1

Advances in the Management of Myelodysplastic Syndromes

Allen S. Yang, MD. Ph.D.Jane Anne Nohl Division of HematologyNorris Comprehensive Cancer Center

University of Southern California

Southwestern Conference on Medicine

May 1, 2009

2

Disclosures:

Celgene, Eisai, Bristol Myers SquibbMethylgene, NovartisTherEpi

3

CASE 1

60 year old retired high school chemistry tearcher. Presents with a 3 month history of feeling “tired”.

WBC: 12.0Hgb/Hct: 8.8/24.0Plt: 191

4

CASE 1

What intervention would you recommend next?

A) ColonoscopyB) Bone Marrow biopsyC) Review of Peripheral SmearD) A trial of iron replacement

5

CASE 2

76 year old retired oil worker with a past medical history of NHL (non-Hodgkin’s lymphoma) cured with CHOP chemotherapy. Patient has a routine CBC as part of an annual physical exam.

WBC: 12.0Hgb/Hct: 8.8/24.0MCV: 95Plt: 56

6

CASE 2

What intervention would you recommend next?

A) ColonoscopyB) Bone Marrow biopsyC) Review of Peripheral SmearD) A trial of iron replacement

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Causes of anemia in elderly

8

Anemia* in the Elderly (Age ≥ 65 Years)

*Anemia was defined as < 13 g Hgb/dL for men and < 12 g Hgb/dL for women.Percentage of persons age 65 and older who are anemic. Source: NHANES III, Phases I and II, 1988–1994.Adapted from Guralnik et al. Hematology. 2005;528-532, with permission.

0

5

10

15

20

Total Population ≥ 65 Y

Perc

enta

ge o

f Per

sons

MalesFemalesTotal

11.010.2 10.6

9

Anemia in the Elderly (Age ≥ 65 Years) (cont)

34Unexplained

32Chronic illness/inflammation or chronic renal failure

34Blood loss/nutrition relatedPercentageType of Anemia

• Unrecognized MDS may represent an important cause of unexplained anemia in the elderly

Guralnik et al. Hematology. 2005;528-532.

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What is MDS?

Other names:- Refractory anemia (1938)- Preleukemia (1953)- Smoldering leukemia (1963)- Dysmyelopoietic anemia (1980)- MDS (1982)

Clonal? Heterogeneous? Myeloid?

11

The Myelodysplastic SyndromesEpidemiology

• 15,000 new cases/year in US (Adults)

• More common than AML

• Median Survival 1-3 years

• Predominantly a disease of the elderly– Median age > 60– Greater incidence in males than females– Incidence increases with age

Kurzrock R. Semin Hematol. 2002 Jul;39(3 Suppl 2):18-25.Steensma DP, Tefferi A. Leuk Res. 2003 Feb;27(2):95-120..Bennett JM, et al. Bennett JM, et al. Int Int J J HematolHematol. 2002 Aug;76 . 2002 Aug;76 Suppl Suppl 2:2282:228--38.38.

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Etiology of MDS

• benzene or toluene

• gasoline or diesel (?)

• pesticides (?)

• virus (?)

• genetic (?)

• secondary to chemotherapy with or without radiation therapy

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Probability of Treatment-related MDS (tMDS) After Autologous

Transplantation for NHL

Friedberg JW, et al. J Clin Oncol. 1999;17(10):3128-35.

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Differential Diagnosis of MDS

• nutritional deficiencies

• heavy metal poisoning

• alcoholism

• metabolic disturbances

• chronic inflammation

• Tuberculosis

• liver disorders

• hypersplenism

• Hodgkin’s disease

• metastatic carcinoma

• recent chemotherapy

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The Myelodysplastic SyndromesOverview

• Clonal disorder characterized by hypercellular marrows, peripheral cytopenias, and cell functional abnormalities

• Dominant feature: Ineffective hematopoiesis with peripheral blood cytopenias

• Bone marrow failure– Majority succumb to infection or bleeding– Transformation to acute leukemia in 35-40% range

• High mortality rate

• Supportive Care has been the standard treatment

Kurzrock R. Semin Hematol. 2002 Jul;39(3 Suppl 2):18-25.Miller KB. Curr Treat Options Oncol. 2000 Apr;1(1):63-9.

