Splenic iron decreased whereas liver iron was stable during luspatercept therapy in some individuals with thalassemia. This suggests a reduction of ineffective erythropoiesis changes the organ ...distribution of iron and demonstrates that liver iron concentration alone may not accurately reflect total body iron content. This article describes data from subjects enrolled in BELIEVE (NCT02604433) and BEYOND (NCT03342404).
Background
Hepatotoxicity and pancreatitis are common treatment‐related toxicities (TRTs) during contemporary treatment regimens for acute lymphoblastic leukemia (ALL). Limited detailed data from ...Children's Oncology Group (COG) regimens has been previously reported to enable identification of patient and treatment risk factors for these toxicities and their impact on outcomes.
Procedure
We analyzed a retrospective pediatric ALL cohort treated at a single institution according to COG regimens from 2008 to 2015. The primary endpoint was cumulative incidence of study‐defined “severe” hepatotoxicity (Common Terminology Criteria for Adverse Events CTCAE Grade ≥ 4 transaminitis or Grade ≥ 3 hyperbilirubinemia) and clinically significant pancreatitis (any grade). Pancreatitis was additionally classified using the Ponte di Legno (PdL) toxicity criteria. Secondary endpoints were chemotherapy interruptions, early disease response (end of induction EOI minimal residual disease MRD), and event‐free survival (EFS).
Results
We identified 262 patients, of whom 71 (27%) and 28 (11%) developed hepatotoxicity and pancreatitis, respectively. Three cases of pancreatitis did not fulfill PdL criteria despite otherwise consistent presentations. Both TRTs occurred throughout therapy, but approximately 25% of hepatotoxicity (18/71) and pancreatitis (8/28) occurred during induction alone. Both obesity and age (≥10 years) were identified as predictors of hepatotoxicity (subdistribution hazard ratio SHR obesity = 1.75, 95% confidence interval 95% CI 1.04–2.96; SHR age ≥10 = 1.9, 95% CI 1.19–3.10) and pancreatitis (SHR obesity = 2.18, 95% CI 1.01–4.67; SHR age ≥ 10 = 2.76, 95% CI 1.19–6.39, P = 0.018). Dose interruptions were common but neither toxicity influenced EOI MRD nor EFS.
Conclusions
Obese and/or older children are particularly at risk for hepatotoxicity and pancreatitis, and may benefit from toxicity surveillance and chemoprotective strategies to prevent or mitigate associated morbidity.
Summary
Kidney iron deposition measured by R2* (magnetic resonance imaging) MRI is posited to result from tubular reabsorption of filtered haemoglobin due to intravascular haemolysis. In chronically ...transfused sickle cell disease (SCD), R2* is elevated and positively correlated with lactate dehydrogenase (LDH). To account for contributions to renal iron from systemic iron overload, we evaluated kidney R2*, urinary iron and haemolysis markers in 62 non‐transfused SCD patients. On multivariate analysis, kidney R2* was associated with urinary iron and LDH (R2 = 0·55, P < 0·0001). Our study confirms that kidney R2* is associated with intravascular haemolysis and raises important questions regarding the role of iron in SCD nephropathy.
Abstract Background Children treated for cancer are at risk for adverse effects of iron due to transfusions administered during prolonged marrow suppression, which may increase exposure to toxic ...forms of iron, extrahepatic iron accumulation, and long‐term organ damage. Objective This study aimed to characterize the severity and organ distribution of clinically significant, multisystem iron overload (IO) in an at‐risk cohort of pediatric cancer patients. Methods This was a retrospective, cross‐sectional study of childhood cancer patients who underwent a magnetic resonance imaging (MRI) due to clinical concern for IO. Data regarding cancer type and treatment, transfusion history, MRI and laboratory results, and treatment for IO were collected. Severity of IO was analyzed by non‐parametric tests with respect to clinical characteristics. Results Of the 103 patients, 98% of whom had a Cancer Intensity Treatment Rating (ITR‐3) of 3 or higher, 53% (54/102) had moderate or greater hepatic siderosis, 80% (77/96) had pancreatic siderosis, 4% (3/80) had cardiac siderosis, and 45% (13/29) had pituitary siderosis and/or volume loss. Pancreatic iron was associated with both cardiac ( p = .0043) and pituitary iron ( p = .0101). In the 73 off‐therapy patients, ferritin levels were lower ( p = .0008) with higher correlation with liver iron concentration (LIC) ( p = .0016) than on‐therapy patients. Fifty‐eight subjects were treated for IO. Conclusion In this heavily treated cohort of pediatric cancer patients, more than 80% had extrahepatic iron loading, which occurs with significant exposure to toxic forms of iron related to decreased marrow activity in setting of transfusions. Further studies should examine the effects of exposure to reactive iron on long‐term outcomes and potential strategies for management.
