Ibrutinib Monotherapy Yields Decade-Long Durable Efficacy in Across CLL Subtypes

Ibrutinib (Imbruvica) monotherapy demonstrated durable efficacy in patients with chronic lymphocytic leukemia (CLL), including those with high-risk TP53 aberrations (17p deletions or TP53 mutations), according to final results from a phase 2 study (NCT01500733) published in Blood.¹

Data showed that at a median follow-up of 10 years, patients with CLL (n =84) achieved a median progression-free survival (PFS) of 7.2 years and an estimated 10-year PFS rate of 37.5%. Moreover, patients experienced a median overall survival (OS) that was not reached (NR), along with 5- and 10-year OS rates of 79.1% and 59.6%, respectively.

Among patients harboring TP53 aberrations (n = 53), the median PFS was 5.6 years; the median PFS was NR for those without TP53 aberrations (n = 31; P = .004); 10-year OS rates were 51.3% vs 75.3% for these respective subgroups (P = .04).

"These results highlight durable benefits and deepening responses with ibrutinib, including in high-risk CLL," lead author Andy Itsara, MD, of the Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute at the National Institute of Health Clinical Center in Bethesda, Maryland, and coauthors wrote in the journal.

How was the phase 2 study evaluating ibrutinib monotherapy in CLL designed?

The phase 2 study enrolled patients with active CLL requiring therapy who either had a TP53 aberration or were 65 years of age or older. Patients also needed to have an ECOG performance status of 2 or less and a platelet count higher than 30,000/µL.² Patients could have newly diagnosed or relapsed/refractory CLL.¹

If patients received radiotherapy, radioimmunotherapy, or chemotherapy 4 weeks prior to treatment, had transformed CLL, impaired hepatic function, or autoimmune hemolytic anemia or thrombocytopenia requiring steroid therapy, they were not included in the trial.²

Patients received ibrutinib at 420 mg orally once daily in 28-day cycles until disease progression or intolerable toxicity.¹

Overall response rate at 6 months (following 6 cycles of treatment) served as the trial’s primary end point.

Baseline characteristics revealed all evaluable patients had a median age of 67 years (range, 34-85), with most having previously untreated disease (61.9%). Most patients had unmutated IGHV (66.7%) and harbored TP53 aberrations (63.1%).

As of July 31, 2024, 10.7% of patients remained on ibrutinib, 46.4% discontinued treatment for progressive disease, and 36.9% discontinued treatment due to adverse effects (AEs). The median duration of treatment was 6.2 years.

How did outcomes differ across subgroups?

The median PFS for previously untreated patients (n = 52) was 9.0 years vs 4.1 years for patients with relapsed/refractory disease (n = 32; P = .018). Ten-year OS rates were 70.8% vs 41.6%, respectively (P = .0033).

Among previously untreated patients harboring TP53 aberrations (n = 34), estimated 10-year PFS and OS rates were 38.6% and 65.7%, respectively. Furthermore, 10-year OS rates were 25.3% for patients who had relapsed or refractory disease with TP53 aberrations (n = 19; P = .0015).

Patients with unmutated IGHV (n = 56) experienced a median PFS of 6.7 years vs NR for those with mutated IGHV (n = 28; P = .047). A median OS of 9.8 years vs NR and 10-year OS rates of 49.5% vs 77.0% (P = .038) were shown for unmutated IGHV vs mutated IGHV subgroups, respectively.

Five-year OS rates were 90.2%, 61.5%, 89.3%, 73.7%, 89.3%, and 73.2% for previously untreated, relapsed/refractory, mutated IGHV, unmutated IGHV, no TP53 aberration, and with TP53 aberration subgroups, respectively.

What were the additional data for long-term Ibrutinib monotherapy?

Undetectable minimal residual disease (uMRD) at 10^-4 sensitivity was achieved in 15.5% of patients after a median of 5 years on ibrutinib. Out of the patients who achieved uMRD, 7 were female, 8 were previously untreated, 5 had relapsed/refractory disease, 7 had TP53 aberrations, and 11 had unmutated IGHV.

At a median follow-up of 11 years, 92.3% of patients who achieved uMRD were progession-free for a median of 3.0 years (range, 1-8). Six of these patients discontinued ibrutinib while in uMRD, and 3 patients maintained uMRD after treatment discontinuation for 1 year or less without CLL-directed therapy.

Among the patients had who achieved an MRD at a sensitivity that was 10^-4 or higher (n = 21), 11 were female, 13 were previously untreated, 8 had relapsed/refractory disease, 11 did not have TP53 aberrations, and 14 had unmutated IGHV. Additionally, among the patients who achieved MRD at a sensitivity of 10-2 after 5 years (n = 17), 12 were male, 16 were previously untreated, 1 had relapsed/refractory disease, 12 had TP53 aberrations, and 10 had mutated IGHV.

Regarding safety, cardiac events were the most frequent cause of AE-related discontinuation, causing 13.1% patients to discontinue treatment — including 4.8% with atrial fibrillation, 3.6% with non-sustained ventricular tachycardia and 1.2% for palpitations, syncope, hypertension, and sudden death. Second primary malignancies led to discontinuation in 8.3% patients, infections in 4.8%, and dementia in 3.6%. Five deaths occurred with patients while receiving treatment, all of which occurred within the first 2 years of treatment, with 4 of which being infection-related, in addition to 1 sudden death.

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 13, 2026. https://clinicaltrials.gov/study/NCT01500733