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Clinical Presentation

• Half of patients are >70 years old

• Half of patients have no symptoms related to MDS

• Most common symptoms are those from anemia

• A few patients have symptoms of bleeding or infection

• Physical findings are unusual; splenomegaly found in <20%

• Some patients present with fever

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Age-Related Incidence of MDS

0 0 2 1 2 2 49

16

26

5259 61

34

10

10

10

20

30

40

50

60

70

20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75- 80- 85- 90- 95-

Williamson PJ, et al. Br J Haematol. 1994;87:743-745.

Age in 5-Year Blocks

Age-Specific Incidence Rates (per 100,000), Years

<50 0.550-59 5.360-69 1570-79 4980 and over 89

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MDS FAB Classification

8-60+1%-20%CMML(Chronic Myelomonocytic Leukemia)

5-1221%-30%RAEB-T(Refractory Anemia with Excessive Blasts in transformation)

7-155%-20%RAEB(Refractory Anemia with Excessive Blasts)

21-76<5%RARS(Refractory Anemia with Ringed Sideroblasts)

19-64<5%RA(Refractory Anemia)

Survival (months)

% Blasts in Bone

MarrowCategory

List AF, et al. The Myelodysplastic Syndromes. In: Wintrobe’s Hematology 2003.

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No. PatientsNo. Patients 4343Female predominanceFemale predominance 29 (67)29 (67)Platelets > 150,000/Platelets > 150,000/µµLL 36 (84)36 (84)Dysplastic megakaryocytesDysplastic megakaryocytes 40 (92)40 (92)Erythyroid Erythyroid hypoplasia hypoplasia 38 (90)38 (90)Leukemia evolutionLeukemia evolution 5 (12)5 (12)Median survival*Median survival* >5 years>5 years

Cancer Genet Cytogenetics 1985; 17: 189.Cancer Genet Cytogenetics 1985; 17: 189. *IPSS.*IPSS.

5q- SyndromeHematologic Features

20

21

AML• >20% Blasts•RAEB-t

WHO Classification

MDSMDS•• RARA -- RARA

-- RCMDRCMD•• RARSRARS-- RARS RARS

-- RCMDRCMD--RSRS••RAEBRAEB-- RAEB I (5RAEB I (5--10% Blasts)10% Blasts)

--RAEB II (11RAEB II (11--19% Blasts)19% Blasts)•• OtherOther-- 5q5q-- SyndromeSyndrome

--MDS MDS --UU

MDS/MPDMDS/MPD•• CMML CMML (>13,000/(>13,000/µµL)L)

•• JMMLJMML

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*Good = normal, -Y, del(5q), del(20q); Intermediate = other karyotypic abnormalities; Poor = complex (≥3 abnormalities) or chromosome 7 abnormalities. †Hgb <10 g/dL; ANC <1800/µL; platelets <100,000/µL.RISK: LOW (0), INT-1 (0.5-1.0), INT-2 (1.5-2.0), HIGH (> 2.5)

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

IPSS Scoring System

• All 3 prognostic variables are required to generate IPSS score

Score Value

2/30/1Cytopenias†

PoorIntermediateGoodKaryotype*

21%-30%11%-20%--5%-10%<5%Bone Marrow Blasts

2.01.51.00.50Prognostic Variable

2323

Survival: MDS vs. Lung CancerSurvival: MDS vs. Lung Cancer

Lung CancerLung CancerMDSMDS

1.21.2IVIV0.40.4HighHigh>2>22.42.4IIIaIIIa1.21.2IntInt--221.51.5--225.45.4IIaIIa3.53.5IntInt--110.50.5--1188IaIa5.75.7LowLow00

