Prognostic value of patient-reported outcome thresholds on survival and adverse events in CLL/SLL: A pooled analysis of ibrutinib trials.

Introduction

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are indolent B-cell malignancies characterized by the clonal proliferation and accumulation of mature lymphocytes. 1 Over the past decade, the treatment landscape of CLL/SLL has been transformed with the introduction of Bruton tyrosine kinase inhibitors, such as ibrutinib, which have significantly improved patient outcomes and prolonged survival. 2 – 5 However, as CLL/SLL transitions into a chronic, manageable condition, new challenges have emerged, including the long-term burden of treatment-related toxicities, persistent disease-related symptoms, and psychosocial distress. 4 , 6 , 7 These factors underscore the need for a comprehensive, patient-centered approach that integrates both clinical and patient-reported outcomes (PROs) to optimize disease management and survivorship care.

Patient-reported outcomes (PROs) are self-reported measures that capture patient perception of health status, including physical, emotional, cognitive, and social well-being. 8 , 9 Unlike clinician-reported toxicities, PROs provide a direct, complementary, patient-centered account of how treatment and disease progression affect daily life, particularly for symptoms and functional impairments that may be underrecognized in clinical assessments. 10 In oncology, growing evidence supports the prognostic and predictive value of PROs, demonstrating their association with key clinical outcomes such as treatment response, toxicity burden, survival, and quality of life (QoL). 11 – 17 In a population-based real-world analysis of the PROFILES registry, Husson et al. demonstrated that the EORTC QLQ-C30 summary score was independently associated with all-cause mortality across several cancer populations, including chronic lymphocytic leukemia, and showed stronger prognostic value than global QoL or physical functioning alone. 18 Furthermore, routine collection and monitoring of PROs have been shown to facilitate early symptom detection, improve symptom control, enhance patient-clinician communication, and even extend survival in patients with advanced cancers. 19

Despite these benefits, the widespread adoption of PROs in routine oncology practice remains slow. 20 , 21 Key barriers include a lack of standardized interpretation frameworks, time constraints for both patients and clinicians, and challenges in integrating PRO data into clinical decision-making. 20 , 21 To address these challenges, the European Organization for Research and Treatment of Cancer (EORTC) has developed thresholds for clinical importance for the Quality of Life Questionnaire Core 30 (QLQ-C30), the most widely used PRO instrument in cancer trials and research. 22 , 23 These thresholds provide a standardized approach for identifying patients experiencing clinically significant functional impairments or symptom burdens, thereby improving the interpretability and clinical applicability of PRO data. 19 , 24 However, these thresholds have primarily been developed and validated in heterogeneous cancer populations with limited exploration in patients with hematologic malignancies such as CLL/SLL. 23 In parallel, the EORTC has recently developed and internationally validated the QLQ-CLL17, a CLL-specific module designed to supplement the QLQ-C30 and capture CLL-relevant domains, including symptom burden, physical condition/fatigue, and worries/fears about health and functioning. Together, these efforts highlight the growing importance of disease-relevant and clinically interpretable PRO assessment in CLL/SLL. 25

Given the increasing reliance on targeted therapies such as ibrutinib for CLL/SLL treatment, there is a critical need to assess the clinical utility of PRO-based thresholds in this patient population. Specifically, understanding how PRO-defined symptom burden correlates with key treatment outcomes—including overall survival (OS), progression-free survival (PFS), and the incidence of high-grade adverse events (AEs)—can provide actionable insights to refine treatment strategies and enhance patient care. 11 – 14

This study aimed to evaluate the clinical relevance of PRO thresholds in CLL/SLL by analyzing pooled data from three clinical trials of ibrutinib-based therapies. The primary objective was to determine the frequency of CLL/SLL patients reporting PRO impairments that met EORTC thresholds for clinical importance at baseline. The secondary objective was to investigate the associations between these PRO domains and key treatment outcomes, including OS, PFS, and incidence of grade ≥3 AEs.

