how i treat hr-mds · 2012. 5. 20. · overall (cr+pr) 29 12 5 12 40 0.0001 cr 17 8 1 8 36 0.02 pr...

1

How I treat HR-MDSHow I treat HR-MDS

Valeria Santini,

UF Ematologia, Università di Firenze

Valeria Santini,

UF Ematologia, Università di Firenze

Santini, Leuk Res 2010

3

OO

NN

NN

NH2NH2

2’-Deoxycytidine2’-Deoxycytidine

OOHOHO

HOHO

OO

NN

NN

NH2NH2

5-aza-2’deoxycitidine5-aza-2’deoxycitidine

OOHOHO

HOHO

NN

OO

NN

NN

NH2NH2

ara-Cara-C

OOHOHO

HOHO

HOHO

OO

NN

NN

NH2NH2

CytidineCytidine

OOHOHO

HOHO OHOH

OO

NN

NN

NH2NH2

5-azacytidine5-azacytidine

OOHOHO

HOHO OHOH

NN

OO

NN

NN

ZebularineZebularine

OOHOHO

HOHO OHOH

Hypomethylating drugs and ARA-C

4

Mechanism of 5-azacytidine and 5-aza-2’ deoxycytidine incorporation into DNA

RNARNA

DNADNA

5-aza-CTP5-aza-CTP5-aza-CDP5-aza-CDP5-aza-CMP5-aza-CMP5-aza-CR5-aza-CR

5-aza-dCTP5-aza-dCTP5-aza-dCDP5-aza-dCDP5-aza-dCMP5-aza-dCMPdecitabinedecitabine

RibonucleotideReductaseRibonucleotideReductaseUridine-Cytidine

KinaseUridine-Cytidine

Kinase

DeoxycytidineKinase

DeoxycytidineKinase

phosphatasephosphatase

phosphatasephosphatase

5

DNMT inhibitors induce DNA hypomethylation

DNMT inhibitors induce DNA hypomethylation

• Azacitidine (AZA) is incorporated into RNA and then DNA• Inactivates DNMT• Leads to formation of newly synthesized DNA with unmethylated cytosine residues• Results in hypomethylation and transcription of previously quiescent genes

• Azacitidine (AZA) is incorporated into RNA and then DNA• Inactivates DNMT• Leads to formation of newly synthesized DNA with unmethylated cytosine residues• Results in hypomethylation and transcription of previously quiescent genes

DACDACDNMTDNMT

ACG

mCG

ACG

mCG

TGCGCm

TGCGCm

:::::

::::: DNMTDNMT

AZAAZA

ACGCG

ACGCG

TGCGC

TGCGC

:::::

:::::

AzAzDMT

DMT

Silverman L. Oncologist 2001;6(S5):8–14Permission from The Oncologist, AlphaMed Press

6

Blood 64:922-927, 1984

No cytotoxicity differentiation

a 20 mg/m2/day for 14 days every 28-42 days.AZA, azacitidine; BSC, best supportive care; CCR, conventional care regimen; chemo, chemotherapy.

AZA-001: Phase 3 Survival Study Design

Fenaux P, et al. Lancet Oncol. 2009;10:223-232.

• Treatment continued until relapse, unacceptable adverse events, or disease progression

• Primary endpoint: overall survival

Low-dose cytarabinea

(n = 94)Best supportive care

(n = 222)Intensive chemo

(n = 42)

AZA(n = 117)

AZA(n = 45)

AZA(n = 17)

BSC(n = 105) (n = 49)

Low-dose cytarabinea

(n = 49)

Chemo(n = 25)

Randomization

Investigator preselection of appropriate CCR

358 patients enrolled

7

Baseline Clinical CharacteristicsN = 358

Baseline Clinical CharacteristicsN = 358

ParameterAZA

N=179CCR

N=179

CCR RegimensBSC Only

N=105LDAC N=49

Std Chemo N=25

Age (yrs) MedianPts ≥ 65 (%)

6968

7076

7077

7186

6552

FAB (%) RAEBRAEB-TCMML

58343

58353

65294

51392

40520

IPSS (%) INT-1INT-2High

34346

73948

94444

44343

81272

AZA-001: Azacitidine vs CCR – Overall Survival

Log-rank P < .0001HR: 0.58; 95% CI 0.43-0.77 Deaths: AZA = 82; CCR = 113

0 5 10 15 20 25 30 35 40Time From Randomization (Months)

0

10

20

30

40

5060

70

80

90

100Pe

rcen

tage

Sur

vivi

ng

CCRAZA

24.5 months

15 months

50.8%

26.2%

AZA, azacitidine; CCR, conventional care regimens; CI, confidence interval; HR, hazard ratio; OS, overall survival.

