or MDS

MDS overview
전남대학교
김여경

2008 WHO Classification of MDS
Name Abbreviation Key Feature Pts, %
Refractory cytopenia, with
unlineage, dysplasia
Refractory anemia with
ring sideroblasts
RA Anemia and erythroid dysplasia 10
RN Neutropenia and granulocytic dysplasia < 1
RT Thrombocytopenia and megak. dysplasia < 1
RARS ≥ 15% ring sideroblasts 5
5q- syndrome del(5q) Isolated 5q31 deletion, anemia,
hypolobated megakaryocytes
Refractory cytopenia with
multilineage dysplasia
Refractory anemia with excess
blasts, type 1
Refractory anemia with excess
blasts, type 2
RCMD
Multilineage dysplasia with > 1 cytopenia
With or without ring sideroblasts
RAEB-1 5% to 9% blasts 20
RAEB-2 10% to 19% blasts ± Auer rods 20
Unclassifiable MDS-U Does not fit other categories 10
Childhood MDS RCC Often hypocellular; pancytopenia Rare
5
20

Case
2000 Isolated thrombocytopenia
BM:
Dx:
Tx:
Normocellular marrow, 46, XY
ITP
corticosteroid, splenectomy
2009 Isolated thrombocytopenia 지속
6,000 /uL (4,200/uL) , 13.4 g/dL, 2,000/uL, LDH 600 IU/L
Spleen scan: asplenia (+)
PBS: H-J body (+)
다음 단계의 검사 혹은 치료는?
1. Danazol
2. Cyclosporin
3. Rituximab
4. Eltrombopag / Romiplostim
5. BM reexamination

Diagnosis
•10~20% : hypocellular marrow (+)
60세 미만 환자:

Differential Diagnosis
•골수내 이형성증이 반드시 클론성 질환이라는 증거는 되지 않기 때
문에 진단 전 골수이형성증을 유발할 수 있는 다른 원인들에 대한 확
인이 반드시 필요
•Vit. B12, folate def.
•Toxic agents : As, alcohol, chemotherpeutic agents,
조혈촉진인자 치료 병력
•감염: HIV, parvovirus B19
•선천성 적혈구 이형성빈혈
•Paroxysmal nocturnal hemoglobinuria (PNH)

Case
2009 Isolated thrombocytopenia
BM: Blast 2%, Megakaryocytes dysplasia,
Cellularity 70%, 46, XY
Dx: ITP, R/O MDS, RT
치료는?
(1) Danazol
(2) Cyclosporin
(3) Rituximab
(4) Eltrombopag / Romiplostim
(5) Azacitidine

Romiplostim in LR-MDS
Some pts: increase in the blast proportion!!
1. Kantarjian HM, et al. Blood. 2010;116:3163-3170. 2. Lyons et al. ASH 2009. Abstract 1770.
3. Kantarjian HM, et al. J Clin Oncol. 2010;28:437-444.

Case
2011.
4,000 /uL (1,600/uL) , 8.0 g/dL, 1,000/uL
BM: blast 7.2%, cellularity 92-95%, 47,XY,+8
Dx: MDS, RAEB-1
치료는?
(1) Darbepoietin
(2) ATG / Cycloporin
(3) Lenalidomide
(4) Azacitidine / Decitabine
(5) Allo SCT

Case
2011.
4,000 /uL (1,600/uL) , 8.0 g/dL, 1,000/uL
BM: blast 7.2%, cellularity 92-95%, 47,XY,+8
Dx: MDS, RAEB-1
Tx: decitabine 4 cycles and allo SCT
2012.
Relapse
Pending state of AML
Tx: RI induction chemoTx and allo SCT

International Prognostic Scoring system (IPSS)
1997
Score value
Variable 0 0.5 1 1.5 2
Marrow blasts (%) < 5 5~10 11~20 21~30
Karyotype* Good Intermediate Poor
Cytotpenia** 0, 1 2, 3
*Good = normal, -Y alone, del(5q) alone, del(20q) alone;
Poor = complex (≥ 3 abnormalities) or chromosome 7 anomalies;
Intermediate = other
**Neutrophil < 1,800/uL, platelets < 100,000/uL, Hb < 10 g/dL
Risk category Overall score Median survival (y) 25% AML progression (y)
Low 0 5.7 9.4
Intermediate-1 0.5~1.0 3.5 3.3
Intermediate-2 1.5~2.0 1.1 1.1
HIgh ≥ 2.5 0.4 0.2
Greenberg P, et al. Blood. 1997;89:2079-2089; correction: 1998;91:1100.

