Long-Term Treatment With Ibrutinib Is Possible in Newly Diagnosed CLL/SLL

Treatment with ibrutinib for at least 5 years showed favorable complete response rates and tolerability in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma who were randomized to receive the BTK inhibitor in the phase 3 RESONATE-2 trial.

Treatment with ibrutinib (Imbruvica) for at least 5 years showed favorable complete response (CR) rates and tolerability in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who were randomized to receive the BTK inhibitor in the phase 3 RESONATE-2 trial (NCT01722487).1

The median follow-up was 89.2 months (range, 61.3-96.6) for patients who remained on ibrutinib for at least 5 years (n = 79), and CR rates were found to grow over time, from 10% (n = 8) at 1 year to 42% (n = 33) at 5 years. Additionally, most patients who achieved CR in the overall ibrutinib-randomized population received long-term treatment with the BTK inhibitor (n = 36/44).

“Efficacy and safety results in patients on long-term ibrutinib treatment for ≥5 years were consistent with those seen in the overall population of ibrutinib-treated patients,” lead study author and physician at The Ohio State University Comprehensive Cancer Center–James, Jennifer A. Woyach, MD, and coauthors, wrote in the poster. “Across patient subgroups, more than half of ibrutinib-randomized patients continued to benefit from long-term ibrutinib treatment for ≥5 years.”

Ibrutinib is a once-daily oral BTK inhibitor that demonstrated a significant improvement in progression-free survival (PFS) and overall survival (OS) vs chlorambucil as frontline therapy in patients with CLL/SLL in the pivotal RESONATE-2 trial.

The study enrolled patients at least 65 years of age with treatment-naïve CLL/SLL without deletion 17p. Patients were randomly assigned to receive 420 mg of ibrutinib once daily until disease progression or unacceptable toxicity (n = 136) or 0.5 mg/kg of chlorambucil on days 1 and 15 of every 28-day cycle for up to 12 cycles (n = 133).

At a median follow-up of 82.7 months (range, 0.1-96.6), ibrutinib showed sustained PFS benefit vs chlorambucil (HR, 0.154; 95% CI, 0.108-0.220); the median PFS was not yet reached with ibrutinib vs 15 months with chlorambucil. The median OS was also not reached with ibrutinib vs 89 months with chlorambucil (0.453; 95% CI, 0.276-0.743).2

In the updated analysis, which was presented at the 2022 SOHO Annual Meeting, baseline characteristics were shown to be comparable between the ibrutinib-randomized patients in the intention-to-treat population and the population who received ibrutinib for at least 5 years.

Notably, several baseline characteristics, including female sex, age up to 73 years, absence of cytopenia, and absence of bulky disease were associated with a greater likelihood of achieving long-term treatment with ibrutinib, but none reached statistical significance.  

The median duration of treatment was 89.2 months (range, 60.4-96.6) with long-term ibrutinib, and the median relative dose intensity of the agent was 98% (range, 47%-100%).

Regarding safety, the incidence of adverse effects (AEs) of clinical interest, including diarrhea, hypertension, arthralgia, fatigue, atrial fibrillation, and major hemorrhage, typically peaked within the first year of treatment and decreased over time.

Dose reductions were used for AE management in 20% (n = 16) of patients who received long-term ibrutinib and were similar to those seen in all ibrutinib-treated patients. Following dose reduction, 14 patients had resolution of the initial AE. AEs did not recur or recurred at a lower grade in 12 of 16 patients.

Dose holds were used for AE management in 57% (n = 45) of patients who were on long-term ibrutinib.

Notably, AEs leading to dose reductions or dose holds for at least 7 days were stable over time in patients on long-term ibrutinib. Dose reductions and dose holds that occurred within the first year, years 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, and 7-8 were as follows, respectively: (n = 6; n = 23), (n = 7; n = 16), (n = 3; n = 15), (n = 4; n = 17), (n = 4; n = 17), (n = 3; n = 21), (n = 2; n = 9), (n = 0; n = 5).

“The safety profile or long-term ibrutinib treatment was consistent with previous reports and no new safety signals were identified,” the study authors concluded. “[Additionally,] dose modification was effective in resolving AEs for the majority of patients, thereby allowing patients to remain on treatment.”


  1. Woyach JA, Barr PM, Kipps TJ, et al. Characteristics and clinical outcomes of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma receiving long-term ibrutinib treatment in the RESONATE-2 study. Presented at: 2022 SOHO Annual Meeting; September 28-October 1, 2022; Houston, TX. Poster CLL-418
  2. Barr PM, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022;6(11):3440-3450. doi:10.1182/bloodadvances.2021006434