1

Early diagnosis, treatment and management in MDS

Uwe Platzbecker

University hospital “Carl Gustav Carus”Dresden, Germany

MDS - a disease of older age

0 02 1 2 2

4

9

16

26

52

5961

34

10

1

0

10

20

30

40

50

60

70

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

Age groups

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

Age-specific incidence

(per 100,000)

< 50 0.5

50–59 5.3

60–69 15

70–79 49

≥≥≥≥ 80 89

Number

2

Erythropoesis Granulopoesis Megakaryopoesis

MDS – bone marrow findings

control

MDS

WHO Type n (%) median survival AML Evolution (months) at 2 y 5 y

MDS with del(5q) 89 (3.7%) 77 8 20RARS 174 (7.3%) 66 3 3RCUD 218 (9.1 %) 58 6 14

RCMD>15% RS 336 (14%) 32 13 20<15% RS 774 (32.3%) 36 13 20

RAEB I 359 (15%) 19 26 44RAEB II 443 (18.5%) 12 55 65

MDS WHO 2008

Germing et al. Ann Hematol. 2008

3

Diagnostic work-up in MDS

Mandatory now:•Cytology•Histology•Flow•Cytogenetics

Mandatory soon:•Molecular studies

How should we define

„low““““ and „high““““-risk ?

4

IPSS (international prognostic scoring system)

Greenberg et al. Blood 1997

Score

Prognostic variable 0 0.5 1.0 1.5 2.0

Bone marrow blasts (%) < 5 5–10 11–20 21–30

Karyotype* Good Intermediate Poor

Cytopenias 0/1 2/3

Score IPSS subgroup Median survival (years)

0 Low 5.7

0.5–1.0 Int-1 3.5

1.5–2.0 Int-2 1.2

>= 2.5 High 0.4

*Karyotype: good: normal, -Y, del(5q), del(20q); poor: complex (≥ 3 abnormalities) or chr 7 anomalies; and intermediate: other abnormalities.

Hb < 10.0 g/dL; ANC < 1.8 ×××× 109/L; platelet count < 100 ×××× 109/L

HR MDS

LR MDS

W(HO)PSS

Variable 0 1 2 3

WHO RA, RARS, del5q− RCMD RAEB-1 RAEB-2

Karyotype Good Intermediate Poor –

RBC no yes – –

Malcovati L, et al. JCO 2007

Score WPSS groupMedian OS (mon)

Italian cohort

Median OS (mon)

German cohort

0 Very low 103 141

1 Low 72 66

2 Intermediate 40 48

3–4 High 21 26

5–6 Very high 12 9

* Karyotype: good: normal, -Y, del(5q), del(20q); poor: complex (≥ 3 abnormalities, chr 7 anomalies); and intermediate: other abnormalities.

HR MDS

LR MDS

5

IPSS vs WPSSScore

IPSS 0 0.5 1.0 1.5 2.0

Bone marrow blasts (%) < 5 5–10 11–20 21–30

Karyotype Good Intermediate Poor

Cytopenias 0/1 2/3

RCMD – RBC TD anemia + PLT110 + HR-caryotype

WPSS 0 1 2 3

WHO RA, RARS, del5q− RCMD RAEB-1 RAEB-2

Karyotype Good Intermediate Poor –

RBC no yes – –

IPSS vs WPSSScore

IPSS 0 0.5 1.0 1.5 2.0

Bone marrow blasts (%) < 5 5–10 11–20 21–30

Karyotype Good Intermediate Poor

Cytopenias 0/1 2/3

WPSS 0 1 2 3

WHO RA, RARS, del5q− RCMD RAEB-1 RAEB-2

Karyotype Good Intermediate Poor –

RBC no yes – –

RAEB-1/2 – RBC TD anemia + neutrop+/-thrombopenia + normal caryotype

6

Design of the new Cytogenetic Prognostic System

Schanz et al., JCO 2011

TET-2 mutations in MDSgood or bad or equal ?

Kosmider et al. Blood 09

TET2+

TET2-

N=355

TET2-

TET2+

N=88

Smith et al. Blood 10

7

Bejar et al., NEJM 2011

Mutations and survival

Poor-risk mutations in MDS(EZH2, TP53, ASXL1, RUNX1, RAS)

Bejar et al. NEJM 2011

IPSS LOW, and mutation

IPSS LOW, no mutation

IPSS INT-1

8

Goals of Treatment

• Improve cytopenias• Improve QoL

• Delay disease progression• Prolong survival

Low R

High R

The real MDS case

2008 Dx RCMD, 46XY, RBC TD, PLT260, EPO 480, Ferritin 2880

9

LOW RISK HIGH RISK

Therapeutic options in MDS

IPSS/WPSS scoring

trials

Not approved but active

approved

Fe-chelation

Iron chelation in MDS

- Background: Impact of transfusion dependency on survival

- Effects at least in part connected to iron overload

- Indication: IPSS LOW/INT-1

- Different thresholds of ferritin (>1000-2500)

