1. MDS: Classification and Advances
in Therapy
BTG2013
S. Varma
PGIMER, Chandigarh
India

2. MDS
• Highly heterogeneous group of disorders
▫ Variable natural history
▫ Variable mortality rate
▫ Variable response to therapy
• Commonest cause of death
▫ Progressive bone marrow failure
▫ Conversion to AML

3. Age-related Incidence of MDS
McNally RJQ et al. Hematological Oncology 1997. 15:173-189
Males
Females
0 10 20 30 40 50 60 70 80
0.01
0.1
1
10
100
Rate
Disease of elderly
Age, years

5. Historical Perspective
• Pseudo-aplastic anemia
• Refractory Anemia
• Pre-leukemia
• Myelodysplastic syndrome
Luzzatto AM. anemia pseudoaplastica Riv Ven 1907;47:193.
Bomford RR, Rhodes CP. Refractory anemia. Q J Med 1941;10:175-281.

6. MDS: FAB Classification 1982
FAB
subtype
Blast % RS% Monocyte
s >1x109/l
Survival
(months)
PB BM
RA <1 <5 <15 - 50
RARS <1 <5 >15 - 75
RAEB <5 5-20 variable - 11
CMML <5 <20 variable + 11
RAEB-T >5;
Auer rods
20-30;
Auer rods
variable +/- 5

7. MDS: Limitations of FAB Classification
• Multilineage cytopenia with <5% BM blasts
• Rough prediction of prognosis
• Cytogenetics not given importance
• Ill defined entities: childhood MDS, T-MDS &
other secondary MDS
• Immunophenotyping and genetic techniques not
included

8. Comparison of MDS Classifications
FAB
classification
WHO Classsification
2001
WHO Classification 2008
RA RA Refractory cytopenia with unilineage dyplasia
• Refractory anemia
• Refractory neutropenia
• Refractory thrombocytopenia
RARS RARS Refractory anemia with ring sideroblasts (RARS)
RCMD RCMD
RCMD-RS RCMD-RS
RAEB RAEB I and 2 RAEB I and 2
RAEB-T RAEB II/ AML RAEB II/ AML
CMML MDS-UC MDS-UC
MDS associated with
isolated del(5q)
MDS associated with isolated del(5q)
Childhood myelodysplastic syndrome
• Refractory cytopenia of childhood

9. WHO 2008
Bone MarrowBloodSubtype
Dysplasia: ≥10% cellsSingle cell line
Mostly erythroid
RCUD
Erythroid dysplasia
>15% ringed sideroblasts
AnemiaRARS
>10%Dysplasia: ≥2 cell lineage
<5%blasts
Bi/pancytopeniaRCMD
Uni-multi lineage dysplasia
5-9% blasts, No Auer rods
Cytopenia
<5% blast
RAEB-1
Uni-multi lineage dysplasia
10-19% blasts or Auer rods
Cytopenia, 5-19% blasts or
Auer rods
RAEB-2
Uni / multilineage/ no dysplasia
Characteristic MDS CG +
CytopeniaMDS-U
Unilineage erythroid dysplasia,
isolated del 5q, <5%blast
Anemia,
normal or ↑Platelets
MDS with 5q

10. Cazzola M. Hemaologica 2011
Outcomes in MDS in Different WHO Subtypes

11. Improved prognostic scores
Disease related variables
Host factors
Appropriate clinical decision
Disease eradication/ control
Prolonging overall survival
Managing complications of disease and therapy
Improving quality of life

12. Prognostic
scores Most widely used
There are
benefits
and
limitations
of all these
scores

13. IPSS: Prognostic Variables
0 0.5 1.0 1.5 2.0
Marrow blasts % <5 5-10 — 11-20 21-30
Karyotype Good Intermediate Poor
Cytopenias 0/1 2/3 - - -
Overall score is the sum of the scores for following parameters:
BM blasts %: score 0 =< 5%; 0.5=5-10%; 1.5=11-19%; 2.0=20-30%.
Cytopenias: score 0 = no/ one cytopenia; 0.5 = 2 or 3 cytopenias.
Cytogenetics: score 0 (good)= Normal karyotype, -Y, 5q- or 20q-;
score 1.0 (poor)= 7q- or -7, complex translocations;
score 0.5 (intermediate)= all others.
Risk group Overall score Median survival (years)
Low 0 5.7
Intermediate 1 0.5 or 1.0 3.5
Intermediate 2 1.5 or 2.0 1.2
Poor >/= 2.5 0.4
Greenberg P et al. Blood 1997;89:2079-2088.

