Download MDS: Classification and Advances in Therapy

MDS: Classification and Advances
in Therapy
BTG2013
S. Varma
PGIMER, Chandigarh
India
MDS
• Highly heterogeneous group of disorders
▫ Variable natural history
▫ Variable mortality rate
▫ Variable response to therapy
• Commonest cause of death
▫ Progressive bone marrow failure
▫ Conversion to AML
Age-related Incidence of MDS
100
Disease of elderly
Rate
10
1
0.1
0.01
0 10
Males
Females
20
30
40
50
60
70 80
Age, years
McNally RJQ et al. Hematological Oncology 1997. 15:173-189
Historical Perspective
• Pseudo-aplastic anemia
• Refractory Anemia
• Pre-leukemia
• Myelodysplastic syndrome
Luzzatto AM. anemia pseudoaplastica Riv Ven 1907;47:193.
Bomford RR, Rhodes CP. Refractory anemia. Q J Med 1941;10:175-281.
MDS: FAB Classification 1982
FAB
subtype
RA
Blast %
PB
BM
<1
RS%
Monocyte Survival
s >1x109/l (months)
<5
<15
-
50
RARS
<1
<5
>15
-
75
RAEB
<5
5-20
variable
-
11
CMML
<5
<20
variable
+
11
+/-
5
RAEB-T
>5;
20-30;
variable
Auer rods Auer rods
MDS: Limitations of FAB Classification
•
•
•
•
Multilineage cytopenia with <5% BM blasts
Rough prediction of prognosis
Cytogenetics not given importance
Ill defined entities: childhood MDS, T-MDS &
other secondary MDS
• Immunophenotyping and genetic techniques not
included
Comparison of MDS Classifications
FAB
classification
WHO Classsification
2001
WHO Classification 2008
RA
RA
Refractory cytopenia with unilineage dyplasia
• Refractory anemia
• Refractory neutropenia
• Refractory thrombocytopenia
RARS
RARS
Refractory anemia with ring sideroblasts (RARS)
RCMD
RCMD
RCMD-RS
RCMD-RS
RAEB
RAEB I and 2
RAEB I and 2
RAEB-T
RAEB II/ AML
RAEB II/ AML
CMML
MDS-UC
MDS-UC
MDS associated with
isolated del(5q)
MDS associated with isolated del(5q)
Childhood myelodysplastic syndrome
• Refractory cytopenia of childhood
WHO 2008
Subtype
Blood
Bone Marrow
RCUD
Single cell line
Mostly erythroid
Dysplasia: ≥10% cells
RARS
Anemia
Erythroid dysplasia
>15% ringed sideroblasts
RCMD
Bi/pancytopenia
>10%Dysplasia: ≥2 cell lineage
<5%blasts
RAEB-1
Cytopenia
<5% blast
Uni-multi lineage dysplasia
5-9% blasts, No Auer rods
RAEB-2
Cytopenia, 5-19% blasts or Uni-multi lineage dysplasia
Auer rods
10-19% blasts or Auer rods
MDS-U
Cytopenia
Uni / multilineage/ no dysplasia
Characteristic MDS CG +
MDS with 5q
Anemia,
normal or ↑Platelets
Unilineage erythroid dysplasia,
isolated del 5q, <5%blast
Outcomes in MDS in Different WHO Subtypes
Cazzola M. Hemaologica 2011
Improved prognostic scores
Disease related variables
Host factors
Appropriate clinical decision
Disease eradication/ control
Prolonging overall survival
Managing complications of disease and therapy
Improving quality of life
Prognostic
scores
Most widely used
There are
benefits
and
limitations
of all these
scores
IPSS: Prognostic Variables
0
0.5
1.0
1.5
2.0
<5
5-10
—
11-20
21-30
Karyotype
Good
Intermediate
Poor
Cytopenias
0/1
2/3
-
-
-
Marrow blasts %
Overall score
Median survival (years)
0
5.7
Intermediate 1
0.5 or 1.0
3.5
Intermediate 2
1.5 or 2.0
1.2
Poor
>/= 2.5
0.4
Risk group
Low
Overall score is the sum of the scores for following parameters:
BM blasts %: score 0 =< 5%; 0.5=5-10%; 1.5=11-19%; 2.0=20-30%.
