7MDS Novel Therapy

8/12/2019 7MDS Novel Therapy

1/70

Epigenetic Therapy in MDS

Jean-Pierre Issa

Leader, Hematologic Malignancies Program

Co-Director, Center for Cancer Epigenetics


2/70

MDS

Clonal bone marrow stem cell neoplasmsHypercellular marrows, peripheral cytopenias,and cell functional abnormalitiesHighly variable natural history

Incidence of Leukemia in the USA

0

2,000

4,000

6,000

8,00010,000

12,000

14,000

16,000

AML ALL CML CLL MDS E s t

i m a

t e d # c a s e s

p e r y e a r

1,613

1,1171,491

361

161

179

4,750

RARARS

RAEBRCMD5q-delt-MDSMDS-NOS


3/70

MDS Epidemiology

14,000 estimated new cases/year in US (adults)Predominantly a disease of the elderly Median age 70

Incidence greater in men than in womenAssociated with exposures (pesticides,benzene, chemotherapy, smoking)

Myelodysplastic syndromes detailed guide. American Cancer Society. Available at www.cancer.org. Accessed 6/20/06.Xie Y, et al. Cancer . 2003;97(9):2229-35; American Cancer Society, www.cancer.org; Aplastic Anemia and MDSInternational Foundation, www.aamds.org; Kurzrock R. Semin Hematol . 2002;39(3 Suppl 2):18-25; Steensma DP,Tefferi A. Leuk Res . 2003;27(2):95-120. Greenberg P, et al. Blood . 1997;89:2079-88.


4/70

Molecular Biology of MDS

Frequent chromosomal changes

Most gene targets unknown

Relatively rare mutations

Frequent epigenetic changes

Key, functionally relevant targets onlybeginning to be identified


5/70

Cytogenetic Changes in MDS

del y, 7%

del17p, 7%

del 5/5q, 8%

del 7, 8%

Trisomy 8, 10%del 5/5q and 7,

15%

Normal, 40%

del20q, 4%

11q23, 1%

MLL

p53

RPS14


6/70

MDS: Two Diseases

Low risk

IPSS low and some INT1 Relatively good outcome (median survival >10

years in young patients, >3 years in older

patients)High risk IPSS INT2 and high

IPSS INT1 and secondary MDS, or platelets


7/70

MDS: Goals of Therapy

Low risk

Symptom control No treatment needed in asymptomatic patients

High risk Prolong life (delay AML)

Treatment indicated regardless of symptoms


8/70

Therapeutic Options in MDS

Supportive care: Transfusions, antibiotics, ironchelationGrowth factors (EPO, gCSF)Immunosuppression (ATG, CsA)Chemotherapy

Allogeneic SCT

Lenalidomide

AzacitidineDecitabine

New therapies


9/70

Epigenetics

Mitotically stable changes in gene expression,thought to be irreversible

DifferentiationPhenotypic differences (e.g. twins)Stem cells vs. committed cells

X-inactivation, imprinting

DNA methylation, Histone modifications

(Histone code), RNA-interference (RNAi)

Morgan et al. Nat Genetics 23, 314 (1999)


10/70

Epigenetic Diseases

Developmental

Fragile X syndrome ( FMR1 ) Rett syndrome ( MECP2 ) ICF syndrome ( DNMT3B )

ATRX syndrome ( ATRX ) Imprinting disorders (Beckwith-Wiedemann etc.) Alpha Thalassemia

Acquired Cancer Age-related diseases


11/70

Cytosine DNA Methylation

NH2

CH 3

N

NO H

5-Methyl-Cytosine

NH2

H

N

NO H

Cytosine

SAM SAH

MTASE

SAM = S-adenosyl methionine; SAH = S-adenosyl homocysteine. w ww.mdanderson.org/leukemia/methylation.


