Mixed-methods research to support the use of new lymphoma-specific patient-reported symptom measures derived from the EORTC item library.

BACKGROUND: No specific measures exist to assess patient-reported symptoms experienced by individuals with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or mantle cell lymphoma (MCL). This study was conducted to elicit patient-reported CLL/SLL- and MCL-related symptoms and their impact on patients' lives. The study qualitatively and quantitatively evaluated sets of conceptually-selected EORTC Item Library items for assessing CLL/SLL- and MCL-related symptoms. METHODS: The qualitative component of the research included a literature review, clinician consultations, and patient interviews. Concepts important to patients were identified and coded; cognitive debriefing of the selected library items was completed with patients. CLL/SLL and MCL-related symptoms and impacts were organized in a structured conceptual model, which was mapped to item sets from the Item Library. The quantitative component comprised exploratory macro-level Rasch measurement theory (RMT) analysis conducted to provide supportive quantitative insight on the item sets. RESULTS: 41 patients (21-MCL; 20-CLL/SLL) and 5 clinicians participated in the qualitative study; 57 unique patients (30-MCL; 27-CLL/SLL) completed the EORTC items. The conceptual models generated from the qualitative work included symptoms and functional impacts of CLL/SLL and MCL. Symptom domains included swollen lymph nodes, B symptoms, abdominal issues, pain, fatigue, subjective cognitive impairment, anemia-related symptoms, bleeding, infection, and other issues (appetite loss, temperature fluctuation, rash, weight gain, sleep problems, cough). Impacts included physical function, role function, and other functions (psychological, social). Cognitive debriefing demonstrated that the separate item sets for CLL/SLL and MCL-related symptoms were well understood and aligned with patients' experiences. All selected items were included in the conceptual models. The exploratory RMT analysis showed that the item sets provided adequate coverage of the continuum of CLL/SLL- and MCL-related symptom severity. CONCLUSIONS: This study gathered qualitative and early quantitative evidence supporting use of the EORTC Item Library to assess CLL/SLL- and MCL-related symptoms and impacts. These items are promising candidates for measurement of patient-reported disease symptoms in these populations. A larger sample size will be essential to establish the psychometric properties necessary to support use in clinical trials. Patients who suffer from rare cancers of the blood, bone marrow, and lymph nodes can experience chronic and debilitating symptoms. At present, however, there are no dedicated instruments for assessing the patient's experience of symptoms of conditions like chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or mantle cell lymphoma (MCL), or for assessing their impact on patients' lives. This research project aimed to address that need. The researchers selected relevant and clinically meaningful symptoms from the EORTC Item Library that assess fatigue, B symptoms, and CLL/SLL- and MCL-specific symptoms. Using patients and clinician interviews as well as quantitative analyses, the research revealed no major concerns with using these item sets to assess symptoms of CLL/SLL and MCL. Interviews with patients demonstrated that the separate item sets for CLL/SLL and MCL-related symptoms were well understood and aligned with patients' experiences. All selected items were included in the conceptual models. Item sets identified in this study can potentially be used to assess patient-reported symptom endpoints in clinical trial settings in these disease areas.

Establishing clinically meaningful within-individual improvement thresholds for eight patient-reported outcome measures in people with relapsing-remitting multiple sclerosis.

