Ten-Year Ibrutinib Data Confirm Durable Efficacy in High-Risk CLL

Final results from a decade-long phase 2 trial (NCT01500733) have established the long-term efficacy and tolerability profile of continuous ibrutinib (Imbruvica) monotherapy in patients with chronic lymphocytic leukemia (CLL) harboring TP53 aberrations or aged 65 years or older.¹

Published in Blood, the study, which carries a median follow-up of 10.0 years, reports a median progression-free survival (PFS) of 7.2 years and a median overall survival (OS) that was not reached at the time of the data cutoff of July 31, 2024. The estimated 10-year PFS rate across all 84 evaluable patients was 37.5%, and 5- and 10-year OS rates were 79.1% and 59.6%, respectively.

Furthermore, the safety profile was consistent with prior ibrutinib data. Cardiac events represented the most frequent cause of adverse event-driven discontinuation, accounting for 13.1% of patients. Specific cardiac causes included atrial fibrillation (4.8%), nonsustained ventricular tachycardia (3.6%), and palpitations, syncope, hypertension, or sudden death (1.2% each). Secondary primary malignancies led to discontinuation in 8.3% of patients, infections in 4.8%, and dementia in 3.6%.

“Our data highlight durable and deepening responses with ibrutinib, including as first-line treatment in patients with TP53-aberrant CLL,” authors Andy Itsara, MD, PhD, and colleagues wrote in the publication.¹ “The experience can help set expectations about long-term outcomes and identify patients who could benefit from consolidation.”

Phase 2 Study Design

The phase 2 trial was a single-center, open-label study initiated in 2012 at the National Institutes of Health (NIH) Clinical Center.² The trial enrolled patients in 2 cohorts: patients aged 18 years or older with active CLL and a confirmed TP53 aberration (cohort 1), and patients aged 65 years or older regardless of TP53 status (cohort 2). TP53 aberration was defined as the presence of del(17p) by fluorescence in situ hybridization or a TP53 mutation. Both treatment-naive and relapsed/refractory patients requiring therapy were eligible within each cohort. All participants received oral ibrutinib 420 mg once daily in 28-day cycles until disease progression or unacceptable toxicity.

Undetectable MRD: An “Unexpected” Finding

A notable observation from the study was the emergence of undetectable minimal residual disease (uMRD) with prolonged therapy, quantified by peripheral blood flow cytometry. At a sensitivity threshold of 10⁻⁴, uMRD was achieved in 13 patients (15.5%) after a median of 5 years on therapy.

Of those 13 patients, 12 maintained uMRD at last follow-up, with the longest ongoing observation reaching 8.0 years. Notably, several patients sustained uMRD even after ibrutinib discontinuation. In an accompanying editorial, Jennifer R. Brown, MD, PhD, Dana-Farber Cancer Institute, noted that this rate of uMRD was unexpected and that the study was enriched with patients harboring multihit TP53 aberrations, whose outcomes were improved relative to historical data but remained inferior to those of patients without TP53 aberrations.

In a complementary finding, 17 patients (42.5%) whose best MRD response was in the high-MRD range (>10⁻²) remained progression free for more than 5 years, suggesting that MRD depth alone may not fully define the durability of disease control with continuous ibrutinib. Consistent with this observation, a 3-year landmark analysis showed no statistically significant difference in PFS between patients with high vs low MRD at year 3 (log-rank P =.6).

“Whether achievement of uMRD could allow drug discontinuation with sustained remission requires prospective study; nonetheless the possibility of deep remission is encouraging that patients who stop the drug for other reasons may remain in remission,” Brown wrote in the commentary.³

Clinical Context: The Continued Value of Continuous Therapy

Since its February 2014 approval in the relapsed/refractory setting⁴ and March 2016 approval in the frontline setting,⁵ ibrutinib has served as a cornerstone of CLL treatment, both as monotherapy and in combination-based approaches with anti-CD20 monoclonal antibodies such as rituximab (Rituxan) or obinutuzumab (Gazyva) as well as venetoclax (Venclexta). However, particularly for patients with TP53 aberrations, the addition of anti-CD20 antibodies has failed to produce meaningful outcomes.¹

As such, while the decade-long dataset arrives at a moment when the CLL treatment landscape is actively evolving with an expansion of the Bruton tyrosine kinase (BTK) inhibitor pathway and fixed-duration options, continuous BTK inhibitor therapy remains a clinically relevant option, especially for patients with high-risk genomic features, where long-term disease control and tolerability are critical considerations.

“Although increasingly replaced by second-generation covalent BTK [inhibitors], ibrutinib, as the first-in-class, set the example for what can be achieved with continuous therapy,” the authors concluded.¹

REFERENCES

1. Itsara A, Rogness VM, Samples L, et al. A decade of ibrutinib for CLL with and without TP53 aberration: final report on an investigator-sponsored phase 2 study. Blood. 2026;147(15):1702-1712. doi:10.1182/blood.2025029971

2. PCI-32765 for Special Cases of Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma. ClinicalTrials.gov. Updated April 28, 2026. Accessed May 19, 2026. https://clinicaltrials.gov/study/NCT01500733

3. Brown JR. Ibrutinib: 10 years and counting. Blood. 2026;147(15):1653-1654. doi:10.1182/blood.2025032468

4. de Claro RA, McGinn KM, Verdun N, et al. FDA Approval: Ibrutinib for patients with previously treated mantle cell lymphoma and previously treated chronic lymphocytic leukemia. Clin Cancer Res. 2015;21(16):3586-3590. doi:10.1158/1078-0432.CCR-14-2225

5. U.S. FDA Approves IMBRUVICA® (ibrutinib) for First-line Treatment of Chronic Lymphocytic Leukemia. News release. Johnson & Johnson. March 4, 2016. Accessed May 20, 2026. https://tinyurl.com/468fs54w