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 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
Personal communication by A. Fabarius, Mannheim
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
Personal communication by A. Fabarius, Mannheim
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
Personal communication by A. Fabarius, Mannheim
MDS-Karyotype: Deletion 20
46,XY,del(20)(q11)
Personal communication by A. Fabarius, Mannheim
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
Greenberg et al. Blood (2012) 120, 2454-2465
IPSS-R and Patients Age
Greenberg et al. Blood (2012) 120, 2454-2465
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
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
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)
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
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
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
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
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
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
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
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
Department of Hematology and Oncology
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
Department of Hematology and Oncology
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
Department of Hematology and Oncology
Campus Benjamin Franklin
Charité – University Hospital Berlin
C. Baldus
O. Hopfer
W. Blau