myelodysplastic syndromes bwi mar 2015.pdfcount monitoring, growth factors, transfusion support ......

1

Myelodysplastic Syndromes

“A Guide to the Disease”

B. Douglas Smith, M.D.Associate Professor

Kimmel Cancer Center @ JH

What Is MDS?

Basic Biology…Basic Work-up…


• 15,000 - 25,000 new cases/year

• Median age > 60 (70% > 50 years) M > F

• Clonal disorder: multilineage hematopoietic progenitor

• Ineffective hematopoiesis with peripheral cytopenias

• Bone Marrow Failure:

• Majority succumb from infection or bleeding

• Transformation to AML in ~ 1 in 3

• Best Supportive Care has been the standard treatment

• count monitoring, growth factors, transfusion support

• Allo BMT only curative option

MDS PathogenesisStage 1

Intrinsic increase in apoptotic response and

inflammation

Stage 2

Acquisition of anti-apoptotic molecules

Stage 3

Initiation of clonal evolution

↑ TNFα-induced apoptosis

↑ ROS ↑ Bcl-2

MPMP

MP

MP

aMP

MPMP

MP

MPMPMP

aMP

aMP

•aMPMP

MP

MPMP

Induction of homeostatic mechanisms Expansion

Telomere erosion andsenescence

Impairedimmunosurveillance

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 marrowAbnormalribosomes

Altered T-cellhomeostasis

•Inflammatorymicroenvironment

Altered MPlocalization

Stromal celldefects

Molecular model of MDS progressionSuppressed

hematopoiesis

High risk for leukemia

transformation

Epling-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.

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

2

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 FoundationAmerican 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 score

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

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 score

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

Performing a bone marrow aspiration

3

•

Courtesy of Dr. Bennett and Dr List.

Cytologic Dysplasia: Bone Marrow

DysErythropoiesis


Cytologic Dysplasia: Marrow and

Blood DysGranulopoiesis


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.

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 AML Progression

IPSS MDS Risk Classification

Higher risk MDS (INT-2, High) is associated with a median

survival of 0.4—1.2 years1

1. Greenberg P, et al. Blood. 1997;89(6):2079-2088.

4

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

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

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%


U.S. MDS Characteristics


• 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%

5

U.S. Classification of MDS PatientsFewer higher-risk established patients


18%

15%

18%29%

23%

26%

Transfusion Burden of MDS Patients


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

Supportive Care

73%

Active

Treatment

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


6

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


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; abstract 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


“A Guide to the Evolving Treatment Paradigms and What’s New”



7

How do we treat MDS?

Oncologist’s perspective…

Therapeutic Options – 1995

Available

• Best Supportive Care

• Growth Factor Support

• Allogeneic BMT options

In Development

• DNA Methyltransferase Inhib• Azacitidine

• Immunomodulatory• Thalidomide


Available



• DNA Methyltransferase Inhibitors

• Azacitidine Decitabine

• Immunomodulatory

• Lenalidomide

• Other Agents

• ↓ dose Ara-C ATG

• Arsenic Amifostine


• alternative BMT options

In Development

• Differentiation Therapy

• Growth Factors

• Clonal Suppression

• Arsenic Trioxide

• Anti-VEGF inhibitors• Bevacizumab

• HDAC inhibitors• Valproic Acid• SAHA MS-275

• FTIs

• Tipifarnib Lonafarnib

• Immunotherapy

• Ipilumumab Vaccines


Available



• DNA Methyltransferase Inhibitors

• Azacitidine Decitabine

• Immunomodulatory

• Lenalidomide

• Other Agents

• ↓ dose Ara-C ATG

• Arsenic Amifostine


• alternative BMT options

In Development

• Differentiation Therapy

• Growth Factors

• Clonal Suppression

• Arsenic Trioxide

• Anti-VEGF inhibitors• Bevacizumab

• HDAC inhibitors• Valproic Acid• SAHA MS-275

• FTIs

• Tipifarnib Lonafarnib

• Immunotherapy

• Ipilumumab Vaccines

Do we NEED to treat MDS?

