Citations

Background: CLL is one of the most common types of leukemia in the United States, with an estimated 20,700 new cases in 2024. Although cBTKis have become the standard of care for CLL/SLL in treatment-naïve and relapsed/refractory patients, cardiovascular (CV) toxicity is a known side effect. Further, clinical outcomes often worsen as patients progress beyond 1st-line therapy (1L), and the frequency of CV adverse events (CVAEs) may increase with age and as patients progress to 2nd-line or later therapies (2L+). This research evaluated the real-world incidence of CVAEs and clinical outcomes in patients who initiated cBTKi between 2020 and 2023. Methods: Adult patients diagnosed with CLL/SLL who initiated cBTKi treatment (index date) between 2020-2023 in the United States were identified using claims data from Optum's de-identified Clinformatics® Data Mart Database and followed up to 36 months post-index. Cohorts were assessed as those initiating 1L or 2L+, reflecting treatment-naïve and relapsed/refractory patients. Results were presented for patients with an incident CVAE (not present pre-index) and those without. Demographics, incident CVAEs, overall survival (OS) and proportion of patients who discontinued index cBTKi therapy, initiated next treatment or experienced death (NT+D) were assessed. Time to CV event (TTCE) for ibrutinib and acalabrutinib were determined using a Kaplan-Meier (KM) model and Log rank test. Results: Overall, 2,163 eligible patients were identified with a mean ± SD age of 73.8 ± 9.2 years, and 40.6% were female. Of these, 1,958 (90.5%) were included in the 1L cohort and 205 (9.5%) in the 2L+ cohort; 619 (31.6%) and 63 (30.7%) patients had CVAEs, respectively. The mean ± SD [median] observation period was 1.6 ± 0.9 [2.0] years in 1L and 1.5 ± 1.0 [1.0] years in 2L+. The most common cBTKi (in 1L and 2L+) at index were ibrutinib (55.5% and 55.6%), followed by acalabrutinib (40.3% and 38.5%), and zanubrutinib (4.1% and 5.9%). At 12-months post-index, the proportion of 1L patients with and without CVAEs who discontinued treatment was 44.9% and 41.6%, rising to 65.6% and 59.0% by 36-months post-index, respectively. For those in 2L+, 50.8% and 40.8% of those with and without CVAEs discontinued treatment by 12-months; 68.3% and 55.6% discontinued by 36-months. Among those with and without CVAEs, NT+D in 1L patients was 35.9% and 22.5% within 12-months post-index and 56.9% and 32.8% by 36-months. In the 2L+ cohort, 46.0% and 31.7% experienced NT+D by 12-months, rising to 63.5% and 41.5% by 36-months. OS in 1L patients was 84.7% and 93.1% in those with and without CVAEs at 12-months and 69.1% and 88.0% at 36-months. For 2L+ patients, OS was 71.4% and 88.0% at 12-months and decreased to 54.0% and 80.3% at 36-months, among those with and without CVAEs, respectively. The most common incident CVAEs following cBTKi initiation in the 1L and 2L+ cohorts were hypertension (31.2% and 21.7%), heart failure (14.6% and 17.7%), atrial fibrillation (13.9% and 18.4%), atrial flutter (13.3% and 16.9%), and ventricular arrythmias (13.0% and 14.5%). The occurrence of incident CVAEs between 1L patients who received acalabrutinib and ibrutinib was 3.4% and 13.2% for atrial fibrillation, 2.7% and 12.7% for atrial flutter, 9.3% and 31.0% for hypertension, and 6.8% and 11.7% for ventricular arrythmias. For 2L+, the proportion experiencing CVAEs with index acalabrutinib or ibrutinib were 8.6% and 14.8% for atrial fibrillation, 7.6% and 14.8% for atrial flutter, 10.5% and 25.0% for hypertension, and 10.1% and 8.8% for ventricular arrythmias. Among acalabrutinib and ibrutinib patients, KM estimates (medians not reached) in 1L showed that 84% and 72% of patients would not experience a CVAE by 12 months, with 57% and 52% not experiencing a CVAE at 36-months (p<0.001); 2L+ KM estimate rates were 77% and 73% at 12-months and 64% and 60% at 36-months (p=0.28). Mean TTCE for acalabrutinib and ibrutinib in 1L was 2.2 and 1.9 years with 1.6 and 1.2 years in 2L+. Summary/Conclusion: Utilizing real-world evidence from patients with CLL/SLL receiving cBTKIs, this study highlights the CV disease burden among patients who incur new CV events in 1L or later lines of therapy. This research underscores the need for innovative therapies with improved efficacy and CV safety profiles that delay progression to later lines of therapy, as well as careful CV monitoring to allow for early management and improved outcomes.

