Meaningful Improvement In Fatigue Research Articles

P119 The effectiveness of drug-induced immunosuppression using biologics and Janus-kinase inhibitors in improving fatigue in adults with rheumatoid arthritis: a systematic review of randomised controlled trials

Abstract Background/Aims Fatigue is a prominent and debilitating symptom. Many clinicians indicate that they may not assess fatigue frequently because there are no guidelines for fatigue treatment; thus, they feel unskilled to appropriately manage it. Previous evidence from a 2016 Cochrane review supported the use of biologics for fatigue among people with rheumatoid arthritis (RA). As of yet, this evidence has not been incorporated into management guidelines. Further, it is outdated and lacks data on newer drugs such as biosimilars and Janus-Kinase inhibitors (JAKis). We aimed to update the evidence on the effectiveness of biologics and JAKis for RA-fatigue, with a view to informing future guidelines. Methods Five electronic databases (Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL and PubMed) were systematically searched, from 2014 to present, for randomised controlled trials (RCTs) evaluating pharmacological interventions in adults with RA. Two reviewers contributed to the screening and analysis of the included papers, and any dispute was resolved through a comprehensive discussion. One reviewer then extracted the data and assessed methodological quality using the Cochrane Risk of Bias Tool. The effectiveness of treatments was determined by extracting change from baseline (CFB) data and/or the proportion achieving the minimal clinically important difference (MCID) in fatigue. Where only CFB data were provided, reviewers compared absolute change values against the relevant MCID to evaluate intervention superiority. Owing to data heterogeneity, a narrative synthesis approach was undertaken. Results A total of 43 RCTs and post hoc analyses were included. No eligible studies were found regarding biosimilars. Drug classes investigated included JAKis (n = 27), interleukin-6 inhibitors (n = 9), anti-CD-20 monoclonal antibody (n = 1), selective so-stimulation modulators (n = 2) and TNF inhibitors (n = 4). Of these studies, four were inactive placebo comparator studies, 33 were active placebo comparator studies (i.e. csDMARDs), and six were head-to-head comparator studies. Studies had a low to unclear risk of bias, perhaps due to the high number of post hoc analyses (n = 28, 65%). In total, 37 studies (86%) determined an advantage to using biologics/JAKis; five (12%) determined that treatment with biologics/JAKis was not superior to csDMARDs. The final study showed no meaningful improvement in fatigue from treatment or control. Conclusion Most studies showed that biologics/JAKis hold the potential for fatigue management. However, fatigue reporting was poor, and few studies focussed on fatigue as a primary outcome in post hoc analyses. Therefore, it is not clear whether these treatments may, in fact, be more effective in certain subgroups of patients, for example, those for whom fatigue is a significant problem. Accordingly, the development of treatment guidelines involving these therapies is currently unlikely. We propose that future clinical trials designating fatigue as a primary endpoint will be crucial to improving the establishment of guidelines to support fatigue management. Disclosure H.J. Ghadanfari: None. J.H. Humphreys: None. K.L. Druce: None.

Patient-Reported Outcomes (PROs) from the Phase 2 TRANSCEND FL Study of Lisocabtagene Maraleucel (liso-cel) in Patients (pts) with Relapsed or Refractory Follicular Lymphoma (FL)

Background: In TRANSCEND FL (NCT04245839), a global, phase 2, open-label, single-arm, multicohort, pivotal study, the CAR T cell therapy liso-cel showed promising efficacy and safety in pts with R/R FL (Morschhauser F, et al. Hematol Oncol 2023;41[S2]:877-880). Here, we present corresponding data for PROs. Methods: Adults with R/R FL after ≥ 1 prior (2L+) line of therapy (LOT) were enrolled in cohorts with 1 (2L), 2 (3L), or ≥ 3 (4L+) prior LOTs. After leukapheresis and lymphodepleting chemotherapy (LDC), pts received 1 infusion of liso-cel (100 × 10 6 CAR + T cells). Pts completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-30 items (EORTC QLQ-C30), Functional Assessment of Cancer Therapy-Lymphoma “Additional Concerns” Scale (FACT-LymS), and the EQ-5D-5L on the following schedule: pretreatment (≤ 7 days before LDC; baseline); before infusion on the day of liso-cel infusion (Day 1); on Days 15, 29, 60, 90, 180, 270, 365, 545, and 730 after infusion; and at the end of study assessment. PROs were evaluated using 6 EORTC QLQ-C30 primary domains of interest preselected for relevance to FL, including global health status/quality of life, physical functioning, role functioning, cognitive functioning, fatigue, and pain, and the FACT-LymS subscale assessing lymphoma-specific symptoms. EORTC QLQ-C30 remaining domains, EQ-5D-5L utility index, and EQ-VAS were examined in exploratory analyses. Unless otherwise stated, analyses were performed in all liso-cel-treated pts with assessments at baseline and ≥ 1 postbaseline visit. Separate analyses were done for pts receiving liso-cel as 2L and 3L+ therapy. Linear mixed-effects models for repeated measures were used to calculate least squares (LS) mean change from baseline for visits with ≥ 10 pts. In individual-level analyses, proportions of pts with clinically meaningful changes over time were calculated using published responder definitions. Time to confirmed deterioration or improvement in PROs was assessed in all PRO-evaluable liso-cel-treated pts by the Kaplan-Meier method. Results: Of 130 liso-cel-treated pts with 2L+ R/R FL, 116 were included in the EORTC QLQ-C30 analysis (median age, 60 years; 63% male; 55% White). Among them, 19 (16%) had received 1 prior line of systemic therapy and 97 (84%) had received ≥ 2 prior LOTs (3L, 44 [38%]; 4L+, 53 [46%]). Assessment completion rates were > 80% across visits. For EORTC QLQ-C30, mean baseline scores in study pts were comparable to EU and US population averages, with a few domains slightly worse than the EU general population. After liso-cel infusion, transient deterioration was observed in physical and role functioning and fatigue up to Day 15. Thereafter, PROs were maintained or showed meaningful improvements relative to baseline that approached or exceeded minimally important difference thresholds at some visits. Overall LS mean changes from baseline showed statistically significant improvements in most primary and some secondary domains of interest (Table 1). In individual-level analyses, from Day 29 onward, most pts (65%‒100% across domains and visits) experienced improvements or no changes in primary domains of interest. For all domains, median time to confirmed deterioration was longer than median time to confirmed improvement, indicating that liso-cel-treated pts had a greater chance of achieving improvement in PROs than of experiencing deterioration. More than half of pts achieved meaningful improvements in fatigue, pain, and FACT-LymS at 26, 5, and 15 weeks post infusion, respectively (Table 2). Across PROs, results were comparable between pts receiving liso-cel as 2L or 3L+ therapy, although those receiving liso-cel as 2L therapy generally demonstrated greater/faster meaningful improvements in most primary domains, including role and cognitive functioning, fatigue, pain, and FACT-LymS scores. Conclusions:In TRANSCEND FL, most pts with 2L or 3L+ R/R FL experienced statistically and clinically significant improvements in PROs after liso-cel treatment, including in quality of life, disease symptoms, and functioning. These data, which include the first report of PROs in pts with 2L FL treated with CAR T cell therapy, represent the direct patient experience with liso-cel treatment and complement liso-cel treatment outcomes demonstrating clinical benefit and manageable safety in pts with R/R FL.