Oncologist’s perspective…

Treatment Goals in MDS


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

Improve marrow function

Decrease Transfusion Needs

Decrease impact of MDS on QOL

Establish careful monitoring plan

Stabilize marrow function withtrilineage improvement

Lower risk AML transformation

Move to definitive therapy

ORMaximize benefit

8



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








ORMaximize benefit

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

Score > +1

Score -1 to +1

Score < -1

RA, RARS, RAEBIntermediate

(23%, n = 31)

Poor

(7%, n = 29)

Good

(74%, n = 34)

Response Probability

Treatment Response Criteria Treatment Response Score

Predictive Model for Response to

Treatment With rhuEPO + G-CSF

CR Stable hemoglobin

> 11.5 g/dL

PR Increase in Hb with >1.5g/dL or total stop in RBC transfusions

S-EPO

U/l

< 100

100-500

> 500

+2

+1

-3

Transf

U RBC/ m

< 2 units/m

≥ 2 units/m

+2

-2

Hellström-Lindberg E, et al. Br J Hematol. 2003;120:1037-1046.

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??

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; 4:314Sterling D Semin Oncol 2001; 28:602

Data on file: Summit, NJ: Celgene Corporation 2005

Thalidomide Lenalidomide

9

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 qd5 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

Most Frequently Observed Hematological

Adverse Events: del 5q MDS Safety Data

N=148 ALL Grades Grade ¾

Neutropenia 58.8% 53.4%

Thrombocytopenia 61.5% 50.0%

Anemia NOS 11.5% 6.1%

Leukopenia NOS 8.1% 5.4%

• Grade ¾ febrile neutropenia reported in 4.1% (6/148) of MDS pts

• In registration trial, G-CSFs were permitted for patients who developed neutropenia or fever in association with neutropenia

• Patients may require the use of blood product support and/or growth factors

Clinical Overlap / Associations:

• AML • PNH• Myeloproliferative Disease

• 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

5q(-)

10

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

5-2-2: 75 mg/m2

N=50

5-2-5: 50 mg/m2

N=51

5: 75 mg/m2

N-50

x 6 IWG

2000 HI

12 Cycles

AZA x 5d

q4-6 wks

Study Design (N = 151)

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

Eligibility

All FAB

Cytopenia

ECOG PS: 0-3

Randomized Phase II Study of Alternative

Azacitidine Dose Schedules

*IWG 2000 criteria

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

Alternate AzaC Dose Schedule Study: Frequency

of Major HI in Evaluable Patients (N = 139)

Lineage HI in

Evaluable Pts,* n (%)

5-2-2

(n = 50)

5-2-5

(n = 51)

5d

(n = 50)

ErythroidMa 19/43 (44) 19/43 (44) 20/44 (46)

RBC-TI 12/24 (50) 12/22 (55) 15/25 (64)

PlateletMa 12/28 (43) 8/30 (27) 11/22 (50)

Any HI 22/50 (44) 23/51 (45) 28/50 (56)

NeutrophilMa 4/23 (17) 4/23 (17) 9/24 (38)

Heme AEs > Gr 3 33/50 (66) 24/48 (50) 17/50 (34)

AE Tx delay 34/50 (68) 30/48 (63) 17/50 (34)

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



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








ORMaximize benefit

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

•4•5

•6•1

•2

•3

CH3

5-adenosyl-methionine

DNMT

•N

•N

NH2

•O

•4•5

•6•1

•2

•3

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

11

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.

Transcription

Unmethylated CpG Islands

Promoter

Transcription Factor

Functional Control of Gene Transcription:Methylation and Gene Silencing

Jones PA and Baylin; Fundamental Role of epigenetic events in Cancer, 2002

•Transcription

Methylated CpG Islands “DNMT”

Promoter

Transcription Factor

Aberrant Methylation Epigenetic

Gene Silencing

Jones PA and Baylin; Fundamental Role of epigenetic events in Cancer, 2002

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:

Azacitidine Key Studies in MDS

Study N AZA Dose Reference

AZA-001:

Azacitidine vs CCR in Patients

with Higher-Risk MDS

(phase 3)

35875 mg/m2/d x 7d SC

q28d

Fenaux et al.

Lancet Oncol.

2009;10:223-332.

Azacitidine in Patients with MDS:

Studies 8421 (phase 2), 8921

(phase 2), and 9221 (phase 3) by

CALGB (azacitidine vs

observation)

30975 mg/m2/d x 7d SC

q28d

Silverman et al.

J Clin Oncol.

2006;24:3895-3903.

