poročilo eha 2012 s j12.pdf · ambaglio i, et al. poster presentation at eha 2010; abstract 0310...

1

Poročilo EHA 2012

Simon Bitežnik

2

Burden of chronic anaemia in patients

with MDS Anaemia is a major clinical problem in patients with

MDS

~80% patients are anaemic at diagnosis1

In patients with MDS, anaemia has a negative impact

on

Survival2

Risk of NLD2

HRQoL3

In patients with MDS, the severity of anaemia

correlates with IPSS category4

1. Kelaidi C, et al. Haematologica 2010;95:892–9

2. Ambaglio I, et al. Poster presentation at EHA 2010; Abstract 0310

3. Jansen AJG, et al. Br J Haematol 2003;121:270–4

4. Kao JM, et al. Am J Haematol 2008;83:765–70

3

Treated with EPO (n=403)

Untreated (n=628)

Overa

ll s

urv

iva

l (%

)

100

80

60

40

20

0

0 2 4 6 8 10 Years*

EPO responders

Non-responders

Untreated

P<0.001

EPO therapy may improve OS in

erythroid responders

Park et al. Blood 2008;111:574–82 *from diagnosis or from EPO treatment initiation

4

Not all MDS patients will respond to

EPO: prognostic factors

At multivariate analysis, factors associated with response were:

Transfusion-independence

Serum EPO levels

Karyotype

Baseline Hb levels

Latagliata et al. Acta Haematologica 2008;120:104–107

For each g/dl increase in pre-treatment Hb, l

the probability of response increased by

98% (p=0.02)

Variables

Hazard Ratio

(95% confidence internal) P

Age 1.011 (0.981–1.042) 0.464

Males 0.792 (0.385–1.628) 0.526

Time from diagnosis 0.995 (0.980–1.010) 0.507

Serum Epo levels 0.993 (0.986–1.000) 0.046

Hb 1.845 (1.235–2.756) 0.003

Cytogenetics 0.479 (0.244–0.938) 0.032

LDH 1.000 (0.999–1.002) 0.720

Ferritin 1.000 (1.000–1.000) 0.845

TD 2.867 (1.354–6.070) 0.006

Univariate Cox regression analysis of response

5

Poor response to EPO in patients with

del(5q) versus non-del(5q) MDS

Kelaidi C, et al. Leuk Res 2008;32:1049–53 DAR = darbepoietin

Retrospective analysis of 345 patients with MDS treated with EPO or DAR

p=0.03 p=0.02

6

MDS-004: significant improvements in RBC-TI in

patients randomised to lenalidomide versus

placebo

Fenaux P, et al. Blood 2011:118;3765–76

†mITT population defined as patients with centrally

confirmed MDS who received ≥1 dose

*

RB

C-T

I (%

)

30

50

60

70

10

0 Protocol defined IWG 2000

(≥26 weeks) (≥8 weeks)

40

20

Placebo (n=51)

LEN 5mg (n=47)

LEN 10mg (n=41)

*p<0.001 versus placebo

Bars represent 95% CI

mITT population†

6

43

56

51

61

8

*

*

*

7

Lenalidomide vs placebo

Erythroid response associated with better

survival

Fenaux P, et al. Blood 2011;118:3765-76

Time (days)

p=0.0085

Leu

kem

ia-f

ree s

urv

iva

l

0.4

0.6

0.8

1.0

0.2

0 0 1 2 3 4 5

Erythroid responders

Erythroid

non-responders

Time (days)

p=0.0028

Overa

ll s

urv

iva

l

0.4

0.6

0.8

1.0

0.2

0 0 1 2 3 4 5

Erythroid responders

Erythroid

non-responders

8

Azacitidine induces erythroid responses

in higher risk MDS

Silverman LR, et al. J Clin Oncol 2002;20:2429–40 BSC = Best supportive care

*P<0.0001; †P<0.01

AZA BSC

Responses (CR + PR) 23 (23%)* 0%

Complete response (CR) 7 (7%)† 0%

Partial response (PR) 16 (16%)† 0%

Haematological improvement 37 (37%) 5%

9

p≤0.0001

HR=0.23 [95% CI: 0.10–0.51]

Time from randomisation

0

0.2

0.4

0.6

0.8

1.0

Su

rviv

al

Patients experiencing haematological

improvement with azacitidine treatment have a

better OS

List AF, et al.Oral presentation at ASCO 2008; Chicago, IL, USA

0 5 10 15 20 25 30 35 40

AZA

CCR 24

71.7%

16.6 mo.s 27.1%

Median not reached

10

Conclusions

Iron chelation therapy in MDS patients receiving transfusions

may be associated with a better outcome

Treatment with ESAs in lower-risk MDS induces erythroid

responses in 40–70% of cases

Responders experience improvements in QoL and a better survival

Lenalidomide in lower-risk MDS with del(5q) induces erythroid

responses and cytogenetic changes


Patients with higher-risk MDS receiving azacitidine may

experience erythroid responses


11

Cytogenetic abnormalities are very common in

patients with MDS

• 52% of patients had clonal abnormalities; 44% of these patients had

>1 abnormality

• The most common abnormality was del(5q)

0

Nu

mb

er

of

cases

Cytogenetic abnormality Haase D, et al. Blood 2007;110:4385–95

Single abnormality

Abnormality present + one additional aberration

Abnormality present within complex karyotype

Analysis of a database of 2,124 patients with MDS

MDS = myelodysplastic syndrome

350

300

250

200

150

100

50

12

Del(5q) MDS is not 5q– syndrome

*del(5q) with ≥2 additional abnormalities

OS = overall survival

1. Greenberg P, et al. Blood 1997;89:2079–88

2. Haase D, et al. Blood 2007;110:4385–95

3. Mallo M, et al. Leukemia 2011;25:110–2

4. Giagounidis A, et al. Hematology 2004;9:271–7

MDS with chromosomal

aberrations

del(5q) MDS

isolated del(5q)

del(5q) + 1

additional

abnormality

complex

abnormalities*

All MDS

WHO MDS with

isolated del(5q) 5q– syndrome

OS = 4.8–68.4 months1

OS = 24 months2

OS = 7–80 months2

OS = 66 months3

OS = 107 months4

13

Additional risk factors in patients with del(5q)

