Health-Related Quality of Life and Patient-Reported Outcomes in Patients Receiving Ofatumumab in Combination with Fludarabine and Cyclophosphamide (FC) Versus FC Alone in the Complement 2 Trial
Authors: Robak Tadeusz , Warzocha Krzysztof , Babu K Govind , Kulyaba Yaroslav , Kuliczkowski Kazimierz , Abdulkadyrov Kudrat , Loscertales Javier , Kryachok Iryna , Kloczko Janusz , Rekhtman Grygoriy , Homenda Wojciech , Blonski Jerzy , McKeown Astrid , Chang Chai-Ni , Manson Stephanie C , Lisby Steen , Gupta Ira V. , Grosicki Sebastian 
Published: October 2019

Abstract
Introduction: The randomized COMPLEMENT 2 study demonstrated a statistically significant improvement in independent reviewer committee-assessed median progression-free survival (PFS) in patients with relapsed chronic lymphocytic leukemia (CLL) who were treated with ofatumumab plus fludarabine and cyclophosphamide (OFC) compared with fludarabine and cyclophosphamide (FC) alone (28.9 vs. 18.8 months, p=0.0032) and that the addition of O was well tolerated (Robak T, et al. Haematologica 2015;100:abstract LB219). Moreover, the median overall survival was 56.4 months in the OFC arm and 45.8 months in the FC arm (p=0.1410) with a median follow-up of 34 months. In addition to the PFS benefit, it is important to consider the impact of adding O to FC on health-related quality of life (HRQoL) and patient-reported symptoms.
Methods: In the COMPLEMENT 2 trial, patients with relapsed CLL (N=365) were randomized to either OFC or FC. F and C were administered as intravenous infusions (F: 25 mg/m2, Days 1-3 every 28 days for 6 cycles; C: 250 mg/m2, Days 1-3 every 28 days for 6 cycles). O was also administered intravenously (Cycle 1: 300 mg Day 1 and 1000 mg Day 8, subsequent cycles: 1000 mg Day 1). During the trial, the EORTC QLQ-C30 v3.0 and the QLQ-CLL16 questionnaires were administered at baseline, during Cycle 4 of 6 and throughout follow-up. Specified patient-reported endpoints were HRQoL as reported by the global health status/QoL domain of the QLQ-C30 questionnaire and a B symptom index including patient-reported symptoms of fatigue, night sweats, temperature changes, and weight loss as reported by certain items of the QLQ-C30 and QLQ-CLL16 questionnaires.
Results: The least square mean change in HRQoL, measured on a scale scored from 0 (worse) to 100 (best), improved between baseline and Cycle 4 by 8.3 points in the OFC arm vs. 4.8 points in the FC arm. Although there was no significant difference between the least square mean changes in the two arms (p=0.09), the OFC arm surpassed the 5-point difference defined as being a clinically relevant change (Osoba D, et al. J Clin Oncol 1998;16;139-144). The least square mean change in B symptom index, measured on a scale of 0-100 with 0 meaning no symptoms, improved from baseline to Cycle 4 by 5.6 points and 4.5 points in the OFC and FC arms, respectively, with no significant difference between the arms (p=0.49). Patients who achieved a complete or partial response to therapy showed a larger mean improvement in B symptoms (OFC 6.5 improvement, FC 7.5 improvement) than those who did not respond (OFC 4.3 improvement, FC 3.5 worsening of symptoms) but these differences between the arms were not significant (p=0.51 and p=0.22, respectively). During follow-up, patients who did not progress maintained a consistent level of HRQoL in both arms (Figure).
Conclusion: This study demonstrates durable improvements in both HRQoL and patient-reported B symptoms for patients being treated for relapsed CLL. Although there are no significant differences observed between the OFC and FC treatment arms in terms of the least square mean change in HRQoL or B symptom scores, the improvement in PFS in the OFC arm reported previously (Robak T, et al. Haematologica 2015;100:abstract LB219) suggests that these patients may enjoy HRQoL and symptom improvements for a longer duration.
Figure 1. Least Squares Mean Change in HRQoL from Baseline Figure 1. Least Squares Mean Change in HRQoL from Baseline

Disclosures
Robak: GlaxoSmithKline: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Off Label Use: Ofatumumab (Arzerra) is approved in the frontline and refractory CLL setting but not in relapsed CLL. This Abstract presents the Health related quality of life and patient reported outcomes in patients receiving ofatumumab in combination with fludarabine and cyclophosphamide (FC) versus FC alone. Kryachok:GlaxoSmithKline: Honoraria, Other: Investigator for Study. Homenda:GlaxoSmithKline: Honoraria, Other: Intestigator in Clinical Trial - OMB110913 (COMPLEMENT 2). Blonski:GlaxoSmithKline: Research Funding. McKeown:GlaxoSmithKline: Equity Ownership; Novartis: Employment, Equity Ownership. Chang:GlaxoSmithKline: Equity Ownership; Novartis: Employment, Equity Ownership. Manson:GlaxoSmithKline: Employment, Equity Ownership; Novartis: Employment, Equity Ownership. Lisby:Genmab: Employment. Gupta:Novartis: Employment, Equity Ownership; GlaxoSmithKline: Equity Ownership.