Methods

Patient population

Individual patient data were pooled from three randomized clinical trials: RESONATE ( NCT01578707 , data cut-off: November 27, 2018), 26 RESONATE-2 ( NCT01722487 , data cut-off: May 4, 2015), 27 and HELIOS ( NCT01611090 , data cut-off: January 23, 2019). 28 Eligible participants in the source trials were adults with a diagnosis of CLL or SLL requiring treatment according to trial-specific criteria. RESONATE enrolled patients with relapsed or refractory CLL/SLL who had received at least one prior therapy and compared ibrutinib with ofatumumab. RESONATE-2 enrolled treatment-naïve patients aged ≥65 years with CLL/SLL and compared ibrutinib with chlorambucil. HELIOS enrolled patients with relapsed or refractory CLL/SLL and compared ibrutinib plus bendamustine and rituximab with placebo plus bendamustine and rituximab. Patients were included in the present pooled analysis if they were randomized in one of the three trials and had available baseline EORTC QLQ-C30 data and relevant clinical outcome data. Patients were excluded from the relevant analyses if baseline PRO data, outcome data, or covariate data required for the corresponding model were unavailable. Details of patient populations, administered treatments, and trial-specific eligibility criteria are provided in the Supplementary Materials and original trial publications.

All trials conformed to the guidelines outlined by the International Conference on Harmonization for Good Clinical Practice and the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants. The secondary analysis of de-identified data presented in this study was approved by the University of Sharjah Ethics Committee (Approval reference number: REC-23-11-07-01-F). Data access followed Pharmacyclics policy through The YODA Project ( https://yoda.yale.edu/ ). The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. 29

Clinical outcomes and definitions

Across all trials, OS was defined as the time from randomization to death from any cause. PFS was defined as the time from patient randomization to either disease progression —assessed by an Independent Review Committee (IRC) according to the International Workshop on CLL (IWCLL) criteria (with clarification for treatment-related lymphocytosis)—or death, whichever occurred first. Event censorings occurred at the last known follow-up date. Grade ≥3 adverse events of any cause were classified in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0.

Patient-reported outcomes

Across all three trials, PRO data were collected using the EORTC QLQ-C30 version 3.0. Baseline (pre-treatment) data were assessed in this study. The QLQ-C30 consists of 30 items grouped into 15 domains. These include five functional domains (physical, role, emotional, cognitive, and social functioning), three symptom domains (fatigue, nausea and vomiting, and pain), a global health status/QoL domain, and six single items symptom scales (dyspnoea, appetite loss, insomnia, constipation, diarrhea, and financial difficulties). Responses were scored and linearly transformed to a standardized 0–100 scale, following the EORTC scoring manual. Higher scores on functional and global health scales indicate better functioning/QoL, while higher scores on symptom and financial difficulty scales indicate greater symptom burden.

Within this study, PRO domains were classified as “clinically important” if they met the EORTC-defined threshold for clinical importance in the direction of impairment. 19 EORTC-defined thresholds were selected rather than study-specific median cut-offs because they are clinically anchored to functional impairments and symptom burdens considered relevant to clinical encounters, whereas median splits are sample-dependent and may not correspond to clinically meaningful impairment. Specifically, functional domains were considered clinically important when scores fell below the threshold, while symptom and financial difficulty domains were considered clinically important when scores exceeded the threshold, indicating greater burden. Table S1 details the thresholds used in the study to define clinically important PRO domains.

Statistical analysis

Descriptive statistics were used to summarize the frequency of clinically important pre-treatment PRO domains across the pooled cohort. Cox modeling was utilized to examine the association between the number of clinically important pre-treatment PRO domains with OS, PFS, and grade ≥ 3 adverse events. The number of clinically important PRO domains was first evaluated as a continuous variable. Exploratory analyses then assessed clinically interpretable PRO burden categories (0, 1–4, and ≥5 domains), based on observed hazard-ratio patterns across increasing PRO burden, as well as the associations between individual clinically important PRO domains and treatment outcomes. Additional exploratory subgroup analyses were conducted by treatment setting, comparing treatment-naïve patients from RESONATE-2 with relapsed/refractory patients from RESONATE and HELIOS combined, to evaluate whether associations between baseline PRO burden and OS, PFS, and grade ≥3 adverse events were consistent across disease settings. All analyses were conducted using R version 4.0. Detailed statistical methods are provided in the Data Supplement.

