1. RECENT ADVANCES IN MDS
DR. R. RAJKUMAR M.D. , D.M
CONSULTANT MEDICAL ONCOLOGIST
GURU HOSPITAL

2. AGENDA
 New biological developments
 Risk assessment and prognostic
factors
 New therapeutic options

3. MYELODYSPLASTIC SYNDROMES
 A group of malignant hematopoietic disorders
characterized by[1]
– Bone marrow failure with resultant cytopenia
and related complications
– Macrocytic anemia is most common presentation
– Dysplastic cytologic morphology is the hallmark of
the disease
– Tendency to progress to AML
 Overall incidence 3.7-4.8/100,000[2]
– ≈ 10,000/yr in United States (true estimates ≈ 37,000-48,000)
– Median age: 70 yrs; incidence: 34-47/100,000 > 75 yrs[3]
1. Bennett J, et al. The myelodysplastic syndromes. In: Abeloff MD, et al, editors. Clinical oncology. New York
NY: Churchill Livingstone; 2004. pp. 2849-2881. 2. SEER data 2000-2009. 3. SEER 18 Data. 2000-2009.

4. MDS EPIDEMIOLOGY
 Overall incidence: 4.4 per 100,000
49.8
50
Overall
40
Males
Females
27.1
30
20
9.2
10
0.2
0
0.8
< 40
40-49
2.5
50-59
60-69
Age at Diagnosis (Yrs)
70-79
≥ 80
SEER Cancer Statistics Review 1975-2008. Section 30, myelodysplastic syndromes (MDS), chronic
myeloproliferative disorders (CMD), and chronic myelomonocytic leukemia (CMML).

5. DIAGNOSIS OF MDS
 The most common presentation is cytopenia
 Diagnosis requires
– Peripheral blood examination
– Bone marrow aspirate and biopsy
– Cytogenetic studies
 The diagnosis requires demonstration of dysplastic
features in 1 or more cell line
Bennett J, et al. The myelodysplastic syndromes. In: Abeloff MD, et al, editors. Clinical oncology. New
York, NY: Churchill Livingstone; 2004. pp. 2849-2881.

6. WHO Revisions 2008: MDS Cytogenetic
Minimal Criteria
 Presence of refractory cytopenia without morphologic features and the
following cytogenetic abnormalities considered ―presumptive
evidence‖ of MDS
Unbalanced
Balanced
Other
-7 or del(7q)
t(11;16)(q23;p13.3)
-5 or del(5q)
t(3;21)(q26.2;q22.1)
i(17q) or t(17p)
t(1;3)(p36.3;q21.1)
Complex karyotype
(≥ 3 abnormalities
either balanced or
unbalanced)
-13 or del(13q)
del(11q)
del(12p) or t(12p)
del(9q)
t(2;11)(p21;q23)
inv(3)(q21q26.2)
t(6;9)(p23;q34)
idic(X)(q13)
Vardiman JW, et al. Blood. 2009;114:937-951.

7. IPSS Is Most Common Tool for Risk
Stratification of MDS
Score Value
Prognostic variable
0
0.5
1.0
1.5
2.0
Bone marrow blasts
< 5%
5% to 10%
--
11% to 20%
21% to 30%
Karyotype*
Good
Intermediate
Poor
--
--
Cytopenias†
0/1
2/3
--
--
--
Total Score
0
0.5
1.0
1.5
2.0
2.5
Risk
Low
Intermediate I
Intermediate II
High
Median survival, yrs
5.7
3.5
1.2
0.4
*Good = normal, -Y, del(5q), del(20q); intermediate = other karyotypic abnormalities; poor = complex
( 3 abnormalities) or chromosome 7 abnormalities.
†Hb < 10 g/dL; ANC < 1800/ L; platelets < 100,000/ L.
Greenberg P, et al. Blood. 1997;89:2079-2088.

11. Revised IPSS MDS Cytogenetic Scoring
System
Cytogenetic
Abnormalities
Median
Survival,*
Yrs
Median AML
Evolution,
25%,* Yrs
HR
OS/AML*
HR
OS/AML†
-Y, del(11q)
5.4
NR
0.7/0.4
0.5/0.5
Good
(72%*/66%†)
Normal, del(5q), del(12p),
del(20q), double including
del(5q)
4.8
9.4
1/1
1/1
Intermediate
(13%*/19%†)
del(7q), +8, +19, i(17q),
any other single or double
independent clones
2.7
2.5
1.5/1.8
1.6/2.2
Poor
(4%*/5%†)
-7, inv(3)/t(3q)/del(3q),
double including 7/del(7q),
complex: 3 abnormalities
1.5
1.7
2.3/2.3
2.6/3.4
Very poor
(7%*/7%†)
Complex: >3
abnormalities
0.7
0.7
3.8/3.6
4.2/4.9
Prognostic
Subgroups, %
Very good
(4%*/3%†)
*Data from patients in this IWG-PM database, multivariate analysis (n = 7012).
†Data from Schanz, et al (n = 2754).
Greenberg PL, et al. Blood. 2012;120:2454-2465.

