Prolonged Improvement in Patient-Reported Outcomes (PROs) and Well-being in Older Patients With
Treatment-Naïve Chronic Lymphocytic Leukemia (CLL) Treated With Ibrutinib: 3-Year Follow-up of the RESONATE-2 Study
Paul Barr, MD, Alessandra Tedeschi, MD, Carolyn Owen, MD, Tadeusz Robak, MD, PhD, Osnat Bairey, MD, Peter Hillmen, MB, ChB, PhD, Steven Coutre, MD, Stephen Devereux, FRCP, FRCPath, PhD, MD, Sebastian Grosicki, MD, PhD,
Helen McCarthy, MBBS, PhD, MRCP, FRCPath, Jianyong Li, MD, PhD, David Simpson, MBChB, FRACP, FRCPA, Tanya Siddiqi, MD, Giri Iyer, MBA, Indu Lal, MD, Jeremiah Trudeau, PhD, Sandra Dai, PhD, MS, James P. Dean, MD, PhD,
Danelle F. James, MD, MAS, Jan A. Burger, MD, PhD, Paolo Ghia, MD, PhD, Thomas J. Kipps, MD, PhD
• Chronic lymphocytic leukemia/small lymphocytic lymphoma
(CLL/SLL) is a disease primarily of older patients who often
have comorbidities and are less able to tolerate aggressive
• Quality of life (QOL) is an important consideration in treatment
decisions; however, patient-reported outcomes (PROs) and
QOL data from randomized trials in CLL/SLL are limited,
particularly in older patients.
• Ibrutinib is a first-in-class, once-daily inhibitor of Bruton’s
tyrosine kinase approved in the US and EU for the treatment
of CLL and allows for treatment without chemotherapy.
• In the phase 3 RESONATE-2 study of first-line treatment in
older patients with CLL/SLL, single-agent ibrutinib reduced
the risk of progression or death by 84% vs chlorambucil
(P<0.001), with a median follow-up of 18.4 months at primary
• Previous reports have shown ibrutinib improves QOL as
assessed by the PRO measures of FACIT-Fatigue and EORTC
QLQ-C30, hematologic function, and disease burden in both
the relapsed/refractory and first-line CLL/SLL settings.3,4
• Given that patients are treated with ibrutinib continuously
until progressive disease (PD) or unacceptable toxicity, it is
important to understand the durability of QOL improvements
throughout longer-term ibrutinib treatment.
• To evaluate QOL parameters and other measures of patient
well-being with extended follow-up in RESONATE-2.
• Among 269 randomized patients, median age was 73 years
and 69% had at least one pre-specified comorbidity.
• Overall, common reasons for initiating therapy included
constitutional symptoms (45%, at least one), progressive
marrow failure (38%), lymphadenopathy (37%), and
• Median follow-up is 35.7 months with ibrutinib and 34.4
months with chlorambucil.
• At the time of analysis, 99 patients (73%) randomized to
ibrutinib continue on study treatment (Table 1).
• In the chlorambucil arm, 64 patients (48%) crossed over
to ibrutinib after PD (Table 1).
• Over time, ibrutinib patients showed consistent improvements
over baseline in FACIT-Fatigue scores (Figure 2A) and EQ-5D-5L
Visual Analog Scale (VAS) scores (Figure 2B), whereas
chlorambucil patients experienced worsening scores on both
measures. These differences were statistically significant (FACITFatigue,
P=0.0021; EQ-5D-5L VAS, P=0.0004) by repeated
• In chlorambucil patients with PD who crossed over to ibrutinib,
a trend towards improvement was observed for both FACITFatigue
scores and EQ-5D-5L VAS scores after crossover, which
was also sustained over time (data not shown, see QR code).
• Ibrutinib resulted in significantly longer PFS (median, not reached
vs 15.0 months with chlorambucil), with an 87% reduction in risk
of progression or death vs chlorambucil (HR 0.130; 95% CI: 0.081,
0.208) (Figure 3).
• PFS rate at 30 months was 85% with ibrutinib vs 28% with
• Disease burden, as assessed by decreased or normalized
lymphadenopathy within 2 months, was improved in
approximately 87% of patients on ibrutinib (vs 52% on
chlorambucil) and was sustained through 36 months.
• Median treatment duration was 34.1 months on ibrutinib vs
7.1 months on chlorambucil.
• The most common adverse events (AEs) of any grade with
ibrutinib were diarrhea (47%), fatigue (33%), and cough (30%).
• Eight grade ≥3 AEs had a prevalence of >3% in ibrutinib patients
over the 3 years of treatment and generally decreased or were
stable over time (Table 2).
• During the first year of treatment, patients on ibrutinib vs
chlorambucil experienced less grade ≥3 neutropenia (8% and
18%), anemia (6% and 8%), and thrombocytopenia (2% and 5%).
— Other common grade ≥3 AEs were pneumonia (5% and 2%),
hypertension (4% and 0%), and infections as combined term
(17% and 8%).
• Grade ≥3 bleeding occurred in 7% of ibrutinib patients over the
• AEs leading to treatment discontinuation occurred in 16% with
ibrutinib over 3 years vs 23% for chlorambucil over 7 months of
• Ibrutinib adherence in populations with increased age,
comorbidities (as measured by CIRS score), and number of
concomitant medications was evaluated and none of these
factors were associated with decreased adherence.
• Q-TWiST is a statistical method5 designed to analyze and
compare treatment outcomes using integrated data on the
patient experience (progression, survival, and toxicity) to
better understand the risk-benefit of treatment, including QOL
• Mean time spent without symptoms of PD or grade 3-4 treatment
toxicity was significantly longer with ibrutinib vs chlorambucil
(501 vs 351 days; mean difference, 150 days; 95% CI: 109, 193;
P<0.001) (Figure 4).