MDS: further chromosomal abnormalities

Mallo M, et al. Leukemia 2011;25:110–20

Retrospective analysis of 541 del(5q) MDS patients assessed

in the pre-lenalidomide era

Cu

mu

lati

ve

su

rviv

al

Time (months)

● Two distinct risk groups: isolated

del(5q) and del(5q)+1; del(5q) + ≥2

● Three distinct risk groups: isolated

del(5q); del(5q) + 1; del(5q) + ≥2

1.0

0.8

0.6

0.4

0.2

0 0 100 200 300 400

n=148

n=275 n=89

p<0.001

p=0.131 (isolated vs + 1)

del(5q)

del(5q)+1

del(5q)+≥2

Pro

ba

bil

ity o

f A

ML

tran

sfo

rmati

on

Time (months)

1.0

0.8

0.6

0.4

0.2

0 0 50 100 150 200 250

n=96

n=43

n=160

p<0.001

p=0.001 (isolated vs + 1)

del(5q)

del(5q)+1

del(5q)+≥2

Additional chromosomal abnormalities

are associated with reduced survival

Additional chromosomal abnormalities

are associated with increased AML

transformation

14 Giagounidis A, et al. Hematology 2004;9:271–7

p=0.00005

Time (months)

Cu

mu

lati

ve

su

rviv

al

360 300 240 180 120 60 0

1.0

0.8

0.6

0.4

0.2

0

≥5% blasts

<5% blasts

del(5q) with <5% BM blasts

del(5q) with ≥5% BM blasts

Additional risk factors in patients with del(5q)

MDS: BM blast percentage Retrospective analysis of 60 patients with isolated

del(5q) MDS; median follow-up = 53 months

BM = bone marrow

15

Combined analysis of MDS-003 and MDS-004:

impact of karyotypic complexity on clinical outcomes

Giagounidis A, et al. Oral presentation at 11th International

Symposium on MDS 2011, Edinburgh, UK. Abstract 58

Karyotype complexity had a negative

impact on OS

Pro

ba

bil

ity o

f s

urv

iva

l

Time to death (years)

1.0

0.8

0.6

0.4

0.2

0

0 1 2 3 4 5 7 6

3.9 years

3.0 years

1.8 years

p<0.01 p<0.05

Time to AML (years)

Pro

bab

ilit

y o

f A

ML

pro

gre

ss

ion

Median OS

Log-rank

p=0.0016


impact on AML progression

Isolated del(5q) del(5q) + 1 del(5q) + ≥2

Analysis included a total of 286 lenalidomide-treated patients with del(5q) MDS

AML = acute myeloid leukaemia

1.0

0.8

0.6

0.4

0.2

0

0 1 2 3 4 5 7 6

Log-rank

p=0.0044

16

TP53 mutations in MDS and their impact on

patient outcomes

Kulasekararaj AG, et al.

Oral presentation at ASH 2011. Abstract 792

Retrospective analysis of the incidence and prognostic impact of TP53 mutations

in patients with del(5q) using next-generation sequencing

Patient characteristics (n=318)

• Median age, years (range): 65 (17–72)

• IPSS risk, n (%)

– low: 71 (24)

– int-1: 101 (32)

– int-2: 58 (18)

– high: 29 (9)

• 40 patients (12%) received BM transplant, IC, azacitidine or lenalidomide

TP53 mutational status

• Patients with mutation, n (%): 30 (9.4)

• Median clone size, % (range): 42 (2.5–93)

TP53 mutations are an independent

prognostic marker in patients with

MDS and del(5q)

OS by TP53 mutational status*

All

patients

Isolated

del(5q) Complex

0

20

40

60

80

Mo

nth

s

9.7

NR

(>66) 66

23

14.1 9.6

p<0.0001 p<0.002

p<0.0001

Wild-type

TP53 mutation

Multivariate analysis†: TP53 mutational

status was the strongest predictor for OS

and PFS (p<0.0001 for both)

*Survival analysis was censored at treatment date †Co-variables: age, sex, WHO subtype, IPSS risk,

±mutations; progression-free survival

17

Commonly retained regions versus commonly

deleted regions in del(5q) MDS Analysis of 1,155 MDS/MPN/AML patients to characterise 5q disorders and

identify the impact of associated genomic lesions, by SNP-A and MC

25

20

15

10

5

0 MDS

(n=473)

MDS/

MPN (n=62)

AML (n=252)

23

8

13

Pati

en

ts w

ith

del(

5q

) b

y

SN

P-A

(%

)

Del(5q) frequency

MC SNP-A 0

50

100

150

Pa

tie

nts

wit

h 5

q le

sio

n, n

5q lesions

MC SNP-A 0

40

20

60

80

100

Pa

tie

nts

(%

)

Additional

abnormalities

5q by MC

5q UPD

No growth by MC

Isolated 5q

5q + additional lesions

Jerez A, et al. J Clin Oncol 2012; Epub ahead of print

MC = metaphase cytogenetics

SNP-A = single-nucleotide polymorphism array

UPD = uniparental disomy

18

Diagnosis of del(5q) MDS: methodology

Standard metaphase

cytogenetics (MC)1

● Standard MC is integral to

the diagnosis of del(5q)

