Annals of Hematology (2020) 99:2837–2846 https://doi.org/10.1007/s00277-020-04021-6 ORIGINAL ARTICLE Health-related quality of life in the phase III GALLIUM study of obinutuzumab- or rituximab-based chemotherapy in patients with previously untreated advanced follicular lymphoma Andrew Davies 1 & Peter Trask 2 & Judit Demeter 3 & Axel Florschütz 4 & Mathias Hänel 5 & Tomohiro Kinoshita 6 & Ruth Pettengell 7 & Hang Quach 8 & Stephen Robinson 9 & Shalal Sadullah 10 & Juan-Manuel Sancho 11 & Miklos Udvardy 12 & Mathias Witzens-Harig 13 & Andrea Knapp 14 & Wenxin Liu 14 Received: 4 October 2019 / Accepted: 2 April 2020 / Published online: 20 April 2020 # The Author(s) 2020 Abstract Health-related quality of life was a secondary endpoint in the phase III GALLIUM study in previously untreated patients with follicular lymphoma who were treated with rituximab- or obinutuzumab-chemotherapy. Patients were randomized 1:1 to receive induction therapy with obinutuzumab- or rituximab-chemotherapy and maintenance in responders. Health-related quality of life was assessed using the Functional Assessment of Cancer Treatment-Lymphoma questionnaire, incorporating well-being and lymphoma-specific subscales. Assessments were performed at baseline, and during induction, maintenance, and follow-up (maximum 84 months). Clinically meaningful responses were defined by minimally important difference values. Of 1202 randomized patients (median follow-up 57.4 months), 557/601 (92.7%; obinutuzumab-chemotherapy) and 548/601 (91.2%; rituximab-chemotherapy) completed all Functional Assessment of Cancer Treatment-Lymphoma scales at baseline. Mean base- line health-related quality of life scores were similar between both arms, with all patients having some functional impairment and lymphoma symptoms. Over the course of treatment, mean health-related quality of life remained similar in both arms. Equal proportions of patients in both arms achieved minimally important difference by the Functional Assessment of Cancer Treatment- Lymphoma lymphoma-specific subscale and summary scales throughout induction, maintenance, and follow-up. On each summary scale, ~ 50% of patients in each arm achieved minimally important difference by maintenance month 2. In GALLIUM, similar improvements in health-related quality of life were seen with obinutuzumab- and rituximab-chemotherapy, suggesting that both treatments reduced lymphoma-related symptoms, and treatment-related side effects did not abrogate these improvements in well-being. ClinicalTrials.gov identifier: NCT01332968. Keywords Follicular lymphoma . Indolent non-Hodgkin lymphoma . Obinutuzumab . Quality of life . Rituximab Introduction NHLs [1]. Rituximab (R), a type I monoclonal antibody (mAb), plus chemotherapy (R-chemo) induction, and mainte- Follicular lymphoma (FL) encompasses approximately 70% nance therapy has resulted in improved outcomes for patients of indolent non-Hodgkin lymphomas (iNHL) and 22% of all with FL [2–5]. Nevertheless, 20–35% of patients experience progressive disease, relapse, or death within 2 years [4, 6], with early disease progression associated with worse progno- This study was presented at the 22nd Congress of European Hematology Association, June 22–25, 2017, Madrid, Spain sis [7, 8]. Obinutuzumab (GA101; G) is the first glycoengineered, Electronic supplementary material The online version of this article type II, humanized anti-CD20 mAb, promoting enhanced (https://doi.org/10.1007/s00277-020-04021-6) contains supplementary material, which is available to authorized users. antibody-dependent cellular toxicity and direct cell death against B cell malignancies when compared with type I * Andrew Davies mAbs [9]. The phase III GALLIUM study (NCT01332968) a.davies@southampton.ac.uk evaluated G-chemotherapy (G-chemo) versus R-chemo as in- duction therapy in patients with previously untreated, Extended author information available on the last page of the article advanced-stage FL, followed by maintenance with the same 2838 Ann Hematol (2020) 99:2837–2846 antibody in responders. In the primary analysis of this study tomography received maintenance with the same antibody (data cut-off January 31, 2016), the primary endpoint of for 2 years or until progressive disease. investigator-assessed progression-free survival (PFS) was Patient selection, study methods, and treatment are de- met, with an improvement in PFS shown for patients treated scribed in detail within the Online Resource (Methods) and with G-chemo versus those treated with R-chemo (median elsewhere [10]. follow-up, 34.5 months; hazard ratio 0.66; 