Transcript Slide 1

Emerging Therapies
in MDS: A Focus on
Epigenetics
Click to edit Master subtitle style
1
Myelodysplastic Syndrome (MDS)
Epidemiology

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10,000-15,000 estimated new cases/year in US (adults)
More common than acute myeloid leukemia (AML)
– 8,000 new cases/year in US
Predominantly a disease of the elderly
– Median age > 60
– Incidence greater in men than in women
– Incidence increases with age
Median survival 3 months to 6 years depending on risk
category
Myelodysplastic syndromes detailed guide. American Cancer Society. Available at www.cancer.org. Accessed 6/20/06.
Xie Y, et al. Cancer. 2003;97(9):2229-35; American Cancer Society, www.cancer.org; Aplastic Anemia and MDS
International Foundation, www.aamds.org; Kurzrock R. Semin Hematol. 2002;39(3 Suppl 2):18-25; Steensma DP,
Tefferi A. Leuk Res. 2003;27(2):95-120. Greenberg P, et al. Blood. 1997;89:2079-88.
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Risk Factors for MDS
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Greatest risk factor appears to be advancing age
– 80%90% of all patients with these disorders > than 60 years
Previous cancer therapy
– Mechlorethamine, procarbazine, chlorambucil, etoposide,
teniposide (with or without concomitant radiation therapy)
and other chemotherapy agents
Exposure to environmental toxins
– Benzene, organic solvents, pesticides, radiation
Tobacco smoke
Cigarette smoking
Congenital disorders
Familial disorder
Male sex
Myelodysplastic syndromes detailed guide. American Cancer Society. Available at www.cancer.org; accessed 6/20/06.
Frogge MH, et al. CE monograph published by Oncology Education Services, Inc. Pittsburgh, PA, 2005.
List AF, et al. Hematology. 2004;297-317.
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Symptoms of MDS
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Many patients have no apparent symptoms, but are diagnosed after routine
laboratory tests uncover abnormalities in the circulating blood cells
Fatigue is the most common symptom of MDS
Early symptoms of MDS may include:
– Bruising
– Increased bleeding (ie, nose and gum bleeds)
– Rash
– Shortness of breath
– Rapid heart rate
– Weight loss
– Fever
– Loss of appetite
None of these symptoms are specific to MDS, and may be attributable to other
conditions
Myelodysplastic syndromes detailed guide. American Cancer Society. Available at www.cancer.org. Accessed 6/20/06.
Frogge MH, et al. CE monograph published by Oncology Education Services, Inc, Pittsburgh, PA, 2005.
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Diagnosis of MDS
Key Features
 Evidence of ineffective hematopoiesis (anemia,
neutropenia, thrombocytopenia)
 Hypercellular marrow (rarely, hypocellular
marrow)
 Evidence of dysplasia by bone marrow
examination – typically in more than one lineage
List AF, et al. Hematology. 2004;297-317.
Myelodysplastic syndromes detailed guide. American Cancer Society. Available at www.cancer.org. Accessed 6/20/06.
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MDS Classification
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French-American-British (FAB)
World Health Organization (WHO)
International Prognostic Scoring System (IPSS)
Bennett J, et al. Br J Haematol. 1982;51:189-99.
Harris N, et al. Ann Oncol. 1999;10:1419-32.
Greenberg P, et al. Blood. 1997;89:2079-88.
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MDS FAB (French-AmericanBritish) Classification
Category
RA
(Refractory anemia)
RARS
(Refractory anemia with ringed sideroblasts)
RAEB
(Refractory anemia with excess blasts)
RAEB-T
(Refractory anemia with excess blasts in
transformation)
CMMoL
(Chronic myelomonocytic leukemia)
% Blasts
in Bone
Marrow
Survival
in
Months
< 5%
19–64
< 5%
21–76
5-20%
7–15
21-30%
5–12
1-20%
8–60+
List AF, et al. The myelodysplastic syndromes. In: Wintrobe’s Hematology 2003.
Bennett J, et al. Br J Haematol. 1982;51:189-99.
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MDS World Health Organization
(WHO) Classification
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Revised MDS classification proposed in 2000
Changes included:
– Eliminated RAEB-T
– Redefined AML as  20% blasts
– Recognize prognostic impact of multilineage
dysplasia in RA and RARS and isolated interstitial
deletion of chromosome 5q
– CMMoL = Myelodysplastic/myeloproliferative
disorder
May provide more uniform and accurate prognostic data