• AZA significantly prolonged OS compared with CCR (P < .0001)‒ Difference in median OS was 9.5 months

Adapted from Fenaux P, et al. Lancet Oncology. 2009;10:223-232 © 2009 with permission from Elsevier.

9

• Median OS was significantly longer with AZA vs LDAC (24.5 vs 15.3 months)– 2-year OS was 54% for AZA and 27% for LDAC

AZA vs LDAC Subanalysis: Overall Survival

AZA, azacitidine; CI, confidence interval; HR, hazard ratio; LDAC, low-dose ara-C; OS, overall survival.

10

Fenaux P, et al. Br J Haematol. 2010;149:244-249.

24.5 months

15.3 months

P = .0006

1.0

0.8

0.6

0.4

0.2

0.00 5 10 15 20 25 30 35 40

Prop

ortio

n Su

rviv

ing

Time From Randomization (Months)

AZA

LDAC

AZA-001: Clinical Responsea to Azacitidine in Higher-Risk MDS1,2

• Of 179 higher-risk patients (RAEB, RAEB-t, or CMML), 91 (51%) achieved a response

– 33% CR (n = 30)

– 23% PR (n = 21)

– 44% HI (n = 40) • 91% of responding patients (CR, PR, or HI) achieved a

response by cycle 6, and the remaining 9% of responders by cycle 12 (except 1 responder at cycle 16)

• 48% of responders achieved an improved response after their first response with continued azacitidine treatment

1. Silverman LR, et al. Cancer (in Press).2. Cheson BD, et al. Blood. 2000;96:3671-3674.

a Per IWG response criteria.2CMML, chronic myelomonocytic leukemia; CR, complete response/remission; HI, hematologic improvement; MDS, myelodysplastic syndromes; PR, partial response/remission; RAEB, refractory anemia with excess blasts; RAEB-t, RAEB in transformation.

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Secondary EndpointsSecondary Endpoints

• Time to AML or death– 13 mos with AZA vs 7.6 mos with CCR, p=0.003

• Time to AML– 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

Secondary Endpoints: IWG (2000) RR and HISecondary Endpoints: IWG (2000) RR and HI

Response

AZA N=179

(%)

CCR N=179

(%)

CCR RegimensBSC Only

N=105(%)

LDAC N=49

(%)

Std Chemo N=25

(%)

P-ValueAZA vs

CCROverall (CR+PR) 29 12 5 12 40 0.0001

CR 17 8 1 8 36 0.02PR 12 4 4 4 4 0.009

IWG HIMajor+Minor 49 29 31 25 28 <0.0001HI-E Major 40 11 8 10 22 <0.0001HI-P Major 33 14 10 19 20 0.0003HI-N Major 19 18 20 11 24 0.87

Additional Analysis: Median OS by Investigator Selection

Additional Analysis: Median OS by Investigator Selection

Treatment

DifferencesK-M OS

Time mosK-M OS

Time mosHazard Ratio

Log-rank P

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

21.1

11.5 9.6 0.56 0.002AZA (N=45)vs LDAC (N=49)

24.5

15.3 9.2 0.58 0.075AZA (N=17) vsStand Chemo (N=25)

25.1

15.7 9.4 0.87 0.75

Grade 3 and 4 Hematologic ToxicityGrade 3 and 4 Hematologic Toxicity% of Patients

Conventional Care Regimens

Grade 3-4 ToxicityAZA

N=175BSC

N=102LDAC N=44

Std Chemo N=19

Neutropenia 91 71 88 94Thrombocytopenia 85 71 98 100Anemia 56 67 76 61Pts with Baseline Grade 0-2 shifting to Grade 3-4 on TxNeutropenia 84 48 79 83Thrombocytopenia 74 54 97 100Anemia 54 61 79 50

Hazard Ratio and 95% CI for Overall SurvivalHazard Ratio and 95% CI for Overall SurvivalITT Subgroups Total - Event / N