Patient-Reported Improvements in Fatigue and Health-Related Quality of Life in the Phase 3 Studies Apply-PNH and Appoint-PNH Evaluating the Use of Iptacopan in C5 Inhibitor-Treated and Treatment-Naïve Patients with Paroxysmal Nocturnal Hemoglobinuria

Introduction: Iptacopan is a first-in-class, oral, selective complement factor B inhibitor that recently demonstrated efficacy and safety as monotherapy in both C5 inhibitor-treated (APPLY-PNH [NCT04558918], Peffault de Latour et al) and treatment-naïve (APPOINT-PNH [NCT04820530], Risitano et al) patients with paroxysmal nocturnal hemoglobinuria (PNH). The primary results of active-comparator controlled APPLY-PNH and single-arm APPOINT-PNH have been reported, showing clinically meaningful increases in hemoglobin levels while controlling intravascular hemolysis and preventing extravascular hemolysis. As patient-perceived benefits of therapies are increasingly important, we present here additional results of the patient-reported outcomes measures (PROMs) including responder analyses of changes from baseline in these two studies based on meaningful within-patient thresholds. Methods: The PROMs included an assessment of fatigue (FACIT-Fatigue) as the basis of a secondary endpoint, a health-related quality of life questionnaire (EORTC QLQ-C30), and a Patient Global Impression of Severity (PGIS) of Fatigue. Both studies analyzed change from baseline in PROMs between Day 1 and Day 168. In APPLY-PNH, another focus was on comparing treatments on the average of model-derived estimates for visits between Day 126 and Day 168. While 5 points on the FACIT-Fatigue was prespecified in the protocol, anchor-based meaningful within-patient change analyses utilizing the PGIS as the anchor determined the range for the magnitude of meaningful change for the FACIT-Fatigue to be 7.5 to 9.5 points (derived from APPLY-PNH); 9 points within the upper segment of the range was chosen as the threshold value used in this analysis. Analyses of the EORTC QLQ C-30 focused on the Physical and Role Functioning subscales and symptoms subscales evaluating Fatigue and Dyspnea. Responder analysis thresholds were determined for all 4 subscales using a combination of anchors including PGIS to determine meaningful change thresholds for each subscale. The ranges and threshold choices were based on the assessment of empirical cumulative distribution function (eCDF) of the scores by scale levels of the anchor and used the visit median values as representative levels to determine the range supporting threshold choices. Results: Ninety-five patients were from APPLY-PNH, of whom 62 received iptacopan and 33 received anti-C5 treatment, and 40 patients were from APPOINT-PNH. In APPLY-PNH, responder analysis showed that more patients in the iptacopan group achieved the threshold of ≥9 points compared with the anti-C5 group (51% vs 11%) ( Table 1). The strength of this result was confirmed by a non-parametric Mann-Whitney test with P values ≤0.0039. In APPOINT-PNH, 56% (95% CI, 43-68) achieved the threshold of ≥9 points and approximately half reached a higher threshold of 11 points ( Table 1). Analyses of EORTC QLQ-C30 further corroborated the results for both trials. Responder analyses in APPLY-PNH of the four subscales using internally derived thresholds showed average proportions of responders in the iptacopan group 39% to 49% and in the anti-C5 group ranging from 9% to 20% ( Table 2). The strength of these results was confirmed by a non-parametric assessment of cumulative distribution functions and Mann-Whitney with P values ≤0.0088. In APPOINT-PNH, the estimated average proportions of responders for EORTC QLQ C30 ranged from 41% to 55% ( Table 2). Conclusion: Both anti-C5-experienced and treatment-naïve patients receiving iptacopan exhibited clinically meaningful improvements in fatigue, health-related quality of life, and disease-related symptoms as measured by predetermined meaningful thresholds of response in FACIT-Fatigue and EORTC QLQ-C30. Together with previous presented primary efficacy data from APPLY-PNH and APPOINT-PNH, these results indicate that iptacopan not only results in clinically meaningful improvements in markers of disease control but provides meaningful improvements in aspects that are important to patients (ie, fatigue and other aspects of health-related quality of life, such as physical functioning and role functioning).

