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1
Myelodysplastic Syndromes
Current Thinking on Disease, Diagnosis and Treatment
Hetty Carraway, MD, MBA, FACP
Associate Professor
Taussig Cancer Institute
Cleveland Clinic
Overview:
Biology and Diagnosis of MDS
Scoring System/Prognosis
Treatment Options for Low Risk MDS
Treatment Options for High Risk MDS
What is MDS? Myelodysplastic Syndromes
• 15,000 - 25,000 new cases/year
• Median age 71 M > F
• Clonal disorder: multi-lineage hematopoietic progenitor
• Ineffective hematopoiesis with peripheral cytopenias
• Bone Marrow Failure State:
• Patients present with fatigue, infection or bleeding
• Transformation to AML in ~ 1 in 3
• Allo BMT only curative option
U.S. Cancer Statistics Working Group 2010;1999-2010, Web Report.
Epidemiology
Age at Diagnosis (Yrs)*P for trend < .05
Rollison DE, et al. Blood. 2008;112:45-52.
0
10
20
30
40
50
< 40 40-49 50-59 60-69 70-79 ≥ 80
0.1 0.72.0
7.5
20.9
36.4*
FemalesMalesOverall
Overall incidence: 3.4 per 100,000
0
10
20
30
40
50
60
Inc
ide
nc
e p
er
10
0,0
00
pe
r Y
ea
r
Age at Diagnosis
Age-Specific (Crude) SEER Incidence Rates, All Races, Both
Sexes, 2000-2009
SEER Program (www.seer.cancer.gov) Research Data (1973-2009), National Cancer Institute, DCCPS, Surveillance
Research Program, Surveillance Systems Branch, released April 2012, based on the November 2011 submission.
28% 72%
2
MDS PathogenesisStage 1Intrinsic increase in
apoptotic response and
inflammation
Stage 2Acquisition of
anti-apoptotic molecules
Stage 3Initiation of
clonal evolution
↑ TNFα-induced
apoptosis↑ ROS ↑ Bcl-2
MPMP
MP
MP
aMP
MPMP
MP
MPMPMP
aMP
aMP
aMPMP
MP
MPMP
Induction of homeostatic
mechanismsExpansion
Telomere
erosion and
senescence
Impaired
immunosurveillance
by NK and T-cells
Stem cell depletionEmergence of abnl clones
with point mutations in
NRas + AML1
Abnormalities in DNA repair
mechanisms with propagation
of abnormal cellsBone marrowAbnormal
ribosomes
Altered T-cell
homeostasis
Inflammatory
microenvironment
Altered MP
localizationStromal cell
defects
Molecular model of MDS progressionSuppressed
hematopoiesis
High risk
for leukemia
transformationEpling-Burnette PK, et al. Curr Opin Hematol. 2009;16:70-76.
KaryotypeArray CGH
SNP ArrayKaryotype / FISH
Genotyping
Sequencing
Genetic Abnormalities in MDS
Translocations/
Rearrangements
Uniparental Disomy/
Microdeletions
Copy Number
Change
Point Mutations
Rare in MDSRare – often at sites of
point mutationsAbout 50% of cases Most common
t(6;9)
i(17q)
t(1;7)
t(3;?)
t(11;?)
inv(3)
idic(X)(q13)
4q - TET2
7q - EZH2
11q - CBL
17p - TP53
del(5q)
-7/del(7q)
del(20q)
del(17p)
del(11q)
+8
-Y
Likely in all cases
~80% of cases have
mutations in a
known gene
Vardiman,JW, et al. Blood. 2009;114(5): 937-951. Tiu R, et al. Blood. 2011;117(17):4552-4560.
Schanz, J, et al. J Clin Oncol. 2011; 29(15):1963-1970. Bejar R, et al. N Engl J Med. 2011;364(26):2496-2506.
Bejar R, et al. J Clin Oncol. 2012;30(27):3376-3382.
MDS: Diagnosis
• No specific clinical feature distinguishes
MDS from other causes of pancytopenia
• Laboratory evaluation often prompted by
signs or symptoms, including:
– Fatigue (anemia)
– Infections (neutropenia)
– Bleeding (thrombocytopenia)
Bennett JM, et al. Int J Hematol. 2002 Aug;76 Suppl 2:228-38.