14. Prediction of survival by IPSS

15. IPSS
Pros
• Simplicity:
▫ Use of only 3 variables
• Applicable at centers
with limited lab support
• Widely used in clinical
practice and research
▫ Bulk of scientific data
on MDS is based of
IPSS
Cons
• Includes patients with
▫ 20-30% blasts
▫ CMML
• Does not consider
severity of cytopenias
▫ Strong predictor of
outcome
• Can not be applied in
pre-treated patients

16. WHO Prognostic Scoring System
*BM fibrosis grade 2-3 shifts risk group by one step

17. WPSS
Pros
• Simplicity: use of only 3
variables
• Accurate prediction of
survival and risk of leukemic
evolution at any time
during the course of their
disease
• Useful in predicting post
transplant outcome
Cons
• Not applicable for
secondary MDS

18. Comparison of IPSS and WPSS (258 MDS Patients)

19. MDACC Prognostic Scoring System (MPSS)
Variable Score 1 Score 2 Score 3
Performance Status ≥ 2
Age in years 60-64 ≥ 65
Platelets x 109/L 50-199 30-49 <30
Hemoglobin gm% <12
Bone marrow blasts 5-10 11-29
WBC x 109/L >20
Karyotyping Chromosome 7 abnormality
Complex karyotype (>2 abn)
Prior transfusion Yes
MPSS risk group Score
Low 0-4
Intermediate 1 5-6
Intermediate 2 7-8
High ≥9
Kantarjian et al
Cancer 2008

20. 2012 Revised IPSS
Schanz J, et al. J Clin Oncol. 2012;30:820-829. Greenberg PL, et al. Blood. 2012;120:2454-2465.
Prognostic
Subgroup
Cytogenetic Abnormality Median OS,
Mos
Median
Time to
AML, Mos
Very good del(11q), -Y 60.8 NR
Good Normal, del(20q), del(5q) alone or double, del(12p) 48.6 NR
Intermediate
+8, del(7q), i(17q), +19, any other single or double,
independent clones
26.0 78.0
Poor
inv(3)/t(3q)/del(eq), -7, double including del(7q),
complex (3)
15.8 21.0
Very poor complex (≥ 3) 5.9 8.2
Fine tune the prognostic impact of
•Cytogenetic abnormalities
•Depth of cytopenia

21. IPSS-R
Risk Category Risk Score
Very low ≤ 1.5
Low >1.5 - 3
Intermediate >3 – 4.5
High >4.5 - 6
Very High >6
Variable 0 0.5 1 1.5 2 3 4
Cytogenetics V. good - Good - Int Poor V. poor
BM blast% ≤2 - >2 - <5 - 5-10 >10 -
Hgb ≥10 - 8-<10 <8 - - -
Platelets ≥100 50-100 <50 - - - -
ANC ≥0.8 <0.8 - - - - -

23. Treatment considerations
• Myelodysplasia are incurable without HSCT
• Highly variable natural history
• Treatment considerations must take into account
many factors, including the
▫ Pathologic diagnosis
▫ The prognosis based on the IPSS or WPSS
▫ Cell line /s affected
▫ Feasibility of performing a clinical trial

24. Tools to treat MDS
• Observation
• Supportive therapy (Transfusions)
• Hematopoietic growth factors
• Iron chelation
• Lenalidomide (Revlimid 2005)
• Hypomethylating agents
▫ Azacitidine (Vidaza 2004)
▫ Decitabine (Dacogen 2006)
• Immunosuppression
• Allogeneic stem cell transplantation
• Newer agents

