Myelodysplastic Syndrome

Dr. Anjali Kelkar DNB(Pathology), IFCAP

Consultant - Diagnostic Haematology
NABL Assessor
Associate Professor in Pathology,
In-charge - Haematology Las,
B!D" #e$ical College an$ Hos%ital, Pune&
1
2
Vemon Louw Vemon Louw
Myelodyplastic Syndrome

Dys%lasia' a catchy $escri%tion of (hat is essentially anormal

$ifferentiation&
Histologic hallmar)s of aerrant hemato%oietic cell $iferentiation
nuclear*cyto%lasmic ratio,
nuclear sha%e,
agranularity
%ersistence of granules (hen they shoul$ e asent at that %articular stage of $ifferentiation
Functional $efects characteristic of anormal $ifferentiation'
+erious infections (ith normal neutro%hil count
serious lee$ing e%iso$es $es%ite reasonale %latelet counts&
3
Myelodyplastic Syndrome

Demonstration of altere$ $ifferentiation '

In ,itro' clonogenic assays

In ,i,o' gene e-%ression $efects in $ifferentiation-relate$ %ath(ays
Bone #arro(' Anormal %roliferation (hy%ercellular marro()'
anormal $ifferentiation' trigger of com%ensatory %roliferation&
#a.or $ifference et(een #D+ an$ A#L' high rate of a%o%tosis myelo$ys%lastic cells
+tri)ing %ara$o-' Clinically one marro( failure syn$rome, $es%ite many of the hallmar)s of a classical neo%lasm
(clonality, hy%ercellularity, %rogression to more a$,ance$ stages, etc)&
4
Myelodysplasia
Diverse group of myeloid neoplasms
Characterise$ y'
/rigin in somatically mutate$ multi%otent haemo%oietic stem cell
Ineffecti,e haemo%oiesis resulting in cyto%enias (ith
normocellular * hy%ercellular marro( ' late %recursor a%o%tosis
Clonal %rogression to A#L
5
6
Case 1

Male / 46

Mild icterus

Hb !"6

#C 32$$

%C &!$$$

MCV 112
'
LDH: 3800 LDH: 3800
Clinical Details, Trial of Haematinics Clinical Details, Trial of Haematinics
!
&
%resentations
!ary1
In$olent 2 mil$ to mo$erate anaemia
#ulti-cyto%enias
Leu)aemia 2 Blasts 3 456
1$
Clinical (eatures

Asym%tomatic

#il$ anaemia * neutro%enia * thromocyto%enia

Loss of sense of (ell eing

Pallor

Dys%nea on e-ertion

7asy ruising * slo( healing

H+megaly

Hy%othalamic malfunction, +(eet syn$rome, Inflammatory

syn$romes
11
12
13
Stem Cell Division
Stem Cell Division
Differentiation:
Progenitors of each cell
lineage
Differentiation:
Progenitors of each cell
lineage
Maturation
Maturation
Multiplication
Mitotic Division
Multiplication
Mitotic Division
Self ene!al to
Maintain the Stem Cell
Pool
Self ene!al to
Maintain the Stem Cell
Pool
"unction
"unction
Cell Death
Cell Death
14
15
1997 IPSS/IMRAW (FAB) 816 pts/ 7 DBs
Marrow blasts,
cyto!"!t#cs,
cytop!"#as
$%%1 W&' class#(#cat#o"
Dysplast#c
s)bro)ps, RA*B+
1,$, ,!l(-.)
$%%7 WPSS 116- pts/ / DBs
W&' s)bro)ps,
IPSS cyto!"!t#cs,
RB0 12"s
$%%1+$%11
3!w (!at)r!s
,!scr#b!, as
poss#bl! a,,#t#o"al
pro"ost#c (actors
$9%% pts/ 4 DBs
3!w (!at)r!s
,!scr#b!, as
poss#bl! a,,#t#o"al
pro"ost#c (actors
$%11
IW5 PM R!(#"!,
co"s!"s)s
syst!6 (IPSS+R)
7%1$ pts/ 18 DBs
M)S Classi*ications
+ew ,H- 2$$! Criteria
16
1'
1!
Minimal Diagnostic Criteria for efractor# C#tpenias of Chil$hoo$ Minimal Diagnostic Criteria for efractor# C#tpenias of Chil$hoo$
.%SS/0 beyond .%SS