Clinical Overlap / Associations:
• Acute Myeloid Leukemia
• Myeloproliferative Disease
• Paroxsymal Nocturnal
Hemoglobinuria
• Autoimmune diseases
• Aplastic Anemia
• LGL leukemia
• Pure Red Cell Aplasia
AML
PRCA
PNH
MDS
AA
LGL MPD
J Maciejewski,M.D. Taussig Cancer Center/ Cleveland Clinic Foundation
American College of Physicians from Young NS. Ann Intern Med. 2002 Apr 2;136(7):534-46
Bone Marrow Failure: Signs and Symptoms
Anemia
• Fatigue, pallor
• Shortness of breath, decreased exercise tolerance
• Exacerbation of heart failure, angina
Neutropenia
• Active infection (bronchitis, sinusitis, pneumonia, etc.)
• Risk of infections
Thrombocytopenia
• Petechiae, bruising, bleeding
• Risk of bleeding
MDS: Diagnostic Evaluation
• Peripheral blood counts + reticulocyte count
• Bone marrow biopsy and aspiration
– Bone marrow blasts %
– Cytogenetics
– Iron stain
– Reticulin stain
• Additional tests
– Iron saturation, ferritin
– B12, folate levels
– EPO level
Establish diagnosis of MDS & determine subtype & prognosis:
– FAB/WHO Classification
– IPSS/IPSS-R score
http://www.nccn.org/professionals/physician_gls/PDF/mds.pdf
http://www.ishapd.org/1996/1996/016.pdf
3
MDS: Diagnostic Evaluation
• Peripheral blood counts + reticulocyte count
• Bone marrow biopsy and aspiration
– Bone marrow blasts %
– Cytogenetics
– Iron stain
– Reticulin stain
• Additional tests
– Iron saturation, ferritin
– B12, folate levels
– EPO level
Establish diagnosis of MDS & determine subtype & prognosis:
– FAB/WHO Classification
– IPSS/IPSS-R score
http://www.nccn.org/professionals/physician_gls/PDF/mds.pdf
http://www.ishapd.org/1996/1996/016.pdf
Performing a bone marrow aspiration
Courtesy of Dr. Bennett and Dr List.
Cytologic Dysplasia: Bone Marrow
DysErythropoiesis
Courtesy of Dr. Bennett and Dr List.
Cytologic Dysplasia: Marrow and
Blood DysGranulopoiesis
Courtesy of Dr. Bennett and Dr List.
Cytologic Dysplasia: Marrow and
Blood DysMegakaryopoiesis
FAB vs WHO Classification
FAB WHO Dysplasia(s)
RA 5q-Syndrome Erythropoietic
RA Erythropoietic
RCMD 2-3 lineages
MDS-U 1 lineage
RARS RARS Erythropoietic
RCMD-RS 2-3 lineages
RAEB RAEB-1 1-3 lineages
RAEB-2 1-3 lineages
RAEB-T AML
CMML CMML (if WBC < 13,000u/l)
Germing U, et al. Leukemia Research 2000:24:983-92.
Harris NL, et al. J Clin Oncol 1999:12:3835-3849.
List AF, et al. The Myelodysplastic Syndromes. In: Wintrobe’s Hematology 2003.
Silverman LR. The Myelodysplastic Syndromes. In: Cancer Medicine. 2000.
4
How Do We Classify MDS?
Greenberg P, et. al. Blood 1997
FAB1970-80
IPSS1997
WHO1999
2002
2008
WPSS2007
IPSS-R2012
IPSS Is Most Common Tool for Risk
Stratification of MDS
Score Value
Prognostic variable 0 0.5 1.0 1.5 2.0
Bone marrow blasts < 5% 5% to 10% -- 11% to 20% 21% to 30%
Karyotype* Good Intermediate Poor -- --
Cytopenias† 0/1 2/3 -- -- --
*Good = normal, -Y, del(5q), del(20q); intermediate = other karyotypic abnormalities; poor = complex ( 3 abnormalities)
or chromosome 7 abnormalities. †Hb < 10 g/dL; ANC < 1800/L; platelets < 100,000/L.
