Should Pirtobrutinib Be Used As Initial Therapy for CLL?
By Dr. John Burke
CLL Society Medical Advisory Board Member and Hematologist/ Medical Oncologist
Rocky Mountain Cancer Centers
Aurora, CO and Dr. Matthew S. Davids
Chief, Division of Lymphoma
Harold and Virginia Lash Endowed Chair in Lymphoma Research
Dana-Farber Cancer Institute
Leader, Lymphoma Program, Harvard Cancer Consortium, Associate Professor of Medicine, Harvard Medical School
One important development in CLL within the past year has been the release of data supporting the use of the noncovalent Bruton tyrosine kinase (BTK) inhibitor pirtobrutinib as initial therapy for patients with treatment-naïve CLL. The data were first reported at the annual meeting of the American Society of Hematology in December 2025 and have since been published.(1,2) NCCN Guidelines have added pirtobrutinib as an option for initial therapy, listing it as “recommended only for older patients with cardiac comorbidities who may only need one lifetime treatment for CLL / SLL since there are no available data on optimal sequencing of therapy for patients with disease progression on pirtobrutinib and development of cross resistance to cBTKi [covalent BTK inhibitors].”(3) CLL patients in need of initial therapy may be wondering whether this would be a good option for them, so in this commentary, we will review the data supporting initial use of pirtobrutinib for CLL and discuss its potential benefits but also its potential downsides as compared with other options.
The two trials that support the use of pirtobrutinib as initial therapy for CLL are called BRUIN CLL-313 and BRUIN CLL-314. In BRUIN CLL-313, patients with treatment-naïve CLL who required therapy and did not have the high risk del(17p) FISH test were randomly assigned to receive the control arm of bendamustine plus rituximab (BR) or the investigational arm of pirtobrutinib.(1) BR was given for 6 cycles, whereas pirtobrutinib was given orally until progression or intolerance. The results indicated a significant improvement in the primary endpoint of the study, progression-free survival (PFS), in the pirtobrutinib arm; the rate of PFS at 2 years was 93.4% in the pirtobrutinib arm and 70.7% in the BR arm. The overall response rate was higher with pirtobrutinib (94.3%) than with BR (80.9%). While overall survival (OS) results are immature, there is a trend in favor of pirtobrutinib (24-month OS 97.8% vs 93% for pirtobrutinib and BR, respectively). Of note, an OS benefit was not previously seen when ibrutinib was compared with BR in the ALLIANCE trial.(4)
The BRUIN CLL-314 trial had a more complex design that included both treatment-naïve and relapsed/refractory patients.(2) For the purposes of this discussion, we focus on the treatment-naïve cohort. Eligible patients were allowed to have del(17p). Patients were randomly assigned to receive either pirtobrutinib or ibrutinib, both given until progression or intolerance. The primary endpoint of overall response rate was higher with pirtobrutinib at 92.9% vs. 85.8% with ibrutinib. With a median follow-up of 22.5 months, the estimated 18-month PFS rates were 95.3% with pirtobrutinib versus 87.6% with ibrutinib; though the PFS results are immature in this interim analysis, the trend seems to favor pirtobrutinib. OS results were also immature. Based on the statistical design of the study, the conclusion of the authors was that “pirtobrutinib demonstrated non-inferiority of overall response rate versus ibrutinib, with a favorable early PFS trend.”
An analysis of the combined results of both BRUIN CLL-313 and the treatment-naïve cohort of BRUIN CLL-314 was reported at the annual meeting of the American Society of Clinical Oncology in 2026.(5) The median age of the patients was 66 years. Six percent had del(17p), and 10% had mutated TP53. The overall response rate with pirtobrutinib was 93.3%, 24-month PFS 93.2%, and 24-month OS 97.5%. Based on the totality of these results, we believe that, as initial therapy in patients with CLL, pirtobrutinib achieves efficacy results that are better than chemoimmunotherapy and at least as good as ibrutinib.
Consideration of the safety results with pirtobrutinib is also critical. In BRUIN CLL-314, the toxicities of pirtobrutinib and ibrutinib were similar, with the exceptions that atrial fibrillation and flutter (2.4% with pirtobrutinib versus 13.5% with ibrutinib) and hypertension (10.6% with pirtobrutinib versus 15.1% with ibrutinib) were less frequent with pirtobrutinib. In the combined analysis, only 4.8% of patients discontinued pirtobrutinib, and only 1.6% of patients did so for treatment-related issues. Atrial fibrillation or flutter occurred in only 2.8%, raising the question of whether pirtobrutinib causes atrial fibrillation at all. Infections occurred in 59.9%, neutropenia in 18.3%, grade 3 or higher bleeding in 2.4%, and hypertension in 10.7%.
So, the potential advantages of using pirtobrutinib as the initial treatment for CLL include its seemingly favorable efficacy rate (probably at least as effective as ibrutinib), its favorable side-effect profile (less cardiac risk and hypertension than ibrutinib), and its oral route of administration.
