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Abstract Introduction: NAVD has become a standard-of-care for frontline (1L) treatment (tx) of advanced stage cHL, based on the results of the S1826 study. S1826 demonstrated a 1-year progression free survival (PFS) of 94% for NAVD compared to 86% for brentuximab vedotin-AVD, which remained durable at 2 years (Herrera et al, NEJM 2024). Adverse events (AEs) and efficacy have not been reported in patients (pts) treated with NAVD outside of a clinical trial. Hence, we sought to evaluate safety profile and efficacy outcomes of pts with cHL treated with 1L NAVD in a real-world setting (RWS). Methods: In this multicenter retrospective cohort study, we included pts ≥18 years with cHL treated with 1L standard of care NAVD between 2023 and 2025 at 20 US academic sites. The safety evaluable cohort received at least 1 cycle of NAVD and included pts who have not completed tx. The efficacy evaluable cohort had completed 6 cycles of tx including end of treatment (EOT) PET-CT and included pts who intended to complete tx but died or discontinued due to progressive disease or AEs. The primary endpoint was EOT overall response rate (ORR). Secondary endpoints included EOT complete response rate (CRR), PFS and overall survival (OS). PFS and OS were calculated from the start date of tx and analyzed using the Kaplan Meier method. Results: A total of 311 pts with cHL were treated with NAVD with 26% of pts with tx ongoing (n=83) and 73% with tx completed (n=228). Baseline demographics included 55% male pts, 60% with stage IV disease (stage IIB, n=4) and 84% with nodular sclerosis subtype. Median age was 37 years (range 18-88), 29% had bulky disease (>7.5 cm), 28% were EBV positive (n=74/268), 8% had history of an autoimmune disease, and 31% had an IPS 4-7. G-CSF was given in 64% of pts. All patients were safety evaluable. Tx was interrupted (any length) in 24%, reduced in 12%, and discontinued in 14%. The most common reason for dose reduction was neuropathy in 4%. Nivolumab was discontinued in 10% and all therapy in 3.7% due to toxicity. Any AE and any grade 3 or higher AE (>G3) were observed in 92% and 62%, respectively. Neutropenia of any grade occurred in 68% (48% >G3), infection in 25% (10% >G3), and neuropathy in 30% (2.8% >G3). Hospitalization for an AE occurred in 20% (4.5% febrile neutropenia). Among pts with complete data (n=305), any immune related AE (irAE) occurred in 78 pts (25.6%) with any >G3 irAE in 23 pts (7.5%). The most common irAEs included hypothyroidism (7.9%, all grade 1-2), hepatotoxicity (1.6% G1/G2, 3.3% >G3), inflammatory arthritis (3% G1/G2, 0.6% >G3), rash (2.6%, all grade 1-2), and colitis (1% G1/G2, 1% >G3). Other notable >G3 irAEs included adrenal insufficiency (n=2), AKI/ATN (n=1), myocarditis (n=1), diabetes (n=1) and pancreatitis (n=1). Of 84 irAE events, 47 (56%) have had complete resolution. Among all pts, 14.4% (n=45) required systemic steroids at any time (intravenous in 4.1%), 3.2% (n=10) require ongoing steroids/immunosuppression and 8.3% other therapy for an irAE (n=23 levothyroxine, n=1 hemodialysis, n=1 heart failure tx, n=1 insulin). Among all pts, 265 (85%) had an interim PET-CT after 2-4 cycles. The ORR and CRR at interim PET-CT were 97% and 78%, respectively. In the efficacy evaluable population (n=228), the EOT ORR and CRR were 96% and 90%. The median follow up was 10.2 mo (range 0.27-28.52). The 1-year PFS and OS estimates were 93.8% (95% CI: 90.8-98.4%) and 99.1% (95% CI: 97.9-100%), respectively. In multivariable analysis (MVA), only IPS score (OR 0.6, 95%CI: 0.59-0.60) was associated with lower CRR. In Cox univariable analysis, EBV+ status (HR=14.8, 95% CI: 3.2-69.2), IPS score (HR=1.5, 95% CI: 1.0-2.2), and ESR (HR=1.02, 95% CI: 1.00-1.04) were associated with worse PFS. Among the 11 pts with progression/relapse, 9 were primary refractory. 10 pts were started on second line (2L) therapy, and all pts are alive (1 pt pending 2L tx initiation). There were 2 deaths: one related to infectious complications and other unknown and both occurred after the first cycle of therapy. Conclusions: Pts treated with NAVD in a large RWS showed comparable response rates and 1-year survival outcomes to those in the pivotal S1826 trial. Most AEs were similar and grade 1-2, but close monitoring of irAEs is necessary given the potential long-term toxicity of checkpoint inhibitors and potential for ≥G3 irAEs (7.5%) in this young patient population. Our data supports the use of NAVD for 1L advanced stage cHL.

