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CT03
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

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Poster CT03

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

INTRODUCTION

• 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

regimens.1

• 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

analysis (PCYC-1115).2

• 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.

OBJECTIVE

• To evaluate QOL parameters and other measures of patient

well-being with extended follow-up in RESONATE-2.

METHODS

• 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

splenomegaly (30%).

• 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).

Efficacy

• 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

measure analysis.

• 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

chlorambucil.

• 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.

Safety

• 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

3-year follow-up.

• AEs leading to treatment discontinuation occurred in 16% with

ibrutinib over 3 years vs 23% for chlorambucil over 7 months of

therapy, respectively.

• 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 Analysis

• 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

considerations.

• 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

analysis.

REFERENCES

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.

DISCLOSURES

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.

ACKNOWLEDGMENTS

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

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