Non-transfusion Dependent Β-thalassemia Research Articles

Luspatercept for the Treatment of Anemia in Non-Transfusion-Dependent β-Thalassemia: Final Safety and Efficacy Data from the BEYOND Trial

Background: Suboptimal anemia management in patients (pts) with non-transfusion-dependent (NTD) β-thalassemia may lead to serious clinical complications. Improvements in hemoglobin (Hb) levels were shown to significantly decrease the risk of developing morbidities (Musallam KM, et al. Ann Hematol 2022;101:203-204; Musallam KM, et al. Ann Hematol 2021;100:1903-1905). There is a need for therapies that increase Hb levels besides red blood cell transfusions (RBCT), which lead to secondary iron overload. Primary and longer-term data from the BEYOND study showed that luspatercept led to significant increases in Hb levels and had a manageable safety profile in pts with NTD β-thalassemia (Taher AT, et al. Lancet Haematol 2022;9:e733-e744; Taher AT, et al. Blood 2022;140[suppl 1];8210-8212). Here we report the final data (up to last patient last visit [LPLV] date Nov 28, 2022), of the phase 2, randomized, double-blind, placebo-controlled BEYOND trial (NCT03342404). Methods: Eligible pts (N = 145) had NTD (defined as receiving ≤ 5 RBC units in the 24 wk before randomization) β-thalassemia or HbE/β-thalassemia, Hb levels ≤ 10 g/dL. Pts were randomized to luspatercept (N = 96; 1.0-1.25 mg/kg) or placebo (N = 49) subcutaneously Q3W for ≥ 48 wk. Pts continued to receive best supportive care when required. Pts who crossed over from placebo to luspatercept were not included in this analysis. Mean Hb increase ≥ 1.0 g/dL (any 12-/24-wk interval) and ≥ 1.5 g/dL from baseline (any 12-wk interval), duration of mean Hb increase ≥ 1.0 g/dL and ≥ 1.5 g/dL from baseline, iron parameters, RBCT, and safety were evaluated up to the LPLV date. Results: As of Nov 28, 2022, 93/134 (69.4%) pts on luspatercept transitioned to the long-term follow-up study (NCT04064060): 66/96 (68.8%) pts in the luspatercept arm and 27/38 (71.1%) pts who crossed over from placebo to luspatercept after study unblinding. A total of 76/96 (79.2%) pts in the luspatercept arm completed 144 wk of treatment (tx), with 55/96 (57.3%) completing 192 wk of tx; 28/96 (29.2%) pts on luspatercept discontinued tx. The median (range) luspatercept tx duration was 202.8 (15.0-242.3) wk (Table) and 61.1 (3.0-138.0) wk with placebo. Pts had a durable increase in Hb ≥ 1.0 g/dL from baseline (by 12-wk interval) through wk 240 of luspatercept tx (Figure). In the luspatercept arm, 91/96 (94.8%) pts had a mean Hb increase ≥ 1.0 g/dL from baseline during any 12-wk interval (Table). The mean (standard deviation [SD]) total duration of mean Hb increase ≥ 1.0 g/dL from baseline (any 12-wk interval) with luspatercept was 1136.0 (491.9) days. The proportion of pts achieving a mean Hb increase ≥ 1.5 g/dL during any 12-wk interval over the entire tx period was 80/96 (83.3%) and 4/49 (8.2%) in the luspatercept and placebo arms, respectively. At baseline, 83/96 and 42/49 pts in the luspatercept and placebo arms, respectively, were RBCT-free. The proportion of pts who remained RBCT-free was 78.1% (75/96) and 57.1% (28/49) in the luspatercept and placebo arms, respectively. For pts who received RBCT, the mean time to first RBCT was 482.0 days with luspatercept and 202.6 days with placebo. The mean change from baseline in serum ferritin (SF) level at wk 96 was +76.45 µg/L with luspatercept (n = 90) and +211.51 µg/L with placebo (n = 35). The mean change from baseline in SF level stabilized with longer luspatercept tx (wk 192: 49.14 µg/L [n = 71]; wk 240: 52.19 µg/L [n = 51]). The mean change from baseline in liver iron content in the luspatercept arm was −1.23 mg/g dry weight (dw) at wk 96 (n = 8) and −0.79 mg/g dw at wk 144 (n = 54). The 10 most frequently reported adverse events (AEs; ≥ 5% of pts) with luspatercept were headache, back pain, bone pain, COVID-19, arthralgia, pyrexia, pain in extremity, fatigue, diarrhea, and hypertension. Rates of serious and grade 3-4 AEs in the luspatercept arm were 24.0% [23/96] and 34.4% [33/96]), respectively. In the luspatercept arm, thromboembolic events were reported in 2/96 pts, extramedullary hemopoietic masses in 10/96 pts (all grade 1-2), and there were no malignancies. Few AEs led to tx discontinuation in the luspatercept arm (5/96 [5.2%]); no new safety signals were identified. Summary: The final results from the BEYOND study show that pts with NTD β-thalassemia treated with luspatercept maintained clinically meaningful and durable erythroid responses. The safety profile of luspatercept was manageable, and extended luspatercept exposure did not raise new safety concerns.

Bone Marrow Sinusoidal Endothelial Cells Are a Site of Fgf23 Upregulation in Murine ß-Thalassemia

