Introduction
Indolent non-Hodgkin lymphoma (iNHL)—including follicular lymphoma (FL) and non-follicular histologies—is mostly slow growing, but rarely cured. FL accounts for approximately 70% of iNHL and 22% of all NHL [
1]. Despite significant improvements in response rates and progression-free survival (PFS) with the addition of rituximab to chemotherapy [
2‐
6], iNHL patients continue to relapse or become refractory to treatment resulting in limited treatment options.
Bendamustine (B) has been shown to be effective in rituximab-refractory (R-refr) patients (75–77% overall response rate), but median PFS is short [
7,
8]. Obinutuzumab (GA101; Gazyva/Gazyvaro; G) is a novel, humanized, glyco-engineered type II anti-CD20 monoclonal antibody, developed to have superior efficacy compared with rituximab. In early clinical trials, G demonstrated encouraging efficacy in relapsed iNHL patients, and responses were observed in R-refr patients [
9‐
11]. In the phase III GADOLIN study evaluating B with or without G in patients with R-refr CD20+ iNHL, prolonged PFS in the G-B arm was demonstrated [
12].
Equally important to improving efficacy outcomes in these patients is understanding the impact of treatment on disease- and treatment-related symptoms and function. Relatively little is known about the health-related quality of life (HRQoL) of relapsed/refractory (Rel/Refr) and R-refr iNHL patients. The majority of information comes from cross-sectional studies of long-term survivors of NHL that have combined different indolent subtypes and required patients to be several months from receipt of chemotherapy [
13‐
15]. In a proportion of these studies, partly because many iNHL patients are asymptomatic at presentation, the HRQoL of iNHL patients is akin to that of the general population. Other studies have highlighted that disease-related symptoms, such as lymphadenopathy, fatigue, and disease-related B symptoms (e.g., weight loss, fever, and night sweats), have a negative impact on patients [
14,
15].
A study by Pettengell reported HRQoL in five categories of FL patients, including one category classified as “active disease-relapsed” [
13]. Although it was a cross-sectional study and unrelated to specific treatment, this study identified that patients with active relapsed disease had the lowest scores on aspects of HRQoL (physical well-being, PWB; functional well-being, FWB; emotional well-being, EWB; and social/family well-being, SWB) and lymphoma-related symptoms. Information on the impact of disease and treatment-related symptoms on the HRQoL of Rel/Refr and R-refr iNHL patients, however, is limited.
In evaluating the efficacy benefit of new treatments in Rel/Refr and R-refr patients, it is important to demonstrate that any improvement in PFS occurs without adversely impacting HRQoL and that there is an increase in the time to patient-reported symptom deterioration with a new treatment. The current study evaluates the impact of G-B and B on patient-reported HRQoL, lymphoma-specific symptoms, and health status of patients with R-refr iNHL in the GADOLIN trial.
Results
Overall, 396 patients were randomized (194 to G-B and 202 to B [198 treated]). Baseline characteristics (e.g., proportion of males/females, ECOG performance scale, iNHL subtype, Follicular Lymphoma International Prognostic Index score, time from initial diagnosis to randomization, and presence of B symptoms) were balanced between arms. Median age was 63 years, and patients had a median of two prior therapies. Primary study analysis was undertaken when 175 Independent Review Committee (IRC)-assessed PFS events were observed. PFS was significantly longer with G-B (median not reached [NR]; 95% confidence interval [CI] 22.5 months—NR) than B (median 14.9 months; 95% CI 12.8–16.6 months); hazard ratio (HR) for progression or death was 0.55 (95% CI 0.40–0.74;
p = 0.0001). G-B followed by G maintenance demonstrated manageable toxicity, with a similar profile to B [
12].
Discussion
For R-refr iNHL patients, G-B treatment provides an important option by achieving an increased PFS over standard of care with B alone [
12]. Of equal importance is understanding the associated impact on HRQoL.
In GADOLIN, individuals in both treatment arms reported slightly impaired HRQoL prior to treatment, with the greatest impairment being observed on the FWB scale whose items include those focused on ability to work, sleep, and enjoy life and fun activities. Scores on the PWB, FWB, SWB, and EWB scales at baseline were roughly 2–3 points lower than the general population averages [
20], 1–3 points lower than scores reported by a disease-free NHL (all subtypes) sample [
21], but 0–7 points higher than a group of active disease-relapsed FL patients [
13]. This observation suggests that patients experienced a clinically meaningful lower HRQoL as compared to the general population, but higher HRQoL than published data on patients with relapsed disease. As 15/34 (44%) of the active disease-relapsed patients in the Pettengell study were receiving chemotherapy at the time of assessment, it is possible that the difference observed is the result of the unspecified chemotherapy regimen received by patients adversely impacting their HRQoL [
13].
During the study, there was minimal change in the overall group average scale scores in both arms. These minimal changes from baseline are consistent with the lack of a significant decline in FACT-Lym TOT, FACT-Lym questionnaire, or the European Organization for Research and Treatment of Cancer QLQ-C30 subscale scores during the study period reported in frontline and previously treated rituximab-exposed iNHL patients [
22,
23]. While no clear improvement in HRQoL was observed with G-B treatment, when looking at the overall sample, results showed no evidence to suggest that G-B treatment reduced patient-reported HRQoL—an important factor in refractory iNHL patients in need of alternative treatment.
