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Myelodysplastic Syndromes:

Current Thinking on the Disease,

Diagnosis and Lower-Risk TreatmentJason Gotlib, MD, MS

Assistant Professor of MedicineAssociate Director, MDS Center

Stanford Cancer Center

AA&MDSIF

July 23, 2011

Disclosures for

Jason Gotlib

Research Support/P.I. Celgene (Lenalidomide in DBA)

Employee None

Consultant Novartis

Major Stockholder None

Speakers’ Bureau None

Scientific Advisory Board None

Myelodysplastic Syndrome (MDS)

Overview (1)

• Acquired stem cell disorder resulting in bone marrow

failure

• Chronic peripheral low blood counts (anemia in >

80% of patients)

• Dysplastic morphology (abnormal shape) of blood

cells

• Abnormal chromosomes in 40-50% of patients

• Heterogeneity: highly variable natural history

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Myelodysplastic Syndrome (MDS)

Overview (2)Morbidity/mortality relate to:

• Cytopenia-related complications

(fatigue, infection, bleeding)

• Evolution to acute myeloid leukemia (30- 40% of

patients)

• Patients’ advanced age / co-morbidities

• Iron overload from chronic RBC transfusions

Age (Median) Newly diagnosed 71 years

Established 72-75 years

Sex (Mean) Male (Newly diagnosed)

(Established)

55%

51-57%

Duration of MDS

(Median)13-16 months

MDS Status Primary 88 – 93%

Secondary 7 – 12%

Secondary Chemotherapy 55 – 80%

Cause Radiation 6 – 21%

Chemical exposure 2 – 9%

Cross-sectional analysis of 4514 MDS patients in the

U.S. in 2005-2007

U.S. MDS Characteristics

Sekeres et al. J National Cancer Inst 2008;100:1542

FAB Classification (1982)Name (Abbreviation) BM Blast PB Blasts RS

Refractory anemia (RA) 0-5% 0% <15%

Refractory anemia 0-5% 0% >15%

with ringed sideroblasts (RARS)

Refractory anemia 6-19% 1-4% Variable

with excess blasts (RAEB)

Chronic myelomonocytic leukemia 0-19% 1-4% <15%

(CMML)

Refractory anemia with excess 20-29% 5-29% Variable

blasts in transformation (RAEB-T)

Bennett JM, et al. Br J Haematol 1982. 51:189-199.

Steensma DP, et al. Leukemia Research 2003. 27: 95-120.

List AF, et al. The Myelodysplastic Syndromes. In: W introbe’s Hematology 2003.Silverman LR. The Myelodysplastic Syndromes. In: Cancer Medicine. 2000.

Classifies MDS according to morphology and % of myeloblasts in

the bone marrow and peripheral blood

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From Greenberg P, et al. International Scoring System for Evaluating Prognosis in Myelodysplastic Syndrom Blood

1997:89:2079-88. Copyright American Society of Hematology, used with Permission.

FAB Classification

years

pe

rce

nt

Survival

125 pts

294 pts

126 pts

208 pts

61 pts

RARS

RA

CMML

RAEB

RAEB-T

100

90

80

70

60

50

40

30

20

10

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Prognostication

Greenberg et al. Blood, Vol 89, No 6 (March 15), 1997: pp 2079-2088

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Survival and Transformation

to AML by IPSS Score

Parameter Low Int-1 Int-2 High

Score 0 0.5-1.0 1.5-2.0 2.5

Median Survival, Years 5.7 3.5 1.2 0.4

Median AML

Transformation, Years9.4 3.3 1.1 0.2

At diagnosis

Greenberg P, et al. Blood. 1997;89:2079-2088.

31% 39% 22% 8%

IPSS Risk

Stratification

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Pathophysiology: Contributing Factors

W ith Permission of J Maciejewski,M.D.

Taussig Cancer Center/ Cleveland Clinic Foundation

MDS

Stem cell dysfunction

Stem cell

Dysfunction

Apoptosis

Stromal/angiogenetic

factors

Epigenetic changes

Immunedysfunction

Environmentaldirect toxicity

Mutations/DNA damage

• BMT is the only known curative modality,

but appropriate/practical only in a small

subset

• Individualize therapy (according to age,

performance status, and IPSS risk group)

• Minimize toxicity

Non-curative Goals:

• Decreased transfusion, infection, increased

quality of life

General Treatment Principles

Cheson BD, et al. Blood 2000. 96:3671-4.