95% confidence interval 0.51–0.85; p = 0.001) [10]. Adverse events (AEs) Patient-reported HRQoL assessments were consistent with the known safety profiles of both study treatments [10]. HRQoL was assessed using the Functional Assessment of Despite the improvements in patient outcomes that have Cancer Treatment-Lymphoma (FACT-Lym) questionnaire come with advancements in immunochemotherapy, the treat- [13], incorporating the FACT-General (FACT-G) scale (phys- ment of conditions like FL can often have a more negative ical well-being [PWB], functional well-being [FWB], emo- impact on the patient than the disease itself [11]. Meaningful tional well-being [EWB], and social/family well-being improvements in health-related quality of life (HRQoL) and [SWB]) and the FACT-Lym lymphoma-specific (LYMS) sub- the effect that serious or persistent treatment-related symp- scale. Summary scales FACT-Lym trial outcome index (TOI), toms have on patients are important factors to consider, nota- FACT-G, and Total (TOT) were also calculated. Further de- bly with the increased chances of prolonged survival follow- tails of these questionnaires can be found within the Online ing treatment. Resource (Methods). Several studies have investigated the impact of treatment Assessments were performed at baseline (cycle on HRQoL in patients with iNHL. In a population of patients [C]1 day [D]1), C3D1, end of induction, during main- with FL, those who were newly diagnosed with active disease tenance months 2 and 12, at the end of maintenance had similar HRQoL compared with patients that were either in (month 24), and then every 12 months during follow- partial/complete remission or disease free, while having better up, up to 84 months. HRQoL than those who had relapsed [11]. In the phase III Clinically meaningful responses were defined by min- GADOLIN trial of patients with relapsed/refractory iNHL, imally important difference (MID) values in FACT-Lym patients treated with G-bendamustine (B) versus B had a de- and FACT-G. A MID reflects the smallest difference in a layed time to worsening and more reports of clinically mean- score that is considered to be clinically important to the ingful improvements in HRQoL [12]. patient [14–16]. Patients who achieved an improved However, previous analyses have primarily been cross- score versus baseline, reaching the upper limits of sectional studies, with none having compared G-chemo FACT-Lym (LYMS, ≥ 3 points; TOI, ≥ 6 points; TOT, with R-chemo in a population of patients with FL. In this ≥ 7 points) and FACT-G (≥ 2–3, excluding the SWB secondary analysis of the GALLIUM study, we compared scale), were classified as responders, with differences be- the changes in HRQoL in first-line patients with FL treat- tween treatment groups assessed [15, 16]. Higher FACT- ed with G-chemo or R-chemo, investigating the potential Lym scores indicate improved functioning, HRQoL, and differences in patient-reported outcomes (PROs) between health status. the two treatments. Statistical analysis Methods PRO analyses included all randomized patients who had a baseline measure and ≥ 1 post-baseline assessment. Study design Missing values were not imputed; however, prorated scores were calculated based on developed guidelines GALLIUM was a phase III, open-label, parallel-group study. [17]. Analyses were performed separately for patients Patients with previously untreated grade 1–3a FL were ran- with FL versus the overall population (data cut-off domized 1:1 to receive induction therapy with G plus chemo- February 12, 2018). therapy (cyclophosphamide, doxorubicin, vincristine, and Questionnaire completion rates were calculated. For prednisone [CHOP]; cyclophosphamide, vincristine, and each FACT-Lym questionnaire scale, descriptive statis- prednisone [CVP]; or B). Six to eight cycles of chemotherapy tics at each visit and changes from baseline are present- were prescribed, depending on the selected chemotherapy ed. After baseline FACT-Lym LYMS, TOI, TOT, and (chosen upfront by investigators at each site; all patients at FACT-G were evaluated, mean score changes from base- the same site received the same regimen). Patients achieving line were calculated for each time point. Finally, the at least a partial response on contrast-enhanced computed proportion of patients with FL achieving the MID for Ann Hematol (2020) 99:2837–2846 2839 each scale, i.e., a clinically meaningful response, was between 5 and 15 points below the possible maximum (de- assessed. pending on the subscale). Here we present only the results up to month 48, due For FACT-G assessments, an initial