Steensma DP, et al. Leuk Res. 2003;27:95-120.
Harris N, Jaffe E, Diebold J, et al. Ann Oncol. 1999;10:1419-32.
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MDS International Prognostic
Scoring System (IPSS)
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The first comprehensive prognostic scoring
system adopted
Patients are stratified into four well-defined
risk groups according to survival and AML
transformation
Scoring system based on percentage of bone
marrow blasts, karyotype, and cytopenias
Greenberg P, et al. Blood. 1997:89(6):2079-88.
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MDS Subtypes IPSS
Score
Prognostic Variable
0
0.5
1.0
1.5
2.0
Bone marrow blast (%)
Karyotype*
Cytopenias
<5
Good
0/1
5-10
Intermediate
2/3
–
Poor
11-20
21-30
Prognosis Score
0
0.5-1.0
1.5-2.0
>2.5
IPSS Subgroup
Median AML
Transformation
(yrs)
Median Survival
(yrs)
Low
Intermediate-1
Intermediate-2
High
9.4
3.3
1.1
0.2
5.7
3.5
1.2
0.4
*Good: Normal, -Y, del(5q), del(20q); Poor: Complex(>3abnl) or Chr 7 abnl; Intermediate: All others.
Greenberg P, et al. Blood.1997:89(6):2079-88.
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Causes of Death in MDS
No. of Patients Who:
No. of
Patients
Died (%)
Low
235
113 (48)
22 (19)
91 (81)
Int-1
295
181 (61)
55 (30)
126 (70)
Int-2
171
147 (86)
49 (33)
98 (67)
High
58
51 (88)
23 (45)
28 (55)
Total
759
492 (65)
149 (30)
343 (70)
Subgroups
Greenberg P, et al. Blood. 1997;89:2079-2088.
Died With
Died Without
Leukemia (%) Leukemia (%)
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Goals of Therapy in MDS
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Select the therapy best suited for the individual
– Performance status, disease classification, IPSS
score (cytogenetics, cytopenias, BM blasts), and
treatment tolerance
Low/Int-1 IPSS: Improve blood counts (decrease
transfusions and infections)
Improve quality of life
Int-2/high-risk IPSS: Prolong survival and delay
leukemic progression
– Possible cure of disease
List AF, et al. Hematology (Am Soc Hematol Educ Program). 2004;297-317. Cheson BD, et al. Blood. 2000:96:3671.
NCCN Myelodysplastic Panel Members. Available at: http://www.nccn.org/professionals/physician_gls/PDF/mds.pdf
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MDS Treatments
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Best supportive care
– Transfusions (RBCs, platelets)
– Chelation therapy
– Colony-stimulating factors (EPO ± G-CSF or
GM-CSF)
Chemotherapy
Anti-thymocyte globulin (ATG) ± cyclosporin in patients with hypocellular
MDS
Stem cell transplant
– Best candidates are younger patients with low % blasts and preserved
platelet counts1
– Median age at transplant (IBMTR data) = 38 yrs old1
Hypomethylating agents
Immunomodulatory drugs
Other novel agents
– HDAC inhibitors, farnesyl transferase inhibitors etc.
1Sierra
J, et al. Blood. 2002;100:1997-2004.
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NCCN Guidelines-Low Risk
IPSS CATEGORY
Treatment
Lenalidomide
del(5q)
Epoetin alfa
(EPO)
± G-CSF
Serum Epo
≤ 500 mU/ml
HLADR-15 +
Clinically
significant
cytopenia(s)
Supportive
care
No
response
Follow appropriate pathway below
Azacitidine/
Decitabine
or
Clinical trial
No
response
Clinical
trial
No
response
Clinical
trial
No
response
ATG
or
Clinical trial
No
response
Anemia
Low,
INT-1
No
response
Serum Epo
> 500 mU/ml
HLADR-15 -
Thrombocytopenia,
neutropenia
Antithymocyte
Globulin (ATG),
Cyclosporin A
Azacitidine/
Decitabine
or
Clinical trial
Azacitidine/
Decitabine
National Comprehensive Cancer Network (NCCN) guidelines v.4.2006. For more information see: http://www.nccn.org. 14
NCCN Guidelines-High Risk
Treatment
IPSS CATEGORY
Yes
Intensive
therapy
Candidate*
Hemopoietic stem cell
transplant (HSCT)
Donor
available
No
INT-2,
HIGH
Not intensive
therapy candidate
*Based
on age, performance status and absence of major comorbid
medical conditions that would preclude high dose therapy.
National Comprehensive Cancer Network (NCCN) guidelines v.4.2006.
High intensity therapyr
or
Supportive care
Azacitidine/Decitabine
or
Clinical trial
or
Supportive care
High-Intensity Therapy:
• Clinical Trials (preferred)
• Investigational therapy preferred.
• Standard induction therapy if investigational
protocol unavailable or as a bridge to HSCT.
(See text for more detail)
• Hemopoietic stem cell transplant (HSCT)
• allogeneic-matched sibling including standard