Median Median Survival Survival

(Yrs)(Yrs)StageStage

Median Median Survival Survival

(Yrs)(Yrs)

RiskRiskGroupGroup

IPSSIPSSScoreScore

Greenberg P, et al. Blood. 1997:89:2079-2088.Adebonojo et al. Chest 1999: 115:1507-1513

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Supportive CareIncludes:• Transfusions• Antibiotics• Chelation agents• Growth factors

– EPO +/- G-CSF (or GM-CSF)– Treatment with growth factors (EPO + G-CSF) have not

demonstrated improvement in survival and/or reduced risk of transformation to AML in MDS patients

Faderl, S. Myelodysplastic Syndromes. In: Cancer Principles & Practice of Oncology. Philadelphia, PA: Lippincott Williams & Wilkins: 2005: 2144-2154.

EPO=erythropoietin; G-CSF=granulocyte colony-stimulating factor;GM-CSF=granulocyte macrophage colony-stimulating factor.

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Erythropoietin + G-CSF in MDS: Patient Selection

Hellström-Lindberg E, et al. Br J Haematol. 2003;120(6):1037-46.

Good response(74%, n=34)

Intermediate response(23%, n=31)

Poor response(7%, n=29)

s-epo <100 +2U/L 100–500 +1

>500 –3Transf <2 units/m +2U RBC/m = or >2 units/m–2

Treatment response score

RA, RARS, RAEBRA, RARS, RAEB

Score > +1Score > +1

Score –1 to +1Score –1 to +1

Score < –1Score < –1

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RBC Transfusions

• Majority of patients will require transfusion support – Thresholds based on symptoms and comorbidities, not just

hemoglobin level

• Multiple transfusions lead to complications– Allo-sensitization– Iron overload

• Iron chelation for 20-30 units pRBC and prolonged life expectancy

– Oral agent (deferasirox) role unknown in MDS• Increased iron absorption may be seen in RARS

Gordon MS. Semin Hematol. 1999;36(4 Suppl 6):21-4.Tricot GJ, et al. Semin Oncol. 1987;14(4):444-53. http:// www.NCCN.org MDS Guidelines

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Deferasirox Study: Reduction in Ferritin During Study

Timepoint

n=176 n=139 n=113 n=75 n=53

List AF, et al. Blood. 2007;110(11):1470a.

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Deferasirox Study: Unanswered Questions

• Does iron chelation improve survival in MDS?• Would require lengthy, controlled study

• Does iron chelation prevent clinical complications in MDS, as it does in congenital anemias?

• Issues may be distinct for heart vs liver

• In which patient groups is iron chelation cost-effective?

• What is the long-term safety and efficacy profile of deferasirox?

List AF, et al. Blood. 2007;110 (11):1470a.

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MDS Treatment Approaches

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Relapse-free Survival Targeted busulfan and cyclophosphamide

(tBuCy)

Deeg HJ, et al. Blood. 2002;100(4):1201-7.

Relapse-free Survival

0 1 2 3 4 5 6 70

20

40

60

80

100

Years from Transplant

Rel

apse

-free

Sur

viva

l (%

)

IPSS 0 (N=16)/ LIPSS .5-1 (N=54)/ I-1

IPSS 1.5-2 (N=24)/ I-2 IPSS >2 (N=8)/ H

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Approximation of Life Expectancy (Years)

2.752.753.20High

2.843.214.93Int-2

5.164.744.61Int-1

7.216.866.51Low

Transplant at Progression

Transplant in 2 Years

Immediate Transplant

From Cutler C, et al. A Decision Analysis of Allogenetic Bone Marrow Transplantation for Myelodysplastic Syndromes: Delayed Transplantation for Low Risk Myelodysplasia is Associated with Improved Outcome. Blood 2004- 1st Ed Publication. Prepublished online March 23, 2004; D01.1182/Blood-2004-01-0338.Copyright American Society of Hematology, used with Permission.

