Transcript Document

Best of ASH 2007
Myelodysplastic Syndromes
Lloyd E. Damon, MD
Hypomethylating Agents in MDS
• 5-azacitidine and decitabine
• Incorporate into DNA
• Block DMT (DNA methyltransferase)
• Critical DNA moieties are not methylated
• Reversal of tumor suppressor gene silencing
in the MDS clone
• Restoration of normal hematopoiesis
Cytosine Analogues
NH2
NH2
CH3
N
N
Cytosine
O
NH2
NH2
N
N
5-methylcytosine
O
N
N
N
N
N
N
O
O
Ribose
Deoxyribose
5-azacytidine
5-aza-2’-deoxycytidine
(decitabine)
• 5-azanucleoside analogues of cytosine have substitution of C by
nitrogen at position 5 of pyrimidine ring
• C5  N associated with hypomethylating activity
CALGB 9221
A Randomized Phase III Controlled Trial of SQ
5-Azacitidine in MDS
No
S
RA
t
r
RARS
a
RAEB
t
RAEB-T
i
CMML
f
y
Continue until
Endpoint (+)
R 1) Supportive
Exit
a
Care* Criteria (+)
n
Yes
d
o
m
i
2) 5-Aza 75mg/m2/d x 7 days q28 x 4
z
e
BM
0
Cycles 1-2
29
BM
57
Cycles 3-4
BM
113
Day
*
Silverman L. The Oncologist 2001. 6 (S5): 8-14.
Silverman LR, et al. J Clin Oncol. May 2002;20(10):2429-2440.
Kornblith AB, et al. J Clin Oncol 2002. 18:2427-39
A
S
S
E
S
S
Response
- Continue Rx
No Response
- Off Study
BM = Bone Marrow
CALGB 9221: Response
Response
Standard
of Care
(n=92)
5-azacitidine
(n=99)
Crossover
(n=49)
CR
0
7 (7%)*
5 (10%)
PR
0
15 (16%)**
2 (4%)
Improved
5 (5%)
38 (37%)**
16 (36%)
Total Better
5 (5%)
60 (60%)**
23 (47%)
*p<0.01; **p<0.001
Silverman L, et al. J Clin Oncol 2002;20:2429-2440
CALGB 9221: Time to AML or
Death
Probability of
Remaining Event-Free
1.0
+
++
++ + ++
0.8
++
+
0.6
Azacitidine
Supportive Care
+
+
+
0.4
+++
+
+
+ +++
++
+
0.2
0.0
0
6
P = 0.007
12
18
24
+ ++ +
+++++ +++
+++
30
+++
+ + ++
36
+
+
++
42
48
Months
Silverman L, et al. Randomized Controlled Trial of Azacitidine in Patients with MDS: A Study of the CALGB
J Clin Oncol 2002. 20:2429-2440..
54
CALGB 9221: Overall Survival
Remaining Event-Free
Probability of
Azacitidine
Supportive Care
Median
20 months
14 months
+ +
+
+ +
++++
++ +++ +++
++
0
6
P = 0.10
12
18
24
30
Months
36
+
++++++ + + +
++
42
48
54
.
Silverman L, et al. Randomized Controlled Trial of Azacitidine in Patients with MDS: A Study of the CALGB
J Clin Oncol 2002; 20:2429-2440.