Remote ischaemic conditioning for fatigue after stroke (RICFAST): A pilot randomised controlled trial

BackgroundPost stroke fatigue (PSF) affects 50 % of stroke survivors, and can be disabling. Remote ischaemic conditioning (RIC), can preserve mitochondrial function, improve tissue perfusion and may mitigate PSF. This pilot randomised controlled trial evaluates the safety and feasibility of using RIC for PSF and evaluated measures of cellular bioenergetics. Methods24 people with debilitating PSF (7 item Fatigue Severity Score, FSS-7 > 4) were randomised (1:1) in this single-centre phase 2 study to RIC (blood pressure cuff inflation around the upper arm 200 mmHg for 5 min followed by 5 min of deflation), or sham (inflation pressure 20 mmHg), repeated 4 cycles, 3 times per week for 6 weeks. Primary outcomes were safety, acceptability, and compliance. Secondary outcomes included FSS-7, 6 min walking test (6MWT), peak oxygen consumption (V̇O2peak), ventilatory anaerobic threshold (VAT), and muscle adenosine triphosphate (ATP) content measured using 31-phosphorous magnetic resonance spectroscopy of tibialis anterior. ResultsRIC was safe (no serious adverse events, adverse events mild) and adherence excellent (91 % sessions completed). Exploratory analysis revealed lower FSS-7 scores in the RIC group compared to sham at 6 weeks (between group difference FSS-7 -0.7, 95 %CI -2.0 to 0.6), 3 months (-1.0, 95 %CI -2.2 to 0.2) and 6 months (-0.9, 95 %CI -2.0 to 0.2). There were trends towards increased VAT, increased muscle ATP content and improved 6MWT in the RIC group. DiscussionRIC is safe and acceptable for people with PSF and may result in clinically meaningful improvements in fatigue and muscle bioenergetics that require further investigation in larger studies.

Effects of Technology Assisted Stepped Collaborative Care Intervention to Improve Symptoms in Patients Undergoing Hemodialysis

Patients with end-stage kidney disease (ESKD) undergoing long-term hemodialysis often experience a high burden of debilitating symptoms for which effective treatment options are limited. To compare the effectiveness of a stepped collaborative care intervention vs attention control for reducing fatigue, pain, and depression among patients with ESKD undergoing long-term hemodialysis. Technology Assisted Stepped Collaborative Care (TĀCcare) was a parallel-group, single-blinded, randomized clinical trial of adult (≥18 years) patients undergoing long-term hemodialysis and experiencing clinically significant levels of fatigue, pain, and/or depression for which they were considering treatment. The trial took place in 2 US states (New Mexico and Pennsylvania) from March 1, 2018, to June 31, 2022. Data analyses were performed from July 1, 2022, to April 10, 2023. The intervention group received 12 weekly sessions of cognitive behavioral therapy delivered via telehealth in the hemodialysis unit or patient home, and/or pharmacotherapy using a stepped approach in collaboration with dialysis and primary care teams. The attention control group received 6 telehealth sessions of health education. The coprimary outcomes were changes in fatigue (measured using the Functional Assessment of Chronic Illness Therapy Fatigue), average pain severity (Brief Pain Inventory), and/or depression (Beck Depression Inventory-II) scores at 3 months. Patients were followed up for 12 months to assess maintenance of intervention effects. There were 160 participants (mean [SD] age, 58 [14] years; 72 [45%] women and 88 [55%] men; 21 [13%] American Indian, 45 [28%] Black, 28 [18%] Hispanic, and 83 [52%] White individuals) randomized, 83 to the intervention and 77 to the control group. In the intention-to-treat analyses, when compared with controls, patients in the intervention group experienced statistically and clinically significant reductions in fatigue (mean difference [md], 2.81; 95% CI, 0.86 to 4.75; P = .01) and pain severity (md, -0.96; 95% CI, -1.70 to -0.23; P = .02) at 3 months. These effects were sustained at 6 months (md, 3.73; 95% CI, 0.87 to 6.60; P = .03; and BPI, -1.49; 95% CI, -2.58 to -0.40; P = .02). Improvement in depression at 3 months was statistically significant but small (md -1.73; 95% CI, -3.18 to -0.28; P = .02). Adverse events were similar in both groups. This randomized clinical trial found that a technology assisted stepped collaborative care intervention delivered during hemodialysis led to modest but clinically meaningful improvements in fatigue and pain at 3 months vs the control group, with effects sustained until 6 months. ClinicalTrials.gov Identifier: NCT03440853.