Limitations of IPSS
•Not validated in numerous patient subsets
Secondary MDS
CMML with WBC > 12 x 10 9 /L
Previously treated patients
Children
•Limited number of karyotypes
Only 3 categories
Many common karyotypes omitted
Does not account for molecular heterogeneity
•Omits validated prognostically relevant information
LDH
Mutations (eg, TP53, TET2)
Performance score
Marrow fibrosis, ALIP
Absolute lymphocyte count

WHO-based Prognostic Scoring System
(WPSS)
Variable
Scores
0 1 2 3
WHO category RCUD, RARS, RCMD RAEB-1 RAEB-2
MDS with isolated del(5q)
Karyotype* Good Intermediate Poor
Severe anemia Absent Present
(Hb < 9 g/dL, male;
< 8g/dL, female)
*Good = normal, -Y alone, del(5q) alone, del(20q) alone; poor = complex (≥ 3 abnorm
alities) or chromosome 7 anomalies; Intermediate = other
WPSS risk
Sum of individual variable scores
Very low 0
Low 1
Intermediate 2
High 3~4
Very high 5~6

Revised International Prognostic Scoring
system (IPSS-R) 2012
Score value
Variable 0 0.5 1 1.5 2 3 4
Cytogenetics* Very good Good Intermediate Poor Very poor
Marrow blasts (%) ≤ 2 > 2~< 5 5~10 > 10
Hemoglobin (g/dL) ≥ 10 8~

IPSS-R: Cytogenetic scoring & risk group
Subgroup Cytogenetics OS AML evolution
yrs 25%, yrs
Very good -Y, del(11q) 5.4 NR
Good normal, del(5q), del(12p), del(20q), 4.8 9.4
double including del(5q)
Intermediate del(7q), +8, +19, i(17q), 2.7 2.5
any other single or double independent clones
Poor -7, inv(3)/t(3q)/del(3q), double including -7/del(7q) 1.5 1.7
complex (3 abnormalities)
Very poor complex (> 3 abnormalities) 0.7 0.7
IPSS-R Overall score Median 25% AML
risk category survival (y) progression (y)
Very low ≥ 1.5 8.8 not reached
Low > 1.5 ~ 3 5.3 10.8
Intermediate > 3 ~ 4.5 3 3.2
High > 4.5 ~ 6 1.6 1.4
Very high > 6 0.8 0.7
Greenberg P, et al. Blood. 2012 in press

IPSS-R Survival related to Age
Formula to generate the age-adjusted risk score in the figure:
(yrs - 70) x [0.05 – (IPSS-R risk score x 0.005)]
Greenberg P, et al. Blood. 2012 in press

http://www.ipss-r.com/
IPSS-R calculator

Fraction Survival
Fraction AML-Free Survival
IPSS-R and MDS outcome
OS
Transformation to AML
1.0
Very good (n = 81; events: 34)
Good (n = 1809; events: 890)
Intermediate (n = 529; events: 312)
Poor (n = 148; events: 109)
Very poor (n = 187; events: 158)
1.0
Very good (n = 72; events: 6)
Good (n = 1611; events: 284)
Intermediate (n = 457; events: 145)
Poor (n = 129; events: 56)
Very poor (n = 167; events: 47)
0.8
Log-rank P < .001
0.8
Log-rank P < .001
0.6
0.6
0.4
0.4
0.2
0.2
0
0
0 50 100 150 200 250 300 350
0
50 100 150 200 250 300
350
Mos
Mos
Schanz J, et al. J Clin Oncol. 2012;30:820-829.

Goals of MDS Therapy
• Select best treatment
-Response according to predictive variables
-Consider type and severity of cytopenia(s), age, and possible
comorbidities
•LR-risk
-Improve blood counts, quality of life; decrease infections
-Decrease transfusion requirement, potentially improve survival
• HR-risk
-Prolong survival, delay progression to AML
Cheson BD, et al. Blood. 2000;96:3671-3674

Treatment: LR-MDS
NCCN Clinical Practice Guidelines ver 2. 2014

Treatment: LR-MDS
NCCN Clinical Practice Guidelines ver 2. 2014

Treatment: HR-MDS
NCCN Clinical Practice Guidelines ver 2. 2014

GESMD Therapeutic algorithm for LR-MDS
Grupo Espanol de Sindromes Mielodisplasicos (GESMD)
Sanz GF, 2013 EHA