Cytopenias: 0/1 20 / 53

WHO: RAEB-1 15 / 31

0.125 0.250 0.500 1 2 4

Favors Azacitidine Favors CCR

≥ 65 150 / 258

Female 61 / 107FAB: RAEB 95 / 207

RAEB-T 80 / 123

RAEB-2 102 / 193IPSS: INT-2 71 / 146

High 98 / 167Cytogenetics: Good 80 / 167

Intermediate 38 / 76Poor 67 / 100

2/3 167 / 290

Karyotype: -7/del (7q) 42 / 57

≥ 21% to < 31% 58 / 99

AGE: < 65 45 / 100

LDH: ≤ 240 U/I 97 / 208

RAEB & RAEB-T: AGE ≥ 65 138 / 240

> 240 U/I 94 / 145

ITT 195 / 358

≥ 75 50 / 87

≥ 11% to < 21% 98 / 192

Male 134 / 251

BM Blasts: ≥ 5% to < 11% 34 / 61

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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%

List, 2008

18

AZA vs CCR: OS in Pts with Best Response of CR


0.00.10.20.30.40.50.60.70.80.91.0

Prop

ortio

n Su

rviv

ing

AZA-CR

CCR-CR

# at riskAZA 30 30 29 24 13 7 3 0 0CCR 14 14 13 10 7 3 1 0 0

26.3 months

21.9 months

Log rank p = 0.078HR=0.39 [95% CI: 0.14–1.15]Death: AZA = 7, CCR = 9Difference: 4.4 months

24

43.7%

78.4%

19

AZA vs CCR: OS in Pts with Best Response of CR + PR

Log rank p=0.314HR=0.66 [95% CI: 0.30–1.48]Death: AZA = 14, CCR = 11


0.00.10.20.30.40.50.60.70.80.91.0

Prop

ortio

n Su

rviv

ing

AZA – CR+PR

CCR – CR+PR24.8 months

24

52.6%

74.7% Median not Reached

List, 2008

20

AZA vs CCR: OS in Pts with Best Response of HI

AZA vs CCR: OS in Pts with Best Response of HI

Log rank p = <0.0001HR=0.23 [95% CI: 0.10-0.51]Death: AZA = 8, CCR = 27

# at riskAZA 40 40 36 25 15 7 2 0 0CCR 41 37 26 18 8 5 3 0 0

0 5 10 15 20 25 30 35 40

Time (months) from Randomization

0.00.10.20.30.40.50.60.70.80.91.0

Prop

ortio

n Su

rviv

ing

AZA - HI

CCR - HI

16.6 months

24

71.7%

27.1%

Median not reached

Patients should be treated with azacitidine for at least 6 cycles

or until disease progression

Santini V, et al. Eur J Hematol

AZA-001: baseline demographics of azacitidine responders*

AZA(N=91)

AZA(N=91)

ECOG status, n (%) IPSS, n (%)†

Grade 0 47 (52) Low 0Grade 1 39 (43) Intermediate-1 3 (3)Grade 2 4 (4) Intermediate-2 38 (42)Missing 1 (1) High 44 (48)

Cytopenias, n (%) Not Applicable 2 (2)1 3 (3) Indeterminable 4 (4)2 30 (33) Transfusion dependent, n (%)3 58 (64) RBC 57 (63)

*IWG 2000 CR, PR, or HI; †Diagnosis by Central Review CommitteeECOG = Eastern Cooperative Oncology Group; RBC = red blood cell; CR = complete responsePR = partial response, or hematologic improvement

Silverman LR, et al Cancer in press

AZA Cycles

IWG 2000 Response Median RangeOverall (n=91) 14.0 2-30

CR (n=30) 16.5 5-30

PR (n=21) 14.0 2-27

HI (n=40) 11.5 3-25

Of 179 patients who received AZA, 91 (51%) achieved an IWG 2000 response (CR, PR, or HI)

Azacitidine treatment cycles received by patients achieving a

response

Silverman LR, et al. Cancer in press

24

Time to First Response (CR, PR, or HI)

Cum

ulat

ive

Prob

abili

ty

Number of Subjects91 34 12 6 3 1 1 1

Time (cycles)