Complement-directed therapy for cold agglutinin disease: sutimlimab

ABSTRACT Introduction Cold agglutinin disease (CAD) is a rare subtype of autoimmune hemolytic anemia defined as a distinct, low-grade lymphoproliferative disorder and characterized by the presence of immunoglobulin M (IgM) antibodies that recognize the ‘I’ antigen on red blood cell membranes. Hemolysis in CAD is mediated by activation of the classical complement pathway by IgM–antigen complexes. Sutimlimab directly targets classical complement pathway activation and has been shown to be generally well tolerated with rapid and sustained effects on hemoglobin levels, hemolytic markers, and fatigue in patients with CAD. Areas covered This review will outline the drug profile of sutimlimab and summarize the key efficacy and safety data focusing on the Phase 3 studies that formed the basis of the approval of sutimlimab in patients with CAD in the US, the EU, and Japan. Expert opinion Sutimlimab provides patients with an approved therapeutic option that can be used as part of a holistic approach to CAD management. The beneficial effects of sutimlimab go beyond rapid inhibition of hemolysis and include sustained meaningful improvements in fatigue and quality-of-life measures. Further, real-world evidence of the effectiveness and safety of sutimlimab in CAD and cold agglutinin syndrome will be assessed via the CADENCE registry.

Concomitant Use of Sutimlimab and COVID-19 Vaccines in Patients with Cold Agglutinin Disease from the Phase 3 Cardinal and Cadenza Studies

Background: Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia, characterized by chronic hemolysis mediated by classical complement pathway activation. The ongoing COVID-19 pandemic has posed an additional challenge in treating patients with CAD. Anti-CD20 therapies (commonly used off-label to treat CAD) increase the risk of serious COVID-19 infection and reduce the immune response to COVID-19 vaccines. Recent evidence has also shown a correlation between CAD exacerbations and both COVID-19 and COVID-19 vaccines; raising concern amongst clinicians as CAD patients are usually elderly with comorbidities and will likely require additional boosters during the ongoing pandemic. Sutimlimab (SUT), recently FDA approved for patients with CAD, is a first-in-class humanized monoclonal antibody which selectively targets C1s in the classical complement pathway; addressing the underlying mechanism of hemolysis in CAD. In the Phase 3 CARDINAL (NCT03347396) and CADENZA (NCT03347422) studies, SUT treatment led to rapid and sustained increases in hemoglobin and clinically meaningful improvements in fatigue and was generally well tolerated - reported adverse events (AE) were consistent with elderly populations. Both studies spanned the period before and during the pandemic; investigators were advised to vaccinate enrolled patients without stopping SUT treatment. However, the impact of SUT on immune response to COVID-19 vaccination is unknown. Objective: To explore concomitant use of COVID-19 vaccines and SUT in patients with CAD Methods: Post-hoc analysis from the open label extension (OLE) part of the CADENZA and CARDINAL studies. COVID-19 cases/diagnoses were collected via the regular AE reporting system. Data on tolerability to COVID-19 vaccine was collected through AE reports. Immunogenicity to COVID-19 vaccines was analyzed in a subset of patients fully vaccinated (2 doses) against COVID-19 and had consented to the use of stored samples (collected no later than 6 months after vaccination). Anti-Sars-CoV-2 Spike (EUROIMMUN Anti-SARS-CoV-2 ELISA) and anti-Sars-CoV-2 Nucleocapsid (Abbott Architect i2000 SR) IgG titers were measured. Three patients who tested positive for COVID-19 during Part A of both studies were excluded from the immunogenicity analysis. Results: Of the 61 completers from both studies, 47 received at least one dose of a COVID-19 vaccine; 14 received none; 11 had an additional booster. All participants, regardless of vaccination status, had similar demographic and clinical characteristics. Among those vaccinated, most (83%) received both doses during the studies; of these, mRNA vaccines were the most common (79%). The mean inter-dose interval for fully vaccinated patients (n=37) was 38 days; those who received 1 booster (n=11) had a mean of 165 days between the last dose and booster. No COVID-19 cases were reported during the OLE. Ten AEs were reported in 8 patients during the 7 days after any vaccine dose, but none more than once, and there were no serious AEs. SUT therapy was postponed/skipped twice due to vaccine administration, at the investigator's discretion. Anemia and hemolysis markers, including hemoglobin and total bilirubin, were measured after vaccination to assess its impact on hemolytic activity. No indications of hemolytic exacerbation were observed (Table 1). The immunogenicity analysis comprised 27 patients. All patients developed an immune response post-vaccination, measured via positive IgG anti-spike antibodies (Figure 1). The mean time between last dose and serum collection was 65 days (range: 25-137). Antibody titers were similar irrespective of gender or age. A further analysis performed on 6 patients with booster vaccinations demonstrated elevated immune responses pre to post booster (mean [95% CI] log10 titer change: 1.82 [0.79-2.85]). To rule out previous asymptomatic COVID-19 infection, anti-nucleocapsid SARS-Cov-2 IgG antibodies were assayed and were negative in all cases. Conclusions: COVID-19 vaccination response was not impaired in patients with CAD being treated with SUT. COVID-19 vaccines were well tolerated, and there were no signs of increased hemolytic marker activity following COVID-19 vaccination in patients receiving SUT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The impact of tofacitinib on fatigue, sleep, and health-related quality of life in patients with rheumatoid arthritis: a post hoc analysis of data from Phase 3 trials

