Meaningful Worsening Research Articles

A single relapse induces worsening of disability and health-related quality of life in patients with neuromyelitis optica spectrum disorder.

Cumulative damage from multiple relapses in neuromyelitis optica spectrum disorder (NMOSD) is associated with poor health-related quality of life (HRQoL) and long-term disability in patients positive for anti-aquaporin 4 antibodies (AQP4+). This study assessed the effect of an individual relapse on HRQoL and disability outcomes in AQP4+ NMOSD. Post hoc analyses of data pooled from the PREVENT study and its open-label extension, which evaluated the efficacy and safety of eculizumab in AQP4+ NMOSD, examined the effect of a single relapse on 3 disability and 4 HRQoL outcome measures. Assuming the effect of 1 relapse extends to multiple relapses, an extrapolation was done to assess the effect of 2 relapses on these outcomes. In 27 patients (placebo: n = 20; eculizumab: n = 7) experiencing an independently adjudicated relapse, 1 relapse led to significantly worse disability (modified Rankin Scale and Expanded Disability Status Scale [EDSS]) and HRQoL (36-item Short-Form Health Survey mental and physical component summaries; European Quality of Life 5-Dimension questionnaire 3-Level visual analogue scale and utility index) scores. In 4 of 7 outcomes, clinically meaningful worsening was more likely for relapsing versus non-relapsing patients (n = 116). Extrapolating the effect of 2 relapses predicted that clinically meaningful worsening was more likely in 6 out of 7 outcomes, including EDSS, for patients experiencing multiple relapses versus patients experiencing no relapses. Findings from these clinical trial data demonstrate that a single NMOSD relapse can worsen disability and HRQoL, underscoring the role of relapse prevention in improving long-term outcomes in patients with AQP4+ NMOSD.

Meaningful Improvement and Worsening in Patients Who Do Not Achieve Low Disease Activity and Switch Therapy to a New Biologic or Targeted Disease-Modifying Antirheumatic Drug: Results From the CorEvitas RA Registry.

The aim of this study was to assess the change in disease activity associated with switching from 1 biologic/targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) to another in patients with rheumatoid arthritis who did not achieve low disease activity (LDA) after 6 to 12 months of their initial treatment. This observational study included patients from the CorEvitas Rheumatoid Arthritis Registry, who initiated a b/tsDMARD at the index visit (prebaseline), had any clinical disease activity index (CDAI) improvement but did not achieve LDA/remission at the subsequent visit (baseline), and switched therapy at baseline or between baseline and follow-up visits. Regardless of the preswitch CDAI value, 2 thresholds of CDAI change were used to define meaningful improvement and worsening for all patients: ≥6 units and ≥12 units; no meaningful change was defined as any change between -6 to +6 units and -12 to +12 units, based on respective thresholds. Of 1226 patients fulfilling the inclusion criteria, 93 (7.6%) switched therapy at baseline or between baseline and follow-up, after an inadequate response at the baseline visit. At follow-up, meaningful worsening occurred in 30.1% and 12.9% of switchers, whereas the remaining switchers achieved meaningful improvement (34.4% and 20.4%) or had no meaningful change (35.5% and 66.7%), based on the thresholds of ≥6 and ≥12 units, respectively. Rheumatoid arthritis patients, who had not achieved LDA and switched b/tsDMARD, were more likely to have meaningful improvement or no change, rather than meaningful worsening. These data may help some patients overcome their hesitancy to switch therapy, potentially improving clinical outcomes.

Post-COVID dyspnea: prevalence, predictors, and outcomes in a longitudinal, prospective cohort

BackgroundThe pathophysiology, evolution, and associated outcomes of post-COVID dyspnea remain unknown. The aim of this study was to determine the prevalence, severity, and predictors of dyspnea 12 months following hospitalization for COVID-19, and to describe the respiratory, cardiac, and patient-reported outcomes in patients with post-COVID dyspnea.MethodsWe enrolled a prospective cohort of all adult patients admitted to 2 academic hospitals in Vancouver, Canada with PCR-confirmed SARS-CoV-2 during the first wave of COVID between March and June 2020. Dyspnea was measured 3, 6, and 12 months after initial symptom onset using the University of California San Diego Shortness of Breath Questionnaire.ResultsA total of 76 patients were included. Clinically meaningful dyspnea (baseline score > 10 points) was present in 49% of patients at 3 months and 46% at 12 months following COVID-19. Between 3 and 12 months post-COVID-19, 24% patients had a clinically meaningful worsening in their dyspnea, 49% had no meaningful change, and 28% had a clinically meaningful improvement in their dyspnea. There was worse sleep, mood, quality of life, and frailty in patients with clinically meaningful dyspnea at 12 months post-COVID infection compared to patients without dyspnea. There was no difference in PFT findings, troponin, or BNP comparing patients with and without clinically meaningful dyspnea at 12 months. Severity of dyspnea and depressive symptoms at 3 months predicted severity of dyspnea at 12 months.ConclusionsPost-COVID dyspnea is common, persistent, and negatively impacts quality of life. Mood abnormalities may play a causative role in post-COVID dyspnea in addition to potential cardiorespiratory abnormalities. Dyspnea and depression at initial follow-up predict longer-term post-COVID dyspnea, emphasizing that standardized dyspnea and mood assessment following COVID-19 may identify patients at high risk of post-COVID dyspnea and facilitating early and effective management.