and (experimental) reduced intensity preparative
approaches or matched unrelated donor (MUD)
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Overview of
Epigenetics and Its
Role in MDS
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Cytosine DNA Methylation
NH2
NH2
CH3
H
N
N
O
O
N
N
H
H
5-MethylCytosine
MTASE
Cytosine
SAM
SAH
SAM = S-adenosyl methionine; SAH = S-adenosyl homocysteine. www.mdanderson.org/leukemia/methylation.
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Hypermethylation and Silencing
M
M
M
Expressed (or ready for expression)
M M MMM M M M
M
Silenced
Imprinted genes, Inactive X
Ectopically Silenced Genes (e.g. tumor suppressor genes)
Courtesy of Issa, JP
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Tumor Suppressor Gene
Methylation
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p15INK4b
– Inhibitor of the cyclin-dependent kinases
CDK4 and CDK6
– Plays a role in transforming growth factor (TGF-)-mediated growth inhibition
– Inactivated by hypermethylation in
hematopoietic neoplasms (AML, ALL, MDS,
and Burkitt’s lymphoma)
Quesnel, et al. Blood. 1998;91:2985.
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Association Between Survival and
p15 Methylation Status in MDS
100
p survival
80
60
Unmethylated
40
Methylated
20
P = .049
0
0
20
40
60
80
100
120
140
t (months)
Quesnel B, et al. Blood. 1998;91:2985-90.
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Hypomethylating
Agents
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Hypomethylating Cytosine
Analogs
NH2
NH2
NH2
NH2
CH3
N
N
Cytosine
N
O
N
N
N
O
5-methyl-cytosine
N
N
N
O
N
O
Ribose
Deoxyribose
5-aza-cytidine
5-aza-2′-deoxycytidine
(azacitidine)
(decitabine)
Santini V, et al. Ann Intern Med. 2001;134(7):573-86.
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How Hypomethylating Agents Work
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Act as cytosine nucleoside analogs that reverse
aberrant DNA methylation
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Incorporate into DNA and trap DNAmethyltransferase, depleting cells of DNAmethyltransferase
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Decitabine contains deoxyribose and is incorporated
into DNA while azacitidine, which contains ribose, is
incorporated into both RNA and DNA
– 10-20% azacitidine incorporation into DNA
Leone G, et al. Haematologica. 2002;87:1324-41; Kuykendall JR. The Annals of Pharmacotherapy.2005;39:1700-1709.
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Mechanism of Epigenetic Therapy
Fully methylated DNA
CH3
CH3 CH3
CH3
CH3
CH3
STOP
CH3
STOP
CH3
CH3 CH3
CH3 CH3
DNA
replication
CH3
CH3
CH3
CH3
CH3
Silencing
CH3
CH3
CH3
Maintained
Silencing
Mtase
Epigenetic
Therapy
CH3
CH3
CH3
Fully methylated DNA
Unmethylated DNA
CH3
Hemi-methylated DNA
Reactivated Gene
Expression
Differentiation - Apoptosis - Senescence - Enhanced Immune Response
Courtesy of Issa JP.
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Phase 3 Clinical
Experience with
Decitabine in Advanced
MDS
25
Decitabine Phase 3
Study Design (D-0007)
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Open-label, 1:1 randomized, multicenter study in US and CA
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Schedule: 3-hour infusion of 15 mg/m2 q 8 hrs x 3 days
Eligible
Patients
(n = 170)
R
A
N
D
O
M
I
Z
E
D
Decitabine + Supportive Care*
(n = 89)
Stratification
• IPSS classification
• Prior chemotherapy
• Study center
*Antibiotics, growth factors, and/or transfusions.
Kantarjian , et al. Cancer. 2006;106:1794-1803.
Supportive Care*
(n = 81)
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Decitabine Phase 3
Patient Eligibility and Study Design
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Patient population
– de novo or secondary MDS
– IPSS  0.5; all FAB subgroups
Primary endpoints
– Overall response rate (CR + PR), IWG criteria
– Time to AML transformation or death
 In the primary endpoint analysis, a P value less than .024
was required to achieve statistical significance
Secondary endpoints
– Duration of response, cytogenetic response rate, transfusion
requirements, QOL, survival, febrile neutropenia, toxicity
Kantarjian HM, et al. Cancer. 2006;106:1794-1803.
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Decitabine Phase 3
IWG Response Criteria
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Independent review of bone marrow and best response