Greenberg P, et al. Blood. 1997;89:2079-2088.
Total Score
0 0.5 1.0 1.5 2.0 2.5
Low Intermediate I Intermediate II High
Median survival, yrs 5.7 3.5 1.2 0.4
Survival and Freedom From AML Progression
IPSS MDS Risk Classification
Higher risk MDS (INT-2, High) is associated with a
median survival of 0.4—1.2 years
Greenberg P, et al. Blood. 1997:89:2079-88.
IPSS-R: Revised June 2012
1. New marrow blast categories
≤2, >2 - <5, 5 - 10, >10 - 30%
2. Refined cytogenetic abnormalities and risk groups
16 (vs 6) specific abnormalities, 5 (vs 3) subgroups
3. Evaluation of depth of cytopenias
clinically and statistically relevant cut points used
4. Inclusion of differentiating features
Age, Performance Status, ferritin, LDH, Beta-2 microglobulin
5. Prognostic model with 5 (vs 4) risk categories
improved predictive power
Greenberg PL, et al. Blood. 2012;120:2454-2465.
P. Variable 0 0.5 1 1.5 2 3 4
Cytogenetics Very
GoodGood Intermediate Poor Very
Poor
BM Blast % ≤2 >2-<5% 5-10% >10%
Hemoglobin ≥10 8-<10 <8
Platelets ≥100 50-<100 <50
ANC ≥0.8 <0.8
Risk Group Risk Score
Very Low ≤1.5
Low >1.5-3
Intermediate >3-4.5
High >4.5-6
Very High >6
IPSS-R: Prognostic Score Variables
IPSS-R: Prognostic Risk Categories/Scores
Greenberg et al. Blood 2012;120:2454-65.
High risk
Mutation Profiling
• Powerful tool
– Diagnose disease (from aging to MDS to AML)
• Prognostic:
– Risk of Progression
– IPSS, IPSS-R and now IPSS-R-M
• Predictive
– Chemo and BMT response/non-response
• Targeted therapies
– SF3B1/TET2/IDH1/IDH2/FLT3
5
CHIP as a Precursor State to
Hematological Neoplasms
David P. Steensma et al. Blood 2015;126:9-16.
Clonal
Hematopoiesis of
Indeterminate
Potential
Clonality
Dysplasia
Cytopenias
Blasts
MDS Mutation Landscape
Steensma, D. Mayo Clinic Proceedings. 2015. 969-83
Unique Mutation Profile Helps
Identify/Confirm Disease
• SF3B31 and JAK2: RAEB-T
• TET2, SRSF2, DNMT3A, ASXL1, SETBP1: CMML
• SRSF2, SF3B1, U2AF1, ASXL1, EZH2, BCOR,
STAG2 can be highly specific for secondary AML
(as compared to de novo AML)
• DDX41: Identify novel germline/inherited disorders
Patnaik M, et al Am J Haem 2016 and Jankowska J, et al. Blood 2011 and Laborde R et al,
Leukemia 2013 and Lindsley R, et al, Blood 2015: 125; 1367-76 and Polprasert C et al, Cancer
Cell 2015; 658-70..
Somatic Mutations Are Associated With
Disease Risk and MDS Subtype
Bejar R, et al. Haematologica 2014:99(6) 956-64 and Bejar R et al. NEJM 2011:364(26)
2496-2506 and Papaemmanuil E, et al. Blood 2013:122(22)3616-27 and Haferlach T, et al.
Leukemia 2014:28(2):241-7.
New Model: IPSS-Rm
• Total of 508 MDS patients from 2000-2012
– 333 as training set
– 175 as validation set
• Use age, IPSS-R, and mutation data
• Dynamic modification of IPSS-R to enhance
predictive ability in MDS patients regardless
of initial/subsequent therapy at any time in
disease course
Nazha A et al. ASH 2015. Oral Pres., Abst 607 and Leukemia, in press
Survival: MDS
Greenberg P, et al. Blood. 1997;89(6):2079-2088. Adebonojo et al. Chest 1999;115:1507-1513.