Improvement or Worsening of Disease Activity After Switch to Sarilumab in Patients With Rheumatoid Arthritis With a Partial Response to Adalimumab.

The aim of this study was to assess the effect of switching from adalimumab to sarilumab monotherapy in partial responders with rheumatoid arthritis from the MONARCH randomized trial and its open-label extension (OLE). Partial response was defined as improvement in Clinical Disease Activity Index (CDAI) of 12 or 6 units (baseline score: >22 or >10 and ≤22, respectively). Proportions of adalimumab partial responders with meaningful worsening or improvement at OLE weeks 12 and 24 were evaluated using 2 CDAI thresholds (≥6 and ≥12 points), 28-joint Disease Activity Score using erythrocyte sedimentation rate (≥0.6 and ≥1.2 points), Health Assessment Questionnaire Disability Index (≥0.22 and ≥0.30 points), Simple Disease Activity Index (≥7 and ≥13 points), physician and patient global assessments (≥10 and ≥20), and 28-joint swollen and tender joint counts (≥1 and ≥2 joints). Outcomes were analyzed using mixed-effect models with repeated measures for observed cases. The p values were produced using Wilcoxon tests. Of 369 enrolled patients, 320 (87%) entered the OLE and 155 switched from adalimumab to sarilumab; 59% (91/155) were partial responders. At week 24, 4%-17% and 2%-12% of partial responders experienced a worsening using the lower and higher thresholds, respectively, whereas 47%-78% and 27%-66% experienced improvement. Partial responders to adalimumab who switched to sarilumab had a low likelihood of experiencing meaningful worsening, with most patients showing meaningful improvement or no change in disease activity. This may help alleviate patients' fears of worsening when considering switching to a treatment with a different mechanism of action.

Patient-Reported Outcomes in Long-Term Survivors of Autologous Hematopoietic Cell Transplantation in Multiple Myeloma

The overall survival in patients with transplantation-eligible multiple myeloma has tripled over the past 2 decades, leading to a growing population of myeloma survivors. However, there is a paucity of data on health-related quality of life (HRQoL), distress, and health behaviors in long-term myeloma survivors who are in stable remission after autologous hematopoietic cell transplantation (AHCT). In this cross-sectional study using data from 2 randomized controlled trials of survivorship care plans and internet-based self-management intervention in transplantation survivors, the primary objective was to measure HRQoL (using the Short Form-12, version 2.0 [SF-12 v2]), distress (using the Cancer- and Treatment-Related Distress [CTXD] instrument), and health behaviors of myeloma survivors in stable remission after AHCT. A total of 345 patients at a median of 4 years (range, 1.4 to 11 years) post-AHCT were included. The mean SF-12 v2 Physical Component Summary (PCS) score was 45.5 ± 10.5, and the mean Mental Component Summary (MCS) score was 51.3 ± 10.1, compared with US population norms of 50 ± 10 for both (P < .001 and P=.021 for PCS and MCS comparisons, respectively). Notably, neither reached the threshold for a minimal clinically important difference. Approximately one-third of the patients had clinically significant distress based on the CTXD total score, with distress reported by 53% of the patients in the Health Burden domain, by 46% in the Uncertainty domain, by 33% in the Finances domain, by 31% in the Family Strain domain, by 21% in the Identity domain, and by 15% in the Medical Demands domain. Preventive care guidelines were adhered to by 81% of the myeloma survivors; however, adherence to exercise and diet guidelines were relatively low, at 33% and 13%, respectively. Myeloma AHCT survivors in stable remission have no clinically meaningful worsening in physical functioning compared with the general population. Survivorship programs should address ongoing distress due to health burden, uncertainty, and finances in myeloma survivors, along with evidence-based targeted interventions for modifiable health behaviors, such as nutrition and exercise.

Abstract P4-07-65: Effect of sacituzumab govitecan vs chemotherapy in HR+/HER2- metastatic breast cancer: patient-reported outcomes from the TROPiCS-02 trial

