Long-Term Follow-Up Supports Early Use of Ibrutinib in CLL

Data from up to 6 years of long-term follow-up shows better progression-free survival, overall survival, objective response rates, and sustained efficacy for patients with chronic lymphocytic leukemia who receive single-agent ibrutinib in earlier lines of treatment, including those with high-risk prognostic factors. According to the poster presented by Paul M. Barr, MD, Division of Hematology/Oncology, Wilmot Cancer Institute, University of Rochester, Rochester, NY, during the 2019 American Society of Hematology Annual Meeting, first-line ibrutinib yielded deeper responses over time with 30% complete responses versus 10% to 12% CR for later lines of treatment.

Paul M. Barr, MD

Data from up to 6 years of long-term follow-up shows better progression-free survival (PFS), overall survival (OS), objective response rates (ORR), and sustained efficacy for patients with chronic lymphocytic leukemia (CLL) who receive single-agent ibrutinib in earlier lines of treatment, including those with high-risk prognostic factors. According to the poster presented by Paul M. Barr, MD, Division of Hematology/Oncology, Wilmot Cancer Institute, University of Rochester, Rochester, NY, during the 2019 American Society of Hematology Annual Meeting, first-line ibrutinib yielded deeper responses over time with 30% complete responses (CR) versus 10% to 12% CR for later lines of treatment.1

This integrated analysis included 5-year follow-up data for patients treated with single-agent ibrutinib in the first-line setting in the RESONATE-2 (NCT01722487) trial and 6-year follow-up data in the relapsed/refractory setting from the final analysis of the RESONATE (NCT01578707) trial.

The objective of the analysis was to evaluate the efficacy and safety outcomes with single-agent ibrutinib by number of prior lines of therapy. Data from patients with deletion (17p) in RESONATE were excluded because they were excluded from RESONATE-2. Subgroups were based on number of prior lines of therapy and those treated with 1 and 2 prior lines were combined due to small numbers in each group.

High-risk prognostic features were defined as having TP53 mutation, deletion (11q), and/or unmutated IGHV. Outcomes included investigator-assessed progression-free survival (PFS) and overall response rate (ORR) based on investigator assessment, OS, and safety.

The analysis of 271 patients included 136 patients in the first-line and 135 patients in the relapsed/refractory groups (1-2 prior lines n = 68; ≥3 prior lines n = 67). Patients in the first-line group were older with a median age of 73 years (range 65—89 years) than those with 1-2 prior lines (median age 65 years, range 30–86 years) and ≥3 prior lines (median age 67 years, range 44–83 years).

The proportion of patients with high-risk prognostic features was lower in the first-line group ( 54%) than in 1-2 prior lines (81%) or ≥3 prior lines (76%). Median follow-up was 59.8 months for first-line, 66.2 months for 1-2 prior lines, and 65.1 for ≥3 prior lines.

A greater proportion of patients treated with ibrutinib in earlier lines remained progression-free or alive at 5-years (first-line: 70%; 1-2 prior lines: 60%; ≥3 prior lines: 33%). Median PFS was not reached for first-line or 1-2 prior lines, and was 40.1 months for ≥3 prior lines.

First-line treatment reduced the risk of disease progression or death by 68% compared with treatment after ≥3 prior lines (HR 0.32; 95% CI 0.21-0.49). Treatment after 1-2 prior lines reduced the risk of disease progression or death compared with treatment after ≥3 prior lines (HR 0.48; 95% CI 0.30-0.77). First-line treatment resulted in a 34% reduction in risk of disease progression or death compared to 1-2 prior lines (HR 0.66; 95% CI, 0.40-1.09).

In patients with high-risk prognostic features treatment in earlier lines resulted in better PFS. At 5 years, PFS rates were higher for patients receiving first-line treatment with single-agent ibrutinib (71%) than for those with 1-2 prior lines (63%), or ≥3 prior lines (37%). Median PFS was not reached for first-line or 1-2 prior lines; PFS was 42.5 months for ≥3 prior lines.

OS at 5 years was higher for patients treated with ibrutinib in earlier lines: 83% for first-line, 72% for 1-2 prior lines, and 58% for ≥3 prior lines. Similar trends for OS were observed with treatment in earlier lines for patients with high-risk prognostic features.

Response rates, including CR, increased over time in all lines of therapy, particularly for first-line therapy. The 5-year ORR was 92% for first-line, 88% for 1-2 prior lines, and 88% for ≥3 prior lines. The CR rate (including CR plus CR with incomplete marrow recovery) was 30% for first-line, 12% for 1-2 lines, and 10% for ≥3 prior lines.

At the time of analysis, 58% for patients in the first-line group were still receiving treatment with ibrutinib; 38% and 18% of patients in the 1-2 prior lines and ≥3 prior lines, respectively, were receiving ibrutinib at study closure.

Only 6% of patients in the first-line group discontinued treatment due to progressive disease, versus 22% and 37%, respectively, in the 1-2 prior lines and ≥3 prior lines groups. Overall, 19% of patients across all lines of therapy discontinued due to adverse events (AE), with no major differences across all lines of treatment. Atrial fibrillation was the most common AE leading to discontinuation. No patients discontinued ibrutinib treatment or required dose reductions due to hypertension.

References

  1. Barr PM, Tedeschi A, Munir T, et al. Using ibrutinib in earlier lines of treatment results in better outcomes for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: American Society of Hematology Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 3054. https://ash.confex.com/ash/2019/webprogram/Paper123327.html
  2. Barr PM, Tedeschi A, Munir T, et al.Blood(2019) 134 (Supplement_1): 3054. https://doi.org/10.1182/blood-2019-123327