negative mean change to the dense censoring that occurs after this time point; from baseline (C1D1) by PWB and FWB subscales was re- results up to month 84 can be found within the Online ported (C3D1, G-chemo vs. R-chemo, PWB – 0.21 vs. – 0.91; Resource. FWB – 0.06 vs. – 0.30; Fig. 2a and b, respectively). Conversely, EWB increased rapidly by the first time point in both treatment arms (C3D1, G-chemo vs. R-chemo, 1.36 vs. Results 1.49; Fig. 2c). Modest increases were then reported in both treatment arms for the PWB, FWB, and EWB scales up to Disposition and updated analysis follow-up month 48. SWB scores decreased versus baseline for both G-chemo and R-chemo (follow-up month 48, − 1.15 In total, 1202 patients with FL were randomized to receive vs. – 0.78; Fig. 2d). Despite the increases seen for PWB, either G-chemo (n = 601) or R-chemo (n = 601) in the FWB, and EWB, scores only exceeded the threshold for clin- GALLIUM trial (Online Resource: Supplementary Fig. 1). ically meaningful change on the FWB subscale (> 2) for pa- Baseline demographic and disease characteristics were well- tients treated with R-chemo. Beyond follow-up month 48, balanced between arms [10]. PWB scores continued to increase, with MID (> 2–3) The efficacy and safety findings of the updated GALLIUM achieved between months 72 and 84 (Online Resource: analysis (data cut-off February 12, 2018; median follow-up, Supplementary Table 2). 57.4 months) were consistent with the primary analysis; G- Over the course of treatment, similar trends were observed chemo continued to provide clinically meaningful improve- in patients treated with G-chemo and R-chemo up to follow- ments in PFS relative to R-chemo (4-year PFS rate, 78.1% vs. up month 48. A rapid increase in FACT-Lym LYMS was seen 67.2%; hazard ratio 0.73; 95% confidence interval 0.59–0.90; from baseline to the first time point for both G-chemo and R- p = 0.0034) [18]. No new safety signals were identified, with chemo (C3D1, 2.73 vs. 2.04, respectively). The mean change grade 3–5 AEs and serious AEs being more common in pa- from baseline continued to increase at each time point for tients treated with G-chemo versus R-chemo, in line with the FACT-Lym LYMS (Fig. 3a), TOI (Fig. 3b), and TOT primary analysis [10, 18]. (Fig. 3c), up to maintenance month 2, at which point MID was achieved (G-chemo vs. R-chemo, LYMS [≥ 3] 4.52 vs. Questionnaire completion rates 4.80; TOI [≥ 6] 7.17 vs. 6.22; and TOT [≥ 7] 8.13 vs. 8.40, respectively). From maintenance month 2 up to follow-up In the G-chemo and R-chemo arms, 557/601 (92.7%) and month 48, the mean change from baseline scores levelled off 548/601 (91.2%) patients completed all scales of FACT-Lym for all scales (for G-chemo vs. R-chemo, LYMS 4.76 vs. 4.50; assessments at baseline, respectively. Throughout the study, TOI 8.51 vs. 7.23; TOT 9.48 vs. 8.98, respectively). Mean the percentage of patients who completed all scales of FACT- changes from baseline continued to increase up to follow-up Lym was well-balanced between arms. Although completion month 84 in all scales in both arms, excluding the FACT-Lym rates did decline over the course of treatment, low rates of LYMS assessment in patients treated with R-chemo (Online attrition during induction, maintenance, and follow-up (up to Resource: Supplementary Table 3). month 48) were seen (Fig. 1). The proportion of patients com- pleting FACT-Lym assessments decreased beyond this time point, and patient numbers declined substantially up to Clinically meaningful improvement in FACT-Lym follow-up month 84 (Online Resource: Supplementary LYMS subscale and FACT-Lym composite (TOI Table 1). and TOT) scores Absolute and mean change in HRQoL questionnaire Equal proportions of patients in the G-chemo and R-chemo scores from baseline arms achieved MID by the FACT-Lym LYMS score, and the composite scores TOI and TOT, throughout induction, main- Mean baseline values for FACT-Lym composite scores TOI tenance, and follow-up (Fig. 4a, b, and c, respectively). At the and TOT and FACT-Lym LYMS subscale and individual first assessment (C3D1), ≥ 30% of patients evaluated achieved FACT-G subscales (PWB, FWB, EWB, and SWB) were com- MID, with approximately 50% of patients reporting clinically parable across treatment arms (Online Resource: meaningful improvements at maintenance month 2 and con- Supplementary Fig. 2). In both treatment arms, patients exhib- tinuing to respond at follow-up month 48 (G-chemo vs. R- ited some level of baseline impairment according to function- chemo, LYMS, 54.2% vs. 55.5%; TOI, 51.8% vs. 49.7%; ing and lymphoma symptom subscales, noted by mean scores TOT, 49.7% vs. 48.0%, respectively). Results beyond 2840 Ann Hematol (2020) 99:2837–2846 Fig. 1 FACT-Lym questionnaire 100 90 completion data for R-chemo vs. 80 G-chemo. The table below the 70 Patients (%) graph shows the number of 60 patients still receiving treatment 50 who completed all FACT-Lym 40 scales at the specified time point. 