Non transfusion dependent thalassemias beta-thalassemia intermedia and hb e beta-thalassemia

Non-transfusion dependent
thalassemias: -thalassemia
intermedia and HbE/-thalassemia

Elizabeth George

1

Treatment of beta-thalassemia
intermedia (TI)

• Terminology
• Clinical diversity
Cli i l di it
• Natural history
• Treatment: Current status
• g
Clinical features & Clinical diagnosis
• Treatment options: Practical approach
• Complications

2

beta thalassemia
beta-thalassemia intermedia
 Terminology: Definition
KEY POINTS

• Refers to patients with clinical manifestations that are too
severe to be minor and too mild to be severe
(``no man’s land’’)
• Age of presentation in the absence of inter-current
infection: >2years old
• Blood transfusion independency (or infrequent)

 Diagnosis: largely clinical
• Extremely diverse clinical phenotypes exist
• E
Encompasses HbE b beta-thalassemia
h l i
3

Clinical diversity of TI
y
Spectrum
Hb levels range from 5.5 to 11 0 gm/dl (arbitrary guideline)
5 5 11.0

Moderate
• HbE beta-thalassemia [IVS1-5(GC)] with Hb 6.5 gm/dl.
Mild to moderate splenomegaly and skeletal abnormalities.
Asymptomatic (adapt to low Hb) requiring no blood
transfusions (BT) or occasional BT. Iron loading in 3-5th
decade.
 Studies indicate Hb<7gm/dl: destined to late
complications
Mild
• HbE-polydenylation A (AATAAA AATAGA) mutation with
Hb>9.5 gm/dl, mild splenomegaly and require no BT
• Homozygous -thalassemia with Hb>9 5gm/dl mild
Hb>9.5gm/dl,
splenomegaly and skeletal changes. Require no BT.
4

Molecular basis of TI
f
Genotype to phenotype correlation
Arbitrary guidelines of possible clinical phenotype

Gene modifiers
 and non  globin chain imbalance: ineffective
erythropoiesis

• Primary: specific alleles
• S d globin genes affecting alpha and b t
Secondary: l bi ff ti l h d beta-
globin chain imbalance

 genes affecting disease process but not globin chain
production
• Tertiary 5

Primary gene modifiers: specific alleles
Pi difi ifi ll l
• 0 / +
• + / + (homozygous compound heterozygous)
(homozygous,
• 0 / 0 + alpha thalassemia or HPFH
• Homozygous  (homozygous)
•  / +
• Dominant -thalassemia
 thalassemia
• Unstable  globin chain variants
• 
-thalassemia trait + triplication of -globin genes
p g g

*includes Hb Variants with + phenotype
6


+ alleles (common in southeast Asia)
• Hb E (CD26 Gl Lys): mild
Glu L ) ild
• Hb Malay (CD19 Asn Ser): mild
• Poly A (AATAAA to AATAGA): mild
• -28 (AG): moderate
28
• IVS 1-5 (GC) severe mutation
• IVS 2-654 (C T) severe mutation
2 654 (CT): t ti

7


Other globin genes that affect globin chain imbalance

• C i h it
Co-inheritance of alpha-thalassemia (
f l h th l i (ameliorate)
li t )
• Triplication of alpha globin genes (aggravate)
• HbF synthesis 
H dit persistence off Hb (HPFH) synthesis
Hereditary i t th i
XMN-1 polymorphism [CD-158 (CT)]
(polymorphism HBG2 at position -158)
158)

• Alpha Hb Globin Stabilizing Protein (AHSP)
Alpha-Hb
8


Other
Oth genes that affect disease process but not
th t ff t di b t t
globin chain production

• Co-inheritance of hemochromatosis gene: iron
g
loading
• Coinheritance of mutation of promoter of
bilirubin (UDP-Glucuronyltransferase gene):
jaundice  gall stones
,
• Bone metabolism
• Hereditary ovalostomatocytosis
H dit l t t t i
9

beta thalassemia
 Natural history: not completely defined in many
y p y y
countries

• Changing phenotypes: environmental factors
(intercurrent infection, nutrition, access to health care
facilities)
• Most studies reported are on hospitalized patients
(miss out on mild cases in the population).
• Molecular studies (gene modifiers) are not available
available.
• Mild cases may be converted to transfusion.
dependency by regular blood transfusions in absence
of guidelines on treatment. 10

beta thalassemia

Current treatment (in absence of guidelines)
• Not in a defined way
• Haphazard way
•DDemand td transfusion
f i
(Asia and southeast Asia)

11


High
Hi h variability of clinical picture
i bilit f li i l i t
Changing phenotypes

 Attending physician is in a dilemma: To treat or
not to treat?