50%, 2 cycles

87%, 6 cycles

Range: 1-22 cycles

Silverman, et al Cancer in press

25

Time to Best Response C

umul

ativ

e Pr

obab

ility

Number of Subjects91 64 31 16 7 2 1 1

Time (cycles)

50%, 4 cycles

Silverman, et al. Cancer in press

0

1

2

3

PR as Best Response After aFirst Response (HI)

CR as Best Response After aFirst Response (HI or PR)

Time from first to best responseContinued azacitidine dosing led to a higher IWG response

category in 48% of patients

Med

ian

Mon

ths

from

Fi

rst t

o B

est R

espo

nse

(n=21) (n=30)

3.2 months(95% CI: 2.4–6.9)

2.3 months(95% CI: 0.3–3.0)

Silverman LR, et al. Cancer in press

• Patients achieving a best response of HI+ with AZA had a significantly longer OS than those achieving an HI+with CCR

AZA, azacitidine; CCR, conventional care regimen; CR, complete response/remission; HI, hematologic improvement; HI+: CR, PR, and/or HI; HR, hazard ratio; OS, overall survival; PR, partial response/remission.

0 3 6 9 12 18 24 30 36

0 3 6 9 12 18 24 30 36

AZA-001 ‒ Multivariate Analysis: Relationship Between OS and HI+

HI+ at 6 Months

HI+ at 9 Months

Gore S, et al. J Clin Oncol. 2010;28:abstract 6503.

0 3 6 9 12 18 24 30 36

HI+ at 3 Months

AZA-001 ‒ Multivariate Analysis: Relationship Between OS and SD at 3 Months

AZA, azacitidine; CCR, conventional care regimen; OS, overall survival; SD, stable disease.

• Overall survival in patients achieving a best response of SD with AZA or with CCR was similar at 3, 6, and 9 months of therapy


AZA-001 ‒ Multivariate Analysis: Continued AZA Improved Responses Beyond Stable Disease

Response at 6 months for patients with SD at 3 months

• 21% of AZA-treated patients compared with 14% of CCR-treated patients with SD at 3 months achieved an HI+ by 6 months

• 14% of AZA-treated patients compared with 0% of CCR-treated patients with SD at 6 months achieved an HI+ by 9 months

AZA, azacitidine; CCR, conventional care regimen; CR, complete response/remission; HI, hematologic improvement; HI+, CR, PR, and/or HI; OS, overall survival; PR, partial response/remission; SD, stable disease.

29


Response at 9 months for patients with SD at 6 months

Azacitidine in MDS – AEs can be managed

• Most common AEs in AZA-001 (≥20%) included non-hematologic (injection site reactions and GI) and hematologic events

• Majority of events were transient (median 13 days), non-serious and resolved during the trial

• Most hematologic events occurred during the first two cycles

• There were no cumulative or delayed toxicities

Santini V, et al Eur J Hematol, 2010 GI = gastrointestinal

Hospitalization rates per patient year

20.1

29.0

21.825.5

31.6

38.8

0

10

20

30

40

50AZA CCR

All* AE

Rat

e Pe

r Pat

ient

-yea

r

RR=0.77P=<0.0001

Transfusions

RR=0.70P=<0.0001

RR=0.82P=<0.0001

Santini V, et al Eur J Hematol, 2010

*Excluding “social” reasons; i.e. pt remained in hospital overnight due to transportation issueRR = response rate; AE = adverse event

AZA-001: Common AEs Consistent with Known Azacitidine Safety Profile

Grade 3/4 AEs AZA-001 (n = 175)Hematologic, %

Anemia 13.7Neutropenia 61.1Thrombocytopenia 58.3

Nonhematologic, %Constipation 1.1Diarrhea 0.6Nausea 1.7Fatigue 3.4Injection site reaction 0.6Pyrexia 4.6

Santini V, et al. Eur J Haematol. 2010;85:130-138. AE, adverse event.

