13 LAL Thalassemia Asians - ucsfcme.com · Alpha thalassemias Pregnancy risk assessment...
Transcript of 13 LAL Thalassemia Asians - ucsfcme.com · Alpha thalassemias Pregnancy risk assessment...
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10/11/19
Ashutosh Lal, MDProfessor of Clinical PediatricsUCSF School of MedicineProgram Director, Comprehensive Thalassemia ProgramUCSF Benioff Children’s Hospital Oakland
UCSF Continuing Medical Education
Thalassemia in the Asian Community: Under-recognized & Under-treated
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Disclosure
§ Company Relationship Type
- Bluebird Bio Site Principal Investigator - Celgene Site Principal Investigator, consultancy, advisory board- La Jolla Pharma Site Principal Investigator- Protagonist Site Principal Investigator- Terumo Site Principal Investigator- Agios Co-Investigator- Sangamo Co-Investigator
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Thalassemias: Defect in globin biosynthesis
Hemoglobin: Tetramer of (Heme + Globin) Globin Chains
Heme
Iron
Thalassemia: Reduced formation of globin chains
Hemoglobinopathy: Abnormal chains, produced at normal rate
Globin deficiency
Iron deficiency
Porphyrin deficiency
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β
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β
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W o r l d
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A f r i c a n R e g i o n
A m e r i c a n R e g i o n
E a s t e r n M e d i t e r r a n e a n
E u r o p e a n R e g i o n
S o u t h - E a s t A s i a n R e g i o n
W e s t e r n P a c i f i c R e g i o n
Annual Births of Severe Thalassemia Syndromes
Modell 2008, Bull WHO
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Thalassemia in AsiaMiddle East, South Asia, South East Asia, Southeast China, East Asia
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Adapted fromZeng & Huang. J Med Genet. 1987 and others
Prevalence of Thalassemia in Asia – China and Taiwan
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Thalassemia: Epidemiology in North America
§ Pattern of immigration to North America in the 20th century from regions with high-prevalence
§ Trend in ethnicity of patients with thalassemia in North America
Vichinsky 2005, Pediatrics
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Thalassemia: Ethnicities in the Western StatesCA, WA, OR, NV, AZ
§ Data from 10 Centers
- n=717
- SE and E Asian: 64%
- South Asian: 8%
- Middle Eastern: 4%
- All Asian background: 76% African American
Caucasian Greek
Italian Hispanic
Asian
Asian, MixedCambodian
Chinese
Filipino
Indonesian
LaoThai
Vietnamese
Iranian
IraqiMiddle Eastern
AfghanAsian Indian
PakistaniMixedOther Unknown Declined
Lal 2018, Transfusion
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Prevalence of Hemoglobinopathies in California at Birth§ Jan 1998 - July 2006§ n = 3,445,000 (approx.) § Only 1:4 patients with thalassemia born
in California are followed by a specialty treatment center
§ Nearly half of the adults with thalassemia in California were born in other states or other countries
§ Is there sufficient recognition of thalassemia in Asian-American population- In the community- Among health care providers
M ichlich 2009, Pediatr Blood CancerPaulukonis 2014, ASH
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Sickle Cell Disease Thalassemia
All Alpha Beta
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P re s e n ta tio n T it le1 0
Providers’ Perspectives on Treating Patients With Thalassemia
CDC survey of providers in California • Targeted 30 cities that account for majority of known patients with thalassemia• Pediatrics, Family Practice, OBG, General Practice, Hematology, Cardiology and others
574 responses (7521 mailed, 8.6%)• 41% had seen 1-5 patients with thalassemia• 17% had seen 6-10 patients• 38% had seen >10 patients
Family Practice Providers• 53% : sole or main responsibility of care for thalassemia patients in their practice• 27% : not familiar with treatment of thalassemia or standards of care• 24% : inadequate support from hematologists• 71% : would like information on guidelines for care and management
Radke et al, J Ped Hematol Onc, 2019
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Thalassemia – a heterogeneous diagnosis
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No Transfusions
Occasional Transfusions
Regular Transfusions
for Symptoms
