the role of allogeneic transplants is really diminishing in CLL with all these other options. When would we consider an allogeneic transplant? I think if a young patient with high-risk disease, del(17p), has been through most of the therapies, including a CAR T-cell, this is a patient for whom you would probably consider an allogeneic transplant. 

Your Thoughts
How will you incorporate these latest clinical trial data into your clinical practice? What questions do you have about managing newly diagnosed patients? Leave a comment for the experts and join the discussion.

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Which of the following studies in CLL that were reported at the ASH 2025 annual meeting is most likely to affect your clinical practice?

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