Persons with sickle cell disease (SCD) exhibit subjective hypersensitivity to cold and heat perception in experimental settings, and triggers such as cold exposure are known to precipitate ...vaso-occlusive crises by still unclear mechanisms. Decreased microvascular blood flow (MBF) increases the likelihood of vaso-occlusion by increasing entrapment of sickled red blood cells in the microvasculature. Because those with SCD have dysautonomia, we anticipated that thermal exposure would induce autonomic hypersensitivity of their microvasculature with an increased propensity toward vasoconstriction. We exposed 17 patients with SCD and 16 control participants to a sequence of predetermined threshold temperatures for cold and heat detection and cold and heat pain via a thermode placed on the right hand. MBF was measured on the contralateral hand by photoplethysmography, and cardiac autonomic balance was assessed by determining heart rate variability. Thermal stimuli at both detection and pain thresholds caused a significant decrease in MBF in the contralateral hand within seconds of stimulus application, with patients with SCD showing significantly stronger vasoconstriction (P = .019). Furthermore, patients with SCD showed a greater progressive decrease in blood flow than did the controls, with poor recovery between episodes of thermal stimulation (P = .042). They had faster vasoconstriction than the controls (P = .033), especially with cold detection stimulus. Individuals with higher anxiety also experienced more rapid vasoconstriction (P = .007). Augmented vasoconstriction responses and progressive decreases in perfusion with repeated thermal stimulation in SCD are indicative of autonomic hypersensitivity in the microvasculature. These effects are likely to increase red cell entrapment in response to clinical triggers such as cold or stress, which have been associated with vaso-occlusive crises in SCD.
Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by polymerization of hemoglobin S upon deoxygenation that results in the formation of rigid sickled-shaped red blood cells ...that can occlude the microvasculature, which leads to sudden onsets of pain. The severity of vaso-occlusive crises (VOC) is quite variable among patients, which is not fully explained by their genetic and biological profiles. The mechanism that initiates the transition from steady state to VOC remains unknown, as is the role of clinically reported triggers such as stress, cold and pain. The rate of hemoglobin S polymerization after deoxygenation is an important determinant of vaso-occlusion. Similarly, the microvascular blood flow rate plays a critical role as fast-moving red blood cells are better able to escape the microvasculature before polymerization of deoxy-hemoglobin S causes the red cells to become rigid and lodge in small vessels. The role of the autonomic nervous system (ANS) activity in VOC initiation and propagation has been underestimated considering that the ANS is the major regulator of microvascular blood flow and that most triggers of VOC can alter the autonomic balance. Here, we will briefly review the evidence supporting the presence of ANS dysfunction in SCD, its implications in the onset of VOC, and how differences in autonomic vasoreactivity might potentially contribute to variability in VOC severity.
In sickle cell disease (SCD), prolonged capillary transit times, resulting from reduced peripheral blood flow, increase the likelihood of rigid red cells entrapment in the microvasculature, ...predisposing to vaso-occlusive crisis. Since changes in peripheral flow are mediated by the autonomic nervous system (ANS), we tested the hypothesis that the cardiac and peripheral vascular responses to head-up tilt (HUT) are abnormal in SCD. Heart rate, respiration, non-invasive continuous blood pressure and finger photoplethysmogram (PPG) were monitored before, during, and after HUT in SCD, anemic controls and healthy subjects. Percent increase in heart rate from baseline was used to quantify cardiac ANS response, while percent decrease in PPG amplitude represented degree of peripheral vasoconstriction. After employing cluster analysis to determine threshold levels, the HUT responses were classified into four phenotypes: (CP) increased heart rate and peripheral vasoconstriction; (C) increased heart rate only; (P) peripheral vasoconstriction only; and (ST) subthreshold cardiac and peripheral vascular responses. Multinomial logistic regression (MLR) was used to relate these phenotypic responses to various parameters representing blood properties and baseline cardiovascular activity. The most common phenotypic response, CP, was found in 82% of non-SCD subjects, including those with chronic anemia. In contrast, 70% of SCD subjects responded abnormally to HUT: C-phenotype = 22%, P-phenotype = 37%, or ST-phenotype = 11%. MLR revealed that the HUT phenotypes were significantly associated with baseline cardiac parasympathetic activity, baseline peripheral vascular variability, hemoglobin level and SCD diagnosis. Low parasympathetic activity at baseline dramatically increased the probability of belonging to the P-phenotype in SCD subjects, even after adjusting for hemoglobin level, suggesting a characteristic autonomic dysfunction that is independent of anemia. Further analysis using a mathematical model of heart rate variability revealed that the low parasympathetic activity in P-phenotype SCD subjects was due to impaired respiratory-cardiac coupling rather than reduced cardiac baroreflex sensitivity. By having strong peripheral vasoconstriction without compensatory cardiac responses, P-phenotype subjects may be at increased risk for vaso-occlusive crisis. The classification of autonomic phenotypes based on HUT response may have potential use for guiding therapeutic interventions to alleviate the risk of adverse outcomes in SCD.
