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

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

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

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

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

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

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 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

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 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 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

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 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

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 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

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

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 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

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

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 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

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