- Retrospective studies show OS by chelation

- Prospective clinical trials runinng (TELESTO)

10

LOW RISK HIGH RISK

Therapeutic options in MDS

IPSS/WPSS scoring

trials

Not approved but active

approved

Epo

Fe-chelation

EPO<500

G-CSF TPO-R

Lenalidomide in del(5q) and non-del(5q) MDS

del(5q) Non-del(5q)

Transfusion independence % 67 26

Total transfusion response % 76 43

Duration of independence ~2 years 41 weeks

Study ongoing

Study discontinued

MDS003 [del(5q)]

MDS002 [other]

Time (weeks)

Proportion transfusion-free patients

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

100 20 30 40 50 60 70

Raza A, et al. Blood. 2008;111;86-93.

List A, et al. N Engl J Med. 2006;355;1456-65.

11

LOW RISK HIGH RISK

Therapeutic options in MDS

IPSS/WPSS scoring

trials

Not approved but active

approved

Epo

Fe-chelation

G-CSF TPO-R

Len +/- Epo +/- HDAC +/-

5-AZA

Len

The real MDS case

2008 Dx RCMD, 46XY, RBC TD, PLT260, EPO 480 ...................RAEB-2, PLT 23

Iron chelation and Lenalidomide

12

LOW RISK HIGH RISK

Therapeutic options in MDS

IPSS/WPSS scoring

trials

Not approved but active

approved

Fe-chelation

Epo G-CSF TPO-R

Len +/- Epo +/- HDAC +/-

5-AZA

Intensive CTx/allo Tx

Hypomethylatingagents

Len

Decitabine: EORTC randomized prospective trial

Progression-free survival (PFS) Overall survival (OS)

Supportive care

Decitabine

Time (months)

100

90

80

70

60

50

40

30

20

10

0

0 6 12 18 24 30

Supportive care

Decitabine

Time (months)

100

90

80

70

60

50

40

30

20

10

0

0 6 12 18 30 4224 36

Median (months): 6.6 vs 3

HR = 0.68, 95% CI (0.52, 0.88)

Logrank test: p = 0.004

Median (months): 10.1 vs 8.5

HR = 0.88, 95% CI (0.66, 1.17)

Logrank test: p = 0.38

Lubbert et al. JCO 2011

3 x 15mg/m2 i.v. q3 days every 6 weeks

Progression-free survival

Overall survival

13

p = 0.0001

24.5 months

15 months

Azacitidine (n = 179)

Conventional care regimen (n = 179)

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

0 10 20 30 405 15 25 35

Time from randomization (months)

Patients surviving (%)

100

80

60

40

20

0

Azacitidine improves survival in higher-risk MDS

Conventional care regimens: best supportive care,

low-dose AraC, standard chemotherapy.

Itzykson et al. Blood 2011

Score 0 1 2

ECOG 0-1 2

PB blasts NO YES

RBC units < 4 U/8 W 4 U/8 W

Karyotype Good Intermediate Poor

Total score 0 1-3 4-5

APSS group Low Intermediate High

Median OS, months Not reached 15 6

AZA prognostic score

14

Genetic prognostic factors with AZA

Mufti et al. ASH 2009

IPSS Int-2 / High risk MDS

with del(5q)

CI: AZA 75mg/m² d1–5 + LEN 10mg d6–19

CII: AZA 75mg/m² d1–5 + LEN 15mg d6–19

CIII: AZA 75mg/m² d1–5 + LEN 20mg d6–19

CIV: AZA 75mg/m² d1–5 + LEN 25mg d6–19

C, cohort; d, days.

“AZALE” STUDY German MDS SG

Platzbecker et al. ASH 2011

ORR 56 % untreated patients

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Combinations with HMA

Disease n combinations CR ORR study

MDS + AML 27 Aza + MS-275 7 44 Gore 06

MDS + AML 53 Aza + VPA + ATRA 22 42 Soriano 07

MDS + AML 37 Aza + MGD0103 11 52 Garcia-Manero 07

MDS +AML 136 Aza +/- Entinostat 7 42 Prebet 10

MDS + AML 23 Aza + Vorinostat 45 82 Silverman 07

MDS + AML 17 Aza + Vorinostat 17 51 Garcia-Manero 10

MDS + AML 54 DAC + VPA 19 22 Garcia-Manero 08

MDS + AML 25 DAC + VPA 16 44 Blum 07

MDS + AML 60 DAC + Vorinostat 18 25 Kirschbaum 08

MDS + AML 27 DAC + Vorinostat 4 16 Yee 07

The real MDS case

2008 Dx RCMD, 46XY, RBC TD, PLT260, EPO 480 ...................RAEB-2, PLT 23

Iron chelation and Lenalidomide.......5-azacytidine

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Allogeneic HCT vs. AZA in MDS patients 60-70 years of age

Platzbecker et al. unpublished

OS PFS

Interventions to improve outcomeafter allogeneic HCT in MDS

Conditioning GvHD prophylaxis

Disease-specific therapy MRD-directed therapy

MaintenanceGraft

Transplant

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CD34+ chimerism detects imminent relapse in CD34+ MDS/AML

8 weeks

Relapse

Bornhäuser M. et al. Haematologica. 2009.