MDS
IPSS
Score
Risk
Group
Median Survival
(Yrs)
0 Low 5.7
0.5-1 Int-1 3.5
1.5-2 Int-2 1.2
>2 High 0.4
6
Survival: MDS
MDS Lung Cancer
IPSS
Score
Risk
Group
Median Survival
(Yrs)
Stage Median Survival
(Yrs)
0 Low 5.7 la 8
0.5-1 Int-1 3.5 lla 5.4
1.5-2 Int-2 1.2 llla 2.4
>2 High 0.4 IV 1.2
Greenberg P, et al. Blood. 1997;89(6):2079-2088. Adebonojo et al. Chest 1999;115:1507-1513.
IPSS-R: Survival by Risk Category
Greenberg PL, et al. Blood. 2012;120:2454-2465.
Pro
po
rtio
n o
f P
ati
en
ts A
live
0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12
Very low
Low
Intermediate
High
Very high
Med Survival, yrs (95% CI)
8.8 (7.8-9.9)
5.3 (5.1-5.7)
3.0 (2.7-3.3)1.6 (1.5-1.7)0.8 (0.7-0.8)
THESE
PATIENTS
UNTREATED
What Does MDS Look Like?
Clinician’s perspective…
Physician Survey Data
• Questionnaires completed by 101 docs
– Geographically representative
– Took place over 1.5 year period from 2005-07
• 4514 surveys returned
– $30 incentive for completing each survey
Sekeres et al. J National Cancer Inst 2008;100:1542
U.S. MDS Characteristics
Age (median) Newly diagnosed 71 years
Established 72-75 years
Sex (mean) Male (Newly diagnosed)
(Established)
55%
51-57%
Duration of MDS
(median)13-16 months
MDS Status Primary 88 – 93%
Secondary 7 – 12%
Secondary Chemotherapy 55 – 80%
Cause Radiation 6 – 21%
Chemical exposure 2 – 9%
Sekeres et al. J National Cancer Inst 2008;100:1542
7
U.S. MDS Characteristics
Sekeres et al. J National Cancer Inst 2008;100:1542
Median Hgb: 9.1 g/dl (IQ range 8-10)
Median Plt: 100,000/mm3 (IQ range 56-151)
Median ANC: 1780/mm3 (IQ range 1070-2800)
Circulating Blasts: 1-5%: 16%
>5%: 10%
Transfusion Burden of MDS Patients
Sekeres et al. J National Cancer Inst 2008;100:1542
What Does MDS Look Like?
The Patient’s perspective…
MDS Patient Survey
• A self-directed, online survey of MDS patients
conducted over a 2-week period in March 2009
– Sponsored by the AA & MDS Intl. Foundation
– MDS pts registered with the AA & MDS Intl. Foundation
• N = 358 people from 46 states
• Results were presented at ASH, December 2009
Who Took the Survey?
• Average age: 65 years old
• Gender: 51% women, 49% men
SupportiveCare
73%
ActiveTreatment
27%
Low/Int-1
67%
Int-2/High
33%
Type of Care IPSS Risk Score
Sekeres et al. ASH 2009; abstract 1771.
How Long Did It Take to Get an MDS Diagnosis?
First abnormal blood test
Diagnosisof MDS
3 years
Sekeres et al. ASH 2009; abstract 1771.
8
4%
6%
7%
7.50%
15%
17%
19%
32%
56%
80%
0% 10% 20% 30% 40% 50% 60% 70% 80% 90%
Hematologic malignancy
Leukemia
Cancer
Other
Syndrome
Thrombocytopenia
Neutropenia
Blood disorder
Anemia
Bone marrow disorder
Percent of total responses
How Doctors First Describe MDS
Sekeres et al. ASH 2009; abst. 1771
What’s My Risk?
13%18%
11%
4%
55%
0%
10%
20%
30%
40%
50%
60%
Low risk Int-1 Int-2 High Don't knowIPSS Risk Score
Sekeres et al. ASH 2009; abst. 1771
What’s My Prognosis?