Studies indicate:
 complications increase later in life in absence of
regular blood transfusions

12


 Clinical features:
• H ll k off di
Hallmark disease: i ff ti erythropoiesis,
ineffective th i i
chronic hemolytic anemia and iron loading
• Age of presentation: any age (>2 years old)

13

Treatment options of TI: Practical
p
approach
KEY POINTS

 Clinical diagnosis: Careful observations for a period of
time before decision is made / proper records kept
 Early diagnosis and regular follow-up for life
follow up

At time of diagnosis
 Complete molecular studies (gene modifiers)
 Comprehensive base line investigations
[Thalassemia Diagnosis (BHES protocol), Blood group
genotype, Liver & Renal Profile, Viral status, Serum
ferritin]
14

To treat or not to treat?

 Treatment options
• N clear guidelines ( id
No l id li (evidence b
based) on optimal
d) ti l
care

 Personalized therapy remains the treatment of
py
choice
 Quality of life, growth puberty & sexual
life growth,
maturation, iron loading
 Prevention of complications
15

To treat or not to treat?
 Treatment options: Caveat
• Patients have an option to best possible care at
diagnosis & prevention of late complications
• Counseling: Outcomes discussed with therapeutic
options / available health care facilities

clinical phenotype: moderate-severe TI (Hb<7gm/dl).
Destined to be short (below 3rd percentile) skeletal
percentile),
abnormalities, splenomegaly, delayed puberty and
at risk of late complications.
16

Indications for blood transfusion
 Failure to thrive / poor quality of life
 Growth retardation (height,, bone age,, sexual maturation)
( g g )
 Intense erythropoiesis
 Skeletal deformities
PProgressive splenomegaly
i l l
 Extramedullary masses
 Iron loading
Special circumstances
p
• Severe infection
• Oxidant drug therapy
• P
Pregnancy
• Heart disease
• Heal leg ulcers
• Surgery 17

Indication for blood transfusion:

 Intense erythropoiesis: surrogate markers
• Xray of 2nd metacarpal bone: measure the internal
diameter for expansion of medullary cavity.
(BMJ 1987, 67:479-485)
• PBF: Hb Nucleated RBCs
• HbF increased >40%
(Haematologica 1995, 80:58-68)
80:58 68)
• Soluble transferrin receptor (sTfR) increased
(Blood 1987, 70:1995-1999)
70:1995 1999)
18

Aim of blood transfusion

• Suppress bone marrow activity
• Promote better growth
g
• Decrease iron absorption from the GIT
*Pretransfusion Hb levels: 8-9 gm/dl
Commence iron chelation therapy

 Risk of alloimmunization significant after 2-3 years
of age
19

Splenomegaly
p g y
Common feature in TI
Chronic severe hemolytic anemia: progressive increase in
spleen size

• plasma volume : high output state (right heart failure)
• P t i (Hb WBC Pl t l t)
Pancytopenia (Hb, WBC, Platelet)
Require blood transfusions
Caution
C ti use of D f i
f Deferiprone (L1) with neutropenia
ith t i

 S l t iis no llonger an accepted ttreatmentt off
Splenectomy t d t
choice
 Blood transfusions indicated (spleen size 3cm/year)
20

Splenectomy: Risk of complications

Indications
• Markedly large spleen and increasing blood transfusion
requirements
i t
• Pregnancy: intrauterine growth restriction

Splenectomy: I
S l t Increased risk of complications
d i k f li ti
 Infections
 Hypercoagulable state
H l bl t t
 Pulmonary hypertension
 Secondary right h
S d i h heart f il
failure
21

Splenectomy: Infections

 Infections
• Streptococcus p
p pneumoniae
• Hemophilus influenzae
• Neisseria meningitidis
• Klebsiella
• Escherichia coli
• Staphyloccus aureus
p y

22

Splenectomy: Infection

 Prevention of Infections
• Antibiotic prophylaxis (penicillin, amoxicillin
erythromycin)
th i )
• Immunization
Streptococcus pneumoniae / 5 yearly
St t i l
Hemophilus influenzae
Neisseria meningitidis
N i i i itidi

C
Counseling: early antibiotic th
li l tibi ti therapy f f
for fever or any sign
i
of infection
 Common cause of mortality in patients in TI patients
23

Hypercoagulable state
 Chronic hemolytic anemia: nucleated RBCs and
damaged RBCs (anionic PL exposed RBC surface)
 Splenectomy: thrombocytosis
• Platelets release: serotonin, platelet derived growth
factor (PDGF), vascular endothelial growth f
f (PDGF) l d h li l h factor
(VEGF)
• Recurrent local thrombosis 
increase thromboxane and endothelin
decrease prostacyclin and nitric oxide (NO)
damage to elastic tissue in vessel wall
24

