9/4/2013

1

MDS: Current Thinking on Disease,

Diagnosis, and Treatment

David Steensma, MD FACPAssociate Professor of Medicine, Harvard Medical School

Adult Leukemia Program, Dana-Farber Cancer Institute

Hematological Oncology Service, Brigham & Women’s Hospital

Aplastic Anemia & MDS International Foundation Patient & Family Conference

Boston (Peabody), Massachusetts – September 2013

Outline

• What are myelodysplastic syndromes (MDS)?

– How common are MDS?

– Why does MDS occur (risk factors)?

• How are MDS diagnosed?

• What is the outlook (prognosis) for patients?

• How can MDS be treated?

– “Supportive care”

– Drug therapy (disease-modifying)

– Stem cell transplantation

What Are MDS?

MDS Is A Stem Cell Disorder

Neutrophil Lymphocyte

“Hematopoietic”

Acquired genetic

(DNA) damage in MDS

occurs at this level

Consequences

noted here

Four defining features of MDS

1) Marrow failure / ineffective

hematopoiesis (cytopenias)

2) Clonal hematopoiesis (abnormal

karyotype, somatic mutations)

3) Characteristic “dysplastic” hematopoietic

cell characteristic morphology

4) Instability / tendency to progress to acute

myeloid leukemia

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2

Age-dependent nature of MDS (US)

Age at MDS diagnosis (years)*P for trend < .05

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 in this analysis: 3.4 per 100,000

� SEER registry: ~13,000 new US cases per year

� Claims-based data: >40,000 US cases per year

Rollison DE et al Blood 2008;112:45-52.

Environmental Inborn

AGING

Exposure to DNA alkylating agents

(chlorambucil, melphalan,

cyclophosphamide)

Exposure to topoisomerase II inhibitors

(etoposide, anthracyclines)

Exposure to ionizing radiation

Familial Platelet Disorder with AML

Predisposition (“FPD-AML”) (RUNX1,

CEBPA)

Environmental / occupational

exposures (hydrocarbons etc.)

GATA2 mutant

(MonoMACsyndrome: monocytopenia,

B/NK lymphopenia, atypical

mycobacteria and viral and other

infections, pulmonary proteinosis,,

neoplasms)

Risk factors for development of MDS

Antecedent acquired hematological disorders

PNH (5-25%)

Aplastic anemia (15-20%)

Other congenital marrow failure

syndromes or DNA repair defects

(Bloom syndrome, ataxia-

telangiectasia, etc.)

Familial syndromes of unknown origin

Fanconi anemia

MDS cause / categorization

De novo

(idiopathic, primary)

Ionizing radiation,

DNA alkylating agents

(chlorambucil, melphalan,

cyclophosphamide, etc.)

Peaks 5-7 years

following exposure

Peaks 1-3 years

following exposure

Topoisomerase II inhibitors

(etoposide, topotecan,

anthracyclines, etc.)

Median age ~71 years;

increased risk with aging

50% normal karyotype;

common abnormal

karyotypes in de novo

disease: del(20q), -Y,

del(5q), +8

-7/del(7q),

-5/del(5q),

complex karyotype (≥3

abnormalities)

t(11)(q23) – MLL;

less commonly,

t(3)(q21q26) – MDS1/EVI

85% 10-15% <5%

How Are MDS Diagnosed?

Required to diagnose MDS

A) Low blood counts

– Especially anemia with high red cell size (MCV)

– No other cause

B) Increased blasts (≥5% but <20%) or

chromosome abnormality (or both)

C) If not B, then lots of dysplasia (cell shape

abnormality)

Low blood counts and dysplasia

are not specific for MDS

Valent P, et al. Leuk Res. 2007;31:727-736.Valent P et al Leuk Res 2007;31:727-736.