Complete response (CR)
– <5% blasts in bone marrow
– Hgb  11, ANC  1500, platelets > 100,000, no blasts
– No dysplasia
– No transfusions or growth factors
– Minimum duration 8 weeks
Partial response (PR)
– 50% decrease in marrow blasts
– Other response criteria same as CR
IWG = international working group; Hgb = hemoglobin; ANC = absolute neutrophil count.
Kantarjian HM, et al. Cancer. 2006;106:1794-1803.
Cheson BD. Blood. 2000;96:3671-74.
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Decitabine Phase 3
Demographics (ITT Population)
Parameters
Decitabine
n = 89 (%)
Supportive Care
n = 81 (%)
Sex (male)
59 (66)
57 (70)
Median Age
70
70
Median Time From Diagnosis (months)
7.3
8.8
Type of MDS
De novo
Secondary
77 (87)
12 (13)
70 (86)
11 (14)
Previous MDS Therapy
20 (22)
16 (20)
IPSS
High risk
Intermediate-2
Intermediate-1
23 (26)
38 (43)
28 (31)
21 (26)
36 (44)
24 (30)
ITT = intent to treat.
Kantarjian HM, et al. Cancer. 2006;106:1794-1803.
29
Decitabine Phase 3
Response to Decitabine (ITT)
IWG Response Rate,
Onset, and Duration*
Decitabine
(n = 89)
Supportive Care
(n = 81)
15 (17%)†
0 (0%)
Complete response (CR)
8 (9%)
0 (0%)
Partial response (PR)
7 (8%)
0 (0%)
12 (13%)
6 (7%)
Overall Response Rate (CR+PR)
Hematologic improvement (HI)
†P
value < .001 from two-sided Fisher’s exact test
Onset and Duration of Response (Months)
Median time to response (CR+PR)
Median duration of response (CR+PR)
3.3 (2.0 – 9.7)
N/A
10.3 (4.1 - 13.9)‡
Best response observed after 2 cycles (median number of cycles = 3)
*Cheson BD. Blood. 2000 96:3671-74.
Kantarjian HM, et al. Cancer. 2006;106:1794-1803.
‡For patients with a confirmed date of progression.
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Response in Patients
with AML at Baseline
Decitabine
n = 9 (%)
5 (56)
Supportive
Care
n = 3 (%)
0 (0)
Complete
Response†
3 (33)
0 (0)
Partial Response
2 (22)
0 (0)
Overall
Response*
*IWG AML Response Criteria. †One patient was a CRi (morphologic complete remission with
incomplete blood count recovery). Cheson et al. J Clin Oncol. 2003;21:4642-49;
Kantarjian HM, et al. Cancer. 2006;106:1794-1803; Data on File, MGI PHARMA.
31
Decitabine Phase 3
Median Time to AML or Death
Decitabine
Months (range)
Supportive Care
Months (range)
Log-rank
P Value
All Patients
12.1 (0.3*-22.3)
n = 89
7.8 (0.3-21.0*)
n = 81
.160
Treatment
Naive
12.3 (0.3*-20.1*)
n = 69
7.3 (0.3-21.0*)
n = 65
.082
Int-2/
High Risk
12.0 (0.4*-22.3)
n = 61
6.8 (0.3-21.0*)
n = 57
.028
High Risk
9.3 (0.4*-19.9)
n = 23
2.8 (0.3-13.5)
n = 21
.010
MDS Group
*Censored data.
Kantarjian HM, et al. Cancer. 2006;106:1794-1803; Data on File, MGI PHARMA.
32
Decitabine Phase 3
Survival by Response
100
90
P = .007
Percent Alive
80
70
60
50
40
30
20
Analyzed population = All patients
Nonresponders (N=155)
10
Responders (N=15)
0
0
50
100 150 200 250 300 350 400 450 500 550 600 650 700 750 800
Days
Kantarjian HM, et al. Cancer. 2006;106:1794-1803.
33
Decitabine Phase 3
Cytogenetic Evaluations
Decitabine
n = 26 (%)
Supportive
Care
n = 21 (%)
Major Response
9* (35)
2 (10)
Minor Response
1 (4)
–
Patients Evaluable for
Cytogenetic Evaluations
Cytogenetic responses
*1 additional patient who was randomized to supportive care crossed over to decitabine and
had a major cytogenetic response and clinical CR.
Kantarjian HM, et al. Cancer. 2006;106:1794-1803.
34
Decitabine Phase 3: Percent of Patients
RBC Transfusion-Free Per Cycle
Decitabine
Supportive Care
100
% of Patients RBC
Transfusion-Free
90
80
70
60
50
40
30
20
10
0
0
Decitabine N=
89
Supportive Care N= 81
1
2
3
4
5
6
83
75
64
63
44
40
37
28
26
23
23
15
Note: Last cycles less than 35 days long with 0 transfusions are not considered in this analysis.
Kantarjian HM, et al. Cancer. 2006;106:1794-1803.
35
Quality of Life Measure
Percent Change from Baseline for
Global Health Status
45
* P < .05
% Change From Baseline
35
Decitabine
Supportive Care
*
*
25
15
5
-5
-15
-25
Cycle 1
Cycle 2
Cycle 3
Kantarjian HM, et al. Cancer. 2006;106:1794-1803.
Cycle 4
Cycle 5
Cycle 6
36
Decitabine Phase 3
Adverse Events (>10% Incidence)
Decitabine
(n = 83)*
Grade 3
Grade 4
Supportive Care
(n = 81)
Grade 3
Grade 4
Hematologic
Neutropenia
10%
77%
25%
25%
Thrombocytopenia
22%
63%
27%
16%
Anemia
11%
1%
14%
1%
Febrile neutropenia
17%
6%
4%
0%
13%
2%
7%
2%
Nonhematologic
Pneumonia
*Exposed to decitabine.
Kantarjian et al. Cancer. 2006;106:1794-1803.
37
Decitabine Phase 3
Summary and Conclusions

