Slide 1: Thalassemia burden of disease
Thalassemia burden of disease THA-ALL-0096 / June 2024
Slide 2: Thalassemias are…
Thalassemias are… …a group of recessively inherited disorders caused by an imbalance of globin chains; excess globin chains aggregate and damage red blood cells, leading to ineffective erythropoiesis, hemolysis, and chronic anemia Pathophysiology Thalassemia Burden of and classification disease epid
Slide 3: Pathophysiology and epidemiology
Pathophysiology and epidemiology THA-ALL-0096 / June 2024
Slide 4: Structure and function of hemoglobin: Overview
Structure and function of hemoglobin: Overview HbA Abnormal Hb in thalassemia ▪ Hemoglobin (Hb) is a tetramer, consisting of 4 protein sub-units ▪ Abnormal Hb compromises the or globin chains1 health of red blood cell (RBC) precursors and RBCs4 ▪ 95% of adult Hb (hemoglobin A [HbA]) contains 2 α- an
Slide 5: IE and chronic hemolysis are pathologic drivers of anemia in thalassemia
IE and chronic hemolysis are pathologic drivers of anemia in thalassemia Mechanism of IE and hemolysis in thalassemia1–3 β-thalassemia1–5 α-thalassemia6–9* Bone marrow ▪ Decrease or loss of α-globin chain production or ▪ Decrease or loss of β-globin chain production1 impaired function ▪ Excessive un
Slide 6: Severity of IE correlates with clinical morbidity in NTDT
NTD β-thal Severity of IE correlates with clinical morbidity in NTDT Correlation between a marker of IE and clinical ▪ Morbidity in patients with NTD severity score in β-thalassemia intermedia1 β-thalassemia is directly proportional to 60,000 Mild Moderate Severe the severity of IE and peripheral he
Slide 7: Global prevalence of thalassemia
Global prevalence of thalassemia ▪ A global systematic literature review on the prevalence of clinically significant forms of α-thalassemia and β-thalassemia found that: ▪ The estimated prevalence of thalassemia was higher in the Middle East, Asia, and Mediterranean than in Europe or North America ▪
Slide 8: Pathophysiology and epidemiology: Key takeaways
Pathophysiology and epidemiology: Key takeaways Thalassemias are a recessively inherited group of disorders of Hb production with a wide range of clinical severity, and they are classified into α-thalassemia or β-thalassemia depending on the affected globin gene1–4 In β-thalassemia, impaired product
Slide 9: Thalassemia classification
Thalassemia classification THA-ALL-0096 / June 2024
Slide 10: Classification and transfusion requirements
Classification and transfusion requirements ▪ Thalassemia is now often classified phenotypically into 2 main groups1–3: NTDT2 ▪ Non–transfusion-dependent thalassemia (NTDT) ▪ Transfusion-dependent thalassemia (TDT) Patients do not require regular transfusion therapy for survival ▪ This classificatio
Slide 11: Transfusion burden across thalassemias
Transfusion burden across thalassemias1–4 Thalassemia minor Thalassemia intermedia Thalassemia major b-thalassemia intermedia, Hb Bart’s hydrops, α- or b-thalassemia trait/minor or mild–moderate HbE/b-thalassemia, α- or b-thalassemia silent carrier b-thalassemia major, or severe HbE/HbC trait or α-t
Slide 12: Thalassemia classification: Key takeaways
Thalassemia classification: Key takeaways Traditionally both α- or β-thalassemia have been categorized as minor, intermedia, or major1,2 Thalassemia is now commonly categorized as NTDT or TDT, as transfusion requirements typically reflect the underlying pathophysiology1–3 Transfusion requirements an
Slide 13: Burden of disease
Burden of disease THA-ALL-0096 / June 2024
Slide 14: Thalassemia complications: Overview
Thalassemia complications: Overview Build slide Facial & bone Infections deformities Extramedullary hematopoietic α- and β-thalassemia pseudotumors risk factors Endocrinopathy Endocrinopathy Endocrinopathy Thrombosis Thrombosis Thrombosis &&& Hemolysis vascular vascular vascular events events events
