PROs vs clinician-reported adverse events in a large clinical trial: findings from the phase 3 POLARIX study.

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most commonly diagnosed form of non-Hodgkin lymphoma and is treated for curative intent. However, the impact of both the disease and the treatment on health-related quality of life (HRQoL) has been understudied. Interpreting HRQoL is further complicated by the variability in symptom presentation and site of disease involvement of DLBCL. Although some individuals may present as asymptomatic, many frequently present with significant symptoms such as enlarged lymph nodes and experience of B symptoms (eg, fever, weight loss, and night sweats). The inconsistency of symptoms at diagnosis adds complexity to discerning the true burden of the disease and the treatment-related effects. Patients with lymphoma often report impaired HRQoL ranging from depleted energy to concerns about infections and ability to enjoy life. 1 Additionally, changes in baseline HRQoL during and after treatment have not been extensively investigated in patients with previously untreated DLBCL, because there are limited dynamic quality of life (QoL) data using patient-reported outcome (PRO) measures over time from large prospective clinical trials in this population. In this context, the patient-reported experience complemented by the clinician-reported experience can provide additional insight into the patient journey with DLBCL, particularly amidst the introduction of novel agents to combination therapy aimed at improving efficacy.

Evaluation of HRQoL through PROs is emerging as a pivotal tool in comprehending the impact of both disease and treatment from the patient perspective. Interestingly, studies in patients with cancer have demonstrated that symptom reporting at baseline is more prevalent when voiced by patients vs when voiced by clinicians. 2 This underscores the importance of incorporating patients’ perspectives in the evaluation and management of cancer, including DLBCL. Such PRO tools can also be helpful in capturing the intensity and impact of symptoms such as fatigue, nausea, vomiting, diarrhea, and constipation. Although PROs offer direct insight into a patient’s experience, patient perceptions of their symptoms may vary significantly, influenced by individual health expectations and experiences. Clinician assessments are essential to contextualize PROs and ensure that clinical decisions are based on comprehensive evaluation. This dual approach is especially important in relation to previously untreated DLBCL, in which treatment decisions may be influenced by nuanced symptom management.

Previous research in a small number of patients with DLBCL (N = 26) treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) as frontline therapy found a temporary decline in physical and role functioning, and an increase in emotional functioning, fatigue, and diarrhea during treatment compared with a healthy reference population. By 3 months after treatment, these symptoms were generally equivalent to those of the reference population, and constipation, nausea, and vomiting were reduced. 3 In a large real-world study, significantly worse HRQoL, including physical function, fatigue, nausea and vomiting, and diarrhea, was observed in patients with DLBCL compared with a general cancer reference population. 4 Furthermore, an international phase 3 study of patients with previously untreated DLBCL (N = 1239) found that pretreatment PROs (European Organization for Research and Treatment of Cancer Quality of Life-Core 30 questionnaire [EORTC QLQ-C30] and the Functional Assessment of Cancer Therapy, Lymphoma lymphoma-specific subscale [FACT-Lym LYMS], physical functioning, QoL, and fatigue) were prognostic for progression-free survival (PFS) and overall survival. 5

Polatuzumab vedotin is an antibody-drug conjugate comprising an anti-CD79b monoclonal antibody 6 and a microtubule inhibitor called monomethyl auristatin E. 7 The phase 3 POLARIX study ( ClinicalTrials.gov identifier: NCT03274492 ) demonstrated superior PFS and a similar safety profile for polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) vs R-CHOP in patients with previously untreated DLBCL. 8 Based on the results from POLARIX, Pola-R-CHP is now approved for the treatment of adult patients with previously untreated DLBCL in a number of countries, including the European Union 9 and the United States. 10

In this analysis, several PROs, including the EORTC QLQ-C30 and FACT-Lym LYMS, were used to investigate the patient perspective of patients with previously untreated DLBCL from POLARIX through their pretreatment, during treatment, and posttreatment journey. Furthermore, the incidence and severity of symptoms by PROs vs clinician-reported adverse events (AEs) were assessed. Here, we report the first analysis of PROs, as well as the comparison of PROs vs clinician-reported AEs, from this large international population of patients with newly diagnosed DLBCL treated with Pola-R-CHP vs R-CHOP therapy.