MRD directed AZA after

allogeneic HCT

1

d 0 d 998 last follow-up

2d 0 d 233 death

3d 0 D 497 last follow-up

4

d 0 d 596 last follow-up

CD34+-DC <80%

CD34+-DC ≥80%

Start of AZA treatment cycle

Platzbecker et al. , Leukemia 2012

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Sockel et al. Haematologica 2011

NPM1+ AML

LOW RISK HIGH RISK

Therapeutic options in MDS

IPSS/WPSS scoring

trials

Not approved but active

approved

Fe-chelation

5-Aza + Len 5-Aza/DAC + HDAC

Clofarabine

Epo

Len

G-CSF TPO-R

Len +/- Epo +/- HDAC +/-

5-AZA

Intensive CTx/allo Tx

Hypomethylatingagents

19

Conclusion

;

• Great clinical heterogeneity of MDS

• Scoring systems: Low-risk vs. High-risk

• Need of better (molecular) scoring

• Paucity of approved drugs

• AZA improves OS compared to BSC

• Allo-HCT in pts <70 years feasible

• Importance of clinical trials

LOW RISK HIGH RISK

Therapeutic options in MDS

IPSS/WPSS scoring

trials

Not approved but active

approved

Fe-chelation

Intensive CTx/allo Tx

Hypomethylatingagents

Epo

EPO<500

Len

G-CSF TPO-R

20

AZA001 study: number of cycles are important

Cumulative probability

50%,

≥ 2 cycles

91%,

6 cycles

Range: 1–22 cycles

... to first response(CR, PR, or HI)

0

0.2

0.4

0.6

0.8

1.0

Time (cycles)

0 3 6 9 12 15 18 21 24

48% of patients improved response

to a higher IWG category with

continued treatment with

azacitidine

Median: 3 cycles

... to best response(after first response)

0

0.2

0.4

0.6

0.8

1.0

Time (cycles)

0 3 6 9 12 15

Silverman LR, et al. Cancer 2011IWG = International Working Group.

Aberrant DNA methylation is a dominant mechanism in MDS progression to AML

Methods: DNA methylation microarray and high-density SNP array

Aberrant methylation was seen in every sample, on average affecting

91 of 1,505 CpG loci in early MDS

179 of 1,505 CpG loci in RAEB/AML

Jiang Y, et al. Blood. 2009;113:1315-25.

% Patients with aberrant methylation % Patients with chromosome lesions detected

by SNP or metaphase cytogenetics

Chromosome

Patients (%)

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

SNP = single nucleotide polymorphism.

21

AZA-001 study: overall survival by best response

Time from randomization (months)

Patients surviving (%)

0 5 10 15 20 25 30 35 40

0

20

40

60

80

100

HI

PRCR

CCR

71.7%

78.4%

26.2%

2-year survival rates

Adapted from List AF, et al. J Clin Oncol. 2008;26 No 15S

(ASCO Annual Meeting Proceedings May 20 Suppl):[abstract 7006].

Malcovati et al. JCO 2007

IPSS vs WPSS

23

45

0

5

10

15

20

25

30

35

40

45

high-risk

IPSS

WPSS

22

FAB Blasts in %

med. OS in months

RA (Refractory Anemia)

RARS (Ringed Sideroblasts)

< 5 3750

RAEB (with Excess of Blasts) 5 – 20 12

RAEB-T (in Transformation) 21 – 30 5

CMMOL 5 – 20 19

Bennett et al. BJH 1982

FAB Blasts in %

med. OS in months

RA (Refractory Anemia)

RARS (Ringed Sideroblasts)

< 5 3750

RAEB (with Excess of Blasts) 5 – 20 12

RAEB-T (in Transformation) 21 – 30 5

CMMOL 5 – 20 19 MDSMDS--MPSMPS

AMLAML

18

10

RAEB-1 (5 - 9 %)

RAEB-2 (10 - 19 %)

11669693332

5q-SyndromeRARARSRCMDRCMD-RS

med. OSin monthsWHO

Bennett et al. BJH 1982, Vardiman et al. Blood 2002, Germing et al. Leuk Res 2000

23

Cytogenetics in MDS29%

21%

16%

9%

8% 7%

7% 6%

6%

5%

4%

4%

3%

13%

0

50

100

150

200

250

300

350

5q-

-7/7q-

+8

-20/20q-

-12/12p-

-17/17p-Anom.

-Y -5

-18/18q-

3q-Anom.

+21

+1/1q+

-21

+Mar

Haase et al. Blood 07