Slide 15: Complications of HbH disease are associated with the severity of chronic anemia
Complications of HbH disease are associated with the severity α-thal of chronic anemia1,2 Characteristic and complications a-thalassemia syndromes (deletional HbH and non-deletional HbH) Presenting age (years) Usually >2 Presenting Hb level (g/dL) 8–11 HbF (%) Not raised, but HbH (b4) and Hb Bart’s
Slide 16: Iron loading anemia is triggered by IE
Iron loading anemia is triggered by IE Iron loading and erythropoiesis2,5,7,8 Kidney ▪ In response to hypoxia and Anemia/hypoxia2,7,8 HIF2-α, increased EPO released from the kidney suppresses ↑ HIF2-α hepcidin via ERFE secretion from erythroblasts in the marrow1–4 ↑ ROS8 EPO5,7,8 ▪ GDF15 is another
Slide 17: IE contributes to iron overload, which drives multiple downstream complications
IE contributes to iron overload, which drives multiple downstream complications in thalassemia IE and iron overload in thalassemia1 ▪ Iron overload can lead to cardiac dysfunction, liver Platelet dysfunction, including activation and IE Endothelial damage increased fibrosis, cirrhosis, or Free Hb Ni
Slide 18: Iron overload is a common clinical complication in thalassemia
Iron overload is a common clinical complication in patients with thalassemia, irrespective of their transfusion status, and is associated with multiple comorbitidies1–6 TDT NTDT • Patients primarily have secondary iron overload1,2 • Patients primarily have primary iron overload1,2 • Iron accumulates
Slide 19: Iron overload-associated complications in α-thalassemia
α-thal Iron overload-associated complications in α-thalassemia ▪ In patients with α-thalassemia, iron overload has been significantly associated with fibrosis and cirrhosis of the liver, as well as heart failure1 ▪ Ferritin level increased significantly with age (p<0.001), regardless of transfusion
Slide 20: IE contributes to hypercoagulation in patients with thalassemia
IE contributes to hypercoagulation in patients with thalassemia via several mechanisms Several mechanisms have been implicated in the pathogenesis of hypercoagulation in thalassemia1–8 Hemolysis IE Release of Hb and heme Heme disintegration results ▪ An elevated (>4-fold) risk of stimulates endothel
Slide 21: Hypercoagulability in NTDT may lead to downstream vascular anomalies and mortality
Hypercoagulability in NTDT may lead to downstream vascular anomalies and mortality1,2 Impact of hypercoagulability in NTDT1,2 Silent strokes ▪ In a retrospective study of patients with NTDT (N=2,033) thrombosis was among the most common causes of death in this patient population2,3 Pulmonary hyperte
Slide 22: Extramedullary hematopoiesis is a complication of IE
Extramedullary hematopoiesis is a complication of IE1,2 ▪ Erythroid expansion caused by IE is associated with ▪ In thalassemia, anemia and hypoxia increase levels extramedullary hematopoiesis (EMH), the homing and of EPO, thus activating JAK2, which acts on erythroid proliferation of erythroid precu
Slide 23: Erythroid expansion caused by IE drives pathologic changes in bone
Erythroid expansion caused by IE drives pathologic changes in bone composition, structure, and morphology1–6 Bone disease in thalassemia Pathogenesis of bone remodeling6 ▪ Erythroid expansion and IE are directly implicated as pathogenic drivers of osteoporosis1 ▪ Bone loss occurs due to an imbalance
Slide 24: Higher rates of complications/comorbidities vs matched controls: Commercial/Medicare
Patients with thalassemia have higher rates of complications/comorbidities compared with their matched controls: Commercial/Medicare population Osteoporosis or osteopenia Cardiovascular disease 30 29.1 29.8 15 25 a-thalassemia (n=1675) 20 10 a-thalassemia matched controls (n=8375) 7.2 7.3 7.3 7.0 7.