A$$e$ refine$ cytogenetic sugrou%s (16 vs 7) 8

%rognostic categories (5 vs 3)

Analy9e$ $e%th of cyto%enias

Im%ro,e$ %re$icti,e %o(er (*more %recise %rognostic

sugrou%s (5 vs 4)

Clear im%act of age an$ a$$itional %re$icti,e features

for sur,i,al 2 P+, ferritin, LDH
1&
2$
(reedom *rom 1ML #rans*ormation
.%SS
.%SS/0
Mont2s
Mont2s
+3'$12
21
Sur4i4al
Mont2s
Mont2s
+3'$12
.%SS
.%SS/0
22
#2e Molecular Li*e Cycle o* M)S in
Stepwise Multi/2it #2eory
23
%at2o5enesis
Hypercellular bone marrow and peripheral blood cytopenias

Primary or ac:uire$ DNA $amage to haemo%oietic %recursor cell

lea$s to myelo$ys%lastic clone

Immune $amage an$ increase$ a%o%tosis lea$s to $amage of

oththe clonal an$ normal haemato%oietic cells

(e-%an$e$ ;-cell %o%ulation 2 (hich can sometimes result in ;-cell

L<L leu)aemia)&
24
25
6pi5enetics""
Stable7 lon5/term re5ulation o* 5ene e8pression
t2at is unrelated to 4ariation in t2e )+1 codin5
se9uence and t2at can sur4i4e across numerous
rounds o* cell di4ision"
26
D%& meth#lation, Post' translational histone tail mo$ifications, Micro'%& e(pression D%& meth#lation, Post' translational histone tail mo$ifications, Micro'%& e(pression
2'
)+1 Met2ylation )+1 Met2ylation
Cytosine Hypomet2ylation Cytosine Hypomet2ylation
%ost #ranslational Modi*ications %ost #ranslational Modi*ications
#2e myelodysplastic syndrome as a
prototypical epi5enetic disease""
M)S is a disease o* disordered di**erentiation
)i**erentiation is an epi5enetic process
M)S cells carry an abnormal epi5enome
M)S s2ows *re9uent epi5enetic e**ector mutations
M)S responds to epi5enetic t2erapy / 1:acitidine7 )ecitabine
-nco5ene acti4ation at t2e transition o* M)S to 1ML
2!
64idence o* Clonality
<=PD mosaicism
Cytogenetic stu$ies' stu$ies re,ealing clones (ith an$ (ithout
trisomy > in %atients (ith si$erolastic anemia
?FLPs of @-chromosome genes
FI+H
7,i$ence of clonality in lym%hoi$ lineages' the #D+ clone arises from
early %luri%otent stem cells ca%ale of myeloi$ an$ lym%hoi$
$ifferentiation&
Aaryoty%ic e,olution an$ com%le- )aryoty%ic changes (ith the
e,olution of many Besca%eC clones may occur (ith %rogression of
#D+ an$ transformation to A#L&
2&
3$
1 model o* M)S *ormation and pro5ression
%&S %&S
)pigenetic Mo$ifications )pigenetic Mo$ifications
%at2o5enesis
;hought to o,erla% (ith
PNH,
A%lastic anaemia
;-L<L leu)aemia
A%lastic anaemia 2 cytogenetic anormalities rare at $iagnosis&
2 D56 y D years an$ E46 $e,elo% #D+ y E4 years&
31
%redisposin5 (actors ;
6pidemiolo5ic 1ssociations
Heritable predisposition
Constitutional genetic $isor$er' Do(n +yn$rome, ;risomy >, Familial monosomy F,
Neurofiromatosis E
<erm cell tumours (emryonal $ysgenesis)
Congenital neutro%enia (Aostmann or +h(achman-Diamon$ +yn$rome)
DNA re%air $eficiencies ' Fanconi anemia, Ata-ia telangiectasia, Bloom syn$rome, @ero$erma
%igmentosum
Mutagen detoxification !"# $%&null'
Ac$uired
"enescence