Fibroblast growth factor-23 (FGF23) is a bone-derived hormonal regulator of mineral metabolism with emerging functions in the bone marrow. FGF23 has been reported to negatively regulate erythropoiesis [PMID:24509850] and promote hematopoietic progenitor mobilization from the bone marrow [PMID:33512467]. Elevated FGF23 levels in the circulation have been described in iron-deficient subjects and also in subjects with the iron-loading anemia β-thalassemia. Recently, we reported bone marrow sinusoidal endothelial cells (BM-SEC) as a novel site of Fgf23 upregulation in mice with chronic iron-deficiency anemia and acute, phlebotomy-induced anemia [PMID:37417950]. We and others have detected Fgf23 mRNA elevation in total bone marrow of Hbb th3/+ mice, a model of non-transfusion dependent β-thalassemia that exhibits systemic iron loading. In the present study, we sought to clarify sites of Fgf23 promoter activity in Hbb th3/+ bone marrow using a reporter allele in which the enhanced green fluorescent protein (eGFP) coding sequence is knocked into the endogenous Fgf23 locus ( Fgf23 eGFP). We generated Hbb +/+ and Hbb th3/+ female littermates that carried either one ( Fgf23 +/eGFP) or zero ( Fgf23 +/+) copies of the Fgf23 reporter allele, which were raised on a standard rodent diet (200 mg/kg iron, 1.0% calcium, 0.7% phosphorus). Fgf23 eGFP/eGFP homozygotes were not generated due to known early growth retardation and mortality in Fgf23 null mice. After blood and tissue collection at 8 weeks of age, phenotypes of the 4 Hbb-Fgf23 genotype combinations were compared by two-way ANOVA. Compared to mice with intact Hbb and Fgf23 alleles ( Hbb +/+ Fgf23 +/+), Hbb th3/+ Fgf23 +/+ mice showed markedly elevated plasma levels of “total” FGF23 (sum of intact, active hormone and C-terminal cleaved fragments). Plasma total FGF23 levels in Hbb th3/+ Fgf23 +/+ and Hbb th3/+ Fgf23 +/eGFP mice were similar, indicating utility of the latter genotype for interrogating sites of increased Fgf23 expression in murine b-thalassemia. We therefore used anti-GFP immunohistochemistry in formalin-fixed bone marrow sections to assess Fgf23 eGFP reporter allele expression in the context of tissue architecture. Hbb th3/+ Fgf23 +/eGFP mice showed GFP expression in BM-SEC throughout the bone marrow, which was more intense than in non-anemic Hbb +/+ Fgf23 +/eGFP mice; controls lacking the Fgf23 eGFP allele confirmed anti-GFP antibody specificity. Hbb th3/+ mice also showed Fgf23 eGFP reporter expression in the thymic vasculature but not vasculature of the liver, spleen, or kidney. In contrast to their marked elevation in plasma total FGF23, Hbb th3/+ Fgf23 +/+ mice showed plasma levels of the intact, biologically-active FGF23 hormone that overlapped with levels in Hbb +/+ Fgf23 +/+ controls. Interestingly, compared with Hbb th3/+ Fgf23 +/+ mice, Hbb th3/+ Fgf23 +/eGFP mice showed 45% lower plasma intact FGF23, suggesting an effect of Fgf23 gene dosage. Given prior reported effects of FGF23 on hematopoiesis, we assessed if Fgf23 gene dosage modulated the severity of ineffective erythropoiesis in Hbb th3/+ mice. Compared to Hbb +/+ Fgf23 +/+ controls, Hbb th3/+ Fgf23 +/+ mice showed reductions in RBC, hemoglobin, and mean corpuscular hemoglobin, as well as increases in RDW and in spleen weight (reflecting extramedullary hematopoiesis). However, the severity of these parameters was not modified by heterozygous Fgf23 disruption ( Hbb th3/+ Fgf23 +/eGFP).While FGF23 has been reported to induce left ventricular hypertrophy [PMID:21985788], Hbb th3/+ Fgf23 +/+ and Hbb th3/+ Fgf23 +/eGFP mice showed similarly increased heart-to-body weight ratios compared to Hbb +/+ Fgf23 +/+ controls. In non-thalassemic mice, heterozygous Fgf23 disruption ( Hbb +/+ Fgf23 +/eGFP) caused a trend ( P=0.10) towards lower plasma intact FGF23 while not impacting hematological parameters or spleen weight. In summary, by showing that Fgf23 gene dosage modulates plasma intact FGF23 levels in Hbb th3/+ mice without altering severity of anemia or splenomegaly, our data suggest that moderate reductions in circulating levels of the intact FGF23 hormone do not alter the severity of ineffective erythropoiesis in Hbb th3/+mice at 8 weeks of age. Our finding that β-thalassemic mice exhibit Fgf23 upregulation in BM-SEC lays the groundwork for future investigation of the functional effects of locally-produced FGF23 in the thalassemic hematopoietic stem cell niche.

Improvement of Underlying Disease Pathophysiology of Ineffective Erythropoiesis in Non-Transfusion-Dependent (NTD) Patients with β-Thalassemia Receiving Luspatercept: Biomarker Analysis from the BEYOND Trial

Background: Ineffective erythropoiesis and chronic hemolytic anemia are hallmarks of β-thalassemia which ultimately lead to extramedullary hematopoiesis (EMH), iron overload and other complications. Patients with hemoglobin levels chronically < 10 g/dL are at higher risk for clinical complications and mortality. A significant proportion of patients treated with luspatercept on the BEYOND study (NCT03342404) achieved ≥ 1.0 g/dL hemoglobin increases from baseline, with a manageable safety profile. This increase of hemoglobin is associated with improvement in health-related quality of life. (Taher et al, Lancet Haematol. 2022; 9(10):e733-e744). Aim: To report biomarker-correlated data demonstrating the benefit of luspatercept on underlying ineffective erythropoiesis, iron homeostasis, and hemolysis. Methods: Serum samples and MRI data were collected from 145 patients (luspatercept [n = 96] and placebo [n = 49]) enrolled in the multi-center, randomized, double-blind, placebo-controlled phase 2 BEYOND trial for this study. Samples were analyzed for levels of hepcidin, erythroferrone (ERFE), erythropoietin (EPO), soluble transferrin receptor (sTFR), fetal hemoglobin (HbF), serum ferritin, growth differentiation factor (GDF) 11, GDF15 and LDH by ELISA at Intertek (San Diego, CA). Liver iron content (LIC) was assessed by R2 MRI. MRI/ultrasound was used to determine spleen volumes. Results: Luspatercept responders, (patients who achieved hemoglobin increase ≥ 1.0 g/dL from baseline) had significantly lower baseline levels of ERFE ( P = 0.0065), EPO ( P = 0.00019), sTFR1 ( P = 0.00043), GDF15 ( P = 4.4e -5), and HbF ( P = 0.00016), and higher hepcidin levels ( P = 0.022), compared with non-responders. Baseline bilirubin, serum ferritin, LIC, and spleen volume were not significantly different between responders and non-responders. Levels of GDF11, a member of the TGFβ superfamily of ligands targeted by luspatercept, were significantly reduced at week 48 in the treatment group compared to baseline ( P = 0.001), though not different between responders and non-responders; no such reduction was observed in the placebo group. In the luspatercept arm, bilirubin and LDH did not significantly change from baseline to week 48 in either responders ( P = 0.289) or non-responders ( P = 1.000). However, reticulocytes increased significantly in responders ( P = 0.028) without any increase in HbF ( P = 0.82), suggesting increased effective erythropoiesis and stabilization of hemolysis. Luspatercept responders had significant reductions in spleen volume at week 48 compared with baseline ( P < 0.001), suggesting reduced EMH. Spleen volumes at week 48 of NR in both arms were not significantly different. Placebo patients had a significant increase in serum ferritin levels at week 48 ( P = 0.030), likely from ongoing ineffective erythropoiesis and dysregulated iron homeostasis. At week 48, serum ferritin levels were significantly decreased in luspatercept responders ( P = 0.003), but not in non-responders ( P = 0.480). No significant changes in LIC were observed in either the placebo or luspatercept groups at week 48 compared to baseline. Conclusions: Analysis of biomarkers suggests that patients with NTD β-thalassemia receiving luspatercept had an improvement in ineffective erythropoiesis, the primary underlying pathophysiologic mechanism. In responders to luspatercept, increase in reticulocytes, without an increase in HbF, suggests more efficient maturation and differentiation in the bone marrow. Furthermore, the reduction in spleen volume suggests that this efficient improvement in marrow erythropoiesis leads to reduction in EMH. At the time of analysis, LIC remained unchanged, which in combination with reduction in serum ferritin, suggests that the improvement in ineffective erythropoiesis may also have improved dysregulated iron homeostasis, with reduction in iron absorption and no further iron loading. Therefore, this analysis shows that luspatercept treatment results in improved ineffective erythropoiesis, reduced EMH and improved iron homeostasis.

