Non-Transfusion-Dependent Thalassemia

Ashutosh Lal, MDNorthern California Thalassemia Center

UCSF Benioff Children’s Hospital Oakland

Thalassemia Syndromes: Many diagnoses

• Oakland Data (n=203)

ß Thal Major38%

ß Thal Int11%

A Trip/ß Thal Trait2%

Eß014%

Eß+6%

Cß00.5%

A Thal Major0.5%

Hb H/CS8%

Hb H19%

ATRX0.5%

What is the proportion of non-transfusion-dependent thalassemia

n=203, Oakland data

• Not a true representation of NTDT• The real number of non-transfused patients is likely 5-10 times

Transfusion-de-pendent

56%In-ter-

mit -tently-trans-fused17%

Non-transfused27%

Age profile of patient population in Oakland• Many non-transfusion-dependent patients stop regular follow up

Oakland data

Age (years)

Num

ber o

f pat

ient

s

5 15 25 35 45 550

10

20

30

40

50

MaleFemale

Non-Transfusion-Dependent

Age (years)

Num

ber o

f pat

ient

s

5 15 25 35 45 55 650

10

20

30 Transfusion-Dependent

MaleFemale

Thalassemia Syndromes: a continuum

No Transfusions Occasional Transfusions

Regular Transfusions

for Symptoms

Regular Transfusions for Survival

Trait Intermedia Major

Causes of Non-Transfusion Dependent Thalassemia

Beta Thalassemia

Intermedia

• Beta 0 and mild beta mutation• Two mild beta mutations• Two beta mutations plus high fetal hemoglobin• One beta mutation plus increased alpha genes• Single unstable beta mutation

E-Beta Thalassemia

• Hb E mutation with beta mutation• E and beta mutations with alpha deletion• E and beta mutations with high fetal hemoglobin

Alpha Thalassemia

• Deletion of three alpha genes• Deletion of 2 alpha genes plus mutation in one

alpha gene

Transfusion Requirement

Oakland data

0

20

40

60

80

Num

ber o

f pat

ient

s

RegularIntermittentNever

ThalIntermedia

Hetero Thal

E 0Thal

E +Thal

HbH HbH/CS

Beta-thalassemia intermedia: Evolving Management

Thal Int, 42 years old

• Diagnosed at 1 year• Hemoglobin 6-7 g/dL• No blood transfusions• At 10 years: heart failure• Splenectomized• Hemoglobin increased to 8• Intermittent transfusions• At 30 years: Pulmonary

hypertension, right heart failure• Started on regular transfusions

Thal Int, 16 years old

• Diagnosed at 2 years• Hemoglobin 6-7 g/dL• No blood transfusions• Good energy level, participates in

sports, swimming and soccer• At 14 years: Fatigue, splenomegaly,

growth delay• No response to hydroxyurea• Started on regular transfusions

E-Beta0 Thalassemia• 11 years old, diagnosed with E beta thalassemia at 2 years

• Well during infancy• Sick as toddler frequent ER visits for fever; pneumonia• School: Tired compared with peers, needs frequent rest, chooses less

active play• 3 transfusions in one winter: fall in hemoglobin during infections

• Baseline hemoglobin from 5.8 to 6.5 g/dL• No response to HU• Started on regular transfusions at 6 years

E-Beta0 Thalassemia plus alpha0 trait

• Younger brother 8 years old

• Hemoglobin level 9.8 g/dl

• Asymptomatic

Heterozygous Beta thalassemia intermedia

• Now 36 years old: Dx at 8 months: a little pale, fatigued, poor appetite• Baseline hemoglobin level 7.5 to 9 g/dL• First transfusion at 18 years for aplastic crisis. • Cholecystectomy at 22 years, transfusion prior to surgery • Pregnancy at 34 years, hemoglobin dropped from 7 to 4 g/dL,

transfused intermittently during pregnancy

• Liver 4 cm, Spleen 8 cm

• Hemoglobin 6.9 g/dL

• Ferritin 1830; Liver iron concentration 31.2 mg/g dry-wt

• Electrophoresis: Hb A2: 4.8%, Hb F 1.2%

• Heterozygous IVSI-1, G->A (β0/βA)β Globin

gene: • Heterozygous alpha anti-3.7 triplication

(ααα/αα)α Globin

gene:

HbH Constant Spring

Transfusion EventsAge in years

Comparison with Thalassemia Major

More in thalassemia major• Iron overload• Early need for effective chelation• Consequences of iron overload

• Endocrinopathies• Hypogonadism• Osteoporosis• Heart disease• Liver disease• Transfusion-transmitted infections

• Hospital visits

More in non-transfusion dependent thalassemia• Anemia

• Sudden fall in hemoglobin• Extramedullary masses• Splenomegaly• Pulmonary hypertension• Thrombosis• Leg ulcers• Silent Cerebral Infarction