Study of Alternative Dosing

Schedules of Azacitidine in

Patients with MDS (phase 2)

148

5-2-2

75 mg/m2 SC

5-2-5

50 mg/m2 SC

5

75 mg/m2 SC

Lyons et al

J Clin Oncol.

2009;27:1850-1856.

Decitabine Key Studies in MDS

Study N Decitabine Dose Reference

Study of Decitabine plus Best

Supportive Care (BSC) vs BSC

(phase 3)

170

15 mg/m2

(3 h q8h)

3 d IV q6wk

Kantarjian et al.

Cancer.

2006;106:1794-1803.

Low-Dose Decitabine versus BSC

(EORTC)

(phase 3)

233

15 mg/m2 on

days 1-3

of 6-wk cycle

Wijermans et al.

ASH. 2008

Abstract 226.

Alternative Dosing with Decitabine –

MD Anderson

(phase 2)

95

20 mg/m2/d IV

x 5 d

20 mg/m2/d SC

x 5 d

10 mg/m2/d IV

x 10 d

Kantarjian et al.

Blood.

2007;109:52-57.

ADOPT, Alternate Dosing for

Outpatient Treatment

(phase 2)

9920 mg/m2/d IV

x 5 d

Steensma et al.

J Clin Oncol.

2008;26

Abstract 7032

12

Efficacy of Azacitidine Compared with that

of Conventional Care Regimens in the

Treatment of higher-risk MDS: A

Randomized, Open-label, Phase III Study

P Fenaux, GJ Mufti, E Hellstrom-Lindberg, V Santini, C Finelli,

A Giagounidis, R Schoch, N Gatterman, G Sanz, A List, S Gore,

J Seymour, J Bennett, J Byrd, J Backstrom, L Zimmerman,

D McKenzie, CL Beach and L Silverman

on behalf of the International Vidaza High-Risk MDS

Survival Study Group

Lancet Oncology 2009

VIDAZA® + BSC

(75 mg/m2/d x 7d SC q28d)

Stratify:

•FAB = RAEB, RAEB-T

• IPSS = INT-2, High

N=179

N=179

Treatment continued until unacceptable toxicity or AML transformation or disease progression

AML=acute myeloid leukemia; BSC=best supportive care; CCR=conventional care regimen; IPSS=international prognostic scoring system; LDAC=low-dose Ara-C.

AZA-001: Trial Design

1. BSC only or

2. LDAC or(20 mg/m2/d SC x 14d q 28-42d)

3. 7+3 chemotherapy (Induction + 1 or 2 consolidation cycles)

CCR

R

A

N

D

O

M

I

Z

E

Physician Choice of 1 of 3 Conventional Care Regimens

AZA-001 Randomization Schema

(N=358)

Physician Choice of 1 of 3

Conventional Care Regimens

(Best Supportive Care (BSC) or LDAC or 7+3

Chemo)

VIDAZA® or BSC

VIDAZA or LDAC

VIDAZA or 7+3 Chemo

R

A

N

D

O

M

I

Z

E

VIDAZA (n=117)

VIDAZA (n=45)

VIDAZA (n=17)

7+3 Chemo (n=25)

n=222

n=94

n=42

BSC (n=105)

LDAC (n=49)

Fenaux, et al, Lancet Oncology 2009

Azacitidine Survival Study Baseline Clinical Characteristics, n = 358

Parameter

AZA

N=179

CCR

N=179

CCR Regimens

BSC

Only

N=105

LDAC

N=49

Std

Chemo

N=25

Age (yrs) Median

Pts ≥ 65 (%)

69

68

70

76

70

77

71

86

65

52

FAB (%) RAEB

RAEB-T

CMML

58

34

3

58

35

3

65

29

4

51

39

2

40

52

0

IPSS (%) INT-1

INT-2

High

3

43

46

7

39

48

9

44

44

4

43

43

8

12

72


Overall Survival: Azacitidine vs CCR ITT Population

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]

Deaths: AZA = 82, CCR = 113


AZA vs CCR: OS with CRs Removed

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

AZA

CCR

# at risk

AZA 149 122 101 61 39 23 7 1 0

CCR 165 118 82 59 25 11 4 0 0

17.3 months

Log-rank P=0.005

HR=0.65 [95% CI: 0.48–0.88]