35%33%
19%
0%
5%
10%
15%
20%
25%
30%
35%
40%
All patients Lower-risk patients
Higher-risk patients
Percentage of MDS patients who never discussedlife expectancy with their doctor
Conclusions: MDS Biology
• MDS is a complex group of bone marrow
malignancies that result in marrow failure
• MDS is rare – but growing cancer
• Challenging to diagnosis
• Marrow testing critical to obtain information
• Morphology, cytogenetics, molecular profiles
• Important to understand your disease
prognosis and implications for therapy
• IPSS – starting point for risk stratification
Treatment Goals in MDS
Low IPSS
INT-1 IPSS
INT-2 IPSS
High IPSS
Improve marrow function
Decrease transfusion needs
Decrease impact of MDS on QOL
Establish careful monitoring plan
Stabilize marrow function
Lower risk transformation
Move to definitive therapy
OR
Trilineage marrow improvement
9
Treatment Options for LR-MDS
• Observation/Watch and Wait
• Supportive Transfusions (RBC and platelets)
• Iron Chelation
• Hematopoietic Growth Factors
• Immunosuppressive Therapy (ATG, cyclosporine)
• Immunomodulatory Drugs (Lenalidomide)
Medications Used for MDS
FDA Approved
• HMT
– Azacytidine
– Deoxyazacitadine
• Immunomodulatory
– Lenalidomide
• Iron chelators
– Deserasirox
– Deferoxamine
– Deferiprone
• Apprvd Other Indications
• Growth Factors
– Epotin alfa/Darbepoetin alpha
– Filgrastim (G-CSF)
– Sargramostim (GM-CSF)
– Rombiplastin (Nplate)
– Eltrombopag (Promacta)
• Immunosuppressive
• Thalidomide
• Chemotherapy/SCT
What are Hematopoietic Growth Factors?
• Synthetic versions of proteins normally made in the body to
stimulate growth of red cells, white cells and platelets
– Promote growth and differentiation
– Inhibitors of apoptosis (cell death)
• RED CELL Growth Factors
– Erythropoietin (EPO,Procrit®, Epogen®)
– Darbepoietin (Aranesp®)
• WHITE CELL Growth Factors
– Granulocyte colony stimulating factor (GCSF, Neupogen®)
– Granulocyte-macrophage colony stim factor (GM-CSF, Leukine®)
– Peg-filgrastim (Neulasta®)
• PLATELET Growth Factors
– Thrombopoietin (TPO, romiplostim, Nplate®)
• Note, these are not FDA-approved for MDS
Patient Selection for ESA
Hellström-Lindberg E et al. BJH:2003:120;1037 and Golshayan et al. BJH:2007:137;125.
Good response
(74%, n=34)
Intermediate response
(23%, n=31)
Poor response
(7%, n=29)
s-epo <100 +2
U/L 100–500 +1
>500 –3
Transf <2 units/m +2
U RBC/m = or >2 units/m –2
Treatment response score
RA, RARS, RAEB
Score > +1
Score –1 to +1
Score < –1
RR~40%
Problem with EPO
• Studies of EPO in solid tumor patients showed increased
heart attacks, stroke, heart failure, blood clots, increased
tumor growth, death, especially when hgb >12
• Has resulted in concern for MDS patients, but NO DATA yet
showing these effects in MDS patients
• Has had major effects on insurance coverage
Stimulating White Blood Cells and PLTS
• White Cell Growth Factors:
• Not routine – DON’T treat the number, treat the patient
• active infections - recurrent/resistant infections
• neutropenic fever
• Can be combined with red cell growth factors to improve responses in some patients
• Side effects: fever, bone pain, injection site reactions
• Does stimulating white blood cells cause leukemia
• Platelet Growth Factors:
• Not routine – Don’t’ treat number, treat the patient
• Bleeding history - Single digit plts
• Romiplostim: Azacitidine Rx pts Romiplostim vs placebo
• Less bleeding events
• Does stimulating platelets cause leukemia??