• The majority of AEs (> 83%) were transient and resolved during therapy

32

Mean hemoglobin change from baseline: azacitidine vs CCR

# at riskAZA 175172172 172172172172172172172172172172172172172172172 172 172 172 172CCR 176159159 159159159159159159159159159159159


-5

-2.5

0

2.5

5

7.5

10

Mea

n (±

SE) H

emog

lobi

n (g

/L)

Cha

nge

from

Bas

elin

e AZA CCR

0 6 10 16 20 26 30 36 402 4 8 12 14 18 22 24 28 32 34 38 42

Celgene, data on file

Mean platelet change from baseline: azacitidine vs CCR

# at riskAZA 167 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164 164CCR 170 153 153 153 153 153 153 153 153 153 153 153 153 153

-25

-15

-5

5

15

25

Mea

n (±

SE) P

late

let (

10%

/L)

Cha

nge

from

Bas

elin

e

AZA CCR

0 6 10 16 20 26 30 36 402 4 8 12 14 18 22 24 28 32 34 38 42

Celgene, data on file


35

a Asterisks (*) indicate transfusions of platelets or packed RBC transfusions given. Dashed lines indicate individualized subject targets: platelets 140 g/L, hemoglobin 133 g/L, blasts 5%. WBC values > 10 g/L are plotted as 10.RBC, red blood cells; RAEB, refractory anemia with excess blasts; WBC, white blood cells.

White male, 69 years of age with RAEB MDS diagnosis at study entry

Azacitidine treatment

Initial Cytopenias Improve With Continued Treatmenta

Data on file.

100

200

300

400

Plat

elet

s (g

/L)

2468

10

WB

C(g

/L)

Hem

oglo

bin

(g/L

)

6080

100120140160 * * * **

48

121620

Bla

sts

(%)

-100 0 100 200 300 400Days From First Exposure to Azacitidine

AZA-001: Most AEs Decreased With Continued Azacitidine Treatment

a All grades. b Multiple reports of the same AE during a cycle were counted once.AE, adverse event; ISR, injection site reaction; Neutro, neutropenia; Thrombo, thrombocytopenia.

Hematologic AEsa Nonhematologic AEsa

• Adverse events occurred early in treatment and decreased in frequency over time

• Adverse events were transient, resolving within 16 days

36

Santini V, et al. Eur J Haematol. 2010;85:130-138.

AZA-001: Approaches to Managing AEsAEs in AZA-001 tended to resolve with continued treatment and management

AZA, azacitidine; AE, adverse event; G-CSF, granulocyte colony-stimulating factor.

Type of AE` AZA Dose Reduction/Delay Management

Hematologic

• 29% events managed by dose delay

• 9% events managed by dose reduction

• Anemia: transfusions (87%)• Thrombocytopenia: transfusions

(29%)• Febrile neutropenia: antibiotics

(15%)• Neutropenia: short course of G-CSF,

if severe

Gastrointestinal ―• Concomitant medication: anti-emetics,

laxatives, stool softeners, and anti-diarrheals

Injection site reactions ―

• Concomitant medication: corticosteroids and/or antihistamines

• Fewer than 12% events required treatment (most were self-resolving)

Fatigue and pyrexia

• 5% (fatigue) and 6%(pyrexia) events managed by dose delay

―

• The majority of patients (86%) received the full dose of AZA during the study with a median cycle length was 28 days

37


Dose modification or cycle delay if:

Baseline WBC ≥ 3 × 109/L and ANC ≥ 1.5 × 109/L and platelets ≥ 75 × 109/L

Baseline WBC < 3 × 109/L or ANC < 1.5 × 109/L or platelets < 75 × 109/L

ANC nadir ≤ 1 × 109/L and/or platelet nadir < 50 × 109/L

WBC or ANC or platelet nadir decreased ≥ 50% from baseline

ANC = absolute neutrophil countG-CSF = granulocyte colony-stimulating factorWBC = white blood cell

Management of hematologic AEs


AEs With Continued Azacitidine in AZA-001: Summary

• Most hematologic events occurred during the first 1-2 cycles (33%-54%) and were reported less frequently in later cycles

• Bleeding and infection rates were not increased in patients treated with azacitidine vs BSC

• Most common AEs should be:– Monitored– Managed by dose delays or reductions – Managed by supportive care

• Most AEs improved with continued treatment– Majority of AEs were transient (> 83%) and resolved with ongoing

treatment

AE, adverse event; BSC, best supportive care.

39


Are there factors predictive of response to azacitidine?