32

The Decision

Time

% S

urvi

val

HCT

No HCT

Cutler C, et al. Blood. 2004;104(2):579-85.

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Available Agents:Indications, Dosing, and MOA

Intravenous infusion (1–3 h)

OralSubcutaneous

Intravenous

Route

45 mg/m2/d x 3 d q 6 wk

10 mg/d75 mg/m2/d x 7 d q 4 wk

Dosing

DNA hypomethylation

All MDS subtypes(FAB classes)

(IPSS: Low, Int-1, Int-2, High)

Azacitidine

DNA hypomethylation

Immune modulation; angiogenesis inhibition

MOA

All MDS subtypes(FAB classes)

IPSS: Int-1, Int-2, HighSecondary MDS

Low-risk MDS(IPSS low or Int-1)with deletion 5q;

Transfusion dependent

Indication

DecitabineLenalidomide

FAB = French-American-British; IPSS = International Prognostic Scoring System.Vidaza [package insert]. Pharmion Corp; 2004.Lyons et al. Poster presented at: ASH 2005 Annual Meeting. Abstract 2517. Revlimid [package insert]. Celgene Corp; 2005.Saba et al. Presentation at: ASCO 2005 Annual Meeting. Abstract 6543.Kantarjian et al. Poster presented at: ASH 2005 Annual Meeting. Abstract 2522.

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Genetics and DNA : “The Code of Life”

35

“Genetics and Epigenetics”

The Phillips Sisters: “Ann Landers” and “Dear Abby”

Epigenetics = “Heritable Information not coded for in the DNA Sequence”

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How are genes turned off?…. DNA Methylation

“ON”“OFF” Gene

Protein

DNA

RNA

Protein

Jones PA, et al. Nat Rev Genet. 2002 ;3(6):415-28.

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Epigenetics in Cancer

Normal

DNA Tumor Suppressor Oncogene

Cancer

38

How DNA Methyltransferase Inhibitors Work

39

• Minimum duration of supportive care=4 months unless transformation to AML; death or platelets <20 x 109/L at week 8 or later

• Growth factors were prohibitedBM=bone marrow.

Supportivecare*

Stratify:• RA• RARS• RAEB• RAEB-T• CMMoL VIDAZA 75 mg/m2/d SC x 7 days every 28 x 4

Exitcriteria

No Continue untilendpoint +

Yes VIDAZA(dose as per arm #2)

ASSESS

Response• Continue Rx

No Response• Off study

BMBM BM0 5729 113

Day

Study 9221: A Randomized Phase III Controlled Trial of Subcutaneous VIDAZA®

(azacitidine for injection) in MDS

Silverman L. The Oncologist. 2001;6:8-14.Silverman LR, et al. J Clin Oncol. 2002;20:2429-2440.Kornblith AB, et al. J Clin Oncol 2002;18:2427-2439.

RANDOMIZE

40

Analysis of ResponseSC AZA Crossover

No. Evaluated 92 99 49

CRCR 0 (0%)0 (0%) 77 (7%)(7%)** 5 5 (10%)(10%)

PRPR 0 (0%)0 (0%) 15 15 (16%) (16%) **** 2 2 ( 4%)( 4%)

ImprovedImproved 5 (5%)5 (5%) 38 38 (37%) (37%) **** 16 16 (36%)(36%)

TotalTotal 5 (5%)5 (5%) 6060 (60%) (60%) **** 23 23 (47%)(47%)

P P -- valuevalue * < 0.01* < 0.01 **<0.001**<0.001

Silverman L, et al. Randomized Controlled Trial of Azacitidine in Patients with MDS: A Study of the CALGBJ Clin Oncol 2002. 18:2414-26. Reprinted with permission from the American Society of Clinical Oncology.

