Non transfusion dependent thalassemia management

1. NTDT Management
Dr. Govind Kendre
Department of hematology,
Seth G.S. medical college & KEM hospital,
Parel,Mumbai

2. Management
Transfusion
therapy
Chelation
therapy
Splenectomy
Fetal Hb
induction
Novel
therapeutic
approaches

3. Transfusion therapy

4. Indications of transfusion therapy
Infection
Pregnancy
Surgery
Any setting with anticipated acute blood loss
Poor growth or development during childhood
For the management of specific complications in
adulthood

5. Factors to be considered
Factors to be taken into account
Patient’s wellbeing with
respect to activity, growth
& development
Early appearance of
skeletal changes
Other disease-
complications
Not to embark on any treatment modality
too hastily

6. Recommendations
Blood
processing &
administration
Blood storage
for <2wks
conditioning to
achieve mean
24hr post
transfusion RBC
survival >75%
Leucoreduced
(<1×10⁶
leucocytes/unit)
Hb content
>40gm
Pre-storage
filtration
preferred
ABO & Rh(D)
matched
Rh(C,c,E,e) &
kell matching
highly
recommanded
Appropriate
infections &
viral screening
&vaccination of
recipient &
donors

7. Recommendations
Hb level should not be
an indicator to start
BT therapy, except for
severe anemia
(Hb<5gm%)
Occasional BT
considered in setting
of :
• Pregnancy
• Surgery
• Infections
Frequent transfusions
in setting of:
• Declining Hb in parallel
with profound
enlargement of spleen (@
rate of >3cm/yr in periods
of max growth)
• Growth failure
• Poor school performance
• Diminished exercise
intolerance
• Signs of bony changes
• Failure of development of
sec sexual characters
May be considered for
pri or sec prevention
of :
• Thrombotic
complications
• Pulmonary hypertension
• Extramedullary
hematopoietic
pseudotumors
• Leg ulcers

8. Benefits of transfusion therapy
Fewer leg ulcers
Decreased risk
of thrombotic
events
Low risk of
pulmonary
hypertension
Decreased risk
of silent brain
infarcts
Management of
hematopoietic
compensatory
extramedullary
pseudotumors

9. Concerns with transfusion therapy
The risk of iron
overload
• In minimally transfused
• Newly transfused patients
• Those at an old age at first transfusion
• In splenectomized patients
• During pregnancy
The risk of
alloimmunization
( 1-1.6% after one
BT)

10. Iron overload assesment in NTDT
•Liver iron concentration by magnetic resonance imaging
•Cardiac T2* MRI in NTDT NOT RECOMMENDED
Recommended
method
•Serial measurements of serum ferritin level every 3 months
are recommendedIn resource-poor
country
•≥10yrs of age(slow kinetics of iron loading & low
prevalence of iron-related morbidities in <10 yrs of age)When to start
assesment
•At 1 to 2 yr intervals
Frequency

11. Iron chelation therapy

12. When to start therapy
Age : ≥10yrs of age, (or
≥15yrs of age in deletional
hemoglobin H disease)
and
Having liver iron concentration
levels 5 mg Fe/g or over dry
weight (or serum ferritin level
≥800 ng/ml)

13. Iron chelators
Deferasirox is the only iron
chelator to have been
evaluated in a randomized
clinical trial in patients with
NTDT
Efficacy and safety of other
iron chelators
(desferrioxamine and
deferiprone) are limited to
case reports and small case
series, although benefits
have been observed

14. Deferasirox
Starting dose: 10mg/kg/day
Iron overload status monitoring:
Liver iron concentration after 6
months of initiation then every
6-12 months therafter & serum
ferritin every 3 months
Dose escalation: to
20mg/kg/day when liver iron
conc >7mg Fe/g dry wt (or serum
ferritin 1500-2000ng/ml) after 6
months & showing <15%
reduction in baseline values
Discontinuation: when reaches
liver iron conc <3mg Fe/g dry wt
(or serum ferritin 300ng/ml)
after 6 months

15. Splenectomy

16. Indications of splenectomy
Worsening anemia leading to poor growth &
development
When transfusion therapy is not possible or
iron chelation therapy is unavailable
Hypersplensim leading to worsening
anemia, leukopenia or thrombocytopenia
and resulting in recurrent bacterial infection
or bleeding
Symptoms due to spleenomegaly: left
upper quadrant pain , early satiety or
massive splenomegaly (largest dimension
>20 cm) with concern about possible
splenic rupture.

