Emerging Therapies in MDS: A Focus on Epigenetics

1
Emerging Therapies in MDS A Focus on Epigenetics

• Click to edit Master subtitle style

2
Myelodysplastic Syndrome (MDS) Epidemiology

• 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 gt 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. 200397(9)2229-35 American Cancer
Society, www.cancer.org Aplastic Anemia and MDS
International Foundation, www.aamds.org
Kurzrock R. Semin Hematol. 200239(3 Suppl
2)18-25 Steensma DP, Tefferi A. Leuk Res.
200327(2)95-120. Greenberg P, et al. Blood.
1997892079-88.
3
Risk Factors for MDS

• Greatest risk factor appears to be advancing age
• 80?90 of all patients with these disorders gt
  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. 2004297-317.
4
Symptoms of MDS

• 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.
5
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. 2004297-317. Myelodys
plastic syndromes detailed guide. American Cancer
Society. Available at www.cancer.org. Accessed
6/20/06.
6
MDS Classification

• French-American-British (FAB)
• World Health Organization (WHO)
• International Prognostic Scoring System (IPSS)

Bennett J, et al. Br J Haematol.
198251189-99. Harris N, et al. Ann Oncol.
1999101419-32. Greenberg P, et al. Blood.
1997892079-88.
7
MDS FAB (French-American- British) Classification
Category
Blasts in Bone Marrow
Survival in Months
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)
lt 5 lt 5 5-20 21-30 1-20
1964 2176 715 512 860
List AF, et al. The myelodysplastic syndromes.
In Wintrobes Hematology 2003. Bennett J, et al.
Br J Haematol. 198251189-99.
8
MDS World Health Organization (WHO) Classification

• 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. 20032795-120. Harr
is N, Jaffe E, Diebold J, et al. Ann Oncol.
1999101419-32.
9
MDS International Prognostic Scoring System (IPSS)

• 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. 199789(6)2079-88.
10
MDS Subtypes IPSS
Score
Prognostic Variable
0
0.5
1.0
1.5
2.0
Bone marrow blast () Karyotype Cytopenias
lt 5 Good 0/1
5-10 Intermediate 2/3
Poor
11-20
21-30
Prognosis Score IPSS Subgroup Median AML Transformation (yrs) Median Survival (yrs)
0 0.5-1.0 1.5-2.0 gt2.5 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(gt3abnl) or Chr 7 abnl Intermediate All
others.
Greenberg P, et al. Blood.199789(6)2079-88.
11
Causes of Death in MDS
No. of Patients Who
Subgroups
No. of Patients
Died ()
Died With Leukemia ()
Died Without Leukemia ()
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)
Greenberg P, et al. Blood. 1997892079-2088.
12
Goals of Therapy in MDS

• 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). 2004297-317. Cheson BD, et al. Blood.
2000963671. NCCN Myelodysplastic Panel
Members. Available at http//www.nccn.org/profess
ionals/physician_gls/PDF/mds.pdf
13
MDS Treatments

• 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. 20021001997-2004.
14
NCCN Guidelines-Low Risk
IPSS CATEGORY
Treatment
No response
del(5q)
Lenalidomide
Follow appropriate pathway below
Azacitidine/ Decitabine or Clinical trial
Epoetin alfa (EPO) G-CSF
No response
Clinical trial
Serum Epo 500 mU/ml
No response
No response
Anemia
Antithymocyte Globulin (ATG), Cyclosporin A
HLADR-15
Serum Epo gt 500 mU/ml
Clinically significant cytopenia(s)
Low, INT-1
Supportive care
Azacitidine/ Decitabine or Clinical trial
No response
Clinical trial
HLADR-15 -
ATG or Clinical trial
No response
Thrombocytopenia, neutropenia
Azacitidine/ Decitabine
National Comprehensive Cancer Network (NCCN)
guidelines v.4.2006. For more information see
http//www.nccn.org.
15
NCCN Guidelines-High Risk
Treatment
IPSS CATEGORY
Hemopoietic stem cell transplant (HSCT)
Yes
Intensive therapy Candidate
Donor available
High intensity therapyr or Supportive care
No
INT-2, HIGH
Azacitidine/Decitabine or Clinical
trial or Supportive care
Not intensive therapy candidate