Abstract INTRODUCTION Outcomes for 1st relapse of pediatric B-lymphoblastic leukemia (B-ALL), especially high/intermediate-risk (HR/IR) relapse, remain unacceptably poor. Limited enrollment of this population on cooperative group clinical trials has impeded our ability to study potentially effective regimens. In the current era, patients can access innovative immunotherapies commercially. However, there is no mechanism to capture outcomes for these off-study patients and no comparative effectiveness data to guide treatment selection. METHODS We conducted a multicenter, retrospective study of patients <30 years who initiated 1st relapse therapy at a participating center from 2018-2022 (ReCALL-1 Study). Objectives were to define real-world survival outcomes, compare response rates of reinduction strategies, describe the post-reinduction treatment landscape, and, for patients with HR/IR relapse, assess the comparative effectiveness (CE) of blinatumomab to hematopoietic cell transplant (blina/HCT) v CD19 CAR T cells (CART). For the CE analysis, we emulated an open-label, randomized study of blina/HCT v CART who achieved an M1/M2 marrow at the end of an intensive reinduction (EoRI). Patients were classified by their intended treatment at EoRI. Cox regression models were used to adjust for unbalanced patient and disease features by arms. The primary outcome was overall survival (OS) from EoRI. RESULTS The full cohort included 479 patients from 33 centers (31 US, 2 international). Median time to relapse was 31 months (m); 77% had bone marrow (BM) involvement and 31% central nervous sytem involvement. With a median follow-up of 49m from relapse, 4 year (y) OS, event-free survival (EFS), and non-relapse mortality (NRM) were 64%, 43%, and 13%, respectively. Among patients with very early BM (<18m, n=79), early BM (18-35m, n=76), late BM (≥36m, n=162), and isolated CNS (n=85) relapses, 4y OS/EFS were 29%/20%, 57%/35%, 78%/49%, and 84%/61%, respectively. Only 19% received reinduction therapy on a clinical trial. Among patients with BM disease, R3 reinduction (n=179) and VXLD (n=61) had identical MRD-negative (<0.01%) CR rates of 38% (p=1.00) and equivalent treatment failure (TF; M3 or extramedullary disease) rates: R3, 8% v VXLD 7%, p=0.79. Blina (n=33) and inotuzumab-based (n=21) reinductions achieved MRD-negative CR rates of 39% and 52%, respectively, but higher TF rates of 39% and 24%. Reinduction mortality was 2%: R3, n=5; VXLD, n=3; 3-drug reinduction, n=1. Overall, as part of 1st relapse therapy, 36% received CART (78% commercial product), 44% HCT, 40% blina, and 11% inotuzumab. The emulated trial included 159 patients, 95 on blina/HCT and 64 on CART. Study arms were well matched by demographics, cytogenetics, and relapse sites, but CART patients were more likely to have relapsed <18m from diagnosis (34% v 24%) and have EoRI M2 marrows (31% v 11%), and less likely to have private insurance (36% v 51%). Unadjusted OS was comparable between arms (log rank p=0.18): CART, 60% at 4y; blina/HCT, 71%, as was NRM (10% v 13% at 4y). EFS was lower for CART (p=0.049): 4y EFS 35% v 49% for blina/HCT. After adjustment for unbalanced covariates, the hazard of death was equivalent for CART as compared to blina/HCT (aHR 1.1, 95% CI 0.6-2.1, p=0.67) and EFS became more comparable (aHR 1.3, 95% CI 0.8-2.1, p=0.22). 