Download Azacitidine - Aplastic Anemia and MDS International Foundation

High Risk MDS and Novel Therapy:
What’s on the Horizon?
Rafael Bejar MD, PhD
Aplastic Anemia & MDS International Foundation
Regional Patient and Family Conference
April 5th, 2014
Overview
• Refining Prognosis and ‘High’ Risk
• Novel Treatments
• Advances in Stem Cell Transplantation
• Examples from the Lab
Refining Prognosis
Low Blood Counts
71 year-old man with big red cells and low blood counts
that developed over the past 6 months.
Normal
Range
1.9
7.9
45
Low Blood Counts
71 year-old man with big red cells and low blood counts
that developed over the past 6 months.
Way too many cells in the bone marrow
4% blasts in aspirate
Normal
Range
1.9
7.9
45
Dysplasia in all three cell types
Normal Karyotype (chromosomes ok)
International Prognostic Scoring System
Greenberg et al. Blood. 1997;89:2079-88; Greenberg et al. Blood. 2012:120:2454-65.
MDA Lower Risk Model
LR-PSS Prognostic Score Value
Prognostic
Category
1
2
Risk
Category
Risk
Score
≥ 60
1
0-2
2
3-4
3
≥5
Not normal or del(5q)
Cytogenetics
Age, years
Hemoglobin, g/dL
< 10
Platelets, × 109/L
50-200
< 50
≥ 4%
BM blasts, %
100
25%-33% of patients are in Category 3
Patients, %
80
The survival of Category 3 patients is
similar to that of Intermediate-2 risk
patients using the IPSS!
60
40
20
0
0
12
24
36
48
60
72
84
Survival, months from referral
96
Garcia-Manero G, et al. Leukemia. 2008;22:538-543.
IPSS-Revised (IPSS-R)
ipss-r.com
Greenberg et al. Blood. 2012:120:2454-65.
Current Therapies
Guidelines for Higher Risk MDS
Goal: to improve DURATION OF LIFE
Hypomethylating Agents
Inhibitors of DNA methyl transferases:
Both incorporate into DNA and cause hypomethylation (DEC > AZA)
AZA preferentially causes DNA damage and induces apoptosis
Azacitidine
AZA-001 Phase III: AZA vs. ld-ARA-C vs. supportive care
OS benefit: + 9.5 mos
Time to AML: 17.8 vs. 11.5 mos
TI: 45% vs. 11%
Azacitidine Response:
ORR: ~50%
CR: ~17%
Median time to response: 3 cycles (81% by cycle 6)
Decitabine
Decitabine Phase III Trial
ADOPT Trial and 3-Schedule Trial
Dosed q8h x 3 days per 28 days
Dosed q24h x 5 days per 28 days
CR: 17%
CR: 17%
CR+PR: 30%
CR+PR: 32%
ORR: 52% (+ heme response)
Best response: 50% at 2 cycles
Major Toxicity:
Neutropenia: 31% (FN 11%)
Thrombocytopenia: 18%
Guidelines for Higher Risk MDS
Goal: to improve DURATION OF LIFE
Special Considerations:
Refer for Transplant Early
- Even patients in their 70’s can benefit from RIC transplant
AZA > DEC (for now)
- AZA has been shown to have a survival advantage, DEC has not (yet)
Don’t forget Quality of Life
- Consider treatment palliative and weigh against patient needs
Look for Clinical Trials
- Few option after AZA are available and none are approved
Outcomes After Azacitidine
Reasons for “failure” in azacitidine failure study
9% didn’t tolerate AZA (69% were not responding, 31% had an initial response)
55% primary failure (progression in 60% , stable disease without response in 40%)
36% secondary failure after initial response (best response: CR 20% , PR 7%, HI 73%)
Outcomes after failure
Median overall survival for whole cohort post-AZA: 5.6 months
2 year survival: 15%
Favorable factors: female, younger (<60), better risk karyotype, <10% blasts, some
response to azacitidine
Comparison to decitabine failures @ MDACC: median survival 4.3 months, n=87
Slide borrowed from Dr. David Steensma
Prébet T et al, J Clin Oncol 2011; Aug 20;29(24):3322-7. Epub 2011 Jul 25.
Jabbour E et al, Cancer 2010; 116:3830–3834.