BACKGROUND: As disease-modifying therapies do not reverse the course of multiple sclerosis (MS), assessment of therapeutic success involves documenting patient-reported outcomes (PROs) concerning health-related quality of life, disease and treatment-related symptoms, and the impact of symptoms on function. Interpreting PRO data involves going beyond statistical significance to calculate within-patient meaningful change scores. These thresholds are needed for each PRO in order to fully interpret the PRO data. This analysis of PRO data from the PROMiS AUBAGIO study, which utilized 8 PRO instruments in teriflunomide-treated relapsing-remitting MS (RRMS) patients, was designed to estimate clinically meaningful within-individual improvement thresholds in the same manner, for 8 PRO instruments. RESULTS: The analytical approach followed a triangulation exercise that considered results from anchor- and distribution-based methods and graphical representations of empirical cumulative distribution functions in PRO scores in groups defined by anchor variables. Data from 8 PRO instruments (MSIS-29 v2, FSMC, MSPS, MSNQ, TSQM v1.4, PDDS, HRPQ-MS v2, and HADS) were assessed from 434 RRMS patients. For MSIS-29 v2, FSMC, MSPS, and MSNQ total scores, available anchor variables enabled both anchor- and distribution-based methods to be applied. For instruments with no appropriate anchor available, distribution-based methods were applied. A recommended value for meaningful within-individual improvement was defined by comparing mean change in PRO scores between participants showing improvement of one or two categories in the anchor variable or those showing no change. A "lower bound" estimate was calculated using distribution-based methods. An improvement greater than the lower-bound estimate was considered "clinically meaningful". CONCLUSION: This analysis produced estimates for assessing meaningful within-individual improvements for 8 PRO instruments used in MS studies. These estimates should be useful for interpreting scores and communicating study results and should facilitate decision-making by regulatory and healthcare authorities where these 8 PROs are commonly employed.

Measuring Overall Severity of Myasthenia Gravis (MG): Evidence for the Added Value of the MG Symptoms PRO.

INTRODUCTION: Accurate measurement of myasthenia gravis (MG) severity is required for appropriate clinical monitoring of patients with MG and assessment of the benefit of new treatments in clinical trials. Our objective was to explore how MG severity can be measured and to determine how the newly developed MG Symptoms Patient-Reported Outcome (PRO) instrument complements the available measures of MG severity. METHODS: The conceptual coverage of the Quantitative MG (QMG), MG Composite (MGC), MG-Activities of Daily Living (MG-ADL), and MG Symptoms PRO was scrutinized against core symptoms of MG: muscle weakness in three muscle groups (ocular, bulbar, and respiratory), muscle weakness fatigability, and physical fatigue. Post hoc analyses of the MG0002 study, a Phase 2a clinical trial of rozanolixizumab in adults with moderate to severe generalized MG, included correlation and Rasch model analyses. RESULTS: The qualitative appraisal highlighted that only the MG Symptoms PRO captured physical fatigue. Data from 541 assessments (43 unique patients) were used for the analyses. Correlations ranged between 0.56 and 0.74 for the MG-ADL, QMG, MGC, and MG Symptoms PRO Muscle Weakness Fatigability score, and between 0.20 and 0.71 for the MG Symptoms PRO scores focusing on independent muscle groups. Analyses with the Rasch model estimated a meaningful continuum of severity of MG, including all items, except ocular muscles, from the four instruments. The QMG and MG Symptoms PRO had the broadest coverage of the MG severity continuum. Muscle fatigability and physical fatigue were more characteristic of low severity while bulbar weakness indicated more severe MG. CONCLUSION: The severity of MG can be reflected in a meaningful continuum underpinned by the MG-specific outcome measures. Only ocular muscle manifestations were shown to reflect a possibly different facet of MG severity. With its modular nature and comprehensive content, the MG Symptoms PRO provides complementary information to the outcome measures widely used in MG. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03052751.

Myasthenia gravis (MG) is a chronic disease affecting the communication between nerves and muscles. People with MG experience muscle weakness that worsens after activity and improves after rest. MG can affect different groups of body muscles (e.g., around the eyes, in the limbs, and face or throat).We show that the various symptoms of MG can be used to summarize the overall severity of the disease: people with mild and moderate MG often report only the fast onset of weakness in their limb muscles and mild physical fatigue, while those with more severe MG report more severe fatigue and also difficulties associated with weakness in facial and throat muscles (leading to difficulty with swallowing or speaking) and in respiratory muscles (making breathing difficult). This ordering of MG manifestations will help create more accurate methods to assess the severity of MG that can be used to evaluate new treatments or to monitor patients in the clinic.We also suggest that weakness of muscles around the eyes (leading to eyelid drooping or double vision) may represent a unique aspect of MG, and may not provide as much information to summarize the severity of MG as other symptoms. However, this needs further investigation as our study did not include participants who had weakness in eye muscles as their only symptom.We also document the ability of the MG Symptoms Patient-Reported Outcome questionnaire, a new questionnaire completed by patients, to provide useful information for measuring the severity of MG.