MDS

● Guidelines stipulate that

≥25 metaphases should be

analysed2

Fluorescence in situ

hybridisation (FISH)1

● May play a supplementary

role to standard MC

especially when insufficient

metaphases are available

● FISH detected del(5q) in 6%

of 637 MDS patients who

had normal karyotype by

MC at diagnosis

SNP array (SNP-A)

karyotyping3

● SNP-A can detect

microdeletions and regions

of UPD that are

undetectable by MC or FISH

● Can improve detection of

del(5q) in conjunction with

MC and FISH

1. Mallo M, et al. Haematologica 2008;93:1001–8; 2. Steidl C, et al. Leuk Res

2005;29:987–93; 3. Makishima H, et al. Leuk Res 2010;34:447–53

UPD: uniparental disomy

SNP: single-nucleotide polymorphism

19

Technological advances: FISH for improving

diagnosis of primary MDS

Luciano L, et al. Poster presentation at EHA 2010,

Barcelona, Spain. Abstract 0917

Patients and methods

• 121 patients with suspected primary MDS

• Conventional cytogenetic analysis of BM samples

– informative karyotype (≥20 metaphases obtained) for 90 patients

• Samples from remaining 31 patients analysed by FISH

Normal

Del(5q)

Trisomy 8

–7/7q–

Other*

Failure

*hypo/hyperdiploid karyotype, complex karyotype,

unusual deletions and/or translocations

37%

27%

20% 9%

7%

70%

18%

6%

5%

Conventional cytogenetics FISH

20

FISH and del(5q)

FISH detected del(5q) in 38/637 (6%) cases

in which MC had not identified 5q–

Mallo M, et al. Haematologica 2008;93:1001–8

Group A

5q– not detected by MC (n=637)

Group B

5q– detected by MC (n=79)

Screening (n=716)

BM analysis by MC

Study design

Authors’ recommendation:

FISH may help in classification of cases with

● Suspected 5q– syndrome

● No metaphases or metaphases are not evaluable

● Abnormal karyotype without evidence of 5q–

21

SNP arrays can detect additional ‘cryptic’

abnormalities

Tiu RV, et al. Blood 2011;117:4552–60

Increased detection of cytogenetic

abnormalities

Newly detected lesions by SNP-A indicated a poorer patient prognosis

Conventional

karyotyping

Conventional

karyotyping +

SNP array

20

0

40

60

80

Ch

rom

oso

mal

ab

no

rmaliti

es d

ete

cte

d (

%)

44%

74%

p<0.0001 N=430

Novel lesions were

detected with SNP in:

• 54% of normal/non-

informative conventional

karyotyping results

• 62% of abnormal

conventional karyotyping

results

22

MC and SNP-A analyses of 5q disorders:

impact of lesions on prognosis

Jerez A, et al. J Clin Oncol 2012; Epub ahead of print

OS PFS

Loss of additional genes in the distal regions of 5q may contribute to a

poorer prognosis in patients with del(5q) abnormalities

1.0

0.8

0.6

0.4

0.2

0.0

0 10 20 30 40 50 60

Time (months)

Ove

rall

su

rviv

al

(pro

po

rtio

n)

5q-syndrome (n=29; events, 5)

Other forms of del(5q) MDS not

involving 5qSy-CRR (n=33; events, 10)

Other forms of del(5q) MDS involving

5qSy-CRR (n=42; events, 28)

P=0.06

P=0.04

1.0

0.8

0.6

0.4

0.2

0.0

0 10 20 30 40 50 60

Time (months)

Pro

gre

ss

ion

-fre

e s

urv

iva

l

(pro

po

rtio

n)

5q-syndrome (n=29; events, 3)

Other forms of del(5q) MDS not

involving 5qSy-CRR (n=33; events, 6)

Other forms of del(5q) MDS involving

5qSy-CRR (n=42; events, 19)

P=0.09

P=0.02

P≤0.001

PFS = progression-free survival

23

Considerations with cytogenetic techniques

Metaphase cytogenetics only Complement with FISH?

FISH is limited by the probes

used; it is too expensive to use

probes against entire genome

FISH must complement, not

replace, metaphase

cytogenetics

SNP-A is much more sensitive

than FISH, but it can miss

chromosomal translocations

If SNP-A becomes routinely

used, it should be in conjunction

with other techniques

24

FISH on enriched CD34+ PB cells to monitor

genetic response to lenalidomide: LE-MON-5 study

Shirneshan K, et al. Poster presentation at

ASH 2011, San Diego, CA. Abstract 1721

Preliminary cytogenetic findings in 37 patients with lower-risk

WHO-defined MDS and isolated del(5q) treated with lenalidomide

Every 6 months

Karyotyping and FISH on BM aspirates

*Based on time to cytogenetic remission †Each line represents one patient

FISH analysis of CD34+ PB cells, in combination with standard MK, could be a

powerful non-invasive tool to monitor response to lenalidomide therapy

Fast responders (n=14)* >50% clone size reduction in

≤2 months†

0 2 4 6 8 10 12 14

100

80

60

40

20

0

100

80

60

40

20

0

0 2 4 6 8 10 12 14 16 18

Months Months

Clo

ne s

ize

(%

)

Non-responders (n=9)* No cytogenetic response

detected

Clo

ne

siz

e (

%)

Slow responders (n=14)* >50% clone size reduction in

>2 months†

Resp

on

se

Study start

Karyotyping and FISH on BM aspirates

FISH on enriched CD34+ PB cells

Every 2–3 months

FISH on enriched CD34+ PB cells

25

1. Haase D, et al. Blood 2007;110:4385–95

2. Giagounidis A, et al. Hematology 2004;9:271–7; 3. Germing U, et al. Leukemia 2012; Epub ahead of print

4. Braulke F, et al. Leuk Res 2010;34:1296–301; 5. Tiu RV, et al. Blood 2011;117:4552–60

Summary and conclusions

• Del(5q) is the most common cytogenetic abnormality in patients

with MDS1

• Some patients with isolated del(5q) MDS have distinct features:

‘5q– syndrome’2

• Del(5q) MDS is highly heterogeneous: a number of factors have a

negative impact on prognosis, e.g.3

– Transfusion dependence

– Elevated blast count

– Additional genomic aberrations

– Thrombocytopenia

– Age >65 years

• Technological advances, e.g. FISH analysis on PB CD34+ cells and

SNP arrays, will facilitate the monitoring of disease evolution and

response to therapy in individual patients4,5

• When considering treatment options, clinicians need to assess the

risk profile of individual patients

26

Lenalidomide

Clinical effects

Cellular effects

Replacement of del(5q)

precursors by normal ones2

Pro-erythroid effect on

normal cells2

Initial worsening of

cytopenias3,4

Median time

to RBC-TI:

4.6 weeks3

Within days?

Median time to

CyR: 8 weeks

>1 year

Targeted apoptosis

of abnormal clone1

Increased normal

erythropoiesis2

Reduced probability of

progression to AML?4

Reduced RBC-transfusion

requirement3,4

Achievement of

RBC-TI3,4

Reduced probability of

non-leukaemic death

Cycle 1–2

RBC-TD patient with lower-risk del(5q) MDS:

severe anaemia; no other cytopenias

Possible link between mechanism of action of

lenalidomide and observed clinical data

1. Wei S, et al. Proc Natl Acad Sci USA 2009;106:12974–9; 2. Ximeri M, et al. Haematologica 2010;95:406–14

3. List AF, et al. N Engl J Med 2006;355:1456–65; 4. Fenaux P, et al. Blood 2011; 118:3765–76

High probability of

cytogenetic remission3

27

*MDS-003: >50,000/Μl †As defined by the IWG 2000 criteria ‡Double-blind phase; at 16 weeks, responders continued

double-blind treatment for 1 year, non-responders entered

open-label treatment or withdrew

MDS-0031

(n=148)

• Primary endpoint:

– erythroid response†

– RBC-TI (for ≥56

consecutive days)

• Secondary endpoints:

– RBC-TI duration

– cytogenetic response

– tolerability

Patient

characteristics

• IPSS low-/int-1-risk

MDS

• Del(5q) ± additional

abnormalities

• RBC transfusion

dependent

• ANC >500 cells/µL

• Platelets >25,000/µL* MDS-0042

(n=205)

Lenalidomide 10mg/day

21/28-day cycles

For 24 weeks

Lenalidomide‡

5mg/day

28-day cycles

Lenalidomide‡ 10mg/day

28-day cycles

Placebo‡

OR

OR

• Primary endpoint:

– RBC-TI for ≥26 weeks

• Secondary endpoints:

– erythroid response

– RBC-TI duration

– cytogenetic response

– time to AML

progression

– QoL

– tolerability

MDS-003 and MDS-004 study design

1. List A, et al. N Engl J Med 2006;355:1456–65

2. Fenaux P, et al. Blood 2011;118:3765–76

28

Achievement of CyR was associated

with significantly longer OS Risk of AML progression appeared to

be higher in patients without CyR

Time to death (years) 0 1 2 3 4 5 6

1.0

0.8

0.6

0.4

0.2

0

7

Pro

ba

bil

ity o

f s

urv

iva

l

CyR No CyR

0 1 2 3 4 5 6

1.0

0.8

0.6

0.4

0.2

0

7

Log-rank

p=0.0517

Log-rank

p<0.0001

Time to AML (years)

Pro

bab

ilit

y o

f A

ML

pro

gre

ss

ion

Analysis included a total of 286 lenalidomide-treated patients with del (5q) MDS


impact of CyR on clinical outcomes


Symposium on MDS 2011, Edinburgh, UK. Abstract 58 CyR = cytogenetic response

29

AML-free survival by RBC-TI for ≥8 weeks

in patients randomised to lenalidomide*

OS by RBC-TI for ≥8 weeks in patients

randomised to lenalidomide*

In patients treated with lenalidomide, achievement of RBC-TI for ≥8 weeks was

associated with improved OS and reduced risk of AML progression

AM

L-f

ree

su

rviv

al

1.0

0.8

0.6

0.4

0.2

0

Time from randomisation (years)

0 1 2 3 4 5

Log-rank p=0.0085

RBC-TI responders

RBC-TI non-responders

Ove

rall

su

rviv

al

1.0

0.8

0.6

0.4

0.2

0

Time from randomisation (years)

0 1 2 3 4 5

Log-rank p=0.0028

RBC-TI responders

RBC-TI non-responders

MDS-004: OS and progression to AML in

patients who achieved RBC-TI

Fenaux P, et al. Blood 2011;118:3765–76 *Landmark 6-month analysis

30


impact on OS

Pro

ba

bil

ity o

f s

urv

iva

l

Time to death (years)

1.0

0.8

0.6

0.4

0.2

0 0 1 2 3 4 5 7 6

3.9 years

3.0 years

1.8 years

p<0.01 p<0.05

Time to AML (years)