Slide 25: Burden of disease: HRQoL burden
Burden of disease: Health-related quality of life (HRQoL) burden THA-ALL-0096 / June 2024
Slide 26: Patients with thalassemia have worse HRQoL than matched controls
Patient with thalassemia have worse HRQoL than matched controls1–4 NTD vs TD β-thalassemia ▪ Adult patients with NTDT may have similar or worse HRQoL compared with patients with TDT ▪ In a systematic literature review of studies in patients with NTDT or TDT1 ▪ Adult patients’ HRQoL total scores were
Slide 27: Burden of disease: Association of Hb with outcomes
Burden of disease: Association of Hb with outcomes THA-ALL-0096 / June 2024
Slide 28: Lower Hb levels are associated with increased risk of iron overload and complications
In patients with TDT and NTDT, lower Hb levels are associated with an increased risk of iron overload and other complications TDT NTDT Low Hb values were significantly associated with: Low Hb levels were significantly associated with: • Severe hepatic iron overload (odds ratio [OR] [95% • Hepatic ir
Slide 29: Variations of Hb level are associated with number of morbidities in NTDT
NTD Variations of 1 g/dL in Hb level are independently associated β-thal with the number of morbidities in NTDT (n=150) Correlation between Hb level and number of morbidities Probability of multiple morbidity development at various Hb levels Sphere sizes represent increments in number of morbidities
Slide 30: Morbidity-free survival vs Hb level in NTDT
NTD β-thal Morbidity-free survival vs Hb level in NTDT The 5-year and 10-year cumulative morbidity-free survival: The 5-year and 10-year cumulative multiple morbidity-free survival: • Patients with Hb level <10 g/dL were 57.9% and 13.2%, respectively • Patients with Hb level <10 g/dL were 94.7% and
Slide 31: Burden of disease: Survival/mortality
Burden of disease: Survival/mortality THA-ALL-0096 / June 2024
Slide 32: Inpatient survival of patients with thalassemia
Inpatient survival of patients with thalassemia ▪ In a study of the US MarketScan® Commercial and Medicare claims data, the authors found that during the variable-length follow-up: ▪ Significantly more inpatient deaths occurred in all cohorts of patients with thalassemia compared with matched contro
Slide 33: Survival in 2033 patients with NTDT: A global registry
NTD Survival in 2033 patients with NTDT: β-thal A global registry All-Cause Mortality 1.0 Median age p<0.001 % among % among 0.9 at death Cause n deaths population (min–max), 0.8 (n=113) (n=2033) years 0.7 Cardiovascular disease Survival Probability (cardiomyopathy, myocardial 0.6 infarction, valvul
Slide 34: Association of pretransfusion Hb levels with mortality in TD β-thalassemia
TD Association of pretransfusion Hb levels with mortality in TD β-thalassemia β-thal ▪ A retrospective study of patients (N=779) with TD β-thalassemia-related mortality according to pretransfusion Hb levels1 β-thalassemia found that ascending pretransfusion Hb levels were associated with a decrease
Slide 35: Disease burden: Key takeaways
Disease burden: Key takeaways The signs, symptoms, complications, and comorbidities of thalassemia are heterogeneous, varying widely depending on a multitude of factors1–5 The disease burden for TD β-thalassemia is well-established, while the disease burden for NTD β-thalassemia is less well-recogni
Slide 36: Back up slides
Back up slides THA-ALL-0096 / June 2024
Slide 37: Pathophysiology
Pathophysiology Taher A, et al. European Hematology Association (EHA) Hybrid Congress, June 13–16, 2024, Madrid, Spain, and Virtual: Plenary Presentation S104. THA-ALL-0096 / June 2024
Slide 38: Pathophysiology of thalassemia