Methods

Study design

POLARIX is an international phase 3 randomized, double-blind, placebo-controlled study evaluating the efficacy of Pola-R-CHP vs R-CHOP in patients aged 18 to 80 years with previously untreated DLBCL. Details of the trial design and clinical outcomes have been reported previously. 8

PRO assessments

PRO instruments, including the EORTC QLQ-C30 and FACT-Lym, were used to evaluate important disease- and treatment-related symptoms with a recall period of 1 week. Both questionnaires are validated and reliable self-report measures of HRQoL. 11 , 12 , 13

The EORTC QLQ-C30 comprises 30 questions that assess 5 functional scales (physical, role, emotional, cognitive, and social), 3 symptom scales (fatigue, nausea and vomiting, and pain), global health status (GHS)/QoL, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The functional and symptom scales, and single items, are scored on a 4-point scale ranging from “not at all” to “very much,” and the GHS/QoL scale is scored on a 7-point scale ranging from “very poor” to “excellent.” An average raw score is calculated for each scale; all scores are standardized by linear transformation to a metric that ranges from 0 to 100. High-scale scores represent higher response levels (ie, higher [“better”] HRQoL or higher [“worse”] level of symptom severity). 14

The full FACT-Lym scale (42 items) comprises the FACT-G subscale (physical, social/family, emotional, and functional well-being; 27 items) and the lymphoma-specific symptom FACT-Lym LYMS subscale (15 items); patients were asked to complete only the FACT-Lym LYMS subscale. Each item is rated on a 5-point response scale that ranges from “not at all” to “very much,” with higher scores indicating better HRQoL.

The EORTC QLQ-C30 and FACT-Lym LYMS were administered to patients using paper forms at clinic visits on day 1 of cycles 1 (baseline), 2, 3, and 5, at end of treatment (EOT), biannually for 2 years after EOT, and then annually for the following 3 years. PROs were not collected after patients experienced disease progression, death, or discontinued from the study for other reasons.

PRO analyses

The PRO-evaluable population was defined as patients who had a baseline PRO measure (ie, before treatment initiation, cycle 1, day 1) and at least 1 additional measure completed at any day after randomization. The PRO expected population for each visit included the PRO-evaluable population minus those patients who experienced disease progression, death, or discontinued from the study before that study visit. PRO compliance and summary statistics at each assessment time point were estimated. A completed PRO measure was defined as completion of ≥80% of the questions per PRO questionnaire. The PRO completion rate for a study visit was the number of patients with completed PROs for that visit divided by the PRO expected population for that visit.

Mean changes from baseline over time in GHS/QoL, functional scales, fatigue, and lymphoma symptom scores were assessed. The proportion of patients in each arm achieving clinically meaningful improvement in EORTC QLQ-C30 physical functioning and/or fatigue, and the FACT-Lym LYMS lymphoma symptom score, were prespecified secondary end points. The proportion of patients with clinically meaningful improvements, worsening, or no change from baseline for GHS/QoL, physical functioning, role functioning, emotional functioning, cognitive functioning, social functioning, fatigue, and lymphoma symptom scores were reported based on validated thresholds described in Table 1 . 15 Distribution of responses for EORTC QLQ-C30 treatment-related symptoms (constipation, diarrhea, nausea, and vomiting) between the 2 treatment arms was also analyzed.

PRO vs clinician-reported AE assessments

The data collection schedule of symptoms by PROs vs clinician-reported AEs, is described in Figure 1 . PROs included those collected using the EORTC QLQ-C30 questionnaire at previously specified clinic visits until EOT. Clinician-reported AEs were collected during the AE reporting period, which was defined as any new or worsening AEs from the first dose of any study drug until 90 days after the last dose of any study drug, or before new antilymphoma therapy. Clinician-reported AE severity grading was based on the National Cancer Institute common terminology criteria for adverse events (CTCAE) version 4.0. 16

PRO vs clinician-reported analyses

Overall incidence and severity of fatigue, constipation, diarrhea, nausea, and vomiting were recorded by PROs and clinician-reported AEs during the study treatment period. PRO and clinician-reported symptom severity were analyzed separately because these scales were not directly comparable. PRO severity scores included “not at all,” “a little,” “quite a bit,” and “very much,” and were based on the patient’s perspective of their symptom severity ( Table 2 ). 14

Institutional review board approval

This manuscript evaluates HRQoL through PRO instruments to fully characterize the patient experience in the POLARIX study. The protocol was approved by the institutional review board or ethics committee at each participating institution.