Clinical Management GuidelinesOakland Standards of Care

The initial clinic visit

Review laboratory results • Hematological• Electrophoresis • DNA tests

Counseling• Discuss probable outcome and uncertainties

• Stress that close follow up is essential to make informed decisions

Introduce the care team• Physician, Nurse Practitioner, Social Worker, Clinic Coordinator,

Dietician, Genetic Counselor• Provide support

Montioring• Frequency of visits

• Initially every month, then 2 months, then 3-12 months• Growth

• Height and weight, pubertal development• Nutrition

• Folate, vitamin D, avoiding supplemental iron• Counseling for risk during infections• Building relationship

• Accessibility, social work assessment, diagnosis card

Management of Fever

Two major risks during fever• Worsening of anemia• Serious sepsis

Patients with fever >100.4 F seen on the same day• Exception – Deletional hemoglobin H disease – can be seen next day

During the clinic or ER visits• Check hemoglobin, reticulocyte count and bilirubin• 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 recommended

Options for treatmentObservation and supportive care• Folate, nutrition, regular monitoring

Hydroxyurea• Other experimental agents to increase fetal hemoglobin

Splenectomy

Regular transfusions

Alternatives to long-term transfusions• Bone marrow transplantation• Gene Therapy

Splenectomy• Splenectomy is NOT recommended as a means to

delay or prevent the need for regular transfusions• Hb H Constant Spring is an exception

Never Occasional Regular0

5

10

15

20

25

30SplenectomizedNon-Splenectomized

Num

ber o

f Pati

ents

E Beta ThalassemiaOakland data

Hydroxyurea • Benefit of Hydroxyurea is uneven • Certain mutations predict better response to hydroxyurea

• XmnI polymorphism• Lepore or δβ-thalassemia

• Patients with extramedullary pseudotumors

• Hydroxyurea starting dose of 10 mg/kg/day, not exceeding 20 mg/kg/day

• Response evaluated after 3 and 6 months of therapy • Hemoglobin level increase of >1 g/dl at 6 months• Discontinue in patients not showing response

Specific Management: Assessing the need for transfusions

Growth problems

Fatigue

Quality of life

Splenomegaly

Extramedullary hematopoiesis

Pulmonary Hypertension

Pain

Intermittent transfusions • Recommended when hemoglobin falls <6 g/dL• Frequent episodes mean regular transfusions needed

Transfusion therapy: When to transfuse

• Patients with hemoglobin consistently <7 g/dL should start regular transfusionsBeta thalassemia

• Many patients do well with hemoglobin 6-7 g/dL• Consider growth, fatigue, splenomegaly

E Beta Thalassemia

• Transfusions are not necessary for managementHemoglobin H Disease

• Intermittent transfusions are generally needed• Regular transfusions are usually not recommended

Hemoglobin H Constant Spring

Iron Overload• 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 • Cardiac iron deposition less common

0

10

20

30

40

Liver Iron Concentrationm

g/g

ThalNo Tx

ThalInt Tx

ThalNo Tx

ThalInt Tx

Upper Limit

Oakland data: NTDT patients

• Liver damage • Hormone deficiencies

Assessment of Iron Overload• Measure serum ferritin• Measure liver iron concentration when ferritin >300 ng/mL• Measure cardiac iron if LIC >15 mg/g• Evaluate for hormone deficiencies

Treatment of Iron Overload• Non-transfused patients >10 years with ferritin >300 ng/mL

and LIC >5 mg/g• Earlier for intermittently transfused patients• Deferasirox is the preferred chelators

• Dose is 50% of that used for thalassemia major• Goal: reduce ferritin <200 ng/mL, LIC <5

• Stop therapy, resume monitoring

Fertility• Fertility is usually not affected• Genetic Counseling: Partner testing is essential Pregnancy• Pregnancy: Consider transfusions during pregnancy when

hemoglobin <8 g/dL

Quality of Life• Monitored for deterioration in QOL with age

• Chronic fatigue, difficulty in coping at work• Family stress• Chronic pain

• Psychosocial assessment, support and counseling

Barriers to Care• Lack of regular follow up• Lack of evaluation at Comprehensive Thalassemia Center• Lack of medical insurance

Northern California Comprehensive

Thalassemia Center Elliott Vichinsky, MD Medical Director of Hem/OncAshutosh Lal, MD Director of Thalassemia ProgramLynne Neumayr, MD Administrative DirectorSylvia Titi Singer, MD Associate HematologistCarolyn Hoppe, MD Director, Hemoglobin Ref Lab

Drucilla Haines, PNP Clinical Nurse PractitionerWendy Murphy, MSW Thalassemia Social WorkLaurice Levine, MA, CCLS Thalassemia OutreachShanda Robertson Database ManagerEllen Fung, PhD Nutrition ScientistMarcela Weyhmiller, PhD Iron Program