Thomas D. Coates

Iron overload is a significant cause of transfusion-related morbidity and mortality. Deferiprone (DFP) is an established oral iron chelator approved for the treatment of transfusional iron overload in patients with thalassemia, sickle cell disease (SCD), or other anemias. Initially approved as a three times-a-day (TID) formulation, a twice-a-day (BID) formulation was developed to improve patient adherence. Here, we assess the safety of DFP BID in patients with thalassemia, SCD, or other anemias in real-world clinical practice in the United States. Data for patients referred for DFP BID between July 1, 2020 to August 31, 2023 were obtained from the Ferriprox® Total Care Registry. The frequency of adverse events (AEs), serious AEs (SAEs), AEs of special interest and fatal outcomes was assessed. Of the 425 patients referred to the registry, 348 received ≥one DFP shipment and had a primary diagnosis of thalassemia syndromes (N=129), SCD (N=189), or other anemias (N=30) (safety analysis group). Mean (SD) DFP exposure was 343.0 (281.9) days. In total, 1021 AEs and 369 SAEs were reported. As seen with the TID formulation, the most common adverse events with DFP BID were predominantly gastrointestinal or related to underlying disease. Cases of neutropenia and agranulocytosis were rare, reported in 1.7% and 0.6% of patients, respectively and all recovered. None of the 26 fatal outcomes reported were assessed as related to DFP treatment. DFP BID was well-tolerated in real-world clinical practice, and the safety profile was consistent with DFP TID. No new safety concerns were observed.

Chronic anemia is observed in individuals with sickle cell disease (SCD) and thalassemia syndromes. It has been associated with a range of neurological complications, particularly progressive silent cerebral infarcts in brain regions with high oxygen extraction—specifically in vascular watershed areas—suggesting that regional tissue hypoxia may play a causal role. However, recent work in sickle cell mice reveals widespread white matter demyelination and chronic neuroinflammation superimposed upon regional ischemia. In light of these findings, we utilized high‐fidelity diffusion imaging and modeling techniques to identify predictors of white matter damage in human subjects diagnosed with SCD ( n = 76) and thalassemia ( n = 20) compared to healthy individuals ( n = 32). Our results demonstrate that white matter damage extended beyond vascular watershed areas in chronically anemic subjects and had MRI changes characteristic of demyelination. These findings were proportional to hemoglobin levels and largely disappeared after controlling for anemia severity. However, patients with SCD exhibited small but significant residual white matter derangements not seen in those with thalassemia. These residual abnormalities disappeared after LDH or reticulocyte count were included as markers of hemolytic rate. From a functional perspective, neuropsychological processing speed was correlated with white matter integrity in chronic anemia subjects, with stronger associations seen in patients with SCD. Taken together, these results demonstrate that chronic anemia is associated with widespread white matter demyelination that cannot be explained by regional blood flow variation and is proportional to anemia severity. Patients with SCD may have more severe disease and functional consequences than patients with thalassemia.

