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Learning Objectives:

• Understand key disease characteristics needed to facilitate diagnosis, staging, and tailored treatment of MDS and Acute Leukemia

• Define individualize treatment goals

• Examine new treatment approaches

• Delineate how treatment strategies fit into current NCCN treatment algorithms

• Discuss how a comprehensive targeted treatment plan may improve overall and transplant outcomes

Images with Permission of L Silverman,MD

Characterizing MDS

Definition:

• A group of clonal bone marrow stem cell disorders, characterized by hypercellular marrows, peripheral cytopenias, and cell functional abnormalities

– Ineffective hematopoiesis

• Heterogeneity: highly variable natural history

• High mortality rate

• Unless permanent control achieved (by alloBMT) death due to bone marrow failure, with or without conversion to AML

Kurzrock R. Semin Hematol 2002. Jul;39(3 Suppl 2):18-25.

Hamblin TJ. Epidemiology of MDS. In: Bennett JM (ed). MDS: Pathobiology and Clinical Management.

New York: Marcel Dekker Inc.; 2002.

http:// www.hmds.org.uk/mds.html

Age-related Incidence of MDS

McNally RJQ et al. Hematological Oncology 1997. 15:173-189,

Cartwright RA,et al. Leukaemia Research Fund, 1997. http://www.lrf.org.uk

Reprinted with Permission of Leukemia Research Fund

Males

Females

0 10 20 30 40 50 60 70 80

0.01

0.1

1

10

100

Ra

te

Predisposition:

Acquired:

Senescence

Mutagen/Genotoxic Stress

Therapeutic

alkylators, Topo-II agents,

-emitters (32P), autoSCT

Environmental/occupational

(benzene)

Tobacco

Aplastic anemia

PNH

List AF, et al. The Myelodysplastic Syndromes. In: Wintrobe’s Hematology 2003.

Heritable:

Constitutional genetic disorders

Trisomy 8 mosaicism

Familial monosomy 7

Neurofibromatosis 1

Embryonal dysgenesis (del12p)

Congenital Neutropenia

Kostmann, Schwachman-Diamond

DNA repair deficiencies

Fanconi anemia, AT, Bloom syndrome

Pharmacogenomic polymorphisms(GSTq1-null)

Clinical Overlap / Associations:

• AML

• Aplastic anemia

• Myeloproliferative disease

• LGL leukemia

• Autoimmune diseases

AML

PRCA

PNHMDS

AA

LGL MPD

With Permission of J Maciejewski,M.D. Taussig Cancer Center/ Cleveland Clinic Foundation

With Permission of American College of Physicians from Young NS. Ann Intern Med. 2002 Apr 2;136(7):534-46

(ACP not responsible for accuracy of figure translation).

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Images with Permission of L Silverman,MD

Diagnosis and Classification:

Basic Diagnostic Evaluation:

• Peripheral blood counts + reticulocyte count

• Bone marrow biopsy and aspiration

– Cytogenetics

• Auxiliary tests

– FISH

– Flow cytometry in indeterminate cases

– Iron saturation, ferritin

– B12, folate levels

– EPO level

Establish diagnosis

Assess

– FAB/WHO classification

– IPSS score (if applicable)

http:// www.NCCN.org MDS Guidelines

http://www.hmds.org.uk/mds.html

WHO Reclassification of FAB MDS Subtypes

MDS (FAB) MDS (WHO)

Refractory Anemia (RA) <5% Blasts

Refractory Anemia (RA)

Refractory cytopenias with

multilineage dysplasia (RCMD)

MDS-Unclassified (MDS-U)

MDS with isolated del(5q) 5q minus

syndrome

RA with ?15% ringed sideroblasts

Refractory Anemia with ringed

sideroblasts (RARS)

Refractory cytopenias with

multilineage dysplasia and ringed

sideroblasts (RCMD-RS)

RA with excess blasts (RAEB): 5-

20% blasts

RA with excess blasts-I (RAEB-I) 6-

10% blasts RA with excess blasts-II

(RAEB-II) 11-20% blasts

RA with excess blasts in

transformation (RAEB-t): 21-30%

blasts

Acute myeloid leukemia

IPSS Score

Prediction of Survival

Prediction of AML

WIPSS Score

Prediction of Survival

Prediction of AML

Time dynamic risk assessment

Uses WHO diagnoses

Accounts for transfuion need

Images with Permission of L Silverman,MD

MDS Treatment

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Goals of Therapy

• PROLONG SURVIVAL

• Select Therapy best suited for the individual

• Minimize toxicity

• Improve blood counts

–Decrease transfusion

–Decrease infections

• Improve quality of life

Cheson BD, et al. Blood 2000. 96:3671-4.

http:// www.NCCN.org MDS GuidelinesImages with Permission of L Silverman,MD

Newer Approaches: Tailoring Therapy

Immunotherapy (IP): Identify Responding Subsets

Rationale:

Supportive Evidence:

Candidates:

A subset of MDS patients have a component of immune

attack contributing to their cytopenias

In four studies, 29% (34/115) response to equine ATG.