12. Revised IPSS: Prognostic Score Values
and Risk Categories/Scores
Score Value
Prognostic
Variable
0
0.5
Cytogenetics
Very
good
--
BM blast, %
≤2
--
Hemoglobin, g/dL
≥ 10
--
≥ 100
50 to <
100
≥ 0.8
< 0.8
Platelets, x
109/L
1.0
Good
> 2 to < 5
8 to < 10
< 50
1.5
2.0
3.0
4.0
Intermediate
Poor
Very
poor
5-10
> 10
Risk
<8
___
___
Score
___
Very low
___
___
≤ ___
1.5
___
---
--
Greenberg PL, et al. Blood. 2012;120:2454-2465.
___
___
Intermediate
> ___ to 4.5
3.0 ___
> 4.5 to 6.0
Very high
--
> 1.5 to 3
High
ANC, x 109/L
Low
>6

13. Revised IPSS: Survival by Risk Category
Very low
Low
Intermediate
High
Very high
Proportion of Patients Alive
1.0
0.8
0.6
Median Survival,
years (95% CI)
0.4
8.8 (7.8-9.9)
0.2
5.3 (5.1-5.7)
0
3.0 (2.7-3.3)
1.6 (1.5-1.7)
0.8 (0.7-0.8)
0
2
4
Greenberg PL, et al. Blood. 2012;120:2454-2465.
6
8
10
12

15. Topic 2: Treatment Options for
Lower-Risk MDS

16. MDS-003: Lenalidomide in MDS With 5q
Deletion Study Design
Eligibility
 IPSS diagnosed
low/int 1 MDS
 del(5q31)
 ≥ 2 U RBC/8 wks
 Platelets > 50,000/µL
 ANC > 500/µL
Wk
R
E
G
I
S
T
E
R
0
R
E
S
P
O
N
S
E
Lenalidomide
10 mg/day PO
Lenalidomide
10 mg PO x 21 days
4
8
12
16
20
Yes
No
Continue
Off study
24

Primary endpoint: transfusion independence

Secondary endpoints: duration of TI, cytogenetic response, minor erythroid response,
pathologic response, safety
List AF, et al. N Engl J Med. 2006;355:1456-1465.

17. MDS-003: Response to Lenalidomide
Therapy
Response (%)
80
Erythroid Response
99/148
(67%)
112/148
(76%)
100
Cytogenetic Response
 Median Hb increase: 5.4 g/dL 62/85
80
 Time to response: 4.6 wks (73%)
 Duration of response: > 2 yrs
Response (%)
100
70
40
70
38/85
(45%)
40
20
20
0
0
TI
TI + Minor
List AF, et al. N Engl J Med. 2006;355:1456-1465.
CCR
CCR + PR

18. MDS-002: Phase II Study of Lenalidomide
in RBC-Dependent Non-del(5q) MDS
Eligibility
 IPSS diagnosed
low/int-1 MDS w/o
del(5q) abnormality
 ≥ 2 U RBC/8 wks
 Platelets > 50,000/µL
 ANC > 500/µL
Wk
R
E
G
I
S
T
E
R
0
R
E
S
P
O
N
S
E
Lenalidomide
10 mg/day PO
Lenalidomide
10 mg PO x 21 days
4
8
12
16
20

Primary endpoint: TI, Hb response

Secondary endpoints: cytogenetic response, safety
Raza A, et al. Blood. 2008;111:86-93.
24
Yes
No
Continue
Off study
Dose reduction
5 mg QD
5 mg QOD

19. MDS-002: Response to Lenalidomide
Therapy
Erythroid Response
Response (%)
Cytogenetic Response
 Median Hb increase: 3.2 g/dL
 Time to response: 4.8 wks
80
 Median duration of response:
41 wks
80
70
40
100
93/214
(43%)
56/214
(26%)
Response (%)
100
70
40
20
20
0
0
TI
TI + Minor
Raza A, et al. Blood. 2008;111:86-93.
4/47
(9%)
CCR
9/47
(19%)
CCR + PR

20. Azacitidine Treatment for Low- or
Intermediate 1–Risk MDS
 Pyrimidine nucleoside analogue of cytidine
 Approved for use in MDS of the following subtypes
– Refractory anemia or refractory anemia with ringed sideroblasts
(if accompanied by neutropenia or thrombocytopenia or requiring
transfusions)
– Refractory anemia with excess blasts
– Refractory anemia with excess blasts in transformation
– Chromic myelomonocytic leukemia
 Causes hypomethylation of DNA and direct cytotoxicity on
abnormal hematopoietic cells in the bone marrow