Results

PRO-evaluable population and completion rates

In POLARIX, a total of 879 patients were enrolled between 14 November 2017 and 27 June 2019, and randomized 1:1 to receive Pola-R-CHP (n = 440) or R-CHOP (n = 439). 8 Median age was 65 years (range, 18-80), and stratification factors and centrally evaluated subtypes of DLBCL were balanced between the 2 arms. 8 At the clinical cutoff date (28 June 2021), the median duration of follow-up was 28.2 months. 8 Analysis of clinically meaningful differences in PROs was based on the PRO-evaluable population (N = 874). PRO expected rates and reasons for PRO not expected at each assessment time point are provided in Table 3 . Among the patients with expected PROs, the PRO completion rates were high (>90%) in both arms during treatment visits (cycle 1 to EOT) and remained high (>80%) in both arms during follow-up. Over the course of the study, fewer patients remained in the R-CHOP arm relative to the Pola-R-CHP arm, owing to a higher number of study discontinuations and PFS events in the R-CHOP arm.

PROs vs clinician-reported AEs

Symptoms of fatigue, diarrhea, constipation, nausea, and vomiting were reported in higher incidence by PROs compared with clinician-reported AEs ( Figure 2 ). Symptoms of any level of fatigue, constipation, diarrhea, and nausea were reported in >50% of patients. In contrast, many of these symptoms were recorded in <30% of patients by clinician-reported AEs. Most incidences of fatigue, constipation, diarrhea, nausea, and vomiting recorded by PROs were of low severity (ie, scores of “a little”). Similarly, symptoms recorded by clinician reporting were primarily low-grade AEs (ie, grade 1). Higher severity PRO scores of “quite a bit” or “very much” were reported in 33% of patients for fatigue, 29% for constipation, 17% for diarrhea, 19% for nausea, and 7% for vomiting ( Figure 2 ). Higher severity AEs (ie, grade ≥2) were reported in 11% of patients for fatigue, 11% for constipation, 11% for diarrhea, 14% for nausea, and 6% for vomiting ( Figure 2 ).

Gastrointestinal symptoms

Symptoms of diarrhea, constipation, nausea, and vomiting were similar in both treatment arms at baseline. Between cycle 2 and EOT, diarrhea symptoms were more frequently reported in patients treated with Pola-R-CHP (range, 17%-34%) than with R-CHOP (range, 18%-24%; Figure 3 A). Conversely, between cycle 2 and EOT, constipation symptoms were reported more frequently in patients treated with R-CHOP (range, 21%-42%) than with Pola-R-CHP (range, 23%-35%; Figure 3 B). Diarrhea and constipation symptoms returned to baseline or improved from baseline by EOT and were reported at lower rates than baseline after treatment completion. Nausea and vomiting symptoms were reported infrequently in both treatment arms (nausea, 12%-33% with Pola-R-CHP vs 11%-30% with R-CHOP; vomiting, 3%-11% with Pola-R-CHP vs 4%-10% with R-CHOP) and returned to baseline levels at EOT ( Figure 3 C-D).

QoL, functional scales, and fatigue

Baseline scores for GHS/QoL, functional scales (physical, role, emotional, cognitive, and social) and fatigue were similar in both treatment arms ( Figure 4 A-F). During treatment, clinically meaningful improvements were observed in both treatment arms for GHS/QoL; physical, role, emotional, and social functioning; and fatigue ( Figure 5 A-F). These improvements were sustained during treatment and plateaued by the first assessment after EOT. Clinically meaningful improvements from baseline were observed in both treatment arms for physical functioning and fatigue over the course of treatment (physical functioning, 42.4% with Pola-R-CHP vs 39.6% with R-CHOP; and fatigue, 74.8% with Pola-R-CHP vs 68.2% with R-CHOP). Cognitive functioning was similar in both treatment arms and was maintained throughout treatment and follow-up ( Figures 4 G and 5 G).