Health-related Quality of Life of Patients with Locally Advanced or Metastatic Urothelial Cancer Treated with Enfortumab Vedotin after Platinum and PD-1/PD-L1 Inhibitor Therapy: Results from Cohort 1 of the Phase 2 EV-201 Clinical Trial.

BACKGROUND: The EV-201 trial (NCT03219333) demonstrated a clinically meaningful and durable response rate and a tolerable safety profile with enfortumab vedotin (EV) in patients with locally advanced/metastatic urothelial carcinoma (LA/mUC) treated with prior PD-1/PD-L1 inhibitor therapy and platinum-containing chemotherapy (cohort 1). Patient-reported outcome (PRO) measures were included in EV-201 as exploratory endpoints. OBJECTIVE: To evaluate PRO data for cohort 1 of EV-201 to better understand the relationship between EV therapy and health-related quality of life (HRQoL). DESIGN, SETTING, AND PARTICIPANTS: Enrolled patients with LA/mUC who received EV were invited to electronically complete two HRQoL instruments (EORTC QLQ-C30 and EQ-5D-3L) at baseline and day 1 of each cycle until treatment discontinuation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patient demographics, completion and compliance rates, and PRO scores were analysed using descriptive statistics. Selected EORTC QLQ-C30 scores were analysed post hoc using a repeated-measures mixed model. RESULTS AND LIMITATIONS: Among treated patients (n = 125), 95% completed both baseline questionnaires. Compliance rates were ≥86% throughout the study. Descriptive analyses showed that global health status, physical functioning, and symptom scores remained stable over time, with average scores similar at each cycle. Lower pain and fatigue scores were observed in responders at cycles following an objective response. Pain was lower at cycle 3 than at baseline in patients with bone metastases. Mean EQ-5D-3L utility score (0.80 at baseline; range from 0.77 at cycle 2 to 0.91 at cycle 10) and visual analogue scale scores (66.9 at baseline; range from 65.5 at cycle 2 to 78.4 at cycle 10) remained similar over time. Variability and the small sample size limited definitive conclusions. CONCLUSIONS: PRO scores remained stable throughout EV treatment, further supporting the overall value of EV in the treatment of patients with LA/mUC. The potential benefit of EV therapy on overall HRQoL and symptoms such as pain and fatigue is currently being explored. PATIENT SUMMARY: In this study of adult patients with advanced cancer of the urinary tract that progressed after previous medications, quality of life, ability to function, and symptoms did not worsen on treatment with enfortumab vedotin, which is an antibody + drug combination. Some improvements in pain and fatigue were reported by patients, but further research needs to be conducted. These data complement the efficacy and safety data from the EV-201 trial.

Measuring patient-reported physical functioning and fatigue in myelodysplastic syndromes using a modular approach based on EORTC QLQ-C30.

PURPOSE: Physical functioning and fatigue are key patient concerns in myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). The objective of this research was to generate supportive quantitative evidence for modular physical functioning and fatigue measures based on the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30) and a customized selection of 10 supplemental items from the EORTC Item Library. METHODS: The 40 items were completed online cross-sectionally by 51 patients (higher risk [HR] MDS: 53%; CMML: 26%; AML: 10%). Psychometric analyses based on Rasch measurement theory (RMT) were conducted on the QLQ-C30 physical functioning and fatigue domains as well as measures combining QLQ-C30 and supplemental items. A measure of anemia-related symptoms composed of QLQ-C30 and supplemental items covering fatigue, dyspnea, and dizziness was also investigated. RESULTS: The QLQ-C30 physical functioning and fatigue domains showed good targeting to the sample and adequate reliability, with few conceptual gaps identified. Combining the QLQ-C30 and supplemental physical functioning and fatigue items improved the conceptual coverage and the reliability of the measures. The patient-reported anemia-related symptom measure showed good measurement performance, underpinned by a clinically meaningful characterization of severity of these symptoms over a spectrum, starting with fatigue, then dyspnea, and finally dizziness (most severe). CONCLUSION: The modular measurement approach of combining EORTC QLQ-C30 and Item Library offers a promising pragmatic solution to the measurement of physical functioning and fatigue, as well as anemia-related symptoms in clinical trials conducted in HR MDS, CMML, and AML.