Overview:

Biology and Diagnosis of MDS

Myelodysplastic Syndromes
Scoring System/Prognosis
Current Thinking on Disease, Diagnosis
and Treatment Treatment Options for Low Risk MDS
Treatment Options for High Risk MDS
Hetty Carraway, MD, MBA, FACP
Associate Professor
Taussig Cancer Institute
Cleveland Clinic

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-Specific (Crude) SEER

Incidence Rates, All Races, Both
Overall incidence: 3.4 per 100,000 Sexes, 2000-2009
60
Incidence per 100,000 per Year

36.4*
50 50
Overall Males Females
40 40

20.9 30
30
20
20
10
7.5 28% 72%
10 0
0.7 2.0
0.1
0
< 40 40-49 50-59 60-69 70-79 ≥ 80
Age at Diagnosis
*P for trend < .05
Age at Diagnosis (Yrs)
SEER Program (www.seer.cancer.gov) Research Data (1973-2009), National Cancer Institute, DCCPS, Surveillance
Rollison DE, et al. Blood. 2008;112:45-52.
Research Program, Surveillance Systems Branch, released April 2012, based on the November 2011 submission.

1
 MDS Pathogenesis Genetic Abnormalities in MDS
Stage 1
Intrinsic increase in Stage 2 Stage 3 Translocations/ Uniparental Disomy/ Copy Number Point Mutations
apoptotic response and Acquisition of Initiation of Rearrangements Microdeletions Change
inflammation anti-apoptotic molecules clonal evolution
Rare – often at sites of
↑ TNFα-induced
Rare in MDS About 50% of cases Most common
↑ ROS ↑ Bcl-2 point mutations
apoptosis
Induction of homeostatic t(6;9) 4q - TET2 del(5q) Likely in all cases
mechanisms
Expansion
i(17q) 7q - EZH2 -7/del(7q)
MP MP MP t(1;7) 11q - CBL del(20q) ~80% of cases have
MP MP MP MP MP aMP del(17p) mutations in a
MP MP aMP t(3;?) 17p - TP53 known gene
Telomere MP MP Impaired MP MP t(11;?) del(11q)
erosion and aMP immunosurveillance aMP
senescence by NK and T-cells inv(3) +8

idic(X)(q13) -Y
Stem cell depletion Abnormalities in DNA repair
Emergence of abnl clones mechanisms with propagation
Abnormal Altered T-cell with point mutations in
ribosomes Bone marrow homeostasis of abnormal cells
NRas + AML1 Array CGH Genotyping
Karyotype Karyotype / FISH
Altered MP Inflammatory SNP Array Sequencing
localization microenvironment
Stromal cell
defects
High risk
Suppressed for leukemia
hematopoiesis Molecular model of MDS progression transformation Vardiman,JW, et al. Blood. 2009;114(5): 937-951. Tiu R, et al. Blood. 2011;117(17):4552-4560.
Epling-Burnette PK, et al. Curr Opin Hematol. 2009;16:70-76. 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 Clinical Overlap / Associations:

• No specific clinical feature distinguishes • Acute Myeloid Leukemia

MDS from other causes of pancytopenia • Myeloproliferative Disease PNH
• Paroxsymal Nocturnal MDS
• Laboratory evaluation often prompted by Hemoglobinuria AA AML
signs or symptoms, including: • Autoimmune diseases
– Fatigue (anemia) • Aplastic Anemia PRCA
MPD
– Infections (neutropenia) • LGL leukemia LGL
– Bleeding (thrombocytopenia) • Pure Red Cell Aplasia

Bennett JM, et al. Int J Hematol. 2002 Aug;76 Suppl 2:228-38. 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 MDS: Diagnostic Evaluation