Lymphoma symptoms

Lymphoma symptom scores were similar in both treatment arms at baseline ( Figure 4 H). Both treatment arms induced a rapid improvement in lymphoma symptom scores in most patients, with >50% achieving a clinically meaningful improvement by cycle 2 ( Figure 5 H). Over the course of the study, clinically meaningful improvement responses were observed in 82.3% of patients receiving Pola-R-CHP and 81.3% of those receiving R-CHOP. Improvements continued during treatment and plateaued by the first assessment after EOT.

Discussion

This analysis of PROs from the phase 3 POLARIX study offers important insight into the patient experience with previously untreated DLBCL from a large international population. Both Pola-R-CHP and R-CHOP treatment regimens led to a rapid and sustained improvement in HRQoL and lymphoma symptoms. Clinically meaningful improvements observed in GHS/QoL, physical functioning, role functioning, emotional functioning, social functioning, fatigue, and lymphoma symptoms were similar across treatment arms. These improvements in functional scales, fatigue, and lymphoma symptoms were generally sustained during treatment and maintained at EOT up to 24 months follow-up, whereas cognitive functioning plateaued and was maintained throughout, providing valuable insight into early survivorship. Symptoms of diarrhea, constipation, nausea, and vomiting were generally similar between treatment arms and returned to baseline levels at EOT. This similarity reflects the generally similar overall safety profiles of Pola-R-CHP and R-CHOP reported in the POLARIX study. 8

When investigating patient vs clinician perspectives, the findings from this analysis of the POLARIX study reveal a noteworthy discordance in symptom reporting between PROs and clinician-reported AEs, not previously reported in the setting of DLBCL. In comparison with clinicians, patients with previously untreated DLBCL undergoing treatment consistently reported a higher incidence of common symptoms including fatigue and gastrointestinal effects. Moreover, despite the use of distinct scales for PROs and clinician-reported AEs, patients described select symptoms with greater severity, indicating a substantial burden on their well-being. This stark contrast in symptom reporting emphasizes the need for tools that can more accurately capture the nuanced patient experience. When considering the integration of PROs and clinician-reported AEs, clinicians should recognize the subjective nature of PROs while providing a balanced assessment that reflects both patient experiences and clinical observations. These data hold significant implications for symptom management strategies, highlighting the importance of thorough physician evaluation and effective communication of symptom experiences by patients. Future exploration into the correlation between PROs and clinician-reported AEs could provide deeper insight into understanding the clinical course of patients with previously untreated DLBCL.

A recent analysis of oncology drug approvals by the US Food and Drug Administration showed that PROs currently do not play a major role in the regulatory review of novel oncology drugs, particularly in hematological malignancies. 17 Our data demonstrate the importance of PROs to truly capture the tolerability of a treatment regimen in the context of lymphoma, and strongly support the longitudinal use of these tools as a critical component to define safety in the context of regulatory approvals. 18 Because PRO measurements are inconsistently used in clinical trials leading to approval of oncology drugs, we advocate for harmonization and standardization of various PRO measurement tools incorporated in prospective clinical trials. 19 Our results may serve as a benchmark for studies in aggressive lymphomas.

Previous studies have investigated changes in HRQoL during lymphoma treatment 3 , 20 , 21 , 22 , 23 , 24 ; however, this study, to our knowledge, is one of the largest investigations to date of HRQoL data from patients with previously untreated DLBCL in the modern era. A small study by Tholstrup et al reported a worsening in GHS/QoL, physical functioning, role functioning, and fatigue during treatment, in contrast to this study’s sustained improvements in these domains. 3 The discrepancy may be attributed to differences in treatment regimens and study designs, including the addition of etoposide in the Tholstrup study, the frequency of treatment administration, and the small sample size. Similar to this study, Tholstrup et al did not observe any direct correlation between treatment and cognitive functioning. Similarly, a study by Oerlemans et al comparing different R-CHOP administration schedules showed variations in HRQoL, attributed to differences in treatment intensity (eg, R-CHOP every 21 days vs every 14 days). 24 The disparity in treatment intensity, differing toxicity profiles of administered agents, and variations in patient populations could contribute to inconsistent results between studies. However, the POLARIX study’s larger study population and randomized design provides robust insights into HRQoL in previously untreated DLBCL.

