1 2 Thalassemias : Defect in globin biosynthesis E u r o p e a n R - PDF document

Disclosure § Company Relationship Type UCSF Continuing Medical Education - Bluebird Bio Site Principal Investigator - Celgene Site Principal Investigator, consultancy, advisory board Thalassemia in the Asian Community : - La Jolla Pharma Site Principal Investigator - Protagonist Site Principal Investigator Under-recognized & Under-treated - T erumo Site Principal Investigator - Agios Co-Investigator Ashutosh Lal, MD Professor of Clinical Pediatrics - Sangamo Co-Investigator UCSF School of Medicine Program Director, Comprehensive Thalassemia Program UCSF Benioff Children’s Hospital Oakland 10/11/19 1 2 Thalassemias : Defect in globin biosynthesis E u r o p e a n R e g i o n 5 5 , 8 7 5 Iron a Globin Hemoglobin: Tetramer of deficiency deficiency A m e r i c a n R e g i o n (Heme + Globin) Iron Globin Chains α E a s t e r n M e d i t e r r a n e a n α W e s t e r n P a c i f i c R e g i o n A f r i c a n R e g i o n b β β Thalassemia: Reduced S o u t h - E a s t A s i a n R e g i o n formation of globin chains Heme Porphyrin Hemoglobinopathy: deficiency Annual Births of Severe Abnormal chains, Thalassemia Syndromes produced at normal rate Modell 2008, Bull WHO W o r l d 3 4 1 | [footer text here]

Thalassemia in Asia Prevalence of Thalassemia in Asia – China and Taiwan Middle East, South Asia, South East Asia, Southeast China, East Asia x x x x x x x x x x x x x x x x x x x x xx x x x x x x x x x x x x x x x x x x x x x x x x x xx x x x x x x x x x x x x x x x x x x x x xx x xx x x x x x x x x x x x xx x x x x x x x xx x x x x x x x x x Adapted from Zeng & Huang. J Med Genet. 1987 and others 5 5 6 Thalassemia: Ethnicities in the Western States Thalassemia: Epidemiology in North America CA, WA, OR, NV , AZ Cambodian Asian, Mixed Chinese § Trend in ethnicity of patients with § Data from 10 Centers thalassemia in North America Filipino Asian Indonesian - n=717 Lao Thai - SE and E Asian: 64% Vietnamese - South Asian: 8% Iranian Hispanic Italian Iraqi - Middle Eastern: 4% Greek Middle Eastern § Pattern of immigration to North America in the Caucasian 20th century from regions with high-prevalence Afghan - All Asian background: 76% African American Asian Indian Declined Pakistani Other Mixed Unknown Vichinsky 2005, Pediatrics Lal 2018, Transfusion 7 8 2 | [footer text here]

Prevalence of Hemoglobinopathies in California at Birth Providers’ Perspectives on Treating Patients With Thalassemia § Jan 1998 - July 2006 CDC survey of providers in California § Only 1:4 patients with thalassemia born § n = 3,445,000 (approx.) in California are followed by a specialty • Targeted 30 cities that account for majority of known patients with thalassemia treatment center 700 • Pediatrics, Family Practice, OBG, General Practice, Hematology, Cardiology and others 574 responses (7521 mailed, 8.6%) 600 § Nearly half of the adults with thalassemia • 41% had seen 1-5 patients with thalassemia 500 in California were born in other states or • 17% had seen 6-10 patients other countries 400 • 38% had seen >10 patients 300 Family Practice Providers § Is there sufficient recognition of 200 thalassemia in Asian-American • 53% : sole or main responsibility of care for thalassemia patients in their practice population • 27% : not familiar with treatment of thalassemia or standards of care 100 - In the community • 24% : inadequate support from hematologists 0 Sickle Cell All Alpha Beta • 71% : would like information on guidelines for care and management - Among health care providers Disease Thalassemia Michlich 2009, Pediatr Blood Cancer Radke et al, J Ped Hematol Onc, 2019 Paulukonis 2014, ASH 10 P resentation T itle 9 10 Thalassemia – a heterogeneous diagnosis Genetic basis of α thalassemia § Two α genes (α2 and α1) are β thal β thal located on each Ch. 16 E β thal E β thal E β thal β thal trait α 2 α 1 α 2 α 1 major intermedia α 2 α 1 X α 1 § Common 1 gene deletions: − -3.7 Kb and -4.2 Kb Normal Silent Carrier Regular Regular No Occasional 4 alpha genes 3 alpha genes, 1 del § Common 2 gene deletions: Transfusions Transfusions Transfusions Transfusions Hgb M: 14.5-16.5; F: 13-15 Hgb M: 13-15.5; F: 11.5-13.5 − SEA, MED, THAI, FIL for Symptoms for Survival § Common alpha mutation: − Constant Spring α 2 α 1 X α 1 α thal trait HbH HbH Constant α thal § α + : 1 intact α gene Deletional Spring major X X X α 1 § α 0 : 0 intact α genes Heterozygous α 0 Trait Homozygous α + Trait Trait Intermedia Major 2 alpha genes, 2 del 2 alpha genes, 2 del Hgb M: 12-14; F: 10.5-12.5 Hgb M: 12-14; F: 10.5-12.5 Non-Transfusion Dependent Transfusion Dependent Thalassemia Thalassemia 11 11 12 3 | [footer text here]

