Non-TransfusionDependent Thalassemia
Ashutosh Lal, MD
Northern California Thalassemia Center
UCSF Benioff Children’s Hospital Oakland
Thalassemia Syndromes: Many diagnoses
ATRX
0.5%
ß Thal Major
38%
Hb H
19%
Hb H/CS
8%
A Thal Major
0.5%
Cß0
0.5%
• Oakland Data (n=203)
ß Thal Int
11%
Eß+
6%
Eß0
14%
A Trip/ß Thal Trait
2%
What is the proportion of
non-transfusion-dependent thalassemia
Non-transfused
27%
Intermittentlytransfused
17%
Transfusiondependent
56%
• Not a true representation of NTDT
• The real number of non-transfused patients is likely 5-10 times
n=203, Oakland data
Age profile of patient population in Oakland
• Many non-transfusion-dependent patients stop regular follow up
30
50
Transfusion-Dependent
20
10
Female
Male
40
Number of patients
Number of patients
Female
Male
Non-Transfusion-Dependent
30
20
10
0
0
5
15
25
35
45
Age (years)
55
65
5
15
25
35
45
55
Age (years)
Oakland data
Thalassemia Syndromes: a continuum
No Transfusions
Trait
Occasional
Transfusions
Intermedia
Regular
Transfusions
for Symptoms
Regular
Transfusions
for Survival
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
N u m b e r o f p a tie n ts
N ever
80
I n te r m itt e n t
R e g u la r
60
40
20
0
 T h a l
H e te ro
E  0
E  +
In te r m e d ia
 T h a l
T h a l
T h a l
H bH
H b H /C S
Oakland data
Beta-thalassemia intermedia:
Evolving Management
Thal Int, 42 years old
Thal Int, 16 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
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%
β Globin gene:
• Heterozygous IVSI-1, G->A (β0/βA)
α Globin gene:
• Heterozygous alpha anti-3.7 triplication
(ααα/αα)
HbH Constant Spring
Age in years
Transfusion Events
Comparison with Thalassemia Major
More in thalassemia
major
More in non-transfusion
dependent thalassemia
• Iron overload
• Early need for effective chelation
• Consequences of iron overload
• Anemia
•
•
•
•
•
•
Endocrinopathies
Hypogonadism
Osteoporosis
Heart disease
Liver disease
Transfusion-transmitted infections
• Hospital visits
• Sudden fall in hemoglobin
• Extramedullary masses
• Splenomegaly
• Pulmonary hypertension
• Thrombosis
• Leg ulcers
• Silent Cerebral Infarction
Clinical Management Guidelines
Oakland 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 treatment
Observation 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
Number of Patients
30
Splenectomized
Non-Splenectomized
25
20
15
10
5
0
Never
Occasional
Regular
E Beta
Thalassemia
Oakland 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
Beta thalassemia
• Patients with hemoglobin consistently <7 g/dL should
start regular transfusions
E Beta
Thalassemia
• Many patients do well with hemoglobin 6-7 g/dL
• Consider growth, fatigue, splenomegaly
Hemoglobin H
Disease
• Transfusions are not necessary for management
Hemoglobin H
Constant Spring
• Intermittent transfusions are generally needed
• Regular transfusions are usually not recommended
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
L iv e r Ir o n C o n c e n tr a tio n
• Liver damage
• Hormone deficiencies
40
m g /g
30
20
10
U p p e r L im it
0
Oakland data: NTDT patients
 Thal
 Thal
 Thal
 Thal
N o Tx
In t T x
N o Tx
In t T x
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
Elliott Vichinsky, MD
Medical Director of Hem/Onc
Ashutosh Lal, MD
Director of Thalassemia Program
Lynne Neumayr, MD
Administrative Director
Sylvia Titi Singer, MD
Associate Hematologist
Carolyn Hoppe, MD
Director, Hemoglobin Ref Lab
Drucilla Haines, PNP
Clinical Nurse Practitioner
Wendy Murphy, MSW
Thalassemia Social Work
Laurice Levine, MA, CCLS
Thalassemia Outreach
Shanda Robertson
Database Manager
Ellen Fung, PhD
Nutrition Scientist
Marcela Weyhmiller, PhD
Iron Program