Hypomethylation:Turning on silenced genes and silencing the critics

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HypomethylationTurning on silenced genes and
silencing the critics?

• Ravi Vij MD

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Hypomethylating Cytosine Analogs
5-aza-cytidine
5-aza-2'-deoxycytidine
5-methyl-cytosine
Cytosine
(decitabine)
(azacitidine)
Santini V, et al. Ann Intern Med.
2001134(7)573-86.
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Mechanism of Epigenetic Therapy
Fully methylated DNA
STOP
STOP
Silencing
Maintained Silencing
DNAreplication
Fully methylated DNA
Mtase
Epigenetic Therapy
Unmethylated DNA
Reactivated GeneExpression
Hemi-methylated DNA
Differentiation - Apoptosis - Senescence -
Enhanced Immune Response
Courtesy of Issa JP.
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Study 9221 A Randomized Phase III Trial of SC
VIDAZA 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

VIDAZA (Dose as below)
Yes
VIDAZA 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
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BMbone marrow.
Silverman L. Oncologist. 200168-14 Silverman
LR, et al. J Clin Oncol. 2002202429-2440.
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Study 9221 Response Rates
Approximately 24 of VIDAZA patients who did not
meet the criteria of PR or better were considered
improved
Excludes patients with adjudicated baseline
diagnosis of AML CRcomplete response PRpartial
response.
5
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Study 9221 Maximizing Response With VIDAZA

• Achievement of PR was initially reported between
  the 2nd and 19th treatment cycles
• Achievement of CR was between the 8th and 15th
  treatment cycles
• Recommended to continue therapy beyond the
  initial benefit to achieve full benefit for
  patients

The median number of cycles needed to achieve a
PR was 7 The median number of cycles needed to
achieve a CR was 8
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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 VIDAZA therapy

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
7
8
RBC Transfusion Independence

• Benefit extended across all MDS subtypes
• Median duration of transfusion independence was
  estimated as 330 days for VIDAZA responders
• Median time to transfusion independence was 2.5
  months

42.5 (17/40)
44 (29/66)
Transfusion-Independent Patients ()
VIDAZA All Patients N66
VIDAZA Higher Risk N40
0 Supportive Care N56
Higher-risk patients are RAEB, RAEB-T, and
CMMoL. RBCred blood cell.
RBC Transfusion Dependent at Baseline
8
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Platelet Transfusion Independence

• 87 (13/15) were higher risk
• Median time to transfusion independence was 2
  months

53 (8/15)
46 (6/13)
Transfusion-Independent Patients ()
0
VIDAZA All Patients N15
VIDAZA Higher Risk N13
Supportive Care N12
Higher-risk patients are RAEB, RAEB-T, and CMMoL.
Platelet Transfusion Dependent at Baseline
9
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Azacitidine Survival Study Study Design

• Phase III, international, multicenter,
  prospective, randomized, controlled,
  parallel-group study
• Inclusion Criteria
• High-Risk MDS pts
• RAEB, RAEB-T or CMML according to FAB
• IPSS score of INT-2 or High

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Azacitidine Survival Study
AZA 75 mg/m2/d x 7 d q28 d
Screening/Central Pathology Review
Investigator CCR Tx Selection
CCR
Randomization

• Best Supportive Care (BSC) only
• Low Dose Ara-C (LDAC, 20 mg/m2/d x 14 d q28-42
  d)
• Std Chemo (7 3)

BSC was included with each arm Tx continued until
unacceptable toxicity or AML transformation or
disease progression
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Baseline Clinical CharacteristicsN 358
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Treatment Cycles and Duration
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Overall Survival Azacitidine vs CCR ITT
Population
Log-Rank p0.0001 HR 0.58 95 CI 0.43,
0.77 Deaths AZA 82, CCR 113
Proportion Surviving
AZA
CCR
Number at riskAZA 179 152 130 85 52 30 10 1CCR
179 132 95 69 32 14 5 0
Time (months) from Randomization
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Overall Survival Azacitidine vs CCR ITT
Population
Log-Rank p0.0001 HR 0.58 95 CI 0.43,
0.77 Deaths AZA 82, CCR 113
Proportion Surviving
AZA
CCR
Time (months) from Randomization
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Secondary Endpoints