Elderly MDS patients respond to azacitidine treatment

1. Fenaux P, et al. Lancet Oncol 2009;10:223–322. Seymour JF, et al. Poster presented at ASH 2008, San Francisco, CA, USA

0102030405060

Azacitidine CCR2-

year

sur

viva

l (%

) 55

15

p<0.0003

0102030405060

Azacitidine CCR

2-ye

ar s

urvi

val (

%) 51

26

p<0.0001

2-year survival(all patients)1

2-year survival(patients aged >75 years)2

AZA-001: azacitidine significantly improves overall survival in elderly

patients (≥75 years)

5544

58

1522

39

0

20

40

60

80

100

2-year OS Transfusionindependence

IWG 2000 HI (any HI)

AZA CCR

p = 0.0193p = 0.139

p = 0.088

Perc

enta

ge

Seymour JF, et al. Poster presented at ASH 2008. [abstract 3629]

AZA-001: azacitidine is well tolerated by elderly patients

(≥75 years)AZA

(n = 38)CCR

(n = 47)

Age, years, median (range) 78 (75–83) 77 (75–88)Male gender, % 71 63Grade 3 and 4 treatment related AEs

Patients with ≥1 AE, % 82 72Discontinuations due to AE, % 13 8Anaemia, % 13 4Neutropenia, % 61 17Thrombocytopenia, % 50 30Infections and infestations, % 40 26

Seymour JF, et al. Poster presented at ASH 2008. [abstract 3629]AE = adverse event

• OS similar in patients aged < 80 and ≥ 80 years (P = .6)

• Median OS 12.1 months; 1- and 2-year OS: 50% and 23.2%

Itzykson, R., et al. Blood. 2009;114(22):705.OS, overall survival.

Azacytidine (AZA) in Higher Risk MDS Patients (pts) Aged ≥ 80 Years : OS1.0

0.8

0.6

0.4

0.2

0.0

5

OS

Time (months)

‘Real-world’ experience with azacitidine in patients with MDS, AML or CMML: Austrian Azacitidine Registry

Pleyer L, et al. Poster presentation at 11th International Symposium on MDS 2011, Edinburgh, UK. Abstract 101

Age <80 years (n=139)

Age ≥80 years (n=44)

p=0.298312.6 months

9.2 months

OS was similar in patients aged <80 years old and patients aged ≥80 years old

Poor karyotype

• There was a trend for a survival advantage with AZA vs CCR in pts with normal karyotype

• Patients with non-complex karyotypes had a substantially longer OS than patients with complex karyotypes, regardless of treatment

AZA, azacitidine; CCR, conventional care regimen; HR, hazard ratio; NR, not reached; OS, overall survival.

NR

25.1

9.9

24.5

5.3

26.3

17.317.2 17.3

4.98.1

4.2

8.74.9

0

5

10

15

20

25

30

35

AZA CCR

Med

ian

Surv

ival

(mon

ths)

HR = 0.63(0.39 – 1.03)

HR = 0.43(0.05 – 3.80)

HR = 0.55(0.29 – 1.05)

HR = 0.33(0.10 – 1.13)

HR = 0.45(0.17 – 1.22)

HR = 0. 20(0.06 – 0.65)

HR = 0.42(0.10 – 1.69)

Deaths: 29 41 3 9 20 23 7 9 11 14 6 11 5 7# pts: 77 76 5 10 29 29 16 11 14 15 16 12 9 9

Normal -5/5q- -7/7q- Trisomy 8Non-complex Complex Non-complex Complex Non-complex Complex

Mufti GJ, et al. Blood. 2009;114(22):697-698.

Effect of Cytogenetic Abnormalities on Overall Survival

AZA-001: Azacitidine vs CCR – Overall Survival By Cytogenetic Risk

AZA vs CCR1

Cytogenetic Parameter Hazard Ratio 95% CI P Value

Poor-prognosisa 0.53 0.32-0.87 .012Intermediate-prognosisa 0.44 0.22-0.88 .021Good-prognosisa 0.59 0.37-0.92 .021-7/del(7q) 0.34 0.17-0.67 .0017

1. Fenaux P, et al. Lancet Oncol. 2009;10:223-232. 2. Yiu RC, et al. Haematologica. 2010;95:abstract 324.

• AZA significantly prolonged OS compared with CCR, regardless of IPSS-defined cytogenetic risk1

• AZA significantly prolonged OS in patients with -7/del(7q) compared with CCR (13.1 vs 4.6 months)1

a IPSS-defined risk.AZA, azacitidine; CCR; conventional care regimens; CI, confidence interval; IPSS, International Prognostic Scoring System; OS, overall survival.