10
Lenalidomide: Pharmacologic
Evolution
• More “potent” immunomodulator than thalidomide- Up to 50,000 times more potent inhibitor of TNFα- ↑ stimulation of T-cell proliferation, IL-2 and IFNγ production
• Anti-angiogenesis impact
Bartlett JB et al Nat Rev Cancer 2004; 4:314
Sterling D Semin Oncol 2001; 28:602
Data on file: Summit, NJ: Celgene Corporation 2005
Thalidomide Lenalidomide
Lenalidomide:
Phase I = Responses:
- Low Risk, INT-1 pts
- History of low # of transfusions
- Del (5) (q31.1)
List et al. NEJM 2005
Primary Endpoint: Transfusion-Independence [Hgb>1g/dl]
Secondary: Cytogenetic response, Path Response
R
E
S
P
O
N
S
E
R
E
G
I
S
T
E
R
10 mg po qd
Eligibility
del 5q31
>2U RBC/8wks
16 wk trnsfn Hx
Platelets >50/109
ANC >500/109
Low/Int-1 Risk
Yes Continue
No Off Study
Week: 0 4 8 12 16 20 24
10 mg po x21
[Schema MDS - 003]
Dose Reduction
5 mg qd
5 mg qod
Lenalidomide MDS - 003Study Design
List, et al. NEJM ; 2006; 355:1456-65.
Kaplan-Meier Estimate of the Duration of Independence from Red-Cell Transfusion
List A et al. N Engl J Med 2006;355:1456-1465
Treatment GOALS in MDS
Low IPSS
INT-1 IPSS
INT-2 IPSS
High IPSS
Improve marrow function
Decrease transfusion Needs
Decrease impact of MDS on QOL
Establish careful monitoring plan
Stabilize marrow function
Lower risk transformation
Move to definitive therapy
OR
Trilineage marrow improvement
11
Treatment Options for HR-MDS
• Azacitdine (Vidaza) or Decitabine (Dacogen)
• Lenalidomide (Revlimid)
• Intensive Chemotherapy
• Bone Marrow Transplant
• Clinical Trials
Epigenetics
Change in gene expression which is heritable and does not
involve a change in DNA sequence (not genetic):
Could inactivate tumor suppressor genes according to
Knudson two-hit hypothesis:
Pathway for the Methylation of Cytosine in the
Mammalian Genome and Effects of Inhibiting
Methylation with 5-Azacytidine
Cytosine 5-Methyl Cytosine
N
N
NH2
O
45
61
2
3
CH3
5-adenosyl-methionine
DNMT
N
N
NH2
O
45
61
2
3
Herman JG, Baylin SG. NEJM 2003;349:2042-54.
Pathway for the Methylation of Cytosine in the
Mammalian Genome and Effects of Inhibiting
Methylation with 5-Azacytidine
N
N N
NH2
O
45
61
2
3
5-Azacytidine
Cytosine 5-Methyl Cytosine
N
N
NH2
O
45
61
2
3
CH3
5-adenosyl-methionine
DNMT
X
N
N
NH2
O
45
61
2
3
Herman JG, Baylin SG. NEJM 2003;349:2042-54.
Hypomethylating AgentsStructural Differences
Kuykendall JR. Ann Pharmacother. 2005:39:1700-9 . Meletis J, et al. Med Sci Monit. 2006, 12(9):RA194-206.
RNA
DNA
Nucleic Acid
Incorporation
VIDAZA x 7 days, every 28
DACOGEN x 5 days every 28
Silverman L, et al. JCO 2002
CALGB #9221 Trial DesignA Randomized Phase III Controlled Trial of Subcutaneous
Azacitidine in Myelodysplastic Syndromes
RA
RARS
RAEB
RAEB-T
CMML
S
T
R
A
T
I
F
Y
R
A
N
D
O
M
I
Z
E
1) Observation*
2) 5AC C 75 mg/m2/d x 7 days q28 x 4
Exit
Criteria
No
Yes
Continue until
Endpoint
5AC
(dose as per arm #2)
A
S
S
E
S
S
Response
- continue Rx
No response
- off study
M M M M M M
0 15 29 57 85 113
QOL QOL QOL
Day
* Minimum duration of observation = 4 months
QOL = Quality-of-life assessment
M = Bone marrow 5AC = azacytidine S.C.
