Prolonged Improvement in PROs and Well-Being in Older Patients with Treatment-Naïve CLL Treated with Ibrutinib: 3-Year Follow-Up of the RESONATE-2 Study

Conference Correspondent - ASH 2017 - Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is primarily a disease of older patients who often have comorbidities and are not as able to tolerate aggressive treatment regimens. Thus, quality of life (QOL) is an important consideration.

Ibrutinib (ibr) is a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase approved for the treatment of CLL, and allows for treatment without chemotherapy. In the phase 3 RESONATE-2 study of older patients with treatment-naïve (TN) CLL/SLL, single-agent ibr reduced the risk for progression or death by 84% versus chlorambucil (clb) (P <.001), with a median 18.4-month follow-up at primary analysis.1 At ASH 2017, the authors reported updated data, with a focus on QOL and measures of well-being with extended follow-up in RESONATE-2.2

In this study, patients aged ≥65 years were randomized 1:1 to receive 420 mg ibr once daily until progressive disease (PD) or clb for up to 12 months. Patients with PD on clb could receive second-line ibr. In RESONATE-2, patient-reported outcomes (PROs) of FACIT-Fatigue (F) and 5-level EuroQol-5D version (EQ-5D-5L) were measured by change from baseline to each assessment time. Among 269 patients, reasons for initiating therapy included progressive marrow failure (38%), lymphadenopathy (37%), splenomegaly (30%), fatigue (27%), and night sweats (25%).

Ibr resulted in significantly longer progression-free survival (PFS; median, not reached vs 15.0 months with clb), with an 87% reduction in risk for progression or death versus clb (hazard ratio, 0.13; 95% confidence interval [CI], 0.08-0.21). The PFS rate at 30 months was 85% with ibr versus 28% with clb. Greater and sustained improvements in PROs were observed with ibr versus clb, with significantly greater improvements over time versus clb in FACIT-F (P = .0021) and EQ-5D-5L visual analog scale (P = .0004) by repeated measures. In clb-treated patients with PD, PROs improved after crossing over to ibr. Disease symptoms, including fatigue and night sweats, improved more frequently with ibr versus clb. A greater proportion of patients with baseline cytopenia showed sustained hematologic improvement with ibr versus clb for hemoglobin (90% vs 45%; P <.0001) and platelets (83% vs 46%; P = .0032).

Moreover, the medical resource utilization burden was less with ibr than with clb in the first year (eg, use of intravenous immunoglobulin, growth factors, or transfusions), and subsequently continued to decrease. The most common adverse events (AEs) of any grade with ibr were diarrhea (47%), fatigue (33%), and cough (30%). During the first year of treatment, patients receiving ibr experienced less grade ≥3 neutropenia (8% and 18%) and anemia (6% and 8%) than those receiving clb. AEs leading to treatment discontinuation occurred in 16% with ibr over 34 months versus 23% with clb over 7 months of therapy, respectively. Based on quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis at primary analysis (median follow-up, 18.4 months), mean time spent without symptoms of PD or grade 3 to grade 4 treatment toxicity was longer with ibr than with clb (501 vs 351 days; mean difference, 150 days; 95% CI, 109-193). Patients receiving ibr therapy also experienced prolonged patient-reported quality-adjusted survival compared with clb (386 vs 329 days; mean difference, 57 days; 95% CI, 25-90).

The authors concluded that with 3 years of follow-up in patients with TN CLL/SLL, ibr continued to show greater and sustained improvements in PROs and more frequent improvements in other measures of well-being, including disease burden and hematologic parameters, as well as increased quality-adjusted survival time, versus clb.

1. Burger JA, et al. N Engl J Med. 2015;373:2425-2437.
2. Tedeschi A, et al. ASH 2017. Abstract 1746.

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Last modified: December 11, 2017
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