Cytopenias: score 0 = no/ one cytopenia; 0.5 = 2 or 3 cytopenias.
Cytogenetics: score 0 (good)= Normal karyotype, -Y, 5q- or 20q-;
score 1.0 (poor)= 7q- or -7, complex translocations;
score 0.5 (intermediate)= all others.
Greenberg P et al. Blood 1997;89:2079-2088.
Prediction of survival by IPSS
IPSS
Pros
Cons
• Simplicity:
▫ Use of only 3 variables
• Applicable at centers
with limited lab support
• Widely used in clinical
practice and research
▫ Bulk of scientific data
on MDS is based of
IPSS
• Includes patients with
▫ 20-30% blasts
▫ CMML
• Does not consider
severity of cytopenias
▫ Strong predictor of
outcome
• Can not be applied in
pre-treated patients
WHO Prognostic Scoring System
*BM fibrosis grade 2-3 shifts risk group by one step
WPSS
Pros
Cons
• Simplicity: use of only 3
variables
• Accurate prediction of
survival and risk of leukemic
evolution at any time
during the course of their
disease
• Useful in predicting post
transplant outcome
• Not applicable for
secondary MDS
Comparison of IPSS and WPSS (258 MDS Patients)
MDACC Prognostic Scoring System (MPSS)
Variable
Score 1
Performance Status
Score 2
≥2
Age in years
60-64
≥ 65
Platelets x 109/L
50-199
30-49
Hemoglobin gm%
<30
<12
Bone marrow blasts
5-10
WBC x 109/L
11-29
>20
Karyotyping
Prior transfusion
Score 3
Chromosome 7 abnormality
Complex karyotype (>2 abn)
Yes
MPSS risk group
Low
Intermediate 1
Intermediate 2
High
Score
0-4
5-6
7-8
≥9
Kantarjian et al
Cancer 2008
2012 Revised IPSS
Fine tune the prognostic impact of
•Cytogenetic abnormalities
•Depth of cytopenia
Cytogenetic Abnormality
Median OS,
Mos
Median
Time to
AML, Mos
del(11q), -Y
60.8
NR
Good
Normal, del(20q), del(5q) alone or double, del(12p)
48.6
NR
Intermediate
+8, del(7q), i(17q), +19, any other single or double,
independent clones
26.0
78.0
inv(3)/t(3q)/del(eq), -7, double including del(7q),
complex (3)
15.8
21.0
complex (≥ 3)
5.9
8.2
Prognostic
Subgroup
Very good
Poor
Very poor
Schanz J, et al. J Clin Oncol. 2012;30:820-829. Greenberg PL, et al. Blood. 2012;120:2454-2465.
IPSS-R
Variable
0
0.5
1
1.5
2
3
4
Cytogenetics
V. good
-
Good
-
Int
Poor
V. poor
BM blast%
≤2
-
>2 - <5
-
5-10
>10
-
Hgb
≥10
-
8-<10
<8
-
-
-
Platelets
≥100
50-100
<50
-
-
-
-
ANC
≥0.8
<0.8
-
-
-
-
-
Risk Category
Risk Score
Very low
≤ 1.5
Low
>1.5 - 3
Intermediate
>3 – 4.5
High
>4.5 - 6
Very High
>6
Treatment considerations
• Myelodysplasia are incurable without HSCT
• Highly variable natural history
• Treatment considerations must take into account
many factors, including the
▫
▫
▫
▫
Pathologic diagnosis
The prognosis based on the IPSS or WPSS
Cell line /s affected
Feasibility of performing a clinical trial
Tools to treat MDS
•
•
•
•
•
•
Observation
Supportive therapy (Transfusions)
Hematopoietic growth factors
Iron chelation
Lenalidomide (Revlimid 2005)
Hypomethylating agents
▫ Azacitidine (Vidaza 2004)
▫ Decitabine (Dacogen 2006)
• Immunosuppression
• Allogeneic stem cell transplantation
• Newer agents
To Trick or Treat
• Treatment should be reserved and potentially diagnosis to be
transmitted to the patient and family, only if there are
symptoms resulting from anemia or other cytopenias or
perhaps pre-symptomatic anemia or severe
thrombocytopenia.
