classification of mds and optimal management strategies in … · 2013. 6. 14. · 0 100 1.0 0.0...

Classification of MDS and

optimal management strategies in

lower and higher risk MDS patients Prof. Wolf-Karsten Hofmann

Classification of MDS and

optimal management strategies in

lower and higher risk MDS patients

Wolf-Karsten Hofmann

Department of Hematology and Oncology

University Hospital Mannheim, Germany

(A) Case Report (Patient)

• 74 years old male

• Since 3 months dyspnea, associated with physical stress

• Peripheral blood

–Hb 7.4 g/dl MCV 96 fl

–WBC 2.4 /nl (42 % Neutro; 45 % Lympho; 7 % Mono; 2 % Baso; 4 % Eos)

–Platelets 123 /nl

• Bone marrow

–Dysplastic lineages, in particular erythropoiesis and

granulopoiesis

–Detection of ringed sideroblasts

–Blast cells <5 %

–Cytogenetics: 46,XY

(A) Case Report (Diagnosis)

Diagnosis: MDS

RARS (FAB)

RARS (WHO 2008)

Intermediate-Risk I (IPSS)

Intermediate-Risk (WPSS)

Pathophysiology of MDS

CD34+

Epidemiology of MDS

• Common bone marrow disorder

• The overall incidence is approximately 4 per 100,000 in the

general population

• Peak incidence occurs at 60–90 years of age

> 20 per 100,000 at age of 70-85 years

> 30 per 100,000 at age 85+

• About 8,200 patients with MDS in Germany

2 0

0,6

0,4

0,2

0,0

0,8

1,0

4 6 8 10 12 14 16 18 20

Years

n=1806

(1970-2003)

Ove

rall S

urv

iva

l

Düsseldorf MDS-Registry, personal communication by U. Germing

Molecular Changes in MDS

Bejar et al. JCO (2011) 29, 504-515

Diagnosis of MDS

• Clinical presentation

• Morphology

-Peripheral blood

-Bone marrow

Classification

• Immunphenotype

• Cytogenetics/FISH

Risk

• Molecular changes

Single gene based

Array based

FAB Classification

RA

RARS

CMML

RAEB

RAEB-T

<5

<5

< 20

5 to 20

21 to 30

< 15

>15

-

-

-

< 1

< 1

<5

<5

> 5

FAB: French-American-British Cooperative Group (1982)

Blasts (%) Subtype Blasts (%) Ringed

Sideroblasts (%) Monocytes

-

-

>1x10³ /µL

-

± >1x10³ /µL

Peripheral Blood Bone Marrow

Bennett et al. BJH (1982) 51, 189-199

WHO Classification (2008)

Entity Dysplasia Blasts pB Blasts BM

Ringsidero-

blasts Cytogenetics

5q- syndrome mostly DysE 0 < 5% < 15% 5q- sole

RCUD

(RA, RN, RT) DysE,N,T 0 < 5% < 15% various

RARS mostly DysE 0 < 5% ≥ 15% various

RCMD (RS) 2-3 lineages 0 < 5% ± 15% various

RAEB-1 1-3 lineages < 5% 5-9% - various

RAEB-2 1-3 lineages

5-19%

Auer rods +/-

10-19%

Auer rods +/- - various

MDS-U 1 lineage ≤ 1% < 5% - various

MDS-Diagnostic: Cytogenetics/FISH

• Cytogenetics

–Classical method for chromosomal analysis

–Short-term culture of bone marrow cells

–Requires metaphases

–Analysis of loss/gain of chromosomes, translocations,

deletions

• Fluorescence in-situ hybridization (FISH)

–Fluorescence-labelled probes

–Specific analysis of loss/gain of chromosomes,

translocations

–More sensitive than standard cytogenetic analysis

Cytogenetic Changes in MDS

Schanz et al. JCO (2011) 29, 1963-1970

7 10 6 10

176

6

59

130

5 19

7 5 17

8 7 6 11 10

48

10 8 7

61

6

150

20

45

98

31

59

188

0

20

40

60

80

100

120

140

160

180

200

Single (n=25) Double

(n=3)