Abstract Background: For HR+/HER2- metastatic breast cancer (MBC) patients, after resistance to endocrine therapy (ET), treatment options are mostly limited to traditional chemotherapies (CT) that offer poor survival and quality of life (QoL), creating an area of unmet need. The antibody-drug conjugate sacituzumab govitecan (SG) comprises an anti-Trop-2 antibody coupled to SN-38 via a hydrolyzable linker. In the phase 3 TROPiCS-02 trial, heavily pretreated patients with relapsed/refractory HR+/HER2- MBC received SG vs single-agent chemotherapy treatment of physician’s choice (TPC). The study met its primary endpoint of improved progression-free survival with SG vs TPC. Here, we report the effect of SG vs TPC on patient-reported outcomes (PROs) from TROPiCS-02. Patients and Methods: Patients who had received ≥1 CDK 4/6 inhibitor, ≥1 ET, and 2-4 prior lines of CT were randomized to receive SG (10 mg/kg intravenous on days 1 and 8 of a 21-day treatment cycle) or TPC (capecitabine, eribulin, gemcitabine, or vinorelbine). In the PRO-evaluable population (all randomized patients with an evaluable assessment at baseline (BL) and ≥1 post-BL visit) SG and TPC were compared regarding time to first clinically meaningful worsening (TTD) or death from BL on the EORTC QLQ-C30 domains (≥10 points), EQ-5D-5L health utility index (≥0.08 points), and EQ-VAS (≥7 points). For the EORTC QLQ-C30 function and global health status/QoL domains, patients with a BL score ≥10 and for symptom scales, patients with a BL score ≤90 were included. In the safety population (all randomized patients who received ≥1 dose of study drug), SG and TPC were compared regarding worst level of toxicities during treatment for the PRO-CTCAE items. For TTD, a stratified Cox proportional hazards regression analysis was conducted and the PRO-CTCAE items were summarized descriptively (numbers and percentages). Results: Of 543 randomized patients, 446 (82%), 445 (82%), and 517 (95%) were included in the PRO-evaluable population (EORTC QLQ-C30: SG vs TPC n=236 vs 210 and EQ-5D-5L: n=238 vs 207) and in the safety population for PRO-CTCAE (SG vs TPC n=268 vs 249), respectively. TTD of EORTC QLQ-C30 global health status/QoL, physical functioning, emotional functioning, fatigue, dyspnea, insomnia, and financial difficulties and EQ-VAS were significantly longer in the SG vs the TPC arm (Table). TTD of EORTC QLQ-C30 diarrhea was significantly shorter for SG vs TPC. For PRO-CTCAE items, decreased appetite, nausea, vomiting, constipation, abdominal pain, shortness of breath, and fatigue were similar between SG and TPC arms, whereas frequency of diarrhea and amount of hair loss were higher in the SG vs TPC arm. Conclusions: In this trial, SG significantly delayed worsening of overall QoL, physical and emotional functioning, and symptoms like fatigue, dyspnea, and insomnia. Overall, our findings suggest that SG has more favorable effects on PROs compared with TPC in pts with HR+/HER2- MBC. Table: Time to First Clinically Meaningful Deterioration PRO Scores Citation Format: Frederik Marmé, Aditya Bardia, Hope Rugo, Peter Schmid, Sara M. Tolaney, Mafalda Oliveira, Andreas Schneeweiss, Ling Shi, Wendy Verret, Mahdi Gharaibeh, Anju Shah, Javier Cortés. Effect of sacituzumab govitecan vs chemotherapy in HR+/HER2- metastatic breast cancer: patient-reported outcomes from the TROPiCS-02 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-65.

Meaningful Clinical Changes in Alzheimer Disease Measured With the iADRS and Illustrated Using the Donanemab TRAILBLAZER-ALZ Study Findings.

To provide relevant background of the Integrated Alzheimer's Disease Rating Scale (iADRS), with examples, to assist the reader with the interpretation of iADRS findings from the TRAILBLAZER-ALZ study. The iADRS is an integrated measure of global Alzheimer disease (AD) severity for use in the clinical trial environment. It provides a single score that captures commonalities across cognitive and functional ability domains, reflecting disease-related impairment, while minimizing noise not related to disease progression that may exist within each domain. In AD, disease-modifying therapies (DMTs) are expected to slow the rate of clinical decline, changing the trajectory of disease progression. The overall percent slowing of disease progression with treatment is a more informative outcome of effect than absolute point differences between treatment and placebo groups at any given time point because the latter is influenced by treatment period and disease severity. The TRAILBLAZER-ALZ trial was a phase 2 study designed to evaluate the safety and efficacy of donanemab in participants with early symptomatic AD; the primary outcome measure was the change from baseline to 76 weeks on the iADRS. In the TRAILBLAZER-ALZ study, donanemab slowed disease progression by 32% at 18 months (p = 0.04 vs placebo), demonstrating clinical efficacy. At the patient level, one can assess whether the DMT effect is clinically meaningful by estimating the threshold of change consistent with clinically meaningful worsening; based on the TRAILBLAZER-ALZ findings, treatment with donanemab would delay reaching this threshold by approximately 6 months. The iADRS is capable of accurately describing clinical changes associated with disease progression and detecting treatment effects and is an effective assessment tool for use in clinical trials of individuals with early symptomatic AD.