• Time to AML or death
• 13 mos with AZA vs 7.6 mos with CCR, p0.003
• Time to AML
• 26.1 mos with AZA vs 12.4 with CCR, p0.004
• RBC Transfusion Independence
• 45 with AZA vs 11 with CCR, plt0.0001
• Infections Requiring IV Antimicrobials
• Reduced by 33 with AZA vs CCR

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Secondary Endpoints RR and HI
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Additional Analysis Median OS by Investigator
Selection
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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.
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Decitabine Phase 3 Response to Decitabine (ITT)
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.
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Decitabine Phase 3 Median Time to AML or Death
Censored data. Kantarjian HM, et al. Cancer.
20061061794-1803 Data on File, MGI PHARMA.
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Decitabine Exposure in Phase 2 and 3 Studies

• 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.
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Phase III Low-Dose Decitabine vs Supportive Care
in MDS Results

• EORTC 06011
• Median age 70 years
• IPSS int-2/high-risk MDS 55/38
• Superior responses and PFS with decitabine vs
  supportive care no improvement in OS or time to
  AML or death

• Poor cytogenetics 46
• Previous treatment 20

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22
Decitabine (n 119)
Supportive care (n 114)
20
15
14
15
13
Patients ()
10
6
5
2
0
0
0
CR
PR
HI
SD
Wijermans P, et al. ASH 2008. Abstract 226.
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3-Arm Dosing Study DataResponses By Treatment Arm
Statistically significant compared to the two
other treatment groups
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Kantarjian H, et al. Blood. 200710952-57.
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3-Arm Dosing Study DataCytogenetic Responses
Median time to cytogenetic response was 2.1
months.
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Kantarjian H, et al. Blood. 200710952-57.
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Updated Response Data Impact on Survival
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Kantarjian H, et al. Cancer, 2007109265-273.
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Decitabine Survival vs Intensive Chemotherapy in
Higher Risk MDS (Matched Group)
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Kantarjian H, et al. Blood, 2007 110 42a-43a
Abstract 115
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Decitabine Response
As assessed by independent expert reviewer Not
Evaluable Not evaluable for response per the
expert review because post-therapy bone marrow
not available 5 pts had comorbid condition
(including metastatic lung cancer, preexisting
ARDS, pulmonary fibrosis, cardiomyopathy) leading
to early withdrawal, 5 pts withdrew (per pt or
family decision) without documentation of study
related adverse event, 5 pts withdrawn based on
clinical judgement of investigator.
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Cheson BD, et al. Blood. 2006108419-25.
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Overall Survival

• The one-year survival rate for decitabine
  treated patients was 66
• and the median survival was 19.4 months.
• 57 patients continued to be followed for
  survival.

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Decitabine in Elderly Patients With AML

• Prospective, open-label, phase II study of
  decitabine in elderly patients with previously
  untreated AML (N 55)
• Treatment decitabine 20 mg/m2 on Days 1-5, every
  4 weeks
• Patient population
• Median age 74 years
• Range 61-87
• ECOG PS 2 18
• Poor cytogenetics 44
• AML transformed from MDS 35

Cashen AF, et al. ASH 2008. Abstract 560.
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Low-Dose Decitabine in Elderly Patients With AML

• Preliminary results from phase II study of
  decitabine in elderly untreated AML patients (15
  with secondary AML) N 33
• Median age 74 years (range 60-83)
• Risk factors
• Older than 70 years of age, AHD, poor
  cytogenetics, ECOG PS 2
• 3 (n 16) 2 (n 15) 1 (n 2)
• Treatment decitabine 20 mg/m2 IV daily x 10
  days/month ? consolidation for 3-5 days/month
• Median cycles 3
• Median cycles to CR 1
• CR 11/22 (50)
• Induction mortality 4 (infections)

Blum W, et al. ASH 2008. Abstract 2957.
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Chemotherapy Trials in Older AML Patients
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Low-Intensity Therapy for Older AML Patients

• Randomized trial of low-dose Ara-C vs.
  hydroxyurea1
• CR rate 18 vs. 1
• Overall survival better with LD Ara-C
• Median OS lt 6 mo. in both arms
• Randomized trial of low-dose Ara-C vs. intensive
  chemo2
• CR rate 20 vs. 52
• Frequency of early deaths 10 vs. 31
• No difference in OS (median 8.8 mo for LD Ara-C)

1Burnett A, et al. Cancer. 20071091114-1124.2Ti
lly H, et al. J Clin Oncol. 19908272-9.
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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

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