• Old and frail patients or those who have equivocal diagnostic
features, benefit from a period of observation.
• Neutropenia without infection is a poor justification for
initiation of therapy.
Stone RM. Blood 2009
Role of Growth Factors
Most widely prescribed class of medications for MDS (55%)
GCSF
Support improves ANC (75% patients)
Has no impact on overall survival.
Not recommended for routine infection prophylaxis
Thrombopoietic
agents
Most have no significant impact on transfusion needs:
Main utility
–Fewer dose modifications of disease modifying agents
–Romiplostim: 500/750mcg weekly
–Eltrombopag: under study
Erythropoiesis
stimulating agents
(ESA)
–First line therapy for IPSS low or Int-1 risk MDS with
EPO <500U/L (NCCN guidelines)
–Response rates; 20-30%, ?OS/PFS/ QOL, durability:2
years
–Epoeitin alpha: 60,000-80,000 U once per week
–Darbopoietin alpha: 500mcg once 3 weekly
Immunologic suppression of normal BM
function, similar to the situation in aplastic
anemia, has been postulated to account for
cytopenias in some MDS patients
Specific candidates- Refractory anemia with
relatively hypoplastic marrow
Predictor of Response to
Immunosuppressant
• HLA-DR-15-positivity
• RA (<5% blasts)
• IPSS Low/Int-1
• Age <60 years
• Brief transfusion history
• Trisomy 8 abnormality
• Normal cytogenetics
• Marrow cellularity <30%
ATG
• Phase II study (N=35) on MDS-RA
• Both equine and rabbit ATG were found to be active
• Response to
▫ Equine ATG: 29% (34/115)
▫ Rabbit ATG: RR 42%.
▫ 75% responders durable response (median 31.5
months).
Stadler M, Leukemia 2004;18:460-5
Jonasova A, Br J Haematol. 1998;100:304-309.
Molldrem JJ, Br J Haematol. 1997;99:699-705.
Chromosomal Abnormality: del13q
22 patients with bone marrow failure
MDS U
Only del (13 q )
Del (13q) plus other
abnormalities
number
16
6
GPI def clone
16
3
Response to IST
100% (14/14)
40% (2/5)
10 yr OSR
83%
63%
Progression to AML
None
2
•MDS-U with del (13q) is a benign disorder with good response to IST
•Del (13q) should not be considered intermediate risk abnormality
Hosokawa et al, Haematologica 2012;97:1845
Biological response modifiers
special case of Del 5q syndrome
Eligibility:
•del(5q)
•IPSS low or Int-1
•platelets > 50K/mm3
•neutrophils > 500/mm3
• transfusion dependent
Study Design
YES
Eligible
Patients
R
e
g
i
s
t
e
r
Week: 0
R
e
s
p
o
n
s
e
10 mg po x 21
4
8
12
16
20
24
Continue
Dose Reduction
5 mg qd
5 mg qod
NO
Off study
Results
Frequency of Cytogenetic Response According to Karyotype Complexity
Len in non del(5q) MDS
• Can be considered for low risk, adequate ANC and platelet
counts
• Expected response rates are similar to other treatment
alternatives
• Use in high risk MDS remains investigational
“Revlimid restores erythropoietic activity to the
MDS clone”
Raza et al. Blood 2008
Hypomethylating agents
•
• Azacytidine and decitabine
are potent DNMT inhibitors
• This leads to
hypomethylation of CpG
dinucleotides in gene
promoters and reactivation
of previously silent genes
• Cytotoxic activity similar to
cytarabine
5 Azacytidine
• AZA001: Euro study despite
CALGB 9221
• Primary endpoint: survival
AZA
Controls
Median survival
24.5 months
15 months
Progression to AML
27 months
13 months
Transfusion independence
45%
11%
Fennaux et al. Lancet Oncol 2009
Decitabine
DAC
Controls
Overall survival
10 months
8.5 months
Progression to AML at 1 yr
22%
33%
CR/ PR/ HI
13/6/5%
0/0/2%
Lubbert et al . JCO 2011
Hypomethylating agents
When to start
– Int/ high risk MDS (IPSS)
– Transfusion dependent/ EPO
failure
– Not yet known if early
treatment is better than late
treatment in MDS
Which drug
– NCCN recommends Azacitidine
preference over Decitabine
– EORTC study failed to show
survival benefit.