Complex

(n=2) IC

n=2901

MDS-Karyotype: Deletion 5

Personal communication by A. Fabarius, Mannheim

46,XX,del(5)(q13q33)

MDS-Karyotype: Monosomy 7

45,XX,-7


Institut für Zell- und Molekularpathologie, Medizinische Hochschule Hannover

MDS-FISH: Trisomy 8

MDS-Karyotype: Complex aberrant

44,XX,der(1)t(1;11)(p36;q12)t(11;19)(q23;p13)del(1)(q22),

der(11)t(1;11)(q22;q12),-13,der(19)t(11;19)(q23;p13),-22


MDS-FISH: Complex aberrant

44,XX,der(1)t(1;11)(p36;q12)t(11;19)(q23;p13)del(1)(q22),d

er(11)t(1;11)(q22;q12),-13,der(19)t(11;19)(q23;p13),-22

#1 and #11 # 19


MDS-Karyotype: Deletion 20

46,XY,del(20)(q11)


IPSS

0

0.5

1.0

1.5

2.0

<5

5-10

-

11-20

21-30

Good (normal. -Y, 5q-, 20q-)

Intermediate (other)

Poor (complex or chrom. 7)

Karyotype Score Value BM-Blasts (%) Cytopenias

0/1

2/3

Risk Groups: Low:

Intermediate-1:

Intermediate-2:

High:

0

0.5-1.0

1.5-2.0

> 2.5

IPSS: International Prognostic Scoring System

Greenberg et al. Blood (1997) 89, 2079-2088

Survival AML-free

IPSS-R

IPSS-R: Revised International Prognostic Scoring System


IPSS-R and Patients Age


Impact of Molecular Markers in MDS

Bejar et al. NEJM (2011) 364, 2496-2506

Comprehensive Molecular Characterization in MDS

• Genomics (SNP)

• Genomics (NGS)

• Functional Genomics (Met)

• Gene Expression

• Computional Science

?

Walter et al. NEJM (2012) 366, 1090-1098

Clinical Management of MDS

RBC-transfusions

Corticosteroids

Vitamines

Danazol

LD-ARA-C

Hydroxyurea

Intensive Treatment

RBC-transfusions

Erythropoietin

G-CSF

Interleukin-3

ATRA

Vitamine E

RBC-transfusions

ATG

Cyclosporine A

Amifostine

RBC-transfusions

Thalidomide

9-cis RA

Lenalidomide

5-Azacytidine

Decitabine

Valproic Acid

RBC-transfusions

Allogenic PBSCT

Erlotinib

Panobinostat

5-Aza+Epo

5-Aza+VPA

Deferasirox

FAB IPSS

1982 1991 1997 2003 2012

IPSS-R

Stem Cell Transplantation in MDS

• Curative

–Relapse Free Survival: 40 %

–Mortality: 20-40 %

–Age related

–Risk adapted indication

• Good prognostic factors for SCT

–<60 years old

–HLA-identical sibling

–Good clinical performance (WHO 0-1)

–Short disease history

• „Mini“-Transplantation (dose reduced condition treatment)

–„Graft versus Leukemia“ effect

(B) Case Report (Diagnosis)

• 69 years old male

• No relevant co-morbidity, “active guy“

• 06/2009: Signs of bleeding (nose-bleeding, petechia)

• 07/2009: Diagnosis of MDS

RAEB II

46,XY,+3,-7,del(11q13),del(5q31)

Thrombocytopenia, Leukopenia, Anemia

IPSS: High-Risk

• Rapid progression of disease with decrease of peripheral blood

values

Treatment Strategies in MDS

• Hematopoietic growth factors (Epo; G-CSF)

• Immunosuppressive Therapy

ATG, CSA

• Immune modulatory drugs

Lenalidomide

• Demethylation

5-Aza-Cytidine

Decitabine

• Intensive Cytotoxic Treatment (AML-like)