Background: Although Covalent BTKis have revolutionized treatment of CLL/SLL, cardiotoxicity is a known side effect, which can increase the total costs to the healthcare system. This study evaluated the real-world healthcare resource utilization (HCRU) and costs in patients who did and did not experience incident cardiovascular adverse events (CVAEs) during cBTKi treatment. Methods: Adult patients diagnosed with CLL/SLL who initiated ibrutinib or acalabrutinib treatment (index date) between 2020-2023 in the United States were identified using claims data from Optum's de-identified Clinformatics® Data Mart Database and followed up to 36 months post-index. Patients were stratified into two cohorts based on the presence of an incident CVAE during treatment with index cBTKi, defined as the occurrence of a CVAE not present in a patient's medical history. HCRU and costs were evaluated on a per 1,000 patient-months basis. Z tests and univariate gamma general linear models were used to compare HCRU and cost rates. HCRU between those who received ibrutinib or acalabrutinib were also assessed. Results: Overall, 2,069 eligible patients were identified with a mean ± SD age of 73.7 ± 9.1 years, and 40.4% were female. The mean ± SD [median] treatment-specific observation period was 11.4 ± 9.5 [8.5] months. Of the total cohort, 442 (21.4%) experienced at least one incident CVAE, while 1,627 patients (78.6%) experienced no CVAEs. Among those without a pre-index history of the specific CV AE of interest, the proportion of patients with incident events were 21.4% for hypertension, 9.8% for atrial fibrillation, 9.2% for atrial flutter, and 9.6% for ventricular arrhythmias. Patients who experienced an incident CVAE had 4,334 total days with medical service compared to 3,138 days in those who did not (p<0.001). The drivers of differences in total medical service days between those with and without CVAEs were inpatient days (690 vs 230), followed by outpatient days (2,798 vs 2,425), other visits (e.g., hospice; 662 vs 375), and emergency room (ER) visits (184 vs 109). Total days with medical service were 3,458 in those who received ibrutinib and 3,410 with acalabrutinib. Total healthcare cost rates in those who experienced an incident CVAE were $20,250,560 compared to $17,413,460 in those without CVAEs (p<0.001). Inpatient costs drove differences in total costs between those with CVAEs and those without ($3,417,948 vs $915,839, p<0.001), followed by outpatient ($2,415,060 vs $1,769,628, p<0.01) and ER costs ($186,820 vs $87,585, p<0.001). Pharmacy costs were the largest contributor to total cost rates for both cohorts ($14,016,900 for those with a CVAE vs $14,473,270 without any CVAEs, p<0.001). Regarding specific incident CVAEs, the cost difference in total costs between those with and without the event were $3,789,820 for atrial fibrillation (higher in those with the event), $3,867,160 for atrial flutter, $3,674,860 for ventricular arrhythmias, and $721,840 for hypertension. Inpatient costs were the largest driver in total cost differences between those with and without the specific CVAE of interest; inpatient cost differences were $3,255,699 higher in those with atrial fibrillation, $3,436,913 with atrial flutter, and $3,299,371 with ventricular arrhythmia. For hypertension, pharmacy costs drove differences in total costs and were $346,570 higher in those with the CVAE. Summary/Conclusion: Overall, the economic burden remains high in patients treated for CLL/SLL, especially in cBTKi patients experiencing an incident CVAE. These findings highlight the importance of careful treatment selection, safety monitoring, and early management of CVAEs in order to improve patient outcomes and reduce the downstream impacts on healthcare resources and costs.

Abstract OBJECTIVES The effect of allograft ischaemic time (AIT) on postoperative events after lung transplantation remains unclear. This study aims to assess the feasibility of extending the duration of AIT. METHODS The United Network for Organ Sharing database was queried for adult lung transplantation from 4 May 2005 to 30 June 2020. Patients were divided as per AIT into standard ischaemic time (<6 h) and prolonged ischaemic time (≥6 h) groups using propensity score matching and evaluated on a continuous scale using restricted cubic splines. The primary outcome was overall 1-year and 5-year survival. RESULTS Among 11 438 propensity-matched recipients, standard ischaemic time and prolonged ischaemic time showed no differences in overall 1-year (P = 0.29) or 5-year (P = 0.29) survival. Prolonged ischaemic time independently predicted early postoperative ventilator support for >48 h (OR = 1.33, 95% CI 1.22–1.44), dialysis (OR = 1.55, 95% CI 1.30–1.84), primary graft dysfunction (PGD; OR = 1.28, 95% CI 1.09–1.50), acute rejection (OR = 1.42, 95% CI 1.24–1.62), and interestingly, decreased 5-year bronchiolitis obliterans syndrome (HR = 0.91, 95% CI 0.85–0.97). In relative risk curves, 1-year mortality, prolonged ventilation, dialysis and PGD steadily increased per hour as AIT extended. The risk of acute rejection and 5-year bronchiolitis obliterans syndrome also showed significant changes between 5 and 8 h of AIT. In contrast, 5-year mortality remained constant despite rising AIT. CONCLUSIONS Prolonged AIT worsened early outcomes such as PGD, but improved bronchiolitis obliterans syndrome freedom at later time points. Despite this, both short- and long-term survival were similar between prolonged ischaemic time and standard ischaemic time patients. Dynamic risk changes in post-transplant events should be noted for prolonged ischaemia lung use.