25. To Trick or Treat
• Treatment should be reserved and potentially diagnosis to be
transmitted to the patient and family, only if there are
symptoms resulting from anemia or other cytopenias or
perhaps pre-symptomatic anemia or severe
thrombocytopenia.
• Old and frail patients or those who have equivocal diagnostic
features, benefit from a period of observation.
• Neutropenia without infection is a poor justification for
initiation of therapy.
Stone RM. Blood 2009

26. Role of Growth Factors
GCSF Support improves ANC (75% patients)
Has no impact on overall survival.
Not recommended for routine infection prophylaxis
Thrombopoietic
agents
Most have no significant impact on transfusion needs:
Main utility
–Fewer dose modifications of disease modifying agents
–Romiplostim: 500/750mcg weekly
–Eltrombopag: under study
Erythropoiesis
stimulating agents
(ESA)
–First line therapy for IPSS low or Int-1 risk MDS with
EPO <500U/L (NCCN guidelines)
–Response rates; 20-30%, ?OS/PFS/ QOL, durability:2
years
–Epoeitin alpha: 60,000-80,000 U once per week
–Darbopoietin alpha: 500mcg once 3 weekly
Most widely prescribed class of medications for MDS (55%)

27. Immunologic suppression of normal BM
function, similar to the situation in aplastic
anemia, has been postulated to account for
cytopenias in some MDS patients
Specific candidates- Refractory anemia with
relatively hypoplastic marrow

28. Predictor of Response to
Immunosuppressant
• HLA-DR-15-positivity
• RA (<5% blasts)
• IPSS Low/Int-1
• Age <60 years
• Brief transfusion history
• Trisomy 8 abnormality
• Normal cytogenetics
• Marrow cellularity <30%

29. ATG
• Phase II study (N=35) on MDS-RA
• Both equine and rabbit ATG were found to be active
• Response to
▫ Equine ATG: 29% (34/115)
▫ Rabbit ATG: RR 42%.
▫ 75% responders durable response (median 31.5
months).
Jonasova A, Br J Haematol. 1998;100:304-309.
Molldrem JJ, Br J Haematol. 1997;99:699-705.
Stadler M, Leukemia 2004;18:460-5

30. Chromosomal Abnormality: del13q
Only del (13 q ) Del (13q) plus other
abnormalities
number 16 6
GPI def clone 16 3
Response to IST 100% (14/14) 40% (2/5)
10 yr OSR 83% 63%
Progression to AML None 2
22 patients with bone marrow failure
MDS U
•MDS-U with del (13q) is a benign disorder with good response to IST
•Del (13q) should not be considered intermediate risk abnormality
Hosokawa et al, Haematologica 2012;97:1845

31. Biological response modifiers
special case of Del 5q syndrome
Eligibility:
•del(5q)
•IPSS low or Int-1
•platelets > 50K/mm3
•neutrophils > 500/mm3
•transfusion dependent

32. Study Design
Dose Reduction
5 mg qd
5 mg qod
Week: 0 4 8 12 16 20 24
Eligible
Patients
R
e
g
i
s
t
e
r
R
e
s
p
o
n
s
e
10 mg po x 21
NO Off study
YES Continue

33. Results
Frequency of Cytogenetic Response According to Karyotype Complexity

34. Len in non del(5q) MDS
• Can be considered for low risk, adequate ANC and platelet
counts
• Expected response rates are similar to other treatment
alternatives
• Use in high risk MDS remains investigational
Raza et al. Blood 2008“Revlimid restores erythropoietic activity to the
MDS clone”

36. Hypomethylating agents
•
• Azacytidine and decitabine
are potent DNMT inhibitors
• This leads to
hypomethylation of CpG
dinucleotides in gene
promoters and reactivation
of previously silent genes
• Cytotoxic activity similar to
cytarabine

37. 5 Azacytidine
• AZA001: Euro study despite
CALGB 9221
• Primary endpoint: survival
AZA Controls
Median survival 24.5 months 15 months
Progression to AML 27 months 13 months
Transfusion independence 45% 11%
Fennaux et al. Lancet Oncol 2009