A recurring trend observed in HRQoL studies, including the present analysis, is an overall improvement in patients’ emotional functioning from baseline. Szeja et al initially identified this trend, observing a higher prevalence of negative emotions in patients during diagnosis, potentially due to uncertainty about their future. 22 They suggested support from friends, family, and medical staff could alleviate these emotions, thus resulting in an improvement in emotional functioning. This trend has also been observed in studies of aggressive lymphoma, 20 , 21 chronic and acute myeloid leukemia, 25 , 26 and multiple myeloma. 27

Strengths of this analysis include the prospective collection of data, the large and diverse global patient population, and the exceptionally high completion rates of PRO assessments throughout the treatment and follow-up periods. In addition, the PRO measurements incorporated, including the EORTC QLQ-C30 and FACT-Lym, provided a comprehensive evaluation of HRQoL and lymphoma symptom burden from a patient’s perspective. Limitations of this analysis include the omission of PRO measurements for patients with disease progression, resulting in the exclusion of subsequent PROs for individuals who had already experienced a PFS event, which occurred more frequently in the R-CHOP arm. Despite this, the PRO compliance rate was similar during the treatment period and slightly higher in the Pola-R-CHP arm at EOT and beyond. Excluding PRO data from patients with disease progression is a limitation of this study, which has 2 potential implications. Firstly, it may contribute to important trends regarding the lived experience of patients with progressive disease to go unnoticed. Secondly, excluding patients with progressive disease reduces the size of the population and may thereby introduce bias into the data. If PRO data from patients with a PFS event had been recorded, a difference between HRQoL in the 2 treatment arms may have been seen. Nonetheless, the findings of this study are noteworthy because they specifically pertain to the lived experience of patients with DLBCL. An additional limitation is the lack of electronic PROs within the study design, the use of which may have provided more flexibility in PRO collection time points on patient-reported symptom changes. Although the 2 PRO instruments used in this study covered a broad range of HRQoL measures, the lack of additional instruments may have limited comprehensive evaluation of HRQoL, including specific measures on fatigue (eg, PROMIS Fatigue 28 ) and frailty (eg, FRAIL 29 ). In addition, the lack of using the PRO-CTCAE measurement tool may have limited the ability to make a closer head-to-head comparison of symptom severity between PROs and clinician-reported AEs, which were assessed using CTCAE. Despite these limitations, the aforementioned strengths of this study represent a robust benchmark for patient-reported HRQoL in frontline DLBCL in the modern era.

In this analysis from the POLARIX study, the Pola-R-CHP regimen demonstrated rapid and sustained improvements in HRQoL in patients with previously untreated DLBCL. Incorporation of PROs into clinical studies, alongside standard clinician-reported AEs, is essential for a comprehensive assessment of treatment efficacy and tolerability, and should be standardized as part of regulatory approvals. These robust data, to our knowledge, the largest in previously untreated DLBCL, underscore the necessity of considering the patient perspective in evaluating the management of DLBCL, and serve as a benchmark for future studies, ultimately leading to more patient-centered and effective care.