Results

Patient population

Individual patient data from a total of 1,238 patients were pooled across three clinical trials. Among these patients, 1,136 (92%) were diagnosed with CLL, and 102 (8%) patients with SLL. A total of 889 (72%) patients experienced at least one grade ≥3 adverse event, and the median comorbidity count was 7 (IQR: 4–12). Bulky disease (≥5 cm) was reported in 52% of patients overall but was less common in RESONATE-2 (35%) than in RESONATE and HELIOS (56–57%). A summary of patient baseline characteristics stratified by study is presented in Table S2 .

The median follow-up time for the pooled cohort was 62.2 months for OS and 19.8 months for PFS. Study-specific follow-up times for OS were 65.4 months (RESONATE), 18.4 months (RESONATE-2), and 63.7 months (HELIOS). Median PFS follow-up times were 64.9, 18.3, and 17.7 months, respectively. Baseline PRO scores, including median and IQR values, are presented in Table S3 . All PRO domains had less than 10% missing data in the pooled cohort at baseline.

Clinically important pre-treatment PRO domains

The frequencies of clinically important pre-treatment PRO domains for each individual domain across the pooled cohort are presented in Table 1 and the distribution of patients by the total number of clinically important pre-treatment PRO domains is shown in Table 2 . Across the pooled cohort, 920 (74%) patients reported at least one clinically important PRO domain, while 395 (32%) reported five or more.

The most frequently observed clinically important PRO domains were physical function (n = 570; 46%), dyspnoea (n = 547; 44%), social function (n = 413; 33%), fatigue (n = 381; 31%), and financial difficulty (n = 371; 30%) ( Table 1 ). These individual domain impairments contribute to the overall cumulative PRO burden, which was categorized into three groups based on the total number of clinically important PRO domains: 0, 1–4, and ≥5. In this stratification, 201 patients (16%) had no clinically important PRO domains, 525 (42%) had 1–4, and 395 (32%) had ≥5 ( Table 2 ).

Across the individual trials, patients in RESONATE exhibited a significantly higher prevalence of clinically important PRO thresholds across several PRO domains, including role function (n = 89; 23%), social function (n = 159; 41%), appetite loss (n = 44; 11%), and diarrhoea (n = 90; 23%), compared to the RESONATE 2 and HELIOS trials. This elevated impairment burden in RESONATE was further reflected in the greater cumulative number of clinically important PRO domains, with a median (IQR) of 3 (1–7), and a higher proportion of patients (n = 136; 35%) reporting ≥5 clinically important PRO domains.

Table S4 presents the baseline clinical and demographic characteristics for patients by PRO group. Patients with ≥5 clinically important domains were significantly more likely to have an ECOG performance status ≥1, a higher comorbidity burden, and a greater incidence of grade ≥3 adverse events compared to those with 0 or 1–4 clinically important domains (all P < 0.001).

Associations of clinically important PRO domains with OS, PFS, and adverse events

Tables 3 and 4 present the associations between the number clinically important PRO domains and OS, PFS, and grade ≥ 3 adverse events.

When evaluated as a continuous variable, each additional clinically important domain was independently associated with worse OS (HR 1.07; 95% CI: 1.04–1.11; P < 0.001), worse PFS (HR 1.03; 95% CI: 1.00–1.06; P = 0.047), and increased risk of grade ≥3 adverse events (HR 1.03; 95% CI: 1.01–1.06; P = 0.006) after adjusting for baseline clinical covariates. No significant heterogeneity was observed in the identified associations between study cohorts ( Figure S1 ).