1.0

0.8

0.6

0.4

0.2

0

Pro

ba

bil

ity o

f A

ML

pro

gre

ss

ion

0 1 2 3 4 5 7 6

Median OS

Log-rank

p=0.0016 Log-rank

p=0.0044


impact on AML progression

Isolated del(5q) del(5q) + 1 del(5q) + ≥2

Analysis included a total of 286 lenalidomide-treated patients with del (5q) MDS

Combined analysis of MDS-003 and MDS-004: impact

of karyotypic complexity on clinical outcomes



31


predictive factors for progression to AML



Covariate Univariate analysis

p-value

Multivariate analysis

Hazard ratio (95% CI) p-value

Transfusion burden,

units/8 weeks

<0.001 1.13 (1.06–1.21) <0.001

del(5q) ≥2 vs isolated del(5q) <0.001 3.97 (1.89–8.33) <0.001

RBC-TI ≥26 weeks (no vs yes) <0.001 NS

Patients with del(5q) MDS and ≥2 additional cytogenetic abnormalities were at ~97% increased

risk of progression to AML than patients with isolated del(5q) MDS

32

Objective: to retrospectively compare AML progression and OS in

lenalidomide-treated vs untreated RBC-TD patients with lower-risk del(5q) MDS

MDS-004

n=205

*Nine centres of MDS

registries in Europe, USA, Australia

Eligibility criteria for present study:

• IPSS low- or int-1 risk MDS with del(5q)

• RBC-TD (≥1 unit/8 weeks)

• ANC ≥500/μL

• Platelets ≥50,000/μL

Lenalidomide-

treated patients

n=295 Median follow-up:

4.3 years

(range 0.02–6.8)

Untreated

patients

n=125 Median follow-up:

4.6 years

(range 0.06–19.4)

Multicentre

registry*

n=459

MDS-003

n=148

Patients were selected from clinical trials and registries

Comparative study of AML progression and OS

with lenalidomide therapy: design

Kuendgen A, et al.

Oral presentation at ASH 2011; San Diego, CA. Abstract 119

33

Comparative study of AML progression and OS with

lenalidomide therapy: baseline characteristics

Kuendgen A, et al. Oral presentation at ASH 2011;

San Diego, CA. Abstract 119

*Nine centres of MDS

registries in Europe, USA, Australia

Baseline characteristics Lenalidomide treated Untreated

Median age, years 65 66

Median RBC transfusions,

units/8 weeks 6 2

BM blasts

5–10%, % 13 16

Median Hb, g/dL 8 8

Cytogenetics, %

isolated del(5q)

del(5q) +1 abn

del(5q) + >1 abn

76

18

5

83

13

4

IPSS risk, %

low-1

int-1

43

57

43

57

34

125 87 66 48 31 24 14

53 101 125 135 127 101

Number of patients at risk

Time (years)

0 1 2 3 4 5 6

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al p

rob

ab

ilit

y

Log-rank p= 0.755

Untreated

OS 3.8 years (95% CI: 2.9–4.8)

LEN-treated

OS 5.2 years (95% CI: 4.5–5.9)


with lenalidomide therapy: OS



35

125 79 58 39 24 18 9

53 97 119 128 120 98

Number of patients at risk Time (years)

0 1 2 3 4 5 6

1.0

0.8

0.6

0.4

0.2

0

Cu

mu

lati

ve

in

cid

en

ce

of

AM

L p

rog

res

sio

n

Untreated

LEN-treated

Median time to AML progression: not reached


with lenalidomide therapy: progression to AML



36

*Only significant when using multivariate

Cox proportional hazard model

Predictive factors for AML progression and OS

Hazard ratio (95% CI)

Age, years

LEN-treated vs untreated

Gender (female vs male)

Transfusion burden,

units/8 weeks

IPSS risk (int-1 vs low) p=0.041

p=0.741

p=0.017

p=0.003*

p=0.723

p=0.002

LEN-treated vs untreated

IPSS risk (int-1 vs low)

Transfusion burden,

units/8 weeks

p<0.001

p=0.003

AM

L p

rog

ressio

n

De

ath

Increased Decreased

Relative hazard (multivariate Cox proportional hazard model)

0.0 0.5 1.0 1.5 2.0 2.5 3.0

Treated patients showed improved survival

Lenalidomide was not associated with increased risk of AML progression


with lenalidomide therapy: predictive factors



37

Summary and conclusions in patients with

del(5q) MDS

Lenalidomide induces durable erythroid responses; ~65% achieved RBC-TI

Lenalidomide treated and untreated patients showed no difference in the risk of AML

Possible risk factors for progression for treated and untreated patients included

Increased medullary blast count

Complex karyotype

Transfusion need

No response to treatment (CyR/ RBC-TI)

P53 mutation?

Advice:

Response assessment at ~4 months, end of treatment in case of non-response

0 24 48 72 96 120 144

Intensive chemotherapy (IC) in patients with

int-2/high-risk MDS: low survival rate

1. Kantarjian H, et al. Cancer 2006;106:1099–109

2. National Cancer Institute. SEER Cancer Statistics Review 1975–2006, MDS

Su

rviv

al

(% p

ati

en

ts)

100

90

80

70

60

50

40

30

20

10

0

Months

OS after 5 years 8%

n=510; Median age 63 years1

CR rate 55%

Induction mortality 17%

Rate

per

10

0,0

00

po

pu

lati

on

Age at diagnosis (years)

MDS & age at diagnosis2

50

40

30

10

0

20

<0 40–49 50–59 60–69 70–79 >80

0.2 0.8 2.3

8.5

24.8

43.9

Survival with palliative treatment of high-risk MDS and

AML in patients aged >60 years not fit for IC

• An analysis of 36 studies (median age: 70 years)1

• Median survival was 4 months in a randomised study (low-dose cytarabine

[LDAC] vs hydroxyurea)2

1. Deschler B, et al. Haematologica 2006;94:1513–22; 2. Burnett AK, et al. Cancer 2007;109:1114–24

Treatment Median survival (weeks)

Low-intensity therapies 12

BSC alone 7.5

No. patients No. events Obs. – Exp.