Differences in Quality of Life and Toxicity for Male and Female Patients following Chemo(radiotherapy) for Bladder Cancer

AimsBC2001, a randomised trial of treatment for muscle-invasive bladder cancer, demonstrated no difference in health-related quality of life (HRQoL) or late toxicity between patients receiving radical radiotherapy with and without chemotherapy. This secondary analysis explored sex-based differences in HRQoL and toxicity. Materials and methodsParticipants completed the Functional Assessment of Cancer Therapy Bladder (FACT-BL) HRQoL questionnaires at baseline, end of treatment, 6 months and annually until 5 years. Clinicians assessed toxicity with the Radiation Therapy Oncology Group (RTOG) and Late Effects in Normal Tissues Subjective, Objective and Management (LENT/SOM) scoring systems at the same timepoints. The impact of sex on patient-reported HRQoL was evaluated using multivariate analyses of change in FACT-BL subscores from baseline to the timepoints of interest. For clinician-reported toxicity, differences were compared by calculating the proportion of patients with grade 3–4 toxicities occurring over the follow-up period. ResultsFor both males and females, all FACT-BL subscores had a reduction in HRQoL at the end of treatment. For males, the mean bladder cancer subscale (BLCS) score remained stable through to year 5. For females, there was a decline in BLCS from baseline at years 2 and 3 with a return to baseline at year 5. At year 3, females had a statistically significant and clinically meaningful worsening of mean BLCS score (–5.18; 95% confidence interval –8.37 to –1.99), which was not seen in males (0.24; –0.76 to 1.23). RTOG toxicity was more frequent in females than males (27% versus 16%, P = 0.027). ConclusionResults suggest that female patients treated with radiotherapy ± chemotherapy for localised bladder cancer report worse treatment-related toxicity in post-treatment years 2 and 3 than males.

Fenfluramine treatment is associated with improvement in everyday executive function in preschool-aged children (

ObjectiveTo evaluate whether fenfluramine (FFA) is associated with improvement in everyday executive function (EF)—self-regulation—in preschool-aged children with Dravet syndrome (DS). MethodsChildren with DS received placebo or FFA in one of two phase III studies (first study: placebo, FFA 0.2 mg/kg/day, or FFA 0.7 mg/kg/day added to stiripentol-free standard-of-care regimens; second study: placebo or FFA 0.4 mg/kg/day added to stiripentol-inclusive regimens). Everyday EF was evaluated at baseline and Week 14–15 for children aged 2–4 years with parent ratings on the Behavior Rating Inventory of Executive Function®—Preschool (BRIEF®-P); raw scores were transformed to T-scores and summarized in Inhibitory Self-Control Index (ISCI), Flexibility Index (FI), Emergent Metacognition Index (EMI), and Global Executive Composite (GEC). Clinically meaningful improvement and worsening were defined using RCI ≥ 90% and RCI ≥ 80% certainty, respectively. The associations between placebo vs FFA combined (0.2, 0.4, and 0.7 mg/kg/day) or individual treatment groups and the likelihood of clinically meaningful change in BRIEF®–P indexes/composite T-scores were evaluated using Somers’d; pairwise comparisons were calculated by 2-sided Fisher’s Exact tests (p ≤ 0.05) and Cramér’s V. ResultsData were analyzed for 61 evaluable children of median age 3 years (placebo, n = 22; FFA 0.2 mg/kg/day, n = 15; 0.4 mg/kg/day [with stiripentol], n = 10; 0.7 mg/kg/day, n = 14 [total FFA, n = 39]). Elevated or problematic T-scores (T ≥ 65) were reported in 55% to 86% of patients at baseline for ISCI, EMI, and GEC, and in ∼33% for FI. Seventeen of the 61 children (28%) showed reliable, clinically meaningful improvement (RCI ≥ 90% certainty) in at least one BRIEF®-P index/composite, including a majority of the children in the FFA 0.7 mg/kg/day group (9/14, 64%). Only 53% of these children (9/17) also experienced clinically meaningful reduction (≥50%) in monthly convulsive seizure frequency, including 6/14 patients in the FFA 0.7 mg/kg/day group. Overall, there were positive associations between the four individual treatment groups and the likelihood of reliable, clinically meaningful improvement in all BRIEF®-P indexes/composite (ISCI, p = 0.001; FI, p = 0.005; EMI, p = 0.040; GEC, p = 0.002). The FFA 0.7 mg/kg/day group showed a greater likelihood of reliable, clinically meaningful improvement than placebo in ISCI (50% vs 5%; p = 0.003), FI (36% vs 0%; p = 0.005), and GEC (36% vs 0%; p = 0.005). For EMI, the FFA 0.7 mg/kg/day group showed a greater likelihood of reliable, clinically meaningful improvement than the FFA 0.2 mg/kg/day group (29% vs 0%; p = 0.040), but did not meet the significance threshold compared with placebo (29% vs 5%; p = 0.064). There were no significant associations between treatment and the likelihood of reliable, clinically meaningful worsening (p > 0.05). SignificanceIn this preschool-aged DS population with high baseline everyday EF impairment, FFA treatment for 14–15 weeks was associated with dose-dependent, clinically meaningful improvements in regulating behavior, emotion, cognition, and overall everyday EF. These clinically meaningful improvements in everyday EF were not entirely due to seizure frequency reduction, suggesting that FFA may have direct effects on everyday EF during the early formative years of neurodevelopment.

Improved upper limb function in non-ambulant children with SMA type 2 and 3 during nusinersen treatment: a prospective 3-years SMArtCARE registry study

BackgroundThe development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months.MethodsSMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM).ResultsData from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score.ConclusionOur results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity.

