Study 9221: A Randomized Phase III Trial of Subcutaneous Azacitidine in MDS

1
Study 9221 A Randomized Phase III Trial of
Subcutaneous Azacitidine in MDS
R A N D O M I Z E
Supportive Care Alone (Observation)
continue until endpoint
No

• Stratify
• RA
• RARS
• RAEB
• RAEB-T
• CMMoL

Exit criteria
A S S E S S

• Response
• Continue Rx
• No Response
• Off study

azacitidine (Dose as below)
Yes
azacitidine 75 mg/m2/d SC X 7 days every 28 d x 4
cycles
BM
BM
BM
Day
0
29
57
113
85
Transfusions and antibiotics used as needed
hematopoietic growth factors were prohibited
BMbone marrow.
Silverman L. Oncologist. 200168-14 Silverman
LR, et al. J Clin Oncol. 2002202429-2440.
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2
Study 9221 Duration of Therapy

• In the pivotal study, 92.9 of responding
  patients achieved initial positive effect by the
  end of 6 treatment cycles
• Responders received a mean duration of 18.2
  months of azacitidine therapy
• Treatment may be continued as long as the patient
  continues to benefit

92.9
Responding Patients (CR PR) Achieving Initial
Positive Effect (N14)
42.9
28.6
21.4
7.1
2
3-4
5-6
gt6
Initial positive effect was defined as the first
day of achievement of target for 4 weeks for at
least 1 cell line abnormality
Number of Cycles
2
Celgene Corporation, Data on File.
3
AZA-001 Trial Survival Results

• Azacitidine provided a significantly improved OS
  compared with CCR in the ITT population (log-rank
  P.0001)
• Azacitidine median OS was 24.5 months compared
  with 15 months for CCR
• Azacitidine 2-year OS was 51 compared with 26
  for CCR (24.6 difference, 95 CI, 13.1-36.1)
• The relative risk of death was 0.58 (95 CI
  0.43-0.77) indicating a 42 less risk for the
  azacitidine group relative to the CCR group
• More deaths were observed on CCR (113) compared
  with azacitidine (82)

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4
MDS-003 Duration Major Erythroid Response
List et al. Blood. 2006108251a.
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Relationship of Lenalidomide-induced
Thrombocytopenia and TI in MDS patients with
del(5q)
76 24
P x.xx
47 53
40 60
63 37
Patients ()
Plt.01
Decline in platelets
No baseline thrombocytopenia (N 106)
Baseline thrombocytopenia (N 42)
Sekeres et al. Blood. 2007110821a
6
Relationship of Lenalidomide-induced Neutropenia
and TI in MDS patients with del(5q)
82 18
P.79
P.02
63 38
56 44
58 42
Patients ()
Decline in ANC
No baseline neutropenia (N 88)
Baseline neutropenia (N 60)
Sekeres et al. Blood. 2007110821a
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EPO GCSF May Improve Survival in MDS with Low
RBC Tx Needs
Comparison of Nordic studies (EPO n123) to
Pavia (no EPO n240) Erythroid response
41 Median response duration 23 mos MVA
survival better with EPO if Tx needs lt 2 URBCs/mo
(HR 0.57 P.015) no effect if higher Tx needs
(P.36) No impact of EPO GCSF on AML in low
(P.75) or high (P.21) Tx needs
Jadersten. Blood. 108 abst 521, 2006
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Improved Survival in MDS with Iron Chelation
Therapy

• 178 patients median age 69 years IPSS lowInt-1
  99/133
• Ferritin gt2,000 µg/L in 28 patients clinical
  evidence of iron overload in 22 patients CHF 5
  liver disease 18, endocrine dysfunction 4
• 18 patients received ICT DFO 0.53 g s.c.
  infusion over 12 hours for 5 days a week
• Cox-regression analysis factors significant for
  survival IPSS score (Plt.008) ICT (Plt.02)
• For low-Int 1 IPSS median survival gt160 months
  with ICT vs 40 months if no ICT (Plt.03)
• Improved LFS in chelated patients

Leitch HA, et al. Blood. 2006108abstract
249., and ASH 2007 poster 1469
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NCCN Guidelines for Management of Iron Overload
in MDS

• NCCN guidelines
• Consider iron chelation therapy for patients with
  MDS, particularly for Low/Int-1 patients
• Monitor iron burden and initiate therapy
• After 2030 units of RBCs
• Serum ferritin levels gt2500 mcg/L

NCCN, National Comprehensive Cancer Network. NCCN
Clinical Practice Guidelines in Oncology.
Myelodysplastic Syndromes. v.1.2007.
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Phase II Study 5-, 7-, 10-day azacitidine dosing
regimensHematologic Improvement
Percent of Pts
Erythroid Major
Platelet Major
Neutrophil Major
Any HI
Pts counted only once for best response in an
improvement category Minor improvement at top
of HI columns
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Phase II Study 5-, 7-, 10-day azacitidine dosing
regimens RBC Transfusion Independence in
Baseline-Dependent Pts
of Pts Who Became Transfusion Independent (95
CI)
All Pts
FAB Low-risk Pts
12
Phase II Study 5-, 7-, 10-day azacitidine dosing
regimens Grade 3/4 Hematologic Adverse Events