Cytopenia(s):

• Hb <11 g/dL, or

• ANC <1500/μL, or

• Platelets <100 x 109L

MDS Decisive criteria:

•>10% dysplastic cells in 1 or

more lineages, or

•5-19% blasts, or

•Abnormal karyotype typical for

MDS, or

•Evidence of clonality (by FISH or

another test)

Other causes of cytopenias (low counts) and morphological changes EXCLUDED:

• Vitamin B12/folate deficiency

• HIV or other viral infection

• Copper deficiency

• Alcohol abuse

• Medications (esp. methotrexate, azathioprine, recent chemotherapy)

• Autoimmune conditions (ITP, Felty syndrome, SLE etc.)

• Congenital syndromes (Fanconi anemia etc.)

• Other hematological disorders (aplastic anemia, LGL disorders, MPN etc.)

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What is “dysplasia”? Rogues’ Gallery #1

Erythroid Myeloid Megakaryocytic

• Megaloblastoid (open

chromatin) maturation

• Multinucleated precursors

• Nuclear budding /

karryorhexis

• Ring sideroblasts

• Hypogranular/agranular

cells

• Hypolobated (pseudo

Pelger-Huët) cells

• Hyperlobated cells

• Hypolobated megs.

(esp. del5q)

• Micromegakaryocytes

• Hypersegmented

megakaryocytes

Images: DPS and Elizabeth A Morgan

How is a chromosome analysis

(karyotype) done?

Cells taken

from patient

Cells taken

from patient

Cells grown in

culture

Cells grown in

culture

Cells harvested

(lysed)

Cells harvested

and broken apart

(lysed)

Cell debris fixed

on a slide

Cell debris fixed

on a slide

Chromosomes

stained

Chromosomes

stainedChromosomes counted /

band pattern analyzed

Karyotype assembled

and reported

Additional genetic techniques

Fluorescent in situ hybridization (FISH)Sanger DNA sequencing

Next-generation DNA sequencingArray-based comparative genomic hybridization (aCGH)

MDS Molecular Genetics

� Major milestone: in the past several years, we have determined the full set

of mutations that cause MDS

� Current research goals: to determine how to use the genetics to guide

clinical care, understand MDS biology, and develop better therapies

Image courtesy Benjamin Ebert, DFCI/BWH

TET221%

Epigenetic regulation

Proliferation

Other

Impaired Differentiation

EZH2

6%

JAK2

3%

NRAS

4%

ASXL1

14%

RUNX1

9%

TP53

8%

DNMT3A

(8%)

ETV63%

CBL CBL

2%2%

KRASKRAS

1%1%

UTX UTX

1%1%

IDH1/2IDH1/2

2%2%

NPM1NPM1(2%)(2%)

SF3B1

22%

GNASGNAS(<1(<1%)%)

BRAFBRAF(<1(<1%)%)

PTENPTEN(<1(<1%)%)

PTPN11PTPN11(<1(<1%)%)

ATRXATRX

<1%<1%

CDKN2A CDKN2A (<1(<1%)%)

IPSS independent good prognosis

IPSS independent poor prognosis

No clear independent effect

ZRSR2

5%

SRSF211%

U2AF18%

Pre-mRNA splicing SF3A1SF3A1

1%1%

PRPF40BPRPF40B

1%1%

U2AF65U2AF65

<1%<1%

SF1SF1

1%1%

SETBP1

7%

Rogues’ Gallery #2: MDS mutation landscape

Steensma DP. Hematology 2009;2009:645-655

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4

World Health Organization MDS categories (2008)

Name Abbrev. Key Feature Proportion of patients (%)

Refractory cytopenia with unilineage

dysplasia

RA Anemia and erythroid dysplasia 10

RN Neutropenia and granulocytic dysplasia <1%

RT Thrombocytopenia and megak. dysplasia <1%

Refractory anemia with ring sideroblasts

RARS >=15% ring sideroblasts 5

5q- syndrome Del(5q)Isolated 5q31 deletion, anemia, hypolobated megakaryocytes

5

Refractory cytopenia with multilineage

dysplasiaRCMD

Multilineage dysplasia with >1 cytopeniaWith or without ring sideroblasts

20

Refractory anemia with excess blasts,

type 1RAEB-1 5-9% blasts 20

Refractory anemia with excess blasts,

type 2RAEB-2 10-19% blasts; ±Auer rods 20

Unclassifiable MDS-U Does not fit other categories 10

Childhood MDS RCC Often hypocellular; pancytopenia Rare

WHO Tumour Classification 4th edition, IARC 2008.