Health-related quality of life in the phase III ASCENT trial of sacituzumab govitecan versus standard chemotherapy in metastatic triple-negative breast cancer

BackgroundThe antibody–drug conjugate sacituzumab govitecan (SG) prolongs progression-free survival and overall survival in patients with refractory/relapsed metastatic triple-negative breast cancer (mTNBC). Here, we investigated its effect on health-related quality of life (HRQoL). MethodsThis analysis was based on the open-label phase III ASCENT trial (NCT02574455). Adults with refractory/relapsed mTNBC who had received ≥2 prior systemic therapies (≥1 in the metastatic setting) were randomised 1:1 to SG or treatment of physician's choice (TPC; capecitabine, eribulin, vinorelbine, or gemcitabine). HRQoL was assessed on day 1 of each treatment cycle using the EORTC QLQ-C30. Score changes from baseline were analysed using linear mixed-effect models for repeated measures. Stratified Cox regressions evaluated time to first clinically meaningful change of HRQoL. ResultsThe analysis population comprised 236 patients randomised to SG and 183 to TPC. For global health status (GHS)/QoL, physical functioning, fatigue, and pain, changes from baseline were superior for SG versus TPC. Compared with TPC, SG was inferior regarding changes from baseline for nausea/vomiting and diarrhoea but non-inferior for other QLQ-C30 domains. Median time to first clinically meaningful worsening was longer for SG than for TPC for physical functioning (22.1 versus 12.1 weeks, P < 0.001), role functioning (11.4 versus 7.1 weeks, P < 0.001), fatigue (7.7 versus 6.0 weeks, P < 0.05), and pain (21.6 versus 9.9 weeks, P < 0.001). ConclusionsSG was generally associated with greater improvements and delayed worsening of HRQoL scores compared with TPC. This supports the favourable profile of SG as an mTNBC treatment.

Health-related quality of life with lisocabtagene maraleucel vs standard of care in relapsed or refractory LBCL

AbstractLisocabtagene maraleucel (liso-cel) has shown promising efficacy in clinical trials for patients with relapsed/refractory large B-cell lymphoma (LBCL). We present health-related quality of life (HRQOL) results from the TRANSFORM study, the first comparative analysis of liso-cel vs standard of care (SOC) as second-line therapy in this population. Adults with LBCL refractory or relapsed ≤12 months after first-line therapy and eligible for autologous stem cell transplantation were randomized 1:1 to the liso-cel or SOC arms (3 cycles of immunochemotherapy in which responders proceeded to high-dose chemotherapy and autologous stem cell transplantation). HRQOL was assessed by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – 30 items and the Functional Assessment of Cancer Therapy-Lymphoma subscale. Patients with baseline and ≥1 postbaseline assessment were analyzed (liso-cel, n = 47; SOC, n = 43). The proportion of patients with meaningful improvement in global health status/quality of life (QOL) was higher, whereas deterioration was lower in the liso-cel arm vs SOC arm from day 126 to month 6. Mean change scores showed meaningful worsening in global health status/QOL at month 6, fatigue at day 29 and month 6, and pain at month 6 with SOC; mean scores for other domains were maintained or improved in both arms. Time to confirmed deterioration favored the liso-cel arm vs SOC arm in global health status/QOL (median: not reached vs 19.0 weeks, respectively; hazard ratio, 0.47; 95% confidence interval, 0.24-0.94). HRQOL was either improved or maintained from baseline in patients with relapsed/refractory LBCL in the liso-cel arm vs SOC arm as second-line treatment. This study is registered at clinicaltrials.gov as #NCT0357531.

Development and Validation of a Juvenile Spondyloarthritis Disease Flare Measure: Ascertaining Flare in Patients With Inactive Disease.

Our objective was to develop and validate a composite disease flare definition for juvenile spondyloarthritis (SpA) that would closely approximate the clinical decision made to reinitiate or not reinitiate systemic therapy after therapy de-escalation. Retrospective chart reviews of children with SpA who underwent systemic therapy de-escalation of biologic or conventional disease-modifying antirheumatic drugs were used to develop and validate the flare outcome. Data on independent cohorts for development (1 center) and validation (4 centers) were collected from large tertiary health care systems. Core measure thresholds and candidate disease flare outcomes were assessed using sensitivity, specificity, positive predictive values (PPVs) and negative predictive values (NPVs), and the receiver operating characteristic (ROC) area under the curve (AUC), with physician assessment of active disease plus re-initiation of standard dose of systemic therapy as the reference standard. Of the candidate definitions, clinically meaningful worsening in ≥3 of the following 5 core measures performed best: caregiver/patient assessment of well-being; physician assessment of disease activity; caregiver/patient assessment of pain, physical function, and active joint count. The ROC AUC was 0.91, PPV 87.5%, NPV 98.1%, sensitivity 82.4%, and specificity 98.7%. Cronbach's α was 0.81, signifying internal consistency, and factor analysis demonstrated that the outcome measured 1 construct. The Juvenile SpA Flare measure had face validity according to 21 surveyed pediatric rheumatologists. Juvenile SpA Flare had an ROC AUC of 0.85, a PPV of 92.3%, and an NPV of 96.8% in the validation cohort. There is initial support for the validity of the Juvenile SpA Flare measure as a tool to identify disease flare in juvenile SpA patients de-escalating therapy, and the measure is potentially applicable in clinical practice, observational studies, and therapeutic trials.