Background: Entrapment of sickled red blood cells in the microvasculature leads to sudden painful vaso-occlusive crises (VOCs) in sickle cell disease (SCD). This is potentially triggered by autonomic nervous system–mediated vasoconstriction in the microvasculature. Indeed, vasoconstriction biomarkers derived from a single night of laboratory-based fingertip photoplethysmography (PPG) recording were predictive of a higher frequency of future VOC in SCD. Noninvasive, remote, and longitudinal monitoring of autonomic vasoreactivity will facilitate the development of predictive biomarkers of imminent VOC. Objective: This study aimed to assess the feasibility and performance of a wearable wristband device to longitudinally monitor nocturnal peripheral autonomic vasoreactivity and to cross-validate the vasoconstriction parameters across the “gold-standard” finger sensor. Methods: A total of 12 patients with SCD and 6 healthy controls were recruited to wear a wristband device (Biostrap) with a PPG sensor on a nightly basis. For cross-validation studies, 50% (3/6) controls wore both the wristband and a sleep monitoring device (AliceNightOne) with a finger PPG sensor. We quantified autonomic vasoreactivity by processing PPG signals and deriving vasoconstriction parameters—magnitude of vasoconstriction (Mvasoc) and photoplethysmography amplitude coefficient of variation (PPGampCV). We performed a correlation analysis of the vasoconstriction parameters within each device to investigate whether Mvasoc and PPGampCV can be used as surrogate markers of vasoconstriction, and then cross-validated the PPGampCV across the wristband and finger PPG devices. Results: A total of 131 nocturnal PPG recordings were made with a wristband device (1‐19 nights per participant; patients with SCD: n=79, 60%; controls: n=52, 40%). A total of 9 nocturnal recordings (3 nights per participant) were made with both wristband and finger sensor devices. Longitudinal continuous PPG recordings were feasible with the wearable device, with significant within-night and night-to-night variability in vasoconstriction parameters, suggesting dynamic changes in autonomic vasoreactivity. Mvasoc and PPGampCV significantly correlated within devices—the maximum overnight correlation was 0.82 ( P <.001) for the finger sensor and 0.69 ( P <.001) for the wristband sensor, suggesting that PPGampCV can serve as a surrogate for Mvasoc. Cross-validation analysis of PPGampCV across wristband and fingertip sensors showed statistically significant correlations on all 9 nights (overnight correlation coefficient ranging from 0.24‐0.7), with some nightly segments of PPGampCV showing very strong correlation across devices. Conclusions: Wearable wristband devices are feasible tools for the collection of continuous PPG measurements and vasoconstriction parameters, which serve as objective markers of autonomic vasoreactivity in users with and without SCD. We have optimized the methods of quantifying vasoconstriction from wearable device PPG signals, and cross-validated them with standardized sensors. These findings enable large-scale, real-time monitoring of autonomic vasoreactivity along with pain outcomes for the development of vasoconstriction parameters as biomarkers imminent VOC in patients with SCD. This biomarker also has the potential to impact other diseases involving autonomic vascular dysregulation.

Before effective iron chelation became available, patients with transfusion-dependent thalassemia often died from iron-induced cardiomyopathy and endocrine failure in their second decade of life. This experience shaped long-standing expectations of poor outcomes and continues to fuel provider and patient anxiety in all conditions associated with iron overload. While severe iron overload and toxicity still cause considerable morbidity and mortality globally, advances in the understanding of iron metabolism, noninvasive organ-specific iron monitoring, and chelation therapy have significantly reduced their impact. Clinical insights from hemoglobinopathies have reinforced iron biology findings from animal models and highlighted shared mechanisms of iron toxicity across disorders, guiding broader management approaches that address the prevention of iron toxicity independently of the removal of organ iron burden. The resulting significant improvement in survival now presents new challenges tied to prolonged exposure to both anemia and iron overload, which must be addressed in long-term treatment planning.

Chronic anemia due to non–transfusion-dependent β-thalassemia (NTDT) can result in clinical morbidities, particularly with inadequate management. Luspatercept was previously shown to improve hemoglobin levels in patients with NTDT in the phase 2, randomized, double-blind, placebo-controlled BEYOND trial (ClinicalTrials.gov identifier: NCT03342404). Here, we report long-term efficacy and safety results from the final analysis of BEYOND spanning an additional 26 months (∼2.2 years) of follow-up. Median treatment duration was 202.8 weeks for luspatercept and 61.1 weeks for placebo. Overall, 94.8% and 22.4% of patients in the luspatercept and placebo arms, respectively, achieved a mean hemoglobin increase from baseline ≥1.0 g/dL during any 12-week interval, with mean durations of response of 1136.0 and 203.3 days, respectively. Patient-reported tiredness and weakness showed sustained improvement with luspatercept treatment. The most common treatment-emergent adverse events in the luspatercept group were headache (45.8% vs 20.4% with placebo), bone pain (43.8% vs 6.1%), back pain (39.6% vs 12.2%), and arthralgia (38.5% vs 16.3%). Treatment-emergent extramedullary hematopoiesis events were reported in 12 (9.0%) and 2 (4.1%) patients receiving luspatercept and placebo, respectively, although differences in treatment exposures prevented informative comparisons. Of the 4 patients receiving luspatercept who reported thromboembolic events, all had >1 risk factor. These results show that luspatercept led to a sustained increase in hemoglobin levels in patients with NTDT for up to ∼4.6 years of treatment, with a consistent safety profile and no new safety findings. Luspatercept is a valuable treatment option for patients with NTDT, addressing the need for effective long-term treatment of anemia. This trial was registered at www.clinicaltrials.gov as #NCT03342404.