Mutagen exposure
<enoto-ic thera%y' Al)ylators, ;o%oisomerase II inhiitors, %hos%horus-D4, Autologous B#;
7n,ironmental or occu%ational e-%osure (egG en9ene)
;oacco
Aplastic anemia( )*H( M)*
32
6pidemiolo5y
#e$ian age =H
Age I5 yrs ' 5&4*E55,555
Age >J yrs ' IJ*E55,555
#ale ' Female '' E&J'E
Kounger a$ults ' "sually %rece$e$ y chemo?- * irra$iation
Chil$ren '
J to EJ yrs ' 5&E*E55,555
#ore a$,ance$ ty%e
Pre$is%osing inherite$ con$ition ' e&g& Fanconi anaemia
33
Laboratory
(eatures
Anaemia '
#acrocytic
Anisocytosis
Anisochromia
Baso%hilic +ti%%ling
n?BC - rare
34
Laboratory
(eatures
Neutro%enia
Pseu$o Pelger-Huet
Hy%ogranularity
#onocytosis
;hromocyto%enia
;hromocytosis 35
36
3'
)ia5nosis
History
Prior e-%osure to chemo* ra$iation
FH of A#L* #D+
Infections, lee$ing, ruising
CBC an$ %eri%heral loo$ film
+&Ferritin, BE4, folate
3!
)ia5nosis
+M Aspirate '
BM study: Not always indicated if not going to change treatment
At least 455 marro( cells an$ 45 mega)aryocytes
shoul$ e e-amine$
Dys%lastic features in at least E56
Pseu$o-%elger neutro%hils, ring si$erolasts,
micromega)aryocytes an$ lasts correlate strongly (ith clonality
Neutro%hil granularity ' ,ariations in stain :uality
3&
4$
)ia5nosis
+M #rephine biopsy
+houl$ e $one if B# in$icate$
ALIPs are %rognostic
Allo(s assessment of cellularity
+M ,ytogenetics
Confirms clonalilty
Prognostic im%lications
41
42
))
7-clu$e
#egalolastic
HI!
Alcohol
?ecent cytoto-ic ?-
+e,ere intercurrent illness
43
M)S / M%) .nternational %ro5nostic Scorin5 System
44
45
Cytogenetic prognostic
subgroups
Cytogenetic abnormalities
Very good -Y, del(11q)
Good Normal, del(5q), del(12p), del(2q), double including del(5q)
!ntermediate
del("q), #$, #1%, i(1"q), any ot&er single or double
independent clones
'oor
-", in(())*t()q)*del()q), double including -"*del("q),
Comple+, ) abnormalities
Very poor Comple+, -) abnormalities
*PSS' C#togenetic ris+ groups *PSS' C#togenetic ris+ groups
46
Pro"ost#c
7ar#abl!
% %8- 1 18- $ / 4
0yto!"!t#cs
9!ry
5oo,
5oo,
I"t!r6!
,#at!
Poor
9!ry
Poor
BM Blast : ;<$ =$+;-: -+1%: =1%:
&!6olob#" =<1% 8+;1% ;8
Plat!l!ts =<1%% -%+;1%% ;-%
A30 =<%88 ;%88
*PSS' Prognostic Score ,alues *PSS' Prognostic Score ,alues
4'
.!/0 C123G4.Y .!/0 /C4.3
Very 5o6 78195
5o6 -195 - )
!ntermediate -) - :95
;ig& -:95 - <
Very ;ig& -<
*PSS' Prognostic is+ Categories-Scores *PSS' Prognostic is+ Categories-Scores
4!
M)S 4/s S11
4&
MDS SAA
&a!6opo#!t#c I">#b#tors *arly sta!s
Pro!"#tor 0!lls I" low+r#s? ro)ps Mar?!,
Marrow c!lls Apoptos#s I" low+r#s? ro)ps Mar?!,
