thalassaemia 2016- lets clear the doubts

8/17/2019 Thalassaemia 2016- Lets clear the doubts

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Thalassaemia- The True Story so far!!!

1



Prognosis

• Persons with thalassemia trait have anormal life expectancy. Persons withbeta thalassemia major live an aver-

age of 17 years an usually ie by "years of age. #ost eaths are causeby the cariac complications of iron

overloa.



#anagement of Thalassaemia$

• %efore$

1& %loo Transfusion---'ron (verloa---)helation---complications

*&%one #arrow transplant with about*+ to ,+ ris to life an latercomplicatons of infertility/ seconarymalignancies/ chronic 023/infections



• 4ow$

• 15*

- 0enetherapy- still a ream

,- 4ovel Therapy- 6ife without

transfusions with meicinesit )844(T 9:3;): T2: 9'S< (= P9:):3'40'9(4 (:96(83. 4( sie e>ects of%one #arrow Transplant



• 8t present/ allogeneic 2S)T is the only means

of curing b-thalassaemia. 't shoul beconsiere if an 268-matche sibling onor isavailable. The ris is low when the transplant isone at an early age. 6ucarelli et al. from 'talyhave reporte the results of more than 1"""allogeneic %#T recipients for b-thalassaemia.

They use busulphan an cyclophosphamiefor conitioning.

• Patients were categori?e accoring to thepresence of ris factors @hepatomegaly/ portalAbrosis an poor Buality of chelation& to$

• )lass '$ 4o ris factors

• )lass ''$ 1C* ris factors

• )lass '''$ 8ll ris factors.



• 'n 'nia/ the largest experience with transplantation for b-

thalassaemia is from the )hristian #eical )ollege/ elloreD in

1"E patients the :=S was EE in class ' patients @nFE&/ G" in

class '' @nF"& an ++ in class ''' @nF7"& at a meian follow up

of *E months @range *CH7 months&

• =or patients I1E years of age/ the probability of survival in

classes '/ '' an ''' is G+/ H7 an HG/ respectively. Similarly/

the event-free survival @:=S& in these classes is G"/ H, an

E,/ respectively.



9elieving ineffective hematopoiesis with T0=-J ligan traps.

FromTargeting a new regulator of erythropoiesis to alleviate

anemia

Robert F PaulsonNature Medicine 20/ ,C+ @*"1,& oi$1".1"HKnm.+*, Publishe

online "7 8pril *"1,

• 'n J-thalassemia or #3S/ efects in erythroi ifferentiation cause

anemia leaing to tissue hypoxia/ which promotes the prouction ofthe erythroi i>erentiation hormone :P(. 3efective erythroii>erentiation in these synromes results in an accumulation of03=11-expressing erythroi progenitors. 03=11 maintains the survivalof these progenitors an inhibits further i>erentiation/ which furtheraggravates the ine>ective erythropoiesis. @b& 3ussiot et al. an

Suragani et al., An that inhibiting 03=11 signaling with sotaterceptor 8):-+E inuces apoptosis of 03=11-expressing erythroiprogenitors/ restoring their ability to i>erentiate an/ hence/alleviating the anemia.

• Katie Vicari



Rationale for HbF induction

! Gamma globin genes are intact"

! HbF will functionally compensate for the absenceof HbA (HPFH homozygotes, genetic compounds (β-thal/HPFH)"

"

! HbF in post-natal life is influenced by physiologicaland genetic factors (pregnancy, acute erythroid expansion,haematological diseases, haemoglobinopathies)"

! High cost of conventional treatment"

! Problems wit blood safety and availability in severalcountries"

HbA = adult haemoglobin; HbF = fetal haemoglobin.



HbF inducers

Class Compound

Hypomethylating/cytotoxic agents 5a!acytidine" decitabine

Cytotoxic agents hydroxyurea

Histone #eacetylase $nhibitors

butyrate analogs" short chain fatty

acids" adipicin" scriptaid"

trichostatin A" %alproic acid"

Antioxidantsres%eratrol" angelicin"

curcumin&&&

'thers(rythropoietin" thalidomide



Atweh g eta l Hematol Incol Clin N Am 2010

• histone hyperacetylation

• p3!"#P$ phosphorylation

• %R$ "#P$ dephosphorylation

• s&'(c&"P pathway activation

• increased mR)# translation

• s&'(c&"P pathwayactivation

• increase of '#"P

• hypomethylationby inhibition of *)#

• hyperacetylation +,-

thalidomide

)echanisms for γ globin induction by pharmacologic agents



#ethoology

O (ur inex case gave me insight into follow up inthese case. 2e ha been transfuse for over "years but Arst transfusion was after 1 year of age.

O ' realise the real e>ect of 2yroxyurea K-Qheatgrass can only be juge by allowing thehemoglobin to fall upto + to E gm with pulse ratenever crossing 1*"Kmin.O This level allows the inherent hemoglobin

synthesis to start i.e 2b= synthesis. 'f a patientoesnRt receive transfusion for over months thenit is translates into T984S=;S'(4 '43:P:43:4):.



• Thalassaemia )ure Score



Thaliomie

• Thaliomie is a synthetic glutamic aci erivative thatwas originally prescribe as a seative an antinauseameicine/ but later withrawn from the maret ue toits teratogenic e>ects.

• 2owever/ thaliomie has mae a remarablecomebac since the iscovery of its immunomoulatoryan anti-inammatory e>ects/ which have le to its useas a treatment for various proinamma- tory anautoimmune conitions.

• 't is currently being use to treat a number of iseases/incluing ermatologic/ infectious/ autoimmune/ anhematologic isorers

• 6eprosy/ Transplant



Thalidomide therapy in patients with thalassemia ma.or/

# genotype –28A→ Ccd!"

genotype IV#1$%cd&&C

100 mg(2g(dHbF 1004

56 mg(2g(dHbF60→ 534

Aguilar$'ope( et al )lood Cell



9uxolitinib in Thalassaemia

• 4o splenctomy

• L8<-* inhibitor- ;se in cancer will beuse in Thalassaemia



Potential use of JAK2 inhbitors in β-thalassemia.

Stefano Rivella Haematologica 201!100"#1$-#%0

*+,-5 by Ferrata .torti Foundation



&#T#!1 and %rythropoietin 'ooperate t o Promote %rythroid 'ell 7urvival by Regulating bcl!89 %8pression

%y Todd &regory/ 'hanning :u/ #veril "a/ 7tuart H/ ;rin/ &erd #/ lobel/ and "itchell </ =eiss



Thalassaemia

• %ehaves lie cancer so has treateas cancer

• Qhy shoul spleen an liver becomelargeU

thalassaemia 2016- lets clear the doubts

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