ANCO 2006 ASH UPDATE MDS

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ANCO 2006 ASH UPDATEMDS

• Joseph M. Tuscano, M.D.
• UC Davis Cancer Center

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Clinical Development of Lenalidomide in MDS
Completed Trials
MDS-001 N43 Phase I/II initiated Feb 2002
Del(5q)
Non-del(5q)
MDS-003 N148 Phase II initiated July 2003
MDS-002 N214 Phase II initiated July 2003
Raza A et al. Presented at ASH Annual Meeting
December 912, 2006 Orlando, FL
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MDS-002 Study Design
R E S P O N S E
R E G I S T E R

• Eligibility
• IPSS diagnosed Low/Int-1 MDS w/o del(5q)
  abnormality
• ?2 U RBC/8 wk
• Platelets gt50,000/µL
• ANC gt500/µL

Yes Continue
Lenalidomide 10 mg po daily
Lenalidomide 10 mg po 21 days
No Off study
Dose reduction 5 mg every day 5 mg every other
day
Week 0 4 8 12 16 20 24
Primary endpoints Transfusion independence (TI)
Hgb response Secondary endpoints Cytogenetic
response safety
Raza A et al. Presented at ASH Annual Meeting
December 912, 2006 108Ab 250
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MDS-002 Patient Characteristics
Raza A et al. Presented at ASH Annual Meeting
December 912, 2006 108Ab 250
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MDS-002 Erythroid Response
Lenalidomide eliminated or reduced transfusion
requirements in 43 of MDS patients without
del(5q) cytogenetic abnormalities
Raza A et al. Presented at ASH Annual Meeting
December 912, 2006 108Ab 250
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MDS-002 Hemoglobin Response
Patients who responded to lenalidomide had a
median Hgb increase of 3.2 g/dL
Raza A et al. Presented at ASH Annual Meeting
December 912, 2006 108Ab 250
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MDS-002 Duration of Transfusion Independence
100
n56
90
Censored
80
Data cut-off July 2006
70
60
Transfusion Independent ()
50
40
Median duration TI 41 wk Range 8.0136.4 wk 35
patients TI 24 wk 20 patients TI 52 wk 19
patients ongoing
30
20
10
0
0
25
50
75
100
125
150
Time (wk)
Censored patients who remain TI at time of data
cut-off or at time of study discontinuation
Raza A et al. Presented at ASH Annual Meeting
December 912, 2006 108Ab 250
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MDS-002 Erythroid Response byFAB Diagnosis
Erythroid Response ()
RAn47
RARSn86
CMMLn20
RAEBn24
Erythroid response is similar in RA, RARS, RAEB,
and CMML
Raza A et al. Presented at ASH Annual Meeting
December 912, 2006 108Ab 250
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MDS-002 Cytogenetic Response
Chromosome marker present at baseline
Raza A et al. Presented at ASH Annual Meeting
December 912, 2006 108Ab 250
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MDS-002 Most Frequent Drug-Related AEs
NCI CTC
Neutropenia and thrombocytopenia

• Similar to baseline
• Manageable with dose reduction or interruption

Raza A et al. Presented at ASH Annual Meeting
December 912, 2006 108Ab 250
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MDS-002 Conclusions

• Lenalidomide is effective in Low and Int-1 risk
  MDS patients without del(5q)1
• TI response in 26 (median duration 41 wk)
• Erythroid improvement in 43
• Neutropenia and thrombocytopenia were similar to
  baseline and manageable with dose reduction or
  interruption
• Lower occurrence than in del(5q) patients2
• Lenalidomide may offer an effective alternative
  to cytokine therapy

Raza A et al. Presented at ASH Annual Meeting
December 912, 2006 108Ab 250
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Decitabine Responses in MDS Patients After Prior
5-Azacitidine1
1. Borthakur G et al. Blood. 2006108157a
abstract 518 2. Cheson BD et al. Blood.
2006108419
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Decitabine Responses in MDS Patients After Prior
5-Azacitidine1

• Decitabine 20 mg/m2 IV/day 5 q4 wk
• 14 patients treated to date median 4 courses
  prior 5-azacitidine (range, 19)
• Median age of enrolled patients was 74 years
  (range, 5885)
• Chromosomal abnormalities in 6 pts (43)
• Patients had previously received a median of 4
  courses of azacitidine (?3 courses in 12 85
  patients)

1. Borthakur G et al. Blood. 2006108157a
abstract 518 2. Cheson BD et al. Blood.
2006108419
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Decitabine Responses in MDS Patients After Prior
5-Azacitidine1

• Responses in 5 patients (35)
• Median remission duration 5.3 mo.
• Median survival 6.0 mo.