12
Time to AML Transformation
P=.001
Pro
ba
bilit
y o
f
Re
ma
inin
gE
ve
nt-
Fre
e
0.0
0.2
0.4
0.6
0.8
1.0
0 6 12 18 24 30 36 42 48 54
Azacitidine
Supportive Care
Months
++++
+
++
+++ ++ ++
+++
++
++++++
+
++ +++ +++++
++++
+++
++
+
+++
+++
p=0.007
Silverman L, et al. JCO 2002
Azacitidine Survival Study (AZA-001)
Screening/Central
Pathology Review
Investigator CCR
Tx Selection
Randomization
5AC 75 mg/m2/d x 7 d q28 d (n=179)
Conventional care regimens
• Best Supportive Care (BSC) (n=105)
• Low Dose Ara-C (LDAC,
20 mg/m2/d x 14 d q28-42 d) (n=49)
• Std Chemo (7 + 3) (n=25)BSC was included with each arm.
Tx continued until unacceptable
toxicity, AML transformation, or
disease progressionFenaux P, et al. Blood. 2007
Overall Survival: Azacitidine vs CCR
0 5 10 15 20 25 30 35 40
Time (months) from Randomization
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
po
rtio
n S
urv
ivin
g
CCRAZA
Difference: 9.4 months
24.4 months
15 months
50.8%
26.2%
Log-Rank p=0.0001
HR = 0.58 [95% CI: 0.43, 0.77]
CR=17%; ORR=35%
Fenaux, et. Al. Lancet Oncology 2009; 10;223-232.
Decitabine (EORTC) Phase III MDS
Trial Study Design
Decitabine + Supportive Care
15mg/m2/ over 3 hours q8h x 3days q6wks
(N=89)
Supportive Care
ABX, GFs and/or Transfusions
(N=81)
Stratification
- IPSS
-Type of MDS
(primary or
secondary)
Eligible
Patients
(n=170)
R
A
N
D
O
M
I
Z
E
D
Kantarjian H, et al. Cancer. 2006
Response assessed after 2nd cycle, with 2 more cycles given if CR
O N Number of patients at risk :
96 114 71 38 22
(months)
0 6 12 18 24 30 36 42
0
10
20
30
40
50
60
70
80
90
100
10 6 3
99 119 83 53 24 15 4 4
Median (months): 10.1 vs 8.5
HR = 0.88 , 95% CI (0.66, 1.17)
Logrank test: p=0.38 Decitabine
Supportive care
EORTC: Overall Survival
Wijermans P, Lubbert M, Suciu S, et al. ASH, December 6-9, 2008
Azacitidine/Decitabine
• Administer every 28 days (once a month)
– AZA 75mg/m2 SC or IV x 7d/mo
– DAC 20mg/m2 IV x 5d/mo
• Administer at least 4-6 cycles
– Side effects: nausea, vomiting, decreased counts
(WBC, RBC, plats), fatigue, fevers, infections
– Side effects are manageable: antibiotics, anti-
emetics and transfusions
List A, NEJM 2006; 355: 1456-65
13
HMT Alone in MDS/AML
77
Reference Dose (mg/m2)
Schedule EvalPts N
CRN (%)
ORR (%) Other
Wijermans 2000 DAC: 15 IV Q8x 3d 66 20% 49% 15mo mOAS
Silverman 2002* 5AC: 75 SC x 7d 191 21%CR/PR
60% 18mo mOAS
Kantarjian 2006* DAC: 15 Q8 IV x3d 170 17% CR/PR 30% 14 mo mOAS
Steensma 2009 DAC: 20 IV x 5d 99 32% 51% 19.4mo mOAS
Blum 2010 DAC: 30 IV x 10d 53 64% 13.8 mo OAS
Fenaux 2010AZA-001
5AC: 75 IV x 7d 179 29%CR/PR
78% 24.5mo OAS
Lubbert 2012 DAC: 15 IV Q8x 3d 227 26% 5.5mo OAS
Garcia-Manero2013
DAC: 20 D1-3 vsD1,8,15
65 16% 23% D1-3 best
Limited Options for Pts Failing HMT
• Increase HMT dose or exposure
– SGI-110 (block deamination/breakdown of HMT drug)
• Switch to alternate HMT agent
• Combination therapy
– HDACi, chromatin modifier or immunomodulatory agent
• Induction chemotherapy
• Stem cell transplant/RIC or nonmyeloablative
• Clinical Trial
Garcia-Manero et al. JCO 2014 and Krevvata et al Blood. 2014.