91% of blina/HCT and 97% of CART received their intended cell therapy; time from EoRI to cell therapy was shorter for CART (67 v 86 days, p<.001). In the CART arm, 34% underwent consolidative HCT; 1/3 were preplanned and 2/3 due to loss of B cell aplasia or NGS-MRD positivity. Of those with a 2nd relapse, CART patients were more likely to be CD19 negative (47% v 10%, p=0.003). CONCLUSION In this multicenter, real-world cohort of children treated for 1st relapse in the immunotherapy era, suboptimal outcomes for early BM relapse persisted, with particularly dismal 4y OS of 29% for relapses <18m after diagnosis. In contrast, survival for late BM and isolated CNS relapses compared favorably to historic data. Only 1 in 5 patients initiated relapse therapy on a clinical trial and although 1st relapse is not an approved indication for commercial CART in pediatrics, 36% received CART. In an emulated trial of post-reinduction blina/HCT v CART, adjusted EFS and OS were comparable, suggesting that CART may be a viable alternative to HCT for select patients. Post hoc analyses will identify whether specific subgroups may benefit more from one strategy.

Objective Mycophenolate mofetil (MMF) can stabilize or improve lung function in systemic sclerosis–related interstitial lung disease (SSc‐ILD). We hypothesized that combining MMF with pirfenidone (PFD) would produce a significantly more rapid and/or greater improvement in lung function. Methods A randomized (1:1), double‐blind, placebo (PLA)‐controlled phase 2 trial was conducted in SSc‐ILD in which patients received PFD or PLA (801 mg three times daily) along with MMF (1,500 mg twice daily) for 18 months. The primary outcome was change in percent predicted forced vital capacity (FVC‐%). Linear mixed‐effects models assessed treatment differences in a modified intention‐to‐treat population. Results Only fifty‐one of 150 intended subjects (34%) were randomized (MMF+PLA, n = 24; MMF+PFD, n = 27). The FVC‐% improved from baseline to 18 months by 2.24 ± 1.35 (least‐squares mean [LSM] ± SEM) in the MMF+PLA group and 2.09 ± 1.28 in the MMF+PFD group (LSM treatment difference −0.14; P = 0.93). Median time to achieve a ≥3% improvement in FVC‐% was numerically faster in the MMF+PFD versus MMF+PLA group (12.3 vs 17.8 months, respectively), but the difference was not significant ( P = 0.33). For secondary outcomes, only the change over 18 months in the Patient‐Reported Outcomes Measurement Information System 29‐item physical function score, favoring MMF+PFD, reached statistical significance ( P = 0.04). Although other related patient‐reported outcomes (PROs) numerically favored the MMF+PFD group, as did quantitative high‐resolution computed tomography measures of ILD, the differences between groups did not reach statistical significance. Early withdrawals from study medication and adverse events of special interest were numerically greater with MMF+PFD (n = 8 vs 2 and n = 20 vs 7, respectively). Conclusion In this underpowered study, there was no statistically significant treatment difference in overall change in FVC‐% between groups. MMF+PFD was not as well tolerated as MMF+PLA.