41

Study 9221: Time to Response

VIDAZA full prescribing information. Data on file, Pharmion Corporation.

• The initial positive effect observed included:*– HgB (18.8%)– Platelets (25%)– WBC (18.8%)– Blasts (37.5%)

* Includes patients with adjudicated baseline diagnosis of AML

*Initial positive effect was defined as the first day of achievement of target for 4 weeks for at least one abnormality.

42

Azacitidine Treatment Prolongs Overall Survival in Higher-Risk MDS Patients

Compared with Conventional Care Regimens: Results of the AZA-001 Phase III Study

P P FenauxFenaux, MD, GJ Mufti, MD, V , MD, GJ Mufti, MD, V SantiniSantini, MD, C , MD, C FinelliFinelli, MD, , MD, A A GiagounidisGiagounidis, MD, R , MD, R SchochSchoch, MD,A List, MD, S Gore, MD, , MD,A List, MD, S Gore, MD, J Seymour, MD, E J Seymour, MD, E HellstromHellstrom--Lindberg, MD, J Bennett, MD, Lindberg, MD, J Bennett, MD,

J Byrd, MD, J J Byrd, MD, J BackstromBackstrom, MD, L Zimmerman, BSN, , MD, L Zimmerman, BSN, D McKenzie, MS, CL Beach, D McKenzie, MS, CL Beach, PharmDPharmD and L Silverman, MD and L Silverman, MD

on behalf of the International on behalf of the International VidazaVidaza HighHigh--Risk MDS Risk MDS Survival Study GroupSurvival Study Group

43

Azacitidine Survival Study

AZAAZA 75 mg/m75 mg/m22/d x 7 d q28 d/d x 7 d q28 d

CCRCCRRandomizationRandomization

BSC was included with each armTx continued until unacceptable toxicity or AML transformation or disease progression

• Best Supportive Care (BSC) only• Low Dose Ara-C (LDAC,

20 mg/m20 mg/m22/d x 14 d q28/d x 14 d q28--42 d42 d))• Std Chemo (7 + 3)

Screening/CentralPathology Review

Investigator CCRTx Selection

44

Overall Survival: Azacitidine vs CCR ITT Population

LogLog--Rank p=0.0001Rank p=0.0001HR = 0.58 [95% CI: 0.43, 0.77]HR = 0.58 [95% CI: 0.43, 0.77]Deaths: AZA = 82, CCR = 113Deaths: AZA = 82, CCR = 113

0 5 10 15 20 25 30 35 40

Time (months) from RandomizationTime (months) from Randomization

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Prop

ortio

n Su

rviv

ing

Prop

ortio

n Su

rviv

ing

CCRCCRAZAAZA

Difference: 9.4 monthsDifference: 9.4 months

24.4 months24.4 months

15 months15 months

50.8%50.8%

26.2%26.2%

45

Secondary Endpoints: IWG (2000) RR and HI

1818

1414

11112929

44

881212

CCR CCR N=179N=179

(%)(%)

0.870.872424111120201919HIHI--N MajorN Major

0.00030.00032020191910103333HIHI--P MajorP Major

<0.0001<0.000122221010884040HIHI--E MajorE Major<0.0001<0.00012828252531314949Major+Minor Major+Minor

0.0090.009

0.020.020.00010.0001

PP--ValueValueAZA vs AZA vs

CCRCCR

IWG HIIWG HI

4444441212PRPR

363688111717CRCR40401212552929Overall Overall (CR+PR)(CR+PR)

Std Std Chemo Chemo N=25N=25

(%)(%)

LDAC LDAC N=49N=49

(%)(%)

BSC BSC Only Only

N=105N=105(%)(%)

AZA AZA N=179N=179

(%)(%)ResponseResponse

CCR RegimensCCR Regimens

46

Additional Analysis: Median OS by Investigator Selection

0.870.87

0.580.58

0.560.56

Hazard Hazard RatioRatio

0.0020.0029.69.6

21.121.1

11.511.5

AZA (N=117)AZA (N=117)vs vs BSC (N=105)BSC (N=105)