Categorical analyses of cumulative PRO burden further demonstrated a graded statistically significant associations with clinical outcomes. Compared to patients with no clinically important PRO domains at baseline, those with 1–4 domains had a significantly higher risk of death (HR 1.50; 95% CI: 1.05–2.15; P = 0.027), while patients with ≥5 domains had a more than twofold increased risk (HR 2.04; 95% CI: 1.42–2.94; P < 0.001). For PFS, the hazard was significantly elevated only in the ≥5 group (HR 1.31; 95% CI: 1.01–1.69; P = 0.043), but not for those with 1–4 domains (HR 1.17; 95% CI: 0.92–1.50; P = 0.214). Similarly, patients with ≥5 clinically important domains had an increased risk of grade ≥3 adverse events (HR 1.47; 95% CI: 1.17–1.85; P < 0.001), while those with 1–4 domains had a moderately increased risk (HR 1.35; 95% CI: 1.09–1.67; P = 0.006), compared with patients with no important PRO domains. Univariable analyses yielded comparable findings ( Tables 3 and 4 ). Figure 1 visualizes the relationship between the categories of clinically important PRO domains and treatment outcomes.

Table 5 summarizes the adjusted associations between individual clinically important PRO domains and clinical outcomes. Physical function was the strongest independent prognostic domain for OS, with patients reporting clinically important baseline scores experiencing significantly worse OS (HR 1.73; 95% CI: 1.38–2.18; P < 0.001) and a higher incidence of grade ≥3 adverse events (HR 1.36; 95% CI: 1.17–1.58; P < 0.001). Other domains independently associated with worse OS included pain, appetite loss, role function, fatigue, constipation, social function, and dyspnoea (all P < 0.05). For PFS, only pain (HR 1.24; 95% CI: 1.02–1.50; P = 0.027) and constipation (HR 1.59; 95% CI: 1.16–2.18; P = 0.004) remained statistically significant in adjusted analyses.

C-statistics (Harrell’s C-indices) for OS models ranged from 0.61 to 0.63, with physical function demonstrating the highest improvement in model discrimination performance (C = 0.63). In contrast, emotional function, cognitive function, and financial difficulty were not significantly associated with OS, PFS, or adverse events. These findings suggest that impairments in physical and role functioning, fatigue, and selected symptom domains, rather than psychosocial or financial aspects, may be the key drivers of the observed associations between pre-treatment PRO burden and clinical outcomes. The corresponding univariable associations of the individual PRO domains are provided in Table S5 .

Exploratory subgroup analyses stratified by treatment setting are presented in Supplementary Table 6 . In the relapsed/refractory cohort, which included patients from RESONATE and HELIOS, each additional clinically important PRO domain was associated with worse OS (HR 1.07; 95% CI: 1.04–1.11; P < 0.001), worse PFS (HR 1.03; 95% CI: 1.00–1.06; P = 0.031), and increased risk of grade ≥3 adverse events (HR 1.03; 95% CI: 1.01–1.06; P = 0.008). In contrast, no significant associations were observed in the treatment-naïve RESONATE-2 cohort for OS (HR 1.00; 95% CI: 0.85–1.17; P = 0.952), PFS (HR 0.99; 95% CI: 0.91–1.08; P = 0.857), or grade ≥3 adverse events (HR 1.01; 95% CI: 0.94–1.10; P = 0.741).

Discussion

This study is the first to comprehensively evaluate the prevalence and clinical implications of clinically important PRO domains, as defined by thresholds for clinical importance from the EORTC QLQ-C30, in patients with CLL/SLL initiating contemporary therapies. While prior real-world evidence has shown that EORTC QLQ-C30 summary, global QoL, and physical functioning scores are prognostic for survival in cancer populations that included CLL, 18 our study is, to our knowledge, the first to apply EORTC-defined thresholds for clinical importance to characterize cumulative baseline PRO burden and evaluate its associations with OS, PFS, and grade ≥3 adverse events in CLL/SLL patients treated in randomized ibrutinib trials. Physical function was the most prognostic individual domain for OS, and the most frequently reported clinically important PRO domains were physical function (46%), dyspnoea (44%), social function (33%), fatigue (31%), and financial difficulty (30%). These findings highlight the substantial burden of impaired QoL in CLL/SLL and its relevance to patient outcomes, thereby positioning PRO thresholds as practical prognostic tools to augment conventional clinical assessments.