17. Recommendations
Age: Avoided in < 5yrs
children
Approach: Laproscopic
approach preferred
Vaccination : With
pneumococcal,
meningococcal , Hib &
influenza and revaccination
as recommended
Prophylactic antibiotics:
• At least 2 yrs following
splenectomy & Child becomes > 5
yr old
• Oral penicillin 125mg bid <2 yrs &
250mg bid for> 2yrs of age
Gallbladder: Should be
inspected & removed
during splenectomy if
evidence of gallstone
Liver biopsy

18. Benefit of splenectomy
• Can increase HB by 1-2 g/dL and avoid
blood transfusion therapy.

19. Adverse events following splenectomy
Hypercoagulable
state
Higher rate of
iron-related
organ morbidity
Infections

20. Adverse events following splenectomy
: Hypercoagulable state
Abnormalities of platelets and
pathological red blood cells causing a
hypercoagulable state
Higher risk of :
-venous thromboembolism (5-fold)
(Median time to development 8yrs )
-pulmonary hypertension (4-fold)
-leg ulcers (4-fold)
-silent cerebral infarction

21. Fetal hemoglobin induction

22. Fetal hemoglobin induction
• Results in improvement in α/β-globin chain imbalance
and more effective erythropoiesis
• The earliest attempts to induce fetal hemoglobin through
DNA methylation inhibition with 5-azacytidine
• Hydroxyurea is now the key therapeutic agent
• Mean increases in total hemoglobin level average
approximately 1.5 g/dL, although results are highly
variable

23. Fetal hemoglobin induction
DNA
hypomethylating
agents
Hydroxyurea Butyrates EPO

24. Favourable effects
Improvement in anemia
is usually associated with
better exercise tolerance,
appetite, and sense of
general wellbeing.
Favorable effects on
certain morbidities such
as pulmonary
hypertension, leg ulcer,
and extramedullary
hematopoietic
pseudotumors.

25. DNA hypomethylating agents
• Azacytidine and decitabine
• Subcutaneous decitabine given at 0.2 mg/kg two times
per week for 12 weeks
• Increases total hemoglobin level by an average of 1
g/dL.
• Favorable changes in red blood cell indices are also
noted.

26. Hydroxyurea
• The effects of hydroxyurea seem to extend beyond fetal
hemoglobin induction and may improve the
hypercoagulable state of the disease through effects on
phosphatidylserine externalization in the red cell.
• However, available evidence on hydroxyurea comes
from small single-arm trials or retrospective cohort
studies.
• It has been difficult to determine predictors of response
or the optimal dose and duration of therapy

27. Indications of Hydroxyurea
May be
considered
β thalassemia
intermedia homozygous
for Xmnl polymorphism
Lepore & δβ thalassemia
Requiring transfusions
but are alloimmunised
With clinical morbidities
such as leg ulcers,
pulmonary
hypertension,
hematopoietic
extramedullary
pseudotumors

28. Hydroxyurea
Starting dose:
10mg/kg/day
Response
evaluation:
After 3 & 6 months of
therapy & should be
defined as total Hb
increase >1gm/dl at 6
months
Re-evaluation at
12,18,24 months to
ensure maintenance
of response
Other parameters:
Growth measures,
exercise tolerance
Dose escalation:
by 3-5mg/kg/day
every 8 wks to max
tolerable dose but
not exceeding
20mg/kg/day
Discontinuation:
when no response
Safety measures:
CBC every 2 wks for
1st 3months then
monthly
LFT, RFT every 2 wks
for 1st 3months then
monthly
Not recommended in
pregnant female

29. Butyrates
• Favorable responses to short-chain fatty acid (butyrate
derivatives) have been observed in small studies,
although effects are less notable in long-term therapy

30. EPO
• Recombinant human erythropoietin (rhEPO) & the newer
erythropoietic stimulating agent darbepoetin alfa
• When combined with fetal hemoglobin inducers in NTDT
patients, has an additive effect on total hemoglobin
augmentation although mostly at high doses.
• However, so far, such treatment options remain
investigational.