Anemia • Peripheral blood counts
+ reticulocyte count
• Fatigue, pallor
• Bone marrow biopsy
• Shortness of breath, decreased exercise tolerance and aspiration
• Exacerbation of heart failure, angina – Bone marrow blasts % Establish diagnosis of MDS
– Cytogenetics & determine subtype &
Neutropenia prognosis:
– Iron stain
– FAB/WHO Classification
• Active infection (bronchitis, sinusitis, pneumonia, etc.) – Reticulin stain
– IPSS/IPSS-R score
• Risk of infections • Additional tests
Thrombocytopenia – Iron saturation, ferritin
– B12, folate levels
• Petechiae, bruising, bleeding
– EPO level
• Risk of bleeding
http://www.nccn.org/professionals/physician_gls/PDF/mds.pdf
http://www.ishapd.org/1996/1996/016.pdf

2
 MDS: Diagnostic Evaluation
Performing a bone marrow aspiration
• Peripheral blood counts
+ reticulocyte count
• Bone marrow biopsy
and aspiration
– Bone marrow blasts % Establish diagnosis of MDS
– Cytogenetics & determine subtype &
prognosis:
– Iron stain
– FAB/WHO Classification
– Reticulin stain
– IPSS/IPSS-R score
• Additional tests
– Iron saturation, ferritin
– B12, folate levels
– EPO level

http://www.nccn.org/professionals/physician_gls/PDF/mds.pdf
http://www.ishapd.org/1996/1996/016.pdf

Cytologic Dysplasia: Bone Marrow Cytologic Dysplasia: Marrow and

DysErythropoiesis Blood DysGranulopoiesis

Courtesy of Dr. Bennett and Dr List. Courtesy of Dr. Bennett and Dr List.

Cytologic Dysplasia: Marrow and FAB vs WHO Classification

Blood DysMegakaryopoiesis 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.
Courtesy of Dr. Bennett and Dr List. List AF, et al. The Myelodysplastic Syndromes. In: Wintrobe’s Hematology 2003.
Silverman LR. The Myelodysplastic Syndromes. In: Cancer Medicine. 2000.

3
 How Do We Classify MDS? IPSS Is Most Common Tool for Risk
Stratification of MDS
Score Value

IPSS WPSS Prognostic variable

Bone marrow blasts < 5%
0 0.5
5% to 10%
1.0
--
1.5
11% to 20%
2.0
21% to 30%
1997 2007
Karyotype* Good Intermediate Poor -- --
Cytopenias† 0/1 2/3 -- -- --

FAB WHO IPSS-R 0 0.5 1.0

Total Score
1.5 2.0  2.5
1970-80 1999 2012 Low Intermediate I Intermediate II High
2002 Median survival, yrs 5.7 3.5 1.2 0.4
2008
*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 Greenberg P, et al. Blood. 1997;89:2079-2088.

Survival and Freedom From AML Progression IPSS-R: Revised June 2012
IPSS MDS Risk Classification
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
Higher risk MDS (INT-2, High) is associated with a
median survival of 0.4—1.2 years
Greenberg PL, et al. Blood. 2012;120:2454-2465.
Greenberg P, et al. Blood. 1997:89:2079-88.

IPSS-R: Prognostic Score Variables

P. Variable 0 0.5 1 1.5 2 3 4
Mutation Profiling
Cytogenetics Very
Good
Good Intermediate Poor Very
Poor
• Powerful tool
BM Blast % ≤2 >2-<5% 5-10% >10% – Diagnose disease (from aging to MDS to AML)
Hemoglobin ≥10 8-<10 <8
≥100 50-<100 <50
• Prognostic:
Platelets
ANC ≥0.8 <0.8 – Risk of Progression

IPSS-R: Prognostic Risk Categories/Scores – IPSS, IPSS-R and now IPSS-R-M

Risk Group Risk Score • Predictive

Very Low ≤1.5
– Chemo and BMT response/non-response
Low >1.5-3
Intermediate >3-4.5 • Targeted therapies
High >4.5-6
High risk – SF3B1/TET2/IDH1/IDH2/FLT3
Very High >6
Greenberg et al. Blood 2012;120:2454-65.