Regular Transfusions for Survival
Trait Intermedia Major
β thal trait
HbHDeletional
HbH Constant Spring
E β thal
α thalmajor
E β thal β thalmajor
β thalintermedia
α thal trait
E β thal
Non-Transfusion Dependent Thalassemia
Transfusion Dependent Thalassemia
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α2 α1
α2 α1
Normal4 alpha genes
Hgb M: 14.5-16.5; F: 13-15
α2 α1
X α1
Silent Carrier 3 alpha genes, 1 del
Hgb M: 13-15.5; F: 11.5-13.5
α2 α1
Heterozygous α0 Trait2 alpha genes, 2 del
Hgb M: 12-14; F: 10.5-12.5
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α1
X α1
Homozygous α+ Trait2 alpha genes, 2 del
Hgb M: 12-14; F: 10.5-12.5
X
Genetic basis of α thalassemia§ Two α genes (α2 and α1) are
located on each Ch. 16
§ Common 1 gene deletions: − -3.7 Kb and -4.2 Kb
§ Common 2 gene deletions: − SEA, MED, THAI, FIL
§ Common alpha mutation:− Constant Spring
§ α+: 1 intact α gene§ α0: 0 intact α genes
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α1
Hemoglobin H Disease1 alpha gene, 3 del
Hgb: M: 10-12; F: 8.5-10.5
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XAlpha Thal Major0 alpha genes, 4 del
Severe Anemia in Fetus
XXX
α1
Hemoglobin H Constant Spring1 alpha gene, 1 mutationHgb: M: 10-12; F: 8.5-10.5
XX
CS
Genetic basis of α thalassemia
§ HbH Disease− Deletion of 3 out of 4 alpha
genes
§ Alpha Thal Major− AKA Bart’s Hydrops Fetalis− Deletion of 4 out of 4 alpha
genes
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P re s e n ta tio n T it le1 4
Alpha thalassemiasPregnancy risk assessment
Genotype HemoglobinMCV/MCH
Electro-phoresis Risk assessment
α+ Thal Trait (Silent carrier)-α/αα
11-13 >80/>28 Normal 25% risk of HbH if partner has α0 thal trait
α+ Thal Trait-α/-α
11-12.5 <80/<28 Normal 50% risk of HbH if partner has α0 thal trait
α0 Thal Trait --/αα
9.5-10.5 <80/<28 Normal25% risk of α Thal Major if partner α0 trait25% risk of HbH if partner heterozygous α+ trait50% risk of HbH if partner homozygous α+ trait
Hb H Disease--/-α
8-9.5 <65/<20 HbH 10-15%25% risk of α Thal Major if partner α0 trait25% risk of HbH if partner heterozygous α+ trait50% risk of HbH if partner homozygous α+ trait
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Types of Thalassemia: Beta thalassemiasCondition Genotype Electro-
phoresisHemo-globin
MCV/MCH Pregnancy risk assessment
No β ThalNORMAL
β/β2 normal β genes
A: 97%A2: 2%F: 1%
12-1413-17 >80 / >28 − No risk
β Thal TraitMILD ANEMIA
β/-1 normal β
A: 92-94%A2: 4-6%F: 1-2%
10-12 <80 / <28
− 25% risk of Thal Major if partner β thal trait
− 25% risk of E β Thal if partner E trait
Hb E TraitNO ANEMIA
β/βE1 normal β1 β has E mutation
A: 65-70%E: 30%F: 1%
12-1413-17 >80 / >28
− 25% risk of E β Thal if partner β thal trait
− No risk if partner E trait
Hb E DiseaseMILD ANEMIA
βE/βE0 normal βBoth have E
mutation
A: 0%E: 90-95%F: 2-4%
10-12 <80 / <28− 50% risk of E β Thal if partner β thal trait
− No risk if partner E trait
β Thal MajorSEVERE ANEMIA
-/-0 normal β
A: 0%F: 90%A2: 2-5%
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E β ThalSEVERE ANEMIA
-/βE0 normal β1 β has E mutation
A: 0%E: 60-70%F: 30-40%
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§ Severe (β0), mild (β+), and silent (β++) mutations causing thalassemia
Weatherall, Nature Reviews Genetics 2001
DEL
Point Mut
§ Spectrum of Mutations in Beta Globin GeneA Large number of mutations can give rise to thalassemia
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Common mild βmutations causing thalassemia intermedia
Weatherall, Nature Reviews Genetics 2001
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Causes of Non-Transfusion Dependent Thalassemia
Beta Thalassemia
Intermedia
• β0 with mild β+ mutation• Two mild β+ mutations• Two β mutations plus high fetal hemoglobin• One β mutation plus increased α genes• Single unstable β mutation
E-Beta Thalassemia
• Hb E mutation with β mutation• E and β mutations with α deletion• E and β mutations with high fetal hemoglobin
Alpha Thalassemia
• Deletion of three α genes• Deletion of 2 α genes plus mutation in one α gene
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NON-TRANSFUSION DEPENDENT THALASSEMIA- CLINICAL ASPECTS
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Diagnosis
In Clinic• Significant anemia (Hb 6-10 g/dL)• MCV <80, MCH <28• Marked anisocytosis, target cells,
NRBC• Hemolysis or ineffective erythropoiesis• Serum iron studies and ferritin usually
normal to elevated• Splenomegaly
