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MDS Therapeutics – Beyond Erythropoietic Stimulating Agents. Alan List, MD Deputy Physician-in-Chief Chief, Malignant Hematology Division H. Lee Moffitt Cancer Center & Research Institute Tampa, FL, USA. Genetic Del(5q) - RPS14 > 90% by SNP. Normal MDS.

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mds therapeutics beyond erythropoietic stimulating agents

MDS Therapeutics – Beyond Erythropoietic Stimulating Agents

Alan List, MD

Deputy Physician-in-Chief

Chief, Malignant Hematology Division

H. Lee Moffitt Cancer Center & Research Institute

Tampa, FL, USA

ineffective erythropoiesis in mds pathogenetic features

Genetic

  • Del(5q) - RPS14
  • >90% by SNP

Normal MDS

Epigenetic

  • Environment
  • Immune suppression
  • Aptogenic cytokines
  • Receptor Signal
  • EPO-R/STAT5
Ineffective Erythropoiesis in MDSPathogenetic Features

Figure adopted from Curry P. Cure:5 (4),2006

slide3

Predictive Model for Response to rEPO + G-CSF

Nordic MDS Group [N=98]

  • Serum EPO mU/mL
    • <100: Score +2
    • 100–500: Score +1
    • >500: Score -3

Score Patients (n) Response

≥2 29 74%

±1 31 23%

<-1 34 7%

  • RBC transfusion
    • <2 units/mo.: Score +2
    • >2 units/mo.: Score -2

Hellstrom-Lindberg et al, Br J Haematol 1997; 99: 344.

influence of transfusion intensity on overall survival in mds without excess blasts
Influence of Transfusion Intensity on Overall Survival in MDS without Excess Blasts

Overall survival

(HR = 1.36; p < 0.001)

Leukaemia-free survival

(HR = 1.40; p < 0.001)

1.0

1.0

0 U PRBC/4 week

1 U PRBC/4 week

2 U PRBC/4 week

3 U PRBC/4 week

4 U PRBC/4 week

0.9

0.9

0.8

0.8

0.7

0.7

0.6

0.6

Cumulative survival

Cumulative survival

0.5

0.5

0.4

0.4

0.3

0.3

0.2

0.2

0.1

0.1

0.0

0.0

0

20

40

60

80

100

120

140

160

180

0

20

40

60

80

100

120

140

160

180

Time (months)

Time (months)

Malcovati L, et al. Haematologica 2006:91:1588.

slide5

Phase III and Case Matching Studies Evaluating

Effect of ESA Treatment on Disease Outcome

Abbrevations: ESA, erythropoiesis-stimulating agent; NA, not available; SC, supportive care; mos, months; HR, Hazard ratio.

*denotes comparison of overall survival in ESA responders vs. non-responders and controls.

Melchart and List. Hematology 2007.

modulators of ligand dependent signals
Modulators of Ligand-Dependent Signals

Thalidomide

Phthaloyl ring

Lenalidomide

VEGF = vascular endothelial growth factor.

bFGF = basic fibroblast growth factor. Rhu-EPO = recombinant human EPO.

TNF = tumour necrosis factor. COX = cyclooxygenase.

Bartlett JB. Nat Rev Cancer. 2004;4:314-22.

mds 002 003 phase ii studies of lenalidomide in transfusion dependent low int 1 mds
MDS-002/003: Phase II Studies of Lenalidomide in Transfusion-Dependent Low/Int-1 MDS

R

E

G

I

S

T

E

R

R

E

S

P

O

N

S

E

Yes Continue

Lenalidomide

10 mg qd x 21 days

  • Eligibility
  •  2 U PRBC/8 weeks
  • Platelets > 50,000/μL
  • ANC > 500/μL

Lenalidomide

10 mg qd daily

MDS-003: del 5q31.1

MDS-002: other

No Off study

Dose reduction

5 mg every day

5 mg every other day

Week 0 4 8 12 16 20 24

Primary end-point: transfusion independence (Hgb 1 g/dL)

Secondary end-points: cytogenetic response, pathological response

List AF, et al. NEJM 2006; 355: 1456

mds 003 erythroid response itt modified iwg 2000
MDS-003 Erythroid Response (ITT)Modified IWG 2000

ITT = intention to treat.

