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. 2023 Jan 13;15(2):507.
doi: 10.3390/cancers15020507.

Characteristics and Clinical Outcomes of Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Receiving Ibrutinib for ≥5 Years in the RESONATE-2 Study

Jennifer A Woyach  1 , Paul M Barr  2 , Thomas J Kipps  3 , Jacqueline C Barrientos  4 , Inhye E Ahn  5 , Paolo Ghia  6 , Vincent Girardi  7 , Emily Hsu  7 , Mandy Jermain  7 , Jan A Burger  8
Affiliations

Characteristics and Clinical Outcomes of Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Receiving Ibrutinib for ≥5 Years in the RESONATE-2 Study

Jennifer A Woyach et al. Cancers (Basel). .

Abstract

Primary results from the phase 3 RESONATE-2 study demonstrated superior efficacy and tolerability with ibrutinib versus chlorambucil in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Here, we describe characteristics and outcomes of patients who received ibrutinib treatment for ≥5 years in RESONATE-2. Patients aged ≥65 years with previously untreated CLL/SLL, without del(17p), were randomly assigned 1:1 to once-daily ibrutinib 420 mg until disease progression/unacceptable toxicity (n = 136) or chlorambucil 0.5−0.8 mg/kg for ≤12 cycles (n = 133). Baseline characteristics in ibrutinib-randomized patients (n = 136) were generally similar between patients on ibrutinib treatment for ≥5 years (n = 79) versus those on treatment for <5 years (n = 57). In patients on ibrutinib treatment for ≥5 years, complete response rates improved over time, reaching 42% by 5 years. Estimated 7-year progression-free survival and overall survival rates were 82% and 94%, respectively. Adverse events (AEs) led to dose reductions in 16/79 patients (20%); these AEs were resolved for 13/16 patients (81%). AEs led to dose holds (≥7 days) in 45/79 patients (57%); these AEs were resolved for 43/45 patients (96%). More than half (58%) of ibrutinib-randomized patients benefitted from ibrutinib treatment for ≥5 years regardless of baseline characteristics. Dose modification resolved AEs for most patients, thereby facilitating continued treatment.

Keywords: chronic lymphocytic leukemia; ibrutinib; long-term outcomes.

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Conflict of interest statement

J.A.W.: consulting/advisory role with AbbVie, AstraZeneca, ArQule, BeiGene, Genentech, Janssen, Loxo, Newave, and Pharmacyclics LLC, an AbbVie Company; research funding from AbbVie, Loxo, Karyopharm, MorphoSys, Schrodinger, and Verastem; P.M.B.: consulting/advisory role with AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, Gilead, Janssen, MEI Pharma, Merck, MorphoSys, Pharmacyclics LLC, an AbbVie Company, Seattle Genetics, and TG Therapeutics; research funding from AstraZeneca and TG Therapeutics; T.J.K.: consulting/advisory role with AbbVie, Celgene, Genentech-Roche, Gilead, and Pharmacyclics LLC, an AbbVie Company; research funding from AbbVie, Genentech-Roche, Oncternal Therapeutics, and Pharmacyclics LLC, an AbbVie Company; J.C.B.: honoraria from Janssen; consulting/advisory role for BeiGene, AbbVie, MEI, and AstraZeneca; research funding from Oncternal Therapeutics, Velosbio/Merck, and Pharmacyclics LLC, an AbbVie Company; I.E.A.: no conflicts of interest; P.G.: honoraria from and consulting/advisory role with AbbVie, AstraZeneca, ArQule/Merck Sharp & Dohme, Celgene/Juno/Bristol Myers Squibb, Janssen, Loxo/Lilly, MEI Pharma and Roche; research funding from AbbVie, AstraZeneca, Janssen, and Sunesis; V.G.: employment with Everest Clinical Research; other relationship with AbbVie; E.H.: employment with Pharmacyclics LLC, an AbbVie Company; stock or other ownership with AbbVie; M.J.: employment and stock or other ownership with Pharmacyclics LLC, an AbbVie Company (self) and Gilead Sciences (family member); J.A.B.: honoraria from Gilead, Janssen, Novartis, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company; consulting/advisory role and speakers bureau for BeiGene, Gilead, Janssen, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company; research funding from AstraZeneca, BeiGene, and Pharmacyclics LLC; an AbbVie Company; travel/accommodations/expenses from Gilead, Janssen, Novartis, TG Therapeutics, and Pharmacyclics LLC; an AbbVie Company. This study was sponsored by Pharmacyclics LLC, an AbbVie Company. The sponsor was involved in study design, data analysis, data interpretation, writing/review of the manuscript, and the decision to publish the results. The sponsor had no role in data collection.

Figures

Figure 1
Figure 1
Forest plot of odds for continued ibrutinib treatment at 5 years according to baseline characteristics. a Odds ratios < 1 favor achievement of ≥5 years of ibrutinib treatment for the subgroup to the left of the plot, while odds ratios > 1 favor achievement of ≥5 years of ibrutinib treatment for the subgroup to the right of the plot. Abbreviations: CIRS, Cumulative Illness Rating Scale; CrCl, creatinine clearance; ECOG PS, Eastern Cooperative Oncology Group performance status; IGHV, immunoglobulin heavy chain variable region; LDH, lactate dehydrogenase.
Figure 2
Figure 2
Efficacy in patients on ibrutinib treatment for ≥5 years (n = 79). (a) Cumulative best response over time; (b) Kaplan–Meier curve of investigator-assessed PFS; (c) Kaplan–Meier curve of OS. Percentages of patients in each category of response may not add up to the overall proportion with a response due to rounding. Abbreviations: CR, complete response; CRi, complete response with incomplete bone marrow recovery; nPR, nodular partial response; OS, overall survival; PFS, progression-free survival; PR, partial response; PR-L, partial response with lymphocytosis; SD, stable disease.
Figure 2
Figure 2
Efficacy in patients on ibrutinib treatment for ≥5 years (n = 79). (a) Cumulative best response over time; (b) Kaplan–Meier curve of investigator-assessed PFS; (c) Kaplan–Meier curve of OS. Percentages of patients in each category of response may not add up to the overall proportion with a response due to rounding. Abbreviations: CR, complete response; CRi, complete response with incomplete bone marrow recovery; nPR, nodular partial response; OS, overall survival; PFS, progression-free survival; PR, partial response; PR-L, partial response with lymphocytosis; SD, stable disease.
Figure 3
Figure 3
Prevalence of AEs over time in patients on ibrutinib treatment for ≥5 years. (a) Most frequent AEs of any grade (occurring in ≥25% of patients overall) by yearly interval; (b) Most frequent grade ≥ 3 AEs (occurring in ≥5% of patients overall) by yearly interval. Prevalence was determined by the proportion of patients with a given AE (existing event or new onset of an event) during each yearly interval. Multiple onsets of the same AE term within a specific yearly interval were counted once, and the same AE term continuing across several yearly intervals was counted in each of the intervals. Abbreviations: AE, adverse event; UTI, urinary tract infection; URTI, upper respiratory tract infection.
Figure 4
Figure 4
Efficacy in patients with and without dose reductions because of AEs in the overall population of ibrutinib-treated patients. (a) Kaplan-Meier curve of investigator-assessed PFS; (b) Kaplan-Meier curve of OS. Abbreviations: AE, adverse event; OS, overall survival; PFS, progression-free survival.
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