Alpha thalassemia is a hemoglobinopathy due to decreased production of the α‐globin protein from loss of up to four α‐globin genes, with one or two missing in the trait phenotype. Individuals with ...sickle cell disease who co‐inherit the loss of one or two α‐globin genes have been known to have reduced risk of morbid outcomes, but the underlying mechanism is unknown. While α‐globin gene deletions affect sickle red cell deformability, the α‐globin genes and protein are also present in the endothelial wall of human arterioles and participate in nitric oxide scavenging during vasoconstriction. Decreased production of α‐globin due to α‐thalassemia trait may thereby limit nitric oxide scavenging and promote vasodilation. To evaluate this potential mechanism, we performed flow‐mediated dilation and microvascular post‐occlusive reactive hyperemia in 27 human subjects (15 missing one or two α‐globin genes and 12 healthy controls). Flow‐mediated dilation was significantly higher in subjects with α‐trait after controlling for age (P = .0357), but microvascular perfusion was not different between groups. As none of the subjects had anemia or hemolysis, the improvement in vascular function could be attributed to the difference in α‐globin gene status. This may explain the beneficial effect of α‐globin gene loss in sickle cell disease and suggests that α‐globin gene status may play a role in other vascular diseases.
Objective
To investigate novel systemic sclerosis (SSc) autoantibodies in autoantibody‐negative patients and establish clinical associations.
Methods
Serum samples and clinical data for 548 patients ...with SSc were collected. Routine serologic techniques were used to test the serum samples for known SSc autoantibodies, and samples with negative results were further investigated by radiolabeled‐protein immunoprecipitation assay. Sera that immunoprecipitated a novel 30‐kd band were analyzed by indirect immunofluorescence and immunoprecipitation, using depleted cell extracts to establish a common reactivity. Mass spectrometry was performed to identify the novel autoantigen, and the results were confirmed using commercial antibodies. Sera from 426 patients with other forms of connective tissue disease, 103 with rheumatoid arthritis, 114 with idiopathic interstitial lung disease (ILD), and 150 healthy subjects were serotyped as controls.
Results
A novel autoantigen with a molecular weight of ∼30 kd was recognized by 7 sera from patients with SSc, 6 of whom had ILD, and by no controls. Six of the patients had diffuse cutaneous involvement, and 4 had overlap features with other autoimmune diseases. Immunodepletion experiments indicated that all samples targeted the same autoantigen, and mass spectrometry identified the novel autoantigen as eukaryotic initiation factor 2B (eIF2B).
Conclusion
We report the identification of a novel autoantibody (anti‐eIF2B) in a small number of patients with SSc (∼1%); this autoantibody is closely associated with diffuse cutaneous manifestations and the presence of ILD.
Sickle cell disease (SCD) is a monogenic hemoglobinopathy associated with significant morbidity and mortality. Cardiopulmonary, vascular and sudden death are the reasons for the majority of young ...adult mortality in SCD. To better understand the clinical importance of multi‐level vascular dysfunction, in 2009 we assessed cardiac function including tricuspid regurgitant jet velocity (TRV), tissue velocity in systole(S′) and diastole (E′), inflammatory, rheologic and hemolytic biomarkers as predictors of mortality in patients with SCD. With up to 9 years of follow up, we determined survival in 95 children, adolescents and adults with SCD. Thirty‐eight patients (40%) were less than 21 years old at initial evaluation. Survival and Cox proportional‐hazards analysis were performed. There was 19% mortality in our cohort, with median age at death of 35 years. In the pediatric subset, there was 11% mortality during the follow up period. The causes of death included cardiovascular and pulmonary complications in addition to other end‐organ failure. On Cox proportional‐hazards analysis, our model predicts that a 0.1 m/s increase in TRV increases risk of mortality 3%, 1 cm/s increase in S′ results in a 91% increase, and 1 cm/s decrease in E′ results in a 43% increase in mortality. While excluding cardiac parameters, higher plasma free hemoglobin was significantly associated with risk of mortality (p=.049). In conclusion, elevated TRV and altered markers of cardiac systolic and diastolic function predict mortality in a cohort of adolescents and young adult patients with SCD. These predictors should be considered when counseling cardiovascular risk and therapeutic optimization at transition to adult providers.
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