Accumulating literature has highlighted the benefits of systematic PRO monitoring in cancer care, including for improved symptom control, earlier identification of unmet needs, better treatment adherence, and enhanced patient satisfaction and QoL. 9 , 30 – 33 However, the integration of PROs in clinical practice remains underutilized, 34 in part due to barriers related to score interpretability and clinical actionability. 22 , 35 For instance, a mixed-methods study highlighted clinicians’ challenges in interpreting PRO scores due to inconsistent scaling and formatting. 36 Therefore, the evaluation of the established thresholds for clinical importance by the EORTC Quality of Life Group across various cancer populations represents an important step toward improving the interpretability and facilitating the implementation of validated PRO measures in clinical practice.

The application of clinically relevant PRO thresholds is particularly relevant in CLL/SLL patients as they often experience significant frailty and impaired QoL, driven by age-related physiological changes, comorbid conditions, and the direct impact of the malignancy itself. 6 , 37 , 38 Despite this, most PRO data in CLL/SLL have been limited to secondary endpoints in trials, with few efforts aimed at identifying domain-specific impairments or linking PROs to survival and toxicity outcomes. 6 This study addresses this gap by being the first to quantify the prevalence and burden of clinically important PRO domains in CLL/SLL in the context of QLQ-C30, thereby enhancing the understanding of unmet patient needs and reinforcing PROs as clinically actionable tools for guiding treatment decisions. Notably, 74% of patients reported at least one clinically important PRO domain, with physical functioning being the most commonly impaired. These findings emphasize the value of integrating PRO data into clinical risk stratification and the need for interventions that address function and symptom burden alongside disease control. 39

In addition to quantifying the cumulative burden of clinically important PRO domains across the pooled cohort, this analysis revealed insights into the variability in PRO impairments across distinct CLL patient populations. Across the three trials, RESONATE demonstrated a higher prevalence of clinically important PRO domains, particularly in role and social functioning, as well as symptom domains like appetite loss and diarrhoea, compared to RESONATE 2 and HELIOS. These differences may be partially explained by variations in patient characteristics and disease settings across the trials. For instance, RESONATE 2 enrolled treatment-naïve CLL patients, who typically exhibit better clinical outcomes than relapsed/refractory populations. 40 Furthermore, while both HELIOS and RESONATE focused on relapsed/refractory CLL, RESONATE included patients with advanced age, a higher burden of comorbidities, and the presence of high-risk genetic features (del 17p), which are all factors associated with rapid disease progression and poor prognosis, potentially reflecting on QoL outcomes. 41 – 43 These findings underscore that the heterogeneity of CLL is reflected not only in clinical and biological characteristics, 44 but in QoL and PRO domains, highlighting the value of integrating PROs into routine assessment to support more individualized and patient-centered care. Exploratory subgroup analyses by treatment setting further suggested that the prognostic and toxicity-related relevance of cumulative PRO burden was primarily observed in the relapsed/refractory cohort, comprising RESONATE and HELIOS. In contrast, no significant associations were observed in the treatment-naïve RESONATE-2 cohort, although these estimates should be interpreted cautiously given the smaller sample size and fewer outcome events.

Various studies have identified PRO domains such as physical function and global health status as independent prognostic factors for OS and PFS across cancers such as breast cancer, 13 , 45 multiple myeloma, 17 urothelial carcinoma, 14 and lung cancer. 13 , 45 , 46 Systematic reviews further report that ≥90% of cancer studies identify at least one PRO domain as prognostic of survival outcomes. 16 , 47 Our findings extend this established prognostic value to EORTC-developed clinical thresholds of PRO impairment, demonstrating that each additional clinically important domain was associated with worsening OS, PFS and grade ≥3 adverse events. Further, when patients were stratified by cumulative PRO burden, those with ≥5 clinically important domains had significantly worse OS and increased toxicity, as well as a modest but statistically significant increase in PFS hazard, compared to those with no clinically important domains. Patients with 1–4 domains had intermediate risk, with significantly worse OS and AEs but no significant difference in PFS. These results support a broader application of PRO thresholds beyond individual domains to characterize the cumulative burden of symptom and function impairment, enabling more precise risk stratification and proactive intervention for patients with high symptom load.