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

Decitabine therapy was superior to supportive care
– Response rate 17% (CR 9%, PR 8%)
– Durable responses (median 10.3 months)
– Responders remained or became transfusion
independent and symptoms improved
Delayed time to AML progression or death
Responders had longer survival
– 24 months responders vs 14 months in nonresponders (P = .007)
Well tolerated with manageable toxicity profile
Kantarjian et al. Cancer. 2006;106:1794-1803.
38
Decitabine Exposure in
Phase 2 and 3 Studies
Phase 2
Phase 3
91-01
95-11
97-19
D-0007
29
66
87
89
ORR (CR + PR)
13 (45%)
17 (26%)
23 (26%)
15 (17%)
CR
8 (28%)
14 (21%)
19 (22%)
8 (9%)
PR
5 (17%)
3 (5%)
4 (5%)
7 (8%)
4
4
4
3
N
Median # cycles
Multiple cycles of decitabine therapy may be
required for optimal response
Saba HI, et al. Blood . 2005;106:706a [abstract 2515]. Kantarjian HM, et al. Cancer. 2006;106:1794-1803. Saba HI, et al. Semin
Hematol. 2005;42(3 suppl 2): S23-S31. Wijermans PW, et al. Leukemia. 1997;11:1-5. Wijermans PW, et al. J Clin Oncol.
2000;18:956-962.
39
Alternative Dosing
with Decitabine
40
Decitabine Reduced-Dose Schedule
(100 mg/m2/course): 3-Arm Dosing Study





3 decitabine treatment arms:
– 10 mg/m2 IV over 1 hr daily x 10 days
– 20 mg/m2 IV over 1 hr daily x 5 days
– 20 mg/m2 SQ (10 mg SQ BID) daily x 5 days
Preferential randomization to arm with higher CR started after 45th
patient
Courses were given every 4 weeks
Total = 100 mg/m2/course (75% of phase 3 MDS trial dose)
Study group
– 95 patients treated (77 MDS, 18 CMML)
– 65% patients Int-2/High Risk
– 69% male, 65% were  60 yrs of age
SQ = subcutaneous; CR = complete response.
Kantarjian H, et al. Blood. 2006;108(in press). First Edition Paper, prepublished online Aug 1, 2006;
DOI 10.1182/blood-2006-05-021162.
41
3-Arm Dosing Study:
Overall Response
Response
Complete Response (CR)
Partial Response (PR)
n = 95 (%)
32 (34)
1 (1)
Marrow CR
10 (11)
Marrow CR + other HI
13 (14)
Hematologic Improvement (HI)
Single lineage
13 (14)
9 (9)
2 or 3 lineage
4 (4)
Objective Response
69 (72%)
Kantarjian H, et al. Blood. 2006;108(in press). First Edition Paper, prepublished online Aug 1, 2006; DOI 10.1182/blood2006-05-021162.
42
Comparison of outcome and side
effects by dose schedule
Parameter
5 Day IV
5 Day SQ
10 Day IV
64
14
17
25 (39)
3 (21)
4 (24)
5
8
9
Median duration of therapy in
mos (range)
5.4 (1.0 – 20.4+)
9.7 (0.5 – 22.9+)
10.8 (1.9 – 17.7+)
Median days to granulocytes
recovery*
24
14
27
Median days to platelet
recovery†
20
31
27
Median days to delivery of
subsequent courses
35
35
40
50 (12)
14 (14)
23 (23)
n
CR / treated (%)
Median no. courses
No. courses requiring
hospitalization (%)
*To 109/L or above; †To 50 x 109/L or above; Kantarjian H, et al. Blood. 2006;108(in press). First Edition Paper,
prepublished online Aug 1, 2006; DOI 10.1182/blood-2006-05-021162.
43
3-Arm Dosing Study Data
Summary