Outcomes After Azacitidine
• Data available on 435 pts
– from AZA001, J9950, J0443, French compassionate program
• Overall median survival after azacitidine failure: 5.6 months
Subsequent therapy
Number of patients (%)
Median survival
Allogeneic transplant
37 (9%)
19.5 months
Investigational therapy
(e.g. IMiD, HDACi, other)
44 (10%)
13.2 months
Intensive cytotoxic therapy
(e.g., 3&7)
35 (8%)
8.9 months
Low-dose chemotherapy
(e.g. LDAC, 6-MP)
32 (7%)
7.3 months
Palliative / supportive care
122 (28%)
4.1 months
Subsequent therapy unknown
165 (38%)
3.6 months
Slide borrowed from Dr. David Steensma
Prébet T et al J Clin Oncol 2011; 29:3322-7
Jabbour E et al Cancer 2010;116(16):3830-4
Treatment of Higher Risk MDS
We need BETTER therapies!
We need MORE therapies!
Better Formulations
Oral Azacitidine
2011 – Oral AZA given 7 days out of 28 is safe and appears effective
2012 – Treating for 14 or 21 days enhances biologic activity
and is effective – 34% ORR and 40% transfusion independent
2013 – Phase III Clinical Trial of Lower Risk Transfusion Dependence
- should lead to FDA approval
PROS
Oral drug that can be taken at home
CONS
Gastrointestinal side effects
May take 6-8 cycles to reach maximum response
SGI-110
Resistant to degradation
Longer half-life
May allow less frequent dosing
- 5 days vs. once weekly
In clinical trials at USC
Yoo C B et al. Cancer Res 2007;67:6400-8.
Combination Therapies
Combination Therapy
Approach: Improve upon existing therapies
Example:
At least 2 clinic trials in development combine:
Azacitidine
+
Deferasirox (Exjade)
Advantage: drugs are already FDA approved for MDS
Positive results can quickly change practice!
Lenalidomide + Azacitidine
• Multicenter, single-arm open-label phase II continuation study (N = 36)
• Patient eligibility
– Higher-risk MDS: CMML-2, RAEB-1 or -2, IPSS intermediate 2 or high
(score ≥ 1.5), or revised IPSS score 4 or 5
– No previous treatment with lenalidomide or azacitidine
• Maximum of seven 28-day treatment cycles administered
– Lenalidomide 10 mg on Days 1-21
– Azacitidine 75 mg/m2 on Days 1-5
– After 7 cycles, patients could continue azacitidine monotherapy off study
• Median patient follow-up: 12 mos (range: 3-55)
Slide borrowed from Dr. Rami Komrokji
Sekeres MA, et al. Blood. 2012;120:4945-4951.
Lenalidomide + Azacitidine
100
CR
Hematologic
improvement
90
Response Rate (%)
80
70
60
28
50
• Median CR duration: 17+ mos
(range: 3-39+)
• Median OS among CR:
37+ mos (range: 7-55+)
40
30
20
44
10
• 8 patients evolved to AML at
median of 18 mos after CR
0
Lenalidomide/
Azacitidine
(N = 36)
Slide borrowed from Dr. Rami Komrokji
• Treatment well tolerated; FN was
most common grade 3/4 AE (22%)
Sekeres MA, et al. Blood. 2012;120:4945-4951.
Azacitidine + Vorinostat
Dose and schedule
Eligibility
Age ≥ 18 years
Untreated MDS (≥ Int-1) or AML
And any of the following:
Total bilirubin ≥ 2 mg/dL
Creatinine ≥ 2 mg/dL
ECOG performance status > 2
Excluded from all other clinical trials:
– Presence of other active
malignancy
AZA 75 mg/m2 IV QD days 1 to 5
Vorinostat 200 mg PO TID days 1 to 5
Cycles repeated every 28 days
Patients (N=30)
CR (%)
CRp (%)
ORR (%)
ALL
8 (26)
1 (3)
30
Diploid (7)
3 (42)
0
42
-5/-7 (16)
3 (10)
1 (3)
13
+8 (3)
2 (66)
0
66
Slide borrowed from Dr. Rami Komrokji
Garcia-Manero et al. Blood 2011
S1117 (US/Canada Intergroup) Study
n=80
Eligible:
Higher-risk MDS or
CMML
n=80
(5-19% blasts or
IPSS Int-2/High)
n=80
Azacitidine monotherapy
(7 days x 75 mg/m2/day)
Power:
81% probability of
detecting a 20%
difference in ORR
(with alpha 0.05)
Azacitidine + lenalidomide
(10 mg/d for 21/28 days)
Azacitidine + vorinostat
(600 mg/day)
Primary endpoint: overall response rate [ORR] (IWG 2006)
Secondary endpoints: overall and progression-free survival, safety
Slide borrowed from Dr. David Steensma
Principal investigator: Mikkael Sekeres, Cleveland Clinic
Novel Agents
Pipeline of Completely New Drugs
Ezatiostat
Suffering
MAP Kinase Inhibitors
TGF-beta Inhibitors
Neddylation Inhibitors
Indolamine Dioxygenase Inhibitors
p53 Modulators
Hedgehog Inhibitors
Aminopeptidase Inhibitors
Options
RNA Pol I Inhibitors
Anti-CD47 Antibodies
Rigosertib (ON-01910)
PLK1 & Cdc25C Inhibition
Currently in Phase III Trial
Multikinase Inhibitor
3-day continuous infusion
ON 01910
Slide borrowed from Dr. Rami Komrokji
Gumireddy K, et. al. Cancer Cell 2005; 7: 275.