Consistent with our findings, a growing body of literature has highlighted pre-treatment PROs—particularly physical and role functioning, fatigue, and select symptom domains—as independent prognostic factors for survival and adverse event outcomes across solid tumors and hematologic malignancies. 13 , 14 , 17 , 45 , 46 Among these PROs, physical functioning consistently emerged as the strongest prognostic indicator. Our study extends this evidence to the CLL/SLL setting, showing that poor baseline physical function was independently associated with worse OS and a higher risk of grade ≥3 adverse events, and demonstrated the highest improvement in the OS model discriminative performance (C = 0.63). These findings are aligned with prior research in CLL emphasizing the clinical impact of frailty and functional decline, and the potential for QoL gains through interventions that improve physical function. 48 , 49 Notably, psychosocial and financial domains—including emotional function, cognitive function, and financial difficulty—were not significantly associated with any clinical outcomes in our cohort. This underscores the relative importance of functional and symptom-related domains over psychosocial aspects in identifying patients at elevated risk of poor outcomes.

Patients with CLL/SLL frequently experience disease- or treatment-related symptoms, underscoring the need for effective symptom management through supportive care to improve patient outcomes. 4 , 8 , 50 However, research indicates a discrepancy between symptom recognition by clinicians and patients, with healthcare providers often underestimating both the presence and severity of symptoms. 51 This suboptimal symptom detection can lead to ineffective management, ultimately affecting treatment outcomes and QoL. 50 Consequently, identifying predictive measures for grade ≥3 adverse events is essential for implementing preventative strategies to mitigate symptom burden in CLL/SLL patients. Our results demonstrate a stepwise increase in the risk of grade ≥3 adverse events with greater baseline PRO burden, suggesting that these thresholds may serve as early warning indicators. Consistent with our results, prior studies have reported associations between specific PRO domains and incidence of grade ≥3 adverse events. 17 , 52 Moreover, accumulating evidence supports the incorporation of PROs for symptom monitoring, demonstrating benefits such as decreased emergency room visits, a reduced incidence of serious adverse events, and higher quality of life. 32 , 50

Limitations

This study has several limitations. First, the generalizability of the findings to real-world populations may be constrained by the eligibility criteria applied in the included randomized clinical trials. In particular, these trials predominantly enrolled patients with ECOG PS 0–1 and therefore underrepresent patients with poorer performance status, including ECOG PS ≥2. This may limit the applicability of our findings to patients with greater functional impairment or frailty, a group in whom CLL-specific PRO instruments such as the EORTC QLQ-CLL17 may be especially informative. Second, molecular prognostic markers, such as IGHV and TP53 mutation status, were unavailable and could not be adjusted for in the models. Third, although baseline PRO missingness was less than 10% across domains in the pooled cohort, complete-case analyses may introduce bias if missingness was not random. Fourth, no formal a priori power analysis was performed, as the study sample was determined by the availability of eligible participants and data from the included completed clinical trials. Finally, as this was a retrospective secondary analysis, the observed associations should not be interpreted as causal and require prospective validation. Despite these limitations, notable strengths of this study include the large pooled dataset (n = 1,238), the inclusion of both treatment-naïve and relapsed/refractory patients from three high-quality randomized trials (RESONATE, RESONATE-2, and HELIOS), and the use of validated, standardized thresholds for PRO interpretation, which together enhance the robustness and clinical relevance of the findings.

Conclusion

This study demonstrates the clinical utility of EORTC QLQ-C30 thresholds for identifying CLL/SLL patients at risk of unfavorable clinical outcomes based on their baseline PRO profile. A higher burden of clinically important PRO domains was independently associated with worse survival and increased toxicity. These findings highlight the potential of cumulative PRO impairment as a clinically actionable metric that may support earlier identification of high-risk patients, individualized treatment planning, and better alignment between therapeutic goals and patients’ functional and symptom burden. Future prospective studies are warranted to validate these findings and evaluate how PRO burden can be integrated with clinical and molecular risk factors to improve risk stratification and patient-centered care in CLL/SLL.