31. Novel therapeutic approaches

32. Novel therapeutic approaches
Hepcidin modulators
JAK2
inhibitors
Apotransferrin
Modulators of
erythropoiesis
and iron
metabolism

33. Hepcidin
Hepcidin deficiency iron overload
Excessive iron
supply to
developing
erythrocytes
Hyperproliferation
of erythroid
precursors
Stimulate
ineffective &
extramedullary
erythropoiesis

34. Hepcidin modulation
Curbing
hyperabsorption
of dietary iron
Help manage iron
loading
Decrease heme
synthesis, limiting
the formation of
hemichromes
Diminish the
severity of
erythroid
pathologies

35. JAK2
JAK2 signaling
molecule
Regulates proliferation,
differentiation, and
survival of erythroid
progenitors in response
to erythropoietin

36. JAK2 signaling in NTDT
Express elevated
levels of
phosphorylated
active JAK2 (pJAK2)
and other
downstream
signaling molecules
Promote proliferation
and inhibit
differentiation of
erythroid progenitors
Erythroid hyperplasia
in the bone marrow,
spleen and liver
Massive
extramedullary
hematopoiesis &
Hepatosplenomegaly

37. JAK2 inhibitors
JAK2i reduces ineffective erythropoiesis
(fewer bone marrow erythroid progenitors)
Decreases splenomegaly with minimal
effect on red blood cell synthesis

38. JAK2 inhibitors in NTDT Vs JAK2
related neoplasms
The activity of JAK2 is mediated by relatively high
erythropoietin levels (and not a mutation in JAK2) and the
progression of splenomegaly and extramedullary
hematopoiesis occur more slowly.
Beneficial effects of JAK2i in NTDT will be achieved with
reduced doses, shorter intermittent courses, and relatively
fewer complications.

39. Apo-transferrin
• Iron is transported between sites of acquisition, storage,
and utilization by transferrin.
• Transferrin circulates in three forms: diferric-transferrin,
monoferric transferrin, and apo-transferrin, depending on
the iron available.
• The main role of this liver synthesized molecule is to
deliver iron to cells by receptor mediated endocytosis.
• Low hepcidin expression causes excess circulatory iron,
saturation of transferrin, and accumulation of toxic non-
transferrin bound iron.

40. Apo-transferrin therapy
• In mice model, daily apo-transferrin injections resulted in
– Increased hemoglobin
– Reduced reticulocytosis
– Smaller red blood cells with lower mean corpuscular hemoglobin
– Normalized red blood cell survival (likely as a consequence of reduced
hemichromes precipitation on red blood cell membranes)
– Decreased erythropoietin
– Improved maturation and decreased apoptosis of erythroid precursors
– Reversed splenomegaly
– Improved extramedullary hematopoiesis
– Increased hepcidin expression.
• It would simultaneously reduce
– Circulating non-transferrin bound iron and
– Aberrant parenchymal iron deposition
• Thus improve anemia and ineffective erythropoiesis, and reduce
further iron overload.

41. Targeted fetal hemoglobin induction
• Promising targets for therapeutic purposes to induce
fetal hemoglobin include BCL11A, MYB, and KLF1
• Correction of sickle cell disease in adult mice by
interference with fetal hemoglobin silencing (inactivation
of BCL11A) has been recently documented.
• Moreover, epigenetic partners of these factors have
been identified for which small molecule inhibitors
already exist.
• The clinical development of therapeutics for these
targets could be the future path for NTDT and other
hemoglobinopathies.