Spriggs DR, et al. Clin Haematol. 1986 Nov;15(4):1081-107.

http:// www.NCCN.org MDS Guidelines

4 FDA-Approved Drugs for MDS

2004 2005 2006 2011

Azacitidine Lenalidomide Decitabine

Deferasirox

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NCCN Guidelines: Lower risk Disease

Erythropoiesis Stimulating

Agents (ESAs) & Other

Recombinant Growth Factors

ESAs for Lower-risk MDS

Golshayan et al. Br J Haem 2007;137:125. ESAs RR ~40%

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Erythropoietin + G-CSF in MDS:

Patient Selection

Hellström-Lindberg E et al. Br J Haematol. 2003;120:1037

Good response

(74%, n=34)

Intermediate response

(23%, n=31)

Poor response

(7%, n=29)

s-epo <100 +2

U/L 100–500 +1

>500 –3Transf <2 units/m +2

U RBC/m = or >2 units/m –2

Treatment response score

RA, RARS, RAEB

Score > +1

Score –1 to +1

Score < –1

Darbepoetin Alfa (DA) in Lower-Risk MDS

3 published studies of fixed dose DA in lower-risk MDS

Dose: 150-300 mcg weekly

Red blood cell response of 40-70% Addition of G-CSF may help some non-responders

Weight based DA: 58% red blood cell response 4.5 mcg/kg wk x 6 wks

9.0 mcg/kg/wk x 6 wks 9.0 mcg/kg/wk + G-CSF 2.5 mcg/kg 2x/wk x 6 wks

Direct comparisons with standard ESAs have not been

performedStasi et al, Ann Oncol, 2005; Musto et al, Br J Haematol, 2005

Mannone et al, Br J Haematol, 2006; Gotlib et al, Am J Hematol, 2009

Survival: Growth factors vs. Best

Supportive Care (BSC)

Jadersten et al. J Clin Oncol 2008;26:3607

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ESAs: Summary

• ESAs are used widely in MDS

• They work in approximately 40% of patients

• EPO+G-CSF upfront for RARS patients

• We have ways of determining in whom they will work best

• They may provide a survival advantage compared to no growth factors or transfusions

• There is no data to suggest that ESAs cause harm in MDS as

it relates to increasing the risk of leukemia, or decreasing overall survival

Phase I/II Study of Romiplostim

S

C

R

E

E

N

I

N

G

Dose Escalation Phasecompleted

Treatment Extension Phaseongoing

Study Week 1

Study Week 4

Option to continue romiplostim SC weekly

after Week 4.

Intra-patient dose

escalation allowed.

E

N

D

O

F

S

T

U

D

Y

1000 mcg

n = 11

300 mcg

n = 6

700 mcg

n = 11

1500 mcg

n = 16

Romiplostim dose cohortsa

StudyWeek 56

Romiplostim given subcutaneously (SC) weekly.Kantarjian et al. JCO 2009

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Romiplostim Platelet Response Rates:

Patients on Treatment Extension

Category N N (%)

HI-P 35 19 (54)

Baseline platelet count

< 20 x 109/L 11 6 (55)

≥ 20 x 109/L 24 13 (54)

For pts achieving HI-P,

plt count > 100x109/L for ≥ 8 consecutive

wks, n (%)

19 12 (63)

Kantarjian et al. JCO 2009.

MDS: Azacytidine +/- Romiplostim4 cycles, Kantarjian et al, Blood 2010

Events Placebo

n=13

500mcg/wk

n=13

750mcg/wk

n=14

T events/cy 50-85% 44-70% 18-64%

Plt txns 69% 46% 36%

Cycle BL 25-88K 40-60K 37-315K

“ nadir 14-44K 35-53K 32-91K

Romiplostim Extension Therapy in

Thrombocytopenic MDS PtsFenaux et al, ASH 12/10, #1885

• N=40, IPSS lower risk pts from prior trials

– Single agent; +decitabine; +lenalidomide

• Median dose 730 mcg/wk

– Baseline median plts 31,000 (19,000-45,000)

• Platelet response: 85%

– median duration : 41 wks

– ≥50,000 @ wk3

• Significant bleeds & platelet transfusions 28% (9/40)0/21

• AML developed in 3 pts @ 6-36 wks

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Romiplostim: Summary

• Platelet responses in 54% of patients; independent of baseline platelet count(≥ 20 x 109/L or < 20 x 109/L)

• Achieving platelet response associated with:

–Fewer transfusions, bleeding events

• Evaluation as a single agent and in combination with AZA, DAC, LEN.

Sloand et al, JCO, 2008

Horse ATG (+/- CSA)

Younger age and HLA-DR15 positivity favor response to immunosuppression

Overall Response 9 of 25 (36%)

Best clinical response for at least 8 weeks duration

Hematologic Improvement after

rabbit (r)ATG Therapy

Response (n=25) 9 (36%)

Major Erythroid 4

Minor Erythroid 1Major Neutrophil 1

Major Platelet 1

Trilineage 1

Major Bilineage 1

No Response (n=25) 16 (64%)

Stable Disease 7Disease Progression 5

Death 3

Withdraw 1

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o Median time to respond was 75 days (range 3 days-114 days)

o Median duration of response was 8.2 months (range 4 months to >22.2 months at time of last follow up)

o No difference observed in time to respond or duration of response by age, HLA-DR15 or IPSS classification

o Two responders progressed during long-term follow up

Median time to progress 17 months (range 12.4 – 21.5 months)