12/70

Hypermethylation and Silencing

MM MM MM

Expressed (or ready for expression)Expressed (or ready for expression)

MMMMMMMMMMMMMMMMMM

SilencedSilencedImprinted genes, Inactive XImprinted genes, Inactive X

Ectopically Silenced Genes (e.g.Ectopically Silenced Genes (e.g. TSGsTSGs))


13/70

Methylation Profile of the NCI60

Cell Line Panel G e n e s

B R E A S T

B R E A S T

B R E A S T

C N S

C N S

C N S

C N S

C N S

C N S

C O L O N

C O L O N

C O L O N

C O L O N

C O L O N

C O L O N

C O L O N

L E U K

L E U K

L E U K

L E U K

L E U K

L E U K

M E L A N O M A

M E L A N O M A

M E L A N O M A

M E L A N O M A

M E L A N O M A

M E L A N O M A

M E L A N O M A

M E L A N O M A

N S C L C

N S C L C

N S C L C

N S C L C

N S C L C

N S C L C

N S C L C

N S C L C

N S C L C

N S C L C

O V A R I A N

O V A R I A N

O V A R I A N

O V A R I A N

O V A R I A N

O V A R I A N

P R O S T A T E

P R O S T A T E

R E N A L

R E N A L

R E N A L

G1

G2G3G4G5G6G7G8G9

G10G11G12G13G14G15G16G17G18

G19G20G21G22G23G24G25G26G27G28

ShenShen , Cancer Res. 2007, Cancer Res. 2007


14/70

Frequent DNA Methylation Targets in

MDS

P15 Cyclin dependent kinase inhibitor RIL ApoptosisCDH1 and CDH13 Adhesion

ER and PGR Differentiation


15/70

Aberrant Methylation in MDS

MDS analyzed samples from 89 patients atbaseline

1

8

4

2

6

1

8

0

7

0

2

2

3

8

0

1

8

1

4

5

2

3

0

4

4

1

9

8

8

1

2

0

0

4

6

1

6

7

6

2

1

6

1

8

1

1

8

8

6

8

1

5

0

5

3

2

0

0

0

4

2

1

0

1

3

1

9

4

0

1

1

5

8

0

2

1

7

6

5

3

1

4

9

2

9

1

9

3

2

2

1

9

4

3

0

2

1

6

4

0

1

9

4

2

9

2

2

0

4

9

1

7

2

3

9

1

8

7

5

9

1

8

9

3

0

2

2

3

7

9

2

0

3

7

3

1

9

4

5

9

2

1

1

6

3

1

9

2

4

6

1

6

7

6

3

1

9

5

0

6

1

7

9

4

2

1

6

7

1

8

1

7

6

9

5

1

8

5

5

0

1

8

7

4

0

2

0

2

6

8

2

0

7

5

4

1

7

6

2

6

1

9

8

2

4

1

8

7

6

3

2

2

9

8

2

2

3

0

4

1

2

2

4

8

8

1

7

6

2

7

2

0

4

7

6

2

0

6

4

7

2

2

5

3

8

1

6

6

0

6

1

8

4

5

2

1

5

6

0

7

1

7

5

4

7

1

9

8

8

7

1

6

6

3

1

1

9

7

5

6

1

8

4

2

4

1

6

0

1

5

2

3

2

1

8

2

2

4

9

4

1

9

6

4

2

1

8

2

1

1

1

8

3

8

4

2

2

3

9

6

2

2

4

8

9

2

0

3

2

3

1

9

1

3

1

1

5

6

8

3

2

0

3

1

5

2

0

2

9

7

2

2

4

3

3

1

8

1

4

6

1

8

2

7

3

2

0

6

5

1

2

2

9

6

3

1

5

4

6

2

1

7

8

4

6

1

7

7

9

3

2

0

4

5

6

1

9

8

0

7

1

9

4

7

8

1

8

1

9

0

1

6

2

6

8

2

0

7

5

5

1

7

6

5

4

1

5

4

7

4

1

9

3

2

3

1

9

8

6

2

2

1

1

6

0

p15-PYROECADRIL-2ER

PGRACDH13NOR1 ND ND

NPM2-s1NPM2-s2OLIG2 ND ND ND ND

RIL-upPGRAPGRBp16 ND ND ND ND ND ND ND ND


16/70

Methylation and Prognosis

0 5 1 0 1 5 2 0 2 5M o n t h s

0

2 0

4 0

6 0

8 0

1 0 0

P e r c e n

t o

f S u r v

i v a

l

M e t h y la t io n H i g h

L o g - R a n k = 8 . 3 , P = 0 . 0 0 4

M e t h y la t io n L o w

0 5 1 0 1 5 2 0 2 5

M o n t h s

0

2 0

4 0

6 0

8 0

1 0 0

P e r c e n t o

f P r o g r e s s

F r e e

S u r v

i v a

l

M e t h y la t io n L o wM e t h y la t io n H i g h

L o g - R a n k = 11 . 5 , P = 0 . 0 0 0 7

ProgressionProgression -- Free SurvivalFree SurvivalOverall SurvivalOverall Survival