BackgroundFatigue, a common symptom of rheumatoid arthritis (RA), is detrimental to health-related quality of life (HRQoL). We evaluated the impact of tofacitinib on fatigue, sleep, and HRQoL and explored associations between fatigue, related patient-reported outcomes (PROs), and disease activity in RA patients.MethodsThis post hoc analysis pooled data from three Phase 3 studies of tofacitinib (ORAL Scan; ORAL Standard; ORAL Sync) in RA patients. Patients received tofacitinib 5 or 10 mg twice daily, placebo, or adalimumab (active control; ORAL Standard only, not powered for superiority) with conventional synthetic disease-modifying antirheumatic drugs. Assessed through Month (M)12 were changes from baseline in disease activity, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Medical Outcomes Study Sleep scale (MOS-SS), and Short Form-36 Health Survey (SF-36) composite/domain scores, and proportions of patients reporting improvements from baseline in FACIT-F total and SF-36 domain scores ≥ minimum clinically important differences (MCIDs) or ≥ population normative values. Pearson correlations examined associations among PROs at M6. Treatment comparisons were exploratory, with p < 0.05 considered nominally significant.ResultsGenerally, active treatment led to significant improvements from baseline in FACIT-F total, and MOS-SS and SF-36 composite/domain scores vs placebo, observed by M1 and maintained through M6 (last placebo-controlled time point). Through M6, more patients achieved improvements from baseline ≥ MCID and achieved scores ≥ population normative values in FACIT-F total and SF-36 domain scores with tofacitinib vs placebo. Through M12, some nominally significant improvements with tofacitinib vs adalimumab were observed. With active treatment at M6, FACIT-F scores were moderately (0.40–0.59) to highly (≥ 0.60) correlated with SF-36 composite/domain scores (particularly vitality), moderately correlated with most MOS-SS domain scores, and highly correlated with MOS-SS Sleep Problems Index I scores. Disease activity correlations were moderate with FACIT-F scores and low (0.20–0.39) to moderate with SF-36 general health domain/composite scores.ConclusionTofacitinib and adalimumab generally conferred significant, clinically meaningful improvements in fatigue, sleep, and HRQoL (including vitality) vs placebo through M6, with improvements maintained to M12. M6 correlations between FACIT-F, PROs of sleep, HRQoL, and disease activity underscore the interrelatedness of multiple PROs and disease activity in RA.Trial registrationClinicalTrials.govNCT00847613 (registered: February 19, 2009); NCT00853385 (registered: March 2, 2009); NCT00856544 (registered: March 5, 2009).

Literature Review of Fatigue Scales and Association with Clinically Meaningful Improvements in Outcomes Among Patients With and Without Paroxysmal Nocturnal Hemoglobinuria.

IntroductionParoxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by anemia and debilitating fatigue. Limited evidence characterizes the association between hemoglobin, an indicator of anemia and disease activity, and patient-reported fatigue scales. This review identifies benchmarks for clinically meaningful improvements in patients with and without PNH.MethodsMEDLINE, Embase, Cochrane, and PsycINFO databases were searched along with Google Scholar to identify publications for patients with and without PNH. Full-text articles and conference abstracts of clinical trials or observational studies that examined patient-reported fatigue or associations between fatigue and hemoglobin were included.ResultsFourteen publications were included in this study. Four clinical trials conducted in patients with PNH reported that patients achieved and sustained clinically meaningful improvements in fatigue. However, these studies did not examine the association between fatigue and hemoglobin. Ten studies conducted in patients with cancer and anemia (with or without chemotherapy) demonstrated an association between increased hemoglobin and improvements in fatigue (P < 0.05). The greatest incremental gain in fatigue improvement was observed when hemoglobin increased from 11 to 12 g/dL.ConclusionEvidence among patients with cancer without PNH demonstrates that increased hemoglobin levels are associated with clinically significant improvements in fatigue. Future studies should validate this relationship among patients with PNH.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02111-7.

Health-related quality of life with idecabtagene vicleucel in relapsed and refractory multiple myeloma

AbstractIdecabtagene vicleucel (ide-cel), a B-cell maturation antigen–directed chimeric antigen receptor T cell therapy, showed deep, durable responses in patients with triple-class exposed, relapsed and refractory multiple myeloma (RRMM) in the phase 2 KarMMa (Efficacy and Safety Study of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma) trial. We assessed health-related quality of life (HRQoL) among KarMMa patients. The European Organization for Research and Treatment of Cancer Quality of Life C30 Questionnaire and its supplementary 20-item multiple myeloma module, as well as the EuroQol 5-dimension 5-level instrument, were administered at screening, baseline (≤72 hours before or same day as lymphodepletion), day of ide-cel treatment, and after ide-cel treatment. Mean changes from baseline that exceeded the predetermined threshold of minimally important difference were deemed clinically meaningful. The proportions of patients experiencing clinically meaningful changes in HRQoL were assessed using within-patient change thresholds. Time to stable improvement (≥2 consecutive visits with clinically meaningful HRQoL improvements) was analyzed by using the Kaplan-Meier method. A total of 126 (98%) of 128 patients treated with ide-cel were included in the HRQoL analysis. Pretreatment baseline RRMM burden was high and meaningfully worse than that in the age- and sex-weighted general population. Statistically significant and clinically meaningful improvements from baseline were observed by month 1 for pain (−8.9) and disease symptoms (−10.2), and by month 2 for fatigue (−7.2), physical functioning (6.1), cognitive functioning (6.7), and global health status/QoL (8.0). Clinically meaningful improvements in fatigue, pain, and physical functioning were most prominent at months 9, 12, and 18, respectively, and were sustained through 15 to 18 months after ide-cel treatment. For triple-class exposed patients with RRMM with a poor prognosis and few treatment options, a single ide-cel infusion provides early, sustained, statistically significant, and clinically meaningful improvements in HRQoL. This study was registered at Clinicaltrials.gov as #NCT03361748.