GESMD Therapeutic algorithm for HR-MDS
Sanz GF, 2013 EHA

Predictive variables for ESA response in MDS
Biological
Clinical
Endogeneous EPO levels < 500 U/L
Marrow blast < 10%
IPSS low, Int-1
Diagnosis of RA
Normal karyotype
Transfusion independence
Short duration of Disease
Santini, et al. The Oncologist 2011;16:35-42

IST of LR-MDS predictors of response
•Age < 60 yrs
•Normal karyotype
•Hypoplastic marrow
•HLA-DRB1-15 Ag
Molldren 2002, Sauntaragiah 2002, 2003, Lim 2007, Sloand 2008

Phase III EPIC Trial: Mean Deferasirox Dose &
Median Change in s-Ferritin
Cappellini MD, et Cappellini al. Haematologica. MD, et al. Haematologica. 2010;95:557-566

Deferasirox in Transfusion-Dependent MDS
(Prospective Study): Results
• Improvement in serum ferritin levels from baseline (-264 ng/mL)
• Deferasirox associated with 15% probability of achieving transfusion
independence
Caveat: only 45% of patients completed planned 1 yr of treatment
• Toxicity profile consistent with previous studies
: 70% experienced toxicity (27% grade ≥ 3)
Angelucci E, et al. ASH 2012. Abstract 425.

AZA-001: Trial Design
Physician choice of 1 of 3 CCRs
1. BSC only
2. LDAC (20 mg/m 2 /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
R
A
N
D
O
M
I
Z
E
Azacitidine + BSC
(75 mg/m 2 /day x 7 days SC
q28 days)
CCR (Conventional care)
(n = 179)
(n = 179)
Treatment continued until unacceptable toxicity or AML transformation
or disease progression
Fenaux P, et al. Lancet Oncol. 2009;10:223-232.

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

Decitabine Phase III MDS Trial:
Study Design
• Open-label, multicenter, 1:1 randomized study
• IPSS: int-1, int-2, and high-risk MDS patients eligible
• Primary endpoints: response, time to AML/death
– IWG response criteria utilized for assessment
Eligible
patients
(N = 170)
R
A
N
D
O
M
I
Z
E
D
Stratification
• IPSS
• Type of MDS
(primary or
secondary)
Decitabine + Supportive Care
15 mg/m 2 / over 3 hrs q8h x
3 days q6w (n = 89)
Supportive Care
ABX, GFs, and/or transfusions
(n = 81)
Kantarjian H, et al. Cancer. 2006;106:1794-1803.

Decitabine Phase III Trial: Response to
Decitabine (ITT)
*For patients with a confirmed date of progression.
†Best response observed after 2 cycles (median number of cycles = 3)
Kantarjian H, et al. Cancer. 2006;106:1794-1803.

Phase III EORTC 06011: LD Decitabine vs BSC in
Elderly, Int- or High-Risk MDS
3-day inpatient schedule
Stratified by IPSS score, primary vs secondary
disease, cytogenetic risk, study center
Stop at 2 cycles beyond
CR or max of 8 cycles
Patients with intermediate- or hi
gh-risk MDS or CMML,
60 yrs of age or older, 11% to 20
% blasts or < 11% with poor cyto
genetics or 21% to 30% with stab
le disease for 1 mo
(N = 233)
Decitabine
15 mg/m 2 IV over 4 hrs
q8h x 9 q6w
(n = 119)
Best Supportive Care
(n = 114)
• Primary endpoint: OS
Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996.

Phase III Study of LD Decitabine vs BSC in Elderly,
Int- or High-Risk MDS: Results
• Median cycles of decitabine: 4
– ≤ 2 cycles: 38%
– Compare with a median of 9 cycles in AZA-001 study
• Responses in treatment arm (IWG 2000 criteria): 34%
– 13% CR, 6% PR, 15% HI
– Median time to best response: 3.8 mos
– Median time to CR: 5.8 mos; PR: 2.9 mos; HI: 3.8 mos
Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996.

Overall Survival: EORTC-06011
100
90
80
70
60
50
40
30
20
10
No difference in median OS: 10.1 mos for decitabine vs
8.5 mos for supportive care (P = .38)
Supportive care
Decitabine
Median (mos): 10.1 vs 8.5
HR: 0.88 (95% CI: 0.66-1.17; log rank P = .3
8)
0
0 6 12 18 24 30 36 42
Mos
O N Patients at Risk, n
96 114 71 38 22 10 6 3
99 119 83 53 24 15 4 4
Wijermans P, et al. ASH 2008. Abstract 226.