17/70

Epigenetic Reprogramming

Can be triggered in adult cells

?Therapy for cancer

Occurs in waves in early embryogenesis, involvingactive (demethylation by an unknown demethylase)and passive (replication in the absence of DNAmethylases) resetting of DNA methylation patterns

Required for normal development and differentiation

Wolf Reik, Wendy Dean, Jorn Walter, Science 2001Wolf Reik, Wendy Dean, Jorn Walter, Science 2001


18/70


19/70

RibonucleotideReductase

Phosphatase

RNA

5-aza-CTP

5-aza-CDP

5-aza-CMP

5-aza-CR

Uridine CytidineKinase

5-aza-dCTP

5-aza-dCDP

5-aza-dCMP

decitabine

DeoxycytidineKinase

Phosphatase

Metabolism of DNAMetabolism of DNA

Hypomethylating AgentsHypomethylating AgentsDNA

(Azacitidine) (Decitabine) Attadia V. Leukemia. 1993;7:9-16.


20/70

Azacitidine in MDS

75 mg/m 2 SQ or IV daily x 7 days, q4 weeks,continued as long as patients are doing well

Responses in multiple studies CR 5-10% PR 5-10%

HI 20-40%Time to response: 2-10 cycles (median 6-8)

Any response HI or better associated with improvedoutcomeToxicities primarily myelosuppression

Azacytidine in MDS: Overall


21/70

Azacytidine in MDS: OverallSurvival in CALGB Study

P r o

b a b i l i t y o

f

P r o

b a

b i l i t y o

f

R e m a

i n i n g

E v e n

t

R e m a

i n i n g

E v e n

t - - F r e e

F r e

e

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

00 66 1212 1818 2424 3030 3636 4242 4848 5454

AzacitidineAzacitidineSupportive CareSupportive Care

p = 0.10p = 0.10

MedianMedian20 months20 months14 months14 months

MonthsMonths

++++++++++++

++++++++

++++++++++

++++

++ ++

++++ ++ ++ ++++++

++ ++ ++ ++ ++

++

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.


22/70

Azacytidine in MDS: Fenaux

Randomized Study

Stratified log-rank P =0.0001Hazard ratio (HR) = 0.58 (95% Cl: 0.43.0.77)

Deaths Aza=82, CCR=113

Time (months) from randomization

P r o p o r t

i o n s u r v

i v i n g

50 1510 2520 3530 400.0

0.10.20.30.4

0.50.60.70.8

0.91.0

AZACCR

Fenaux et al. ASH 2007 (Abstract 817)


23/70

Decitabine in MDS

European phase II studies 1

15 mg/m 2 IV over 8h x 9 doses q6w, median 4 cycles CR 24%, OR 49%US multi-institution randomized study 2

15 mg/m 2 IV over 8h x 9 doses q6w, median 3 cycles CR 9%, OR 30%MD Anderson phase II study 3

20 mg/m 2 IV over 1h daily x5 q5w, median 8 cycles CR 39%, OR 72%

US multi-institution confirmatory phase II study 4 20 mg/m 2 IV over 1h daily x5 q5w, median 5 cycles CR 20%, OR 61% (evaluable patients)

1Wijermans et al. Ann Hematol 2005;84(Suppl 13):9 , 2Kantarjian et al. Cancer 2006;106:1794, 3KantarjianH, et al. Blood,2007; 110: 42a-43a Abstract 115, 4Steensma et al. ASH 2007 (Abstract 1450)

Phase 3 decitabine vs supportive care:


24/70

Phase 3 decitabine vs supportive care:Time to AML or death:

Int-2 and high-risk patients (n=118)

0

20

40

60

80

100

0 100 200 300 400 500 600 700

Survival (days) without AML

P e r c e n

t a

l i v e w

i t h o u

t A M

L Decitabine (n=61)Supportive care (n=57)

0

20

40

60

80

100

0 100 200 300 400 500 600 700

2-sided log-rank test for homogeneity of survival distributions ( P =0.028)

Kantarjian et al. Cancer 2006;106:1794


25/70

D it bi 3 A D i St d


26/70

Decitabine 3-Arm Dosing Study

DemographicsParameter N = 95 (%)

Median Age 65

5% - 9% 29 (31)

10% - 19% 37 (39)

20% - 9% 6 (6)

Duration of MDS 3.2 mos. median

IPSS Int-1/Int-2/High/NA* 19(33)/26(46)/11(20)

CMML 18 (19)

Secondary MDS 30 (32)Prior Therapy 58 (61)

Hb < 11 g/dl 81 (85)Platelets < 100 x 10 9/L 68 (72)

Granulocytes < 1 x 10 9/L 42 (44)

BM blasts:


27/70

3-Arm Dosing Study Data

Responses By Treatment Arm

Schedule No. CR/Total (%)20 mg/m 2 IV x 5 days 25/64 (39)*

20 mg/m 2 SQ x 5 days 3/14 (21)

10 mg/m 2 IV x 10 days 4/17 (24)

*Statistically significant compared to the two other treatment groups

Kantarjian H, et al. Blood. 2007;109:52-57.

3 A D i S d D


28/70


Decitabine ResponsesResponse n = 95 (%)

Complete Response (CR) 32 (34)Partial Response (PR) 1 (1)

Marrow CR 10 (11)

Marrow CR + other HI 13 (14)

Hematologic Improvement (HI) 13 (13)Single lineage 9 (9)2 or 3 lineage 4 (4)

The median number of courses to CR was 3 (range 1-7)

and the median number of cycles for patients was 7.


3 A D i St d D t


29/70


Cytogenetic Responses

Patients Evaluable forCytogenetic Evaluation N=51/95

Total Cytogenetic ResponseComplete CG Response

57%17 (33%)

Partial CG Response 12 (24%)

Median time to cytogenetic response was 2.1 months.


3 A D i St d D t


30/70


Side Effects Grade 3-4Extramedullary n = 95 (%)

Nausea & vomiting, diarrhea, skin rashes, fatigue 0

Bone aches 5 (5)

Liver dysfunction 4 (4)

Myelosuppression # Events/622 courses (%)

Fever of unknown originDocumented bacterial infections

Sepsis aloneMinor infections

Pneumonias + other infectionsBleedingHospitalization

23 (4)

7 (1)24 (4)

20 (3.5)7 (1)

110 (18)Kantarjian H, et al. Blood. 2007;109:52-57.

P i F f R d


31/70

Prognostic Factors for Response andSurvival with Decitabine

Poor prognostic factors for IWG CR: Prior therapy for MDS

MDS rather than CMML Longer duration of MDS disease Patients with none, 1, 2, or 3 adverse factors had CR rates

of 53%, 16%, and 7% respectively

Poor prognostic factors for survival: Chromosome 5 or 7 abnormalities

Older age Prior MDS treatment, excluding growth factors Patients with none, 1, or 2 or 3 adverse factors had

estimated 18-month survival rates of 82%, 50%, and 33%

respectively.

Kantarjian H, et al. Cancer, 2007;109:265-273.

