An analysis of the phase 2 IbruOnOff trial, presented at the 2024 EHA Congress, indicates that response-based, intermittent ibrutinib (Imbruvica) dosing is safe and feasible for patients with chronic lymphocytic leukemia (CLL). The study (NCT04771507) explored the efficacy of an on-off-repeat dosing strategy for ibrutinib in CLL patients who had previously responded to continuous treatment.
Key Findings from the IbruOnOff Trial
The trial enrolled 49 patients with CLL who had achieved a complete response (CR) or partial response (PR) after receiving continuous ibrutinib. After stopping treatment upon enrollment, no rapid CLL rebound was observed. A notable 73.5% of patients remained off treatment for more than 12 months during their first off-treatment cycle, and 28.6% stayed off treatment for over 24 months after the initial discontinuation.
Of the participants, 33 patients needed to restart ibrutinib due to early progressive disease; however, only 2 of these patients did not remain sensitive to the BTK inhibitor. As of the data cutoff in May 2024, 13 patients had entered their second off-treatment cycle, and 3 were in their third. Among 8 patients who experienced disease progression during an on-treatment cycle, 6 were screened for resistance mutations, with 3 harboring BTK C481 mutations.
Safety Profile
The safety analysis revealed a grade 3 or higher infection rate of 4% during the first 12 months of the off-treatment cycle, compared to 33% during the 12 months prior to study entry. The rate of atrial fibrillation was consistent at 4% during both the first 12 months of the off-treatment cycle and the 12 months before enrollment.
According to lead study author Dr. Jeanette Lundin, MD, PhD, from Karolinska University Hospital, "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."
Study Design and Patient Characteristics
The phase 2 trial enrolled patients aged 18 years or older with CLL or small lymphocytic lymphoma who had received at least 6 months of ibrutinib and achieved a PR or better. 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 (with exceptions for treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast).
Patients discontinued ibrutinib upon enrollment and entered an off-treatment phase until signs of progressive disease emerged, such as an increase in white blood cell count above 30 x 109 cells/L or the development of new or growing lymph nodes. Ibrutinib was then reintroduced for an on-treatment cycle, with subsequent off-treatment cycles permitted upon achieving another PR or better. The study did not predefine a maximum number of on/off cycles.
The primary endpoint was time to clinical ibrutinib resistance or unacceptable toxicity necessitating permanent drug cessation and a switch to alternative therapies.
The median age of enrolled patients was 70 years (range, 53-87), with 69% being male. Fifty-seven percent of patients had 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. 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.
Implications for CLL Treatment
While time-limited therapy has been established for venetoclax-based regimens in CLL, the study authors emphasized that a similar strategy for BTK inhibitors has been relatively unexplored. This phase 2 study aimed to address this gap by investigating the clinical efficacy and safety of intermittent, repeated ibrutinib cycles, suggesting a potential avenue for optimizing treatment strategies and reducing long-term toxicities in CLL management.
