Ibrutinib Cessation Following Prolonged Exposure Supports Intermittent Investigation in CLL

Stable peripheral disease levels lasting 12 months were reported in patients with treatment-naïve chronic lymphocytic leukemia (CLL) following 6 years of continuous treatment with ibrutinib (Imbruvica), according to findings from the phase 3 FLAIR trial (ISRCTN01844152) presented at the 2023 International Workshop on CLL.¹

“Treatment-naïve patients with CLL who have received 6 years of continuous ibrutinib treatment have stable peripheral disease levels for 12 months after stopping ibrutinib in most cases. Intermittent treatment with BTK inhibitors may provide equivalent disease control to continuous exposure,” lead study author Andy C. Rawstron, PhD, wrote in the conclusion of the presentation. Rawstron is a clinical scientist in the Hematological Malignancy Diagnostic Service at Leeds Cancer Centre in the United Kingdom (UK).

FLAIR was an open-label, randomized, controlled, phase 3 trial that was conducted in treatment-naïve patients with CLL across 101 UK National Health Service hospitals.² To be eligible for enrollment, patients had to be between 18 and 75 years of age with a WHO performance status of 2 or less who required treatment per International Workshop on CLL criteria. Patients were excluded if more than 20% of their CLL cells had 17p deletion.

Patients were randomly assigned 1:1 to 420 mg of ibrutinib per day plus 375 mg/m² of rituximab (Rituxan) on day 1, cycle 1 and 500 mg/m² on day 1 of cycles 2 through 6 (n = 386), or 24 mg/m² of fludarabine and 150 mg/m² of cyclophosphamide per day on days 1 through 5, plus 6 cycles of rituximab (FCR; n = 385). Ibrutinib was administered for up to 6 years, and rituximab was administered in 28-day cycles.

Progression-free survival (PFS) in the intention-to-treat population served as the primary end point. Prior findings previously published in the Lancet Oncology demonstrated improved PFS but not overall survival (OS) with ibrutinib plus rituximab vs FCR. At a median follow-up of 53 months (interquartile range, 41-61), median PFS was not reached with ibrutinib/rituximab and 67 months with FCR (HR, 0.44; 95% CI, 0.32-0.60; P < .0001). Median OS was not reached in either arm but did not favor the ibrutinib combination (HR, 1.01; 95% CI, 0.61-1.68; P = .96).

A total of 200 patients who had been randomly assigned to ibrutinib plus rituximab before August 2016 were able to complete 6 years of the combination with 1 year of additional follow up after the end of treatment (EOT).¹ Of these patients, 140 stopped treatment at 6 years, and peripheral blood minimal residual disease (MRD) levels were available in 131 patients. A total of 99 samples were available for analysis 6 months after EOT and 97 were available 12 months after EOT.

Results showed that the log change in CLL MRD level remained largely stable over time, with a median 0.02 log change in peripheral blood MRD levels 12 months after stopping ibrutinib. In addition to reporting similar disease levels in peripheral blood and bone marrow at EOT in the ibrutinib arm, investigators showed partial recovery of normal B cells 12 months after stopping ibrutinib.

Based on these findings, the randomized, phase 3 STATIC trial (ISRCTN51675454) will compare continuous treatment with ibrutinib vs intermittent treatment with the BTK inhibitor in 800 patients with CLL. At baseline, patients will undergo demographic and standard evaluations, and submit quality of life (QOL) and health economics questionnaires. Following randomization, patients will be treated until active disease in the continuous arm or until treatment strategy failure in the intermittent arm. Patients will be stratified by prior treatment status in FLAIR (yes vs no), MRD, and treatment center.

Patients will be followed for 36 months, during which time investigators will evaluate the primary end point of time to treatment failure. Secondary end points include OS, time to next treatment, response to retreatment or next treatment, QOL and cost effectiveness, and evolution of resistant sub-clones.

The study is currently open to recruitment.

References

1. Rawstron AC, Webster N, Allsup D, et al. Stopping ibrutinib after 6 years of continuous exposure results in decreased or stable CLL levels for at least a year in most patients, providing further support for the STATIC trial evaluating intermittent BTKi treatment. Presented at: 2023 International Workshop on CLL; October 6-9, 2023. 1554106
2. Hillmen P, Pitchford A, Bloor A, et al. Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24(5):535-552. doi:10.1016/S1470-2045(23)00144-4