Although there were no differences between arms in the overall sample average scores, there were differences in patients who reported clinically meaningful changes over the course of the study: a longer time to clinically meaningful deterioration in lymphoma-related HRQoL in the G-B arm compared with B alone. In addition, G-B followed by G maintenance resulted in a greater proportion of patients reporting a meaningful improvement in HRQoL throughout the study. This improvement occurred in the G-B arm even during induction, despite similar clinical response rates [
12], and the benefit was sustained over time despite the delivery of additional G treatment.
In the primary GADOLIN manuscript, subgroup analyses of efficacy demonstrated that the benefit of G-B was seen in the majority of subgroups tested, including FL (81% of ITT), in whom the stratified HR for IRC-assessed PFS in the G-B arm relative to B alone was 0.48 (95% CI 0.34–0.68) [
12]. It was important to determine whether the clinical benefit observed in FL patients was consistent for HRQoL, which would provide additional support for the benefit of G-B treatment. As noted, results of HRQoL analysis were similar between the overall ITT population and FL subpopulation.
The primary limitation of this study is the decreased number of patients completing the HRQoL questionnaires over time. Although completion rates in the B arm started to reduce, the degree of missing data among those who were progression free and evaluable to complete the questionnaires was not markedly different between treatment arms. Therefore, it is likely that the scores are a reflection of the HRQoL of treated patients. At 18 months from EOI, 75 evaluable patients remained in the G-B arm and 25 in B. This was due to a combination of PD, death, study discontinuation, and the study being reported after reaching statistically significant results in PFS at interim analysis. If completion rates are examined based on the proportion of FACT-Lym questionnaire data missing, due to attrition and non-compliance, the difference between arms is more pronounced than due to compliance alone. Specifically, the proportion of data missing was higher in the B arm during follow-up/maintenance (61% in B arm at 6 months after EOI; 76% at 12 months after EOI; 81% at 18 months after EOI) than the corresponding numbers for G-B (41, 52, 57%, respectively), which is in line with the higher attrition rates due to PD and death in the B arm. A further limitation is that after PD, HRQoL questionnaires were only collected at study treatment/follow-up termination visit, and <50% of patients with PD completed them, which could potentially have biased the results. The proportion of patients that were event free with respect to progression or death in the G-B versus B arm was 76.6 versus 57.4% after 1 year and 59.4 versus 35.4% after 1.5 years from randomization. If we consider progression to have an adverse impact on HRQoL data, then data reported only from the non-progressed patients are likely an overestimate of the true HRQoL. As the progression rate was significantly greater in the B arm (and thus the relapse-free follow-up shorter), this could be interpreted as the change from baseline in HRQoL is biased upwards to a greater extent in the B arm compared with G-B.
As the aim of treatment for R-refr iNHL patients is to maximize PFS, maintain HRQoL, and minimize treatment-related morbidity, the results of GADOLIN highlight the benefit that G-B treatment confers over B alone in some patients, while maintaining pre-treatment levels of HRQoL. There was no evidence to suggest that G-B treatment reduced patient-reported HRQoL, and in a proportion of patients, resulted in meaningful improvements in lymphoma-related symptoms. Our results suggest that improved PFS is not at the expense of an increase in treatment-related toxicity that could lead to a reduction in a patient’s HRQoL.
Compliance with ethical standards
The protocol was approved by the ethics committees of participating centers and is registered at
ClinicalTrials.gov.
Conflict of interest
BDC has performed in a consulting or advisory role for Celgene, Gilead, Pharmacyclics, Astra Zeneca, Spectrum, and Astellas, and his institution has received research funding from Pharmacyclics, Acerta, Seattle Genetics, and Gilead. PCT is an employee of Genentech, Inc. and owns stock in Roche/Genentech. JGG has received honoraria from Roche/Genentech, Celgene, Pharmacyclis, Janssen, Gilead, Mundipharma, TG Therapeutics, and Acerta. ND is an employee of Roche and owns stock in Roche and GSK. EK has received honoraria from Janssen, Gilead, Celgene, and AbbVie; has performed in a consulting or advisory role for Janssen, Baxalta, and AbbVie; and has received research funding and drug support from—and worked on transitional research with—Pfizer. PJL has performed in a consulting or advisory role for Celgene, Mundipharma, and Servier. CT has performed in a consulting or advisory role for Janssen, Gilead, and Roche and has received travel, accommodation, and expenses support from Janssen and Gilead. EW-F is an employee of F. Hoffmann-La Roche Ltd. AL is an employee of F. Hoffmann-La Roche Ltd., owns stock in Novartis, and has received travel, accommodation, and expenses support from Roche and Novartis. LHS has received honoraria from Roche/Genentech, Celgene, Seattle Genetics, AbbVie, Janssen, Gilead, Amgen, and TG Therapeutics and has performed in a consulting or advisory role for Roche/Genentech, Celgene, Gilead, Janssen, Pfizer, Amgen, Seattle Genetics, AbbVie, Lundbeck, and TG Therapeutics.
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