LD Ara-C 103 100 −22.0

HU 99 99 22.0

p=0.0009

Pe

rce

nta

ge

sti

ll a

live

100

75

50

25

0 0 1 2 3

Years from entry

Total number of HSCTs*

25,563

Allogeneic

39% Autologous

61%

Indication for HSCT

Lymphoproliferative

disorders

Acute lymphoblastic

leukaemia

Solid tumours

Non-malignant

disorders

Chronic lymphocytic

leukaemia

Chronic myeloid

leukaemia

Myeloproliferative

syndromes

AML + MDS

20%

Gratwohl A, et al. Bone Marrow Transplant 2009;43:275–91

In 613 centres in 42 countries

RIC = reduced-intensity conditioning

1. Effective consolidation therapy [ex. haemopoieitc stem cell transplant

(HSCT) including RIC-HSCT]

How can survival be improved in elderly patients with

high-risk MDS and AML?

Median follow-up 42 months (n=256), median age 62 years

OS

(%

)

OS = 40%

Years after HCT Years after HCT

DF

S (

%)

DFS = 35%

Years after HCT

RI

(%)

RI = 48%

Years after HCT

NRM = 27%

NR

M (

%)

Al-Ali HK, et al. Oral presentation at EHA 2011

Outcome at 5 years after RIC-HCT in MDS and AML

1.0

0.8

0.6

0.4

0.2

0 0 5 10

1.0

0.8

0.6

0.4

0.2

0 0 5 10

1.0

0.8

0.6

0.4

0.2

0 0 5 10

1.0

0.8

0.6

0.4

0.2

0 0 5 10

Azacitidine prolongs overall survival in patients with

IPSS Int-2 or High-risk MDS

Cytogenetic

risk group Patients, % (n/N)

Median OS, months

Aza CCR HR

Good 47 (167/358) Not reached 17.1 0.59

Intermediate 21 (76/358) 26.3 17.0 0.44

Poor 28 (100/358) 17.2 6.0 0.53

CCR = conventional care regimen

Pati

en

ts s

urv

ivin

g (

%)

Time since randomisation (months)

Intent-to-treat population

0

20

40

60

80

100

0 5 10 15 20 25 30 35 40

Aza (OS 24.5 months; 82 deaths)

CCR (OS 15.0 months; 113 deaths)

p=0.0001

Fenaux P, et al. Lancet Oncol 2009;10:223–32

Gotze KS, et al. Cancer Manag Res 2009;1:119–30

LDAC

1. Kantarjian H, et al. Cancer 2006;106:1099–109; 2. Burnett AK, et al. Cancer 2007;109:1114–24

Only CR has a favorable impact on survival with

chemotherapy in MDS and AML

IC in MDS1

Median survival of 66 days in

non-remitters vs 575 days in patients

with CR (overall CR rate of 18%)2

1.0

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n s

urv

ivin

g

0 24 48 72 96 120 144

Months

Total Dead

Complete

response 252 192

Other 154 135

p<0.0001

AML 14 non-intensive – overall survival

Favourable/intermediate

Pe

rce

nta

ge s

till a

live

100

75

50

25

0

0 1 2 3 Years from entry


Adverse


Pe

rce

nta

ge s

till a

live

100

75

50

25

0

p=0.4

p=0.004

LD Ara-C

HU

LD Ara-C

HU

The CR rate was similar in the AZA and CCR groups, suggesting that

AZA-mediated improvement in OS occurred independently of response

Fenaux P, et al. J Clin Oncol 2010;28:562–9 *WHO-defined AML

0

5

10

15

20

25

AZA

(n=55)

CCR

(n=58)

Pati

en

ts w

ith

CR

(%

)

18 16

p=0.8

0

20

40

60

80

100

0 5 10 15 20 25 30 35 40

Pati

en

ts s

urv

ivin

g (

%)


CCR (n=58)

AZA (n=55)

Median OS

2-y

ear

OS

rate

AZA-001: response in elderly patients with

20–30% blasts*

Adapted from List AF, et al. Oral presentation at

ASCO 2008, Chicago, IL, USA

Time from randomisation (months)

Pati

en

ts s

urv

ivin

g (

%)

0 5 10 15 20 25 30 35 40 0

20

40

60

80

100

HI (p<0.0001)

PR (p=0.006)

CR

CCR

71.7%

78.4% (p<0.0001)

26.2%

2-year survival rates

AZA-001: OS by best response

OS by best response (IWG, 2000)

0 1 2 3

Survival according to

cytogenetics1

1. Knipp S, et al. Cancer 2007;110:345–52; 2. Burnett AK, et al. Cancer 2007;109:1114–24

Adverse cytogenetics has a strong negative impact on

survival after chemotherapy in MDS and AML

Pa

tie

nts

su

rviv

ing

(%

)

Duration (years)

0 1 2 3 4 5 6 7 8 9 10 11

100

Normal

Abnormal, non-complex

Complex

p=0.0001

No CR with LDAC in adverse

cytogenetics!!2

After IC

LDAC


Favourable/intermediate

Pe

rce

nta

ge s

till a

live

100

75

50

25

0



Adverse

Years from entry

Pe

rce

nta

ge s

till a

live

100

75

50

25

0

p=0.4

p=0.004

80

60

40

20

0

LD Ara-C

HU

LD Ara-C

HU

AZA 001: AZA vs LDAC in patients with IPSS

Int-2- or High-risk MDS regarding cytogenetics

AZA LD Ara-C

n 45 49

Median number of cycles 9 4.5

Median OS 24.5 15.3 p<0.001

OS good-risk cytogenetics NR 19 HR=0.46

OS poor-risk cytogenetics 24.5 2.9 HR=0.07

CR + PR 31% 12% p=0.047

HI 53% 25% p=0.006

Transfusion independent 45% 13% p=0.01

Severe infections/patient-year 0.44 1 p=0.017

Median days in hospital/patient-year 18 27 NR

Fenaux P, et al. Br J Haematol 2010;149:244–9; Fenaux P, et al. Lancet Oncol 2009;10:223–32