• Patients on ibrutinib therapy also experienced significantly
prolonged PRO quality-adjusted time without symptoms or
toxicity compared with chlorambucil (386 vs 329 days; mean
difference, 57 days; 95% CI: 25, 90; P=0.001).
• In the phase 3 RESONATE-2 study with 3 years of
follow-up in patients with CLL/SLL treated in the firstline
setting, PROs improved with ibrutinib over time
and worsened with chlorambucil, showing significantly
greater and sustained improvements with ibrutinib.
• Common iwCLL indications for therapy, including
disease burden (as assessed by lymph node size),
as well as disease symptoms (such as weight loss,
fatigue, night sweats) and hematologic parameters
(hemoglobin and platelets) (data not shown, see QR
code), improved more frequently with first-line ibrutinib
treatment compared with chlorambucil.
• Results of the Q-TWiST analysis, which assessed the
integrated value of study treatment across multiple
measures of the patient experience, showed that
ibrutinib was associated with significantly increased
quality-adjusted time without disease symptoms or
toxicity compared with chlorambucil at time of primary
1. Thurmes et al. Leuk Lymphoma. 2008;49:49-56.
2. Burger et al. N Engl J Med. 2015;373:2425-37.
3. Barrientos et al. Blood. 2014;124. Abstract 4696.
4. Ghia et al. Haematologica. 2016;101(s1). Abstract P217.
5. Gelber et al. Am Stat. 1995;49:161-9.
PB: consultancy/advisory role for Pharmacyclics LLC, an AbbVie Company, AbbVie,
Celgene, Novartis, Seattle Genetics, and Infinity; research funding from Pharmacyclics
LLC, an AbbVie Company; AT: consultancy/advisory role for Janssen and AbbVie;
honoraria from Janssen, AbbVie, Gilead, and Roche; CO: consultancy/advisory role for
Roche; honoraria from Roche, Lundbeck, Merck, Gilead, Janssen, AbbVie, Celgene, and
AstraZeneca; research funding from Roche, Gilead, and Pharmacyclics LLC, an AbbVie
Company; TR: honoraria and consultancy/advisory role for AbbVie and Janssen; research
funding from AbbVie, Pharmacyclics LLC, an AbbVie Company, and Janssen; travel
expenses from AbbVie; OB: consultancy/advisory role for AbbVie; research funding from
Janssen; PH: consultancy/advisory role for and honoraria from AbbVie, Janssen, Gilead,
and Acerta; research funding from AbbVie, Pharmacyclics LLC, an AbbVie Company
(institution), Janssen (institution), Gilead (institution), Roche (institution), and GSK
(institution); speakers bureau for AbbVie, Janssen, Gilead, and Acerta; SC: consultancy/
advisory role for AbbVie, Gilead, Novartis, Celgene, Janssen, and Pharmacyclics LLC,
an AbbVie Company; research funding from AbbVie, Gilead, Novartis, Celgene, and
Pharmacyclics LLC, an AbbVie Company; SDevereux: consultancy/advisory role for and
honoraria from Janssen, AbbVie, MSD, and Gilead; speakers bureau for and travel expenses
from Janssen and Gilead; SG: no relevant relationships; HM: consultancy/advisory role for
Janssen; honoraria and travel from Janssen, AbbVie, Novartis, and Roche; JL: no relevant
relationships. DS: honoraria from Roche, Celgene, Janssen, and Merck; research funding
from Amgen; TS: speakers bureau for Pharmacyclics LLC, an AbbVie Company, and
Seattle Genetics; GI: patents and royalties with Optimal Strategix Group; employment
of an immediate family member at Eli Lilly; IL: employment with Pharmacyclics LLC,
an AbbVie Company, and husband’s employment with The Permanente Medical Group
(TPMG); equity ownership with AbbVie, Gilead Sciences, Clovis, Infinity, TPMG, and Reviva
Pharmaceuticals; JT: employment and equity ownership with Janssen Global Services,
LLC; SDai: employment with Pharmacyclics LLC, an AbbVie Company; equity ownership
with AbbVie; JPD: employment and equity ownership with Pharmacyclics LLC, an
AbbVie Company, and CTI BioPharma Corp; DFJ: employment with Pharmacyclics LLC,
an AbbVie Company, and husband’s employment with AbbVie; equity ownership self/
husband with AbbVie; patents/royalties/other intellectual property with AbbVie; JAB:
consultancy/advisory role for and honoraria and travel accommodations from Gilead, TG
Therapeutics, Pharmacyclics LLC, an AbbVie Company, Novartis, and Janssen; research
funding from Pharmacyclics LLC, an AbbVie Company; PG: consultancy/advisory role for
AbbVie, Adaptive, Gilead, Janssen, Pharmacyclics LLC, an AbbVie Company, and Roche;
research funding from Gilead, Janssen, AbbVie, and Novartis; speakers bureau for Gilead;
TJK: consultancy/advisory role for AbbVie, Genentech, Gilead, and Pharmacyclics LLC,
an AbbVie Company; research funding from AbbVie, Genentech, Pharmacyclics LLC, an
AbbVie Company, and Oncternal.
We thank the patients who participated in this study and their
supportive families, as well as the investigators and clinical
research staff from the study centers. This study was sponsored by
Pharmacyclics LLC, an AbbVie Company. Editorial support was
provided by Rebecca Miles, PhD, and funded by Pharmacyclics
LLC, an AbbVie Company.
Poster presented at the Hematology/Oncology Pharmacy Association (HOPA) 14th Annual Conference, March 21-24, 2018, Denver, CO