TI = transfusion independent.

List AF, et al. NEJM 2006; 355: 1456

mds 003 mean non transfused hemoglobin by treatment cycle
MDS-003: Mean Non-Transfused Hemoglobin by Treatment Cycle

14

Median timeto response

Maximum Hb, g/dL [range]

Baseline 7.8 [5.3–10.4]

Lenalidomide 13.4 [9.2–18.6]

Median Hb 5.4 [1.1–11.4]

12

Normalized, perNCCN guideline

Hb (g/dL)

10

8

Responders

Non-responders

6

0

2

4

6

8

10

12

14

16

18

Cycle (28 days)

95% CI is provided when n > 3Hb values in the 30 days following transfusion were excluded, unless the values were

on or  3 days preceding a transfusion date.

List AF, et al. NEJM 2006; 355: 1456

mds 003 ti rate by cytogenetic pattern
MDS-003: TI rate by Cytogenetic Pattern

* Excludes 1 patient defined by FISH only.

FISH = fluorescence in situ hybridization.

List AF, et al. NEJM 2006; 355: 1456

slide11

Duration of Major Erythroid ResponseDeletion 5q

Data as of 07May07 (N=113)

Median duration TI =2.2 years

Median F/U: 3.2 yr (Min 0.3 – Max 4.8 yr)

§Symbols are censored patients who remain TI at time of data cut-off or at time of study discontinuation.

mds 003 cytogenetic response by karyotype complexity
MDS-003: Cytogenetic Response by Karyotype Complexity

List AF, et al. NEJM 2006; 355: 1456

slide14

100

PR, N=35, Median OS=unestimable

90

80

70

CR, N=55,

60

Median OS=unestimable

50

50

Cumulative Survival

40

30

20

10

NR/NE, N=78, OS=28 mnth

0

0

24

48

72

96

120

144

168

192

216

240

Months

Survival from MDS Diagnosis by Cytogenetic Response

[N=168]

P<0.0001

[a] Product-Limit survival estimates adjusted for left-truncation.

Note: CR=Complete Cytogenetic Response, PR=Partial Cytogenetic Response, NR=No Cytogenetic Response, NE=Not evaluable

aml evolution from diagnosis by cytogenetic response left truncation kaplan meier analysis

100

N=168

90

80

67%

70

NR/NE (9/77)

60

50

Cum Risk of AMLEvolution

P=0.010

40

30

15%

20

CCR/PCR (7/89)

10

0

0

24

48

72

96

120

144

168

192

216

240

Months

AML Evolution from Diagnosis by Cytogenetic ResponseLeft Truncation Kaplan-Meier Analysis
mds 002 erythroid response itt modified iwg 2000

Demographics n (%) [range]

No. patients 214

Median age, years 72 [27–94]

Male 138 (64)

>2 PRBC U/month 139 (65)

IPSS Low/Int-1 168 (78)

Int-2/High 8 (4)

Unclassified 38 (18)

FAB RA/RARS 127 (62)

Abnl karyotype 47 (22)

TI

TI + minor

43

26

MDS-002 Erythroid Response (ITT)Modified IWG 2000

Erythroid response

80

Median TI duration: 41 wks (8-136 wks)

Median Time to Response: 5 wks

Median Hgb  :3.2 g/dL (range:1-9.8)

70

60

50

Erythroid response (%)

40

30

20

[n=56; 92]

10

0

ITT

BLOOD 2008; 11: 86-93

mds 002 003 drug related adverse events nci ctc 2 0
MDS-002/003: Drug-Related Adverse Events (NCI CTC 2.0)

List AF, et al. NEJM 2006; 355: 1456

BLOOD 2008; 11: 86-93

slide18

Independent Co-Variates for TI Response Del(5q) MDS-003 Multivariate Analysis*

*Logistic regression analysis using categorized variables

^Continuous variable.

Sekeres M, et al. ASH 2007; Abstr 821.

slide19

Independent Co-variates for TI ResponseMDS-002 Multivariate Analysis*

Sekeres M, et al. Florence MDS Symp. 2007.