Conflict-of-interest disclosure: M.T. reports consultancy for Takeda, Bristol Myers Squibb (BMS), Incyte, AbbVie, Amgen, F. Hoffmann-La Roche Ltd, Gilead Sciences, Janssen, MorphoSys, Novartis, and Zentiva; research funding from F. Hoffmann-La Roche Ltd, Takeda, and Novartis; and honoraria from Takeda, BMS, Incyte, AbbVie, Amgen, F. Hoffmann-La Roche Ltd, Gilead Sciences, Janssen, MorphoSys, Novartis, and Zentiva. F. Morschhauser reports consultancy for F. Hoffmann-La Roche Ltd, Gilead Sciences, and AbbVie and membership on an entity’s board of directors or advisory committees for F. Hoffmann-La Roche Ltd, Gilead Sciences, Novartis, BMS, AbbVie, Genmab, Miltenyi, Allogene Therapeutics, AstraZeneca, and Janssen. G.S. reports consultancy for AbbVie, BeiGene, BMS/Celgene, Epizyme, Genentech, Inc./F. Hoffmann-La Roche Ltd, Genmab, Incyte, Janssen, Kite/Gilead Sciences, Loxo, Miltenyi, Molecular Partners, MorphoSys, Nordic Nanovector, Novartis, RAPT Therapeutics, Takeda, and Debiopharm/VelosBio/Ipsen; stocks/stock options from Owkin; and honoraria from AbbVie, Bayer, Incyte, Kite/Gilead Sciences, MorphoSys, Novartis, and Regeneron. P.M.R. reports consultancy for Kite and Caribou Bio and research funding from Genentech, Inc. and Seagen. M.H. reports advisory and/or honoraria from F. Hoffmann-La Roche Ltd, Takeda, Otsuka, BeiGene, Gilead Sciences, Janssen, Novartis, and Mundipharma. C. Thieblemont is an employee of Hôpital Saint-Louis; reports honoraria from F. Hoffmann-La Roche Ltd, Incyte, Novartis, Kite/Gilead Sciences, Amgen, and Takeda; reports research funding from F. Hoffmann-La Roche Ltd; and reports membership on an entity's board of directors or advisory committees at F. Hoffmann-La Roche Ltd, Incyte, Novartis, Kite/Gilead Sciences, Amgen, and Takeda. G.F. is an employee of Florida Cancer Specialists and reports honoraria from MorphoSys, Pfizer, and Amgen. B.H. reports membership on an entity's board of directors or advisory committees at BeiGene, Incyte, and ADC Therapeutics. W.S.K. reports research funding from Sanofi, BeiGene, Boryung, F. Hoffmann-La Roche Ltd, Kyowa Kirin, and Dong-A. M.M. reports a speakers bureau role at Gilead Sciences, Novartis, Takeda, and F. Hoffmann-La Roche Ltd and membership on an entity’s board of directors or advisory committees for Gilead Sciences, Novartis, Takeda, F. Hoffmann-La Roche Ltd, Eusapharma, Sandoz, and Celgene. A.M. is an employee of the University of Alabama at Birmingham; reports consultancy for Gilead Sciences, AstraZeneca, Pharmacyclics, Seagen, Incyte, MorphoSys/Incyte, TG Therapeutics, Kyowa Kirin, Novartis, BMS, and BeiGene; reports research funding from Incyte, Takeda, Forty Seven Inc/Gilead Sciences, Juno Pharmaceuticals/BMS, Celgene/BMS, Innate Pharmaceuticals, Seagen, TG Therapeutics, Affimed, Merck, Kite/Gilead Sciences, F. Hoffmann-La Roche Ltd/Genentech, Inc., and I-MAB; and reports a speakers bureau role with Gilead Sciences, AstraZeneca, Pharmacyclics, Seagen, Incyte, MorphoSys/Incyte, Kyowa Kirin, BMS, and BeiGene. A.S. and M.Y. are employees of, and equity holders at, F. Hoffmann-La Roche Ltd/Genentech, Inc. J.H. was an employee of Genentech, Inc. during the conduct of the study and reports stocks at F. Hoffmann-La Roche Ltd. M.S. is an employee of, and equity holder at, Genentech, Inc. C.L. was an employee of Genentech, Inc. during the conduct of the study and reports equity from F. Hoffmann-La Roche Ltd. J.P.S. reports honoraria from Pharmacyclics LLC (an AbbVie Company), ADC Therapeutics, Lilly, AstraZeneca, BeiGene, and AbbVie; reports research funding from AbbVie, AstraZeneca, ADC Therapeutics, BeiGene, BMS, Lilly, and TG Therapeutics; reports consultancy for ADC Therapeutics, Araris Biotech AG, Lilly, Merck, TG Therapeutics, AstraZeneca, Genentech, Inc., BMS, BeiGene, and AbbVie; and is a current holder of stock options in a privately held company and reports membership on an entity's board of directors or advisory committees for Araris Biotech AG. N.M.