Updated Health-Related Quality of Life Results from the KarMMa Clinical Study in Patients with Relapsed and Refractory Multiple Myeloma Treated with the B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy Idecabtagene Vicleucel (ide-cel, bb2121)

Updated Health-Related Quality of Life Results from the KarMMa Clinical Study in Patients with Relapsed and Refractory Multiple Myeloma Treated with the B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy Idecabtagene Vicleucel (ide-cel, bb2121)

S851 Health-Related Quality of Life With Ustekinumab vs Adalimumab for Induction and Maintenance Therapy in Biologic-Naïve Patients With Moderate-To-Severe Crohn’s Disease: PROMIS-29 in the SEAVUE Study

Introduction: Patients (pts) with Crohn’s disease (CD) suffer from systemic symptoms, including fatigue, that negatively affect health-related quality of life (HRQoL). In SEAVUE, we evaluated the changes in systemic symptoms through 1 year with ustekinumab (UST) vs adalimumab (ADA) in biologic-naïve pts with CD using the Patient-Reported Outcome Measurement Information System-29 (PROMIS-29) questionnaire. PROMIS-29 measures anxiety, depression, fatigue, sleep disturbance, pain interference, pain intensity, physical function, and ability to participate in social roles and activities. Methods: SEAVUE was a multicenter, randomized, blinded, parallel-group, active-controlled study in biologic-naïve adults with CD Activity Index (CDAI) scores ≥220/≤450. Pts were randomized 1:1 to UST (⁓6mg/kg IV at baseline then 90mg SC every 8 weeks) or ADA (160/80mg SC at baseline/Week 2, then 40mg SC every 2 weeks) per US-approved regimens. Dose modification was not allowed. Mean changes and clinically meaningful improvement from baseline were assessed for each PROMIS-29 domain. Results: Among 386 randomized pts, baseline mean PROMIS-29 scores were similar between treatment groups (anxiety: 60 UST, 60 ADA; depression: 57 UST, 57 ADA; fatigue: 62 UST, 61 ADA; sleep disturbance: 54 UST, 53 ADA; pain interference: 61 UST, 60 ADA; pain intensity: 6 UST, 5 ADA; physical function: 43 UST, 44 ADA; ability to participate in social roles and activities: 44 UST, 45 ADA). In both groups, improvements in all PROMIS-29 domain scores were observed as early as Week 8 (data not shown) and continued through Week 52 (Table). Improvements from baseline to Week 52 were similar between groups for all domains. When clinically meaningful improvement from baseline to Week 52 (change ≥5 points) was evaluated, significantly more pts in the UST vs ADA group achieved this endpoint for the fatigue (decrease ≥5 points: 58.6% UST, 47.7% ADA; nominal p=0.030) and ability to participate in social roles and activities (increase ≥5 points: 58.6% UST, 47.7% ADA; nominal p=0.032) domains; there was no significant difference between groups for the other domains. Conclusion: PROMIS-29 domain scores improved similarly with UST and ADA through Week 52 in biologic-naïve pts with moderate-to-severe CD. Clinically meaningful improvement in fatigue and ability to participate in social roles and activities scores was more commonly observed with UST vs ADA, potentially reflecting better HRQoL in biologic-naïve pts with CD.Table 1.: Change from baseline to Week 52 in PROMIS-29 domain scores and the percentage of pts who achieved a clinically meaningful improvement between baseline and Week 52.

Comparative effectiveness of pegcetacoplan versus ravulizumab in patients with paroxysmal nocturnal hemoglobinuria previously treated with eculizumab: a matching-adjusted indirect comparison

Objective In the absence of a head-to-head study, we assessed the comparative effectiveness of pegcetacoplan, a targeted C3 complement inhibitor, vs. ravulizumab, a C5 complement inhibitor, among patients with paroxysmal nocturnal hemoglobinuria (PNH) previously treated with eculizumab using matching-adjusted indirect comparison methodology. Methods Individual patient data from the PEGASUS study (NCT03500549) comparing pegcetacoplan and eculizumab enabled adjustment for baseline differences compared with published results from the ALXN1210-PNH-302 study (NCT03056040), comparing ravulizumab and eculizumab. Adjusted differences and 95% confidence intervals (CIs) were computed via weighted Wald tests for comparisons of pegcetacoplan vs. ravulizumab, anchored to the common comparator eculizumab. Results Sixty-eight patients from PEGASUS (36 pegcetacoplan; 32 eculizumab) and 195 from ALXN1210-PNH-302 (97 ravulizumab; 98 eculizumab) were included. Compared with ravulizumab, treatment with pegcetacoplan was associated with more transfusion avoidance (adjusted difference [95% CI] = +71.4% [53.5%, 89.3%]), hemoglobin level stabilization (+75.5% [56.4%, 94.6%]), lactate dehydrogenase (LDH) level normalization (+64.0% [41.8%, 86.1%]), and fewer blood transfusions (−5.7 units [−7.2, −4.2]). Additionally, patients who received pegcetacoplan experienced clinically meaningful improvements in fatigue (+8.2 points [3.8, 12.6]), global health status (+9.6 points [0.1, 19.0]), physical functioning (+11.5 points [3.6, 19.5]), and fatigue symptoms (−13.3 points [−23.7, −3.0]), compared with ravulizumab. Mean change from baseline in LDH level was not significantly different for pegcetacoplan vs. ravulizumab. Conclusions Results suggest that among patients previously treated with eculizumab, clinical, hematological, and quality of life endpoints were better for patients who received the C3 complement inhibitor pegcetacoplan vs. patients who received ravulizumab, a C5 complement inhibitor.