0.750.759.49.4

25.125.1

15.715.7

AZA (N=17) AZA (N=17) vsvsStand Chemo (N=25)Stand Chemo (N=25)

0.0750.0759.29.2

24.524.5

15.315.3

AZA (N=45)AZA (N=45)vs vs LDAC (N=49)LDAC (N=49)

LogLog--rank P rank P

KK--M OS M OS Time Time mosmos

KK--M OS M OS Time Time mosmosTreatmentTreatment

DifferencesDifferences

47

Azacitidine extends overall survival (OS) in higher-risk MDS

without the necessity for complete remission

Azacitidine Azacitidine extends overall extends overall survival (OS) in highersurvival (OS) in higher--risk MDS risk MDS

without the necessity for without the necessity for complete remission complete remission

Alan List, Pierre Alan List, Pierre FenauxFenaux, , Ghulam Ghulam Mufti, Eva Mufti, Eva HellstromHellstrom--LindbergLindberg, Steven Gore, John , Steven Gore, John Bennett, Lewis Silverman, Jay Bennett, Lewis Silverman, Jay BackstromBackstrom, and CL Beach on behalf of the , and CL Beach on behalf of the

International International VidazaVidazaHighHigh--Risk MDS Survival Study GroupRisk MDS Survival Study Group

ASCO 2008ASCO 2008

48

OS with AZA by Best Response (IWG 2000)OS with AZA by Best Response (IWG 2000)OS with AZA by Best Response (IWG 2000)

0 5 10 15 20 25 30 35 40Time (months) from Randomization

0.0

0.1

0.2

0.3

0.40.5

0.60.7

0.8

0.91.0

Prop

ortio

n Su

rviv

ing

HI

PRCR

SDCCR

DP

24

67.5% (p=0.006)

71.7% (p<0.0001)

41.3% (p=0.041)

78.4% (p<0.0001)

26.2%

49

Azacitidine5-azacytidine

Decitabine5-aza-2‘-deoxycytidine

DNARNA

50

Cytidine Analogs

51

Decitabine Phase 3 Study Design

OpenOpen--label, 1:1 randomized, multilabel, 1:1 randomized, multi--center study center study in the US and Canada in the US and Canada

Eligible Patients (n = 170)

Decitabine + Supportive Care* Decitabine + Supportive Care* (n = 89)(n = 89)

RANDOMIZED

Supportive Care*Supportive Care*(n = 81) (n = 81)

Stratification• IPSS Classification• Prior Chemotherapy• Study Center

Study DStudy D--00070007*Antibiotics, Growth Factors and/or TransfusionsSaba HI, et al. J Clin Oncol. 2005;23(suppl 16S):570s. Abstract 6543..

52

Decitabine Phase 3 Dose and Administration

Cycle

15 mg/m2

3 hour15 mg/m2

3 hour15 mg/m2

3 hour

135 mg/m2

3 days

6 week cycle

8 hours 8 hours 8 hours

ThreeConsecutive

Days

Schedule: 3 hour infusion q 8 hrs x 3 daysSchedule: 3 hour infusion q 8 hrs x 3 days

Median number of cycles/patient: 3 (Range = 0 Median number of cycles/patient: 3 (Range = 0 -- 9)9)

Study D-0007Saba HI, et al. J Clin Oncol. 2005;23(suppl 16S):570s. Abstract 6543.

53

Decitabine Phase III MDS Trial Results

7%13%Hematologic Improvement (IWG)

7%30%Overall Clinical Benefit (CR + PR + Hematologic Improvement)

Not assessed288d (116-388)Median Duration of Response (CR + PR)

Not assessed93d (55-272)Median Time to Response (CR + PR)

0%8%Partial Response0%9%Complete Response0%17%Overall Response (IWG Criteria)†

Supportive Care (N=81)

Decitabine*(N=89)ITT Analysis

†P<0.001.