4
 CHIP as a Precursor State to
MDS Mutation Landscape
Hematological Neoplasms

Clonal
Hematopoiesis of
Indeterminate
Potential

Clonality
Dysplasia
Cytopenias
Blasts

David P. Steensma et al. Blood 2015;126:9-16. Steensma, D. Mayo Clinic Proceedings. 2015. 969-83

Unique Mutation Profile Helps Somatic Mutations Are Associated With

Identify/Confirm Disease Disease Risk and MDS Subtype

• 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, Bejar R, et al. Haematologica 2014:99(6) 956-64 and Bejar R et al. NEJM 2011:364(26)
Leukemia 2013 and Lindsley R, et al, Blood 2015: 125; 1367-76 and Polprasert C et al, Cancer 2496-2506 and Papaemmanuil E, et al. Blood 2013:122(22)3616-27 and Haferlach T, et al.
Cell 2015; 658-70.. Leukemia 2014:28(2):241-7.

New Model: IPSS-Rm Survival: MDS

• Total of 508 MDS patients from 2000-2012 MDS

– 333 as training set IPSS Risk Median Survival
– 175 as validation set Score Group (Yrs)
0 Low 5.7
• Use age, IPSS-R, and mutation data
0.5-1 Int-1 3.5
• Dynamic modification of IPSS-R to enhance
predictive ability in MDS patients regardless 1.5-2 Int-2 1.2
of initial/subsequent therapy at any time in
disease course >2 High 0.4

Nazha A et al. ASH 2015. Oral Pres., Abst 607 and Leukemia, in press Greenberg P, et al. Blood. 1997;89(6):2079-2088. Adebonojo et al. Chest 1999;115:1507-1513.

5
 Survival: MDS IPSS-R: Survival by Risk Category
MDS Lung Cancer
1.0 Very low
Low
IPSS Risk Median Survival Stage Median Survival
Intermediate
Score Group (Yrs) (Yrs) 0.8 THESE High

Proportion of Patients Alive

Very high
0 Low 5.7 la 8
0.6 PATIENTS
0.5-1 Int-1 3.5 lla 5.4 UNTREATED Med Survival, yrs (95% CI)
0.4 8.8 (7.8-9.9)

1.5-2 Int-2 1.2 llla 2.4 5.3 (5.1-5.7)

0.2
3.0 (2.7-3.3)
1.6 (1.5-1.7)
>2 High 0.4 IV 1.2 0.8 (0.7-0.8)
0
0 2 4 6 8 10 12

Greenberg P, et al. Blood. 1997;89(6):2079-2088. Adebonojo et al. Chest 1999;115:1507-1513.

Greenberg PL, et al. Blood. 2012;120:2454-2465.

What Does MDS Look Like?

Clinician’s perspective…

Physician Survey Data U.S. MDS Characteristics

Age (median) Newly diagnosed 71 years

• Questionnaires completed by 101 docs Established 72-75 years

Sex (mean) Male (Newly diagnosed) 55%
– Geographically representative
(Established) 51-57%
– Took place over 1.5 year period from 2005-07 Duration of MDS
13-16 months
(median)
MDS Status Primary 88 – 93%
Secondary 7 – 12%
• 4514 surveys returned Secondary Chemotherapy 55 – 80%
– $30 incentive for completing each survey Cause Radiation 6 – 21%
Chemical exposure 2 – 9%

Sekeres et al. J National Cancer Inst 2008;100:1542 Sekeres et al. J National Cancer Inst 2008;100:1542

6
 U.S. MDS Characteristics Transfusion Burden of MDS Patients

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%

Sekeres et al. J National Cancer Inst 2008;100:1542

Sekeres et al. J National Cancer Inst 2008;100:1542

MDS Patient Survey

• A self-directed, online survey of MDS patients

conducted over a 2-week period in March 2009
What Does MDS Look Like? – Sponsored by the AA & MDS Intl. Foundation
– MDS pts registered with the AA & MDS Intl. Foundation

The Patient’s perspective…

• N = 358 people from 46 states

• Results were presented at ASH, December 2009

Who Took the Survey?

How Long Did It Take to Get
• Average age: 65 years old
an MDS Diagnosis?
• Gender: 51% women, 49% men
First abnormal Diagnosis
blood test of MDS
Type of Care IPSS Risk Score 3 years
Active Treatment
27% Int-2 / High
33%

Low / Int-1
67%
Supportive Care
73%

Sekeres et al. ASH 2009; abstract 1771. Sekeres et al. ASH 2009; abstract 1771.