– MDACC regimen (5 day
20mg/m2/d) highest CR
– Aza vs Decitabine head to head
trial results awaited
Optimal dose, schedule, route
– Azacitidine:
– 7 day 75mg/m2/d sc q 28 days (52-2 or 50mg/m2 5-2-5 schedule)
– Decitabine:
– 3 day 15mg/m2/dose IV 8 hrly
(total dose 135mg/m2) inpatient
– 5 day 20mg/m2 /d over 1 hr (total
dose 100mg/m2) outpatient
Duration
– Optimal duration- not known
– To treat responding pts till disease
progression, as long as tolerated
– At least 4 cycles recommended for
adequate response
Steensma et al. Hematol Oncol clin N Am 2010
Predictive Factors for Achieving Response
to Hypomethylating Agents
Positive
• Negative
• Mol/ Cyto:
▫ Mutated TET2
▫ Mutated EZH2
▫ Phosphoinositase –
Phospholipase C beta 1
hypomethylation
• Clinical Variable
▫ Doubling of Platelets
• Mutated P 53
• Abnormal/ complex
karyotype
•
•
•
•
BM Blasts >15%
Previous therapy
Transfusion dependency
BM fibrosis grade 3
Santini V, ASH 2012
MDS
Low risk
(low or Int 1, BM blasts <10%)
High Risk
(Int 2, High risk, blasts>10%)
Any age
Iron Chelation
Growth factors
DMT Inhibitors
Lenolidamide
Immunomodulation
Clinical trial
Age <60
Intensive chemo
DMTI
Clinical trial
Failure
Age≥60
DMTI
Clinical trial
Intensive Chemo
Failure
Progression/ failure
HSCT
Attallah: Cancer Therap 2008;26:208-16
What’s on the Horizon?
• In the quest of effective therapy, currently there
are approximately 200 clinical trials are ongoing
and numerous agents are at various stages of
drug development
• The need for a novel agent is particularly noted
in patients failing hypomethylating agents who
are ineligible for stem cell transplant
Kulasekararaj AG, Semin Hematol ,2012; 49:350-60
Agent
Action
Current status
Erlotinib
Oral TKI tageting EGFR
Phase 2,
hypomethylating agent
failed MDS cases
ORR 15%
Stable disease 32%
Tosedostat
Aminopeptidase
inhibitor
Phase 1/ 2,
ORR 28% in AML/MDS
patients >60 years
Ezatiostat
Glutathione analogue
Phase 2 , 40 % efficacy
in lenalidomide treated
MDS patients
Siltuximab
Chimaric monoclonal
Ab neutralising IL6
Phase 2 for Anemia
related to MDS
Kulasekararaj AG, Semin Hematol ,2012; 49:350-60
Agent
Action
Current status
BMN673
PARP inhibiotrs
Phase 1 , open label
trial for AML, MDS,
MCL, CLL
MLN4924
Small molecule
inhibitor of
Neddylation
activating enzyme
Phase 1, AML and
MDS
PF-04449913
Hedgehog pathway
inhibitor
Phase 1/ 2, for
myelofibrosis, AML,
MDS
SCIO496
MAP kinase inhibitors Phase 1/ 2 for low
and intermediate risk
MDS
Kulasekararaj AG, Semin Hematol ,2012; 49:350-60
Take Home Message
• Myelo-dysplastic syndromes are heterogeneous
disorders
• Prognostic scores are evolving with use of cytogenetics and molecular markers
• Treatment depends upon the prognostic and host
factors
• MTI and IMIDs are being increasingly used
• HSCT is the only curative treatment
• Treatment paradigms are evolving