ABSTRACT
Transfusional iron overload represents a substantial challenge in the management of patients with sickle cell disease (SCD) who receive chronic or episodic red blood cell transfusions. Iron-induced cardiomyopathy is a leading cause of death in other chronically transfused populations but rarely seen in SCD. Study objectives were to: (i) examine the extent of myocardial and hepatic siderosis using magnetic resonance imaging (MRI) in chronically transfused SCD patients, and (ii) evaluate the relationship between long-term (over the 5 years prior to enrolment) mean serum ferritin (MSF), spot-ferritin values and liver iron content (LIC) measured using MRI and liver biopsy. Thirty-two SCD patients (median age 15 years) with transfusional iron overload were recruited from two U.S. institutions. Long-term MSF and spot-ferritin values significantly correlated with LIC by MRI-R2* (r = 0·77, P < 0·001; r = 0·82, P < 0·001, respectively). LIC by MRI-R2* had strong positive correlation with LIC by liver biopsy (r = 0·98, P < 0·001) but modest inverse correlation with cardiac MRI-T2* (r = -0·41, P = 0·02). Moderate to severe transfusional iron overload in SCD was not associated with aberrations in other measures of cardiac function based on echocardiogram or serum biomarkers. Our results suggest that SCD patients receiving chronic transfusions may not demonstrate significant cardiac iron loading irrespective of ferritin trends, LIC and erythropoiesis suppression.
Subject(s)
Anemia, Sickle Cell/complications , Iron Overload/diagnosis , Iron Overload/etiology , Liver/pathology , Myocardium/pathology , Transfusion Reaction , Adolescent , Adult , Anemia, Sickle Cell/diagnosis , Anemia, Sickle Cell/therapy , Biomarkers , Biopsy , Chelation Therapy , Child , Echocardiography , Female , Ferritins/blood , Humans , Iron/metabolism , Iron Overload/drug therapy , Iron Overload/metabolism , Liver/metabolism , Magnetic Resonance Imaging , Male , Myocardium/metabolism , ROC Curve , Young AdultABSTRACT
African Americans and Blacks have low participation rates in clinical trials and reduced access to aggressive medical therapies. Hematopoietic cell transplantation (HCT) is a high-risk but potentially curative therapy for sickle cell disease (SCD), a disorder predominantly seen in African Americans. We conducted focus groups to better understand participation barriers to HCT clinical trials for SCD. Nine focus groups of youth with SCD (n=10) and parents (n=41) were conducted at 3 sites representing the Midwest, South Atlantic, and West South Central US. Main barriers to clinical trial participation included gaps in knowledge about SCD, limited access to SCD/HCT trial information, and mistrust of medical professionals. For education about SCD/HCT trials, participants highly preferred one-on-one interactions with medical professionals and electronic media as a supplement. Providers can engage with sickle cell camps to provide information on SCD/HCT clinical trials to youth and local health fairs for parents/families. Youth reported learning about SCD through computer games; investigators may find this medium useful for clinical trial/HCT education. African Americans affected by SCD face unique barriers to clinical trial participation and have unmet HCT clinical studies education needs. Greater recognition of these barriers will allow targeted interventions in this community to increase their access to HCT.
Subject(s)
Anemia, Sickle Cell/ethnology , Anemia, Sickle Cell/surgery , Black or African American , Clinical Trials as Topic , Health Services Accessibility , Hematopoietic Stem Cell Transplantation , Adolescent , Adult , Anemia, Sickle Cell/psychology , Child , Child, Preschool , Female , Focus Groups , Health Knowledge, Attitudes, Practice , Humans , Male , Parents/psychologyABSTRACT
BACKGROUND: The TOURMALINE-MM4 trial demonstrated a significant and clinically meaningful progression-free survival (PFS) benefit with ixazomib versus placebo as postinduction maintenance in nontransplant, newly-diagnosed multiple myeloma patients, with a manageable and well-tolerated toxicity profile. MATERIALS AND METHODS: In this subgroup analysis, efficacy and safety were assessed by age (< 65, 65-74, and ≥ 75 years) and frailty status (fit, intermediate-fit, and frail). RESULTS: In this analysis, PFS benefit with ixazomib versus placebo was seen across age subgroups, including patients aged < 65 years (hazard ratio [HR], 0.576; 95% confidence interval [CI], 0.299-1.108; Pâ¯=â¯.095), 65-74 years (HR, 0.615; 95% CI, 0.467-0.810; P < .001), and ≥ 75 years (HR, 0.740; 95% CI, 0.537-1.019; Pâ¯=â¯.064). PFS benefit was also seen across frailty subgroups, including fit (HR, 0.530; 95% CI, 0.387-0.727; P < .001), intermediate-fit (HR, 0.746; 95% CI, 0.526-1.058; Pâ¯=â¯.098), and frail (HR, 0.733; 95% CI, 0.481-1.117; Pâ¯=â¯.147) patients. With ixazomib versus placebo, rates of grade ≥ 3 treatment-emergent adverse events (TEAEs; 28-44% vs. 10-36%), serious TEAEs (15-29% vs. 3-29%), and discontinuation due to TEAEs (7-19% vs. 5-11%) were higher or similar across age and frailty subgroups, and generally somewhat higher in older age groups and intermediate-fit/frail patients in both arms. Treatment with ixazomib versus placebo did not adversely affect patient-reported quality-of-life scores across age and frailty status subgroups. CONCLUSION: Ixazomib is a feasible and effective maintenance option for prolonging PFS across this heterogeneous patient population.
