Impact Of Low-Grade Adverse Events (AEs) On Health-Related Quality Of Life (HRQoL) In Adult Patients With Newly Diagnosed Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia In Chronic Phase (Ph+ CML-CP) From The Enestnd Trial: 48-Month Follow-Up
Authors: Chen Lei , Guerin Annie , Marynchenko Maryna , Ionescu-Ittu Raluca , Hiscock Robert , Nitulescu Roy , Pooja Chopra , Hsu Ling-I , Keir Christopher , Wu Eric Qiong 
Published: October 2019

Abstract

Background
In the randomized, phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients) trial, the superior efficacy of nilotinib (NI) compared with imatinib (IM) has been firmly established in patients with newly diagnosed Ph+ CML-CP. Based on the 36 month ENESTnd data, both NI and IM demonstrated good safety and AE profiles, with low-grade AEs (grades 1/2) being reported more frequently than grade 3/4 AEs. AEs, even mild and moderate in nature, may negatively impact HRQoL. This post-hoc analysis evaluated the association between low-grade AEs and HRQoL using the 48-month update of ENESTnd.

Methods
846 newly diagnosed Ph+ CML-CP patients were randomized to NI 300 mg BID (n = 282), NI 400 mg BID (n =281), or IM 400 mg QD (n = 283). HRQoL was assessed using the Functional Assessment of Cancer Therapy – Leukemia (FACT-Leu) and the Short Form 36 Health Survey (SF-36). Derived HRQoL scores included FACT-Leu Total (FLT), SF-36 mental component summary (MCS) and SF-36 physical component summary (PCS). Questionnaires were scheduled to be administered at enrollment and the end of 3, 12, 24, 36 and 48 months or at early discontinuation. Low-grade AEs were classified based on the 26 system organ classes (SOCs) and assessed during a 7-day and 28-day observation period prior to each administration date of FACT-Leu and SF-36 questionnaires, respectively, which corresponds to the periods over which these HRQoL outcomes were measured. Only AEs with a prevalence ≥1% during the observation period were analyzed. The change in HRQoL outcomes from baseline was compared between patients with low-grade AEs and those without any AEs during the observation period (excluding patients with grade 3/4 AEs) using linear mixed effects models, adjusting for potential confounders. Subsequently, adjusted Poisson regression models were used to compare frequencies of low-grade AEs that were found to significantly impact HRQoL over the course of 48 months among the three treatment arms.

Results
Overall, the occurrence of gastrointestinal (GI) (e.g. nausea, diarrhea), general (e.g. fatigue, peripheral edema), musculoskeletal (e.g. muscle spasms, arthralgia) and psychiatric disorders (e.g. insomnia, anxiety) had a statistically significant negative impact on change in HRQoL from baseline (Table 1). Both NI treatment arms had a significantly lower incidence of GI and musculoskeletal disorders compared with IM (Table 2).

Conclusions
Some low-grade AEs impaired HRQoL in patients treated with NI or IM. These AEs were less frequent in patients treated with NI.
1. Linear mixed effect models adjusted for demographics, prior treatment, clinical measures and other low grade AEs with < 1% prevalence during the observation period combined together.
2. “-“ indicates that the AE SOC prevalence was < 1% during the observation period.
3. N represents the number of individual HRQoL assessments across all patients included in the analysis.
1. Poisson regression models adjusted for demographics, prior treatment and clinical measures.

Disclosures:
Chen: Novartis: Employment, Equity Ownership. Guerin:Novartis Pharmaceuticals: Consultancy, employee of Analysis Group Inc., which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Marynchenko:Novartis Pharmaceuticals: Consultancy, employee of Analysis Group Inc., which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Ionescu-Ittu:Novartis Pharmaceuticals: Consultancy, employee of Analysis Group Inc., which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Hiscock:Novartis Pharmaceuticals: Consultancy, employee of Analysis Group Inc., which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Nitulescu:Novartis Pharmaceuticals: Consultancy, employee of Analysis Group Inc., which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Pooja:Novartis Pharmaceuticals: Consultancy, employee of Analysis Group Inc., which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Hsu:Novartis: Employment, Intern Other. Keir:Novartis: Employment, Equity Ownership. Wu:Novartis Pharmaceuticals: Consultancy, employee of Analysis Group Inc., which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding.