1. Myelodysplasia: Recent Advances
James M. Rossetti, D.O.
Associate Director,
Blood and Marrow Transplantation Program
Western Pennsylvania Cancer Institute

2. Myelodysplastic Syndromes
Incidence in U.S.
15-25,000 cases per year
Prevalence in U.S.
55,000 cases
Types of MDS
2/3 of the cases belong to the lower risk categories

3. Myelodysplastic Syndromes: Predisposing Factors
Unknown in more than 80% of patients
Older age (Median age > 60 yrs, 70% > 50 yrs)
Secondary MDS
Ionizing radiation
Chemotherapy
Industrial chemicals
Hair dyes

4. Myelodysplastic Syndromes
CLINICAL PARADOX OF
Variable cytopenias in a hypercellular bone marrow

5. Myelodysplastic Syndromes: Dysplastic Features

6. Myelodysplastic Syndromes: Biologic Features Driving the Phenotype
Genetic abnormalities
Epigenetic DNA modification
Accelerated apoptosis
Proliferation
Stromal dysregulation
Medullary angiogenesis

7. Myelodysplastic Syndromes: Cytogenetic Abnormalities
About half of MDS patients present with a genetic abnormality
Chromosomal Abnormality Frequency in Primary MDS
–5/del(5q) %–20% +8 10% –7/del(7q) 5%–10% –Y 10% 17p- 7% del(20q) 5% t(11q23) 5%–6% Complex karyotypes 10%–20%
Heaney ML et al. N Engl J Med. 1999;340:1649 Rosenfeld C et al. Leukemia. 2000;14:2

8. MDS - Therapeutic Challenge
Ineffective
Hematopoiesis
AML
Evolution

9. Evolution of MDS Classification Systems
Based on survival and blast number
WHO
1997, 2001
Based on survival and blast number
FAB
IPSS
IPSS-BM Path
1976, 1982
2003
1997
ALIPs, CD-34+ Increase risk within IPSS categories
Based on time to AML; % blasts, karyotype, # of cytopenias
FAB=French American British Classification WHO=World Health Organization IPSS=International Prognostic Scoring Systems
1. Bennett JM, Catovsky D, Daniel MT et al. Proposals for the classification of the acute leukemias, French-American-British (FAB) co-operative group. Br J Haematol. 1976;33:
2. Bennett JM, Catovsky D, Daniel MT et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51:
3. Harris NL, Jaffe ES, Diebold J et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November J Clin Oncol. 1999;17:
4. Brunnig R, Bennett JM, Flandrin G et al. Myelodysplastic syndromes: introduction. In: Jaffe ES, Harris NJ, Stein H et al, eds. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001:63-73.
5. Greenberg P, Cox C, LeBeau MM et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:
6. Verburgh E, Achten R, Maes B et al. Additional prognostic value of bone marrow histology in patients subclassified according to the International Prognostic Scoring System for myelodysplastic syndromes. J Clin Oncol. 2003;21:

10. Myelodysplastic Syndromes: Survival Based on FAB Classification
RA (Refractory anemia) <5% blasts 70 60
RARS (RA with 15% ringed sideroblasts) 50 40
RAEB (RA with excess of blasts) 5%–20% blasts
Mean Survival (Months) 35 35 30 18
RAEB-t (RA with excess of blasts in transfor-mation) 21%–30% blasts 20 12 6 10
CMML (Chronic myelo-monocytic leukemia) RA
RARS
CMML
RAEB
RAEB-t
Low Risk
High Risk
Bennett JM et al. Br J Haematol. 1982;51:189 Gallagher A et al. Haematologica. 1997;82:191

11. WHO Revised MDS Classification
MDS/MPD
CMML-1 (<10% BM blasts)
CMML-2 (10-19% blasts)
CMML-Eos (AEC>1500/L)
JMML
MDS
RA - RA*
- RCMD
RSA - RARS
- RCMD-RS
5q- Syndrome
RAEB-1 (5-9% BM blasts)
RAEB-2 (10-19%;Auer rods)
MDS-U^
AML
The World Health Organization has recommended changes in the IPSS/IWG classification system, to incorporate additional prognostic factors and some cytogenetic elements as well. The major difference between the WHO and the FAB is that single lineage dysphasia's meet the threshold for the diagnosis. The other major change is the elimination of RAEB-t, lowered the threshold for AML down to >20% blasts. WHO also created the new category of myelodysplastic/myeloproliferative, including juvenile myelomonocytic leukemia, the pediatric counterpart of CMML, as well as CMML in adults. Within the latter category, CMML is broken down into three different types: type 1, with <10% blasts in marrow; type 2, with 10-19% blasts, and a third subtype called CMML with eosinophilia (this is the type that is very sensitive to imatinib mesylate Gleevec treatment).
The remainder of the WHO classification incorporates more traditional types of MDS. The WHO has broken these down with the goal of adding more prognostic specificity to the categories. 5q- syndrome is now recognized as a separate entity. There is a new category, MDS-unclassified, for those patients with a dysplastic lineage other than erythroid.
Because the WHO classification lacks the prognostic detail of the IPSS system, the latter is still used in clinical trials.
20% blasts
*Single lineage erythroid dysplasia.
^MDS-U denotes single non-erythroid lineage dysplasia.
Harris N, et al. J Clin Oncol 1999;17:3835.

12. IPSS: International Prognostic Scoring System
All 3 prognostic variables required to generate IPSS score
Score Value
Prognostic Variable
Bone marrow blasts (%) <5 5–10 – 11–20 21–30
Karyotype* Good Intermediate Poor –
Number of 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; platelet count <100,000/L
Greenberg PL et al. Blood. 1997;89:2079
Greenberg PL, Cox, C, LeBeau M et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:

13. Survival and Evolution to AML by IPSS
Parameter Low Int-1 Int-2 High
Score 0 0.5– –2.0 2.5
Median survival, yr
25% AML evolution,
median, yr
From diagnosis in untreated patients
Greenberg PL et al. Blood. 1997;89:2079

14. Cytogenetic abnormalities found in 24% of RA and 29% of RARS patients
FAB versus IPSS
Cytogenetic abnormalities found in 24% of RA and 29% of RARS patients
List A, Molldrem J, Sanders, J. Prognosis and treatment of myelodysplastic syndromes. Slide show presented at: Annual Meeting of the American Society of Clinical Oncology; June 5, 2004; New Orleans, La. Slide 11.

15. Outcomes of Allogeneic Stem Cell Transplant in Patients With MDS
Only curative therapy is high-dose chemotherapy with allogeneic BMT
Up to 50% cure rate
Morbidity and mortality increases with age
Allogeneic SCT appropriate for fewer than 5% of MDS patients
Non-ablative SCT increasingly an option (?)

16. Transplant at Progression
Allogeneic Stem Cell Transplantation for MDS: Approximation of Life Expectancy (Years)
Immediate Transplant
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
From Cutler C, et al. A Decision Analysis of Allogeneic Bone Marrow Transplantation for Myelodysplastic Syndromes: Delayed Transplantation for Low Risk Myelodysplasia is Associated with Improved Outcome. Blood st Ed Publication. Prepublished online March 23, 2004; D /Blood
Copyright American Society of Hematology, used with Permission.

17. Allogeneic Stem Cell Transplantation for MDS
Cutler, C. S. et al. Blood 2004;104:
Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.

18. SURVIVAL AFTER MYELOABLATIVE TRANSPLANTS FOR MYELODYSPLASTIC SYNDROMES, 1996-2001, Age > 20 Years
100 20 40 60 80
HLA-identical sibling, RA/RARS (N = 254)
PROBABILITY, %
Unrelated, RA/RARS (N = 92)
Unrelated, RAEB/RAEB-T/CMML (N = 257)
HLA-identical sibling, RAEB/RAEB-T/CMML (N = 648) 1 2 3 4 6 5
YEARS

19. International Working Group Criteria: Hematologic Improvement
Erythroid response, if Hgb <11 g/dL
Major: Rise by >2; transfusion independence
Minor: Rise by 1–2; reduce transfusion dependence by 50%
Platelet response, if <100,000/L
Major: Rise by >30k; transfusion independence
Minor: Rise by 50% (at least 10,000/L)
Neutrophil response, if ANC <1500/L
Major: Rise by 100% or 500/L
Minor: Rise by 100% but <500/L
Cheson BD et al. Blood. 2000;96:3671

20. International Working Group: Response Criteria in MDS
CR: duration 2 months
BM: <5% blasts; no dysplasia; normal maturation
Blood: Hgb >11 g/dL; ANC >1500/L; platelets >100,000/L; no blasts; no dysplasia
PR: same as for CR, except blast decrease by >50% or lower FAB
Stable disease (SD): no progression for 2 months
Progressive disease (PD)
Cheson BD et al. Blood. 2000;96:3671

21. Survival Rates Before (1980s) and
After (1990s) the Use of Chemotherapy
1.0
0.8
0.6
0.4
0.2
0.0 50
100
150
200
260
310
360
410
460
520
Weeks
Survival Probability
Era Total Fail
1980s
1990s
With Permission of E Estey, MD

22. Erythropoietin for MDS
EPO response rate 15-20%
Best if EPO level < U/l
Dose 10,000 u/day (or 40,000 u twice a week)
Best responses in low grade MDS
Hellstrom-Lindberg, 1995

23. Darbepoetin Alfa for MDS
May induce response in EPO non-responders
Low EPO level may not be as important (?)
Newer studies suggest higher doses more effective

24. EPO + G-CSF for MDS
Higher responses to EPO + G-CSF (reduced caspase induced apoptosis)
Synergy as late addition of G-CSF converts non-responders to PR and CR
RA, RARS, RAEB – 38% RR
Duration 24 months
Hellstrom-Lindberg, 1998

25. Predictive Model
British Journal of Hematology, 2003

26. Bimonthly PRBC Transfusions
Epo + G-CSF  Synergy
81 year old female diagnosed with MDS-RARS in 6/94:
Hgb (G/DL)
Bimonthly PRBC Transfusions
Epo
Epo + G-CSF

27. Strategies Directed at the BM Microenvironment
Immunomodulatory (ATG, cyclosporine)
Anti-TNF
Antiangiogenic (VEGF-A)
Cytoprotective (amifostine)

28. Immunosuppressive Therapy for MDS
ATG  steroids  cyclosporine:
40 – 70% responses in hypoplastic MDS
Responses greatest in younger patients, shorter duration, and HLA DRB1*15
Responses 5 years or more

29. Thalidomide in MDS
Anticytokine
Antiangiogenic
Immune modulator

30. Thalidomide Phase II Trial 16/83 (19%) RBC transfusion responders
Rare responders in WBC or PLT
Intolerant of > 200mg/day
16 weeks to respond (12-20)
Response was 29% in patients completing 12 weeks of therapy
Raza, 2001

31. Survival Curve: After Starting Treatment With Thalidomide
Response Code
1.2
Responders
Responders-alive
1.0
Non-responders .8
Non-responders-alive
Cum Survival .6 .4 .2
-200
200
400
600
800
1000
1200
1400
Survival in days
Median non-responders = 317 days
Median responders = none reached P =<

32. Thalidomide
Major Side Effects
Sedation
Constipation
Neuropathy

33. Revlimid (lenalidomide)
Encouraging early response rates in low-grade MDS: 10 –40% CR + PR
Largely devoid of thalidomide side effects
Like thalidomide, mainly erythroid responses
Well tolerated, but thrombocytopenia is dose limiting

34. 5q- Syndrome: A Subset of MDS
Isolated chromosome 5q deletion
Hematologic features
Refractory anemia
Mild leukopenia
Atypical megakaryocytes, normal to elevated platelets
Transfusion dependence
Extended survival with low frequency of AML transformation

35. Revlimid (lenalidomide) 5q- Syndrome
Very high response rate
10/12 reversed the cytogenetic abnormality
Now more than 70 patients treated – many with excellent responses
May see an early aplastic phase during treatment
Recently FDA approved for low-risk MDS patients with transfusion dependence and 5q-

36. Lenalidomide Phase II Experience
ADVERSE EVENTS
MDS-003 (5q-)
MDS-002 (non-5q-)
Neutropenia
57.0%
24.0%
Thrombocytopenia
58.0%
19.0%
Pruritis
32.0%
21.0%
Rash
28.0%
22.0%
Diarrhea
13.0%
Fatigue
12.0%
Constipation NR
14.0%
PATIENT DEATHS
Deaths
15 (10.1%)
20 (9.3%)
Suspected drug related by investigator
2 (1.4%)
2 (0.9%)
List. ASCO 2005 Plenary Session. Celgene data on file.

37. TRISENOX® (arsenic trioxide) Mechanisms of Action
Differentiation
G1 arrest (p21,p27)
SMRT corepressor-P
Histone acetylation
DNA-MT inhibition
Apoptosis
NF-B inhibition
Bcl-2 downregulation
Microtubule disruption
Caspase activation
Angiogenesis
VEGF suppresion
COX-2 repression
Endothelial apoptosis

38. Study Design Multi-center, open-label, 2-stage Two patient cohorts
Lower-risk MDS (IPSS Risk Category Low or Int-1)
Higher-risk MDS (IPSS Risk Category Int-2 or High)
4-week cycles
ATO given 5 days per week for 2 weeks followed by 2 weeks with no dosing
ATO 0.25 mg/kg/dose given as a 1 to 2 hour IV infusion

39. Disease Response Summary
Patients with Response (as defined in the IWG Criteria):
Lower Risk Higher Risk Patients Patients
Complete Remission Hematologic Response Stable Disease 11 4
Progressive Disease 0 5
Total (CR + HR) (35%) (31%)
List A et al. 7th Intl Symposium on MDS. 2003;Abstract

40. Study Design European multicenter, open-label, 2-stage
Two patient cohorts
Lower-risk MDS (IPSS Risk Category Low or Int-1)
Higher-risk MDS (IPSS Risk Category Int-2 or High)
16-week cycles
ATO given 5 days for 1 week, followed by 2 doses/week for at least 15 weeks
ATO 0.30 mg/kg/dose given as a 1 to 2 hour IV infusion (loading), followed by 0.25 mg/kg/dose twice weekly

41. Conclusions
There were hematologic responses in 9 of 37 (24%) evaluable MDS patients
Treatment led to transfusion independence or decreased transfusion requirements in 6 patients
Some platelet and WBC responders
Twenty-three additional patients (62%) maintained stable disease
Responses seen within 8 to 12 weeks of therapy
Responses were durable, lasting up to 300+ days (range days)

42. Myelodysplastic Syndromes: Epigenetic DNA Modifications
Epigenetic Gene Silencing
DNA hypermethylation - Promoter, global DNA
hypermethylation common in MDS
Therapeutic Strategy
DNA methyltransferase inhibitors (eg, azacitidine, decitabine) promote hypomethylation of DNA, allowing expression of previously silenced genes

43. Decitabine Phase III Trial: Study Design
Open-label, multicenter, 1:1 randomized study in U.S. and Canada
Int-1, Int-2 and High Risk MDS patients eligible
Primary Endpoints: Response, Time to AML/death R A N D O M I Z
E D
Decitabine + Supportive Care*
15mg/m2/q8h x 3days q6wks
(N=89)
Stratification - IPSS
- Prior chemo
- Type of MDS - Site
Eligible
Patients (n=170)
Supportive Care
*ABX, GFs and/or Transfusions
(N=81)
Saba et al. Proc ASCO. 2005; Poster Presentation.

44. Decitabine Phase III Trial: Results
Decitabine (n=81)
Supportive Care (n=81)
Overall Response (IWG)*
17% 0%
Complete Response 9%
Partial Response 8%
Hematologic Improvement (IWG)
13% 7%
Median Time to Response
89d (55-153)
N/A
Median Duration of Response
266d ( )
Median Time to AML/Death**
12.1 months
7.8 months
*p<0.01
**p=0.16
Saba et al. Proc ASCO. 2005; Poster Presentation.

45. Decitabine Phase III Trial: Adverse Events
Decitabine (n=83)
Supportive Care
(n=81)
Grade 3
Grade 4
Neutropenia
10%
77%
25%
Thrombocytopenia
22%
63%
27%
16%
Anemia
11% 1%
14%
Febrile neutropenia
17% 6% 4% 0%
Pneumonia
13% 2% 7%
- Major grade 3/4 adverse event: Febrile neutropenia
Saba et al. Proc ASCO. 2005; Poster Presentation.

46. CALGB 9221 A Randomized Phase III Controlled Trial of Subcutaneous Azacitidine in Myelodysplastic Syndromes M 57 29
113
1) Supportive Care*
QOL RA
RARS
RAEB
RAEB-T
CMML S t r a i f y R n d o m z e
2) Aza C 75mg/m2/d x 7 days q28
Exit
Criteria No
Continue until Endpoint
Yes
Aza C (dose as per arm #2) A E
Response
Continue Rx
No Response
- Off Study
Day
* Minimum duration of supportive care = 4 months unless transform to AML; death or plts ≤ 20 x 109/L at week 8 or later
QOL – Quality of Life Assessment
M = Bone Marrow Aza C – Azacitidine S.C.
Silverman L. The Oncologist (S5): 8-14.
Silverman L, et al. J Clin Oncol :
Kornblith AB, et al. J Clin Oncol :

47. CALGB Trial of Azacitidine vs. Supportive Care
Transformation to Treatment Response Time to leukemia or death* AML as 1st event
Aza C CR = 7% 21 months 15% (n = 99) PR = 16% Improved = 37% (Overall = 60%)
Supportive care CR = 0% 13 months 38% (n = 92) PR = 0% Improved = 5% (Overall = 5%)
Quality of life significantly improved with treatment: fatigue (P = 0.001), dyspnea (P = ), physical functioning (P = ), positive affect (P = ), and psychological distress (P = 0.015)
*Not IWG Criteria of Response; Cross-over design did not allow proof of survival advantage.
Silverman LR et al. J Clin Oncol. 2002;20:2429

48. Response Rates (CR + PR + Major HI) Using IWG MDS Response Criteria by Study41 40 36
Percent of Patients 18 7
8421 Azacitidine N=48
9221 Azacitidine N=99
9221 Supportive care only N=41
8921 Azacitidine N=70
9221 Azacitidine after Supportive care N=51 IV SC
Silverman et. al. ASH Meeting Dec 9-13, Abstract 2526 and Poster Presentation.

49. Time to AML Transformation
Remaining Event-Free
Probability of
0.0
0.2
0.4
0.6
0.8
1.0 6 12 18 24 30 36 42 48 54
Azacitidine
Supportive Care
Months +
p=0.007
Silverman L, et al. Randomized Controlled Trial of Azacitidine in Patients with MDS: A Study of the CALGB
J Clin Oncol : Reprinted with permission from the American Society of Clinical Oncology.

50. Survival: Landmark Analysis12 24 30 42 54 6 18 36 48
Probability of Survival
0.0
0.2
0.4
0.6
0.8
1.0
Months
Azacitidine
Supportive Care
p=0.1
0.0
0.2
0.4
0.6
0.8
1.0
Probability of Survival
Months from 6-month Landmark
Induction Azacitidine
Crossed before 6 months
Did not cross before 6 months 10 20 30 40 50 5 15 25 35 45
p=0.03
Silverman L, et al. Randomized Controlled Trial of Azacitidine in Patients with MDS: A Study of the CALGB
J Clin Oncol : Reprinted with permission from the American Society of Clinical Oncology.