Azacitidine Prolongs Overall Survival
in High-Risk MDS Patients Compared
with Conventional Care Regimens:
AZA-001 Phase III Study
Pierre Fenaux et al
ASH 2007 Abstract # 817
The International Vidaza High-Risk MDS Survival Study
Group
Eligibility
• RAEB, RAEB-T or CMML (FAB)
• IPSS score of INT-2 or High
Objectives
• Primary
Overall Survival (OS)
• Secondary
Time to AML or Death
Time to AML
Hematologic response and improvement
Transfusion independence
Schema
AZA 75 mg/m2/d x 7 d q28 d
Central Path Review
CCR Selection
CCR
Randomization • Best Supportive Care (BSC) only
• Low Dose Ara-C (LDAC,
20 mg/m2/d x 14 d q4-6 weeks)
• Std Chemo (7 + 3)
CCR (conventional care regimen) continued until
unacceptable toxicity or AML
Patient Features
n = 358
AZA
CCR
N=179 N=179
Age (yrs) Median
Pts ≥ 65 (%)
FAB (%)
RAEB
RAEB-T
CMML
IPSS (%) INT-1
INT-2
High
69
68
58
34
3
3
43
46
70
76
58
35
3
7
39
48
Patient Features by CCR Type
CCR Regimens
BSC
Std
AZA
CCR
Only LDAC Chemo
N=179 N=179 N=105 N=49
N=25
Age (yrs) Median
69
70
70
71
65
Pts ≥ 65 (%)
68
76
77
86
52
FAB (%) RAEB
58
58
65
51
40
RAEB-T
34
35
29
39
52
CMML
3
3
4
2
0
IPSS (%) INT-1
3
7
9
4
8
INT-2
43
39
44
43
12
High
46
48
44
43
72
Treatment Cycles and Duration
Cycles
(Median #)
Duration
(Median mos)
AZA
9
10.4
BSC only
7
6.2
4.5
5.7
1
1.5
LDAC
Std Chemo
Overall Survival: Azacitidine vs CCR
p = 0.0001
HR = 0.58 [ 0.43 - 0.77]
1.0
Proportion Surviving
0.9
0.8
F/U = 21 mo
0.7
0.6
0.5
0.4
AZA
0.3
CCR
0.2
0.1
0.0
0
Number
at risk
AZA
179
CCR
179
5
10
15
20
25
30
35
Time (months) from Randomization
152
132
130
95
85
69
52
32
30
14
10
5
1
0
40
Overall Survival: Azacitidine vs CCR
1.0
Proportion Surviving
0.9
0.8
Difference: 9.4 months
0.7
50.8%
24.4 months
0.6
0.5
0.4
15 months
26.2%
AZA
0.3
CCR
0.2
0.1
0.0
0
5
10
15
20
25
30
Time (months) from Randomization
35
40
Hazard Ratios for OS
ITT Subgroups
Total - Event / N
ITT
RAEB & RAEB-T: AGE ≥ 65
AGE: < 65
≥ 65
≥ 75
Male
Female
FAB: RAEB
RAEB-T
WHO: RAEB-1
RAEB-2
IPSS: INT-2
High
Cytogenetics: Good
Intermediate
Poor
Karyotype: -7/del (7q)
Cytopenias: 0/1
2/3
BM Blasts: ≥ 5% to < 11%
≥ 11% to < 21%
≥ 21% to < 31%
LDH: ≤ 240 U/I
> 240 U/I
195 / 358
138 / 240
45 / 100
150 / 258
50 / 87
134 / 251
61 / 107
95 / 207
80 / 123
15 / 31
102 / 193
71 / 146
98 / 167
80 / 167
38 / 76
67 / 100
42 / 57
20 / 53
167 / 290
34 / 61
98 / 192
58 / 99
97 / 208
94 / 145
0.125
0.250
0.500
Favors Azacitidine
1
2
4
Favors CCR
Secondary Endpoints
• Time to AML or death
13 mos AZA vs 7.6 mos, p=0.003
• Time to AML
26.1 mos AZA vs 12.4, p=0.004
• RBC Transfusion Independence
45% vs 11% , p<0.0001
Secondary Endpoints:
IWG (2000) RR and HI
Response
Overall (CR+PR)
AZA
CCR
N=179 N=179
(%)
(%)
P Value
29
12
0.0001
CR
17
8
0.02
PR
12
4
0.009
Major+Minor
49
29
<0.0001
HI-E Major
40
11
<0.0001
HI-P Major
33
14
0.0003
HI-N Major
19
18
0.87
IWG HI
OS by CCR Treatment
Median
OS (mo)
AZA (N=117)
vs
BSC (N=105)
21.1
AZA (N=45)
vs
LDAC (N=49)
24.5
AZA (N=17)
vs
Stand Chemo (N=25)
25.1
11.5
15.3
15.7
Hazard Log OS (mo) Ratio rank P
9.6
0.56
0.002
9.2
0.58
0.075
9.4
0.87
0.75
Conclusions
Abstract # 817
• AZA prolongs OS compared with CCR
• Consistent effect across demographic and risk
subgroups
• AZA was well tolerated
• Azacitidine should now be the standard of care
for high-risk MDS
Results of the initial treatment
phase of a study of three
alternative dosing schedules
of azacitidine (Vidaza®) in
patients with myelodysplastic
syndromes
Lyons RM et al
Abstract # 819
5-Azaciditidine
• FDA label
– 75 mg/m2 SQ daily X 7 doses Q28 days
– 75 mg/m2 IV daily X 7 doses Q28 days
• Investigational formulation
– Oral
• Schedule?