• High-Intensity Therapy
• Clinical Trials (preferred)
• Investigational therapy preferred.
• Standard induction therapy if investigationalprot
  ocol unavailable or as a bridge to HSCT.(See
  text for more detail)
• Hemopoietic stem cell transplant (HSCT)
• allogeneic-matched sibling including standardand
  (experimental) reduced intensity
  preparativeapproaches or matched unrelated donor
  (MUD)

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.
16
Overview of Epigenetics and Its Role in MDS
17
Cytosine DNA Methylation
5-Methyl- Cytosine
MTASE
Cytosine
SAM
SAH
SAM S-adenosyl methionine SAH S-adenosyl
homocysteine. www.mdanderson.org/leukemia/methylat
ion.
18
Hypermethylation and Silencing
M
M
M
Expressed (or ready for expression)
M
M
M
M
M
M
M
M
M
Silenced Imprinted genes, Inactive X Ectopically
Silenced Genes (e.g. tumor suppressor genes)
Courtesy of Issa, JP
19
Tumor Suppressor Gene Methylation

• 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 Burkitts lymphoma)

Quesnel, et al. Blood. 1998912985.
20
Association Between Survival and p15 Methylation
Status in MDS
Unmethylated
Methylated
P .049
Quesnel B, et al. Blood. 1998912985-90.
21
Hypomethylating Agents
22
Hypomethylating Cytosine Analogs
NH2
NH2
NH2
NH2
CH3
N
N
N
N
N
N
O
O
O
O
N
N
N
N
Ribose
Deoxyribose
5-aza-cytidine
5-aza-2'-deoxycytidine
5-methyl-cytosine
Cytosine
(decitabine)
(azacitidine)
Santini V, et al. Ann Intern Med.
2001134(7)573-86.
23
How Hypomethylating Agents Work

• Act as cytosine nucleoside analogs that reverse
  aberrant DNA methylation
• Incorporate into DNA and trap DNA-methyltransferas
  e, depleting cells of DNA-methyltransferase
• 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. 2002871324-41
Kuykendall JR. The Annals of Pharmacotherapy.2005
391700-1709.
24
Mechanism of Epigenetic Therapy
CH3
Fully methylated DNA
CH3
CH3
CH3
STOP
STOP
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Silencing
Maintained Silencing
CH3
CH3
CH3
CH3
CH3
CH3
DNAreplication
Fully methylated DNA
Mtase
CH3
Epigenetic Therapy
CH3
Unmethylated DNA
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Reactivated GeneExpression
CH3
CH3
Hemi-methylated DNA
Differentiation - Apoptosis - Senescence -
Enhanced Immune Response
Courtesy of Issa JP.
25
Phase 3 Clinical Experience with Decitabine in
Advanced MDS
26
Decitabine Phase 3 Study Design (D-0007)

• Open-label, 11 randomized, multicenter study in
  US and CA
• Schedule 3-hour infusion of 15 mg/m2 q 8 hrs x 3
  days

RANDOMIZED
Decitabine Supportive Care (n 89)

• Stratification
• IPSS classification
• Prior chemotherapy
• Study center

Eligible Patients (n 170)
Supportive Care(n 81)
Antibiotics, growth factors, and/or transfusions.
Kantarjian , et al. Cancer. 20061061794-1803.
27
Decitabine Phase 3Patient Eligibility and Study
Design

• 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. 20061061794-1803.
28
Decitabine Phase 3 IWG Response Criteria