Old age is not a contraindication to treatment with AZA

0

0.2

0.4

0.6

0.8

1.0

0 10 20 30 40

Time from randomisation (months)

AZA

CCR

HR: 0.48 (95% CI: 0.26–089); p=0.0193

No. at Risk AZA 38 31 27 14 9 3 0 0 0

CCR 49 37 23 16 5 3 1 0 0

10.8 months

15%

55%

Pro

po

rtio

n s

urv

ivin

g

Seymour JF, et al. Crit Rev Oncol Hematol 2010;76:218–27

AZA-001 sub-group analysis ≥75 years of age

Azacitidine in patients with AML

0

20

40

60

80

100

0 5 10 15 20 25 30 35 40

24.5 months

16.0 months

Pati

en

ts s

urv

ivin

g (

%)


p = 0.004

CCR (n=58)

Azacitidine (n=55)

50.2%

15.9%

*WHO-defined AML Fenaux P, et al. J Clin Oncol 2010;28:562–9

Azacitidine prolongs overall survival in elderly patients with

20–30% blasts*

AZA-001: analysis of patients with 20–30% blasts

(WHO AML) – infections and hospitalisation

Rates of

hospitalisation

Rates of infection requiring

i.v. antibiotics

0

0.4

0.8

1.2

AZA CCR

p=0.003

Ra

te p

er

pa

tie

nt

ye

ar

0.6

1.1

p=0.05

0

1

2

3

4

5

AZA CCR

Ra

te p

er

pa

tie

nt

ye

ar

3.4

4.3

Number of days

in hospital

Fenaux P, et al. J Clin Oncol 2010;28:562–9

0

20

40

60

AZA CCR

p<0.001

Da

ys

pe

r p

ati

en

t ye

ar

26

51

• AZA 75 mg/m2/day subcutaneously for 5 days every 4 weeks

• Median follow-up duration was 13 months (range: 9–16 months)

OSHO trial: AZA in patients with newly diagnosed or

relapsed/refractory AML

Characteristic

All patients

(n=40)

Newly

diagnosed

(n=20)

Relapsed or

refractory

(n=20)

Median age, years 72 78 67

Male, n (%) 19 (48) 11 (55) 8 (40)

Median BM blasts, % 42 44 40

Median WBC count × 109/L 3.6 3.4 3.6

Cytogenetics,† n (%)

Intermediate risk

High risk

28 (70)

12 (30)

15 (75)

5 (25)

13 (65)

7 (35)

Al-Ali HK, et al. Leuk Lymph. 2012;53:110–7

OS in patients with newly diagnosed

or relapsed/refractory AML

Median OS for patients with SD was 4 months, whereas median OS for patients with

CR, PR, or HI was not reached (p=0.045); (median bone marrow blasts 42%)

OS according

to haematological response

Pa

tien

ts s

urv

ivin

g (

%)

Duration (months)

18 12 6 0

100

80

60

40

20

0

SD censored

CR/PR/HI censored

SD (n=15)

PD or NR (n=2)

CR, PR, or HI (n=12)

NE (n=11) 100

80

60

40

20

0 0 2 4 6 8 10

2.9 months

7.7 months

Pa

tien

ts s

urv

ivin

g (

%)

Duration (months)

Newly diagnosed (n=20)

Relapsed or refractory (n=20)

p=0.04

AZA improves survival in AML patients with HI or

better and newly diagnosed patients have longer OS

Al-Ali HK, et al. Leuk Lymph 2012;53:110–7

Bories P, et al. ASH 2011. Abstract 2614

n=98

Median age 76 years

WBC >10 g/L 14 (14.2%)

Median BM blasts, % 35 (20–85)

Cytogenetic risk, n (%)

Favourable: 0

Intermediate: 48 (48.9)

Adverse: 44 (44.8)

AZA

• 75 mg/m2/day x 7

days, 28-day

cycles

– median 6

(1–27) cycles

AZA in elderly AML patients unfit for IC

13

56

26

0

5

10

15

20

25

30

Pati

en

ts (

n)

ORR (CR + CRi + PR + HI) = 51%

CR CRi PR HI

Toxicity

• 60 (61.2%) patients required

hospitalisation for infections

• Death rate in first 2 months: 17%

– from AML progression: 83%

– from infections: 17%

HR (CI) p value

Performance status (≥2 vs <2) 0.98 (0.49–1.96) 0.96*

LDH (>normal vs ≤normal) 1.98 (1.02–3.88) 0.045

Cytogenetics (adverse vs intermediate) 2.38 (1.29–4.41) 0.005

AZA appears to be a valuable option for AML patients considered unfit for CT

OS by patient characteristics: multivariate analysis

OS (n=98) OS by cytogenetics (n=92)

100

75

50

25

0 0 6 12 18 24 30 36 42 48 54 60

Months

Pa

tien

ts s

urv

ivin

g (

%)

Months

p=0.005

Intermediate

Adverse

1-year OS: 50%

2-year OS: 28%

Pa

tie

nts

su

rviv

ing

(%

)

AZA in elderly AML patients unfit for IC

100

75

50

25

0 0 6 12 18 24 30 36 42 48 54 60

Bories P, et al. ASH 2011. Abstract 2614

AZA versus IC or BSC in 182 elderly WHO-AML

patients

Serrano J, et al. ASH 2011. Abstract 2612

Retrospective study of AZA compared with IC or BSC on OS

in patients >60 years old

AZA†

(n=67)

IC

(n=47)

BSC†

(n=68) p value

Median age, years

(range)

71 (60–84) 65 (60–75) 76 (62–89) 0.04,

<0.01*

Median leucocyte count,

×109/L (range)

4.4

(0.2–17.5)

28.6

(0.8–166)

17.6

(0.4–211)

0.01,

<0.01*

Median BM blasts count,

% (range)

34 (20–84) 64 (24–93) 47 (21–90) 0.003,

<0.01*

ECOG ≥2, n (%) 45 (67) 7 (15) 60 (88) <0.01,

<0.01*

Cytogenetics, n (%)

Intermediate

Adverse

NT

46 (68.6)

15 (22.3)

6

32 (68)

12 (25.5)

3

39 (57.3)

12 (17.6)

17

0.86*

Patient characteristics

*IC vs AZA groups; †patients not eligible for IC

AZA group: • AZA 75–100 mg/m2/day s.c.