Longer wait time after identification of peripartum depression symptoms is associated with increased symptom burden at psychiatric assessment

Untreated peripartum depression (PD) affects one in seven women and is associated with negative maternal outcomes. This retrospective observational study used health record data from an integrated health system in Texas to assess the extent to which time to access reproductive psychiatry influences the mental health of peripartum women. Women with at least one screening for depression symptoms conducted in obstetric or pediatric settings between May 2014 and October 2019 and subsequently seen by the reproductive psychiatry clinic (n=490) were included. Descriptive and inferential statistics were used to assess timing and factors related to psychiatry follow-up. Findings from this study demonstrated that the average time between a positive screen and a psychiatry assessment was 5 weeks. At psychiatry referral appointments, 85% of women continued to screen positive for PD symptoms. Depression symptom scores at the psychiatry appointment were significantly higher than scores precipitating the referral (p = 0.002). Wait time between initial positive screen and referral appointment was positively correlated with clinically meaningful increases in depression symptom scores (p < 0.001). Each week spent waiting for an appointment produced a 13% increase in odds of clinically meaningful worsening of PD scores and 9% increase in odds of developing new self-harm ideation. Given the findings that a longer period between primary care referral and subspecialty appointment has a negative impact on the mental health of women, this study supports the need for earlier psychiatric assessment to minimize decompensation. Expansion of reproductive psychiatry services are needed to support peripartum women and improve maternal outcomes.

Abstract P4-10-02: Patient-reported outcomes in EA1131: A randomized phase III trial of platinum vs. capecitabine in patients with residual triple-negative breast cancer after neoadjuvant chemotherapy

Abstract Background: Understanding health-related quality of life (HRQOL), including side effects, is critical to guide supportive care during chemotherapy. The EA1131 trial demonstrated that Platinum (Plat) was unlikely to improve outcomes compared to capecitabine (Cape) in patients with stage II-III triple-negative breast cancer (TNBC) of basal subtype and ≥1 cm residual disease after neoadjuvant chemotherapy (NAC), supporting Cape as the continued standard of care. Patient-reported outcomes (PRO) were administered as a sub-study to understand HRQOL and symptoms from the patient’s perspective. Methods: EA1131 was amended in 9/2017 to add PRO endpoints and all patients enrolled after this amendment were eligible for the PRO sub-study. The Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index (FBSI) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity Subscale (NtxS; Plat arm only) were administered at baseline (BL), cycle 3 day 1 (C3D1), and following treatment at 6 and 15 months. Due to early trial termination, the PRO sub-study target accrual (n=362) was not reached. It was hypothesized that HRQOL, assessed by the FBSI-Treatment Side Effect (TSE) subscale (range 0-16, higher score = less side effects, better HRQOL), would indicate fewer post-treatment side effects at 6 and 15 months following Plat compared to Cape. The Wilcoxon rank sum test was used to compare FBSI-TSE subscale scores and total FBSI scores (range 0-64, higher score = better overall HRQOL) between arms at BL, C3D1, 6 months and 15 months. Two-sample t-tests were used to compare change in FBSI-TSE subscale scores and total FBSI scores from BL to C3D1 between arms. Change in NtxS scores (range 0-44, higher score = less neurotoxicity) from BL to C3D1 was evaluated with the paired t-test. Analyses were exploratory and p-values &amp;lt;0.05 considered significant without multiple comparisons adjustment. Results: Of 331 patients eligible for the PRO sub-study (156 Plat arm, 175 Cape arm), 296 (89.4%) completed ≥1 PRO. Mean FBSI-TSE subscale scores were better for Cape at BL (Cape 14.5, Plat 13.9, p-value 0.02), for Plat at C3D1 (Cape 13.5, Plat 14.0, p-value 0.04), and did not differ at 6 months (Cape 14.6, Plat 14.7, p-value 0.70) or 15 months (Cape 14.9, Plat 14.5, p-value 0.44). FBSI-TSE subscale scores worsened from BL to C3D1 for Cape but not for Plat (mean change Cape -0.72, mean change Plat 0.15, p-value 0.003). FBSI-TSE subscale change scores from BL to C3D1 exceeded the threshold for clinically meaningful worsening (&amp;gt; 1.5 points) in 27% of patients on Cape and 23% of patients on Plat (p-value 0.51). Mean total FBSI scores did not differ between arms at any time (BL: Cape 50.6, Plat 49.7; C3D1: Cape 48.1, Plat 48.0; 6 months: Cape 49.9, Plat 51.1; 15 months: Cape 53.3, Plat 50.3; all p &amp;gt; 0.05). Mean change in total FBSI scores from BL to C3D1 did not differ between arms (Cape -2.20, Plat -1.83, p = 0.75). Mean (standard deviation) NtxS scores for the Plat arm were 38 (6.3), 36.1 (7.8), 36 (7.1) and 34.5 (7.9) at BL, C3D1, 6 months and 15 months, respectively. Mean NtxS score decreased (indicating worsening neurotoxicity) from BL to C3D1 (p-value 0.006). Conclusions: Despite more frequent severe toxicity by CTCAE criteria for Plat than Cape, patient-reported side effects worsened during treatment with Cape but not Plat. Overall, changes in HRQOL were small for both arms and resolved after therapy. However approximately one-fourth of patients had clinically meaningful worsening side effects on both arms. PRO-assessed neurotoxicity increased in the Plat arm. This PRO sub-study demonstrates that PROs capture toxicities beyond CTCAE criteria and provides novel data about patients’ experience during adjuvant chemotherapy following NAC for TNBC. Citation Format: Karen L Smith, Fengmin Zhao, Ingrid A Mayer, Amye J Tevaarwerk, Sofia F Garcia, Carlos L Arteaga, William F Symmans, Ben H Park, Brian L Burnette, Della F Makower, Margaret Block, Kimberly A Morley, Chirag R Jani, Craig Mescher, Shabana J Dewani, Ursa Brown-Glaberman, Lisa E Flaum, Erica L Mayer, William M Sikov, Eve T Rodler, Angela M DeMichele, Joseph A Sparano, Antonio C Wolff, Kathy D Miller, Lynne I Wagner. Patient-reported outcomes in EA1131: A randomized phase III trial of platinum vs. capecitabine in patients with residual triple-negative breast cancer after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-02.