51. Hazard ratio (HR)=0.52 (95% CI: 0.32, 0.85)
Time to Death or AML Transformation in RAEB and RAEB-T Patients ≥ 65 Years of Age
Log-rank P=0.008
Hazard ratio (HR)=0.52 (95% CI: 0.32, 0.85)
48% less risk of death or AML
92% prolongation to death or AML
9.9 month difference (95% CI: 1.5, 15.5)1
Proportion Surviving
24% difference (95% CI: 5%, 43%)2
Supportive care (N=37)
Azacitidine (N=31) 24
Time (28 day months)
1 Hodges, Lehmann. Ann Math Statistics. 1963;34:
2 Greenwood M. The Natural Duration of Cancer
Silverman et. al. ASH Meeting Dec 9-13, Abstract 2524 and Poster Presentation.

52. Median Survival: FAB-based Risk Groups
Similar findings for Predicted Survival Risk Groups.

53. Adverse Events Leukopenia: 43% (43 Pts) Neutropenia: 58%
Thrombocytopenia: 52% (51 Pts)
Erythema at Injection Site: 35%
N&V: 4% (6 Pts)*
Treatment Related Mortality: <1% (4 Pts- 3 Infections)
No Diarrhea*, Elevated Transaminases
*Pertains only to adverse events with CALGB 9221.
Silverman LR, et. al. J Clin Oncol 2002;20:
Silverman L. Cancer Medicine. 2000a; Edition 5:
Silverman L, et. al. Cancer Inves. 1999;17(Suppl):4-5:[5a].
Silverman LR, et. al. Proc Am Soc Clin Oncol 1998;17:53a.

54. Number of Patients (number of patients per patient-year of exposure)
Rates of Bleeding and Infection in Patients Treated with Azacitidine vs. Supportive Care: CALGB 9221
Number of Patients (number of patients per patient-year of exposure)
Azacitidine
Supportive Care
All Patients
N=150
N=92
Infections - Total
89 (0.64)
41 (0.95)
Bleeding - Total
77 (0.56)
26 (0.60)
Patients with RAEB & RAEB-t  65 years
N=51
N=37
Infection - Total
31 (0.38)
19 (0.76)
26 (0.32)
11 (0.44)
Silverman et. al. ASH Meeting Dec 9-13, Abstract 2525 and Poster Presentation.

55. 5-aza in MDS-RA Platelet Response
15 Eligible
Major Response = 47%
aTTR = 3 cycles
aRD = 17 cycles+ (2 – 68)
aTTR = average time to response
aRD = average response duration

56. 5-aza in RARS

57. 5-aza in MDS
Response (%)

58. 5-aza in MDS: CMML CMML (MDS) (MPD) N 6 18 CR 33% PR 0% 22%
Time to Response 1 2
Response Duration
13+ 7+

59. Cumulative Probability
Times to First Response and from First Response to Best Response Using IWG MDS Response Criteria
Cumulative Probability
Time (cycles)
Silverman et. al. ASH Meeting Dec 9-13, Abstract 2526 and Poster Presentation.

60. G-CSF Increases Hematological Response Among Patients with MDS Treated with Azacitidine
Retrospective review of 86 MDS patients treated with Azacitidine (avg 10.8 cycles)
49 also received EPO, G-CSF or both, 37 did not
2 groups did not differ in number of cycles of aza received or FAB MDS subtype
The addition of G-CSF improved overall hematological response, erythroid and platelet response
Rossetti et al. Blood 2006;108(11):A4868.

61. G-CSF Increases Hematological Response Among Patients with MDS Treated with Azacitidine
Treatment
Overall Hematological Response
P -value
Aza Alone
51% (19/37)
Aza + EPO
50% (6/12)
P=.09
Aza + G-CSF +/- EPO
84% (31/37)
Aza without G-CSF
51% (25/49)
P=.003
Rossetti et al. Blood 2006;108(11):A4868.