Should we immediately consider pirtobrutinib as the preferred BTK inhibitor to be used as initial therapy for treatment-naïve CLL? There are several potential risks to doing this. First, the advantages of pirtobrutinib listed above also apply to the other widely used BTK inhibitor drugs, acalabrutinib and zanubrutinib. The efficacy of these second-generation BTK inhibitors in multiple trials appears to be at least as good as ibrutinib, and the rates of atrial fibrillation are consistently less than those of ibrutinib in various trials. Second, the duration of follow up in BRUIN CLL-313 and BRUIN CLL-314 is significantly less than the follow up in frontline studies of covalent BTK inhibitors; though unlikely, it is not inconceivable that longer follow up could demonstrate poorer than expected duration of efficacy benefit or additional risks of pirtobrutinib that we are not aware of today. Third, the wholesale acquisition cost (WAC) of pirtobrutinib is about $21,000 per month, whereas the WACs of ibrutinib, acalabrutinib, and zanubrutinib are about $15,000-$16,000 per month, and the negotiated Maximum Fair Price (MFP) for ibrutinib is $9319 per month. Considering that these drugs are usually given for years, these differences in monthly costs would add a considerable amount to the cost of treating CLL if pirtobrutinib were substituted for covalent BTK inhibitors in all cases. Fourth, the mechanism of action of pirtobrutinib involves noncovalent binding to BTK that does not involve the cysteine-481 (C481) residue. Since mutations in C481 confer resistance to covalent BTK inhibitors, pirtobrutinib has been shown to be effective even when CLL has become resistant to covalent BTK inhibitors, and the earlier BRUIN phase 1/2 trial clearly demonstrated that pirtobrutinib has activity even in patients whose CLL is resistant to covalent BTK inhibitors and when C481 resistance mutations are present. However, we do not know that the reverse is true; that is, we do not know whether covalent BTK inhibitors are effective in patients whose CLL has become resistant to frontline pirtobrutinib. Studies of the mechanisms of resistance to pirtobrutinib indicate that it selects for other variants like T474 and L528W that differ from C481.(6,7) Such variants also confer cross-resistance to covalent BTK inhibitors, suggesting that covalent BTK inhibitors may not be effective once resistance to pirtobrutinib develops.(8) Thus, patients treated with frontline pirtobrutinib whose CLL becomes resistant could effectively “lose” a line of therapy, which in theory could compromise long-term outcomes.
Putting these considerations together, we agree with the NCCN Guidelines in suggesting that currently, the most prudent approach to use of pirtobrutinib in the frontline management of CLL would be to use it primarily for patients with significant cardiovascular disease in whom it may be risky to consider other BTK inhibitors, in those who might have difficulty tolerating obinutuzumab infusions and/or difficulty with the logistics of starting venetoclax, and in elderly patients who, if their CLL were to be well controlled, may need only one line of therapy during their lifetime. Given the novelty of BRUIN CLL-313 and BRUIN CLL-314, it is certainly possible that these suggestions may evolve with longer follow up and additional progress made in the field.
References
1. Jurczak W, Kwiatek M, Czyz J, Roberto de Mattos E, Eom KS, Egle A, et al. BRUIN CLL-313: Randomized Phase III Trial of Pirtobrutinib Versus Bendamustine Plus Rituximab in Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2026 Feb 20;44(6):466–75. doi:10.1200/JCO-25-02380 PubMed PMID: 41363773; PubMed Central PMCID: PMC12904224.
2. Woyach JA, Qiu L, Grosicki S, Wrobel T, Capra M, Czyz J, et al. Pirtobrutinib Versus Ibrutinib in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2026 Feb 20;44(6):476–85. doi:10.1200/JCO-25-02477 PubMed PMID: 41353787; PubMed Central PMCID: PMC12904240.
3. NCCN Guidelines. Chronic lymphocytic leukemia/small lymphocytic lymphoma [Internet]. Version 1.2027. 2026 Aug 20;Version 1.2027. Available from: https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf.
4. Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, et al. Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL. N Engl J Med. 2018 Dec 27;379(26):2517–28. doi:10.1056/NEJMoa1812836 PubMed PMID: 30501481; PubMed Central PMCID: PMC6325637.
5. Wierda WG, Jurczak W, Garvia Cela JA, Capra M, Musuraca G, Kwiatek M, et al. ASCO Abstracts [Internet]. 2026 [cited 2026 Sep 13]. Pirtobrutinib in treatment-naïve patients with CLL / SLL: Pooled results from BRUIN CLL-313 and BRUIN CLL-314. Available from: https://www.asco.org/abstracts-presentations/261602/poster
6. Wang E, Mi X, Thompson MC, Montoya S, Notti RQ, Afaghani J, et al. Mechanisms of Resistance to Noncovalent Bruton’s Tyrosine Kinase Inhibitors. N Engl J Med. 2022 Feb 24;386(8):735–43. doi:10.1056/NEJMoa2114110 PubMed PMID: 35196427; PubMed Central PMCID: PMC9074143.
7. Brown JR, Desikan SP, Nguyen B, Won H, Tantawy SI, McNeely S, et al. Genomic Evolution and Resistance during Pirtobrutinib Therapy in Covalent BTK-Inhibitor (cBTKi) Pre-Treated Chronic Lymphocytic Leukemia Patients: Updated Analysis from the BRUIN Study. Blood. 2023 Nov 2;142(Supplement 1):326. doi:10.1182/blood-2023-180143
8. Blombery P, Chatzikonstantinou T, Gerousi M, Rosenquist R, Gaidano G, Pospisilova S, et al. Resistance to targeted therapies in chronic lymphocytic leukemia: Current status and perspectives for clinical and diagnostic practice. Leukemia. 2025 Sep;39(9):2049–60. doi:10.1038/s41375-025-02662-y