Rabbit ATG: RR 42%. 75% responders durable response

(median 31.5 months).

Poor survival in IPSS Int-2 and High categories

HLA-DR-15-positive RA (<5% blasts)

Age <60 Brief transfusion history

Trisomy 8 abnormality Normal cytogenetics

IPSS Low/Int-1 Marrow cellularity <30%

Killick GS et al. Br J Haematol 2003: 120:679.

Lim ZY et al Leukemia 2007: 21, 1436-1441

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Lenalidomide in 5q Deletion:

Phase II Study Design

Dose Reduction

5 mg qd

5 mg qod

Week: 0 4 8 12 16 20 24

Eligible

Patients

R

e

g

i

s

t

e

r

R

e

s

p

o

n

s

e

10 mg po x 21

10 mg po qd

NO Off study

YES Continue

List et al NEJM 2006; 355;14 1456-1464.

Eligibility: del(5q); IPSS low or Int-1; platelets > 50K/mm3;neutrophils > 500/mm3; transfusion dependent

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Lenalidomide: Efficacy

3.6 (2.3–6.1)4.5 wk (3.6–5.3)Median time to response

Total erythroid response 110 (74%)

10 mg qd x 21 d

(n = 45)

10 mg qd

(N = 103)

All Patients

del(5q)

52.3 wk

5.2 g/dL (1.1–11.4)

79 (77%)

9 (8%)

70 (68%)

Erythroid response (intent-to-treat analysis; n = 148)*

6 (13%)

25 (56%)TI (≥ 8 wk)

Minor (≥ 50% decrease in transfusions)

Cytogenetic response (n = 111 evaluable) 75 (68%)

Median duration of transfusion independence

Median Hgb increase

31 (69%)TI + minor

Complexity n CyResponse CcyR

5q- only 64 77% 45%

5q- plus one 15 67% 40%

5q- plus two 6 50% 50%

21

Lenalidomide:

Adverse Events (N = 148)

108 (72) Final dose (5 mg qd or qod)

Deaths on study 10 (7)

Dose modifications 118 (80)

32 (22)Discontinuation due to AEs

3 (1.4)Suspected drug-related by

investigator

(5)(31)Fatigue

(3)(49)Diarrhea

(7)(36)Rash

(2)(42)Pruritus

(53)(59)Neutropenia

(50)(62)Thrombocytopenia

≥ Grade 3, %All Grades, %All Patients del(5q)

AEs = adverse events.

Revlimid [package insert]. Celgene; 2005.

Lenalidomide (Revlimid). Briefing Document NDA 21-880. ODAC Meeting; September 14, 2005.

FDA. Lenalidomide (Revlimid). Briefing Document NDA 21-880. ODAC Meeting; August 11, 2005.

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Revlimid in non-5q MDS patients

• 214 patients with > 2 years followup• 78% Low/Int I

– 26% response to RBC TI (median 4.8 weeks)• Duration 41 weeks (8-136.4)• Median hgb rise 3.2 g/dl• 17% had 50%reduction in PRBC needs

– Overall RBC TI RR 43%

• TI occurred in non-5q without clonal suppression

• Response seen in patients >2U PRBC/mo

• “Revlimid restores erythropoietic activity to the

MDS clone”

Raza et al Blood Epub Sept 24 2007 Images with Permission of L Silverman,MD

DNA Methyltransferase Inhibitors(MTIs)

Images with Permission of L Silverman,MD

Mechanism of Action

DNMTs

Azacitidine

5-azacytidine

Decitabine

5-aza-2’-deoxycytidine

DNARNA

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

RA

ND

OM

IZE

26

Physician Choice of 1 of 3 Conventional Care Regimens

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

port

ion S

urv

ivin

g

CCRVIDAZA

Log-rank P=0.0001

HR=0.58 (95% CI: 0.43-0.77)

24.5 months

15 months

AZA-001 Trial: VIDAZA® SignificantlyImproves Overall Survival (OS)

CI=confidence interval; HR=hazard ratio; ITT=intent-to-treat. 27

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AZA-001 Trial: Survival Results