Abstract P5-18-13: Compression therapy and goshajinkigan for prevention of nab-paclitaxel-induced peripheral neuropathy in patients with operable breast cancer

Abstract Purpose: Peripheral neuropathy (PN) is one of the most common toxicities of taxane. Grade2-4 PN occurs in 27-35% of patients treated with taxane and 50-80% of them have persistent symptoms after chemotherapy. PN may result in dose reduction or treatment discontinuation and negatively affect quality of life (QOL). However, there are no established methods for preventing chemotherapy-induced PN. Therefore, we conducted the phase II study to evaluate the efficacy of compression therapy with elastic stockings and oral goshajinkigan (GJG), a traditional Japanese herbal medicine, for prevention of chemotherapy-induced PN in breast cancer patients who treated with dose-dense (DD) nab-paclitaxel (nab-PTX) followed by epirubicin and cycrlophosphamide (EC) as neoadjuvant chemotherapy. Patients and methods: Patients with clinical stage I-III human epidermal growth factor 2 (HER2)-negative breast cancer were included in the study. Nab-PTX (260mg/m2) followed by epirubicin (90mg/m2) plus cycrlophosphamide (600mg/m2) administered every 2 weeks with pegfilgrastim support. Patients wore elastic stockings (ALCARE, Tokyo, Japan) for 24 h from the beginning of each treatment. Oral GJG (7.5g/day) was initiated on day 1 of first cycle of nab-PTX and continued to last cycle of EC. The primary endpoint was the rates of pathological complete response (pCR). Secondary endpoints were clinical response rate, breast conservation rate, safety, and health-related QOL using the Functional Assessment of Cancer Therapy-Neurotoxicity (FACT-NTX). An 11-item FACT-NTX component of FACT-Taxane scale assessed chemotherapy-induced PN at baseline, after each cycle of nab-paclitaxel and EC, and 2 months after last cycle of EC. Lower score indicates worse PN and a 10% or greater decrease in FACT-NTX score was defined as a clinically meaningful worsening of PN. Results: From February 2017 to August 2019, 58 patients were enrolled and 55 of these patients were included in the analysis. Overall, pCR was observed in 13 (23.6%) patients. In patients with triple-negative disease, 10 (38.5%) of 26 achieved pCR, whereas it was observed in 3 (10.3%) of 29 patients with luminal disease. Objective response (complete response or partial response) was achieved in 46 (83.6%) patients, overall. Of 36 patients originally deemed to require mastectomy, conversion to breast-conserving surgery after NAC was achieved by 11 (20.0%) patients. The most common adverse events of grade 3 or higher were myalgia (16.4%), fatigue (14.5%) and transaminase elevation (9.1%). Grade 3 peripheral sensory neuropathy and motor neuropathy occurred in 4 (7.3%) and 3 (5.5%) patients, respectively. No patient experienced grade 4 PN. The dose of nab-PTX had to be reduced in 8 (14.5%) patients, two (3.6%) of whom were due to PN. The EC dose was reduced in 10 (18.2%) patients, this occurred more frequently for non-hematological adverse events (14.5%). The average relative dose intensity of nab-PTX and EC part was 97.4% and 96.3%, respectively. Adverse events led to treatment discontinuation in 8 (14.5%) patients, but there was no discontinuation due to PN. After last cycle of nab-PTX, the average decrease in FACT-NTX scores was 19.9% from baseline, however, it improved to 8.6% decrease at 2 months after last cycle of EC. Conclusions: Compression therapy with elastic stockings and GJG were effective to prevent PN associated with DD nab-PTX regimen. Preventive approach for PN may improve dose intensity of taxane and long-term QOL of breast cancer patients. Citation Format: Akiko Matsumoto, Yuka Maeda, Ayana Sato, Miki Yamada, Tatsuhiko Ikeda, Hiromitsu Jinno. Compression therapy and goshajinkigan for prevention of nab-paclitaxel-induced peripheral neuropathy in patients with operable breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-13.