7
How Doctors First Describe MDS What’s My Risk?
60%
55%
Bone marrow disorder 80%
50%
Anemia 56%
Blood disorder 32% 40%
Neutropenia 19%
30%
Thrombocytopenia 17%
Syndrome 15% 20% 18%
Other 7.50% 13% 11%
Cancer 10%
7% 4%
Leukemia 6% 0%
Hematologic malignancy 4%
Low risk Int-1 Int-2 High Don't
0% 10% 20% 30% 40% 50% 60% 70% 80% 90%
IPSS Risk Score know
Percent of total responses
Sekeres et al. ASH 2009; abst. 1771 Sekeres et al. ASH 2009; abst. 1771

What’s My Prognosis? Conclusions: MDS Biology

Percentage of MDS patients who never discussed
life expectancy with their doctor • MDS is a complex group of bone marrow
malignancies that result in marrow failure
40%
35% • MDS is rare – but growing cancer
35% 33%
30% • Challenging to diagnosis
25%
20% 19% • Marrow testing critical to obtain information
• Morphology, cytogenetics, molecular profiles
15%
10% • Important to understand your disease
5%
prognosis and implications for therapy
0%

All patients Lower-risk Higher-risk • IPSS – starting point for risk stratification
patients patients

Treatment Goals in MDS

Low IPSS INT-2 IPSS
INT-1 IPSS High IPSS

Improve marrow function Stabilize marrow function

Decrease transfusion needs Lower risk transformation

Decrease impact of MDS on QOL Move to definitive therapy

OR
Establish careful monitoring plan Trilineage marrow improvement

8
 Treatment Options for LR-MDS Medications Used for MDS
FDA Approved • Apprvd Other Indications
• Observation/Watch and Wait
• HMT • Growth Factors
• Supportive Transfusions (RBC and platelets) – Azacytidine – Epotin alfa/Darbepoetin alpha
– Deoxyazacitadine – Filgrastim (G-CSF)
• Iron Chelation
– Sargramostim (GM-CSF)
• Hematopoietic Growth Factors • Immunomodulatory
– Rombiplastin (Nplate)
– Lenalidomide
– Eltrombopag (Promacta)
• Immunosuppressive Therapy (ATG, cyclosporine)
• Iron chelators
• Immunomodulatory Drugs (Lenalidomide) • Immunosuppressive
– Deserasirox
– Deferoxamine • Thalidomide
– Deferiprone
• Chemotherapy/SCT

What are Hematopoietic Growth Factors? Patient Selection for ESA

• Synthetic versions of proteins normally made in the body to
stimulate growth of red cells, white cells and platelets Score > +1 Good response
(74%, n=34)
– Promote growth and differentiation
– Inhibitors of apoptosis (cell death)
RA, RARS, RAEB Score –1 to +1 Intermediate response
(23%, n=31)
• RED CELL Growth Factors
– Erythropoietin (EPO,Procrit®, Epogen®)
– Darbepoietin (Aranesp®) Score < –1 Poor response
(7%, n=29)
• WHITE CELL Growth Factors
– Granulocyte colony stimulating factor (GCSF, Neupogen®)
Treatment response score
– Granulocyte-macrophage colony stim factor (GM-CSF, Leukine®)
– Peg-filgrastim (Neulasta®) s-epo <100 +2
U/L 100–500 +1
• PLATELET Growth Factors
– Thrombopoietin (TPO, romiplostim, Nplate®)
Transf
>500
<2 units/m
–3
+2
RR~40%
U RBC/m = or >2 units/m –2
• Note, these are not FDA-approved for MDS
Hellström-Lindberg E et al. BJH:2003:120;1037 and Golshayan et al. BJH:2007:137;125.