PURPOSE The difference in time to serum calcium normalization and rates of subsequent refractory hypocalcemia between bisphosphonates requires further investigation. Our primary objective was to assess the difference in normalization of serum calcium between pamidronate and zoledronic acid during treatment of hypercalcemia of malignancy (HCM) and rates of subsequent, refractory hypocalcemia following therapy. METHODS A retrospective review of patients with cancer who received pamidronate or zoledronic acid inpatient at Mayo Clinic for treatment of HCM between January 2018 and January 2024 was conducted. Logistic regression evaluated the association between treatment groups and outcomes. Multivariable modeling was adjusted for baseline differences, including severity of hypercalcemia. RESULTS We evaluated 856 patients. The median age was 68 (IQR, 59-75) years, and 476 (55.6%) were male. The most common cancer diagnoses were lymphoma (n = 158, 18.5%), followed by multiple myeloma (n = 145, 16.9%) and lung cancer (n = 111, 13%). Overall, 292 (46.8%) patients and 154 (32.8%) patients achieved serum calcium normalization by hospital day 4 and day 7, respectively. The rate of normalization was similar between all bisphosphonates, regardless of pamidronate dose. Significantly higher rates of hypocalcemia were observed on day 4 for patients who received zoledronic acid 4 mg once compared with either dose (60 mg once and 90 mg once) of pamidronate (40.7% v 27.6% v 26.8%, P = .049, respectively). No significant difference in rates of hypocalcemia were observed on day 7 (56.8% v 50% v 42.9%, P = .26, respectively) and day 30 (39.1% v 39.0% v 37.5%, P = .50, respectively). CONCLUSION Bisphosphonates were equally efficacious in normalizing serum calcium in patients with HCM. Pamidronate 90 mg was not more efficacious than 60 mg. Rates of refractory hypocalcemia were similar.

Abstract Background and Aims Upadacitinib (UPA)—an oral, reversible selective Janus kinase inhibitor—has a favorable benefit–risk profile for patients with Crohn’s disease (CD) and ulcerative colitis (UC). We evaluated the benefit–risk of UPA in select subgroups with CD or UC. Methods Patients were randomized to UPA 45 mg (UPA45) once daily (QD) or placebo (PBO) induction for 12 (CD: U-EXCEED, U-EXCEL) or 8 weeks (UC: U-ACHIEVE, U-ACCOMPLISH). Clinical responders were re-randomized to QD UPA 15 mg (UPA15), UPA 30 mg (UPA30), or PBO for 52-week maintenance (CD: U-ENDURE; UC: U-ACHIEVE). This exploratory post hoc analysis assessed efficacy and safety outcomes (adverse events of special interest [AESIs]: serious infections, major adverse cardiovascular [CV] events, malignancies, and venous thromboembolic events) by CV risk, prior treatment failure, and age. Results This analysis included 1021 patients with CD and 1097 with UC during induction, and 673 with CD and 746 with UC during maintenance. Improved efficacy outcomes comparable to the overall study populations were observed with UPA versus PBO across subgroups. Patients receiving UPA30 generally showed numerically higher rates of improvements versus UPA15. AESI rates were generally comparable between UPA and PBO across subgroups except for numerically higher rates of herpes zoster and serious infections in CD with UPA. Conclusions UPA resulted in consistent benefit versus placebo across CV risk, prior treatment failure, and age subgroups. No treatment differences were seen in AESIs across subgroups except herpes zoster and serious infections, reinforcing the favorable benefit–risk profile for UPA in CD and UC seen in the overall study populations. Clinical trial numbers NCT02819635, NCT03653026, NCT03345836, NCT03345849, NCT03345823

Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .

Background: Cardiac disease is the leading cause of premature mortality in Friedreich Ataxia (FA). However, validated prognostic indicators or early imaging biomarkers that can reliably predict cardiac events are lacking. To address this gap, we created a multicenter FA cardiac registry to characterize disease progression and identify early echocardiographic (echo) predictors of major adverse cardiac events (MACE). Methods: FA subjects from 6 North American centers with at least two echos performed ≥5 years apart were included. Demographics, FA-specific disease characteristics, and MACE (a composite of death, heart failure hospitalization, aborted sudden cardiac death, and/or life-threatening arrhythmia) were abstracted. Digital echo images were re-read at a centralized core lab. Paired T tests were utilized for comparison of the normally distributed first and second echo parameters, and logistic regression models were utilized to evaluate for predictors of MACE. Results: Of 115 subjects, 52 (45%) were female. Mean age at diagnosis was 10 ± 3 years, median GAA1 repeat length (a marker of genetic severity) was 700 (range 66–1200), and median age at first analyzed echo was 12 years (range 4-36). MACE occurred in 35 (30%) of the cohort. Serial echocardiograms demonstrated progressive worsening of multiple cardiac parameters over time, including markers of ventricular thickness and hypertrophy, chamber size, systolic function, and novel markers of atrial and ventricular strain (Table 1). On univariate analysis, several markers of hypertrophy and systolic function from the earliest analyzed echo predicted MACE. However, after adjusting for age of diagnosis, GAA1 repeat length, and collinearity among variables, only posterior wall thickness in diastole (PWTd) remained an independent predictor of MACE (odds ratio 1.8 per mm increase, 95% CI 1.1–3.3, p = 0.028). Conclusions: This multicenter FA registry identifies early posterior wall thickness as a significant and independent predictor of major adverse cardiac events in FA. Each millimeter increase in PWTd on early echo is associated with nearly double the odds of MACE. This commonly acquired parameter is often overlooked and may serve as a powerful early marker of cardiac risk. Further investigation of PWTd as a potential surrogate endpoint for therapeutic trials in FA is warranted.

A 63-year-old female with mixed connective tissue disease on long-term immunosuppression (prednisone, azathioprine, hydroxychloroquine (HCQ)) was referred to a tertiary care center for evaluation of progressive dyspnea and exertional chest discomfort. Cardiac history included transient complete heart block and ventricular tachycardia with dual-chamber AICD, and severe aortic stenosis with bicuspid aortic valve. Laboratory evaluation was notable for NT pro-BNP > 5000 pg/mL and elevated but adynamic troponin (300-500 ng/L). Electrocardiogram revealed atrial pacing with first degree atrioventricular block. Echocardiogram confirmed severe aortic stenosis, elevated filling pressures, abnormal left ventricular longitudinal strain and LV hypertrophy. Cardiac MRI, sarcoid PET, and PYP SPECT/CT were without any evidence of edema, scar, inflammation or amyloid deposition. Catheterization revealed severe pulmonary hypertension and elevated filling pressures, without significant coronary disease. Medical treatment included empagliflozin (discontinued due to urosepsis), bumetanide, spironolactone, and metoprolol succinate. Neither TAVR nor transition to biventricular pacing improved LV function. Ultimately, endomyocardial biopsy was performed, revealing histologic features of HCQ-induced cardiotoxicity, including myocyte hypertrophy and interstitial fibrosis. HCQ was discontinued. She was referred to Rheumatology for alternative treatments. HCQ induced cardiomyopathy represents <2% of adverse events of patients treated with HCQ, presenting as hypertrophic or restrictive cardiomyopathy with conduction abnormalities. Mean treatment duration in HCQ cardiomyopathies is approximately 12.7 years. Confirmation of diagnosis requires endomyocardial biopsy, as imaging findings are often non-specific. Management involves discontinuing the offending agent and optimizing heart failure therapy. Around 45% of patients with HCQ cardiomyopathy exhibit resolution of cardiac function following medication discontinuation. This case emphasizes the importance of a systematic approach to unexplained heart failure, particularly in patients with long-term HCQ use. Infiltrative or toxic cardiomyopathies should be considered when imaging suggests myocardial dysfunction. Multimodal imaging and biopsy are crucial for diagnosis. Early recognition is essential to prevent irreversible myocardial damage and improve long-term outcomes.