Erythroferrone exacerbates iron overload and ineffective extramedullary erythropoiesis in a mouse model of β-thalassemia.

β-thalassemia is characterized by chronic hepcidin suppression and iron overload, even in patients who have not undergone transfusion. The HbbTh3/+ (Th3/+) mouse model of nontransfusion-dependent β-thalassemia (NTDBT) partially recapitulates the human phenotype but lacks chronic hepcidin suppression, progressive iron accumulation into adulthood, or the interindividual variation of the rate of iron loading observed in patients. Erythroferrone (ERFE) is an erythroid regulator that suppresses hepcidin during increased erythropoiesis. ERFE concentrations in the sera of patients with NTDBT correlate negatively with hepcidin levels but vary over a broad range, possibly explaining the variability of iron overload in patients. To analyze the effect of high ERFE concentrations on hepcidin and iron overload in NTDBT, we crossed Th3/+ mice with erythroid ERFE-overexpressing transgenic mice. Th3/ERFE-transgenic mice suffered high perinatal mortality, but embryos at E18.5 showed similar viability, appearance, and anemia effects as Th3/+ mice. Compared with Th3/+ littermates, adult Th3/ERFE mice had similarly severe anemia but manifested greater suppression of serum hepcidin and increased iron accumulation in the liver, kidney, and spleen. The Th3/ERFE mice had much higher concentrations of serum ERFE than either parental strain, a finding attributable to both a higher number of erythroblasts and higher production of ERFE by each erythroblast.Th3/+ and Th3/ERFE mice had similar red blood cell count and shortened erythrocyte lifespan, but Th3/ERFE mice had an increased number of erythroid precursors in their larger spleens, indicative of aggravated ineffective extramedullary erythropoiesis. Thus, high ERFE concentrations increase the severity of nontransfusional iron overload and ineffective erythropoiesis in thalassemic mice but do not substantially affect anemia or hemolysis.

Profile of Luspatercept in the Treatment of Anemia in Adults with Non-Transfusion-Dependent β-Thalassemia (NTDT): Design, Development and Potential Place in Therapy.

Over the past decade, evidence has been mounting on the detrimental clinical sequelae of untreated anemia in patients with non-transfusion-dependent β-thalassemia (NTDT). There are no pharmacologic agents that are specifically approved for the management of anemia in NTDT, and available options such as splenectomy, transfusion therapy, and hydroxyurea each come with their own shortcomings, especially for long-term use. Luspatercept is an erythroid maturation agent that has been evaluated in a Phase 2, randomized trial and showed a significant benefit in raising hemoglobin level by at least 1 g/dL in adults with NTDT and a baseline hemoglobin level ≤10 g/dL. These data led to luspatercept's approval by the European Commission for the treatment of anemia in adults with NTDT and presents the first evidence-based approach for a novel agent that is able to ameliorate anemia in this patient population.

A Closer Look at Changes in Hemoglobin Levels in Patients with Non-Transfusion Dependent β-Thalassemia Treated with Luspatercept: Post Hoc Analysis of the Phase 2 BEYOND Trial

Introduction: β-thalassemia is characterized by ineffective erythropoiesis and subsequent anemia of varying severity. Patients with non-transfusion dependent β-thalassemia (NTDT) have historically remained transfusion-independent due to the perception that their anemia is mild to moderate. However, recent evidence has consistently highlighted that in patients with NTDT, hemoglobin (Hb) levels < 10 g/dL are associated with greater long-term morbidity and mortality, with increases of 1 g/dL associated with significant risk reduction. Apart from red blood cell transfusions (RBCTs) administered in certain clinical situations, there is no approved treatment for NTDT-related anemia. RBCTs may provide symptom relief but are associated with adverse events such as iron overload and their own treatment burden related to transfusion requirements. The randomized, double-blind, placebo-controlled phase 2 BEYOND trial (NCT03342404) demonstrated the efficacy and safety of luspatercept, a first-in-class erythroid maturation agent, in patients with NTDT and Hb ≤ 10 g/dL. The study met the primary endpoint with 77.1% and 0% of patients in the luspatercept and placebo groups, respectively, achieving ≥ 1.0 g/dL increase from baseline in mean Hb. This post hoc analysis evaluated the proportion of patients receiving luspatercept who transitioned to Hb thresholds with lower morbidity/mortality risk and who achieved clinically relevant Hb increases across different baseline Hb subgroups. Methods: The methods of the BEYOND trial have been reported previously (Taher AT, et al. HemaSphere 2021;5(suppl 2). EHA Abstract S101). Briefly, 145 adults (≥ 18 years) with non-transfusion dependent (≤ 5 RBC units [1 unit = 200-350 mL transfused packed RBCs]/24 weeks, and RBCT-free > 8 weeks before randomization) β-thalassemia or HbE/β-thalassemia and Hb ≤ 10.0 g/dL were randomized 2:1 to luspatercept 1 mg/kg (up to 1.25 mg/kg; n = 96) or placebo (n = 49) subcutaneously every 3 weeks for ≥ 48 weeks. All patients continued receiving best supportive care, including sporadic RBCTs and iron chelation therapy. This analysis evaluated the proportion of patients receiving luspatercept who achieved Hb > 10.0 g/dL at Weeks 12, 24, 36, and 48, and the proportion of patients treated with luspatercept who achieved a mean Hb increase ≥ 1.0 g/dL during any rolling 24-week period by baseline Hb level (< 7.0 g/dL, ≥ 7.0 and ≤ 8.5 g/dL, and > 8.5 g/dL). All findings were analyzed descriptively. Results: A total of 96 patients receiving luspatercept in the BEYOND intention-to-treat population were eligible and included in the analysis. Median age was 39.5 years (range, 18.0-71.0) and 58.3% of patients were female. At baseline, the median Hb level was 8.2 g/dL (range, 5.3-10.1). Increasing proportions of patients treated with luspatercept achieved Hb > 10.0 g/dL, from 55.2% (n = 53/96) at Week 12, 63.0% (n = 58/92) at Week 24, 67.0% (n = 61/91) at Week 36, to 69.7% (n = 62/89) at Week 48 (Figure 1). A ≥ 1.0 g/dL increase from baseline in mean Hb level during any rolling 24-week period was achieved by 68.4% (n = 13/19) of patients treated with luspatercept with baseline Hb < 7.0 g/dL, 88.9% (n = 32/36) of those with baseline Hb ≥ 7.0 and ≤ 8.5 g/dL, and 87.8% (n = 36/41) of those with baseline Hb > 8.5 g/dL. Conclusions: This analysis of the BEYOND clinical trial showed the majority of patients with NTDT receiving luspatercept achieved Hb > 10.0 g/dL over time, a threshold that is consistently associated with reduced morbidity and mortality in the literature. Clinically relevant Hb increases of ≥ 1.0 g/dL were observed across all baseline Hb levels. These findings further support the ability of luspatercept to achieve clinically meaningful increases in Hb for the majority of patients with NTDT, irrespective of baseline severity of anemia. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Burden of β-Thalassemia: Findings from a Multinational Medical Record Abstraction Study