D it bi S i l i Hi h Ri k MDS


32/70

Decitabine Survival in Higher Risk MDSPatients by Prior Therapy

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

Comparison of Decitabine


33/70

Total Intensive Chemotherapy Decitabine

Total/evaluable 115 124% CR 46 44

% PR 0 2% MarrowCR/clinical benefit

0 33

% Death within- 6 weeks 13 3

- 3 months 23 8

Comparison of Decitabine

vs Intensive Chemotherapy


D it bi S i l I t i Ch th


34/70

Decitabine Survival vs Intensive Chemotherapyin Higher Risk MDS (Matched Group)



35/70

Courses to CR (MDS and AML)

Courses Patients CR Deaths/off studyafter course

Received nextcourse

1 104 7 (7%) 2/15 80

2 80 16(20%)

4/12 48

3 48 10(21%)

0/6 32

4 32 5 (16%) 0/5 22

5 22 3 (14%) 0/3 16

6 16 1 (6%) 1/3 11

715 11 1 (9%) 1/9 0Estey et al. ASH 2007 (Abstract 1448)

P15 Expression Induction by


36/70

p yResponse

0 10 20 30-22

-21

-20

-19

-18

-17

-16 CR

non-CR

Days

D e l

t a C T

5.4 foldp=0.011

3.9 foldp=0.012

Yasuhiro Oki Yasuhiro OkiKantarjian H, et al. Blood . 2007


37/70

Confirmatory US Phase II Study

ObjectiveEvaluation of IV dosing of decitabine over 1 hour once daily for 5 days

PatientsMedian age 72 years; 72% male; 89% de novo MDS, median time fromdiagnosis 154 days, and 27% received prior therapyLow 1%; Int-1 53%; Int-2 23%; High 23%

Results: (ITT: 99 patients; 87 patients evaluable for efficacy; 99 for safety)

Best response ITT Eval

CR + mCR 32% 38%

Overall improvement rate (CR + PR + HI) 51% 60%

Stable disease (SD) 24% 29%

Progressive disease (PD) 10% 12%

mCR: marrow CRSteensma et al. ASH 2007 (Abstract 1450)


38/70

ff f d b l b


39/70

Effect of decitabine cycle number on

outcome

0 1 2 3 4 5 6 7 8 905

10

15

20

25

30

35

40

45

Median cycle number

C R ( % )

0 1 2 3 4 5 6 7 8 90

5

10

15

20

25

Median cycle number

S u r v

i v a l ( m o s

)

Complete Response Median Survival

2Kantarjian et al. Cancer 2006;106:1794, 3KantarjianH, et al. Blood, 2007; 110: 42a-43a Abstract 115, 4Steensma et al. ASH 2007 (Abstract 1450)


40/70

Decitabine After Azacitidine Failure

Study Group (n=14) Adults with MDS who progressed

or failed to respond after at least

three courses of azacitidine IPSS Risk Int-2/High 86%(12/14)

BM blast 10% - 86% (12/14) Cytopenias 72% (10/14)

Treatment Decitabine 20 mg/m IV d x 5every four weeks

Results CR 21% (3); Marrow CR with

HI-P 7% (1) Improvement of thrombocytopenia

in 40% (2/5) 27% (4/14) extramedullary toxicity 33% (5/14) febrile neutropenia Median survival 6 months

Borthakur G, et al. Blood, 2006;108:157a [abstract 518].

CR Marrow CR/HI-P0

10

20

30

Response

P a t i e n

t s ( % )

Response to DAC After AZA Failure


41/70

Response to DAC After AZA Failure

0

2

4

6

8

10

12

14

1-Oct Nov-04 Fe b-05 Aug-05 Se p-05 Oct-05 Nov-05 De c-05

H g

b ( g / d L ) , A N C ( x 1 0 + 9

0

50

100

150

200

250

300

350

400

P l t ( x 1 0 + 9 /

Hgb ANC Plt

Azacytidine Decitabine

Blasts 7 1 15 7 1

0

2

4

6

8

10

12

14

1-Oct Nov-04 Fe b-05 Aug-05 Se p-05 Oct-05 Nov-05 De c-05

H g

b ( g / d L ) , A N C ( x 1 0 + 9

0

50

100

150

200

250

300

350

400

P l t ( x 1 0 + 9 /

Hgb ANC Plt

Azacytidine Decitabine

Blasts 7 1 15 7 1

b l d


42/70

Decitabine: Practical ConsiderationsIndications for treatment: MDS INT1 and above, regardless of symptoms, with

response as an endpoint In low risk disease, reserve decitabine for life-threatening

situations: Thrombocytopenia

Severe refractory anemia with high-level transfusiondependenceMyelosuppression most pronounced in first 1-2 months;patients need frequent monitoring and support withtransfusions, prophylactic antibiotics and growth factors forneutropeniaOptimal duration of treatment unknown current practice is tokeep patients on decitabine as long as the response ismaintained and the drug well tolerated