• Stem Cell Transplantation

• Experimental treatment

MD

S-R

isk (

IPS

S)

Su

pp

ort

ive

ca

re

• Transfusion of RBC depending on clinical performance

• Transfusion of platelets exclusively if there are signs of bleeding

Never ever prophylactical platelet transfusion

• Early antibiotics

• Treatment of accompanying diseases

–Heart failure

–Lung diseases

Supportive Treatment in MDS

Transfusion of RBC in MDS

• 75 % of patients will become

transfusion dependent

• Intervall of RBC: 2-16 weeks

8-52 U of RBC per year

• About 13,000 mg iron per year

• Loss of iron per year:

400-500 mg 200–250 mg Iron

Transfusion of RBC and Survival in MDS

0.0

0.2

0.4

0.6

0.8

0.1

0.3

0.5

0.7

0.9

1.0

0 20 40 60 80 100 120 140

Su

rviv

al

Months

RBC independent

RBC dependent

Cazzola & Malcovati NEJM (2005) 352, 536-538

Non-Leukemic Death and RBC in MDS

Malcovati et al. JCO (2005) 23, 7594-7603

Cu

mu

lati

ve r

isk

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 20 40 60 80 100 120 140 160 180

Survival time (months)

Transfusion-independent

Transfusion-dependent

Iron Chelation in MDS – Impact on Survival (1) S

urv

ival

0.00

0.25

0.50

0.75

1.00

Months

0 50 100 150 200 250

Chelat-Therapy

No Chelat-Therapy

Median Survival:

• 115 versus 51 months (p< 0.0001)

• Total population 63 months

Rose et al. Leuk Res (2010) 34, 864-870

Iron Chelation in MDS – Impact on Survival (2)?

Lyons et al. ASH2012 #3800

(n=336) (n=264) (n=200)

P<0.0001 for non-chelated vs. both chelated groups

Comorbidities in Transfusion Dependent MDS

Goldberg et al. JCO (2010) 28, 2847-2852

82.4

44.4

62.9

1.0

81.0

14.6

67.1

37.1 40.4

0.7

55.7

6.2

0

50

100

Cardiac

events

2003–2005

Diabetes

2003–2005

Dyspnoea

2003–2005

Hepatic

events

2003–2005

Infectious

complications

2003–2005

Fungal

infection

2003–2005

Pati

en

ts (

%)

With transfusion (n = 205)

Without transfusion (n = 307)

EPIC: Improvement in All Lineages

Gattermann et al. Haematologica (2012) 97, 1364-1371

0

5

10

15

20

25

Pat

ien

ts (%

)

22.6

14.0

19.6

Hematological response

0

50

100

150

200

250

Me

dia

n t

ime

to

re

spo

nse

(day

s)

109 99

115

169

226

Hematological response

Hb

Trans.

Hematological response Time to hematological response

Hb/Trans.

DFX in MDS (GIMEMA MDS0306)

• Prospective, non-randomized trial using Deferasirox in MDS

• 152 patients with MDS (IPSS low and int-1 risk) and transfusion

dependence (> 20 units)

• Median age: 72 years (66-77)

• 22 patients acquired transfusion independence

• Risk of disease progression or death was 13 % and 25 % (at 6

and 12 months, respectively)

Emanuele Angelucci

Angelucci et al. ASH2012 #425

https://ash.confex.com/data/abstract/ash/2012/1/9/Paper_51991_abstract_87831_0.png

Iron Chelation Guidelines in MDS - Summary

Despite some differences between the guidelines, common

recommendations include:

• Iron chelation should be started in transfusion

dependent patients

- with MDS with serum ferritin at 1,000 µg/L

(after approx. 20–25 RBC units)