How do MDS behave?

Natural history of MDS: competing risks

MDS Diagnosis

Death from cytopenias and functional cell defects

prior to leukemic transformation

(INFECTION, bleeding, anemia-related ischemia)

Death with MDS, not directly from MDS

Death after progression to AML

50% of

patients

30%

20%

Dayyani F et al Cancer 2010; 116:2174-9

The “ABCDEFGHI” of MDS Prognosis

• Age

• Blast proportion

• Cytogenetics

• Degree and number of cytopenias

• Evolution of disease (kinetics)

• Functional status (performance score, comorbidities)

• Genetics (molecular)

• Health care access

• Immunologic status (e.g. absolute lymphocyte count)

“Old Familiar”: 1997 International Prognostic Scoring System (IPSS)

- still used for many clinical trials and for transplant assessment

Score

Prognostic Variable 0 0.5 1.0 1.5 2.0

Marrow blasts (%) <5% 5-10% -- 11-20% 21-30%***

Karyotype class* Good Intermediate Poor -- --

# of cytopenias** 0 or 1 2 or 3 -- -- --

From Greenberg P et al Blood 1997; 89:2079-2089 (correction 1998; 91:1100)

*Karyotype risk groups: Good = normal, -Y, del(5q) alone, del(20q) alone; Poor = chromosome 7 abnormalities or

complex; Intermediate = other karyotypes

** Qualifying Cytopenias: Hb < 10 g/dL, ANC <1800/μL, platelets <100,000/μL

*** 20% or more blasts now (WHO) considered AML, but was still MDS (FAB) at the time this system was developed

Score sum IPSS Risk Category

Median survival for

over age 60 group

(years)

Time until 25% get

AML

(years)

0 Low 5.7 9.4

0.5-1.0 Int-1 3.5 3.3

1.5-2.0 Int-2 1.2 1.1

>=2.5 High 0.4 0.2

1997 IPSS Risk Stratification

Redrawn by DPS from Greenberg P et al Blood 1997; 89:2079-2089 (correction 1998; 91:1100)

(n=816)Death AML

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IPSS limitations

• Valid only in adult patients with de novo

disease

• Validated only at time of diagnosis for

patients treated with supportive care alone

• Limited number of karyotypes (5) included

• Insensitive to the degree of cytopenias

• Missing many key variables

Risk group Included karyotypes

Median

survival,

years

25% of

patients to

AML, years

Proportion

of patients

in this group

Very good del(11q), -Y 5.4 N/R 4%

Good

Normal, del(20q), del(5q)

alone or with 1 other

anomaly, del(12p)

4.8 9.4 72%

Intermediate

+8, del(7q), i(17q), +19, any

other single or double

abnormality not listed

2.7 2.5 13%

Poor

Abnormal 3q, -7, double

abnormality include -

7/del(7q), complex with 3

abnormalities

1.5 1.7 4%

Very poorComplex with >3

abnormalities0.7 0.7 7%

From: Greenberg P et al Blood 2012 Sep 20;120(12):2454-65. Epub 2012 Jun 27

Cytogenetic (chromosome) classification used in IPSS-R

Parameter Categories and Associated Scores

Cytogenetic risk

group

Very good Good Intermediate Poor Very Poor

0 1 2 3 4

Marrow blast

proportion

≤2% >2 - <5% 5 - 10% >10%

0 1 2 3

Hemoglobin≥10 g/dL 8 - <10 g/dL <8 g/dL

0 1 1.5

Absolute

neutrophil

count

≥0.8 x 109/L <0.8 x 109/L

0 0.5

Platelet count≥100 x 109/L 50 - 100 x 109/L <50 x 109/L

0 0.5 1

Possible range of summed scores: 0-10

From: Greenberg P et al Blood 2012 Sep 20;120(12):2454-65. Epub 2012 Jun 27

IPSS-R calculation

Risk group Points

% patients

(n=7,012;