*Logistic regression analysis categorical variables.

slide20

Gene Expression Signature for LEN Response  STAT5 & GATA-1 Gene Target Expression[N=16 Non-del5q]

Ebert BL, et al. PLoS Med 2008; 5(2):e35.

slide21

Gene Set Enrichment Score Z-Score Discrimination of Response Potential

[N=16]

Ebert BL, et al. PLoS Med 2008; 5(2):e35.

slide22

*

*

*

C

Validation of LEN Response SignatureResponse Score in Non-Del(5q) & Del(5q) MDS [N=26]

* Prediction accuracy = 85%. Ebert BL, et al. PLoS Med 2008; 5(2):e35.

slide23

Lenalidomide Response Signature in MDSSummary

  • LEN responsive MDS share a common molecular profile characterized by profound impairment in erythroid differentiation
  • STAT5A & GATA-1 transcriptional targets are markedly decreased in LEN responsive patients
  • LEN exerts direct effects on erythroid progenitors to restore differentiation potential
  • These findings suggest that LEN may modify key regulators of the EPO-R/STAT5 transcriptional response

Ebert BL, et al. PLoS Med 2008; 5(2):e35.

slide24

Lenalidomide

STAT5 Phosphorylation

X

STAT5

STAT5

STAT5

Lenalidomide Relieves Epo-R Signal Repression in non-Del(5q) Epo-Progenitors

Modulation of Epo-R Jak/STAT5 Signal

CD45

List A,F et al. ASH 2006.

Adopted from: Pennington JM. Nature Immunol 2001.

lenalidomide enhances epo stat5 signal in mds cd117 cd71 hi erythroid precursors

IgG isotype control

120

120

EPO 3 U/mL

Lenalidomide + EPO

100

100

80

80

60

60

40

40

20

20

0

0

Lenalidomide Enhances EPO/STAT5 Signal in MDS CD117+/CD71Hi Erythroid Precursors

MDS

Normal

IgG isotype control

EPO 3 U/mL

Lenalidomide + EPO

Counts

100

101

102

103

104

100

101

102

103

104

p-STAT5

p-STAT5

List A,F et al. ASH 2006.

MFI = mean fluorescence intensity.

slide26

Thalidomide

Lenalidomide

Lenalidomide Inhibits rHu-CD45 PTP Activity

[IC50 = 10nM]

CD45-specific PTP activity assayed using the BIOMOL GreenTM CD45 Tyrosine Phosphatase Assay Kit. rhu-CD45 (Calbiochem) [75U] was incubated for 1H at 37o C with the indicated IMiD then pp60c-Src substrate [200 uM] was added and incubated for 1H and read on a plate reader at 620nm.

summary target of lenalidomide action in non del 5q mds
Summary Target of Lenalidomide Action in Non-Del 5q MDS
  • Lenalidomide is a PTP inhibitor that enhances EPO receptor signaling and CFC in non-del5q erythroid precursors.
  • Lenalidomide relieves CD45 repression of EPO ligand-dependent Jak2 and Lyn kinase mediated STAT5 activation.
  • Protein tyrosine phosphatase inhibition is selective without inhibition of SHP-1 or SHP-2 PTP activity
  • These findings suggest that combined treatment with LEN + ESA may improve erythroid response in non-Del(5q) MDS.
slide28

MER Continue

PK & Efficacy Study of LEN+EPO in rhuEPO FailuresLow/INT-1 IPSS [PK-002]

M

O

N

O

T

H

E

R

A

P

Y

R

E

S

P

O

N

S

E

LEN 10mg/d [N=25]

  • Eligibility
  • Low/Int-1 IPSS
  • Epo failure

LEN 15mg/d [N=15]

No LEN + EPO*

*40,000 Units/wk

Week: 0 4 8 12 16 20 24

Primary Objectives: LEN PK vs cytopenias,IWG 2000 MER

List et al. . ASH 2007.

slide29

Pilot Study LEN + rhu-EPO in Low/Int-1 MDSMajor Erythroid Response by Treatment Stage

List et al. . ASH 2007.

slide30

Phase III Intergroup Study of Lenalidomide (LEN)vs LEN + Epoetin Alpha in Low/Int-1 MDS