Subject(s)
Frailty , Multiple Myeloma , Aged , Humans , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Dexamethasone/therapeutic use , Frailty/diagnosis , Multiple Myeloma/diagnosis , Multiple Myeloma/drug therapyABSTRACT
Acute chest syndrome (ACS) is defined as fever, respiratory symptoms and a new pulmonary infiltrate in an individual with sickle cell disease (SCD). Nearly half of ACS episodes occur in SCD patients already hospitalized, potentially permitting pre-emptive therapy in high-risk patients. Simple transfusion of red blood cells may abort ACS if given to patients hospitalized for pain who develop fever and elevated levels of secretory phospholipase A2 (sPLA2). In a feasibility study (PROACTIVE; ClinicalTrials.gov NCT00951808), patients hospitalized for pain who developed fever and elevated sPLA2 were eligible for randomization to transfusion or observation; all others were enrolled in an observational arm. Of 237 enrolled, only 10 were randomized; one of the four to receive transfusion had delayed treatment. Of 233 subjects receiving standard care, 22 developed ACS. A threshold level of sPLA2 ≥ 48 ng/ml gave optimal sensitivity (73%), specificity (71%) and accuracy (71%), but a positive predictive value of only 24%. The predictive value of sPLA2 was improved in adults and patients with chest or back pain, lower haemoglobin concentration and higher white blood cell counts, and in those receiving less than two-thirds maintenance fluids. The hurdles identified in PROACTIVE should facilitate design of a larger, definitive, phase 3 randomized controlled trial.
Subject(s)
Acute Chest Syndrome/diagnosis , Acute Chest Syndrome/etiology , Anemia, Sickle Cell/complications , Phospholipases A2, Secretory/blood , Acute Chest Syndrome/blood , Adolescent , Adult , Anemia, Sickle Cell/blood , Anemia, Sickle Cell/diagnosis , Child , Feasibility Studies , Female , Humans , Male , Prognosis , Young AdultABSTRACT
The reproducibility of tricuspid regurgitant jet velocity (TRJV) measurements by Doppler echocardiography has not been subjected to systematic evaluation among individuals with sickle cell disease (SCD) undergoing screening for pulmonary hypertension. We examined sources of disagreement associated with peak TRJV in children and young adults with SCD. Peak TRJV was independently measured and interpreted a week apart by separate sonographers and readers, respectively, in 30 subjects (mean age, 15.8 ± 3.3 years) who provided 120 observations. We assessed intra-/inter-reader, intra-/inter-sonographer, sonographer-reader, and within subject agreement using Intraclass Correlation Coefficient (ICC) and Cohen's kappa (κ). Agreement was examined graphically using Bland-Altman plots. Although sonographers could estimate and measure peak TRJV in all subjects, readers designated tricuspid regurgitation nonquantifiable in 10-17% of their final interpretations. Intra-reader agreement was highest (ICC = 0.93 [95% CI 0.86, 0.97], P = 0.0001) and within subject agreement lowest (ICC = 0.36 [95% CI 0.02, 0.64], P = 0.021) for single TRJV measurements. Similarly, intra-reader agreement was highest (κ = 0.74 [95% CI 0.53, 0.95], P = 0.0001) and within subject lowest (κ = 0.14 [95% CI -0.17, 0.46], P = 0.38) when sonographers and readers categorized TRJV measurements. On Bland-Altman plots, absolute differences in observations increased with higher mean TRJV readings for intra-/inter-reader agreement. Peak TRJV measurements in individual children and young adults with SCD are affected by several sources of disagreement, underscoring the need for methodological improvements that ensure reproducibility of this screening modality for making clinical decisions in this population.
Subject(s)
Anemia, Sickle Cell/complications , Hypertension, Pulmonary/diagnostic imaging , Tricuspid Valve Insufficiency/diagnostic imaging , Adolescent , Adult , Anemia, Sickle Cell/physiopathology , Child , Echocardiography, Doppler , Female , Genotype , Humans , Hypertension, Pulmonary/etiology , Hypertension, Pulmonary/physiopathology , Male , Observer Variation , Reproducibility of Results , Sickle Cell Trait/complications , Sickle Cell Trait/physiopathology , Tricuspid Valve Insufficiency/etiology , Tricuspid Valve Insufficiency/physiopathology , Young Adult , beta-Thalassemia/complicationsABSTRACT
The study purpose was to evaluate a computer-based questionnaire (SCKnowIQ) and CHOICES educational intervention using cognitive interviewing with childbearing-aged people with sickle cell disease (SCD) or trait (SCT). Ten control group participants completed the SCKnowIQ twice. Ten intervention group participants completed the SCKnowIQ before and after the CHOICES intervention. Most participants found the questionnaire items appropriate and responded to items as the investigators intended. Participants' responses indicated that the information on SCD and SCT and reproductive options was understandable, balanced, important, and new to some. Internal consistency and test-retest reliability were adequate (.47 to .87) for 4 of the 6 scales, with significant within-group changes in knowledge scores for the intervention group but not for the control group. Findings show evidence for potential efficacy of the intervention, but proof of efficacy requires a larger randomized study.