Stimulating White Blood Cells and PLTS

Problem with EPO
• White Cell Growth Factors:
• Not routine – DON’T treat the number, treat the patient
• Studies of EPO in solid tumor patients showed increased • active infections - recurrent/resistant infections
heart attacks, stroke, heart failure, blood clots, increased • neutropenic fever
tumor growth, death, especially when hgb >12 • Can be combined with red cell growth factors to improve
responses in some patients
• Side effects: fever, bone pain, injection site reactions
• Has resulted in concern for MDS patients, but NO DATA yet • Does stimulating white blood cells cause leukemia
showing these effects in MDS patients
• Platelet Growth Factors:
• Has had major effects on insurance coverage • 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??

9
 Lenalidomide: Pharmacologic
Evolution Lenalidomide:
Phase I = Responses:
- Low Risk, INT-1 pts
- History of low # of
transfusions
- Del (5) (q31.1)
Thalidomide Lenalidomide

• 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 List et al. NEJM 2005
Data on file: Summit, NJ: Celgene Corporation 2005

Lenalidomide MDS - 003

Study Design
[Schema MDS - 003]
R R
Eligibility E E Yes Continue
G 10 mg po x21 S
del 5q31
I P Dose Reduction
>2U RBC/8wks O
S 5 mg qd
16 wk trnsfn Hx 5 mg qod
Platelets >50/109 T N
ANC >500/109 E 10 mg po qd S
Low/Int-1 Risk R E No Off Study

Week: 0 4 8 12 16 20 24

Primary Endpoint: Transfusion-Independence [Hgb>1g/dl]

Secondary: Cytogenetic response, Path Response
List, et al. NEJM ; 2006; 355:1456-65.

Kaplan-Meier Estimate of the Duration of Independence from Red-Cell

Transfusion
Treatment GOALS in MDS
Low IPSS INT-2 IPSS
INT-1 IPSS High IPSS

Improve marrow function Stabilize marrow function

Decrease transfusion Needs Lower risk transformation

Decrease impact of MDS on QOL Move to definitive therapy

OR
Establish careful monitoring plan Trilineage marrow improvement

List A et al. N Engl J Med 2006;355:1456-1465

10
 Treatment Options for HR-MDS Epigenetics
Change in gene expression which is heritable and does not
involve a change in DNA sequence (not genetic):

• Azacitdine (Vidaza) or Decitabine (Dacogen) Could inactivate tumor suppressor genes according to
Knudson two-hit hypothesis:
• Lenalidomide (Revlimid)
• Intensive Chemotherapy
• Bone Marrow Transplant

• Clinical Trials

Pathway for the Methylation of Cytosine in the

Pathway for the Methylation of Cytosine in the
Mammalian Genome and Effects of Inhibiting
Mammalian Genome and Effects of Inhibiting
Methylation with 5-Azacytidine
Methylation with 5-Azacytidine
NH2
5-Azacytidine
N 4 N
3 5
2 6
Cytosine 5-Methyl Cytosine 1
O N
NH2 NH2
CH3 5-Methyl Cytosine
N 4 N 4 Cytosine
3 5 DNMT 3 5
NH2 NH2
2 6 2 6
1 5-adenosyl-methionine 1
O N O N 4
X 4 CH3
N N
3 5 DNMT 3 5
2 6 2 6
1 5-adenosyl-methionine 1
O N O N

Herman JG, Baylin SG. NEJM 2003;349:2042-54. Herman JG, Baylin SG. NEJM 2003;349:2042-54.

Hypomethylating Agents CALGB #9221 Trial Design

A Randomized Phase III Controlled Trial of Subcutaneous
Structural Differences Azacitidine in Myelodysplastic Syndromes
No Continue until
Nucleic Acid S R 1) Observation* Exit Endpoint
Incorporation RA T A
Criteria A
R N
RARS Response
D S
RAEB A Yes 5AC - continue Rx
O
RAEB-T T (dose as per arm #2) S
M E
RNA CMML I No response
I S
VIDAZA x 7 days, every 28 F Z 2) 5AC C 75 mg/m2/d x 7 days q28 x 4 - off study
S
Y E

QOL QOL QOL

M M M M M M
0 15 29 57 85 113
DNA Day
DACOGEN x 5 days every 28 QOL = Quality-of-life assessment
* Minimum duration of observation = 4 months M = Bone marrow 5AC = azacytidine S.C.