1!lo6!r! S>ort"#" Pr!s!"t Mar?!,
0lo"al &a!6opo#!s#s @!s Rar! (*2c!pt P3&)
5 a", 5M 0SF Pro,)ct#o"
Hypocellular M)S 4s" 11
Hy%ocellular #D+ res%on$s etter to immuno-su%ressi,e
thera%y than normocellular #D+
Erythroid dyslasia is found in !! and cannot "e used to
distinguish
!"normal #aryotye favours M$% "ut not 1&&'
5$
Speci*ic Syndromes
Clonal +i$erolastic Anaemia
Clonal Non-+i$erolastic Anaemia
Clonal #ulticyto%enia (ith Hy%ercellular #arro(
;he J:- +yn$rome
#onosomy F Associate$ +yn$romes
/ligolastic #yeloi$ Leu)emias
;hera%y relate$ #D+
51
52
59/ Syndrome
FL#
+e,ere anaemia, erythrolasto%enia
;hromocytosis
;y%ical $ysmega)aryo%oiesis
Fa,ourale outcome
Progression to A#L is rare (E56)
Pre,iously iron o,erloa$ (as a ma.or %rolem
53
59/ Syndrome
Lenali$omi$e results in transfusion in$e%en$ence in 4*D,
an$ in 4*D res%onses %ersist after 4 years
Com%lete %athological an$ cytogenetic res%onses may also
e achie,e$
<ra$e D or I neutro%enia an$ thromocyto%enia
Preliminary results suggest Lenali$omi$e also acti,e in
J:- (ith other cytogenetic anormalities or LJ6 lasts
54
0ibosomopat2ies
6tiolo5y in 59/
Distinct mutations in the
riosome iogenesis
%ath(ay
Ha%loinsufficiency of
riosomal %roteins
(?Ps)
?e$uce$ m?NA
translation
55
0ibosomopat2ies
6tiolo5y in 59
Merafish mo$els $emonstrate the
relationshi% et(een
ha%loinsufficiency of r%sEI an$
%rofoun$ anaemia&
;reatment (ith m?NA translation
acti,ator L-Leucine amino aci$
results in mar)e$ im%ro,ement of
anaemia&
56
Lenalinomide
Immunomo$ulatory $rug
+u%%ression of %ro-inflammatory cyto)ine %ro$uction
7nhancement of ; an$ NA cell acti,ation
Anti-angiogenic an$ anti-;NF %ro%erties
Non-teratogenic in animal mo$els, ut %regnancy still
contrain$icate$
DoesnNt lea$ to %eri%heral neuro%athy
5'
Lenalinomide
Lan$mar) %a%er y List et al
Lenali$omi$e ga,e an erythroi$ res%onse in J56 of transfusion
$e%en$ant lo( ris) #D+
>D6 in %atients (ith$elJ:
Large %hase II trialof Lenali$omi$e an$ J:-
=F6 achie,e$ transfusion in$e%en$ence
#e$ian time to in$e%en$ence I (ee)s
Com%lete cytogenetic res%onse in IJ6
<ra$e D or I myelosu%ression in aout J56, ten$e$ to im%ro,e
after =-> (ee)s
+tu$ies comining Lenali$omi$e an$ other $rugs (es% 7P/) in lo(
ris) #D+ (ith anaemia are in %rogress
5!
Monosomy ' associated
syndromes
Common cytogenetic anormality in #D+
Post Chemo * ?a$iation
Commonly transforme$ to A#L
In chil$ren' Aty%ical myelo%roliferations
5&
Case 2
I4 * F
/%erate$ case of Ca Breast Dyears ago
?ecei,e$ treatment (ith Do-oruicin (;o%oisomerase II inhiitor)
No( %resents (ith