*FDA approval based on response analysis; decitabine treatment did not significantly delay the median time to AML or death versus supportive care.

Dacogen™ (decitabine for injection) full prescribing information. May, 2006.

54

Decitabine Exposure in Phase 2 and 3 Studies

Multiple cycles of decitabine therapy may be required for optimal response

3444Median # cycles

7 (8%)4 (5%)3 (5%)5 (17%) PR

8 (9%)19 (22%)14 (21%)8 (28%) CR

15 (17%)23 (26%)17 (26%)13 (45%)ORR (CR + PR)

89876629N

D-000797-1995-1191-01

Phase 3Phase 2

Saba HI, et al. Saba HI, et al. BloodBlood . 2005;106:706a [abstract 2515]. . 2005;106:706a [abstract 2515]. Kantarjian Kantarjian HM, et al. HM, et al. CancerCancer. 2006;106:1794. 2006;106:1794--1803. Saba HI, et al. 1803. Saba HI, et al. Semin Semin HematolHematol. 2005;42(3 . 2005;42(3 suppl suppl 2): S232): S23--S31. S31. Wijermans Wijermans PW, et al. PW, et al. LeukemiaLeukemia. 1997;11:1. 1997;11:1--5. 5. Wijermans Wijermans PW, et al. PW, et al. J J Clin Clin OncolOncol..2000;18:9562000;18:956--962.962.

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Survival and Efficacy of Decitabine in Myelodysplastic Syndromes (MDS), Analysis of the 5-Day IV Dosing Regimen

ASH 2007 Abstract #115

Hagop Kantarjian, Guillermo Garcia-Manero, Susan O'Brien, Zeev Estrov, Farhad Ravandi, Jorge Cortes, Jianqin Shan, Jan Davisson, Jean-Pierre Issa

clinicaloptions.com/oncology

Clinical Issues and Future Directions in Hematologic Malignancies

Kantarjian H, et al. ASH 2007. Abstract 115.

Patients with intermediate-1, -2, or

high-risk MDS or CMML + leukocytosis;

performance status 0-2

(N = 124)

Decitabine 20 mg/m2 IV over 1 hr daily for 5 days*(n = 93)

Decitabine 20 mg/m2 SQ daily for 5 days*(n = 14)

Decitabine 10 mg/m2 IV over 1 hr daily for 10 days*(n = 17)

*Every 4 weeks up to 24 courses.

Evaluation of 5-Day IV Decitabine Schedule in MDS

57

Comparison of outcome and side effects by dose schedule

273120Median days to platelet recovery†

23 (23)14 (14)50 (12)No. courses requiring hospitalization (%)

403535Median days to delivery of subsequent courses

271424Median days to granulocytes recovery*

10.8 (1.9 – 17.7+)9.7 (0.5 – 22.9+)5.4 (1.0 – 20.4+)Median duration of therapy in mos (range)

9

4 (24)

17

10 Day IV

8 5 Median no. courses

3 (21)25 (39)CR / treated (%)

1464n

5 Day SQ5 Day IVParameter

*To 10o 1099/L or above/L or above; †To 50 x 10To 50 x 1099/L or above/L or above; Kantarjian H, et al. Blood. 2006;108(in press). First Edition Paper, prepublished online Aug 1, 2006; DOI 10.1182/blood-2006-05-021162.

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Decitabine Survival vs Intensive Chemotherapy in Higher Risk MDS (Matched Group)

Kantarjian H, et al. Blood, 2007; 110: 42a-43a Abstract 115

59

“A Silver Lining from Tragedy…”

60

61

62

63

Questions?Allen Yang

USC/Norris Cancer Center

(323) 865-3950

(800) NORRIS1

allenyan@usc.edu

www.mds-foundation.org