Kuykendall JR. Ann Pharmacother. 2005:39:1700-9 . Meletis J, et al. Med Sci Monit. 2006, 12(9):RA194-206. Silverman L, et al. JCO 2002

11
 Time to AML Transformation Azacitidine Survival Study (AZA-001)
1.0
+
++
5AC 75 mg/m2/d x 7 d q28 d (n=179)
Remaining Event-Free

0.8 ++ + ++
+ Azacitidine
Screening/Central
Probability of

+ Supportive Care
+
0.6 ++
+
++
+
Pathology Review
+ +++
+ +++
Investigator CCR
0.4 + +++
+
++
++ +++ Tx Selection
+ +++
+++ + Conventional care regimens
+ + ++
0.2 Randomization
+
++ • Best Supportive Care (BSC) (n=105)
P=.001
• Low Dose Ara-C (LDAC,
0.0 20 mg/m2/d x 14 d q28-42 d) (n=49)
0 6 12 18 24 30 36 42 48 54
• Std Chemo (7 + 3) (n=25)
Months BSC was included with each arm.
p=0.007 Tx continued until unacceptable
toxicity, AML transformation, or
Silverman L, et al. JCO 2002 disease progression
Fenaux P, et al. Blood. 2007

Overall Survival: Azacitidine vs CCR Decitabine (EORTC) Phase III MDS

Log-Rank p=0.0001 Trial Study Design
1.0
HR = 0.58 [95% CI: 0.43, 0.77]
0.9
CR=17%; ORR=35%
0.8 Decitabine + Supportive Care
Proportion Surviving

Difference: 9.4 months R 15mg/m2/ over 3 hours q8h x 3days q6wks

0.7 A
(N=89)
0.6 50.8% N Stratification
Eligible D
0.5 24.4 months O - IPSS
Patients
0.4 15 months (n=170) M -Type of MDS
26.2% I (primary or
0.3 AZA Z secondary) Supportive Care
0.2 CCR E ABX, GFs and/or Transfusions
D (N=81)
0.1
0.0
0 5 10 15 20 25 30 35 40 Response assessed after 2nd cycle, with 2 more cycles given if CR
Time (months) from Randomization

Fenaux, et. Al. Lancet Oncology 2009; 10;223-232. Kantarjian H, et al. Cancer. 2006

EORTC: Overall Survival Azacitidine/Decitabine

100

90 • Administer every 28 days (once a month)

80
– AZA 75mg/m2 SC or IV x 7d/mo
70 Median (months): 10.1 vs 8.5
60 HR = 0.88 , 95% CI (0.66, 1.17) – DAC 20mg/m2 IV x 5d/mo
Decitabine Logrank test: p=0.38
• Administer at least 4-6 cycles
50

40
30 – Side effects: nausea, vomiting, decreased counts
Supportive care (WBC, RBC, plats), fatigue, fevers, infections
20
10 – Side effects are manageable: antibiotics, anti-
0 (months) emetics and transfusions
0 6 12 18 24 30 36 42
O N Number of patients at risk :
96 114 71 38 22 10 6 3
99 119 83 53 24 15 4 4 List A, NEJM 2006; 355: 1456-65
Wijermans P, Lubbert M, Suciu S, et al. ASH, December 6-9, 2008

12
 HMT Alone in MDS/AML
Reference Dose Schedule Eval CR ORR (%) Other
Limited Options for Pts Failing HMT
(mg/m2) Pts N N (%)

Wijermans 2000 DAC: 15 IV Q8x 3d 66 20% 49% 15mo mOAS • Increase HMT dose or exposure
Silverman 2002* 5AC: 75 SC x 7d 191 21% 60% 18mo mOAS – SGI-110 (block deamination/breakdown of HMT drug)
CR/PR