– Are there other equally effective dosing
schedules for 5-azacitidine?
Alternative Dosing Schedules
Daily SQ Doses - Monthly Cycles
RA
RARS
RAEB
RAEB-IT
CMMoL
R
A
N
D
O
M
I
Z
E
5-2-2 75 mg/m2 X5, 2 days off, X2
(total = 525 mg/m2)
5-2-5 50 mg/m2 X5, 2 days off, X5
(total = 500 mg/m2)
5
75 mg/m2 X5
(total = 375 mg/m2)
Hematologic Improvement
(IWG)
5-2-2
5-2-5
5
Erythroid
33
39
39
Platelets
22
18
18
Neutrophils
7
9
8
Major + Minor HI (%) 44
52
57
RBC Transfusion
Independence (%)
56
61
Major HI (%)
60
No statistical difference between comparisons
Abstract # 819 Conclusions
• Across monthly 5-azacitidine doses of 375
to 525 mg/m2, HI and RBC TxIndependence appear equivalent
• Across monthly 5-azacitidine schedules of
5 to 10 doses per cycle, HI and RBC TxIndependence appear equivalent
• The 5-2-2, 5-2-5, and 5 regimens appear
equivalent to the FDA-approved dose and
schedule
AMG 531
• Two identical peptides bound to two human
IgG1 Fc fragments
• Fc prolongs the circulatory half-life
• The peptides bind to the human
thrombopoietin receptor, Mpl
• Stimulates thrombopoiesis
• Effective in ITP*
• Administered SQ
*NEJM, 2006; 355: 1672-81
AMG 531
NEJM, 2006; 355: 1672-81
Phase 1/2 study of AMG 531 in
thrombocytopenic patients
with low-risk myelodysplastic
syndrome: update including
extended treatment.
Kantarjian H, et al
Abstract # 250
Eligibility - Design
•
Eligible
– IPSS Low or Int-1 (not CMML)
– Platelets ≤50
– Supportive care only
•
Treatment
– Sequential cohorts
– 300, 700, 1000, and 1500 mcg SQ weekly X 3
– Continue weekly therapy if responding
•
End points
– Platelet response at week 4 and duration of response
– # platelet transfusions
– safety
Outcomes of AMG 531
• Platelet response
– 41% overall (n=40 evaluable)
• 41% if baseline platelet ≥20
• 40% if baseline platelet <20
– Median duration of response 23 weeks
• Transfusions
– 104 Tx given to 39% of patients
– 17% of patients with a platelet response needed a TX
• Safety
– 17 patients with AE, no deaths
– 2 cases of AML, 6 cases of increasing blasts
AMG 531 Conclusions
Abstract # 250
• A substantial proportion of severely
thrombocytopenic MDS patients respond to AMG
531
• The duration of response is nearly 6 months
• There is no clear indication that AMG 531
accelerates AML transformation
• AMG 531 has very few side effects