21. Randomized Phase II Study of Alternative
Azacitidine Dose Schedules
Study Design (N = 151)
5-2-2: 75 mg/m2
Eligibility
 All FAB
 Cytopenia
 ECOG PS: 0-3
(n = 50)
x6
5-2-5: 50 mg/m2
(n = 51)
5: 75 mg/m2
(n = 50)
Lyons RM, et al. J Clin Oncol. 2009;27:1850-1856.
IWG
2000 HI
12 Cycles
AZA x
5 days
q4-6 wks

22. Topic 3: Treatment Options for
High-Risk MDS

23. Treatment Algorithm 2013:
Intermediate 2–/High-Risk MDS
Favorable
SCT
Allogeneic
donor
Unfavorable
SCT
candidate
No donor
Azanucleosides
Investigational
Field T, et al. Mediterr J Hematol Infect Dis. 2010;2:e2010019. Adapted from NCCN. Clinical practice
guidelines in oncology. MDS. v.2.2013.

24. Approximate Life Expectancy After
Ablative Allogeneic Transplantation
Risk
Group, Yrs
Low
Int 1
Int 2
High
Transplantation at
Diagnosis
6.51
4.61
4.93
3.20
Transplantation at
Yr 2
6.86
4.74
3.21
2.75
Transplantation at
Progression
7.21
5.16
2.84
2.75
 Median age: 42 yrs
 Data precede all FDA-approved drugs for MDS
Cutler C, et al. Blood. 2004;104:579-585.

25. Pre-Transplantation Chemotherapy as a
Bridge to Transplantation

Retrospective data[1,2]
– No benefit from induction chemotherapy prior to transplantation
– No survival benefit from azacitidine over chemotherapy prior to transplantation
– Caveats: 1) data from 1990s, 2) retrospective, 3) poor description of
chemotherapies used
– Improved survival in those achieving CR before transplantation

Feasibility data[3-5]
– Feasible to give azacitidine or decitabine before transplantation
– Rapid donor cell engraftment

Prospective clinical trials needed
1. Nakai K, et al. Leukemia. 2005;19:396-401. 2. Damaj G, et al. J Clin Oncol. 2012;30:4533-4540.
3. De Padua Silva L, et al. Bone Marrow Transplant. 2009;43:839-843. 4. Cogle CR, et al. Clin Adv Hematol
Oncol. 2010;8:40-46. 5. Field T, et al. Bone Marrow Transplant. 2010;45:255-260.

26. AZA-001: Trial Design
Physician choice of 1 of 3 CCRs
1. BSC only
2. LDAC (20 mg/m2/day SC x
14 day q28-42 days)
3. 7 + 3 chemotherapy (induction +
1-2 consolidation cycles)
Stratified by
 FAB: RAEB, RAEB-T
 IPSS: int 2, high
Azacitidine + BSC
R
A
N
D
O
M
I
Z
E
(75 mg/m2/day x 7 days SC
q28 days)
CCR
Treatment continued until unacceptable toxicity or AML transformation or
disease progression
Fenaux P, et al. Lancet Oncol. 2009;10:223-232.
(n = 179)
(n = 179)

27. Proportion Surviving
AZA-001 Trial: Azacitidine Significantly
Improves OS
HR: 0.58 (95% CI: 0.43-0.77;
log-rank P = .0001)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
24.5 mos
15.0 mos
Azacitidine
CCR
0
5
10
15
20
25
30
Mos From Randomization
Fenaux P, et al. Lancet Oncol. 2009;10:223-232.
35
40

28. EORTC-06011 Decitabine Phase III Trial:
Study Design

Open-label, multicenter, 1:1 randomized study

IPSS: int-1, -2, and high-risk MDS; ≥ 60 yrs (n = 223)

Primary endpoint: survival
Stratification
 Cytogenics
risk group
 IPSS
 Primary vs
secondary
 Study center
R
A
N
D
O
M
I
Z
E
20 mg/m2/day IV
recommended in PI
Decitabine 15 mg/m2 IV x
4 hrs q8h x 3 days q6w
(max 8 cycles)
(n = 119)
Best Supportive Care
(n = 114)
Response assessment q2 cycles; HI, CR, PR, and SD continue for up to 8 cycles
Exception: CR—2 additional cycles.
Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996.