Clinically significant changes in health-related quality of life in head and neck cancer patients following intensive nutritional care during radiotherapy.

This study aimed to explore whether adherence to intensive nutritional care during radiotherapy would avoid a meaningful worsening in quality of life in head and neck cancer patients; and whether adherence was associated with better nutritional outcomes. Observational prospective study that assessed head and neck cancer patients treated with radiotherapy at a large oncology hospital, between August 2018 and April 2019. The main outcome was minimal clinically important difference in quality of life, assessed with EORTC QLQ-C30 and EORTC QLQ H&N35, between baseline and 12 weeks. To illustrate clinically significant changes in quality of life over timeby adherence, a heat map analysis was performed. We also evaluated nutritional outcomes. Eighty patients were included, half of them (53.8%) were considered adherent. There were no significant difference in quality of life between groups at baseline, with the exception of swallowing (p=0.029) and coughing (p<0.01). After treatment, the heat map demonstrated that adherent patients had nonsignificant clinical change in function scales, while non-adherent patients had a clinically significant worsening in physical, cognitive and social function. The prevalence of malnutrition increased significantly only in non-adherent patients (p<0.01). Adherence to intensive nutritional care may be able to avoid a meaningful worsening in quality of life and result in better nutritional outcomes in head and neck cancer patients. Our results may help to increase the awareness of the assessment of adherence and minimal clinically important difference in quality of life for research purposes and clinical practice.

Treating Insomnia with High Risk of Depression Using Therapist-Guided Digital Cognitive, Behavioral, and Circadian Rhythm Support Interventions to Prevent Worsening of Depressive Symptoms: A Randomized Controlled Trial

Introduction: The global disease burden of major depressive disorder urgently requires prevention in high-risk individuals, such as recently discovered insomnia subtypes. Previous studies targeting insomnia with fully automated eHealth interventions to prevent depression are inconclusive: dropout was high and likely biased, and depressive symptoms in untreated participants on average improved rather than worsened. Objective: This randomized controlled trial aimed to efficiently prevent the worsening of depressive symptoms by selecting insomnia subtypes at high risk of depression for internet-based circadian rhythm support (CRS), cognitive behavioral therapy for insomnia (CBT-I), or their combination (CBT-I+CRS), with online therapist guidance to promote adherence. Methods: Participants with an insomnia disorder subtype conveying an increased risk of depression (n = 132) were randomized to no treatment (NT), CRS, CBT-I, or CBT-I+CRS. The Inventory of Depressive Symptomatology – Self Report (IDS-SR) was self-administered at baseline and at four follow-ups spanning 1 year. Results: Without treatment, depressive symptoms indeed worsened (d = 0.28, p = 0.041) in high-risk insomnia, but not in a reference group with low-risk insomnia. Therapist-guided CBT-I and CBT-I+CRS reduced IDS-SR ratings across all follow-up assessments (respectively, d = –0.80, p = 0.001; d = –0.95, p < 0.001). Only CBT-I+CRS reduced the 1-year incidence of clinically meaningful worsening (p = 0.002). Dropout during therapist-guided interventions was very low (8%) compared to previous automated interventions (57–62%). Conclusions: The findings tentatively suggest that the efficiency of population-wide preventive strategies could benefit from the possibility to select insomnia subtypes at high risk of developing depression for therapist-guided digital CBT-I+CRS. This treatment may provide effective long-term prevention of worsening of depressive symptoms. Trial registration: the Netherlands Trial Register (NL7359).

Meaningful Changes in Patient-Reported Outcomes in Relation to Best Clinical Response and Disease Progression: Post Hoc Analyses from MAIA

Meaningful Changes in Patient-Reported Outcomes in Relation to Best Clinical Response and Disease Progression: Post Hoc Analyses from MAIA

Clinical burden of relapses in aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder: A single center cohort analysis

A retrospective, observational analysis of 47 patients with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD) enrolled at the University of Utah healthcare system was conducted. Visual acuity, neurological disability, and pain medication use were compared in relapsing versus non-relapsing patients. The median observation period was 3.6 years (range: 0.0–11.4 years); the annual relapse rate was 0.1376 (95% confidence interval: 0.0874, 0.191). Relapsing patients (n = 14) exhibited diminished visual acuity, clinically meaningful worsening of neurological disability, and greater pain medication use than non-relapsing patients (n = 33). Therapies that reduce the risk of relapses should be considered when making treatment decisions.