• VIDAZA® provided a significantly improved OS compared

with CCR in the ITT population (log-rank P=0.0001)

• VIDAZA median OS was 24.5 months compared with 15

months for CCR

• VIDAZA 2-year OS was 51% compared with 26% for

CCR (24.6% difference, 95% CI, 13.1-36.1)

• The relative risk of death was 0.58 (95% CI: 0.43-0.77)

indicating a 42% less risk for the VIDAZA group relative

to the CCR group

– More deaths were observed on CCR (113) compared with VIDAZA

(82)

28

AZA-001: First Occurrence of Treatment

Emergent Hematologic AEs* with VIDAZA®

29Celgene Corporation, Data on File.

Cycles 1-2 Cycles 3-4 Cycles 5-6 Cycles 7-12 Cycles 13-24

Thrombocytopenia 95 (54.3%) 8 (5.4%) 6 (4.6%) 6 (5.6%) 5 (8.9%)

Neutropenia 88 (50.3%) 16 (10.9%) 2 (1.5%) 7 (6.5%) 2 (3.6%)

Anemia 57 (32.6%) 11 (7.5%) 9 (6.9%) 8 (7.5%) 4 (7.1%)

Per

cent

*All grades

30

Decitabine Phase III MDS Trial Study

Design

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

• IPSS: Int-1, Int-2, and high-risk MDS patients eligible

• Primary end points: response, time to AML/death

– IWG response criteria utilized for assessment

Decitabine + supportive care

15 mg/m2 over 3 h q 8 h x 3 d q 6 wk

(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

Saba et al. Presented at: ASCO 2005 Annual Meeting. Abstract 6543.

31

Decitabine Phase III MDS Trial: Efficacy

*P < .001 from 2-sided Fisher’s exact test.†P = .16 by log-rank test.

Kantarjian Cancer 2006;1 106;1794-80

7.812.1 Median time to AML/death,* mo†

N/A9.5

(4.7–12.4)

Median duration of response (CR + PR)

N/A3.2

(2–5.5)

Median time to response (CR + PR), mo

713Hematologic improvement (IWG), %

08PR, %

09CR, %

017Overall response (IWG criteria), %*

Supportive Care

(n = 81)

Decitabine

(n = 89)

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Decitabine Phase III MDS Trial: Adverse

Events

Median number of courses: 3

52% received >3 courses

26% received >6 courses

04617Febrile neutropenia

27213Pneumonia

114111Anemia

16276322Thrombocytopenia

25257710Neutropenia

Grade 4Grade 3Grade 4Grade 3

Supportive Care, %

(n = 81)

Decitabine, %

(n = 83)*

What Drug, What Patient?

• Transfusion/CSF support: RARS, EPO for low serum EPO levels at dx– EPO/G if <2U PRBC/mo

• IP therapy- +8, hypoplastic, IPSS low, minimal transfusion burden

• Revlimid: 5q- cytogenetics, IPSS low/int-1, RBC response only– Best if <4 PRBC/8 weeks

• Trisenox: Low IPSS risk patients failing prior therapy- third line drug

• Dacogen: possibly as bridge for secondary AML

• Vidaza: All FAB types, including CMML, all IPSS scores, use early when intervention required

– Maintenance concept- able to use indefinitely

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Images with Permission of L Silverman,MD

Bone Marrow Transplantation

Remission Durability Requires Stem Cell Directed Therapy

Non-dividingMDS cells

Low QualityMDSStem Cell

Chemotherapy

Relapse

Stem Cell -DirectedTherapy

Remission

Approximation of Life Expectancy (Years)

2.752.753.20High

2.843.214.93Int-2

5.164.744.61Int-1

7.216.866.51Low

Transplant at Progression

Transplant in 2 Years

Immediate Transplant

From Cutler C, et al. A Decision Analysis of Allogenetic Bone Marrow Transplantation for Myelodysplastic Syndromes: Delayed

Transplantation for Low Risk Myelodysplasia is Associated with Improved Outcome. Blood 2004- 1st Ed Publication. Prepublished

online March 23, 2004; D01.1182/Blood-2004-01-0338.

Copyright American Society of Hematology, used with Permission.

To view the most recent and complete

version of the NCCN Acute Leukemia and

MDS Clinical Practice Guidelines in

Oncology (Version 2.2007), go online to

www.nccn.org.

NEW AGENTS ON THE HORIZON… NEW AGENTS ON THE HORIZON…

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NEW AGENTS ON THE HORIZON… NEW AGENTS ON THE HORIZON…