Death: AZA = 75, CCR = 104

Difference: 3.4 months

24

24.8%

44.9%

13.9 months

13

EORTC-06011 Decitabine Phase III Trial Study Design

• Open-label, multicenter, 1:1 randomized study

• IPSS: Int-1,2, and high-risk MDS; > 60years (n=223)

• Primary endpoint: Overall Survival

Stratification

- IPSS

- Primary vs.

secondary

R

A

N

D

O

M

I

Z

E

Decitabine 15 mg/m2/ over 3H

q8h x 3 days q 6 wks

(max 8 cycles) [n=119]

Supportive Care (SC)

[n=114]

Response assessment q2 cycles; HI, CR, PR & SD continue for up to 8 cycles;

Exception: CR – 2 additional cycles.

Wijermans P, Lubbert M, Suciu S, et al. ASH, December 6-9, 2008

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

Outcome After Azanucleoside Failure

in Higher-Risk MDS and CMML

Institution N AZA Failures

n

AML Progression

n (%)

Med OS

(mos)

OS @

12 mos (%)

Moffitt [1] 151 59 12 (20.3) 5.8 30

GFM * [2] 435 NR NR 5.6 29

MDACC † [3] NR 87 25 (29) 4.3 28

* Includes AZA001, J9950, J0443 studies† Decitabine only

1. Duong V, et al. Clin Lymph Myel Leuk. 2013;13:711-715. Abstract 2913.

2. Prebet T, et al. J Clin Oncol. 2011;29:3322-3327.

3. Jabbour E, et al. Cancer. 2010;116:3830-3834.

Type of Salvage N ORR Median OS, Mos

Unknown 165 NA 3.6

Best supportive care 122 NA 4.1

Low-dose chemotherapy 32 0/18 7.3

Intensive chemotherapy 35 3/22 8.9*

Investigational therapy 44 4/36 13.2*

†

Allogeneic transplantation 37 13/19 19.5*

†

Prébet T, et al. J Clin Oncol. 2011;29:3332-3327.

* Log-rank comparison of BSC vs intensive CT (P = .04), investigational therapy (P < .001), or alloSCT (P < .001).

† Intensive CT vs investigational therapy (P = .05), intensive CT vs ASCT (P = .008), or IT vs ASCT (P = .09).

Salvage Therapy After Azacitidine

Failure: GFM and AZA001 Studies

100

75

50

25

00 365 730 1095 1460

OS

(%

)

Days Since AZA Failure

Investigational

Allo-SCT

Allogeneic BMT for MDS: General Principles and the Decision

Time

% S

urv

ival

HCT

No HCT

With Permission of C. Cutler,MD

BMT is potentially curative:

- however part of the benefit is lost

due to its morbidity + mortality

Many patients are not eligible for SCT:

- stable medical condition

- stable disease

- available donor

- age (@ JH up to 76 birthday)

Approximation of Life Expectancy

for Alternative Transplant Strategies

Transplant at

Diagnosis

Transplant

in 2 Years

Transplant at

Progression

Low 6.51 6.86 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 July 2004; 104:2

14


“What’s New?”



Revised IPSS: Prognostic Score Values

and Risk Categories/Scores

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

Score Value

Prognostic

Variable0 0.5 1.0 1.5 2.0 3.0 4.0

CytogeneticsVery

good

--Good

-- Intermediat

e

Poo

r

Very

poor

BM blast, % ≤ 2--

> 2 to < 5--

5-10 > 10--

Hemoglobin,

g/dL≥ 10

--8 to < 10 1.5 to 3

Intermediate > 3.0 to 4.5

High > 4.5 to 6.0

Very high > 6

Revised IPSS: 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 lowLowIntermediateHighVery high

Median Survival (95% CI)

8.8 (7.8-9.9) years

5.3 (5.1-5.7) years

3.0 (2.7-3.3) years

1.6 (1.5-1.7) years

0.8 (0.7-0.8) years

Azacitidine

Azacitidine + Lenalidomide

Azacitidine + Vorinostat

Patients with higher-risk MDS or CMML (IPSS >

1.5 or blasts > 5%)

(Planned N = 267)

Phase II SWOG-S1117 Study: Aza + Len or

Vorinostat in Higher-Risk MDS/CMML

• Primary endpoint: 20% RR improvement (2006 IWG criteria)

• Secondary endpoints: OS, RFS, LFS, toxicity, cytogenetic responses

• 81% power (P = .05 for each combination arm vs azacitidine alone)

Groups: SWOG, ECOG,CALGB, NCIC

Anticipated time: 2.5 yrs

ClinicalTrials.gov. NCT01522976.