Low-dose schedules of decitabine have significant activity
– 34% complete response rate* and a 73% objective response
rate† across all 3 arms
The optimal dose was 20 mg/m2 IV x 5 days (CR = 39%)
Primary toxicity across all arms was myelosuppression
– Lower frequency vs. higher dose regimen
The dose of 10 mg/m2 IV x 10 days was associated with higher
incidence of myelosuppression and hospitalization
A dose schedule of 20 mg/m2 IV x 5 days represents an excellent
therapeutic option and offers an alternative dosing schedule
*Response
criteria for CR and PR were as for AML but required response durability for at least 4 weeks (PR also
requiring that blasts decrease by >50%). †CR + PR + marrow CR + HI.
Kantarjian H, et al. Blood. 2006;108(in press). First Edition Paper, prepublished online Aug 1, 2006; DOI
10.1182/blood-2006-05-021162.
44
Phase 3 Clinical
Experience with
Azacitidine in MDS
45
Azacitidine Phase 3
Study Design (CALGB 9221)


Randomized, crossover trial
Schedule: 75 mg/m2/day SQ x 7 days q 28 days
Eligible
Patients
(n = 191)
R
A
N
D
O
M
I
Z
E
D
Supportive Care
(n = 92)
Azacitidine
+ Supportive
Care
(n = 99)
A
S
S
E
S
S
CR: 3 Cycles
HI: Continue
NR: Off study
SC: Pts worsening
azacitidine
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
46
Azacitidine Phase 3
Patient Eligibility and Study Design


Patient population
– FAB classification for MDS
– Symptomatic cytopenia requiring active therapy
– Cancer-free for 3 years with no radiation or
chemotherapy for 6 previous months
Endpoints
– Analysis of response (CR, PR, improved)
– Time to treatment failure
– Effects on RBC and platelets
– Quality of life
– Overall survival
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
47
Azacitidine Phase 3
Response Criteria



Complete response (CR)
– Normal bone marrow or < 5% blasts in the bone marrow
– Normal peripheral blood counts
– No blasts
– No transfusions
Partial response (PR)
– ≤ 50% initial bone marrow blasts
– Trilineage response
– No blasts
– No transfusions
Improved
– Monolineage or bilineage response
– Transfusions ≤ 50% of baseline
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
48
Azacitidine Phase 3
Demographics (ITT Population)
Parameters
Azacitidine
n = 99 (%)
Supportive Care
n = 92 (%)
Sex (male)
72 (73)
60 (65)
Median Age
69
67
Median Time From Diagnosis (days)
77
87
Previous MDS therapy
16 (16)
17 (18)
FAB
RA
RARS
RAEB
RAEB-T
CMMoL
Other*
17 (17)
5 (5)
32 (32)
27 (27)
7 (7)
11 (11)
20 (22)
3 (3)
34 (37)
18 (20)
7 (8)
10 (11)
*Includes 19 AML, one classifiable acute leukemia, and one undefined MDS.
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
49
Azacitidine Phase 3
Response Rates
Overall Response (CR + PR)
Complete response
Partial response
Hematologic improvement
Azacitidine
(n = 99)
Supportive
Care
(n = 92)
16 (16.2%)*
0%
6 (6.1%)
0%
10 (10.1%)
0%
19 (19%)
6%
*P < .0001 (CR + PR)
Median Duration of Response
(CR + PR + improved) (months)
†95%
15†
N/A
CI, 11 to 20 months
Kaminskas E. Clin Cancer Res. 2005;11:3604-8. Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
50
Azacitidine Phase 3
Duration of Response
Probability of
Continuing in Remission
1.0
Azacitidine
Supportive Care
0.8
0.6
0.4
0.2
0.0
0
6
12
18
24
30
36
42
Months
Number of Patients at Risk
Azacitidine
60
51
34
25
15
8
2
1
Observation
1
1
1
0
0
0
5
1
Median duration of response (CR + PR + improved) = 15 months
(95% CI, 11- 20 months)
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
51
Azacitidine Phase 3
Time to AML Transformation or Death
Probability of
Remaining Event-Free
1.0
Azacitidine
Supportive Care
0.8
P = .007
0.6
0.4
0.2
0.0
0
6
12
18
24
30
36
42
48
54
Months
Number of Patients at Risk
Azacitidine
89
69
55
39
28
16
9
2
0
0
Observation
38
22
15
10
8
3
1
1
82
51
Median time to AML or death: azacitidine – 21 months (95% CI, 16-27
months) and supportive care – 12 months (95% CI, 8-15 months)
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
52
Azacitidine Phase 3
Effects on RBC and Platelets