- with expected survival >1 year

• Iron chelation should be started in transfusion

dependent MDS patients who are candidates for allo-

SCT

• Treatment goal: serum ferritin <1,000 µg/l

RBC Transfusion and Allo PBSCT in MDS

Alessandrino et al. Hematologica (2010) 95, 476-484

0

1.0

0.0

0.8

0.6

0.4

0.2

20 40 60 80 100 120 140 160

0.9

0.7

0.5

0.3

0.1

0

1.0

0.0

0.8

0.6

0.4

0.2

20 40 60 80 100 120 140 160

0.9

0.7

0.5

0.3

0.1

Transfusion independent, n = 73

Transfusion dependent, n = 135

Transfusion independent, n = 73

Transfusion dependent, n = 135

Lower overall survival in

transfusion-dependent patients

Higher non-relapse mortality in

transfusion-dependent patients

HR = 1.76

p = 0.03

HR = 1.70

p = 0.02

Cu

mu

lati

ve

pro

po

rtio

n s

urv

ivin

g

No

n-r

ela

ps

e m

ort

ali

ty (

pro

ba

bil

ity)

Time (months) Time (months)

Iron Chelators

Property Deferoxamine Deferiprone Deferasirox

Chelator:iron

binding 1:1 3:1 2:1

Usual dose

(mg/kg/day) 25–40 75 20–30

Route of

administration

Subcutaneous,

intravenous

(8-12 hours, 5

days/week)

Oral 2-3 times daily Oral once daily

Half-life 20–30 minutes 3–4 hours 12–16 hours

Excretion Urinary, fecal Urinary Fecal

Adverse effects

Local reactions,

opthalmologic,

auditory, bone

abnormalities,

allergic reactions

Gastrointestinal

disturbances,

agranulocytosis/

neutropenia,

arthralgia

Gastrointestinal

disturbances, rash

Deferasirox versus Deferoxamine: Application

Arborettil et al. Eur J Clin Pharmacol (2001) 56, 915-922

Cappellini et al. Clin Ther (2007) 29, 909-917

Deferoxamine Deferasirox

Quality of care Quality of life

Degree of discomfort caused by therapy

None/little

discomfort 11% (36/317) 11% (36/303)

Some

discomfort 21% (40/193) 23% (44/187)

Great

discomfort 23% (35/152) 40% (59/146)

Arborettil et al. Eur J Clin Pharmacol 2001 Cappellini et al. Clin Ther 2007

DFX in MDS: US versus EU Data

• Two studies; EPIC (n=341) and US03 (n=176).

• Inclusions: SF ≥ 1000 ng/ml; > 20 units RBC

• Deferasirox 20 mg/kg daily

Time (months) EPIC (ng/ml)

US03 (ng/ml)

0 2729 3397

3 2358 3057

6 2209 2802

9 2076 2635

12 1903 2501

Gattermann et al. Leuk Res (2010) 34, 1143-1150

List et al. JCO (2012) 30, 2134-2139

US03: Changes of Labile Plasma Iron

Months from baseline

0

0.4

0.6

0.8

1.0

Baseline 6 9 12

LP

I (

mo

l/L

)

3

0.4

Threshold of normal LPI

Deferasirox controls toxic LPI over a 24-hour period

resulting in normalized LPI values in 100% of

patients over 12 months

List et al. JCO (2012) 30, 2134-2139

Deferasirox in MDS: Side Effects

Adverse event Number (%)

Diarrhoea

111 (32.6)

Nausea 45 (13.2)

Vomiting 26 (7.6)

Abdominal pain 26 (7.6)

Upper abdominal pain 25 (7.3)

Rash 23 (6.7)

Constipation 21 (6.2)