AML data on

6,485)

Median

survival,

years

Median

survival for

pts under 60

years

Time until

25% of

patients

develop

AML, years

Very low 0-1.5 19% 8.8 Not reached Not reached

Low 2.0-3.0 38% 5.3 8.8 10.8

Intermediate 3.5-4.5 20% 3.0 5.2 3.2

High 5.0-6.0 13% 1.5 2.1 1.4

Very high >6.0 10% 0.8 0.9 0.7

Only valid for:

Adults

De novo disease

Treated with supportive care

At the time of diagnosis

From: Greenberg P et al Blood 2012 Sep 20;120(12):2454-65.

Epub 2012 Jun 27

IPSS-R (see: http://www.mds-foundation.org/ipss-r-calculator/)

How can MDS be treated?

Hypomethylating agents / Hypomethylating agents /

DNA methyltransferase inhibitors /

epigenetic drugs

Azacitidine (Vidaza ®)

Approved May 2004

Azacitidine (Vidaza ®)

Approved May 2004

Decitabine (Dacogen ®)

Approved May 2006

Decitabine (Dacogen ®)

Approved May 2006

Iron chelators

Lenalidomide (Revlimid ®)

Approved December 2005

Lenalidomide (Revlimid ®)

Approved December 2005

FDA Approved for MDS-Related Indications FDA Approved for Other Indications

Immunomodulatory drug (iMiD)

Deferasirox (Exjade ®)

Approved November 2005

Deferasirox (Exjade ®)

Approved November 2005

Blood cell (hematopoietic)

growth factors

Epoetin alfa (Procrit ®)

Darbepoetin alfa (Aranesp ®)

Filgrastim, G-CSF (Neupogen ®)

Pegfilgrastim (Neulasta ®)

Red cell growth factors

White cell / myeloid growth factors

Romiplostim (NPlate ®)

Eltrombopag (Promacta ®)

Platelet growth factors

Immunosuppressive drugs (ATG, CsA)Immunosuppressive drugs (ATG, CsA)

Chemotherapy or stem cell transplantChemotherapy or stem cell transplant

Thalidomide, androgens, other biologicsThalidomide, androgens, other biologicsDeferoxamine (Desferal ®)

Approved 1968

Deferoxamine (Desferal ®)

Approved 1968

Medications currently commonly used for patients with MDS

9/4/2013

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An approach to MDS

Cytopenia(s) Disease feature First-line therapy

Anemia only Del (5q) Lenalidomide

No del(5q), sEPO <500 ESA ± G-CSF

No del(5q), sEPO >500 ?Immunotherapy

Neutropenia or

thrombocytopenia or both

None established;

observation, growth factors,

aza/decit reasonable

Lower-risk MDS (assessed using IPSS-R, etc.)

Higher-risk MDS

Allogeneic SCT candidate? Therapeutic approach

Yes Proceed to transplant ASAP; a hypomethylating agent (HMA)

or cytotoxic chemotherapy may be useful as a “bridge”

No Azacitidine; decitabine as alternate

Supportive care for all (transfusions and antimicrobials PRN, ?iron chelation)

Partly based on 2013 NCCN guidelines; see www.nccn.org

Who is likely to respond to Erythropoiesis

Stimulating Agents (ESAs) in MDS?