RBC transfusions decreased over the course of
the study with azacitidine treatment –
transfusions remained stable or increased on
supportive care
Patients treated with azacitidine:
– 51% had an RBC lineage response
– 47% had a platelet lineage response
– 41% had a WBC lineage response
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
53
Azacitidine Phase 3
Quality of Life


Azacitidine patients had significantly greater
improvement over time in: fatigue (P = .001),
physical functioning (P = .002), dyspnea (P = .0014),
psychosocial distress (P = .015), and positive affect
(P = .0077)
Patients on supportive care experienced declining
QOL, but significant improvements were noted in
fatigue (P = .0001), physical functioning (P = .004),
dyspnea (P = .0002), and general well-being (P =
.016) after crossover to azacitidine treatment
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
54
Azacitidine Phase 3
Overall Survival
Probability of Survival
1.0
P = .10
Azacitidine
Supportive Care
0.8
0.6
0.4
0.2
0.0
0
6
12
18
24
30
36
42
48
54
Months
Number of Patients at Risk
Azacitidine
99
82
71
52
42
30
21
11
2
0
Observation
92
73
58
38
25
19
12
6
2
1
Median survival: azacitidine – 20 months (95% CI, 16-26 months) and supportive
care – 14 months (95% CI, 12-14 months)
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
55
Azacitidine Phase 3
Adverse Events

For azacitidine patients, the most common
treatment-related toxicity was myelosuppression
– Grade 3 or 4 leukopenia = 43%
– Grade 3 or 4 granulocytopenia = 58%
– Grade 3 or 4 thrombocytopenia = 52%

Toxicity was transient – recovery by the next
treatment cycle
Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
56
Azacitidine Phase 3
Summary and Conclusions




Responses occurred in 35% of patients treated with
azacitidine (6% CR, 10% PR, 19% improved) compared
with 5% (improved) of supportive care patients
Median time to AML or death was significantly
increased with azacitidine treatment (21 months
compared with 13 months for supportive care)
Survival increased with azacitidine treatment (20
months compared with 14 months for supportive care)
Significant improvements in QOL criteria were noted
Kaminskas E. Clin Cancer Res. 2005;11:3604-8; Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.
57
Comparison of Decitabine/D-0007 and
Azacitidine/9221 Phase 3 Trials
Parameters
Crossover
Response Criteria
% of IPSS Int-2/High
% of prior therapy
Median duration of MDS (months)
Median number of treatment cycles
Response Rates
Decitabine
D-00071
Azacitidine
CALGB 92212,3
< 5%
IWG4
53%
CALGB
69
22
7.3
3
NA
16
2.8
9
CR + PR = 15 (16.9%)
CR = 8 (9.0%)
PR = 7 (7.8%)
CR + PR = 14 (16.2%)
CR = 6 (6.1%)
PR = 10 (10.1%)
Differences in study design make it difficult to compare efficacy
1Kantarjian
et al. Cancer. 2006;106:1794-1803.; 2Silverman LR, et al. J Clin Oncol. 2002;20:2429-40; 3Kaminskas E.
Clin Cancer Res. 2005;11:3604-8; 4Cheson BD. Blood. 2000;96:3671-74. NA = Not available.
58
Alternative Dosing
with Azacitidine
59
Azacitidine Alternative Dosing Schedules
3-Arm Dosing Study





Phase 2, multicenter, randomized, open-label trial
Objective: treatment response in schedules that do not
require weekend injections
3 azacitidine treatment arms:
– 75 mg/m2/day x 5 days, followed by 2 days of no
treatment, followed by 75 mg/m2/day x 2 days
– 50 mg/m2/day x 5 days, followed by 2 days of no
treatment, followed by 50 mg/m2/day x 5 days
– 75 mg/m2/day x 5 days
Eligible patients must have a life expectancy of  7 months
and ECOG grade of 0-3
FAB classification of RA, RARS, RAEB, RAEB-T, CMML
Anthony S, et al. J Clin Oncol. 2006;24(abstr 6574).
60
3-Arm Dosing Study Data
Summary of Preliminary Results




75 patients were randomized at the time of presentation;
49 were evaluable
61% male, median age 74.5 yrs
RA and RARS were the most common subtypes
Of 24 patients RBC transfusion dependent at baseline,
13 (54%) became independent
– AZA 5-2-2: 8/14 (57%)
– AZA 5-2-5: 3/5 (60%)
– AZA 5: 2/5 (40%)