BMT: How To Decide
• Insurance coverage?
• Is there a donor?
• Need to balance the risk of disease
progression to risk of treatment
(infection/GVHD, organ damage,death)
• Is the patient strong/fit enough for BMT?
– How to evaluate/Comorbidity Index/Age
Sorror ML, et al Blood 106:2912-19, 2005
Cure: Bone Marrow Transplant
• Allogeneic HCT offers long term DFS for pts
with MDS (30-50%)
• Decreased ability to offer HCT due to
comorbidities (not age per se)
• Optimize Performance Status/QOL
“BOSTON STRONG”
Colben Sime, Age 81
Boston Marathon, 2015
What Pre-Transplant Therapy
is Best?
• Cytoreduction/Control disease
– HMT vs Induction chemotherapy vs None
– No definitively superior approach
– Allow time for maximal GVL effect
• Ongoing prospective studies• Kröger/Platzbecker (5AC alone vs 5AC to RIC)
• EORTC 1301 (10d DAC to BMT vs 3+7 to BMT)
• BMT CTN 1102 (HMT alone vs HMT to RIC-BMT)
• When to proceed with HCT/timing?Scott BL, et al. Biol Blood Marrow Trans. 2005 Jan;11(1):65-73. Gerds AT, et al. Biol Blood
Marrow Transplant. 2012 Aug;18(8):1211-8. Damaj G, et al. J Clin Oncol. 2012 Dec
20;30(36):4533-40.
MDS Disease Burden Pre-HCT
and Relapse Risk Post-HCT
Warlick E, et al. Biol Blood Marrow Transplt 2009, Lubbert et al. JCO 2012.
14
Cytogenetic Risk and Relapse
Post Transplant
Deeg HJ, et al. Blood 2012 Aug 16; 120(7): 1398-408
HCT Decision Analysis
Estimated Life expectancy (years) after HCT for MDS (age < 60)
Immediate HCT HCT in 2 years HCT at progression
IPSS
RIS
K
Low 6.51 6.88 7.21
Int-1 4.61 4.74 5.16
Int-2 4.93 3.21 2.84
High 3.20 2.75 2.75
Cutler C, et al. Blood. 2004 Jul 15;104(2) 579-85
HCT: Decision Analysis, RIC
Estimated Life expectancy (years) after RIC-HCT
for MDS (age ≥ 60)
Non-HCT Early HCT
IPS
SR
ISK
Low/I
nt-1
Overall LE 6.42 3.17
QALE: TI 5.42 2.92
QALE: TD 3.83 2.92
Int-
2/Hig
h
Overall LE 0.24 3.00
QALE: HR-
MDS1.25 2.75
QALE: GvHD 1.25 1.83
Koreth et al. JCO 2013;31:2662
ASBMT/EBMT: Panel Recommendations
• Early HCT for higher-risk MDS and poor-risk
lower risk MDS
• No rec for pre-HCT induction chemo/HMT
• No rec for related vs unrelated donor
• No rec for RIC vs high-dose conditioning
Oliansky et al. BBMT 2009;15:137
Conclusions• Effective therapy for MDS exists
– IPSS and IPSS-R; starting point risk stratification
– Important to set goals of therapy
• Growth factors, transfusions, Len to ↓ transfusions
• Epigenetic tx for high risk and 5AC improves OAS
• Allogeneic HCT offers cure but also toxicity
• Future trials will incorporate molecular mutations for
prognostic models to individualize therapy and to
inform treatment decisions upfront
Thank you
Cleveland Clinic, Taussig Cancer Center
Leukemia and MDS Program
Anjali Advani, MD
Brian Bolwell, MD
Jennifer Carew, PhD
Aaron Gerds, MD, MS
Betty Hamilton, MD
Matt Kalaycio, MD
Jaroslaw Maciejewski, MD, PhD
Sudipto Mukherjee, MD, PhD
Navneet Majhail, MD
Aziz Nazha, MD
Yogen Saunthararajah, MD
Mikkael Sekeres, MD, MS