Feasibility of investigating methylphenidate for the treatment of sarcoidosis-associated fatigue (the FaST-MP study): a double-blind, parallel-arm randomised feasibility trial

IntroductionSarcoidosis-associated fatigue (SAF) is a common clinical problem with limited treatment options. This study was undertaken to determine the feasibility of performing a definitive trial to determine the clinical efficacy...

Assessment of Outcomes After Stopping Tyrosine Kinase Inhibitors Among Patients With Chronic Myeloid Leukemia

Tyrosine kinase inhibitors (TKIs) have been associated with improved survival of patients with chronic myeloid leukemia (CML) but are also associated with adverse effects, especially fatigue and diarrhea. Discontinuation of TKIs is safe and is associated with the successful achievement of treatment-free remission (TFR) for some patients. To evaluate molecular recurrence (MRec) and patient-reported outcomes (PROs) after TKI discontinuation for US patients with CML. The Life After Stopping TKIs (LAST) study was a prospective single-group nonrandomized clinical trial that enrolled 172 patients from 14 US academic medical centers from December 18, 2014, to December 12, 2016, with a minimum follow-up of 3 years. Participants were adults with chronic-phase CML whose disease was well controlled with imatinib, dasatinib, nilotinib, or bosutinib. Statistical analysis was performed from August 13, 2019, to March 23, 2020. Discontinuation of TKIs. Molecular recurrence, defined as loss of major molecular response (BCR-ABL1 International Scale ratio >0.1%) by central laboratory testing, and PROs (Patient-Reported Outcomes Measurement Information System computerized adaptive tests) were monitored. Droplet digital polymerase chain reaction (ddPCR) was performed on samples with undetectable BCR-ABL1 by standard real-time quantitative polymerase chain reaction (RQ-PCR). Of 172 patients, 89 were women (51.7%), and the median age was 60 years (range, 21-86 years). Of 171 patients evaluable for molecular analysis, 112 (65.5%) stayed in major molecular response, and 104 (60.8%) achieved TFR. Undetectable BCR-ABL1 by either ddPCR or RQ-PCR at the time of TKI discontinuation (hazard ratio, 3.60; 95% CI, 1.99-6.50; P < .001) and at 3 months (hazard ratio, 5.86; 95% CI, 3.07-11.1; P < .001) was independently associated with MRec. Molecular recurrence for patients with detectable BCR-ABL1 by RQ-PCR was 50.0% (14 of 28), undetectable BCR-ABL1 by RQ-PCR but detectable by ddPCR was 64.3% (36 of 56), and undetectable BCR-ABL1 by both ddPCR and RQ-PCR was 10.3% (9 of 87) (P ≤ .001). Of the 112 patients in TFR at 12 months, 90 (80.4%) had a clinically meaningful improvement in fatigue, 39 (34.8%) had a clinically meaningful improvement in depression, 98 (87.5%) had a clinically meaningful improvement in diarrhea, 24 (21.4%) had a clinically meaningful improvement in sleep disturbance, and 5 (4.5%) had a clinically meaningful improvement in pain interference. Restarting a TKI resulted in worsening of PROs. In this study, TKI discontinuation was safe, and 60.8% of patients remained in TFR. Discontinuation of TKIs was associated with improvements in PROs. These findings should assist patients and physicians in their decision-making regarding discontinuation of TKIs. Detectable BCR-ABL1 by RQ-PCR or ddPCR at the time of TKI discontinuation was associated with higher risk of MRec; clinical application of this finding should be confirmed in other studies. ClinicalTrials.gov Identifier: NCT02269267.

Safety, Efficacy, and Patient-Reported Outcomes of Venetoclax in Combination with Azacitidine for the Treatment of Patients with Higher-Risk Myelodysplastic Syndrome: A Phase 1b Study

Safety, Efficacy, and Patient-Reported Outcomes of Venetoclax in Combination with Azacitidine for the Treatment of Patients with Higher-Risk Myelodysplastic Syndrome: A Phase 1b Study

Functional Assessment of Fatigue and Other Patient-Reported Outcomes in Patients Enrolled in the Global aHUS Registry

IntroductionAtypical hemolytic uremic syndrome (aHUS) is a progressive and potentially life-threatening disease characterized by complement-mediated thrombotic microangiopathy. Patients with aHUS may experience fatigue, which can negatively impact their lives, but there is a knowledge gap regarding disease burden in these patients.MethodsIn this longitudinal study, patients with aHUS from the Global aHUS Registry who completed patient-reported outcome assessments (Functional Assessment of Chronic Illness Therapy-Fatigue scale [FACIT-Fatigue], general health status, and work status) at ≥2 time points were assessed relative to treatment status: (i) never treated with eculizumab; (ii) on eculizumab at registry enrollment and continued therapy; and (iii) started eculizumab after registry enrollment.ResultsPatients who started eculizumab after the baseline visit (n = 23) exhibited improvements in fatigue (nearly 75% achieved clinically meaningful improvement), improved general health status (55%), and 25% to 30% rate reduction in symptoms of fatigue, weakness, irritability, nausea/vomiting, and swelling at last follow-up. Among patients already on eculizumab at registry enrollment (n = 295) and those never treated (n = 233), these parameters changed minimally relative to the baseline. Emergency room visits and hospital admissions were similar between groups. The number of health care provider visits and work days missed were higher in patients who started eculizumab after registry enrollment.ConclusionThese real-world findings confirm the detrimental effects of aHUS on patients’ daily lives, including high levels of fatigue and impairments in general health status. The results suggest clinically meaningful improvement in fatigue, other patient-reported outcomes, and symptoms with eculizumab initiation after enrollment into the aHUS registry.