Genetic basis of α thalassemia Alpha thalassemias Pregnancy risk assessment X α 1 CS α 1 § HbH Disease MCV/ Electro- Genotype Hemoglobin Risk assessment − Deletion of 3 out of 4 alpha phoresis X X X X MCH genes Hemoglobin H Disease Hemoglobin H Constant Spring α+ Thal Trait 25% risk of HbH if partner has α 0 thal trait (Silent carrier) 11-13 >80/>28 Normal 1 alpha gene, 3 del 1 alpha gene, 1 mutation § Alpha Thal Major -α/αα Hgb: M: 10-12; F: 8.5-10.5 Hgb: M: 10-12; F: 8.5-10.5 − AKA Bart’s Hydrops Fetalis α+ Thal Trait 11-12.5 <80/<28 Normal 50% risk of HbH if partner has α 0 thal trait − Deletion of 4 out of 4 alpha -α/-α genes 25% risk of α Thal Major if partner α 0 trait X X α0 Thal Trait 25% risk of HbH if partner heterozygous α + trait 9.5-10.5 <80/<28 Normal --/αα 50% risk of HbH if partner homozygous α + trait X X Alpha Thal Major 25% risk of α Thal Major if partner α 0 trait 0 alpha genes, 4 del Hb H Disease 8-9.5 <65/<20 HbH 10-15% 25% risk of HbH if partner heterozygous α + trait Severe Anemia in Fetus --/-α 50% risk of HbH if partner homozygous α + trait 14 P resentation T itle 13 14 Types of Thalassemia: Beta thalassemias A Large number of mutations can give rise to thalassemia Electro- Hemo- Pregnancy risk Condition Genotype MCV/MCH § Spectrum of Mutations in Beta Globin Gene phoresis globin assessment A: 97% No β Thal 12-14 β/β A2: 2% >80 / >28 − No risk NORMAL 13-17 2 normal β genes F: 1% − 25% risk of Thal Major if A: 92-94% DEL β Thal Trait β/- partner β thal trait A2: 4-6% 10-12 <80 / <28 − 25% risk of E β Thal if MILD ANEMIA 1 normal β F: 1-2% partner E trait A: 65-70% β/βE − 25% risk of E β Thal if Hb E Trait 12-14 E: 30% >80 / >28 1 normal β partner β thal trait NO ANEMIA 13-17 Point Mut 1 β has E mutation F: 1% − No risk if partner E trait βE/βE A: 0% − 50% risk of E β Thal if Hb E Disease 0 normal β E: 90-95% 10-12 <80 / <28 partner β thal trait MILD ANEMIA Both have E − No risk if partner E trait F: 2-4% mutation A: 0% β Thal Major -/- § Severe (β 0 ), mild (β + ), and silent (β ++ ) mutations causing F: 90% 3-6 SEVERE ANEMIA 0 normal β thalassemia A2: 2-5% Weatherall, Nature Reviews Genetics 2001 A: 0% -/βE E β Thal E: 60-70% 4-8 0 normal β SEVERE ANEMIA 1 β has E mutation F: 30-40% 15 16 4 | [footer text here]

Common mild β mutations causing thalassemia intermedia Causes of Non-Transfusion Dependent Thalassemia • β0 with mild β+ mutation Beta • Two mild β+ mutations Thalassemia • Two β mutations plus high fetal hemoglobin Intermedia • One β mutation plus increased α genes • Single unstable β mutation • Hb E mutation with β mutation E-Beta • E and β mutations with α deletion Thalassemia • E and β mutations with high fetal hemoglobin • Deletion of three α genes Alpha Thalassemia • Deletion of 2 α genes plus mutation in one α gene Weatherall, Nature Reviews Genetics 2001 17 18 Diagnosis In Clinic Newborn screening • Significant anemia (Hb 6-10 g/dL) • All α thalassemias (Bart’s elevated) • MCV <80, MCH <28 • All E thalassemias (FE or FEA) • Marked anisocytosis, target cells, • All β0/β0 thalassemia (F only) NRBC NON-TRANSFUSION DEPENDENT THALASSEMIA • Most, but not all, beta thal intermedia • Hemolysis or ineffective erythropoiesis - CLINICAL ASPECTS • Serum iron studies and ferritin usually normal to elevated • Splenomegaly Confirmation • Hemoglobin electrophoresis or HPLC • Alpha and beta globin mutations and deletions • Specialized investigation for rare mutations, large deletions 19 19 20 5 | [footer text here]