• Independent review of bone marrow and best
  response
• Complete response (CR)
• lt5 blasts in bone marrow
• Hgb ? 11, ANC ? 1500, platelets gt 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.
20061061794-1803.Cheson BD. Blood.
2000963671-74.
29
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. 20061061794-1803.
30
Decitabine Phase 3 Response to Decitabine (ITT)
IWG Response Rate,Onset, and Duration
Decitabine (n 89)
Supportive Care(n 81)
Overall Response Rate (CRPR) Complete response
(CR) Partial response (PR) Hematologic
improvement (HI)
15 (17)8 (9)7 (8)12 (13)
0 (0)0 (0)0 (0)6 (7)
P value lt .001 from two-sided Fishers exact test
Onset and Duration of Response (Months) Median
time to response (CRPR) Median duration of
response (CRPR)
3.3 (2.0 9.7)10.3 (4.1 - 13.9)
N/A
Best response observed after 2 cycles (median
number of cycles 3)
Cheson BD. Blood. 2000 963671-74. Kantarjian
HM, et al. Cancer. 20061061794-1803.For
patients with a confirmed date of progression.
31
Response in Patients with AML at Baseline
Decitabine n 9 ()
Supportive Care n 3 ()
Overall Response
5 (56)
0 (0)
3 (33)
Complete Response
0 (0)
2 (22)
Partial Response
0 (0)
IWG AML Response Criteria. One patient was a
CRi (morphologic complete remission with
incomplete blood count recovery). Cheson et al.
J Clin Oncol. 2003214642-49 Kantarjian HM, et
al. Cancer. 20061061794-1803 Data on File, MGI
PHARMA.
32
Decitabine Phase 3 Median Time to AML or Death
MDS Group
DecitabineMonths (range)
Supportive Care Months (range)
Log-rankP 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
Censored data. Kantarjian HM, et al. Cancer.
20061061794-1803 Data on File, MGI PHARMA.
33
Decitabine Phase 3 Survival by Response
100
P .007
90
80
70
60
Percent Alive
50
40
30
Analyzed population All patients
20
Nonresponders (N155)
10
Responders (N15)
0
Days
Kantarjian HM, et al. Cancer. 20061061794-1803.
34
Decitabine Phase 3 Cytogenetic Evaluations
Patients Evaluable for Cytogenetic Evaluations
Decitabinen 26 ()
Supportive Caren 21 ()
Cytogenetic responses Major Response Minor
Response
9 (35) 1 (4)
2 (10)
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.
20061061794-1803.
35
Decitabine Phase 3 Percent of Patients RBC
Transfusion-Free Per Cycle
Decitabine
100
Supportive Care
90
80
70
of Patients RBC Transfusion-Free
60
50
40
30
20
10
0
0
1
2
3
4
5
6
Decitabine N 89 83 64 44 37 26 23
Supportive Care N 81 75 63 40 28 23 15
Note Last cycles less than 35 days long with 0
transfusions are not considered in this analysis.
Kantarjian HM, et al. Cancer.
20061061794-1803.
36
Quality of Life Measure Percent Change from
Baseline for Global Health Status
45
P lt .05
Decitabine
Supportive Care
35


25
15
Change From Baseline
5
-5
-15
-25
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Kantarjian HM, et al. Cancer. 20061061794-1803.
37
Decitabine Phase 3 Adverse Events (gt10
Incidence)
Decitabine (n 83)
Supportive Care (n 81)

Grade 3
Grade 4
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
Nonhematologic
Pneumonia
13
2
7
2
Exposed to decitabine.
Kantarjian et al. Cancer. 20061061794-1803.
38
Decitabine Phase 3 Summary and Conclusions

• 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
  non-responders (P .007)
• Well tolerated with manageable toxicity profile

Kantarjian et al. Cancer. 20061061794-1803.
39
Decitabine Exposure in Phase 2 and 3 Studies
Phase 2
Phase 3
91-01
95-11
97-19
D-0007
N
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)
Median cycles
4
4
4
3

• Multiple cycles of decitabine therapy may be
  required for optimal response

Saba HI, et al. Blood . 2005106706a abstract
2515. Kantarjian HM, et al. Cancer.
20061061794-1803. Saba HI, et al. Semin
Hematol. 200542(3 suppl 2) S23-S31. Wijermans
PW, et al. Leukemia. 1997111-5. Wijermans PW,
et al. J Clin Oncol.200018956-962.
40
Alternative Dosing with Decitabine
41
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. 2006108(in
press). First Edition Paper, prepublished online
Aug 1, 2006 DOI 10.1182/blood-2006-05-021162.
42
3-Arm Dosing Study Overall Response
Response
n 95 ()
Complete Response (CR)
32 (34)
Partial Response (PR)
1 (1)
Marrow CR
10 (11)
Marrow CR other HI
13 (14)
Hematologic Improvement (HI)
13 (14)
Single lineage
9 (9)
2 or 3 lineage
4 (4)
Objective Response
69 (72)
Kantarjian H, et al. Blood. 2006108(in press).
First Edition Paper, prepublished online Aug 1,
2006 DOI 10.1182/blood-2006-05-021162.
43
Comparison of outcome and side effects by dose
schedule
Parameter
5 Day IV
5 Day SQ
10 Day IV
n
64
14
17
4 (24)
CR / treated ()
25 (39)
3 (21)
9
Median no. courses
5
8
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
No. courses requiring hospitalization ()
50 (12)
14 (14)
23 (23)
To 109/L or above To 50 x 109/L or above
Kantarjian H, et al. Blood. 2006108(in press).
First Edition Paper, prepublished online Aug 1,
2006 DOI 10.1182/blood-2006-05-021162.
44
3-Arm Dosing Study DataSummary