Does Kidney Transplantation Affect Sleep and Fatigue in Patients With Kidney Disease?

Sleep disorders and fatigue are highly prevalent in chronic kidney disease (CKD) and end-stage kidney disease (ESKD) patients but there is limited evidence on the effect of kidney transplant (KTx) on these. In a prospective cohort study of patients with advanced CKD (estimated glomerular filtration rate<30 mL/min/1.73 m2) or ESKD, polysomnography and patient-reported symptom assessments were conducted. Pre- and post-KTx changes in sleep apnea (SA) severity (measured by apnea hypopnea index [AHI]) were analyzed and compared with patients who did not receive KTx. Regression models were used to examine predictors of SA severity. Among 77 patients (mean age 51 y, BMI 29 kg/m2, 66% males, 23% ESKD), 61% had SA at baseline. Among 39 KTx recipients, 56% had SA, with 39% having moderate-severe SA after 10 ± 5.6 months post-KTx. There was no difference in AHI in either the KTx (median 6 versus 8; P = 0.37) or no-KTx (median 15 versus 16; P = 0.61) groups after an average of 19.9 ± 8.9 months. KTx led to significant clinically meaningful improvements in fatigue and health-related quality of life (adjusted effect size 0.3-0.6). In multivariable regression, baseline AHI was the only significant predictor of SA severity (adjusted β = 3.6/5 units, 95% confidence interval 2.1, 5.2) after adjusting for KTx status, age, sex, and body mass index. More than half of the KTx recipients had SA. There was no significant change in SA severity with KTx. Clinically meaningful moderate size improvements in patient-reported fatigue and health-related quality of life may be seen with KTx.

Wednesday, September 26, 2018 7:35 AM–9:00 AM ePosters

BACKGROUND CONTEXT The primary goal of surgery for lumbar degenerative disease is to reduce pain and improve physical function. However, patients often experience problems in other areas of health and wellness. In setting expectations for outcomes of lumbar spine surgery, it is beneficial to understand how changes in pain and physical function may influence these other domains. PROMIS is a multidimensional assessment that measures spine patients’ pain, physical function, fatigue, anxiety, depression, sleep disturbance and social participation with a population mean of 50 (SD 10). PURPOSE To investigate whether treatment of pain and physical limitation with surgery for lumbar degenerative disease will result in improvements in other domains of health and wellness. STUDY DESIGN/SETTING Longitudinal study. PATIENT SAMPLE A total of 1,246 visits of 490 unique patients. OUTCOME MEASURES PROMIS domain change scores (preoperative vs. postoperative). METHODS Patients undergoing surgery for degenerative lumbar disease completed PROMIS surveys preoperatively and 6 weeks and 3, 6 and 12 months postoperatively. Between Dec. 2014 and Jan. 2018, PROMIS data was collected for 1,246 visits of 490 unique patients. Repeated measures logistic regression was used to calculate the odds of a meaningful improvement (MCID) in PROMIS domains given a 5-point improvement in either pain or physical function. RESULTS A 5-point decrease in pain was associated with a 59% increased odds of MCID in fatigue (95% CI 1.26–2.01, p= CONCLUSIONS Decreases in pain yield meaningful improvements in fatigue, anxiety, sleep disturbance and social participation. Additionally, gains in physical function result in meaningful improvements in both fatigue and social role participation. Although patients undergo lumbar spine surgery primarily due to pain and physical limitations, our results suggest that improvement in these domains will lead to gains in other areas of health and wellness.

Friday, September 28, 2018 4:05 PM–5:05 PM abstracts: new concepts: cervical spine: 241. Improvements in pain and physical function after cervical spine surgery predict betterment in other areas of health and wellness

BACKGROUND CONTEXT The primary goal of surgery for cervical degenerative disease is to reduce pain and improve physical function. However, patients often experience problems in other areas of health and wellness. In setting expectations for outcomes of cervical spine surgery, it would be beneficial to understand how improvements in pain and physical function may influence these other health domains. PROMIS is a multidimensional assessment that measures spine patients’ pain, physical function, fatigue, anxiety, depression, sleep disturbance, and social participation with a population mean of 50 (SD 10). PURPOSE To investigate whether pain and physical limitation with surgery for cervical degenerative disease will result in improvements in other domains of health and wellness. STUDY DESIGN/SETTING Longitudinal study. PATIENT SAMPLE A total of 561 visits of 220 unique patients. OUTCOME MEASURES PROMIS domain change scores (preoperative vs. postoperative). METHODS Patients undergoing surgery for degenerative cervical disease completed PROMIS surveys preoperatively and 6 weeks and 3, 6 and 12 months postoperatively. Between December 2014 and January 2018, PROMIS data was collected for 561 visits of 220 unique patients. Repeated measures logistic regression was used to calculate the odds of a meaningful improvement (MCID) in PROMIS domains given a 5-point improvement in either pain or physical function. RESULTS A 5-point decrease in pain was associated with 76% increased odds of MCID in fatigue (95% CI 1.18, 2.62 p=.006), 57% increased odds for anxiety (CI 1.02, 2.42, p=.039), 76% increased odds for sleep disturbance (CI 1.33–2.33, p CONCLUSIONS Decreases in pain yield meaningful improvements in fatigue, anxiety, sleep disturbance, and social participation. Additionally, gains in physical function result in meaningful improvements in social role participation. Although patients present for cervical spine surgery primarily due to pain and limitations in physical function, our results suggest that improvement in these domains will lead to improvements in other areas of health and wellness.