30 C, cycle; chemo, chemotherapy; 20 D, day; EOI, end of induction; 10 EOM, end of maintenance; FACT- 0 Baseline C3D1 EOI Maint, Maint, EOM FU, FU, Lym, Functional Assessment of month 2 month 12 month 36 month 48 Cancer Treatment-Lymphoma; No. of patients FU, follow-up; G, obinutuzumab; R-chemo 548 519 486 368 378 389 339 290 G-chemo 557 500 485 401 412 419 386 320 Maint, maintenance; R, rituximab R-chemo G-chemo follow-up month 48 are reported in Online Resource: follow-up, month 48 was the average HRQoL of patients re- Supplementary Table 4. ceiving G-chemo clinically worse than those receiving R-che- mo. Patients in both arms experienced clinically meaningful improvements in FACT-Lym LYMS and in the summary Discussion scales (i.e., TOI and TOT). These results suggest that lymphoma-related symptoms improved in both treatment For first-line patients with FL, treatment with G-chemo results arms to a degree recognizable by patients, subsequently driv- in improved PFS when compared with the current standard- ing improvement in composite summary scales. Importantly, of-care treatment, R-chemo [10, 18]. However, achieving im- this was despite the higher AE rates observed in the G-chemo provements in PROs is just as important as improving clinical arm as reported in both the primary and updated analyses of outcomes such as PFS. In the current analysis of the GALLIUM [10, 18]. GALLIUM study, similar improvements in HRQoL were seen Findings are further supported by the number of patients with G-chemo and R-chemo treatment in patients with FL, reporting clinically meaningful improvements in both treat- with no clear differences between treatment groups reported ment arms, with approximately half having achieved a MID at any time point. Within the context of improved PFS, these by maintenance month 2, sustained up to follow-up month 48. results further support the positive benefit-risk balance of G- When coupled with lack of deterioration in PWB and FWB, chemo over R-chemo in previously untreated patients with these results suggest that improvements in well-being were FL. not abrogated by the increased number of treatment-related In the current study, PWB, FWB, EWB, and SWB scores side effects reported in patients receiving G-chemo versus were similar at baseline, albeit lower than previously reported R-chemo. This is in line with results reported from the values in patients with newly diagnosed active FL. In a study GADOLIN study of patients with relapsed/refractory iNHL, by Pettengell et al. of patients with newly diagnosed active whereby patients treated with G-B had improved HRQoL disease, scores were higher in all FACT-Lym subscales (range scores when compared with those treated with B alone, and 0–8 points) versus those enrolled in GALLIUM [11]. It is benefits in PFS seen with G-B were not abrogated by important to note that some of the active disease-newly diag- treatment-related toxicity [12]. Previously, the majority of pa- nosed group were on a watch and wait strategy, which could tients who survived iNHL still feared the probability of relapse indicate a lower disease burden compared with the patients and second malignancy [19]. Therefore, patients who have enrolled in GALLIUM [11]. A study of HRQoL in long- responded to therapy should still be monitored post-response term survivors of iNHL and aggressive NHL found that, at diagnosis, patients with stage III/IV aggressive NHL had sig- Fig. 2 Mean change from baseline in FACT-G PWB, FWB, EWB, and„ nificantly worse HRQoL than those with stage I/II aggressive SWB, by treatment arm. a PWB, b FWB, c EWB, and d SWB. *Changes or iNHL [19]. These findings demonstrate that first-line pa- of 2–3 points are considered meaningful on the PWB, FWB, and EWB scales. A meaningful change has not yet been defined for the SWB scale. tients with FL may experience an improved HRQoL com- The number of patients still receiving treatment who completed the pared with patients with relapsed disease (although worsened FACT-G questionnaire at the specified time point is specified below the compared with the general population [20]) and support the graph. C, cycle; chemo, chemotherapy; D, day; EOI, end of induction; view that HRQoL differs according to disease