Total Score (from below)IWG 2000 erythroid

response rate (patients)

High likelihood of response: > +1 74% (n=34)

Intermediate likelihood: -1 to +1 23% (n=31)

Low likelihood of response: < -1 7% (n=39)

Hellstrom-Lindberg E et al Br J Haem 2003; 120:1037

International Working Group (IWG) 2000 Erythroid Response Criterion: >1.5 g/dL Hb increment, or transfusion independence

Serum EPO level (U/L) RBC transfusion requirement

<100 = +2 pts <2 Units / month = +2 pts

100-500 = +1 pt ≥2 Units / month = -2 pts

>500 = -3 pts

Romiplostim efficacy in MDS with low platelets

Plt Ct(x109/L) Clinically Relevant Endpoints Results in this study

20-50 Platelet transfusions not routine:

Bleeding ReductionCSBE reduced RR = 0.35 (95% CI: 0.21, 0.59)

p<0.0001, n = 120, 48%

<20 Patients transfused commonly:

Platelet Transfusion ReductionPTE reduced RR = 0.71 (95% CI: 0.61, 0.82)

p<0.0001, n = 130, 52%

<10 Worst group:

Platelet Count ImprovementHI-P improved responses7% vs. 30%

Diff = 23% (95% CI: -6%, 46%)p = 0.23, n = 34, 14%

CSBE = clinically significant bleeding events, PTE = protocol-defined PLT Tx events

Dose: 750 μg SC or IV weekly (n=168) vs placebo (n=82) x 58 weeks

IPSS Low/Int-1 with mean platelet count ≤50 × 109/L with bleeding history, or ≤20 × 109/L

57% complete response rate (@8 weeks >100 × 109/L) 8% major response (>30 increment)

Most common AEs: fatigue and headache

Romiplostim Placebo Total

Study-defined AML 15 (8.9%) 7 (8.5%) 22 (8.8%)

Kantarjian H et al ASH 2012 abstract Steensma D, Hussein K. Chapter 19, MDS Pathobiology and Clinical Management. 2008

Anti-T cell therapies

• Anti-thymocyte

globulin (ATG)

• Cyclosporin A

• Tacrolimus

• Alemtuzumab

• Others

Proposed predictors of response to immunotherapy in MDS (none very

• HLA DRB15

Proposed predictors of response to immunotherapy in MDS (none very

good!):

• Hypoplastic marrow

• PNH clone

• Normal karyotype / trisomy 8

• Younger age (especially <55… but is that really MDS?)

• Minimal transfusion needs

• HLA DRB15

Suppression of hematopoiesis by an expanded cytotoxic T lymphocyte clone

Lenalidomide clinical trials in MDS

Del(5q) Non-del(5q)

MDS-001

N = 43, Phase I/II initiated Feb 2002

List A et al NEJM 2005

MDS-003

N=148, Phase II initiated July 2003

List A et al NEJM 2006

MDS-002

Raza A et al Blood 2008

MDS-002

N = 214, Phase II initiated July 2003

Raza A et al Blood 2008

Eligibility:

>2 U pRBCs/8 weeks

Platelet >50 x 109/L

ANC >500/uL

MDSMDS--004004

N=205, Phase III initiated July 2005N=205, Phase III initiated July 2005

Finished accrual June 2008Finished accrual June 2008

MDS-005

N = 375, Phase III initiated Nov. 2009

Final report pending

67% transfusion independence

Median duration of response >2 years

45% complete cytogenetic remission

26% transfusion independence

Median duration of response 41 weeks

9% complete cytogenetic remission

No difference in dose reductions w/ 5 vs 10 mg

↑cytogene^c CR with 10 mg 21/28 d vs 5 mg/d

AZA-001 Survival Study (Higher risk MDS):

Azacitidine vs “Conventional Care”

Log-Rank p=0.0001

HR = 0.58 [95% CI: 0.43, 0.77]

Deaths: Aza = 82, Control = 113

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

Control arm(BSC, 3&7, LDAC)

Azacitidine

Difference: 9.4 months

24.4 months

15 months

Fenaux P, et al. Lancet Oncology 2009 10: 223–232

Probably better to give 7 days than <7 days

IV same as SC

9/4/2013

7

Decitabine (D-0007) registration study

outcomes

Time to death or AML, all

patients (p=0.16)