Introduction: β-thalassemias are rare genetic conditions characterized by mutations in the HBB gene, resulting in defective β-globin production and ineffective erythropoiesis. The severity of disease varies according to genotype. Periodic red blood cell transfusions (RBCTs) are the standard of care, but long-term dependence on RBCTs is associated with risk of iron overload and other clinical sequelae. As new treatment options are available, understanding the clinical burden of β-thalassemia and RBCTs is essential to optimal clinical care. Methods: This retrospective observational study analyzed anonymized medical records from adults (≥ 23 years of age) with transfusion dependent β-thalassemia (TDT) or non-transfusion dependent β-thalassemia (NTDT) who visited a participating physician on or after January 2016. Physicians in the UK, France, Germany, Spain, and Canada abstracted medical records for eligible patients with ≥ 5 years of medical history in their practice. Clinical characteristics, transfusion patterns, and RBCT utilization were analyzed descriptively. Results: A total of 214 patients were included: 118 (55%) with TDT and 96 (45%) with NTDT. Mean age was 36 years and body mass index was approximately 24 kg/m2 in both groups; 71% and 61% of patients with TDT and NTDT, respectively, were male. Mean (median) duration of patient medical history in the practice was 8.5 (7.5) and 8.6 (6.9) years for patients with TDT and NTDT, respectively. Among the TDT group, the mean (standard deviation [SD]) age at first diagnosis and first treatment of β-thalassemia was 11.1 (10.2) and 13.7 (11.2) years, respectively. The most common reasons for initiating RBCTs were: hemoglobin (Hb) levels < 8 g/dL (32%), < 7 g/dL (21%), < 6 g/dL (14%), and to maintain Hb > 10 g/dL (25%). The majority of patients (n = 87 [74%]) received β-thalassemia mutation testing; of these, 31 (36%) were β0/β0, 19 (22%) were β0/β+, and 23 (26%) were β+/β+. More than one-third (n = 41 [35%]) of patients with TDT had progressed from NTDT, at a mean (SD) age of 31.4 (11.7) years. The mean (SD) pre-transfusion Hb level in the TDT group was 6.9 g/dL (1.30) (n = 94). At the time of data abstraction, most patients with TDT (n = 90/118 [76%]) had an RBCT at least every 3 weeks (Figure 1), receiving a mean (SD) of 2.4 (0.64) RBC units (n = 101) per session. Approximately one-third (n = 43/118 [36%]) of patients with TDT received 3 RBC units per session, on average (Figure 2). Patients with TDT received their most recently reported RBCT regimen for a mean (SD) of 72.6 (72.43) months (n = 83). Adverse events (AEs) associated with the most recent transfusion regimen included allergic reactions (n = 3/118 [3%]), non-hemolytic febrile transfusion reactions (n = 2/118 [2%]), and transfusion-associated circulatory overload (n = 1/118 [1%]). Among the NTDT group, the mean (SD) age at first diagnosis and first treatment of β-thalassemia was 14.5 (11.8) and 18.8 (12.0) years, respectively. Approximately two-thirds (n = 63 [66%]) of patients with NTDT received β-thalassemia mutation testing; of these, 7 (11%) were β0/β0, 19 (30%) were β0/β+, and 20 (32%) were β+/β+. Among patients with NTDT, who had ≥ 1 RBCT (n = 81 [84%]), the mean (SD) number of RBCTs received was 15.9 (15.88) (in the physician's practice or as history noted in the medical record). The most common reasons for receiving RBCTs were: Hb levels < 8 g/dL (33%), < 7 g/dL (20%), and < 6 g/dL (14%), infection exacerbating anemia (16%), and to maintain Hb > 10 g/dL (15%). The mean (SD) pre-transfusion Hb level was 7.4 g/dL (1.18) (n = 67) and a mean (SD) of 2.2 (0.57) RBC units (n = 66) was transfused per session. AEs for patients with NTDT included allergic reactions (n = 4/96 [5%]), alloimmunization (n = 1/96 [1%]), autoimmune hemolytic anemia (n = 1/96 [1%]), and nonhemolytic febrile transfusion reaction (n = 1/96 [1%]). Conclusions: This study provides much needed insight into the real-world clinical needs of patients with β-thalassemia. About one-third of patients with TDT had progressed from NTDT. Patients with TDT had a high transfusion burden, requiring RBCTs every 2-4 weeks and 2-3 RBC units per session, on average. Additionally, patients with NTDT had low pre-transfusion Hb and required 2 RBC units per transfusion, on average. New therapeutic options are needed that can reduce RBCT dependency for patients with TDT, and improve pre-transfusion Hb levels and transfusion requirements for patients with NTDT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Erythroid Response in Patients with Non-Transfusion-Dependent β-Thalassemia Treated with Luspatercept: Long-Term Data from the BEYOND Trial

Introduction: Long-term, untreated anemia in patients with non-transfusion-dependent (NTD) β-thalassemia can lead to serious clinical complications. Several studies have shown that increasing hemoglobin (Hb) levels by ≥ 1 g/dL can significantly decrease the risk of developing morbidities (Musallam KM, et al. Ann Hematol 2022;101:203-204; Musallam KM, et al. Ann Hematol 2021;100:1903-1905). Although there are no available treatments for NTD β-thalassemia-associated anemia, previous studies showed that luspatercept improved erythropoiesis leading to a decrease in transfusion burden in pts with transfusion-dependent β-thalassemia, and durably increased Hb levels in pts with NTD β-thalassemia (Cappellini MD, et al. N Engl J Med 2020;382:1219-1231; Taher AT, et al. HemaSphere 2021;5[Suppl 2]. Abstract S101). Here, we report the long-term efficacy update of luspatercept in patients with NTD β-thalassemia in the BEYOND trial (NCT03342404). Methods: Eligible patients (N = 145) with NTD β-thalassemia or HbE/β-thalassemia (defined as receiving 0-5 RBC units in the 24 weeks [wk] prior to randomization) and Hb levels ≤ 10 g/dL were randomized to luspatercept (1.0-1.25 mg/kg) or placebo subcutaneously for ≥ 48 wk. Assessment groups were based on patient assignment at randomization: patients in the luspatercept arm were assessed while remaining on treatment and patients in the placebo arm were assessed up to discontinuation or crossover to luspatercept. Mean change from baseline in Hb was assessed for continuous 12-wk intervals up to wk 144. Erythroid response was defined as mean Hb change from baseline of ≥ 1 g/dL and was assessed over rolling 12-wk intervals. The incidence of RBC transfusions (events and units) was also assessed. Results: As of September 22, 2021, 83 (86.5%) patients in the luspatercept arm and 16 (32.7%) in the placebo arm completed ≥ 96 wk of treatment. Moreover, 72 (75.0%) patients in the luspatercept arm completed ≥ 120 wk of treatment. The median (range) treatment duration was 150.1 (15.0-185.4) wk in the luspatercept arm and 61.1 (3.0-138.0) wk in the placebo arm. Patients in the luspatercept and placebo arms received a median (range) of 42.0 (3.0-61.0) doses and 20.0 (1.0-46.0) doses per patient, respectively. Mean (standard error [SE]) Hb change from baseline in the luspatercept arm was 1.28 (0.069) g/dL during wk 1-12 and 1.48 (0.078) g/dL during wk 13-24, and the increase was maintained among patients remaining on study through all time points. Improvements in Hb levels from baseline were nominally significant versus placebo at assessed 12-wk intervals up to wk 96 (Figure). The proportion of patients experiencing an erythroid response during any 12-wk interval increased from 91.7% (88/96 patients) at the primary data cutoff date (September 14, 2020), to 93.8% (90/96 patients) at the current data cutoff date. Among responders, the proportion of patients in the luspatercept arm with more than one 12-wk rolling response increased from 35.2% (31/88 patients) to 61.1% (55/90 patients) between the primary and current data cutoff dates, and the mean (standard deviation [SD]) total duration of erythroid response among patients with at least one 12-wk rolling response also increased, from 611.1 (243.3) to 873.1 (363.4) days. During wk 1-96, a smaller proportion of patients in the luspatercept arm compared to the placebo arm (10.4% [10/96 patients] vs 32.7% [16/49 patients]) had ≥ 2 RBC transfusions. During the same period, the mean number of transfusion events (0.4 vs 1.3) and RBC units transfused (0.7 vs 2.2) per patient was lower in the luspatercept arm than in the placebo arm. During wk 97-144, the mean number of transfusion events and units per patient in the luspatercept arm remained stable (0.2 events and 0.2 units, respectively). Conclusions: Long-term luspatercept treatment resulted in sustained and significantly improved Hb levels in patients with NTD β-thalassemia. The duration of erythroid response increased with an additional year of luspatercept treatment. Few patients required RBC transfusions and the cumulative incidence of RBC transfusions remained low and relatively stable through 144 wk. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Predictors of Hematologic Responses in Patients with Non-Transfusion-Dependent β-Thalassemia Receiving Thalidomide Therapy