state. EOM, end of maintenance; EWB, emotional well-being; FACT-G, Functional Assessment of Cancer Treatment-General; FU, follow-up; Over the course of treatment, similar improvements in FWB, functional well-being; G, obinutuzumab; Maint, maintenance; FACT-Lym composite scores, and thus HRQoL, were ob- MID, minimally important difference; PWB, physical well-being; R, served in both treatment arms. At no time point up to rituximab; SWB, social/family well-being Ann Hematol (2020) 99:2837–2846 2841 2842 Ann Hematol (2020) 99:2837–2846 to ensure improvements in HRQoL are sustained. In the cur- reflect a certain degree of expectation toward treatment out- rent analysis, slight improvements in average scores, though come, which may have impacted patients’ reporting of less than the MID, were seen with PWB, FWB, and EWB HRQoL in either treatment arm. Any influence that knowl- scores, with very small deterioration (approximately − 1 edge of therapy may have had on patient reporting of HRQoL point) seen in the SWB scores, throughout the study period was likely to have resolved over the course of treatment as in both treatment arms. When interpreting these data, it is patients either experienced or did not experience improve- important to consider that GALLIUM was an open-label ments in their condition. study, and patients were aware of their treatment regimen. It At the first time point in the GALLIUM and GADOLIN is possible that the initial post-treatment HRQoL scores may trials (C3D1 and C5D1, respectively), a decline compared Fig. 3 Mean change from baseline in FACT-Lym LYMS, TOI, and TOT scores, by treatment arm. a LYMS, b TOI, and c TOT. The number of patients still receiving treatment who completed the FACT-Lym questionnaire at the specified time point is specified below the graph. C, cycle; chemo, chemotherapy; D, day; EOI, end of induction; EOM, end of maintenance; FACT- Lym, Functional Assessment of Cancer Treatment-Lymphoma; FU, follow-up; G, obinutuzumab; LYMS, lymphoma-specific; Maint, maintenance; MID, minimally important difference; R, rituximab; TOI, trial outcome index; TOT, total Ann Hematol (2020) 99:2837–2846 2843 Fig. 4 Proportion of patients with FL achieving MID on FACT-Lym LYMS score (≥ 3), TOI score (≥ 6), and TOT score (≥ 7). a LYMS (≥ 3), b TOI (≥ 6), and c TOT (≥ 7) score. The number of patients still receiving treatment who achieved MID at the specified time point is specified below the graph. C, cycle; chemo, chemotherapy; D, day; EOI, end of induction; EOM, end of maintenance; FACT-Lym, Functional Assessment of Cancer Treatment-Lymphoma; FL, follicular lymphoma; FU, follow- up; G, obinutuzumab; LYMS, lymphoma-specific; Maint, maintenance; MID, minimally important difference; R, rituximab; TOI, trial outcome index; TOT, total with baseline in both PWB and FWB was reported, with mod- CVP). The results reported here do not address differences est increases reported thereafter [10, 12]. As patients enrolled in HRQoL that may have been seen between chemotherapy in GALLIUM were previously untreated, this decline indi- regimens. Furthermore, patients received either six or eight cates further measures should be taken during early induction cycles of chemotherapy depending on chemotherapy regimen, to ensure the provision of G plus combination therapy does which may also have led to subgroup differences in HRQoL not negatively influence physical and functional well-being. that have not been addressed here. Additionally, there is the In GALLIUM, the chemotherapy regimen was selected possibility that the length of time between assessments may upfront by each participating center, with all patients at the have missed changes that occurred in symptom burden during same center receiving the same regimen (i.e., B, CHOP, or the initial weeks of treatment; a finding that has been noted 2844 Ann Hematol (2020) 99:2837–2846 outside of hematology studies (i.e., non-small-cell lung cancer Compliance with ethical standards during the first week following chemotherapy treatment) [21]. Therefore, the timing of HRQoL assessment should be care- Conflict of interest AD, research funding (Celgene), research support (F. Hoffmann-La Roche Ltd., Gilead/Kite, Takeda, GSK, Karyopharm, fully considered in the design of future trials, as this may Pfizer, Acerta Pharma), advisory board participation (Celgene, F. influence the chances of detecting differences between treat- Hoffmann-La Roche Ltd., Gilead/Kite,Takeda, Karyopharm, Acerta ment regimens. Pharma), honoraria (Celgene, F. Hoffmann-La Roche Ltd., Gilead/Kite, It should be noted that questionnaire completion