38. Decitabine
DAC Controls
Overall survival 10 months 8.5 months
Progression to AML at 1 yr 22% 33%
CR/ PR/ HI 13/6/5% 0/0/2%
Lubbert et al . JCO 2011

39. Hypomethylating agents
When to start
– Int/ high risk MDS (IPSS)
– Transfusion dependent/ EPO
failure
– Not yet known if early
treatment is better than late
treatment in MDS
Which drug
– NCCN recommends Azacitidine
preference over Decitabine
– EORTC study failed to show
survival benefit.
– MDACC regimen (5 day
20mg/m2/d) highest CR
– Aza vs Decitabine head to head
trial results awaited
Optimal dose, schedule, route
– Azacitidine:
– 7 day 75mg/m2/d sc q 28 days (5-
2-2 or 50mg/m2 5-2-5 schedule)
– Decitabine:
– 3 day 15mg/m2/dose IV 8 hrly
(total dose 135mg/m2) inpatient
– 5 day 20mg/m2 /d over 1 hr (total
dose 100mg/m2) outpatient
Duration
– Optimal duration- not known
– To treat responding pts till disease
progression, as long as tolerated
– At least 4 cycles recommended for
adequate response
Steensma et al. Hematol Oncol clin N Am 2010

40. Predictive Factors for Achieving Response
to Hypomethylating Agents
Positive
• Mol/ Cyto:
▫ Mutated TET2
▫ Mutated EZH2
▫ Phosphoinositase –
Phospholipase C beta 1
hypomethylation
• Clinical Variable
▫ Doubling of Platelets
• Negative
• Mutated P 53
• Abnormal/ complex
karyotype
• BM Blasts >15%
• Previous therapy
• Transfusion dependency
• BM fibrosis grade 3
Santini V, ASH 2012

41. MDS
Low risk
(low or Int 1, BM blasts <10%)
Any age
Iron Chelation
Growth factors
DMT Inhibitors
Lenolidamide
Immunomodulation
Clinical trial
Progression/ failure
HSCT
High Risk
(Int 2, High risk, blasts>10%)
Age <60 Age≥60
Intensive chemo
DMTI
Clinical trial
DMTI
Clinical trial
Intensive Chemo
Failure
Attallah: Cancer Therap 2008;26:208-16
Failure

43. What’s on the Horizon?
• In the quest of effective therapy, currently there
are approximately 200 clinical trials are ongoing
and numerous agents are at various stages of
drug development
• The need for a novel agent is particularly noted
in patients failing hypomethylating agents who
are ineligible for stem cell transplant
Kulasekararaj AG, Semin Hematol ,2012; 49:350-60

44. Agent Action Current status
Erlotinib Oral TKI tageting EGFR Phase 2,
hypomethylating agent
failed MDS cases
ORR 15%
Stable disease 32%
Tosedostat Aminopeptidase
inhibitor
Phase 1/ 2,
ORR 28% in AML/MDS
patients >60 years
Ezatiostat Glutathione analogue Phase 2 , 40 % efficacy
in lenalidomide treated
MDS patients
Siltuximab Chimaric monoclonal
Ab neutralising IL6
Phase 2 for Anemia
related to MDS
Kulasekararaj AG, Semin Hematol ,2012; 49:350-60

45. Agent Action Current status
BMN673 PARP inhibiotrs Phase 1 , open label
trial for AML, MDS,
MCL, CLL
MLN4924 Small molecule
inhibitor of
Neddylation
activating enzyme
Phase 1, AML and
MDS
PF-04449913 Hedgehog pathway
inhibitor
Phase 1/ 2, for
myelofibrosis, AML,
MDS
SCIO496 MAP kinase inhibitors Phase 1/ 2 for low
and intermediate risk
MDS
Kulasekararaj AG, Semin Hematol ,2012; 49:350-60

46. Take Home Message
• Myelo-dysplastic syndromes are heterogeneous
disorders
• Prognostic scores are evolving with use of cyto-
genetics and molecular markers
• Treatment depends upon the prognostic and host
factors
• MTI and IMIDs are being increasingly used
• HSCT is the only curative treatment
• Treatment paradigms are evolving