1. Non-Transfusion-Dependent Thalassemia
Ashutosh Lal, MD
Northern California Thalassemia Center
UCSF Benioff Children’s Hospital Oakland

2. Thalassemia Syndromes: Many diagnoses
Oakland Data (n=203)

3. What is the proportion of non-transfusion-dependent thalassemia
Looked at this way, <50% patients are thal intermedia, but this is misleading as shown in the next slide.
Not a true representation of NTDT
The real number of non-transfused patients is likely 5-10 times
n=203, Oakland data

4. Age profile of patient population in Oakland
Many non-transfusion-dependent patients stop regular follow up
We follow patients of all ages in our program. These are patients seen in the last 3 years.
Oakland data

5. Thalassemia Syndromes: a continuum
No Transfusions
Occasional Transfusions
Regular Transfusions for Symptoms
Regular Transfusions for Survival
Trait
Intermedia
Major

6. 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
So, to recap, three categories of NTDT, each arising from multiple underlying genotypes

7. Transfusion Requirement
More E0 patients than E+ are transfused. Transfusions are unlikely in heterozygous beta thal, not needed in HbH, and intermittent in HCS.
Oakland data

8. 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

9. E-Beta0 Thalassemia E-Beta0 Thalassemia plus alpha0 trait
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

10. 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:

11. HbH Constant Spring
Age in years
Transfusion Events

12. 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
Endocrinopathies
Hypogonadism
Osteoporosis
Heart disease
Liver disease
Transfusion-transmitted infections
Hospital visits
Anemia
Sudden fall in hemoglobin
Extramedullary masses
Splenomegaly
Pulmonary hypertension
Thrombosis
Leg ulcers
Silent Cerebral Infarction

13. Clinical Management Guidelines
Oakland Standards of Care

14. 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

15. Montioring Frequency of visits Growth Nutrition
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

16. 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

17. Options for treatment Observation and supportive care Hydroxyurea
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

18. Splenectomy
Splenectomy is NOT recommended as a means to delay or prevent the need for regular transfusions
Hb H Constant Spring is an exception
E Beta Thalassemia
Oakland data

19. 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

20. 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

21. Transfusion therapy: When to transfuse
Patients with hemoglobin consistently <7 g/dL should start regular transfusions
Beta thalassemia
Many patients do well with hemoglobin 6-7 g/dL
Consider growth, fatigue, splenomegaly
E Beta Thalassemia
Transfusions are not necessary for management
Hemoglobin H Disease
Intermittent transfusions are generally needed
Regular transfusions are usually not recommended
Hemoglobin H Constant Spring

22. 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
Liver damage
Hormone deficiencies
Oakland data: NTDT patients

23. 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

24. Fertility Quality of Life Barriers to Care
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

25. Northern California Comprehensive Thalassemia Center
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