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