Progression-Free Survival: EORTC-06011
100
90
80
70
60
50
40
30
20
10
Supportive care
•No difference in progression to AML: 8.8 mos for decitabine vs
6.1 mos for supportive care (P = .24)
Decitabine
•Modestly but significantly improved median PFS
(including higher-risk MDS)
: 6.6 mos for decitabine vs 3.0 mos for supportive care
(P = .004)
0
0 6 12 18 24 30 36
Mos
O N Patients at Risk, n
105 114 33 15 7 3 1
113 119 62 32 11 2 0
Wijermans P, et al. ASH 2008. Abstract 226.

LD-Decitabine & OS in elderly MDS
• Not optimal decitabine schedule
(3-day inpatient vs ≥ 5-day outpatient treatment)
• Small numbers of cycles
– 40% received 2 cycles or less
– Median of 4 cycles vs 9 cycles in AZA-001
• Higher-risk patient group
– Control arm lived
median of 15 mos in AZA-001 vs 8.5 mos in EORTC study
Lübbert M, et al. J Clin Oncol. 2011;29:1987-1996.

Hypomethylating Agents
• Relative merits of azacitidine vs decitabine
• Role for 1 hypomethylating agent when the other has failed
• Is there a survival advantage when decitabine is administered using current c
ommon practice (ie, 5-day regimen, more cycles)?
• Optimal dose/schedule
• What to do once patient achieves CR (ie, maintenance dosing question; need
for maintenance seems to be established)
• What to do in patients without a response
• Molecular predictors of response
• Use in combination therapies
• Actual mechanism of action

Predictive factors
for response to hypomethylaing agents
Clinical Positive Negative
Doubling platelets BM blasts > 15%
Previous therapy
Transfusion dependency
Marrow fibrosis gr 3
Molecular Positive Negative
Mutated TET2 Mutated p53
Mutated DNMT3a Abnormal/complex karyotype
Mutated IDH1/2
Mutated ASXL1
Mutated EZH2
Santini V. 2012 ASH

TET2 mutations & response to azacitidine
Itzykson et al. Leukemia 2011

Mutational status in LR-MDS
Bejar et al. JCO 2012

IPSS-R in Azacitidine-Treated MDS
• Retrospective study of 265 patients with intermediate-2- or high-risk MDS
treated in French tertiary care centers
• AZA prognostic scoring system (reported previously by GFM):
low risk = 0, intermediate risk = 1-3, high risk = 4-5
• R-IPSS used to examine response to azacitidine and OS
GFM: Groupe Francais des Myelodysplasies
Ades L, et al. ASH 2012. Abstract 422.

IPSS-R in Azacitidine-Treated MDS
• R-IPSS strongly prognostic for OS in
azacitidine-treated patients with
Overall Sruvival
high-risk MDS
1.00
– Not predictive of
response to azacitidine
– Prognostic value
refined with use of
azacitidine scoring
systems
0.75
0.50
0.25
0
P = .0001
0 20 40 60 80
Months
Ades L, et al. ASH 2012. Abstract 422

Continued Azacitidine treatment
after first response?
Time to 1 st response in HR-MDS
Silverman LR et al. Cancer 2011;117:2697-702

Continued Azacitidine treatment
after first response?
Continued azacitidine Tx after 1 st response improves quality of response in HR-MDS
52%: 1 st response = best response
48%: improvement in their 1 st response with continued therapy
(1 st R: HI -> PR or CR)
Silverman LR et al. Cancer 2011;117:2697-702

Combination therapy with
hypomethylating agents in MDS
N ORR
Azacitidine Phenylbutyrate 32 34%
Azacitidine Valproic acid, ATRA 62 46%
Azacitidine Entinostate 136 43%
Azacitidine Lenalidomide 18 71%
Azacitidine Thalidomide 36 58%
Decitabine G. O. 33 42%
Azacitidine Entanercept 32 72%
Azacitidine Erythropoietin 32 44%
Azacitidine Romiplostim 40 23%
Decitabine Romiplostim 40 16%
Santini V. 2012 ASH

Outcome After Azcitidine Failure in MDS
*Includes AZA001, GFM, and JHU studies.
†
Decitabine only.
1. Lin K, et al. ASH 2010. Abstract 2913.
2. Prebet T, et al. ASH 2010. Abstract 443.
3. Jabbour E, et al. Cancer. 2010;116:3830-3834.