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease characterized by complement-mediated hemolysis. OPERA is the first US longitudinal real-world study on C3 inhibitor therapy, known as pegcetacoplan. Methods: OPERA enrolled US patients with PNH, age ≥18, who were prescribed pegcetacoplan, and data were collected from routine care. Hemoglobin was reported by patients during regular follow-up (censored from transfusions). The Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (0–52 score) and Patient-Reported Outcomes Measurement Information System scale for Cognitive Function Abilities (PROMIS-CF; 23.27–67.09 t-score) were completed electronically (low score = negative outcome). Patients self-reported incidence of healthcare resource utilization (HCRU). Results: By January 2024, 70 patients (mean age 44.6 years; 57.1% female) reported up to 9 months of pegcetacoplan treatment, with a median [IQR] follow-up of 6.6 [3.8] months. The latest reported hemoglobin levels improved by a mean (SD) of 2.6 (1.9) g/dL from baseline. At 3, 6 and 9 months, patients reported clinically meaningful improvements (≥5 points) in FACIT-F (53.3–69.0%) and (≥2 points) PROMIS-CF (46.7–55.2%). Patients reported a <10% incidence rate per person month of all HCRU events. Conclusions: This first longitudinal real-world US study indicates a positive trend in Hb, fatigue, and cognition with limited HCRU during pegcetacoplan treatment in adults with PNH.

Autosomal dominant polycystic kidney disease (ADPKD) is a predominant genetic disease, which is caused by mutations in PKD genes and is associated with DNA damage in cystic cells. The intrinsic stimulator of interferon genes (STING) pathway is crucial for recognizing damaged DNA in the cytosol, triggering the expression of inflammatory cytokines to activate defense mechanisms. However, the precise roles and mechanisms of STING in ADPKD remain elusive. In this study, we show that Pkd1 mutant mouse kidneys show upregulation of STING, which is stimulated by the DNAs of nuclear and mitochondrial origin. The activation of STING promotes cyst growth through increasing (1) the activation of NF-κB in Pkd1 mutant cells and (2) the recruitment of macrophages in the interstitial and peri-cystic regions in Pkd1 mutant mouse kidneys via NF-κB mediating the upregulation of TNF-α and MCP-1. Targeting STING with its specific inhibitor C-176 delays cyst growth in an early-stage aggressive Pkd1 conditional knockout mouse model and a milder long-lasting Pkd1 mutant mouse model. Targeting STING normalizes mitochondrial structure and function, decreases the formation of micronuclei, induces Pkd1 mutant renal epithelial cell death via p53 signaling, and decreases renal fibrosis in Pkd1 mutant mouse kidneys. These results support that STING is a novel therapeutic target for ADPKD treatment.

Heterotopic ossification (HO), defined as the formation of extraskeletal bone in muscle and soft tissues, is a diverse pathological process caused by either genetic mutations or inciting trauma. Fibrodysplasia ossificans progressiva (FOP) is a genetic form of HO caused by mutations in the bone morphogenetic protein (BMP) type I receptor gene activin A receptor type 1 ( ACVR1 ). These mutations make ACVR1 hypersensitive to BMP and responsive to activin A. Hedgehog (Hh) signaling also contributes to HO development. However, the exact pathophysiology of how skeletogenic cells contribute to endochondral ossification in FOP remains unknown. Here, we showed that the wild-type or FOP-mutant ACVR1 localized in the cilia of stem cells from human exfoliated deciduous teeth with key FOP signaling components, including activin A receptor type 2A/2B, SMAD family member 1/5, and FK506-binding protein 12kD. Cilia suppression by deletion of intraflagellar transport 88 or ADP ribosylation factor like GTPase 3 effectively inhibited pathological BMP and Hh signaling, subdued aberrant chondro-osteogenic differentiation in primary mouse or human FOP cells, and diminished in vivo extraskeletal ossification in Acvr1 Q207D , Sox2-Cre ; Acvr1 R206H/+ FOP mice and in burn tenotomy–treated wild-type mice. Our results provide a rationale for early and localized suppression of cilia in affected tissues after injury as a therapeutic strategy against either genetic or acquired HO.