Total number 341

Gattermann et al. Leuk Res (2010) 34, 1143-1150

Practical Guide to Manage Diarrhea

• Mild: <4 runs a day

- Loperamide

- Re-Hydration

- Timing of Deferasirox administration

• Moderate: 4-6 runs a day

- Management as described for “Mild“

- Dose reduction of Deferasirox to 10 mg/kg

• Severe: >6 runs a day

- Management as described for “Moderate“

- i. v. Re-Hydration

- Hold Deferasirox

Nolte et al. Leuk Res (2011) 49, 528-533

Re-Initiation of Deferasirox

• After cessation of diarrhea no new episodes

• Discontinuation of loperamide

• With sufficient hydration GFR stable > 60 ml/min

10 mg/kg/d

20 mg/kg/d

15 mg/kg/d

Discontinuation of

DFX

Nolte et al. Leuk Res (2011) 49, 528-533

• 2 units RBC every two weeks

• Start Epo/G-CSF: no response after 3 months

• After 30 units RBC (Ferritin: 2800 mg/dl):

Start with Deferasirox 30 mg/kg

• After first dose: Diarrhea (moderate: 4-6 runs a day)

• Diarrhea continued for additional 5 days

(A) Case Report (Course)

• Actual duration of treatment with Deferasirox has been 22

weeks

• Treatment is well tolerated with no additional episodes of

diarrhea

• Serum ferritin level dropped to 1800 ng/ml

• Transfusion requirement 2 units/2 weeks

• Measurement of liver iron content by MRI is pending

(A) Case Report (Outcome)




ATG, CSA


Lenalidomide

• Demethylation

5-Aza-Cytidine

Decitabine




MD

S-R

isk (

IPS

S)

Su

pp

ort

ive

ca

re

Erythropoietin (±G-CSF) in MDS

RA, RARS, RAEB Score -1 bis +1

Score < -1

Score > +1 High response (75 %)

Intermediate response (23 %)

Low response (7 %)

-3

+1

+2

>500

100-500

<100 Endogenous serum

Epo-level [U/l]

-2

+2 <2/month Transfusions per months

Hellström-L. et al, BJH (1997) 99, 344-351

≥2/month




ATG, CSA


Lenalidomide

• Demethylation

5-Aza-Cytidine

Decitabine




MD

S-R

isk (

IPS

S)

Su

pp

ort

ive

ca

re

Immuno-Suppressive Treatment in MDS

•Total of 88 patients with MDS

•Randomized trial

–45 patients with ATG/CSA

–43 patients BSC (RBC transfusion, Epo)

•Response rates:

-ATG/CSA: 13/45 (29 %)

-BSC: 4/43 (9 %)

•Overall survival at 2 years

-ATG/CSA: 49 %

-BSC: 63 %

Passweg et al. JCO (2011) 29, 303-309




ATG, CSA


Lenalidomide

• Demethylation

5-Aza-Cytidine

Decitabine




MD

S-R

isk (

IPS

S)

Su

pp

ort

ive

ca

re

Lenalidomide in MDS 5q- (1)

• Randomized trial (MDS004) in MDS 5q- to evaluate efficacy

and safety of two different dosages of Lenalidomide

• Number of transfusion-independent patients?

• Number of cytogenetical remissions?

• Randomized phase III trial

• 205 patients randomized, 138 evaluable

Placebo: Best supportive care

Arm 1: 5 mg Lenalidomide daily (28 days)

Arm 2: 10 mg Lenalidomide daily (21 days)

• Overall study duration 52 weeks

Fenaux et al. Blood (2011) 118, 3765-3776

Lenalidomide in MDS 5q- (2)

Fenaux et al. Blood (2011) 118, 3765-3776

• Transfusion independency:

Placebo: 6 %

5 mg: 41 %

10 mg: 56 %

• Toxicity equal in both arms

• More cytogenetical remissions in the 10 mg arm

• High Drop-off rate (37 %) because of missing bone marrow

cytologies (hypocellular bone marrow)

52 weeks of treatment

0

10

20

30

40

50

60

70

RB

C-T

I (%

)

41

56

6




ATG, CSA


Lenalidomide

• Demethylation

5-Aza-Cytidine

Decitabine




MD

S-R

isk (

IPS

S)

Su

pp

ort

ive

ca

re

Progress of MDS: Increasing DNA-Methylation

Jiang et al. Blood (2009) 113, 1315-1325

DNA-Methylation Analysis by Methylation Microarray

Epigenetic Treatment in MDS

Azacytidine

CALGB 5-Aza Phase III in MDS

Silverman et al. JCO (2002) 20, 2429-2440

CR

PR

Improved

Total

5-Aza

(%)

7

16

37

60

Supportive

(%)

0

0

5

5

Cross-over

(%)

10

4

33

47

AZA001: Study Design

Fenaux et al. Lancet Oncol (2009) 10, 223-232

Azacitidine 75mg/m2/day x 7 days q.28d.