To explore the predictors of hematologic responses of non-transfusion-dependent β-thalassemia (NTDT) to thalidomide. 33 patients with NTDT who treated with thalidomide in the 923rd Hospital of the Joint Logistics Support Force of the People's Liberation Army from May 2016 to June 2019 were included in the study. The basic data, hematological indexes, degree of treatment response and genetic background of the patients were analyzed. The baseline fetal hemoglobin (HbF) level of main responders (MaR) was significantly higher than that of minor responders (MiR) and no responders (NR) (P=0.001). And the baseline HbF level was positively correlated with hemoglobin increment after treatment (r=0.601). Genetic background analysis showed that the frequencies of the genotype CT of HBG2 rs7482144 (P=0.031), the genotypes CT/CC (P=0.030) and the minor allele C (P=0.015) of HBS1L-MYB rs9399137, the genotypes AT/TT (P=0.030) and the minor allele T (P=0.028) of HBS1L-MYB rs4895440, the genotypes AG/GG (P=0.030) and the minor allele G (P=0.028) of HBS1L-MYB rs4895441 (P=0.030) in MaR group were significantly higher than those in MiR and NR groups. Comparing the area under the ROC curve (AUC) of the above indicators to predict the main response, the results demonstrated that the predictive value of baseline HbF level was significantly better than rs7482144 (0.91 vs 0.72, P=0.003), rs9399137 (0.91 vs 0.74, P=0.022), rs4895440 (0.91 vs 0.74, P=0.023) and rs4895441 (0.91 vs 0.74, P=0.023), but there was no significant difference in the predictive value between combined single nucleotide polymorphisms (SNPs) (0.91 vs 0.88, P=0.658）and baseline HbF combined SNPs (0.91 vs 0.97, P=0.132). The AUC value of baseline HbF predicting the efficacy of thalidomide as the main response was 0.91, the cut-off value was 27.4%, the sensitivity was 100%, and the specificity was 58.3% (P=0.001). The hematologic response of NTDT to thalidomide is variable and complex. Compared to genetic background, baseline HbF may be a simpler and more efficient tool to predict efficacy response.

Luspatercept in patients with non-transfusion dependent β-thalassaemia

Ineffective erythropoiesis leads to the development of chronic anaemia and iron overload in patients with non-transfusion dependent β-thalassemia, which is associated with significant morbidity, risk of mortality, and loss of health-related quality of life (HRQoL) especially in patients who have haemoglobin concentrations lower than 10 g/dL.1 There are no approved drugs directed at the management of anaemia in patients with non-transfusion dependent β-thalassemia, leaving supportive care with occasional red blood cell transfusions and iron chelation as the only approved therapeutic options for these patients.

Long-term safety and erythroid response with luspatercept treatment in patients with β-thalassemia.

β-thalassemia is a hereditary blood disorder resulting in ineffective erythropoiesis and anemia. Management of anemia with regular blood transfusions is associated with complications including iron overload. Here, we report long-term safety and efficacy results of the first clinical study of luspatercept in β-thalassemia, initiated in 2013, enrolling adults with both nontransfusion-dependent (NTD) and transfusion-dependent (TD) β-thalassemia. The objective was to report long-term safety data, for up to 5 years of treatment, for 64 patients with TD or NTD β-thalassemia, and long-term efficacy data for a subset of 63 patients with β-thalassemia who received high-dose luspatercept (0.6-1.25 mg/kg): 31 NTD and 32 TD patients. The study was a phase 2, noncontrolled, open-label trial comprising a dose-finding base phase and a 5-year extension phase. Endpoints include safety; erythroid response over a continuous 12-week period [NTD: hemoglobin increase from baseline ⩾1.0 or ⩾1.5 g/dl; TD: red blood cell (RBC) transfusion burden reduction, ⩾20%, ⩾33%, or ⩾50%]; and changes in biomarkers of ineffective erythropoiesis, iron metabolism parameters, Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) scores, and 6-min walking distance. Median duration of luspatercept exposure for NTD and TD patients was 910 days (range, 40-1850) and 433 days (range, 21-1790), respectively. Seventeen of 31 (54.8%) NTD patients achieved a mean hemoglobin increase of ⩾1.5 g/dl and 19 of 32 (59.4%) TD patients achieved ⩾50% reduction in RBC transfusion burden, during any continuous 12-week period. Median cumulative duration of response was 1126 days (range, 127-1790) for NTD patients and 909 days (range, 87-1734) for TD patients. The most common treatment-related adverse events of any grade were bone pain, headache, and myalgia. Long-term assessment of patients with β-thalassemia showed luspatercept was associated with sustained increases in hemoglobin levels in NTD patients and sustained transfusion burden reductions in TD patients. (ClinicalTrials.gov Identifiers: NCT01749540 and NCT02268409). Long-term safety and erythroid response with luspatercept treatment in patients with β-thalassemia Background: β-thalassemia is a genetic blood disorder caused by mutations in the β-globin gene, which encodes one of the proteins that comprise hemoglobin, a key constituent of red blood cells. Patients with β-thalassemia experience anemia, the main treatment for which is blood transfusions. Long-term repeated blood transfusions lower patients' quality of life, use hospital resources, and the resulting accumulation of excess iron can cause organ failure and decrease life expectancy. The severity of the anemia experienced by patients with β-thalassemia varies; patients with transfusion-dependent β-thalassemia require regular blood transfusions, compared with those with nontransfusion-dependent β-thalassemia who require infrequent transfusions, or even none at all, to manage their symptoms. Luspatercept (Reblozyl®) is an agent that stimulates the production of red blood cells and is used to treat anemia caused by β-thalassemia. However, the long-term effects of luspatercept treatment on patients with β-thalassemia are not known.Objective: In this study, we report the long-term safety of luspatercept in 64 adult patients with either transfusion-dependent or nontransfusion-dependent β-thalassemia, and the long-term efficacy of high-dose luspatercept (0.6-1.25 mg/kg) in a subset of 63 patients.Results: The average time period that patients were treated with luspatercept was 910 days for nontransfusion-dependent β-thalassemia and 433 days for transfusion-dependent β-thalassemia. We report that in patients with nontransfusion-dependent β-thalassemia, luspatercept treatment was associated with sustained increases, just over 3 years, in hemoglobin levels. Likewise, in transfusion-dependent β-thalassemia, luspatercept treatment was associated with a sustained reduction, 2.5 years, in the amount of blood transfusion required to manage their anemia. Long-term treatment with luspatercept was not associated with any new side effects compared with previous short-term treatment studies. The most common side effects were headache (27 patients), bone pain (20 patients), and muscle pain (14 patients) with more than 90% of these patients experiencing these side effects as mild severity.Conclusion: The results of this study show that in patients with either transfusion-dependent or nontransfusion-dependent β-thalassemia, luspatercept provides lasting reduction in anemia with mostly mild and predictable side effects.