50

Overall OS in MDS Patients with -7/del(7q)AZA vs CCR (AZA-001)


0.00.10.20.30.40.50.60.70.80.91.0

Prop

ortio

n Su

rviv

ing

AZA

CCR

# at riskAZA 30 22 20 9 5 1 0 0 0CCR 27 10 5 4 2 1 1 0 0

HR = 0.33 (95% CI: 0.16, 0.68)log-rank p-value: 0.002

4.6 months

13.1 months

Methylation status

53

Gene methylation and prolonged OSCDH1 methylation 0.00

Time (months) from randomization

Pro

porti

on s

urvi

ving

7.2 months

AZA

CCR

12.0 months†HR: 0.68, 95% CI (0.30–1.55)

p=0.353

† Relative to CCR methylation 0.00 Herman JG, et al. Presented at AACR 2009 [Abstract 4746]

54

Gene methylation and prolonged OS


19.5 months†HR: 0.51, 95% CI (0.25–1.06)

p=0.071

26.3 months†HR: 0.26, 95% CI (0.12–0.53)

p<0.001

AZA

CCR

CDH1 methylation >0 – ≤0.62

† Relative to CCR methylation 0.00

Pro

porti

on s

urvi

ving

Herman JG, et al. Presented at AACR 2009 [Abstract 4746]

55


Pro

porti

on s

urvi

ving

18.7 months†HR: 0.40, 95% CI (0.20–0.83)

p=0.013

25.1 months†HR: 0.39, 95% CI (0.20–0.76)

p=0.006

AZA

CCR

CDH1 methylation >0.62 – ≤1.62




56

12.3 months†HR: 0.74, 95% CI (0.38–1.41)

p=0.355

17.1 months†HR: 0.44, 95% CI (0.22–0.89)

p=0.022

AZA

CCR

CDH1 methylation >1.62




Pro

porti

on s

urvi

ving


Methylation pattern and response

Shen , 2010

Methylation pattern and responseto therapy

Shen , 2010

AZA in AML

• AML in the elderly carries a poor prognosis even when treated with intensive chemotherapy (IC) (median survival of 7 to12 months) and most elderly AML patients cannot receive IC due to their age and/or comorbidities

• 1/3 of pts in AZA-001 had WHO AML with 20-30% of marrow blasts

Overall Survival in AML /RAEB-T: AZA vs CCR Fenaux et al. JCO, 2010

OS in Patients AML/RAEB-TUnfit for IC Fenaux et al. JCO, 2010

Marrow CR Rates in AML/RAEB-T pts

% o

f pts

with

CR p=0.80

(10/55) (9/58)

CCR Regimens

(3/20) (6/11)(0/27)

Fenaux et al. JCO, 2010

Hem

oglo

bin

(g/d

l)N

eutr

ophi

ls

(x 1

09/l)

azacitidine 100 mg 5gg 11 cy azacitidine 75 mg/m2 7 gg 3 cy

0,000,400,801,201,602,002,40

02468

1012

Which is the best dose? Courtesy MT Voso

Comorbidities

Italian registry for MDS (1617pts)age distribution

A. Levis, 2011 data on file

Italian registry for MDSpresence of comorbidities

(388 pts)

63% withcomorbidities (CIRS)

Grade 0-2

37% 37% 20% 18%

A. Levis, 2011 data on file

67

IWG Response to azacitidine is not adversely influenced by comorbidities

Sanna A, et al. Oral Presentation at ASH 2010, Orlando, USA

0

20

40

60

80

100

Charlson Comorbidity Index

Cumulative Illness Rating Scale

Adult Comorbidity Evaluation-27

Res

pons

e ra

te*

(%)

0 1 2 3 50

20

40

60

80

100

Res

pons

e ra

te*

(%)

0 1 2 3 4 6

ScoreScore

0

20

40

60

80

100

Res

pons

e ra

te*

(%)

Non

e

Mild

Mod

erat

e

Sev

ere

Score

A single centre study of 59 elderly patients with MDS treated with azacitidine§ Mean age, years (range) = 69 (50–82)§ Mean number of cycles, n (range) = 9 (2–42)