Newborn screening• All α thalassemias (Bart’s elevated)• All E thalassemias (FE or FEA)• All β0/β0 thalassemia (F only)• Most, but not all, beta thal intermedia
Confirmation• Hemoglobin electrophoresis or HPLC• Alpha and beta globin mutations and deletions• Specialized investigation for rare mutations, large deletions
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The initial hematology clinic visit
§ Review laboratory results − Hematological− Electrophoresis
− DNA tests§ DNA testing to identify alpha and beta globin mutations§ Hemoglobin Reference Laboratory if uncommon mutations suspected
§ Counseling− Discuss probable outcome and uncertainties
− Stress that close follow up is essential to make informed decisions for many syndromes
§ Introduce the care team− Physician, Nurse Practitioner, Social Worker, Clinic Coordinator, Dietician, Genetic Counselor
− Provide support
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Follow-up
§ Frequency of visits− Initially every month for 2-3 visits after diagnosis− Eventually every 3 -12 months depending on severity
§ Measure at each clinic visit− Height and weight, head circumference (infants)
− Growth velocity, pubertal development
§ Nutrition− Folic acid 0.4 to 1 mg per day to all patients− Vitamin D level check once a year and provide supplement if needed
§ Laboratory tests− CBC with reticulocyte count at each visit, liver function test every 6-12 months
− Serum ferritin every year
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Management of Fever
§ Two major risks during fever− Worsening of anemia− Serious sepsis
§ Patients with fever >101 F seen on the same day− Exception – Deletional HbH disease can be seen next day
§ During the clinic or ER visits− Check hemoglobin, reticulocyte count and liver function tests
− Check for common infections − Admit for observation or transfusion if the hemoglobin low
− Antibiotic treatment may be needed
§ Splenectomized patients with a fever − Should be seen on the same day
− Given a dose of intravenous antibiotic− Admission is recommended until sepsis can be excluded
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Case: HbH Constant Spring
§ Transfusion events during febrile illnesses
Age in years
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Complications in Non-transfusion-Dependent Patients
Complication Potential Outcome– Severe Anemia Acute, life-threatening fall in Hgb during
illnesses– Poor growth Stunting, poor nutrition– Allo-immunization Difficult or impossible transfusion therapy
– Skeletal and vertebral changes Severe facial changes and chronic back pain
– Splenomegaly Hypersplenism, post-splenectomy care
– Iron overload (gastrointestinal or transfused) Need for chelation therapy
– Liver disease Fibrosis, cirrhosis hepatocellular carcinoma– Hypercoagulability thromboembolism, including stroke– Pulmonary hypertension Fatigue, right heart failure– Osteoporosis Fractures, chronic back pain– Decreased quality of life Professional and personal limitation
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Under-Treatment of ThalassemiaE Beta Thalassemia: Lack of transfusions associated with severe pulmonary hypertension
§ 27 year old Asian Male, born and grew up in California§ Diagnosed as E Beta Thal when few years old
- Started on regular monthly transfusions- Chelation with desferal. Later switched to Deferasirox
§ Splenectomy at 12 years due to blood requirements and large spleen size- Post-splenectomy placed on intermittent transfusions, every 3-4 months initially, then 1-2 times per year- Progressive symptoms of worsening respiratory distress, edema, weakness, home O2
§ Acute decompensation- Echo LV ejection fraction 13% and severe pulmonary hypertension RVSP 74- Transferred to UCSF
§ Inotrope infusions§ Losartan, eplerenone and tadalafil
- LV function improved§ Placed on regular transfusions
- Symptoms resolved, now with normal pulmonary pressures and
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Under-diagnosis of thalassemiaCase Discussion: HbH managed as iron deficiency anemia
§ 63 year old woman § Hemoglobin H disease deletional, --SEA/-3.7α§ Born in the Philippines, noted to have anemia at age 7, no treatment
§ 1983: Moved to the US- Noted to be anemic Hgb lower than 10- Started on iron pills once daily 1985-89, then 3x daily 1989-2000
§ 2000: diagnosed with cirrhosis
