Response-Based Intermittent Ibrutinib Dosing Shows Safety, Feasibility in CLL

Response-based, intermittent treatment with ibrutinib (Imbruvica) did not lead to new safety signals in patients with chronic lymphocytic leukemia (CLL), according to data from the phase 2 IbruOnOff trial (NCT04771507) presented at the 2024 EHA Congress.¹

At study entry, all patients (n = 49) had been receiving treatment with continuous ibrutinib and achieved a complete response (CR) or partial response (PR). After enrolling and stopping treatment, no instances of rapid CLL rebound were observed. Additionally, 73.5% of patients remained off treatment for more than 12 months during the first off-treatment cycle, and 28.6% of patients stayed off treatment for more than 24 months after stopping treatment for the first time.

Thirty-three patients restarted ibrutinib due to early progressive disease; however, only 2 of these patients did not remain sensitive to the BTK inhibitor. As of the May 2024 data cutoff, 13 patients had entered their second off-treatment cycle, and 3 patients were in their third off-treatment cycle. Among 8 patients who experienced disease progression during an on-treatment cycle, 6 were screened for resistance mutations; 3 of these patients harbored BTK C481 mutations.

Regarding safety, the rate of grade 3 or higher infections was 4% during the first 12 months of the off-treatment cycle compared with 33% during the 12 months prior to study entry. The rate of atrial fibrillation was 4% during both the first 12 months of the off-treatment cycle and the 12 months prior to study enrollment.

“This interim analysis of the first study using an on-off-repeat dosing strategy for ibrutinib in CLL shows that the concept appears to be safe with no unexpected safety signals,” lead study author Jeanette Lundin, MD, PhD, of Karolinska University Hospital in Solna, Sweden, and colleagues wrote in a poster presentation of the data.

Although time-limited therapy has been established for venetoclax (Venclexta)-based regimens in CLL, study authors noted that the application of a similar strategy for BTK inhibitors remains underexplored. This phase 2 study aimed to address this gap by investigating the clinical efficacy and safety of intermittent, repeated ibrutinib cycles.

Study Design

Investigators enrolled patients at least 18 years of age with CLL or small lymphocytic lymphoma who received at least 6 months of ibrutinib and achieved a PR or better.² Patients were required to have an ECOG performance status of 0 or 2; adequate hematologic, renal, and liver function; and be disease-free from prior malignancies for at least 2 years, except for currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast.

Once enrolled, patients discontinued ibrutinib and entered an off-treatment phase until they experienced early signs of progressive disease, such as an increase in white blood cell count to above 30 x 10⁹ cells/L and/or the development of new or growing lymph nodes.¹ At that point, ibrutinib was reintroduced for an on-treatment cycle. Patients were allowed to enter another off-treatment cycle if they achieved another PR or better. The maximum number of on/off cycles was not predefined by study protocol.

The primary end point was time to clinical ibrutinib resistance or unacceptable toxicity requiring permanent drug cessation and a switch to alternative therapies.

Patient Demographics

The median age of patients enrolled in phase 2 was 70 years (range, 53-87), and 69% of patients were male. Fifty-seven percent of patients harbored 13q deletions; 37% had TP53 mutations or 17p deletions; 16% had 11q deletions; 10% had trisomy 12; 14% had normal cytogenetics; and 8% did not undergo testing.

Patients received a median of 1 prior line of therapy (range, 1-6). Notably, 67% of patients received ibrutinib in the second line or later, and the remaining 33% got ibrutinib as first-line therapy. At study entry, the median duration of prior ibrutinib treatment was 22.7 months (range, 6.9-77.4). Sixty-three percent of patients had a PR to ibrutinib, and 37% had a CR.

The median duration of the first off-treatment cycle was 16.7 months (range, 2.9-60.5), and 11 patients experienced two off-treatment cycles. Eleven patients started another treatment beyond ibrutinib.

References

1. Lundin J, Andersson M, Kättström M, et al. A clinical phase II study on intermittent and repeated dosing (“on-off-repeat”) of ibrutinib treatment for patients with chronic lymphocytic leukemia. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract P660.
2. A pilot study on intermittent ibrutinib in patients with advanced-phase chronic lymphocytic leukemia (CLL) (IbruOnOff). ClinicalTrials.gov. Updated February 25, 2024. Accessed October 8, 2024. https://clinicaltrials.gov/study/NCT04771507