[ECOG 2905]

R

A

N

D

O

M

I

Z

E

  • Eligibility
  • IPSS Low/Int-1
  • Hgb <9.5g/dL
  • Poor EPO Resp

Profile or failed EPO

S

T

R

A

T

I

F

Y

R

E

S

P

O

N

S

E

MER Continue

A. LEN 10mg/d x 21d

  • Stratify
  • del(5)(q)
  • sEPO
  • Prior EPO/DA

B. LEN + Epoetin

No Combination

[Arm A]

Week: 0 4 8 12 16

Principal Objective: Modified IWG 2000 MER

Secondary: CD45 isoform, LEN p-STAT5 

slide32

Randomized Phase II Study of Alternative AzaC (Vidaza™) Dose Schedules

Study Design [N=151]

A. 5-2-2: 75 mg/m2

N=50

  • Eligibility
  • All FAB
  • cytopenia

x6

IWG

2000 HI

B. 5-2-5: 50 mg/m2

12 Cycles

AZA x 5d

Q4-6 wks

N=51

C. 5: 75 mg/m2

N=50

Lyons et al. ASH 2007; Abstr 819.

slide33

Alternate AzaC Dose Schedule Study

Frequency of Major HI in Evaluable Patients [N=139]

*IWG 2000 criteria. Lyons et al. ASH 2007; Abstr 819.

slide34

Onset of IWG-Defined Hematologic Improvement

Lyons et al. ASH 2007; Abstr 819.

aza 001 phase iii survival study schema
AZA-001 Phase III Survival Study Schema

AZA-C 75 mg/m2 x 7 daysEvery 28 days

[N=358]

[N=179]

Stratify (FAB, IPSS)

  • Eligibility
  • RAEB, RAEB-t, CMML
  • 10-29% blasts
  • IPSS-2/High risk

[N=179]

Conventional Care Regimen (CCR):

1. BSC only [n=105]

2. Low Dose Ara-C [n=49]

3. Induction/Consolidation [n=25]

Primary Endpoint: Overall survival

Fenaux P, et al. ASH 2007; Abstr 817.

overall survival azacitidine vs ccr itt analysis

1.0

0.9

0.8

0.7

50.8%

0.6

24.4 months

0.5

15 months

26.2%

0.4

0.3

0.2

0.1

0.0

0

5

10

15

20

25

30

35

40

Overall Survival: Azacitidine vs CCR ITT Analysis

Log-Rank p=0.0001

HR = 0.58 [95% CI: 0.43, 0.77] Deaths: AZA = 82, CCR = 113

Difference: 9.4 months

Proportion Surviving

AZA

CCR

Time (months) from Randomization

slide37

AZA-001 Phase III Study vs CCRSurvival According to CCR and Cytogenetics

Fenaux P, et al. ASH 2007; Abstr 817.

overall survival azacitidine vs ccr secondary endpoints
Overall Survival: Azacitidine vs CCR Secondary Endpoints
  • Time to AML or death
    • 13 mos with AZA vs 7.6 mos with CCR, p=0.003
  • Time to AML (During Treatment)
    • 26.1 mos with AZA vs 12.4 with CCR, p=0.004
  • RBC Transfusion Independence
    • 45% with AZA vs 11% with CCR, p<0.0001
  • Infections Requiring IV Antimicrobials:
    • Reduced by 33% with AZA vs CCR
slide39

Epo<200mU/ml

<2U RBC/mo

Epo>200mU/ml

RCMD

>2U RBC/mo

Del (5q)

ESA

Age

Del5q

Lenalidomide

>60 <60

MTI

+GCSF

IST*

*Consider trisomy 8.

Anemia Management Algorithm - 2007Low/Int-1 Risk MDS

Anemia

  • Decision Elements for Treatment Selection
  • EPO response profile
  • Karyotype
  • Age
slide40

Acknowledgements

Moffitt Collaborators

Ann Williams Wayne Guida

Myka Estes PK Burnette

Yuki Ozawa Gary Reuther

Ruth Heaton Julie Djeu

Lubomir Sokol Sheng Wei

E. Sotomayor