Int-2 at baseline

Time to Respond and Durability

of Response to rATG

Lenalidomide

MDS-001 N = 43

Phase I/II initiated Feb 2002

Del 5q

MDS-003 N = 148

Phase II initiated July 2003

MDS-002 N = 214

Phase II initiated July 2003

Non del 5q

Lenalidomide in Low/Int-1-risk MDS:

Completed Trials

Slide courtesy of A. Raza

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Lenalidomide in del (5q) MDS: Transfusion Response

FeatureMDS-02/03

(%)

MDS-01/PK

(%)

Total

(%)

No. Patients 149 19 168

Erythroid response, n (%)

TI

Minor (> 50% )

TI + minor

99 (66)

13 (9)

112 (75)

15 (79)

1 (5)

16 (84)

114 (68)

14 (8)

128 (76)

Time to response, weeks

Median

Range

4.6

1-49

7.7

2-40

4.7

1-49

List et al. Blood 2006;108:251a.

LEN in del (5q) MDS: Duration Major Erythroid Response

0 1 2 3 4 50

10

20

30

40

50

60

70

80

90

100

Years

Perc

en

t R

esp

on

din

g

Median duration TI =2.2 yearsMedian F/U: 1.3 yr (Min 0.1 – Max 4.4 yr)

Data as of 04Dec06 (N=114)

List et al. Blood 2006;108:251a.

Variable No. Pts. (%)

MDS-02/03

No. Pts. (%)

MDS-01/PK

No. Pts. (%)

Total

No. Evaluable 86 18 104

Cytogenetic Response*

Complete (CCR)

Minor (>50%)

CCR in 5q + 1

CCR in complex (>3)

63 (73)

38 (44)

25 (29)

15 (83)

12 (67)

3 (17)

78 (75)

50 (48)

28 (27)

9 (50)

3 (50)

LEN in del (5q) MDS:

Cytogenetic Response

*All cytogenetic responders achieved an erythroid response.

List et al. Blood 2006;108:251a.

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Lenalidomide treatment of

non-del(5q) MDS: MDS 002 Study

Pts (Low/Int-1)

Dose, mg

HI-E Txn Independence

Minor HI-E (≥50% Txns)

HI-E Total

Median time to response

HI-E duration

Abnormal cytogenetics

Cytogenetic response

214 (78%+)

10/d or q21/28d

26%

17%

43%

4.5 weeks

10 months

47/214 (22%)

9/47 (19%)Raza et al. Blood 111:86, 2008

LEN in Non-del (5q): Duration of TI

0 25 50 75 100 125 150

0

10

20

30

40

50

60

70

80

90

100

Time (Weeks)

Tra

nsfu

sio

n In

dependent

(%)

Median duration TI: 41 weeks

Range: 8.0–136.4+ weeks

Censored§

N = 56

Raza et al. Blood 2008;111:86.

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Lenalidomide: Summary

• First line treatment for del(5q) MDS

• An option for non del (5q) MDS with lower rates of red blood cell and cytogenetic responses

• Not useful for high risk MDS with low platelet counts

and/or with del(5q) and increasing # cytogenetic abnormalities

• A randomized trial is needed to determine whether there is any increased risk of AML from lenalidomide

NCCN Guidelines for

Iron Chelation in MDS

• NCCN guidelines recommend considering chelation after 20-30 transfusions, when ferritin > 2500 ng/ml

Development of Diabetes & Cardiac

Complications: Follow-up- 3 Years

48%

32% 33%

0%

20%

40%

60%

80%

100%

p=0.0001

p=0.02

Diabetes

RBC-TD MDS OverallMDS no RBCs Medicare

Population

80%

69%

42%

0%

20%

40%

60%

80%

100%

Cardiac Events*

*MI, CHF, arrythmia, other.

RBC-TD MDS OverallMDS no RBCs Medicare

Population

p=0.001

p=0.002

Goldberg S, et al. ASH 2008; #636

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Iron Chelation and Deferasirox:

Open Questions

• At what ferritin level should treatment be initiated?

• To date, there are no prospective data on the

usefulness of deferasirox in MDS

– Progression-free and overall survival

– improvement in blood counts

• The current randomized trial of deferasirox vs.

placebo will aim to answer these questions

• (TELESTO trial)

Treatment Strategies for MDS Based on

Risk (IPSS Score) and Biology

Low/Int-1

Anemia EPO, Darbepoietin

RARS EPO + G-CSF

Del (5q) Lenalidomide

Clinical trials for relapsed/refractory disease

Int-2/High Azacitidine, Decitabine

Clinical trials for relapsed/refractory disease

HLA-matched allogeneic stem cell transplant (younger)

HLA-matched non-myeloablative allogeneic stem cell

transplant (older)