29. EORTC-06011: OS With Decitabine
Treatment
1.0
BSC
Decitabine
Log-rank test P = .38
OS (%)
80
60
40
20
0
0
Pts at Risk, n
BSC
Decitabine
6
12
18
Mos
24
30
71
83
38
53
22
24
10
15
6
4
Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996.
36

30. Salvage Therapy After Azacitidine Failure:
GFM and AZA001 Studies
Type of
Salvage
Investigational
OS (%)
25
0
0
165
NA
3.6
122
NA
4.1
Low-dose
chemotherapy
32
0/18
7.3
Intensive
chemotherapy
35
3/22
8.9*
44
4/36
13.2*†
Allogeneic
transplantation
50
Median
OS, Mos
Investigational
therapy
Allo-SCT
ORR
Best supportive
care
75
N
Unknown
100
37
13/19
19.5*†
365
730 1095 1460
Days Since AZA Failure
*Log-rank comparison of BSC vs intensive CT (P = .04), investigational therapy (P < .001), or alloSCT (P < .001).
†Comparison of intensive CT vs investigational therapy (P = .05), intensive CT vs ASCT (P = .008), or IT vs ASCT (P = .09).
Prébet T, et al. J Clin Oncol. 2011;29:3332-3327.

31. Selected Novel Agents Under Investigation
Agent
Patient Population
Response
Higher-risk MDS
(n = 58)
ORR: IV-15 41%; IV-30 29%
Median OS with response: 13.4 mos
Median OS: 7.4 mos
MDS, CMML, AML
(n = 41)
ORR (previous treated): 35% (6/17)
ORR (tx naive): 73% (11/15)
MDS (n = 60)
HMA failure (n = 39)
31% (16/51) ≥ 50% blast decrease
Median OS with response: 11 mos
Sapcitabine[4]
Phase I refractory AML/MDS
(n = 47)
Objective Response: 28%
Erlotinib[5]
HMA failure higher-risk MDS
(n = 35)
ORR (evaluable): 19% (5/26)
Median OS with response: 16.8 mos
Median OS: 6.8 mos
Clofarabine[1]
Oral azacitidine[2]
Rigosertib[3]
Dasatinib[6]
HMA failure higher-risk MDS,
ORR: 16.7%
CMML, AML
(n = 18)
1. Faderl S, et. al. Cancer. 2012;118:722-728. 2. Garcia-Manero G, et al. J Clin Oncol. 2011;29:2521-2527.
3. Raza, et al. ASH 2011. Abstract 3822. 4. Kantarjian H, et al. J Clin Oncol. 2010;28:285-291. 5. Komrokji R,
et al. ASH 2011. Abstract 1714. 6. Vu D, et al. Leuk Res. 2013;37:300-304.

32. Combination Therapy: Lenalidomide +
Azacitidine in Higher-Risk MDS
 Multicenter, single-arm open-label phase II continuation study (N = 36)
 Patient eligibility
– Higher-risk MDS: CMML-2, RAEB-1 or -2, IPSS intermediate 2 or high
(score ≥ 1.5), or revised IPSS score 4 or 5
– No previous treatment with lenalidomide or azacitidine
 Maximum of seven 28-day treatment cycles administered
– Lenalidomide 10 mg on Days 1-21
– Azacitidine 75 mg/m2 on Days 1-5
– After 7 cycles, patients could continue azacitidine monotherapy off study
 Median patient follow-up: 12 mos (range: 3-55)
Sekeres MA, et al. Blood. 2012;120:4945-4951.

33. Lenalidomide + Azacitidine in Patients
With Higher-Risk MDS: Results
 Median CR duration: 17+ mos
(range: 3-39+)
100
CR
Hematologic
improvement
Response Rate (%)
90
80
 Median OS among CR:
37+ mos (range: 7-55+)
70
60
28
50
40
30
20
44
10
0
Lenalidomide/
Azacitidine
(N = 36)
Sekeres MA, et al. Blood. 2012;120:4945-4951.
 8 patients evolved to AML at
median of 18 mos after CR
 Treatment well tolerated; FN
was most common grade 3/4
AE (22%)
 Randomized trial planned to
compare azacitidine vs
lenalidomide/azacitidine vs
azacitidine/vorinostat in higherrisk MDS

34. SWOG-S1117: North American Intergroup
Randomized Phase II MDS/CMML Trial
AZA
(n = 80)
Higher-risk
MDS (IPSS
> 1.5 or
blasts > 5%)
AZA + Lenalidomide
(n = 80)
AZA + Vorinostat
(n = 80)
Clinicaltrials.gov. NCT01522976
Groups:
SWOG, ECOG,CALGB, NCIC
Total sample size: 240
Primary objective: 20%
improvement of RR
based on 2006 IWG
Criteria
Secondary objectives: OS,
RFS, LFS
Power 81%, alpha 0.05 for
each combo arm vs AZA
Anticipated time: 2.5 yrs