Time to death or AML,

higher-risk patients

(p=0.028)

What we can expect with

“hypomethylating agent” (azacitidine, decitabine)

monotherapy in MDS

Outcome Comments

Improved survival (higher-risk pts) 9.4 months w/ azacitidine [AZA-001]

Delayed progression to AML 4-6 months [EORTC 06011, D-0007, AZA-001]

Low complete response rate (IWG 2006) ~10-15% rate; probably no cures

Moderate hematological response rate ~30-60%

Improved patient-reported outcomes /

hrQOL

Formally studied in CALGB 9221

Variable duration of response Median for CR: 11-17 months; less for other

Low early treatment-related mortality Varies by study population, but usually <10%

Poor survival after HMA failure <6 months

Itzykson R, Fenaux P. Curr Hematol Rep 2012; 19:65-70.

Prébet T, Gore SD et al. J Clin Oncol 2011; 29:3322-7.

Lübbert M, Suciu S et al. J Clin Oncol 2011; 27:1987-1996.

Lee JH, Jang JH et al. Haematologica 2011; 96:1441-1447.

Silverman LR, Fenaux P et al. Cancer 2011; 117:2697-2702.

Lyons RM, Cosgriff T et al. J Clin Oncol 2009; 27:1850-1856.

Steensma DP, Baer MR et al. J Clin Oncol 2009; 27:3842-3848.

Fenaux P, Mufti GJ et al. Lancet Oncology 2009; 10:223-232.

Kantarjian H, Oki Y et al. Blood 2007; 109:52-57.

Kantarjian H, Issa J-P et al. Cancer 2006; 106:1794-1803.

Silverman LR, Demakos EP et al. J Clin Oncol 2002; 20:2429-40.

Kornblith AB, Herndon JE 2nd et al. J Clin Oncol 2002; 20:2441-52.

Allogeneic stem cell transplantation

for MDS<10% of patients with MDS currently undergo allogeneic SCT

“Only curative therapy”

Survives transplant;

MDS cured!

Survives transplant;

MDS persists

Patients who go in to RIC allo SCT with <10% blasts appear to have lower relapse

Transplant candidate

Donor identified

Dies from complication

of transplant ± MDS

Optimal timing, pre-transplant therapy, conditioning unclear;

usually reserved for IPSS Int-2/High (IBMTR Markov analysis)

Cutler C et al Blood 2004; 104(2):579-85

Sekeres M et al JNCI 2008;100(21):1542-51.

Role of HMAs peri transplant, e.g. to dissect GVH from GVL?

Cumulative probability of survival among 374 MDS patients at Pavia, Italy, 1992–2002

(Transfusion-associated hazard ratio for death, 1.58; P=0.005)

Redrawn by DPS from Cazzola M and Malcovati L NEJM 2005; 352:536-8

“The risk of RBC transfusion dependence In MDS”

Malcovati L. Leukemia Research 31S3 (2007) S2–S6

Correlation between ferritin and poorer outcome in lower-

risk MDS – but does chelation change this? Unclear!

Based on 426 patients evaluated in Pavia, Italy

No correlation in RAEB

RA/RARS/5q- syndrome

(p<0.001)

RCMD/RCMD-RS

(p=0.07)

Thank you!

• AA&MDS International Foundation– John Huber (Executive Director), Alice Houk, Stephanie Chisolm,

Catrell Harris, Jacqueline Kallenbach

• DFCI Adult Leukemia Program– Richard M Stone, MD, Director

– Daniel J DeAngelo, MD PhD

– Martha Wadleigh, MD

– Gabriela Motyckova, MD PhD

• Research Collaborators– Benjamin Ebert, MD PhD – BWH

– R. Coleman Lindsley, MD PhD - BWH

– Mark Fleming, MD DPhil - CHB

– Rafael Bejar, MD PhD - UCSD

– Mei Wu, PhD – MGH

• Research Funding: Edward P. Evans Foundation MDS Clinical Research Consortium