RUNX1

ETV6

WT1 PHF6

GATA2

DNMT3AEZH2

ASXL1

IDH1 & 2

UTX

TP53

Transcription FactorsTyrosine Kinase Pathway

Epigenetic Dysregulation

SF3B1

Splicing Factors

JAK2

NRAS

BRAFKRAS

RTKs

PTPN11

NOTCH?MAML?

ZSWIM4?UMODL1?

CBL

NPM1

ATRX

Others

SRSF2

U2AF1ZRSF2

SETBP1

SF1SF3A1

PRPF40BU2AF2

PRPF8

BCOR

TET2

Genes Recurrently Mutated in MDS

Bejar R.

Selective JH and Cooperative Trials

Low Risk (IPSS 0 or INT 1)

E2905 Open EPO+/-

Revlamid

Prior EPO failure OR epo level >500

(treatment naïve)

IPSS Low or INT 1

Cytogenetics required

Untransfused Hb

15

Selective JH and Cooperative Trials

High Risk (IPSS INT 2 or High)

S1117 Interim

Analysis

– on hold

AZA+ Revlamid

vs

AZA

vs AZA+ vorinostat

Treatment naïve

RAEB1 or 2

CMML1 or 2

IPSS INT 2 or High Risk

IPSS INT 1 if blasts >5%

No AML

SWOG PI: DeZern

RN: Cecelia

J1276 Open Ipilumimab Must fail demethylating agents or

lose response

IPSS INT 2 or High Risk

IPSS INT 1 if blasts >5%

Relapsed transfusion dependence

CTEP PI: Smith

RN: Anna

J1229 Open Hedgehog Inhibitor Treatment naïve

RAEB 2 or High Risk (BMBx 10-19%

blasts)

AML

Pfizer PI: Smith

RN: Joan

The Hope Project

Sidney Kimmel Comprehensive Cancer

Center at Johns Hopkins

Anna Ferguson, RN, BSN

Research Nurse Hematologic Malignancies

Hope is…

• A belief, a sense, an idea that something good

can come from something bad

• The anticipation of positive things to come

• A positive state of being or feeling

Hope is…

• An alternative to despair

• A guide

• A sustaining force and reservoir of strength

• Associated with:

– less depression

– less fear

– stronger relationships with caregivers and providers

– better quality of life

Hope is not…

• Optimism

• Stoicism

• “Looking at the bright side…”

• Blind faith

The Hope Project seeks to…

• Elevate the concept of Hope beyond its

association with cure

• Bring the concept of Hope to the forefront of

the care we deliver

• Generate discussion in our SKCCC

community about the importance of Hope

16

What are you hoping for?

What is important to you?

What are you most worried about?

What brings you joy?

As a patient…caregiver…family

member…friend…

Hope Matters… MDS Treatment Paradigm - 2015

Low + INT-1 IPSS

with 5q-

Low + INT-1 IPSS

(non-5q-)

INT-2 + High IPSS

Lenalidomide

Azacitidine Decitabine

Low + INT-1 IPSS

Is therapy needed clinically?

Will Growth Factors help?

Azacitidine

Decitabine

LenalidomideAllogeneic BMT

@ progression

Conclusions: Optimizing Therapy

• Effective treatments for MDS exist

• IPSS – starting point for risk stratification

• Important to set GOALS of therapy

• Growth Factors, support

• Lenalidomide = lower risk, goal ↓ transfusions

• DNA methyltransfer inhibitors = high risk

• 5-aza associated with ↑ survival vs CCR

• Allogeneic SCT remains curative but toxic

Acknowledgements

• JH Leukemia Program• Mark Levis Amy DeZern

• Ivana Gojo Keith Pratz

• Margaret Showel Michael McDevitt

• Gabrielle Prince Gabriel Ghiaur

• Lukasz Gondek

• Stem Cell Biology• Rick Jones Bill Matsui

• Hope Project• Anna Ferguson

myelodysplastic syndromes bwi mar 2015.pdfcount monitoring, growth factors, transfusion support ......

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