Supplemental material

Supplemental material - Prognostic value of patient-reported outcome thresholds on survival and adverse events in CLL/SLL: A pooled analysis of ibrutinib trials

Supplemental material for Prognostic value of patient-reported outcome thresholds on survival and adverse events in CLL/SLL: A pooled analysis of ibrutinib trials by Ahmad Y. Abuhelwa, Sara A. Almansour, Humaid O. Al-Shamsi, Ziad Abuhelwa, Mohamad A Ziade, Yasser Bustanji, Mohammad H. Semreen, Mohammad A. Y. Alqudah, Ross A. McKinnon, Karem H Alzoubi, Michael J. Sorich, and Ashley M. Hopkins in Therapeutic Advances in Hematology.

Acknowledgments

This study, carried out under YODA Project 2022-5066, used data obtained from the Yale University Open Data Access Project, which has an agreement with JANSSEN RESEARCH & DEVELOPMENT, L.L.C.. The interpretation and reporting of research using this data are solely the responsibility of the authors and does not necessarily represent the official views of the Yale University Open Data Access Project or JANSSEN RESEARCH & DEVELOPMENT, L.L.C..

Author contributions: A.Y.A. and A.M.H. contributed to the conception and design of the study. A.Y.A. and A.M.H. contributed to the development of the methodology. A.Y.A. acquired the data. A.Y.A., S.A.A., H.O.A., Z.A., C.A.Z., Y.B., M.H.S., M.A.Y.A., R.A.M., K.H.A., M.J.S., and A.M.H. contributed to data analysis, interpretation of results, and/or critical review of the findings. A.Y.A. and S.A.A. drafted the initial manuscript. All authors contributed to writing, review, and/or revision of the manuscript. A.Y.A. provided administrative, technical, or material support. A.Y.A. supervised the study. All authors read and approved the final version of the manuscript.

Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the University of Sharjah Targeted Research Grant No. 2301110392 and publication support from Burjeel Cancer Institute, Abu Dhabi. .

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: HOA is on the advisory board of ROCHE, MSD, BMS, ASTRAZENECA, and Novartis. All other authors have no competing interest to disclose.

Clinical trial registration: N.B. The manuscript is a secondary analysis of clinical trials. The NCT numbers of clinical trials used in this analysis are provided below. RESONATE: NCT01578707 , https://clinicaltrials.gov/study/NCT01578707 . RESONATE2: NCT01722487 , https://clinicaltrials.gov/study/NCT01722487 . HELIOS: NCT01611090 , https://clinicaltrials.gov/study/NCT01611090 .

Supplemental material: Supplemental material for this article is available online.

ORCID iD

Ahmad Y. Abuhelwa https://orcid.org/0000-0002-4182-065X

Ethical considerations

All included clinical trials conformed to the guidelines outlined by the International Conference on Harmonization for Good Clinical Practice and the principles of the Declaration of Helsinki. The secondary analysis of de-identified clinical trial data presented in this study was approved by the University of Sharjah Research Ethics Committee (Approval reference number: REC-23-11-07-01-F).

Consent to participate

Written informed consent was obtained from all participants in the original clinical trials.

Consent for publication

This study used de-identified individual participant data from completed clinical trials and does not contain identifiable individual-level information.

Data Availability Statement

Data were accessed according to YODA policy and process for clinical study data sharing and is available for request at https://yoda.yale.edu/ .

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Associated Data

Supplementary Materials

Supplemental material - Prognostic value of patient-reported outcome thresholds on survival and adverse events in CLL/SLL: A pooled analysis of ibrutinib trials

Supplemental material for Prognostic value of patient-reported outcome thresholds on survival and adverse events in CLL/SLL: A pooled analysis of ibrutinib trials by Ahmad Y. Abuhelwa, Sara A. Almansour, Humaid O. Al-Shamsi, Ziad Abuhelwa, Mohamad A Ziade, Yasser Bustanji, Mohammad H. Semreen, Mohammad A. Y. Alqudah, Ross A. McKinnon, Karem H Alzoubi, Michael J. Sorich, and Ashley M. Hopkins in Therapeutic Advances in Hematology.

Data Availability Statement

Data were accessed according to YODA policy and process for clinical study data sharing and is available for request at https://yoda.yale.edu/ .