Pulmonary hypertension
 Pulmonary hypertension
y yp
• Vessel wall
Vasoconstriction (serotonin)
Hypertrophy of smooth muscle (PDGF VEGF)
H t h f th l (PDGF,
Endothelial dysfunction & diffuse elastic tissue injury
• Recurrent local thrombosis
 Prevention: antiplatelet aggregating agents ( )
p gg g g g (ASA)
 Treatment of pulmonary hypertension
• Endothelin receptor antagonists: (Bosetan)
• P t li analogs
Prostaclin l
• Inhibitor of cyclic guanosine monophosphate specific
p osp od es e ase 5 (Sildenafil): se ec e smooth usc e
phosphodiesterase-5 (S de a ) selective s oo muscle
relaxant
25

Cardiac disease
 High cardiac output state
• High HbF
• Age related elastic tisisue damage (
g g (endocardium,,
cardiac valves and pericardium)
• Pulmonary hypertension ( )
y yp (60%)
• Iron loading (in absence of blood transfusions)
• Right heart failure (right ventricular dysfunction) >
left heart failure
• Congestive heart failure (7% >35 years of age)
• Left ventricular failure (important in older patient)
26

Bone abnormalities
 Intense ineffective erythropoiesis
(Enhanced medullary hematopoiesis)
• Skeletal abnormalities
• Osteopenia: increase risk of fractures due minor trauma
• Bone pain
 Pre ention
Prevention
• Blood transfusions
• Exercise (Non contact sports activities)
 Treatment
• Hydroxycarbamide (Hydroxyurea)
• 25-OH vitamin D and calcium carbonate
• Biphosphonates (inhibition of osteoclast activity)
27

Extramedullary masses
 Intense ineffective erythropoiesis
(Extramedullary
(E tramed llar hematopoiesis) : Masses
• thorax
• spine
i

PPrevention
ti
 Treatment
• Bl d transfusions
Blood f i
• Hydroxycarbamide (Hydroxurea)
• Radiotherapy
28

leg ulcers
 Chronic hemolytic anemia
 Beta-thalassemia intermedia > HbE-beta-thalassemia (High
Beta thalassemia HbE beta thalassemia
HbF concentration)
 Vascular dysfunction & elastic tissue damage
• M di l malleolus
Medial ll l

 Prevention
 Treatment
• Pressure dressing
• H b i oxygen chamber
Hyperbaric h b
• Zinc ointments
 Outcome: difficult to heal / recurrent 29

liver disease

 Progressive iron overload
• Liver cirrhosis
• Risk of hepatocellular cancer (iron loading & viral
hepatitis synergistic)
Monitor -fetoprotein and ultrasonography of liver

 Prevention
• Viral status determined at diagnosis: immunization done
g
• Monitor liver iron overload
(including in the absence of blood transfusions).

Treatment: Iron chelation therapy

30

Pregnancy
• Fertile in the absence of iron loading
 Chronic hemolytic anemia: restricted intra-uterine
growth of fetus (small by weight gestation)
th f f t ( ll b i ht t ti )
• Blood transfusions may be required
 Splenomegaly: interferes with uterine development
• Splenectomy
 Skeletal abnormalities
• Caesarian section
31

Age related late complications

• Chronic hemolytic anemia
y
• Absence of blood transfusions
 Hypoxia: Increased erythropoietin
• Hb lower: quality of life affected
q y
• Intense erythropoiesis: bone pain
• Extramedullary hematopoiesis
a edu a y e a opo es s
 Iron loading
 Hypercoagulable state
 Post-splenectomy complications
 Cardiac disease
32

Bone-marrow transplantation

• HLA matched sibling donor (stem cells from bone
marrow and umbilical cord)
• Transplant related mortality ~5%
• Severe HbE beta thalassemia intermedia
beta-thalassemia

33

Supplements

• Free radical formation (globin chain excess and free
labile iron): vitamin E (400 IU daily)
• Zinc deficiency: Chelated zinc
• Inhibit iron absorption via GIT: Green tea
consumption ( 2 cups)
(~
• Folic acid (1 mg daily)

34

Summary
• TI is a clinical definition. Clinical phenotype is between
thalassemia minor and major.
• Diagnosis requires careful observations over a period of
Di i i f l b ti i d f
time.
• Hb levels and identification of gene modifiers are arbitrary
g y
guidelines as to possible clinical phenotype.
• Patients with Hb<7gm/dl are destined to be short (below 3rd
centile of growth chart) have splenomegaly and skeletal
abnormalities. Late complications occur in the absence of
regular blood transfusions.
• Splenectomy i not a t t
S l t is t treatment of choice.
t f h i
• Personalized therapy remains the treatment of choice.
• Patients with Hb levels <7gm/dl and moderate-severe TI with
moderate severe
access to good quality care facilities should be have regular
blood transfusions/iron chelation or stem cell transplantation.
• Supplements: vitamin E, folic acid zinc and drinking of tea
E acid,
are recommended. 35

``A journey of a thousand miles begins with the first step’’

thank you

36

Non transfusion dependent thalassemias beta-thalassemia intermedia and hb e beta-thalassemia

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