H =&H

;C IE55 ANC E455

PC EE5555

No organomegaly

LDH D45
6$
61
#2erapy related M)S
t-#N a%%ro-imately E5 to 45 %ercent of all cases of A#L,
#D+, an$ #D+*#PN&
Inci$ence ,aries accor$ing to the un$erlying $isease, s%ecific
agents, timing of e-%osure, an$ $ose&
#e$ian age at $iagnosis' =5 years&
OO heritale %re$is%osition in some %atients&
62
M)S and < #2alassemia
1#M)S
63
Ac:uire$ Al%ha thalassemia is the est
characteri9e$ of the ac:uire$ re$ loo$ cell
$isor$ers in %atients (ith hematologic
malignancy
Almost al(ays associate$ (ith a myelo$ys%lastic
syn$rome&
#olecular mechanisms'
Ac:uire$ $eletion of the al%ha-gloin gene cluster
limite$ to the neo%lastic clone
Inacti,ating somatic mutations of the trans-acting
chromatin-associate$ factorA;?@, (hich cause
$ramatic $o(n- regulation of al%ha-gloin gene
e-%ression
64
Sur4i4al
08
#reatment decisions on t2e
basis o* .%SS
"upportive care
.ither for patients with good prognosis or poor prognosis when age or
comorbidity prevent other treatments
Anaemia
"% to >56 ha,e HB PE5 at $iagnosis
;ransfusion an$ iron chelation
Chelation once recei,e$ Jg iron (4J transfusions) an$ li)ely to nee$ long term
transfusion su%%ort
Au$iometry an$ o%hthalmology efore $esferrio-amine an$ annually
;arget ferritin P E555
Desferrio-amine at time of transfusion has no asis
/ral iron chelators no( a %ossiility
65
#reatment decisions on t2e
basis o* .%SS
.po /0& !,"1
?A or ?A7B, sym%tomatic of anaemia, (ith no* lo( transfusion re:uirement
(P4*month) an$ a asal e%o of P 455 e consi$ere$ for a trial of 7%o at
E5,555 $aily for = (ee)s
Non-res%on$ers, a$$ <C+F or $oule $ose of 7%o
<C+F escalate$ (ee)ly FJ-EJ5-D55 to maintain ($ et(een =-E5
?A?+, sym%tomatic anaemia an$ asal e%o PJ55, transfusion P4*month
Comine$ 7%o an$ <C+F from outset
66
#reatment decisions on t2e
basis o* .%SS
2mmunosuppression
AL<* CsA
Hy%o%lastic #D+ an$ PNH
;hromocyto%enia
Platelet su%%ort
Antifirinolytics
QInfection
QPro%hyla-is
QNo e,i$ence for %ro%hyla-is
QConsi$er <C+F to )ee% neutro%hil LE
6'
+on/intensi4e C2emot2erapy
,MM3
Hy$ro-yurea is %referre$ to oral 7to%osi$e
J-A9acyti$inean$ Decitaine sho(%romise
4F6 (ith ?A an$ ?A?+ achie,e$ a C? or P? (ith IN;-E #D+ (ith A9a
EI6 (ith Decitaine
#ulti%le courses are re:uire$ (ith a me$ian time to re%onse of 4-I months
Duration of res%onse generally PE year
Preliminary analysis of a large trial (L455) (ith non J:-, lo( IP++ #D+ treate$
(ith Lenali$omi$e re%orte$ transfusion in$e%en$ance in 4J6
In ol$er %atients, unsuitale for trans%lant J-a9a an$ $ecitaine can e
consi$ere$
Ne(er agents such as Clofaraine ha,e sho(n %romise
6!
.ntensi4e C2emot2erapy or SC#

Long term 7F+ in D4-JI6 in those eligile

Im%ro,e$ outcome

Kounger age

+horter $isease $uration

HLA com%atiility

Primary #D+

PE56 lasts

<oo$ ris) cytogenetics

6&
.ntensi4e C2emot2erapy or SC#
IP++ lo(
Not recommen$e$ as me$ian sur,i,al (ithout treatment is
J an$ E4 years (L=5 an$ P=5 years)
IP++ Int E
P=J years
Assesse$ for +C; A+AP
PJ5 years an$ siling $onor, alati,e +C;
J5-=J, non-alati,e
Intensi,e cytore$ucti,e thera%y %rior to +C; is not recommen$e$
'$
.ntensi4e C2emot2erapy or SC#
IP++ Int 4* high
Chemothera%y %lus +C;
+C; only for those (ho res%on$ to remission in$uction
chemothera%y
/utcome for non-res%on$ers ,ery %oor
For those (ithout a siling or matche$ $onor, consi$er auto
Chemothera%y alone
L=Jor younger ut not eligile, consi$er intensi,e chemo alone
#ost ha,e 4 courses
'1
Case 3
M / 62
%resented wit2 malaise
-/6 %allor7 Mild splenome5aly
+o lymp2adenopat2y
Hb !"17 #C 2!$$7 1+C '$$7 %C 62$$$
=one marrow study =lasts $4>" (eatures o* dysplasia present in all
t2ree cell linea5es" +o rin5ed sideroblasts seen"
)ia5nosis on =M 0CM)
Cyto5enetics Comple8 ?aryotype
'2
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