Patients ()
Modified IWG criteria2
1. Borthakur G et al. Blood. 2006108157a
abstract 518 2. Cheson BD et al. Blood.
2006108419
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Erythropoietin and G-CSF in MDS Patients With Low
Transfusion Need
Jadersten M et al. Blood. 2006108158a abstract
521
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Erythropoietin and G-CSF in MDS Patients With Low
Transfusion Need

• Retrospective analysis of Epo G-CSF (n123) vs
  untreated (n240) patients
• All were transfusion dependent (n176) or had Hgb
  level lt10 g/dL (n187)
• Erythroid response (TI) was observed in 41 of
  treated patients
• Median response duration was 23 mo (3-116).

Jadersten M et al. Blood. 2006108158a abstract
521
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Erythropoietin and G-CSF in MDS Patients With Low
Transfusion Need
Multivariate Cox regression analysis
Jadersten M et al. Blood. 2006108158a abstract
521
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Comparative Meta-Analysis of Erythroid Response
Rates for Epo and Darbepoetin (DARB)

• Identified 9 Epo (N619) and 8 DARB (N442)
  studies for comparison
• Baseline characteristics, age, gender, baseline
  Hgb, FAB subtypes were comparable
• Baseline sEpo levels were significantly higher
  for the Epo group (376 vs 133, p0.0026)
• Average dose of Epo 47,851 (30-80,000) vs DARB
  176 (100-315)
• Higher doses of EPO 60-80,000 or DARB (gt150 mcg)
  showed higher ER rates (EPO 48 vs 63, DARB 52
  vs 71)

Mundle S et al. Blood. 2006108755a abstract
2672
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Comparative Meta-Analysis of Erythroid Response
Rates for Epo and Darbepoetin

• Erythroid response rates (IWG criteria) were
  comparable between epoetin alfa (Epo) and
  darbepoetin studies
• Higher initial dose and lower baseline serum Epo
  predicted for higher response for both therapies

Mundle S et al. Blood. 2006108755a abstract
2672
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Allogeneic SCT for MDS Patients 50 Years Study
Population
Lim ZY et al. Blood. 2006108157a abstract 520
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Allogeneic SCT for MDS Patients 50 Years Study
Population

• Retrospective analysis of factors influencing
  outcomes for 1000 matched sibling (72) and 385
  (28) matched unrelated donor SCT

• Patients treated with reduced intensity (30 RIC
  vs 14 SMC) conditioning were older (age gt60 yr)
  plt0.001
• Those with standard myeloablative conditioning
  had more advanced disease
• No difference in donor type for reduced vs
  standard intensity groups

Lim ZY et al. Blood. 2006108157a abstract 520
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Allogeneic SCT for MDS Patients 50 Years
Multivariate Analysis
TRM treatment-related mortality
Lim ZY et al. Blood. 2006108157a abstract 520
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Allogeneic SCT for MDS Patients 50 Years
Multivariate Analysis

• On multivariate analysis of 4-year outcome
  parameters,
• age gt60 years, use of reduced intensity
  conditioning, and advanced disease stage
• at transplantation were associated with an
  increased relapse rate
• The use of reduced intensity conditioning was
  associated with lower treatment-related
• mortality, and advanced disease was associated
  with higher treatment-related mortality
• Advanced disease stage at transplantation was the
  only independent variable
• associated with an inferior 4-year OS
• Whereas patients aged gt60 years had an increased
  relapse rate, there was
• no significant difference in OS compared with
  those aged 5060 years

Lim ZY et al. Blood. 2006108157a abstract 520