2 patients were platelet transfusion dependent at
baseline; both became independent
Anthony S, et al. J Clin Oncol. 2006;24(abstr 6574).
61
Considerations
When Using
Hypomethylating
Agents
62
Azacitidine for Injectable
Suspension



Indications
– For treatment of the following MDS subtypes: RA, RARS,*
RAEB, RAEB-T, and CMMoL
Preparation
– Cytotoxic drug, caution should be used in handling
Stability
– Reconstituted azacitidine may be stored for up
to 1 hour at 25C or up to 8 hours between 2 and 8C
*If accompanied by neutropenia or thrombocytopenia or requiring transfusions.
Vidaza [package Insert]. Boulder, CO: Pharmion Company; 2004.
63
Decitabine for Injection



Indications
– Previously treated and untreated, de novo and secondary MDS of all FrenchAmerican-British subtypes (RA, RARS, RAEB, RAEB-T, and CMMoL) and Int-1,
Int-2, and high-risk IPSS groups
Preparation
– Cytotoxic drug, caution should be used in handling
– Aseptically reconstituted with 10 mL of Sterile Water for Injection (USP);
immediately after reconstitution, the solution should be further diluted with
0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer’s
injection to a final drug concentration of 0.1 – 1.0 mg/mL
Stability
– Unless used within 15 minutes of reconstitution, the diluted solution must be
prepared using cold (2°C - 8°C) infusion fluids and stored at 2°C - 8°C (36°F 46°F) for up to 7 hours
DacogenTM [package insert]. Bloomington, Minn; MGI Pharma; 2006.
64
Safety Considerations of
Decitabine and Azacitidine

Most commonly occurring adverse reactions:
–
–
–
–
–
–
–



Nausea
Anemia
Thrombocytopenia
Vomiting
Pyrexia
Leukopenia
Diarrhea
–
–
–
–
–
–
–
–
Fatigue
Injection site erythema
Constipation
Neutropenia
Ecchymosis
Cough
Petechiae
Hyperglycemia
Patients should be premedicated for nausea and vomiting
Blood and platelet counts should be performed at a minimum before each
dosing cycle; dose adjustment or delay should be made based on
hematology laboratory values
Consider need for early institution of growth factors and/or antimicrobial
agents
VidazaTM [package Insert]. Boulder, CO: Pharmion Company; 2004. DacogenTM [package insert].
Bloomington, Minn; MGI Pharma; 2006. Kantarjian HM, et al. Cancer. 2006;106:1794-1803.
65
Future Directions for
Hypomethylating Agents



Other hematologic malignancies: AML, CML
Solid tumors
Further studies
– Alternative dose schedules
– Mechanisms and targets
– Decitabine combinations with:
 Histone deacetylase inhibitors
 Colony-stimulating factors
 Immunomodulators
66
Other Emerging
Therapies in MDS:
Lenalidomide
67
Lenalidomide Overview





An immunomodulatory drug derived from thalidomide
Encouraging data have been presented in lower risk MDS patients
Recently approved by FDA for treatment of MDS patients with
del(5q)
Careful monitoring of the patients’ blood counts during the
treatment period is necessary, particularly in patients with renal
dysfunction
Further studies are required to determine the efficacy of this drug
and other agents for non-del(5q) MDS patients
68
Phase 2 Trial of Lenalidomide


Study design
– Multicenter phase 2 trial
– Lenalidomide administered 10 mg/day for 21 days or 10 mg/day
– 148 anemic RBC transfusion-dependent MDS patients with del(5q),
with or without additional cytogenetic abnormalities
Results
– RBC TI at 24 weeks in 67% of patients in an ITT analysis
– Median TI duration not reached after 104 weeks’ median follow-up
– Cytogenetic responses in 73% of patients; 45% complete
cytogenetic response
– Common adverse events (in ~50% of patients) required treatment
interruption or dose reduction for potentially serious but generally
transient neutropenia and/or thrombocytopenia
TI = transfusion independence; ITT = intention-to-treat
List AF, et al. Proc ASCO. 2005;23[suppl 16S]:2S [abstract 5].
69
Summary


Hypomethylating agents:
– Provide a new and exciting treatment option for an underserved
MDS population
– Offer encouraging response rates, transfusion-independence
(TI), and delayed time to AML or death compared with
supportive care
– Are well tolerated with manageable adverse events
– Can be considered the treatment of choice for Int-2/high-risk
patients who are not transplant candidates
– Future directions for hypomethylating agents include
alternative dosing regimens that may help to optimize response
Lenalidomide is effective in lower-risk patients with del(5q),
inducing TI and cytogenetic responses in a high proportion of
patients
70
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and Post Test Exam
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
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here:
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

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71