62. Azacitidine Survival Study
Azacitidine Survival Trial Study Design
Open label, randomized, parallel-group
Patient Population:
MDS with RAEB or RAEB-t
IPSS score INT-2 or High
Status:
358 enrolled (354 planned)- enrollment complete Aug 7, investigators in 15 countries.

63. Azacitidine Survival Study
Survival Study Design
Azacitidine 75 mg/m2 x 7 days Every 28 days
Standard of care options consist of:
1. Best supportive care
2. Low-dose Ara-C
3. Standard chemotherapy
Patient randomized.
BSC included in both arms.

64. Results Median survival: Aza extends overall survival by 74%
24.4 months for Azacitidine vs 15 months for conventional care regimens (p-value = )
9.4 months median survival benefit for patients on azacitidine compared to CCR
Aza extends overall survival by 74%
HR = 0.58 (95% CI: )
Two-year survival rate:
50.8% for azacitidine vs 26.2% for CCR (p < )

65. Treatment Algorithm SCT Candidate Yes No
Int-2/High Low/Int Int-2/High
? MTIs
AlloSCT EPO/G-CSF MTIs Thalidomide MTIs Revlimid (5q-)
? MTIs
No Response
Clinical Trial (HDAC, FTI)

66. Evaluable Patients (n = 12)
Maintenance Azacitidine Post Allo-SCT in AML & High-Risk MDS: Dose/Schedule Study 5
Unrelated 7
Related
Donor HLA Compatibility 8
Refractory disease 4
In remission
Disease Status at Time of Transplant
Patients with MDS
Patients with AML
56 (25-66) years
Median Age (Range)
Evaluable Patients (n = 12)
Soriano et al. Blood 2006;108(11):A3668.

67. Maintenance Azacitidine post Allo-SCT in AML & High-Risk MDS: Dose/Schedule Study
At a median follow-up of 5 months post Allo-SCT, no pts had relapsed
No drug-related induction of GVHD was observed
All pts were 100% donor chimeras at azacitidine initiation
At 8 mg/m2 /day, azacitidine produced detectable hypomethylation
Soriano et al. Blood 2006;108(11):A3668.

68. Response Rates (CR + PR + HI) for WHO AML Patients Using MDS Response Criteria by Study48 37 32
Percent of Patients 16
8421 Azacitidine N=25
8921 Azacitidine N=28
9221 Azacitidine as Randomized N=27
9221 Azacitidine after Supportive care N=13
9221 Supportive care N=12 IV SC
Silverman et. al. ASH Meeting Dec 9-13, Abstract 1848 and Poster Presentation.

69. 5-aza in AML ( 20% BM blasts)
Percent
15 patients, mean age = 68 yrs

70. Azacitidine in AML: WPCI (WHO Criteria)
Mean age = 68 yrs (44-80)
CR = 4 (20%)
PR = 5 (25%)
HI = 3 (15%)
ORR = 60%

71. 5-aza in AML (BM blast count 30%)
Mean age = 75 yrs (68-79)
Avg. survival = 13.5 months
CR = 25%
PR = 50%

72. 5-aza in AML: Survival Months CR PR SD NR
= Taken to HSCT
+ = Mean
Months
CR PR SD NR
Average survival in responders = 15+ months (All with PS ≤ 1 while being treated)

73. Azacitidine + Gemtuzumab as Induction and Consolidation in High-Risk MDS and AML
10 of 13 (77%) patients achieved a CR
Reductions in BM & peripheral blasts observed in all patients
10 of 13 pts required 2 courses of induction therapy
12 of 13 pts were treated in an outpatient setting
6 of 13 pts required no hospitalization
7 of 13 pts hospitalized (median: 16 days [range: 4-47])
Nand et al. Blood 2006;108(11):A1981

74. Azacitidine + Gemtuzumab as Induction and
Consolidation in High-Risk MDS and AML .1 .2 .3 .4 .5 .6 .7 .8 .9
1.0
Cumulative Survival 2 4 6 8 10 12 14 16 18
Months
Nand et al. Blood 2006;108(11):A1981

75. Thank You