Luspatercept Improves Quality of Life and Reduces Red Blood Cell Transfusion Burden in Patients with Non-Transfusion-Dependent β-Thalassemia in the BEYOND Trial

Luspatercept Improves Quality of Life and Reduces Red Blood Cell Transfusion Burden in Patients with Non-Transfusion-Dependent β-Thalassemia in the BEYOND Trial

A Comprehensive Analysis of the Erythropoietin-erythroferrone-hepcidin Pathway in Hereditary Hemolytic Anemias.

A Comprehensive Analysis of the Erythropoietin-erythroferrone-hepcidin Pathway in Hereditary Hemolytic Anemias.

Role of malonaldehyde as a surrogate biomarker for iron overload in the β-thalassemia patient: A systematic meta-analysis

Malonaldehyde (MDA), a biomarker of oxidative stress is found to be increased in many individuals suffering from β-thalassemia. This may possibly be attributed to iron overload that is seen occurring in varying degrees in the condition as evident from increased ferritin (the storage form of body iron) levels in afflicted individuals. This study hypothesized that MDA may be used as a surrogate marker for iron overload in β-thalassemia. We performed a systematic review and meta-analysis of case-control studies for both parameters. The mean difference (MD) and confidence interval at 95% was calculated using a random effect model after exclusion of unsuitable data and study imputed of bias by trim-fill analysis. The study subjects were divided into two groups; transfusion-dependent β-thalassemia (TDT) and non-transfusion-dependent β-thalassemia (NTDT). The study population for MDA comprised of 2001 candidates (1159 Cases and 842 Controls) and 429 individuals (289 Cases and 140 Controls) respectively, for TDT and NTDT groups. While 1332 (803 Cases vs. 529 Controls) and 342 (234 Cases vs. 108 Controls) candidates were included in the analysis of ferritin in the aforesaid two groups. It was found that MDA levels were significantly increased in TDT [MD 2.221 (1.80-2.646), p<0.001] as well as in NTDT [MD 1.89 (1.20-2.581), p<0.001] when compared with normal individuals. Ferritin level is also found to be significantly increased in these two groups: in TDT [MD 2.288 (1.883-2.693), p<0.001] and in NTDT [MD 1.946 (0.883-3.009), p<0.001] when compared with normal individuals. In conclusion, it is seen that all β-thalassemia patients irrespective of blood transfusion dependency suffer from the curse of iron overload-induced oxidative stress.

2021 update on clinical trials in β-thalassemia.

The treatment landscape for patients with β-thalassemia is witnessing a swift evolution, yet several unmet needs continue to persist. Patients with transfusion-dependent β-thalassemia (TDT) primarily rely on regular transfusion and iron chelation therapy, which can be associated with considerable treatment burden and cost. Patients with non-transfusion-dependent β-thalassemia (NTDT) are also at risk of significant morbidity due to the underlying anemia and iron overload, but treatment options in this patient subgroup are limited. In this review, we provide updates on clinical trials of novel therapies targeting the underlying pathology in β-thalassemia, including the α/non-α-globin chain imbalance, ineffective erythropoiesis, and iron dysregulation.

Long-term safety and efficacy of hydroxyurea in patients with non-transfusion-dependent β-thalassemia: a comprehensive single-center experience.

Over the past 20years, hydroxyurea (HU) has emerged as an effective therapeutic agent in thalassemic patients to improve anemia and decrease the transfusion dependency. We evaluated long-term safety and clinical response to HU in patients with non-transfusion-dependent β-thalassemia (NTDT). In this retrospective study, medical records of 181 patients with NTDT were evaluated during October to December 2020 in Southern Iran. No requirement to blood transfusion was considered as sustained transfusion independence response. All patients were regularly examined and monitored for the occurrence of any adverse event (AE) of HU. The mean duration of HU consumption ± SD was 18.2 ± 4.0 (8-22) years. Overall, 149 patients (82.3%) had sustained transfusion independence response. β-globin gene mutations and XmnI polymorphisms were not significantly associated with clinical response (P > 0.05). Mild and transient AEs were reported in 60 patients (33%) with no requirement to drug interruption. Hydroxyurea with the dose of 8-15mg/kg can be used as a safe and effective treatment in NTDT patients. It was well tolerated in long term without any serious complication or secondary malignancy. No relationship between XmnI or β-globin gene mutations with HU response was observed in this geographic area of the world.