Myelosuppression After Hypomethylating


43/70

Myelosuppression After HypomethylatingDrugs

Myelosuppression generally refers to loss ofnormal hematopoietic cellsIn MDS (and AML/CMML) most circulating cells arepart of the clone (not normal cells)

Myelosuppression in MDS/AML is thought to bepart of clearing the clone and obtaining a responseUsual Myelosuppression is not part of the MTD

determination in drug development in leukemias A more accurate measure of myelosuppression canbe seen by treating patients in CR

Myelosuppression:


44/70

y ppDelay, Dose Reduce, Carry On?

Suggest: Support the patient e.g. prophylactic antibiotics, transfusions

NCCN & ASCO guidelinesConsiderations: Continue full dose vs. dose reduction vs dose delay vs

discontinue RxSuggestions: In the first 3 months, try to continue full dose especially if

platelets back to baseline

If in doubt, check Bone marrow; continue if unchanged orimproved. Delay if empty

For patients treated in remission (>cycle 3) , consider dosereduction by 25% (or by one day) for severe myelosuppression

Hypomethylating Agents in the


45/70

yp y g gSetting of Stem Cell TransplantationSCT is safe in patients who have received hypomethylatingagents

No delayed engraftment No excess toxicityCurrent research:

Do hypomethylating agents peri-transplant boost GVL? Post SCT maintenance with hypomethylating drugs in

high risk AML (and CML)

Future Directions for


46/70

Hypomethylating AgentsDuration of treatmentOther hematologic malignancies: AML, CMLSolid tumorsFurther studies

Alternative dose schedules Mechanisms and targets Decitabine combinations with:

Histone deacetylase inhibitors Colony-stimulating factors Immunomodulators

Chemotherapy

MDS 2008 Treatment Algorithm


47/70

MDS 2008 Treatment Algorithm

SCT Candidate

NoYes

Int-2/High Low/Int-1 Int-2/High

InductionInduction((MTIsMTIs ))

11 stst : EPO+/: EPO+/ -- gCSFgCSF22ndnd /3/3 rdrd :: MTIsMTIs ,,LenalidomideLenalidomide 5q5q-- ::

LenalidomideLenalidomide

HypoplasticHypoplastic ::ATG/ATG/ CsA MTIsMTIs+ SCCsA + SC

CR/PRCR/PR NRNRaSCT aSCT No ResponseNo ResponseProgression ClinicalClinical

trialContinueContinue

TxProgression

trialTx

#30, RAEBT, Untreated


48/70

20 16 18 20

50

100

150

200

250

2 / 2 0 / 2 0 0 1

2 / 2 7 / 2 0 0 1

3 / 6 / 2 0 0 1

3 / 1 3 / 2 0 0 1

3 / 2 0 / 2 0 0 1

3 / 2 7 / 2 0 0 1

4 / 3 / 2 0 0 1

4 / 1 0 / 2 0 0 1

4 / 1 7 / 2 0 0 1

4 / 2 4 / 2 0 0 1

5 / 1 / 2 0 0 1

P l a t e l e t s

0

500

1000

1500

2000

2500

3000

3500

4000

4500

N e u

t r o p

h i l s

WBC

BLSTS

PLTS

Delayed Molecular Responses After MTI


49/70

Therapy

0

25

50

75

100

125

NPM1 mut

LINE

Treatment

N P M 1 m u

t a n t ,

L I N E %

0 25 50 75 100 125 150 175 200 225 250 275 300

Day

0 25 50 75 100 125 150 175 200 225 250 275 300

0

5

10

15 Hb

Plt

0

100

200

300

400

500

600

WBC

Day

H e m o g

l o b i n g

/ d L

P l a

t el

e t 1

0 9

/ L

CR

Case History


50/70

0

5

10

15

20

25

30

35

4 -

F e

b

1 8 -

F e

b

4 -

M a r

1 8 -

M a r

1 -

A p r

1 5 -

A p r

2 9 -

A p r

1 3 -

M a y

2 7 -

M a y

1 0 -

J u n

2 4 -

J u n

8 -

J u l

2 2 -

J u l

5 -

A u g 0

50

100

150

200

250

300

350

400

450

500BM BlastsANCPLTDACDAC

100% 45% 30% 0%

A b n o r m a

l

A b n o r m a

l

X s X s

A b n o r m a

l

A b n o r m a

l

X s X s

73 yo man. MDS (15% blasts) in 5/03; treated withPKC412; AML (29% blasts) in 02/04;

