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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

α

β

α

β

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W o r l d

5 5 , 8 7 5

a

b

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

XX

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

XXX

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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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%

3-6

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


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

/g

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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13 lal thalassemia asians - ucsfcme.com · alpha thalassemias pregnancy risk assessment...

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