• 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
gt50). CR PR marrow CR HI.Kantarjian H,
et al. Blood. 2006108(in press). First Edition
Paper, prepublished online Aug 1, 2006 DOI
10.1182/blood-2006-05-021162.
45
Phase 3 Clinical Experience with Azacitidine in
MDS
46
Azacitidine Phase 3 Study Design (CALGB 9221)

• Randomized, crossover trial
• Schedule 75 mg/m2/day SQ x 7 days q 28 days

R A N D O M I Z E D
Supportive Care
A SSESS
CR 3 Cycles
(n 92)
Eligible Patients (n 191)
HI Continue
Azacitidine SupportiveCare
NR Off study
SC Pts worsening
(n 99)
azacitidine
Silverman LR, et al. J Clin Oncol.
2002202429-40.
47
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.
2002202429-40.
48
Azacitidine Phase 3 Response Criteria

• Complete response (CR)
• Normal bone marrow or lt 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.
2002202429-40.
49
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.
2002202429-40.
50
Azacitidine Phase 3Response Rates
Azacitidine(n 99)
Supportive Care(n 92)
Overall Response (CR PR) Complete
response Partial response Hematologic improvement
16 (16.2) 6 (6.1) 10 (10.1) 19 (19)
0 0 0 6
P lt .0001 (CR PR)
Median Duration of Response (CR PR improved)
(months)
15
N/A
95 CI, 11 to 20 months
Kaminskas E. Clin Cancer Res. 2005113604-8.
Silverman LR, et al. J Clin Oncol.
2002202429-40.
51
Azacitidine Phase 3 Duration of Response
1.0
Azacitidine
0.8
Supportive Care
0.6
Probability of Continuing in Remission
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
5
1
1
1
1
0
0
0
Median duration of response (CR PR improved)
15 months (95 CI, 11- 20 months)
Silverman LR, et al. J Clin Oncol.
2002202429-40.
52
Azacitidine Phase 3 Time to AML Transformation
or Death
1.0
Azacitidine
0.8
P .007
Supportive Care
0.6
Probability of Remaining Event-Free
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
1
1
Observation
82
51
38
22
15
10
8
3
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.
2002202429-40.
53
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.
2002202429-40.
54
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.
2002202429-40.
55
Azacitidine Phase 3 Overall Survival
1.0
P .10
Azacitidine
0.8
Supportive Care
0.6
Probability of Survival
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
2
1
Observation
92
73
58
38
25
19
12
6
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.
2002202429-40.
56
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.
2002202429-40.
57
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. 2005113604-8
Silverman LR, et al. J Clin Oncol.
2002202429-40.
58
Comparison of Decitabine/D-0007 and
Azacitidine/9221 Phase 3 Trials
Parameters
Decitabine D-00071
Azacitidine CALGB 92212,3
Crossover Response Criteria
lt 5 IWG4
53 CALGB
of IPSS Int-2/High of prior therapy Median
duration of MDS (months) Median number of
treatment cycles
69 22 7.3 3
NA 16 2.8 9
Response Rates
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. 20061061794-1803.
2Silverman LR, et al. J Clin Oncol.
2002202429-40 3Kaminskas E. Clin Cancer Res.
2005113604-8 4Cheson BD. Blood.
2000963671-74. NA Not available.
59
Alternative Dosing with Azacitidine
60
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. 200624(abstr
6574).
61
3-Arm Dosing Study DataSummary 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. 200624(abstr
6574).
62
Considerations When Using Hypomethylating Agents
63
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.
64
Decitabine for Injection

• Indications
• Previously treated and untreated, de novo and
  secondary MDS of all French-American-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 Ringers
  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
  (2C - 8C) infusion fluids and stored at 2C -
  8C (36F - 46F) for up to 7 hours

DacogenTM package insert. Bloomington, Minn
MGI Pharma 2006.
65
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. 20061061794-1803.
66
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

67
Other Emerging Therapies in MDS Lenalidomide
68
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

69
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.
200523suppl 16S2S abstract 5.
70
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

71
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