Acknowledgements


51/70

Lanlan Shen Yasuhiro Oki

Ryan CastoroHagop Kantarjian

Gail MorrisRitva TormaBrenda Sassman

Newer Drugs in MDS


52/70

Newer Drugs in MDS

Clofarabine

TipifarnibHistone deacetylase inhibitors

Valproic acid Vorinostat MGCD0103Newer thalidomide derivatives


53/70

Clofarabine in MDS


54/70

30 pts with higher risk MDS Rx with IV clofarabine 15vs 30 mg/m 2/Dx5 (n=15) or PO clofarabine 40 30mg/m 2/Dx5 Q4-6 wksMedian age 68 yrs; prior AZA or DAC 67%; CGabnormal 80%

27 evaluable: CR 7 (26%), HI 2 (7%), CB 2 (7%). OR11/27 = 41%

Responses with IV clofarabine 6/15 = 40%

Faderl. Blood 110:abst 1455, 2007

miRNA 124a Induction and Response


55/70

Mature miR-124a-1 Expression

D a y 1 r

e s p o

n d e r

D a y 1

N o n - r e

s p o n

d e r s

D a y 5 r

e s p o

n d e r

D a y 5

N o n - r e

s p o n

d e r s

D a y 1

2 r e s

p o n d

e r

a y 1 2

N o n - r e

s p o n

d e r s

D a y 3

0 r e s

p o n d

e r

a y 3 0

N o n - r e

s p o n

d e r s

-17

-16

-15

-14

-13

-12

-11

R N U 6 b - m

i r - 1

2 4

ExpressionExpression

CDK6Actin

CDK6 expression by response

D a y

1 r e s p o n

d e r

D a y

1 N o n - r e s p o n

d e r s

D a y

5 r e s p o n

d e r

D a y


d e r s

D a y

1 2 r e s p o n

d e r

D a y

1 2 N o n - r e s p o n

d e r s

D a y

3 0 r e s p o n

d e r

D a y


d e r s

-7

-6

-5

-4

-3

D e l

t a C ( t ) G a p

d h - C

D K 6

MethylationMethylation

RyanRyan CastoroCastoro

Epigenetic Reprogramming Drug Targets


56/70

p g p g g g g

In the clinic: DNA methylation

Histone deacetylationIn development: Methyl-binding proteins

Histone H3K9, H3K27 methylasePotentially: HP1

PCG

Hypomethylating Cytosine


57/70

Analogues

AzacitidineAzacitidine DecitabineDecitabine

AzacitidineAzacitidine Phase IIIPhase IIIOverall SurvivalOverall Survival


58/70

Overall SurvivalOverall Survival

P r o b a

b i l i t y o

f

P r o b a

b i l i t y o

f

R e m a

i n i n g

E v e n

t

R e m a

i n i n g

E v e n

t - - F r e e

F r e e

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

00 66 1212 1818 2424 3030 3636 4242 4848 5454

AzacitidineAzacitidineSupportive CareSupportive Care

p = 0.10p = 0.10

MedianMedian20 months20 months14 months14 months

MonthsMonths

++++++++++++

++++++++

++++++++++

++++

++ ++

++++ ++ ++ ++++++

++ ++ ++ ++ ++

++

Silverman L, J Clin Oncol 2002. 18:2414-26.