*CR+PR+HI

Distribution per score of 127 IPSS HR MDS pts treated with azacitidine

none

mildmoderatesevere

01>=2

01 and 2

>=3

ACE 27CCI

CIRS

LowINTHigh

MDS-CI

Sanna et al, abs1756, ASH 2010

OS from diagnosis: AZA vs CCR

CIRS TrattamentoK-M OS

Dalla diagnosi

DifferenzeK-M OS

Differenza mesi

Log Rank p

Tutti i patienti

AZA (n 172)vsCCR (n 157)

36

17

19 0.000

0AZA (n 64)vsCCR (n 118)

50

21

29 0.002

1-2AZA (n 84)vsCCR (n 33)

29

9

20 0.000

>=3AZA (n 17)vsCCR (n 5)

14

11

3 0.429

A Prognostic Score for Overall Survival (OS) with Azacitidine (AZA) In Higher Risk MDS

282 HR- MDS ; 74/282 sMDS treated with AZA;

• Prognostic factors for response: prior therapy, marrow blasts, poor cytogenetics

• PF for OS: secondary MDS, cytogenetics, PB blaststransfusion dependency and PS

• 1 point for ECOG performance status >= 2• 1 point for Presence of circulating blasts• 1 point for RBC TD 4 RBC units/8 weeks• 1 for IPSS intermediate- cytogenetics• 2 points IPSS poor-risk cytogenetics * Itzykson , Blood 2011

•3 risk categories: Low (score 0)Intermediate (score 1-3)High (score 4-5)

* Itzykson , Blood 2011

Occurrence of adverse eventsduring azacitidine therapy is notsignificantly influenced by agenor moderate comorbidities.

.

Age per se should not drivetherapeutical decisions in HR-MDS .

Careful scoring of comorbitiesmay help in decision making.

.

Clinical case• Female patient aged 78 with two previous acute

myocardial infarctions, diabetes, but otherwise in good general condition, still active at work, referred for pancytopenia

Clinical assessment: DyspnoeaWBC: 2.1 x109/LANC: 0.45 x109/L Hb: 8.6g/dLPlatelets: 79 x109/LBone marrow aspirate: 10% blastsKaryotype: 45XX, –7WHO classification: RAEB-2IPSS: Score 2 = Int-2

Question: what is your first-line treatment?

1. Intensive anthracycline–AraC chemotherapy (3+7)

2. Supportive care only

3. Low-dose AraC

4. Fludarabine + AraC + G-CSF (FLAG)

5. Azacitidine

Treatment decision

• Treatment decision: azacitidine 75 mg/m2/day for 7 days every 28

• Patient was treated in a hospital near home because she had her hat factory to run and manage

Treatment follow-up

• After 2 courses, the referring and treating haematologists called our Centre– blood counts were unchanged– patient required 2 RBC units every 2 weeks– marrow blasts 9%, karyotype unchanged

• The patient claimed that her symptoms were getting worse (dyspnoea, fatigue) and she was not as active as before

• She was very disappointed and wanted to stop treatment

Question: what would you do at this stage?

1. Continue azacitidine

2. Switch to low-dose Ara-C

3. Switch to intensive chemotherapy


5. Proceed to HLA typing with the idea of an allogeneic SCT transplantation

Question: How would you manage pancytopenia?

1. Delay the following cycle for one week

2. Wait until counts are normal

3. Start cycle 3 with dose reduced to 75% (=100mg, one vial)

• During the first three cycles, thepatient claims severe stipsis andinjection site reactions.

AZA-001: injection site reactions

No injection site reaction required adjustment ofazacitidine dosing or resulted in discontinuation

• The median duration of injection site reactionswas 12 days

• Overall, <12% of injection site reactions, including erythema, required treatment with concomitant medications

Santini V, et al. Eur J Haematol 2010;Epub ahead of print

Patient Follow-up

• Cycle 6 transfusion independent, PR

• Very active at work

• No complaints

Question: what would you do at this stage?

1. Continue azacitidine

2. Switch to low-dose Ara-C

3. Switch to intensive chemotherapy


5. Proceed to HLA typing with the idea of an allogeneic SCT transplantation

Patient Follow-up

• Patient has completed 18 cycles

• Still hematological response

• Bone marrow response to be checked

MDS group in FlorenceMDS group in Florence

how i treat hr-mds · 2012. 5. 20. · overall (cr+pr) 29 12 5 12 40 0.0001 cr 17 8 1 8 36 0.02 pr...

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