S48 EXABS-138-LYM Measuring Physical Function and Tolerability on Treatment in Patients With Hematologic Malignancies Ajay Major, MD, MBA1, Amylou Dueck, PhD2, and Gita Thanarajasingam, MD3,* 1Division of Hematology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado 80045, USA 2Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Scottsdale, Arizona 85259, USA 3Division of Hematology, Mayo Clinic, Rochester, Minnesota 55906, USA *Corresponding author: thanarajasingam.gita@mayo.edu Keywords Toxicity, tolerability, patient-reported outcomes, adverse events, physical function, symptoms Introduction There has been an unprecedented expansion of therapeutics for hematologic malignancies over the past two decades beyond traditional cytotoxic chemotherapies, including monoclonal and bispecific antibodies, molecularly-targeted agents, and cellular therapies such as CAR T-cell therapy. These novel therapeutic agents, when used as monotherapy or in combination with conventional chemotherapy both in clinical trials and in real-world practice, confer unique profiles of treatment-related toxicities and symptomatic adverse events (AEs). Given that patients with many types of blood cancers are living longer with these treatment advances, and these treatment paradigms often involve chronic or time-intensive upfront administration, consideration of the tolerability of these therapies and their effect on health-related quality of life (HRQoL) is paramount. Historically, clinical trials have focused on the efficacy and safety of therapies, although “safety” is frequently presented as “tolerability” in publications and conference presentations. While related to safety, “tolerability” is a distinct construct that is defined as the extent to which symptomatic and non-symptomatic AEs impact a patient’s willingness to continue with current treatment dosing, as well as how these AEs impact how patients feel and function while undergoing therapy.1–3 Assessment of tolerability requires the systematic and rigorous measurement of patient-reported outcomes (PROs). The U.S. Food and Drug Administration has proposed five core PRO domains for measurement in registration trials for anti-cancer therapies intended to demonstrate an effect on survival, tumor response, or delay in the progression of a malignancy. The core domains include disease-related symptoms, symptomatic AEs, physical function, role function, and overall side effect bother, with the latter four domains measuring aspects of tolerability (Figure 1).1–4 Of these five core domains, there have been numerous efforts to better characterize disease-related symptoms and symptomatic AEs from the patient perspective, using PRO measurement systems such as the Functional Assessment of Chronic Illness Therapy (FACIT), Patient-Reported Outcome Measurement Information System (PROMIS), European Organisation for Research and Treatment of Cancer (EORTC), and PRO-CTCAE questionnaires as the main validated tools.5–8 These PRO frameworks were developed with comprehensive input from patients and clinicians, and utilize robust qualitative and quantitative psychometric methodologies to generate instruments that are valid and reliable across multiple cancer types. However, while robustly applied for the study of patient-reported symptoms and AEs, comparatively less is known about the measurement of physical function, defined as the ability to carry out day-to-day activities that require physical effort, including both basic and instrumental activities of daily living.9 Given that novel therapies used in the treatment of hematologic cancers may induce AEs such as neuropathy or fatigue which can cause physical debility and reduced physical functioning, there is a pressing need to understand how physical function can be rigorously measured and how it affects treatment tolerability and overall HRQoL. Material and Methods Guidance from consensus consortia defining best practices regarding the collection and analysis of tolerability data are summarized. Efforts to integrate PROs and physical function assessment within clinical trials in hematologic malignancies and routine clinical practice were reviewed in published literature and presented results. Results and Discussion Several consortia have been founded to establish best practices for the collection, analysis, and presentation of PRO and tolerability data, including physical functioning. These include the PatientReported Outcomes Tools Engaging Users and Stakeholders (PROTEUS) Consortium, the Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data (SISAQOL) Consortium, the United States National Cancer Institute Cancer Moonshot U01 Tolerability Consortium, the FDA’s Project Patient Voice, and the Lancet
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