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

2. MDS Highly heterogeneous group of disorders Commonest cause of death
Variable natural history
Variable mortality rate
Variable response to therapy
Commonest cause of death
Progressive bone marrow failure
Conversion to AML
Myelodysplastic syndromes are a group of heterogeneous disorders characterized by persistent cytopenias, hypercellular marrow and presence of dysplasia that results from increased proliferation as well as increased apoptosis

3. Age-related Incidence of MDS
0.01
0.1 1 10
100
Rate
Disease of elderly
Males
Females
This graph shows that it is a disease of the elderly. The outcomes are related not only to severity of the cytopenias and progression of the disease but also to the co-morbidities in the elderly
Age, years
McNally RJQ et al. Hematological Oncology :

4. Classification

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:

6. MDS: FAB Classification 1982
FAB subtype
Blast %
RS%
Monocytes >1x109/l
Survival (months) PB BM RA
<1
<5
<15 - 50
RARS
>15 75
RAEB
5-20
variable 11
CMML
<20 +
RAEB-T
>5;
Auer rods
20-30;
+/- 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
Refractory cytopenia with unilineage dyplasia
Refractory anemia
Refractory neutropenia
Refractory thrombocytopenia
RARS
Refractory anemia with ring sideroblasts (RARS)
RCMD
RCMD-RS
RAEB
RAEB I and 2
RAEB-T
RAEB II/ AML
CMML
MDS-UC
MDS associated with isolated del(5q)
Childhood myelodysplastic syndrome
Refractory cytopenia of childhood

9. WHO 2008 Bone Marrow Blood Subtype Dysplasia: ≥10% cells
Single cell line
Mostly erythroid
RCUD
Erythroid dysplasia
>15% ringed sideroblasts
Anemia
RARS
>10%Dysplasia: ≥2 cell lineage
<5%blasts
Bi/pancytopenia
RCMD
Uni-multi lineage dysplasia
5-9% blasts, No Auer rods
Cytopenia
<5% blast
RAEB-1
10-19% blasts or Auer rods
Cytopenia, 5-19% blasts or Auer rods
RAEB-2
Uni / multilineage/ no dysplasia
Characteristic MDS CG +
MDS-U
Unilineage erythroid dysplasia, isolated del 5q, <5%blast
Anemia,
normal or ↑Platelets
MDS with 5q
Shows the peripheral blood and bone marrow criteria for diagnosis of various subtypes of MDS that are dependent upon cytopenia, number of blasts, presence of dysplasia and cytogenetic abnormalities.

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

11. Advances in Management
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. There are benefits and limitations of all these scores
Prognostic scores
Most widely used
There are benefits and limitations of all these scores

13. IPSS: Prognostic Variables
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 -
Risk group
Overall score
Median survival (years)
Low
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
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.
Greenberg P et al. Blood 1997;89:

14. Prediction of survival by IPSS

15. IPSS Pros Cons 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 Cons 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
Intermediate
Intermediate
High ≥9
Kantarjian et al
Cancer 2008

20. 2012 Revised IPSS Fine tune the prognostic impact of
Cytogenetic abnormalities
Depth of cytopenia
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
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
AML, acute myeloid leukemia; IPSS, International Prognostic Scoring System; IPSS-R, revised IPSS; MDS, myelodysplastic syndromes; NR, not reached; OS, overall survival.
Schanz J, et al. J Clin Oncol. 2012;30: Greenberg PL, et al. Blood. 2012;120:

21. IPSS-R Variable 0.5 1 1.5 2 3 4 Cytogenetics V. good - Good Int Poor
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
Risk Category
Risk Score
Very low
≤ 1.5
Low
>
Intermediate
>3 – 4.5
High
>
Very High
>6

22. Advances in therapy of MDS

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
Most widely prescribed class of medications for MDS (55%)
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

27. Newer approaches- Immunosuppressants
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 months).
Stadler M, Leukemia 2004;18:460-5
Jonasova A, Br J Haematol. 1998;100:
Molldrem JJ, Br J Haematol. 1997;99:

30. Chromosomal Abnormality: del13q
22 patients with bone marrow failure
MDS U
Only del (13 q )
Del (13q) plus other abnormalities
number 16 6
GPI def clone 3
Response to IST
100% (14/14)
40% (2/5)
10 yr OSR
83%
63%
Progression to AML
None 2
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 Eligible Patients
Week:
Eligible
Patients
Register
Response
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
“Revlimid restores erythropoietic activity to the MDS clone”
Raza et al. Blood 2008

35. Hypomethylating agents

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
EORTC/GMDSSG 3 day schedule, inter cycle interval 6 weeks, cap of max 8 cycles
EORTC/GMDSSG
3 day schedule, inter cycle interval 6 weeks, cap of max 8 cycles
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 ( or 50mg/m 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 HSCT Low risk (low or Int 1, BM blasts <10%) High Risk
(Int 2, High risk, blasts>10%)
Any age
Age <60
Age≥60
Iron Chelation
Growth factors
DMT Inhibitors
Lenolidamide
Immunomodulation
Clinical trial
Intensive chemo
DMTI
Clinical trial
DMTI
Clinical trial
Intensive Chemo
Failure
Failure
Progression/ failure
HSCT
Attallah: Cancer Therap 2008;26:208-16

42. Unconventional and upcoming agents

43. Arsenic Trioxide* - Response by IWG Criteria
4 (16%)
8 (38%)
Total patients with response 4
Major
All lineages
Minor 1 31
Neutrophil
(<1.5 x 109/L) 2
HR Pts (n = 25) 3
LR Pts (n = 21) 36
Platelet
(<100x 109/L) 40
Erythroid
(Hgb <11 g/dL)
Response Type
Pts Deficient in Lineage at Baseline
Lineage Response
*Dose & Schedule: 0.25 mg/kg/d M-F x 2 q 4 weeks.
List AF, et al. Blood (11): 1539a.

44. 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

45. 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

46. 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
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

47. 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