Survival after Azacitidine failure
with Salvage treatments in HR-MDS/AML
‣Palliative care vs. Intensive CTx p=0.04
vs. Investigational Tx. p

AlloSCT in MDS
•Transplantation is the only curative method in MDS
•Best results with
young age, marrow blasts < 5%, absence marrow fibrosis,
interval to SCT < 5 years, matched sibling donor
•Very limited
donor availability, advanced age
75% of pts with MDS >60
•Treatment-related mortality 34-55%
Relapse 19-34%
• High treatment-related morbidity
: Patients may have RFS, but not truly DFS
25%
33%
42%
TRM DFS Relapse

HSCT outcomes in MDS
Ghulam J. M. et al. ASH 2012

Timing of Transplantation
Approximate Life Expectancy (Yrs) for Ablative Allogeneic Transplantation
Transplantation at
Diagnosis
Transplantation in 2
Yrs
Transplantation at
Progression
Low 6.51 6.86 7.21
Int-1 4.61 4.74 5.16
Int-2 4.93 3.21 2.84
High 3.20 2.75 2.75
Low & Int-1
: benefit for delaying SCT
Int-2 & high
: delay in time to SCT is associated
with a loss in survivorship
Cutler et al. Blood 2004

Timing of Transplantation
Gain in expected survival since diagnosis according to IPSS & WPSS models
under different policies with respect to a non-transplantation policy
Alessandrino E. P. et al. GITMO, Am J Hematol 2013 in press

Timing of Transplantation
Allo SCT offers optimal survival benefit
when it is performed early in INT-1 IPSS or Intermediate WPSS
Alessandrino E. P. et al. GITMO, Am J Hematol 2013 in press

Induction prior to alloSCT
•Disease stage & cytogenetics: predictors of OS, relapse and NRM
•Before alloSCT
-decrease pre-transplant disease burden
-time to find optimal donor
•Infection or comorbidity
-lose a chance for transplantation

Pre-transplant Azacitidine
3 yr OS
Relapse
Damaj et al, JCO 2012;30:4533-4540

Pre-transplant Azacitidine
aGVHD: N-S
extensive cGVHD: higher in AZA-ICT group (p=0.049)
TRM
For the purpose of reducing tumor burden before alloSCT
AZA showed comparative OS, EFS, relapse and NRM compare with ICT
Damaj et al, JCO 2012;30:4533-4540

Pre-transplant Hypomethylating Agents
2yr DFS
• 49 AZA, 4 DEC, 3 AZA-DEC
•Response to HMT
G-COR: continued response
G-NoC: no change
G-LOR: loss of response
G-DP: progression
G-stable
Yahng SA et al. Eur J Haematol 2013;90:11-20

Pre-transplant Hypomethylating Agents
• Independent risk factor
for DFS, relapse
: Response to HMA
& Karyotype at HSCT
Yahng SA et al. Eur J Haematol 2013;90:11-20

Post-transplant Salvage
•Usually relapse within 1 or 2 years after HSCT
•Number of patients relapsing after alloSCT
as a function of time elapsed from transplantation
26
24
22
20
18
16
14
12
10
8
6
4
2
0
0 50 150 250 350 450 550 650 750 850 > 900
Days post Transplant

Post-transplant Salvage
MRD based preemptive 5-Aza Tx
in MDS/AML after alloSCT (RELAZA trial) (n=20)
DC, donor chimerism
Platzbecker U. et al. Leukemia 2012;26:381-389

Post-transplant Salvage
Platzbecker U. et al. Leukemia 2012;26:381-389
Major R Minor R no Response
Relapse
no Relapse
Relapse
•Response: 16/20 (80%)
•Hematologic Relapse: 65%
•Relapse was delayed median 231 days
after initial decrease of CD34+ chimerism to

Post-transplant Salvage
Azacitidine + DLI in AML (28) or MDS (2) relapsing after alloSCT
(AZARELAR trial)
AZA: 8 cycles, D1-5 (median 3)
DLI: every 2 nd AZA cycle
ORR: 30% (CR 23%, 2 PR)
aGVHD 37%, cGVHD 17%
CR or CRi
: longer OS
Schroeder et al. Leukemia 2013

감사합니다!!