Pathophysiology of thalassemia RBC, red blood cell Taher A, et al. N Engl J Med 2021;384(8):727–43. THA-ALL-0096 / June 2024
Slide 39: Pathophysiology of thalassemia
Pathophysiology of thalassemia RBC, red blood cell Taher A, et al. N Engl J Med 2021;384(8):727–43. THA-ALL-0096 / June 2024
Slide 40: Pathophysiology of thalassemia
Pathophysiology of thalassemia RBC, red blood cell Taher A, et al. N Engl J Med 2021;384(8):727–43. THA-ALL-0096 / June 2024
Slide 41: Management guidelines
Management guidelines THA-ALL-0096 / June 2024
Slide 42: TIF management guidelines: Overview and assessments
α-thal TIF management guidelines: Overview and assessments Deletional HbH Domain Management Frequency of clinic visits Every 3 months for the first 2 years, then annually for life Check ferritin annually Check liver magnetic resonance imaging (MRI) for LIC if ferritin >200 ng/mL Iron overload assess
Slide 43: TIF management guidelines: Anemia (1/3)
α-thal TIF management guidelines: Anemia (1/3) Deletional HbH ▪ Regular transfusions are not required ▪ Episodic transfusions are not needed during most febrile illnesses, unless the Hb level drops below 6 g/dL in young children or 6.5 g/dL in adolescents Transfusions and adults ▪ Transfusion may be
Slide 44: TIF management guidelines: Anemia (2/3)
NTD β-thal TIF management guidelines: Anemia (2/3) IE/anemia-related Hb level IE/anemia-related intervention considerations and treatment objectivesa symptoms or morbidities No Long-term intervention to raise Hb level by ≥1 g/dL and prevent symptoms or morbidities <10 g/dL ▪ Short/limited-term inter
Slide 45: TIF management guidelines: Anemia (3/3)
TDT TIF management guidelines: Anemia (3/3) TDT Criteria for initiating transfusion ▪ Confirmed diagnosis of thalassemia therapy ▪ Laboratory criteria: ▪ Hb <7 g/dL on 2 occasions, >2 weeks apart (excluding all other contributory causes such as infections) AND/OR ▪ Clinical criteria irrespective of
Slide 46: TIF management guidelines: Iron overload (1/2)
α-thal TIF management guidelines: Iron overload (1/2) Deletional HbH Non-deletional HbH ▪ Check ferritin annually ▪ Check liver MRI for LIC if ferritin >200 ng/mL ▪ Patients with NTDT: Monitor serum ferritin levels with ▪ Mild-to-moderate iron overload is observed in every clinical visit and measure
Slide 47: TIF management guidelines: Iron overload (2/2)
TIF management guidelines: Iron overload (2/2) NTD β-thalassemia1 TDT2 ▪ Serum ferritin concentration is measured at least every 3 months (1–3 months) ▪ Target value is currently between 500–1000 µg/L ▪ Measuring the trends in serum ferritin over a period All patients with NTDT aged ≥10 years should
Slide 48: TIF management guidelines: Endocrine and bone disease (1/2)
TIF management guidelines: Endocrine and bone disease (1/2) Deletional and non-deletional HbH1 NTD β-thalassemia2 ▪ Hypogonadism (adults): Routine assessment for infertility, secondary hypogonadism, impotence ▪ Hypothyroidism (≥10 years): Annual assessment of free thyroxine If onset of puberty is de
Slide 49: TIF management guidelines: Endocrine and bone disease (2/2)
TDT TIF management guidelines: Endocrine and bone disease (2/2) TDT ▪ Periodic evaluation for endocrine complications should be carried out in patients with TDT with iron overload ▪ Sub-clinical hypothyroidism (basal TSH 5–8 mUI/mL) requires regular follow-up and optimizing chelation therapy Endocri
Slide 50: TIF management guidelines: Splenectomy
TIF management guidelines: Splenectomy Deletional and non-deletional HbH1 NTD β-thalassemia2 TDT3 Deletional: Not indicated Non-deletional HbH: ▪ The spleen size should be examined in clinical ▪ Splenectomy is not currently recommended ▪ Splenectomy can increase Hb levels visits and splenectomy shou