Decitabine in MDS3-Arm Dosing Study


59/70

3-Arm Dosing Study

3 decitabine treatment arms: 10 mg/m 2 IV over 1 hr daily x 10 days 20 mg/m 2 IV over 1 hr daily x 5 days 20 mg/m 2 SQ (10 mg SQ BID) daily x 5 daysPreferential randomization to arm with higher CR started after 45 th

patient

Courses were given every 4 weeksTotal = 100 mg/m 2 /course (75% of phase 3 MDS trial dose)Study group

95 patients treated (77 MDS, 18 CMML) 65% patients Int-2/High Risk 69% male, 65% were 60 yrs of age

Kantarjian H, et al. Blood . 2007



60/70

Decitabine Responses By Treatment Arm

Schedule No. CR/Total (%)

20 mg/m 2 IV x 5 days 25/64 (39)

20 mg/m 2 SQ x 5 days 3/14 (21)

10 mg/m 2 IV x 10 days 4/17 (24)

Total 32/95 (34)

Overall (IWG) CR= 34%, PR/HI= 39%, Total Response=74%Overall (IWG) CR= 34%, PR/HI= 39%, Total Response=74%

Kantarjian H, et al. Blood . 2007


61/70

Kantarjian H, et al. Cancer . 2007

Evidence for an Epigenetic Mechanism ofAction of Hypomethylating Agents


62/70

Action of Hypomethylating Agents

Slow responses

Delayed clonal eliminationLoss of responses at higher doses (that favorcytotoxicity)

Correlations between response and early epigeneticmodulation

Sustained hypomethylation Sustained gene expression activation

Epigenetic Silencing MechanismsEpigenetic Silencing Mechanisms


63/70

DNA Methylation andHistone H3-K9 Methylation

Dependent Gene Silencing Loop

Histone H3-K27 Tri-MethylationDependent Gene Silencing

HistoneH3-K27Tri-Methylation

Recruitment ofPcG (e.g.PRC2)

HDACEZH2

Recruitment ofPcG (e.g.PRC1)

Gene silencing

?

DNAmethylation

Histone H3-K9Methylation

DNA Methyl BindingProtein binding

Recruitment of HMT

Recruitment

of DNMT

Recruitmentof HP1

Recruitment of HDAC

RNAi

Yutaka KondoYutaka Kondo

Histone Deacetylase Inhibitors


64/70

y

Valproic AcidButyrate

PhenylbutyrateDepsipeptide

Vorinostat

MS-275LBH-589

MGCD-0103

PXD-101

DAC + Valproic Acid: Synergistic,Schedule Dependent GFP Activation


65/70

Schedule Dependent GFP Activation

0%

10%

20%

30%

40%

50%

60%

70%

80%

C V P

A 2 V P

A 4

D A C

1 0 0

D D D V

P 2

D D D V

P 4

V P 2 D

D D

V P 4 D

D D

G F P P

o s

i t i v e

( % )

VazganushVazganush GharibyanGharibyan

Combination Epigenetic Therapyin Leukemias


66/70

Decitabine + Valproic Acid

Azacitidine + Valproic acid + ATRADecitabine + DepsipeptideDecitabine + Vorinostat

Azacitidine + MGCD0103 Azacitidine + Phenylbutyrate Azacitidine + MS-275 Azacitidine + Vorinostat

Combination Epigenetic Therapyin Leukemias


67/70

Decitabine + Valproic Acid Azacitidine + Valproic acid + ATRADecitabine + DepsipeptideDecitabine + Vorinostat

Azacitidine + MGCD0103 Azacitidine + Phenylbutyrate Azacitidine + MS-275 Azacitidine + Vorinostat

Summary


68/70

The epigenome is markedly abnormal incancer cellsEpigenetic abnormalities accumulate withdisease progression in leukemias and conferpoor prognosisEpigenetic therapy works, particulalry in MDSand AML. But why, how and in whom?The combination of DNA methylation inhibitionand histone deacetylation shows someevidence of synergy in-vivo in patients withsensitive disease

Decitabine/Azacitidine Complete ResponsesDecitabine/Azacitidine Complete Responses(including cytogenetic)


69/70

(including cytogenetic)

Myelodysplastic syndrome, ~5-40%

Acute Myelogenous Leukemia, ~10-30%

Chronic Myelogenous Leukemia, ~30%


70/70

7MDS Novel Therapy

Documents

Transcript of 7MDS Novel Therapy