CCR

Randomisation

BSC was included in each arm

Treatment continued until unacceptable toxicity, relapse or disease progression

BSC only

LDAC

Std-CT

Screening/

central pathology review

Investigator CCR

treatment selection

BSC = best supportive care

CCR = conventional care regimens

q.28d. = every 28 days

LDAC = low-dose cytarabine

Std-CT = standard chemotherapy

AZA001: Survival Benefit in MDS

Fenaux et al. Lancet Oncol (2009) 10, 223-232

0 10 20 30 40 50 60 70 800.00

0.25

0.50

0.75

1.00

AML-like therapy

AZA001: No. of Cycles to First Response

Silverman et al. Cancer (2011) 117, 2697-2702

Cu

mula

tive p

roba

bili

ty o

f re

spo

nse

Number of cycles

87% of first responses achieved

with six cycles of treatment

Range: 1–22 cycles

0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21 24

(B) Case Report (Treatment)

1994

•Induction treatment (IdAV I)

→no CR

•IdAV II

→no CR

•LD-ARA-C

→severe thrombocytopenia

•Supportive treatment

•Course: ?

•Survival:

9 months vs. 12 months

2009

•5-Azacytidine s.c.

(4 cycles)

•CR with low peripheral

blood values

•Search for a donor

•Mini-allogeneic SCT

•Acute GvHD, sensitive to

corticosteroids

•Continuous CR

•Survival:

9 months vs. 30+ months

1994

•Induction treatment (IdAV I)

→no CR

•IdAV II

→no CR

•LD-ARA-C

→severe thrombocytopenia

•Supportive treatment

•Course:?

•Survival:

9 months vs. 12 months

Epigenetic Treatment in MDS

Decitabine

DAC Phase II/III for MDS

European phase II US phase III

91-01 95-11 97-19 D-0007

n 29 66 87 89

CR + PR, % 45 26 26 17

CR, % 28 21 22 9

PR, % 17 5 5 8

Hematological improvement, %

7 12 15 13

Median duration of CR+PR, days 217 250 146 288

Median no. of cycles 4 4 4 3

Saba et al. Semin Hematol. 2005; Wijermans et al. JCO 2000 and Leukemia 1997; Kantarjian et al. Cancer 2007

DAC-EORTC: Study Design

Lübbert et al. JCO (2011) 29, 1987-1996

DAC-EORTC: Overall Survival

Lübbert et al. JCO (2011) 29, 1987-1996

0 6 12 18 24 30 36 42

0

10

20

30

40

50

60

70

80

90

100

Median (months): 10.1 vs 8.5

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

Logrank test: p=0.38

Decitabine

Best Supportive Care

Ove

rall s

urv

iva

l

Months


University Hospital Frankfurt/Main

H. Serve

D. Hoelzer

University of California Los Angeles

H.P. Koeffler (Hematology)

S. deVos (Hematology)

J.W. Said (Pathology)

German MDS Study-Group

A. Ganser

U. Germing

U. Platzbecker


University Hospital Mannheim

F. Nolte D. Nowak

S. Kreil M. Mossner

N. Müller V. Nowak

G. Metzgeroth C. Schumann

Munich Leukemia Laboratory (MLL)

T. Haferlach


Campus Benjamin Franklin

Charité – University Hospital Berlin

C. Baldus

O. Hopfer

W. Blau

classification of mds and optimal management strategies in … · 2013. 6. 14. · 0 100 1.0 0.0...

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