Slide 51: TIF management guidelines: Pulmonary hypertension (PHT)
TIF management guidelines: Pulmonary hypertension (PHT) Deletional and non- NTD β-thalassemia2 TDT3 deletional HbH1 ▪ Annual ECHO for the assessment of tricuspid-valve regurgitant ▪ Clinical examination, electrocardiogram, jet velocity (TRV) ▪ TRV >2.5 m/s and asymptomatic: “possible” to have PHT ch
Slide 52: TIF management guidelines: Hypercoagulability and thrombotic disease
NTD TIF management guidelines: Hypercoagulability β-thal and thrombotic disease NTD β-thalassemia ▪ Patients who present with unprovoked, spontaneous thrombosis at unusual sites should also be worked up for thrombophilia, especially in regions with high prevalence of common mutations ▪ High-risk pat
Slide 53: Burden of disease: Healthcare resource utilization (HCRU) burden
Burden of disease: Healthcare resource utilization (HCRU) burden THA-ALL-0096 / June 2024
Slide 54: Patients with thalassemia have higher costs and HCRU than matched controls
Patients with thalassemia have higher costs and HCRU than matched controls1–3 TD β-thalassemia ▪ A study comparing adults with TDT (all β-thalassemia) vs healthy controls found that the mean annual total, drug, emergency room (ER), inpatient (IP), and outpatient (OP) costs were significantly higher
Slide 55: Healthcare utilization in the Commercial/Medicare population during 12-month follow-up
Healthcare utilization in the Commercial/Medicare population during 12-month follow-up Proportion with IP admissions Proportion with ER visits 35 25 * * * 29.3 29.1 * 19.8 * 20.0 * 20.0 30 27.9 28.5 28.2 20 25 * 15.1 15 20 17.1 17.6 16.5 % % 15 10 7.7 5.6 5.9 5.7 10 5 5 0 0 n= 467 1435 715 3674 1157
Slide 56: Healthcare costs in the Commercial/Medicare population
Healthcare costs in the Commercial/Medicare population during 12-month follow-upa IP costs Total OP costsb ER visit costs 7682 90000 *** 2500 12000 74,442 80000 * 10000 1211 US dollars, mean (SE) 70000 2000 *** 8000 *** *** 60000 6587 6127 6376 1500 50000 6000 40000 *** *** 3146 1000 *** 779 4000 30
Slide 57: Healthcare costs in the Commercial/Medicare population
Healthcare costs in the Commercial/Medicare population during 12-month follow-upa OP pharmacy costs Total medical costs Total healthcare costs (total OP + IP) (total medical + OP pharmacy) *** *** 90000 78,160 100000 *** 180000 160,285 82,124 80000 90000 160000 80000 US dollars, mean (SE) 70000 1400
Slide 58: Healthcare costs in the Medicaid population
Healthcare costs in the Medicaid population during 12-month follow-upa IP costsb Total OP costsc ER visit costs 40000 23,890 30000 800 *** 22,422 617 35000 25000 700 *** US dollars, mean (SE) *** 533 30000 600 20000 472 25000 500 *** *** *** 20000 16,270 15000 400 256 15,127 15,944 15000 *** *** ***
Slide 59: Healthcare costs in the Medicaid population
Healthcare costs in the Medicaid population during 12-month follow-upa OP pharmacy costs Total medical costs Total healthcare costs (total OP + IP) (total medical + OP pharmacy) 35000 23,274 45000 60000 45,696 25,853 40000 30000 50000 US dollars, mean (SE) 35000 25000 26,377 30000 *** *** *** 22,422
Slide 60: In patients with NTDT, lower Hb levels are associated with higher HCRU
NTDT In patients with NTDT, lower Hb levels are associated with higher HCRU ▪ A US retrospective claims analysis study using Merative MarketScan Commercial, Medicare, and Lab results databases, for the 12-month follow-up period found that: All NTDT (α or β) α-NTDT subgroup n=898 n=400 HCRU: Incidenc