Kantarjian 2006* DAC: 15 Q8 IV x3d 170 17% CR/PR 30% 14 mo mOAS

• Switch to alternate HMT agent

Steensma 2009 DAC: 20 IV x 5d 99 32% 51% 19.4mo mOAS

• Combination therapy
– HDACi, chromatin modifier or immunomodulatory agent
Blum 2010 DAC: 30 IV x 10d 53 64% 13.8 mo OAS
Fenaux 2010 5AC: 75 IV x 7d 179 29% 78% 24.5mo OAS • Induction chemotherapy
AZA-001 CR/PR

Lubbert 2012 DAC: 15 IV Q8x 3d 227 26% 5.5mo OAS • Stem cell transplant/RIC or nonmyeloablative
Garcia-Manero DAC: 20 D1-3 vs 65 16% 23% D1-3 best
2013 D1,8,15 • Clinical Trial
77
Garcia-Manero et al. JCO 2014 and Krevvata et al Blood. 2014.

BMT: How To Decide Cure: Bone Marrow Transplant

• Insurance coverage? • Allogeneic HCT offers long term DFS for pts
with MDS (30-50%)
• Is there a donor?
• Decreased ability to offer HCT due to
• Need to balance the risk of disease
comorbidities (not age per se)
progression to risk of treatment
(infection/GVHD, organ damage,death) • Optimize Performance Status/QOL
• Is the patient strong/fit enough for BMT?
– How to evaluate/Comorbidity Index/Age
“BOSTON STRONG”
Colben Sime, Age 81
Boston Marathon, 2015
Sorror ML, et al Blood 106:2912-19, 2005

What Pre-Transplant Therapy MDS Disease Burden Pre-HCT

is Best? and Relapse Risk Post-HCT
• 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 Warlick E, et al. Biol Blood Marrow Transplt 2009, Lubbert et al. JCO 2012.
20;30(36):4533-40.

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 Cytogenetic Risk and Relapse
HCT Decision Analysis
Post Transplant
Estimated Life expectancy (years) after HCT for MDS (age < 60)

Immediate HCT HCT in 2 years HCT at progression

Low 6.51 6.88 7.21

IPSS RISK
Int-1 4.61 4.74 5.16

Int-2 4.93 3.21 2.84

High 3.20 2.75 2.75

Deeg HJ, et al. Blood 2012 Aug 16; 120(7): 1398-408 Cutler C, et al. Blood. 2004 Jul 15;104(2) 579-85

HCT: Decision Analysis, RIC ASBMT/EBMT: Panel Recommendations

Estimated Life expectancy (years) after RIC-HCT • Early HCT for higher-risk MDS and poor-risk
for MDS (age ≥ 60)
lower risk MDS
Non-HCT Early HCT

Overall LE 6.42 3.17

Low/I
QALE: TI 5.42 2.92 • No rec for pre-HCT induction chemo/HMT
IPSS RISK

nt-1
QALE: TD 3.83 2.92 • No rec for related vs unrelated donor
Overall LE 0.24 3.00 • No rec for RIC vs high-dose conditioning
Int-
QALE: HR-
2/Hig
MDS
1.25 2.75
h
QALE: GvHD 1.25 1.83
Oliansky et al. BBMT 2009;15:137
Koreth et al. JCO 2013;31:2662

Conclusions Thank you

• Effective therapy for MDS exists Cleveland Clinic, Taussig Cancer Center
– IPSS and IPSS-R; starting point risk stratification Leukemia and MDS Program

– Important to set goals of therapy Anjali Advani, MD

Brian Bolwell, MD
• Growth factors, transfusions, Len to ↓ transfusions Jennifer Carew, PhD
Aaron Gerds, MD, MS
• Epigenetic tx for high risk and 5AC improves OAS Betty Hamilton, MD
Matt Kalaycio, MD
• Allogeneic HCT offers cure but also toxicity Jaroslaw Maciejewski, MD, PhD
Sudipto Mukherjee, MD, PhD
• Future trials will incorporate molecular mutations for Navneet Majhail, MD
Aziz Nazha, MD
prognostic models to individualize therapy and to Yogen Saunthararajah, MD
inform treatment decisions upfront Mikkael Sekeres, MD, MS

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