§ 2007: Liver biopsy in 2007 showed cirrhosis, iron overload, steatosis- Iron chelation treatment given with exjade, but stopped due to renal dysfunction
§ 2013: decompensated cirrhosis, frequent hospitalizations and blood transfusions for GI bleed
§ 2018: transferred to UCSF with decompensated liver failure, underwent OLT
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Under-Diagnosis of ThalassemiaOther recent examples
§ Severe alpha thalassemia in 30 year old male- Previous diagnosis of congenital dyserythropoietic anemia- On intermittent transfusions all his life
- Genetic testing revealed Alpha thalassemia: HbH disease (Adana)
§ Undiagnosed 42 yo with E-Beta Thalassemia- Severe anemia all his life: hemoglobin 6 g/dL, splenomegaly
- Seen by hematologist and referred to UCSF
- Diagnosis confirmed as E Beta 0 thalassemia- Now receiving regular transfusions
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Undiagnosed Thalassemia in pregnancy
§ 32 year old with HbH§ Case Presentation:
- First pregnancy for 32 year old who had been told in the past that she had thalassemia and told not to take iron supplements for anemia
- During pregnancy, she was prescribed parenteral iron for anemia, which she refused- Referral to MFM and genetic counseling- Dad has alpha 0 thalassemia trait- Baby born with HbH- Each offspring has 25% risk of Bart’s hydrops
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HbH Diagnosis on Newborn Screening
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Ø Annual births with HbH disease in California is 30
Ø In nearly all cases, parents are unaware of their trait status
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Proposed Prenatal Screening for Thalassemia Trait
Under development, not to be shared
Suspect all microcytic anemia to be thalassemia trait if high-prevalence ethnic group, even if iron deficiency is present
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Options for treatment
Observation and supportive care• Folate, nutrition, regular monitoring
Hydroxyurea• Appropriate for beta thalassemias
Splenectomy• Often performed for incorrect reasons• Increased risk of long-term complications
Regular transfusions• Decision is individualized• Appropriate in some cases, more likely to be
needed for beta thalassemia intermediaAlternatives to long-term transfusions
• Bone marrow transplantation• Emerging Therapies: Proper diagnosis is
essential for consideration of new options• Gene Therapy• Other Emerging therapies (erythropoietic
modulators)
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Iron Overload in Non-Transfusion Dependent Thalassemia
§ Development of iron overload is inevitable irrespective of transfusion status
§ Extra iron is absorbed from food§ Iron deposition is cumulative and age-
dependent§ Serum ferritin under-estimates the liver
iron § Liver damage and hormone deficiencies
can develop
0
1 0
2 0
3 0
4 0
L i v e r I r o n C o n c e n t r a t i o n
mg
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b T h a l
N o T x
b T h a l
I n t T x
a T h a l
N o T x
a T h a l
I n t T x
U p p e r L i m i t
Oakland data: This data is from NTDT patients selected to undergo evaluation of LIC
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Other Considerations§ Genetic Counseling
− Partner testing is essential before pregnancy
§ Pregnancy− Routine transfusions during pregnancy offered when baseline hemoglobin <7 g/dL− May be needed at higher hemoglobin for symptoms
− High risk for allo-immunization
§ Quality of Life− Older patients should be monitored for deterioration in QOL
§ Chronic fatigue§ Difficulty in coping at work§ Family stress§ Chronic pain
§ Social work assessment and support§ Psychological counseling
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A partnership to approach thalassemia as a public health issue in the Asian Community§ Thalassemias occur at high frequency in Chinese and other Asian Communities in the SF
Bay Area
§ Screening for thalassemia should be promoted in primary care for children and adults§ The wide spectrum of thalassemia and the underlying mutations requires hematology
consultation for evaluation
§ Non-transfused patients are at risk for complications related to anemia and iron overload
§ Universal screening of all pregnant women from high-risk ethnic groups for thalassemia
§ Early Detection of Bart’s hydrops fetalis during pregnancy requires high index of suspicion
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