rates were Takeda, Janssen, Pfizer, Acerta Pharma), and travel to scientific confer- ences (Takeda). PT, employment (Genentech Inc). HQ, research funding high at baseline, and a low rate of attrition was observed (Celgene, Amgen) and advisory board participation (Celgene, Amgen, throughout the study in both treatment arms. This suggests GSK, Karyopharm, Takeda). SR, advisory board participation, speaker that issues with non-compliance should not deter the imple- fees, and honoraria (F. Hoffmann-La Roche Ltd., Takeda, Novartis, mentation of PRO measures in the design of future clinical Gilead, Sandoz). TK, research funding (Chugai, Takeda, Solaisia, Ono, Gilead, MSD, Zenyaku) and personal fees (Chugai, Ono, Gilead, MSD, trials. In addition, the high compliance rates provide confi- Zenyaku, Bristol, Kyowa Kirin, Eisai, Janssen). RP, personal fees (CTI dence in the representativeness of the HRQoL in patients treat- Life Sciences Ltd., Roche, Servier, Takeda) and advisory board partici- ed with G-chemo and R-chemo in the GALLIUM trial. pation (CTI Life Sciences Ltd., G1 Therapeutics Inc., Immune Design, This analysis of the secondary endpoint HRQoL of the Pfizer, F. Hoffmann-La Roche Ltd., Servier, Takeda, TEVA). JMS, hon- oraria (F. Hoffmann-La Roche Ltd., Gilead, Janssen, Celgene, Novartis, GALLIUM study sought to compare changes in HRQoL in Mundipharma, Kern-Pharma, Sanofi) and advisory board participation (F. first-line patients with FL treated with G- or R-based chemo- Hoffmann-La Roche Ltd., Gilead, Janssen, Celgene, Celltrion, Sandoz, therapy. These results demonstrate that aspects of HRQoL and Bristol-Myers Sqibb). MH, honoraria (Novartis, Amgen, F. Hoffmann-La lymphoma symptoms improved over the course of treatment, Roche Ltd) and advisory board participation (Celgene, Takeda). SS, ad- visory board participation (Takeda, NAPP Pharmaceuticals) and personal and there were a high number of patients in both treatment fees (Janssen, Novartis). AK and WL, employment (F. Hoffmann-La arms that experienced a clinically meaningful improvement in Roche Ltd). The remaining authors declare no conflicts of interest. HRQoL. In addition, as PRO scores were similar between arms throughout induction, maintenance, and follow-up, Ethical approval GALLIUM was conducted in accordance with the treatment-related toxicity did not abrogate improvements in Declaration of Helsinki and the International Council for Harmonisation guidelines for Good Clinical Practice. The protocol was approved by the well-being in those patients who did not experience clinically ethics committees of participating centers and is registered at meaningful responses. Furthermore, there was no evidence of ClinicalTrials.gov. cumulative side effects. Both clinical outcomes and PROs should be considered in future clinical trials in patients with Informed consent Informed consent was obtained from all individual FL. participants included in the study. Open Access This article is licensed under a Creative Commons Acknowledgments The authors would like to thank all of the patients Attribution 4.0 International License, which permits use, sharing, who participated in the GALLIUM study, and acknowledge all of the adaptation, distribution and reproduction in any medium or format, as study investigators and their staff as well as the GALLIUM study team. long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if Authors’ contributions Conception and design, AD and PT; Provision of changes were made. The images or other third party material in this article study materials or patients, AD, HQ, TK, JMS, MH, RP, and SS; are included in the article's Creative Commons licence, unless indicated Collection and assembly of data, AD; Data analysis and interpretation, otherwise in a credit line to the material. If material is not included in the AD, PT, HQ, TK, and RP; Manuscript writing, all authors; Final approval article's Creative Commons licence and your intended use is not of manuscript, all authors; Accountable for all aspects of the work, all permitted by statutory regulation or exceeds the permitted use, you will authors. need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Funding information GALLIUM was sponsored by the F. Hoffmann-La Roche Ltd. Third-party medical writing assistance, under the direction of Andrew Davies, was provided by the Russell Craddock and Louise Profit of Gardiner-Caldwell Communications, and was funded by the F. Hoffmann-La Roche Ltd. References Data availability Qualified researchers may request access to individual 1. (1997) A clinical evaluation of the International Lymphoma Study patient level data through the clinical study data request platform (www. Group classification of non-Hodgkin's lymphoma. The Non- clinicalstudydatarequest.com). Further details on Roche’s criteria for Hodgkin's Lymphoma Classification Project. Blood 89(11):3909– eligible studies are available here (https://clinicalstudydatarequest.com/ 3918 Study-Sponsors/Study-Sponsors-Roche.aspx). For further details on 2. Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Roche’s Global Policy on the sharing of clinical information and how Schmits R, Reiser M, Metzner B, Harder H, Hegewisch-Becker S, to request access to related clinical study documents, see here (https:// Fischer T, Kropff M, Reis HE, Freund M, Wormann B, Fuchs R, www.roche.com/research_and_development/who_we_are_how_we_ Planker M, Schimke J, Eimermacher H, Trumper L, Aldaoud A, work/clinical_trials/our_commitment_to_data_sharing.htm). Parwaresch R, Unterhalt M (2005) Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vin- cristine, and prednisone (CHOP) significantly improves the Ann Hematol (2020) 99:2837–2846 2845 outcome for patients with advanced-stage follicular lymphoma Hiddemann W (2017) Obinutuzumab for the first-line treatment of compared with therapy with CHOP alone: results of a prospective follicular lymphoma. New Engl J Med 377(14):1331–1344. https:// randomized study of the German Low-Grade Lymphoma Study doi.org/10.1056/NEJMoa1614598 Group. Blood 106(12):3725–3732. https://doi.org/10.1182/blood- 11. Pettengell R, Donatti C, Hoskin P, Poynton C, Kettle PJ, Hancock 2005-01-0016 B, Johnson S, Dyer MJ, Rule S, Walker M, Wild D (2008) The 3. Marcus R, Imrie K, Solal-Celigny P, Catalano JV, Dmoszynska A, impact of follicular lymphoma on health-related quality of life. Ann Raposo JC, Offner FC, Gomez-Codina J, Belch A, Cunningham D, Oncol : 19(3):570–576. https://doi.org/10.1093/annonc/mdm543 Wassner-Fritsch E, Stein G (2008) Phase III study of R-CVP com- 12. Cheson BD, Trask PC, Gribben JG, Dimier N, Kimby E, pared with cyclophosphamide, vincristine, and prednisone alone in Lugtenburg PJ, Thieblemont C, Wassner-Fritsch E, Launonen A, patients with previously untreated advanced follicular lymphoma. J Sehn LH (2017) Health-related quality of life and symptoms in Clin Oncol : 26(28):4579–4586. https://doi.org/10.1200/jco.2007. patients with rituximab-refractory indolent non-Hodgkin lympho- 13.5376 ma treated in the phase III GADOLIN study with obinutuzumab 4. Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von plus bendamustine versus bendamustine alone. Ann Hematol Grunhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, 96(2):253–259. https://doi.org/10.1007/s00277-016-2878-5 Balser C, Kaiser U, Weidmann E, Durk H, Ballo H, Stauch M, 13. Webster K, Cashy J, Cella D (2005) Measuring quality of life Roller F, Barth J, Hoelzer D, Hinke A, Brugger W (2013) (QOL) in patients with non-Hodgkin's lymphoma (NHL): the Bendamustine plus rituximab versus CHOP plus rituximab as Functional Assessment of Cancer Therapy-LYmphoma (FACT- first-line treatment for patients with indolent and mantle-cell lym- LYM). Qual Life Res 14(9):Abstract 650 phomas: an open-label, multicentre, randomised, phase 3 non- 14. McGlothlin AE, Lewis RJ (2014) Minimal clinically important dif- inferiority trial. Lancet (London, England) 381(9873):1203–1210. ference: defining what really matters to patients. JAMA 312(13): https://doi.org/10.1016/s0140-6736(12)61763-2 1342–1343. https://doi.org/10.1001/jama.2014.13128 5. Salles GA, Seymour JF, Feugier P, Offner F, Lopez-Guillermo A, 15. Harrison CN, Mesa RA, Kiladjian JJ, Al-Ali HK, Gisslinger H, Belada D, Xerri L, Bouabdallah R, Catalano J, Pauline B, Caballero Knoops L, Squier M, Sirulnik A, Mendelson E, Zhou X, Copley- D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, Merriman C, Hunter DS, Levy RS, Cervantes F, Passamonti F, Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Barbui T, Barosi G, Vannucchi AM (2013) Health-related quality Ferme C, Gomes da Silva M, Sebban C, Lister A, Estell JA, of life and symptoms in patients with myelofibrosis treated with Milone G, Sonet A, Coiffier B, Tilly H (2013) Updated 6 year ruxolitinib versus best available therapy. Br J Haematol 162(2): follow-up of the PRIMA study confirms the benefit of 2-year ritux- 229–239. https://doi.org/10.1111/bjh.12375 imab maintenance in follicular lymphoma patients responding to 16. Carter GB, Liepa AM, Zimmermann AH, Morschhauser F (2008) frontline immunochemotherapy. Blood 122(21):509 Validation of the functional assessment of cancer therapy– 6. Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J, lymphoma (FACT-LYM) in patients with relapsed/refractory man- Solal-Celigny P, Offner F, Walewski J, Raposo J, Jack A, Smith P tle cell lymphoma. Blood 112:2376 (2005) CVP chemotherapy plus rituximab compared with CVP as 17. Webster K, Cella D, Yost K (2003) The Functional Assessment of first-line treatment for advanced follicular lymphoma. Blood Chronic Illness Therapy (FACIT) measurement system: properties, 105(4):1417–1423. https://doi.org/10.1182/blood-2004-08-3175 applications, and interpretation. Health Qual Life Outcomes 1:79. 7. Casulo C, Byrtek M, Dawson KL, Zhou X, Farber CM, Flowers https://doi.org/10.1186/1477-7525-1-79 CR, Hainsworth JD, Maurer MJ, Cerhan JR, Link BK, Zelenetz 18. Townsend W, Buske C, Cartron G, Cunningham D, Dyer M, AD, Friedberg JW (2015) Early relapse of follicular lymphoma Gribben JG, Hess G, Ishikawa T, Keller U, Kneba M, Malladi R, after rituximab plus cyclophosphamide, doxorubicin, vincristine, Neidhart JD, Rusconi C, Zhu J, Catalani O, Knapp A, Zeuner H, and prednisone defines patients at high risk for death: an analysis Herold M, Hiddemann W, Marcus R (2018) Obinutuzumab-based from the National LymphoCare Study. J Clin Oncol : 33(23):2516– immunochemotherapy prolongs progression-free survival and time 2522. https://doi.org/10.1200/jco.2014.59.7534 to next anti-lymphoma treatment in patients with previously un- 8. Seymour JF, Marcus R, Davies A, Gallop-Evans E, Grigg A, treated follicular lymphoma: four-year results from the phase III Haynes A, Herold M, Illmer T, Nilsson-Ehle H, Sokler M, GALLIUM study. ASH Annual Meeting: Abstract 1597 Dunzinger U, Nielsen T, Launonen A, Hiddemann W (2018) 19. Kang D, Cho J, Kim IR, Kim MK, Kim WS, Kim SJ (2018) Health- Association of early disease progression and very poor survival in related quality of life in non-Hodgkin lymphoma survivors: a pro- the GALLIUM study in follicular lymphoma: benefit of spective cohort study. Cancer Res Treat : 50(4):1051–1063. https:// obinutuzumab in reducing the rate of early progression. doi.org/10.4143/crt.2017.207 Haematologica. https://doi.org/10.3324/haematol.2018.209015 9. Mossner E, Brunker P, Moser S, Puntener U, Schmidt C, Herter S, 20. Arden-Close E, Pacey A, Eiser C (2010) Health-related quality of Grau R, Gerdes C, Nopora A, van Puijenbroek E, Ferrara C, life in survivors of lymphoma: a systematic review and methodo- Sondermann P, Jager C, Strein P, Fertig G, Friess T, Schull C, logical critique. Leuk Lymphoma 51(4):628–640. https://doi.org/ Bauer S, Dal Porto J, Del Nagro C, Dabbagh K, Dyer MJ, 10.3109/10428191003587263 Poppema S, Klein C, Umana P (2010) Increasing the efficacy of 21. Kristensen A, Solheim TS, Amundsen T, Hjelde HH, Kaasa S, CD20 antibody therapy through the engineering of a new type II Sorhaug S, Gronberg BH (2017) Measurement of health-related anti-CD20 antibody with enhanced direct and immune effector cell- quality of life during chemotherapy - the importance of timing. mediated B-cell cytotoxicity. Blood 115(22):4393–4402. https:// Acta Oncol 56(5):737–745. https://doi.org/10.1080/0284186X. doi.org/10.1182/blood-2009-06-225979 2017.1279748 10. Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Publisher’s note Springer Nature remains neutral with regard to jurisdic- Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, tional claims in published maps and institutional affiliations. 2846 Ann Hematol (2020) 99:2837–2846 Affiliations Andrew Davies 1 & Peter Trask 2 & Judit Demeter 3 & Axel Florschütz 4 & Mathias Hänel 5 & Tomohiro Kinoshita 6 & Ruth Pettengell 7 & Hang Quach 8 & Stephen Robinson 9 & Shalal Sadullah 10 & Juan-Manuel Sancho 11 & Miklos Udvardy 12 & Mathias Witzens-Harig 13 & Andrea Knapp 14 & Wenxin Liu 14 1 8 Cancer Research UK Centre, Centre for Cancer Immunology, University of Melbourne and St. Vincent’s Hospital, Faculty of Medicine, University of Southampton, Southampton Melbourne, Australia General Hospital, Southampton SO16 6YD, UK 9 Bristol Haematology and Oncology Centre, Bristol, UK 2 Genentech Inc., South San Francisco, CA, USA 10 James Paget Hospital, Great Yarmouth, UK 3 Semmelweis University, Budapest, Hungary 11 ICO-IJC-Hospital Germans Trias i Pujol, Barcelona, Spain 4 Städtisches Klinikum Dessau, Dessau-Roßlau, Germany 12 Medical and Health Science Centre, University of Debrecen, 5 Klinikum Chemnitz gGmbH, Chemnitz, Germany Debrecen, Hungary 6 13 Aichi Cancer Center Hospital, Aichi, Japan Uniklinik Heidelberg, Heidelberg, Germany 7 14 St George’s University, London, UK F. 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