Direct Medical Care Cost Associated with β-Thalassemia Care in Turkey

Background: β-thalassemia is a common disorder in Turkey relative to many other countries. To our knowledge, there are no recent data in the literature on the direct medical care costs associated with β-thalassemia. We conducted a β-thalassemia treatment center survey and chart review to estimate the numbers of patients with transfusion-dependent (TD) or non-transfusion-dependent (NTD) β-thalassemia currently receiving care and the associated direct medical care costs in Turkey.Methods: A preliminary list of β-thalassemia-treating centers was generated from the IMS Health audit of hospitals and treatment centers across Turkey based on the use of iron chelation therapy (ICT) agents. One or more hematologists or pediatricians in each potential hospital ward were contacted to determine the number of patients managed in their ward with β-thalassemia major, TD β-thalassemia intermedia, and NTD β-thalassemia intermedia. TD status was determined using local definitions by each physician. A geographically stratified sample of 60 physicians was then asked to complete a web-based questionnaire on healthcare resource utilization for the four most recent patients under their care: one patient with β-thalassemia major, one with TD β-thalassemia intermedia, one with NTD β-thalassemia intermedia, and one patient at their discretion. Healthcare resource utilization focused on transfusions, ICT, laboratory work, β-thalassemia-associated complications, and inpatient hospital stay. The unit cost of each healthcare utilization was extracted from relevant literature and published government fee schedules. For prescription drug prices, IMS Health sales data in USD were referenced.Results: We identified 107 treatment centers, 91 (85%) of which were successfully surveyed. A total of 2,637 TD β-thalassemia patients (2,059 with β-thalassemia major plus 578 with TD β-thalassemia intermedia) and 2,040 NTD β-thalassemia intermedia patients were reported. Taking into consideration the sampling frame, missing data, infrequent care for NTD β-thalassemia patients, and errors (including the fact that ICT can be used to manage conditions other than β-thalassemia), we estimated there are approximately 4,000 TD and 4,000 NTD β-thalassemia patients in Turkey. A total of 212 β-thalassemia patient records were reviewed (72 β-thalassemia major, 72 TD β-thalassemia intermedia, and 68 NTD β-thalassemia intermedia). Both the mean and median ages were about 20 years old, and the ages were similar between patients with TD and NTD β-thalassemia. For patients with β-thalassemia major, the total annual direct costs per patient were USD 14,360, of which ICT was the most expensive cost component at USD 9,919, followed by in-hospital stay (USD 1,786), transfusions (USD 1,718), complications (USD 800), and laboratory tests (USD 193). Patients with TD β-thalassemia intermedia incurred nearly identical medical care costs of USD 14,940, of which USD 10,301 was attributable to ICT. Not all TD β-thalassemia patients received transfusions at β-thalassemia treatment centers. For patients who did receive transfusions at β-thalassemia treatment centers (n = 85), patients with β-thalassemia major (n = 45) and TD β-thalassemia intermedia (n = 40) received on average 1.6 and 1.5 red blood cell units per month, respectively. Every patient with TD β-thalassemia received ICT, and deferasirox was the most commonly administered chelation treatment, prescribed to 91 of 144 patients. The annual direct cost per patient with NTD β-thalassemia intermedia was lower at USD 9,286, primarily owing to lower healthcare utilization of ICT and transfusions. Combining the costs of TD and NTD β-thalassemia treatment, we estimated that the total annual direct medical care cost was approximately USD 95,491,900 in Turkey, with TD β-thalassemia patients accounting for USD 58,347,900 (61.1%).Conclusions: β-thalassemia remains a prevalent disease in Turkey where there are an estimated 4,000 TD and 4,000 NTD patients. The disease is associated with significant consumption of healthcare resources, with the total annual direct medical care cost estimated to be over USD 95 million. The costs reported in this study were likely underestimated, as many patients who received transfusions outside of β-thalassemia treatment centers were not captured in the chart review. DisclosuresAntmen:Celgene: Honoraria, Other: Advisory for the project Burden of illness in thalassemia; Novartis: Other: Advisory board; Jazz: Other: Advisory board . Angelucci:Roche: Other: Advisory board: biosimilars; Celgene: Other: protocoll ACE 536 B-Thal 001: DMC Chair; Bluebird Bio: Other: Advisory board: Gene therapy in Thalassemia; Novartis Oncology: Other: Protocol Telesto: sterring committee Chair; Jazz: Other: Advisory board: AML; Novartis Oncology: Other: Advisory board: iron toxicity; Celgene: Honoraria, Other: Advisory: research project ; Novartis Oncology Swiss: Other: Invited speakers sponsored satellite meeting during . Losi:QuintilesIMS: Consultancy; Celgene: Other: Commissioned to carry out the data collection survey as specified in the abstract as an employee of QuintilesIMS. Burrows:QuintilesIMS: Consultancy; Celgene: Other: Commissioned to carry out the data collection survey as specified in the abstract as an employee of QuintilesIMS. Bartiromo:Celgene: Employment, Equity Ownership. Hu:Celgene: Employment, Equity Ownership.

Direct Medical Care Costs Associated with β-Thalassemia Care in Italy

Background: β-thalassemia is a prevalent disease in Italy relative to many other countries. There is a paucity of data in the literature on the direct medical care costs associated with β-thalassemia. We conducted a β-thalassemia treatment center survey and chart review to estimate the numbers of patients with transfusion-dependent (TD) or non-transfusion-dependent (NTD) β-thalassemia currently under care and the associated direct medical care costs in Italy.Methods: A preliminary list of β-thalassemia treatment centers was generated from the IMS Health audit of hospitals and treatment centers across Italy based on the use of iron chelation therapy (ICT) agents. One or more hematologists or pediatricians in each potential hospital ward were contacted, by telephone or in-person interview, and asked about the number of patients with β-thalassemia major, TD β-thalassemia intermedia, and NTD β-thalassemia intermedia managed in their ward. TD status was determined using local definitions by each physician. Subsequently, a geographically stratified sample of 60 physicians was asked to complete a web-based questionnaire on healthcare resource utilization for the four most recent patients under their care: one patient with β-thalassemia major, one with TD β-thalassemia intermedia, one with NTD β-thalassemia intermedia, and one patient at their discretion. Healthcare resource utilization focused on five categories: transfusions, ICT, laboratory work, β-thalassemia-associated complications, and inpatient hospital stay. Unit costs of each healthcare utilization were extracted from relevant literature and published government fee schedules. For prescription drug prices, IMS Health sales data were referenced (values were provided in EUR).Results: We identified 124 treatment centers, 114 (92%) of which were successfully surveyed. A total of 5,748 TD β-thalassemia patients (4,515 with β-thalassemia major plus 1,233 with TD β-thalassemia intermedia) and 1,296 NTD β-thalassemia intermedia patients were reported. Taking into consideration the sampling frame, missing data, infrequent care for NTD β-thalassemia intermedia patients, and errors (such as the fact that ICT can be used to manage conditions other than β-thalassemia), we estimated that there are approximately 6,500 TD and 6,000 NTD β-thalassemia intermedia patients in Italy. A total of 205 β-thalassemia patient records were reviewed (109 β-thalassemia major, 53 TD β-thalassemia intermedia, and 43 NTD β-thalassemia intermedia); the median ages for patients with β-thalassemia major, TD β-thalassemia intermedia, and NTD β-thalassemia intermedia were 37, 44, and 43 years, respectively. For patients with β-thalassemia major, the total annual direct cost per patient was EUR 31,883, of which ICT was the most expensive cost component at EUR 22,519, followed by transfusions (EUR 6,115), complications (EUR 1,427), in-hospital stay (EUR 1,213), and laboratory tests (EUR 392). Patients with TD β-thalassemia intermedia incurred nearly identical medical care costs at EUR 31,183, of which EUR 22,963 was attributable to ICT. Of the 162 TD patient records reviewed, 83 patients required 1-2 red blood cell (RBC) units per month, whereas 78 patients required ≥ 3 RBC units per month (1 patient had missing data). Every patient with TD β-thalassemia received ICT, and deferasirox was the most commonly administered chelation agent, prescribed to 103 of 162 patients. The annual direct cost per patient with NTD β-thalassemia intermedia was lower at EUR 13,496, largely owing to lower healthcare utilization of ICT and transfusions. Combining the costs of TD and NTD β-thalassemia treatment, we estimated that the total annual direct medical care cost was approximately EUR 287,162,500 in Italy, of which TD patients accounted for EUR 204,682,000 (71.3%).Conclusions: β-thalassemia remains a prevalent disease in Italy with about 6,500 TD and 6,000 NTD β-thalassemia patients. Management of the disease consumes significant healthcare resources, with the total annual direct medical care cost for β-thalassemia treatment estimated to be approximately EUR 287 million. DisclosuresAngelucci:Bluebird Bio: Other: Advisory board: Gene therapy in Thalassemia; Novartis Oncology: Other: Protocol Telesto: sterring committee Chair; Roche: Other: Advisory board: biosimilars; Celgene: Other: protocoll ACE 536 B-Thal 001: DMC Chair; Jazz: Other: Advisory board: AML; Novartis Oncology: Other: Advisory board: iron toxicity; Novartis Oncology Swiss: Other: Invited speakers sponsored satellite meeting during ; Celgene: Honoraria, Other: Advisory: research project . Antmen:Jazz: Other: Advisory board; Novartis: Other: Advisory board; Celgene: Honoraria, Other: Advisory for the project Burden of illness in thalassemia. Losi:QuintilesIMS: Consultancy; Celgene: Other: Commissioned to carry out the data collection survey as specified in the abstract as an employee of QuintilesIMS. Burrows:QuintilesIMS: Consultancy; Celgene: Other: Commissioned to carry out the data collection survey as specified in the abstract as an employee of QuintilesIMS. Bartiromo:Celgene: Employment, Equity Ownership. Hu:Celgene: Employment, Equity Ownership.