(7 days of 28-day cycle)

• Median cycles: 6 (1–24)

• Median follow-up:

7.4 (1–28.3) months

IC group: • Cytarabine

100–200 mg/m2/day c.i.v.

(7 days)

• + Idarubicin

9–12 mg/m2/day (3 days)

• + HSCT


13 (2–46) months

BSC group: • Oral CT agents

• Transfusions

• Antibiotics with G-CSF


5 (0–10) months

13 13

16

Response to AZA

Significantly better survival with AZA

was associated with:

CR, PR or HI (p=0.018)

ORR = 38%

1- and 2-year OS

Pa

tien

ts (

%)

p=0.75 AZA vs IC

OS

0 10 20 30 40 50

AZA or ICT vs BSC:

p<0.001

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n a

live

BSC (n=68)

AZA (n=67)

IC (n=47)

2.03 mo

13.7 mo 11.2 mo

Months

In elderly patients with AML not

eligible for IC, AZA led to an OS

comparable to the one observed

in patients treated with IC

AZA versus IC or BSC in 182 elderly WHO-AML

patients: outcomes

0

5

10

15

20

CR PR HI

AZA IC BSC

1 year

2 years

0

20

40

60

Serrano J, et al. ASH 2011. Abstract 2612

Damaj G, et al. ASH 2011. Abstract 160

Prior to HSCT

Characteristics

BSC

(n=171)

AZA

(n=49)

Induction CT

(n=180)

AZA + induction CT

(n=17) p value

IPSS, n (%)

Low/Int-1

Int-2/High

108 (64)

60 (36)

16 (33)

32 (67)

73 (42)

102 (58)

7 (41)

10 (59)

0.0001

Retrospective analysis: 417 patients receiving allogeneic HSCT between 1999 and 2009

Characteristics BSC (n=171)

AZA

(n=49)

Induction CT

(n=180)

AZA + induction CT

(n=17) p value

Median age, years (range) 51 (44–57) 60 (30–62) 56 (18–61) 58 (32–61) 0.0001

Disease progression, n (%) 32 (19) 7 (15) 95 (53) 10 (59) 0.0001

BM blasts <5%, n (%) 77 (52) 33 (67) 131 (74) 9 (53) 0.0003

Responders, n (%) – 33 (69) 131 (73) 9 (53) 0.30

Characteristics at diagnosis, per pre-HSCT therapy

Characteristics at transplantation, per pre-HSCT therapy

AZA & allogeneic HSCT in MDS and AML

3-year NRM per prior treatment 3-year OS per prior treatment

p=0.036* 3-y

ea

r O

S

AZA

Induction CT

AZA + induction CT

p=0.027*

200 400 600 800 1,000 1,200 0

0.4

0

0.2

0.6

0.8

1.0

Time (days)

p=0.10

200 400 600 800 1,000 1,200 0

0.4

0

0.2

0.6

0.8

1.0

Time (days)

p=0.138

3-y

ea

r N

RM

AZA & allogeneic HSCT in MDS and AML

AZA monotherapy appears a valid pre-allogeneic HSCT treatment approach

*Azacitidine vs azacitidine + induction CT

AZA

Induction CT

AZA + induction CT

Prior to HSCT: OS and NRM by treatment

Damaj G, et al. ASH 2011. Abstract 160

1. Jabbour E, et al. Cancer. 2009;115:1089–905

2. Schroeder T et al. ASH 2011. Abstract 656; 3. Goodyear O et al. Blood, 2012;119:3361–9

AZA & allogeneic HSCT in MDS and AML After HSCT

● AZA alone or in combination with donor lymphocyte infusions may induce

durable remissions for patients with acute leukaemia who develop disease

recurrence after HSCT1,2

● AZA is well tolerated and not associated with exacerbation of GVHD

● AZA increases the

expansion of regulatory

T-cells after allogeneic

HSCT in patients with AML3

These data support the further examination of AZA after HCT as a mechanism

of augmenting a GVL effect without a concomitant increase in GVHD

2.0x102

1.5x102

1.0x102

5.0x102

0

CD

4+

CD

25

+C

D1

27lo

Fo

x

P3

+c

ell

s/L

P=0.0127

Conclusions

• Although high CR rates are achieved with standard chemotherapy,

long-term survival rates remain low in patients with high-risk MDS

& AML

• AZA improves OS versus CCR independent of response, adverse

cytogenetics, age and comorbidities in high-risk MDS & AML

(20–30% blasts)

• The exact role of AZA in AML (>30% blasts) in older patients is

being assessed in the AML-001 study

• AZA has a manageable safety profile and can often be administered

in an outpatient setting

• AZA appears to be a valid pre-allogeneic HSCT treatment approach

• Early data indicate that post-HSCT AZA may augment a GVL effect

without a concomitant increase in GVHD

poročilo eha 2012 s j12.pdf · ambaglio i, et al. poster presentation at eha 2010; abstract 0310...

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