-S. reports a consulting or advisory role at Acrotech, Autolus, Ono Pharmaceuticals, Kyowa Kirin Secura Bio, AstraZeneca, Genentech, Inc./Hoffmann-La Roche AG, Janssen, and Pfizer and reports research funding from BMS, Genentech, Inc./F. Hoffmann-La Roche Ltd, Celgene, Verastem, Innate Pharma, Corvus Pharmaceuticals, AstraZeneca, MorphoSys, C4 Therapeutics, Daiichi Sankyo, Yingli Pharma, Dizal Pharma, and the Leukemia Lymphoma Society (scholar in clinical research). C.R.F. reports a consulting or advisory role at Bayer, Gilead Sciences, Spectrum Pharmaceuticals, AbbVie, Celgene, BeiGene, Denovo Biopharma, Karyopharm Therapeutics, Pharmacyclics/Janssen, Genentech, Inc,/F. Hoffmann-La Roche Ltd, Epizyme, Genmab, Seagen, Foresight Diagnostics, BMS/Celgene, Curio Science, AstraZeneca, and MorphoSys; reports stock and other ownership interests at Foresight Diagnostics and N Power; and reports research funding from Acerta Pharma, Janssen Oncology, Gilead Sciences, Celgene, TG Therapeutics, Genentech, Inc./F. Hoffmann-La Roche Ltd, Pharmacyclics, AbbVie, Millennium, Alimera Sciences, Xencor, 4D Pharma, Adaptimmune, Amgen, Bayer, Cellectis, EMD Serono, Guardant Health, Iovance Biotherapeutics, Kite/Gilead Sciences, MorphoSys, Nektar, Novartis, Pfizer, Sanofi, Takeda, and Ziopharm Oncology. H.T. reports a consulting or advisory role at F. Hoffmann-La Roche Ltd, Incyte, Celgene/BMS, and ADC Therapeutics; reports travel, accommodations, or expenses funding from Janssen and Gilead Sciences; reports honoraria from BMS and F. Hoffmann-La Roche Ltd; and reports research funding from F. Hoffmann-La Roche Ltd/Genentech, Inc. N.C. reports a consultancy or advisory role at Bayer, Amgen, Merck, F. Hoffmann-La Roche Ltd (Canada), Seagen, and Incyte; reports honoraria from AbbVie; and reports research funding from F. Hoffmann-La Roche Ltd/Genentech, Inc. T.M.K. reports consulting or advisory roles at Amgen, AstraZeneca/MedImmune, Boryung, Daiichi-Sankyo, HK inno.N, IMBdx, Inc, Janssen, Novartis, Regeneron, F. Hoffmann-La Roche Ltd/Genentech, Inc., Samsung Bioepis, Takeda, and Yuhan. The remaining authors declare no competing financial interests.

Acknowledgments

The authors acknowledge Piotr Smolewski’s and Veronica Craine's contributions to this research.

The POLARIX study ( ClinicalTrials.gov identifier: NCT03274492 ) was sponsored by F. Hoffmann-La Roche Ltd and Genentech, Inc. Third-party editorial assistance, under the direction of the authors, was provided by Jonike Dreyer of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann-La Roche Ltd.

Authorship

Contribution: All authors reviewed the data, confirmed the completeness and accuracy of the results and the study’s fidelity to the protocol and statistical analysis plan, reviewed the manuscript, and agreed on its submission for publication.

Footnotes

Presented, in part, at the 64th annual meeting of the American Society for Hematology, New Orleans, LA, 10 to 13 December 2022.

For eligible studies, qualified researchers may request access to individual patient–level clinical data through a data request platform. At the time of writing this request, the platform is Vivli ( https://vivli.org/ourmember/roche/ ). For up-to-date details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here: https://go.roche.com/data_sharing . Anonymized records for individual patients across >1 data source external to Roche cannot, and should not, be linked because of a potential increase in risk of patient reidentification.

There is a Blood Commentary on this article in this issue.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

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