Physical Activities in Patients with β-Thalassemia As Measured By Fitbit in Association with Patient-Reported Outcomes

Background: Tiredness, weakness, and shortness of breath are the most commonly reported symptoms in patients with β-thalassemia, and they may also adversely affect the quality of life (QoL) of patients. We aimed to explore the associations between β-thalassemia symptom severity and QoL in relation to physical activities, as tracked by Fitbit wearable electronic devices (Fitbit, Inc., San Francisco, CA).Method: Adult patients with β-thalassemia under routine clinical care were enrolled in a prospective observational study. All patients completed Short Form 36 Health Survey version 2 (SF-36v2) and Functional Assessment of Cancer Therapy (FACT)-Anemia (An) questionnaires at baseline and then once every 3 weeks using a hand-held electronic device. Patients with transfusion-dependent (TD) β-thalassemia also completed the Transfusion-dependent QoL (TranQoL) questionnaire, a disease-specific QoL instrument developed for TD patients, with the same scheduling. Transfusion dependent was defined as receiving ≥ 6 red blood cell units in the 24 weeks prior to study entry and no transfusion-free period for ≥ 35 days during that period. Patients with non-transfusion-dependent (NTD) β-thalassemia were instructed to complete the NTDT-PRO© daily, a symptom diary developed specifically for patients with NTD β-thalassemia with 2 domains: tiredness/weakness (T/W; score range: 0-40) and shortness of breath (SoB; score range: 0-20) with higher scores indicating more severe symptoms. Physical activities were passively tracked by a Fitbit wearable electronic device in terms of steps taken and floors climbed. This analysis examined the association between physical activities at week 1 of the study with QoL measurements and β-thalassemia symptom severity at baseline. For this analysis, average daily steps taken and floors climbed were grouped into quartile categories for those patients who had 4 or more days of Fitbit data during week 1.Results: A total of 102 patients with β-thalassemia (52 TD and 50 NTD) were enrolled; the mean age of patients was 31.2 years and 70 (68.6%) were females. A total of 91 patients had Fitbit data and, on average, they took 10,811 steps (median: 9,656) and climbed 16.0 floors (median: 10.0) daily. There were no associations observed between the number of steps taken and QoL measurements and β-thalassemia symptom severity. The floors climbed, however, were associated with SF-36v2 Physical Functioning and General Health domains. Patients in the lowest quartile for floors climbed had statistically significant lower Physical Functioning and General Health scores compared with patients in the highest quartile for floors climbed (47.0 vs 52.3; P < 0.01; and 42.1 vs 46.3; P= 0.01, respectively). Floors climbed were also associated with the NTDT-PRO© symptom severity scores for T/W and SoB domains. Patients in the lowest quartile for floors climbed had T/W and SoB domain scores of 12.8 and 4.6, respectively, compared with those patients in the highest quartile for floors climbed who had scores of 4.9 and 0.8 (P < 0.01 and P= 0.02).Conclusions: Steps taken tracked by Fitbit did not appear to be associated with QoL and symptom severity in patients with β-thalassemia. Floors climbed, however, were associated with SF-36v2 Physical Functioning and General Health domains, and β-thalassemia symptom severity. Floors climbed is likely to be a more sensitive endpoint as a measurement for physical activities in clinical studies. DisclosuresKattamis:Bristol-Myers Squibb: Consultancy; National and Kapodistrian University of Athens: Employment; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Sutcharitchan:Chulalongkorn University: Consultancy, Employment; Celgene: Research Funding. Taher:Novartis Pharmaceuticals: Honoraria, Research Funding; Celgene: Research Funding. Cappellini:Sanofi-Genzyme: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria; Vifor: Honoraria; Novartis: Speakers Bureau. Mahmoud:Celgene: Employment. Pariseau:Celgene: Employment. Laadem:Celgene: Employment, Equity Ownership. Khan:Nathan S. Kline Institute for Psychiatric Research; Manhattan Psychiatric Center: Employment. Hu:Celgene: Employment, Equity Ownership. Viprakasit:Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Consultancy, Research Funding; Siriraj Hospital: Employment; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Evaluation of Adipokines Concentration in Iraqi Patients with Major and Minor Beta Thalassemia.

Beta thalassemia (β-thalassemia) is a type of inherited blood disorder characterized by the impaired production of beta globin chains. β-Thalassemia can be categorized into three subtypes according to symptom severity: β-thalassemia minor, β-thalassemia intermedia, and β-thalassemia major. Adipose tissue functions as an endocrine gland by synthesizing and secreting an array of bioactive peptides including leptin, adiponectin, and resistin. We recruited 30 participants who were transfusion dependent β-thalassemia patients (major) and 30 participants who were non-transfusion dependent β-thalassemia patients (minor). The control group consisted of 20 healthy individuals. Analysis of the demographic profile, hematological profile, biochemical parameters, and serum adipokine concentrations (leptin, adiponectin and resistin) were performed for all participants. Our results showed that leptin serum levels were significantly lower in the β-thalassemia major group compared with the β-thalassemia minor group or healthy individuals, while serum levels of adiponectin were significantly higher in β-thalassemic patients compared with healthy controls. Serum levels of resistin were significantly higher in β-thalassemic patients compared with the healthy control group. A significant negative correlation was noted between adiponectin and BMI in β-thalassemic patients, whereas leptin was observed to have a significant positive correlation with BMI in the control group. Leptin was observed to have a significant negative correlation with adiponectin and ferritin in the β-thalassemia major group. The changes we observed in adipokine levels may play a role in the development of the complications related to β-Thalassemia and disease severity.