Rigosertib after Azacitidine
N
BM CR (+HI)
HI
ORR
All patients
32
6 (1)
4
10/32 (31%)
3-day infusions
17
4 (1)
3
7/17 (41%)
3-day pivotal (1800 mg/d)
13
4 (1)
2
6/13 (46%)
100
OS by Marrow
Blast Response
Survival probability (%)
80
BM Blast Response
Not Assessed
Progressive Disease
Stable BM Blast Count
50%+ BM Blast Decrease
Median:
68 wks
60
40
20
0
0
Slide borrowed from Dr. Rami Komrokji
20
40
Weeks
60
80
Raza et al. Blood 2011; 3822
Hedgehog Inhibitors
Pathway important for stem cells
Several inhibitors in development
Drug PF-04449913
Phase I in AML and MDS had
several responders (7/21)
Combination of PF-04449913 and
decitabine is open and will be
available at UCSD to previously
untreated MDS patients.
Slide borrowed from Dr. Rami Komrokji
Gumireddy K, et. al. Cancer Cell 2005; 7: 275.
Ezatiostat (Telintra)
ESAs
TPO mimetics
G-CSF (neupogen)
Stimulates differentiation pathway downstream of growth factor receptors
Ezatiostat (Telintra)
Target population are lower risk patients, but trials show activity
in heavily pretreated patients!
Phase II Study:
- 56% had previously received Azacitidine or Decitabine
- 38% had previously received Lenalidomide
- 77% had previously received Erythropoietin
Results:
- 22% had a red cell response
- 19% had a neutrophil response
- 20% had both
- 29% had reduced transfusion needs
- average time to response was 8 WEEKS!
- very little toxicity!!
Raza et al. Cancer. 2013. 118(8) 2138-47.
Stem Cell Transplantation
Trends in Transplantation
Goal of Hematopoietic Stem Cell Transplantation:
#1) Replace a dysfunction host hematopoietic
system with normal, healthy donor marrow.
#2) Allow the donor immune system to destroy the
abnormal, diseased host cells (MDS).
Donor Cells
Conditioning
Engraftment
Graft-vs.-MDS
Allogeneic Stem Cell
Transplantation for MDS
<5% of patients with MDS currently undergo allogeneic SCT
“Only curative therapy”
Patients who go in to RIC allo SCT with <10% blasts appear to have lower relapse
Optimal timing, pre-transplant therapy, conditioning unclear;
usually reserved for IPSS Int-2/High (IBMTR Markov analysis)
Transplant candidate
Donor identified
Survives transplant;
MDS cured!
(35-40%)
Slide borrowed from Dr. David Steensma
Survives transplant;
MDS recurs/persists
(30-40%)
Dies from complication
of transplant
(20-25%)
Cutler C et al Blood 2004; 104(2):579-85
Sekeres M et al JNCI 2008;100(21):1542-51.
Obstacles to Transplantation
Graft Rejection
– need to suppress the host immune system
Toxicity
– infection
– organ damage
– graft versus host disease
Finding a Donor
– siblings match only 25% of the time
– and are often too old or ill to donate
Overcoming Obstacles
Avoiding Graft Rejection
– better approaches to immune suppression
Less Toxicity
– better supportive care
– better antigen matching
– reduced intensity conditioning
Alternative Sources for Stem Cells
– haploidentical – “half” match
– umbilical cord blood stem cells
100
Trends in Allogeneic Transplants
by Transplant Type and Recipient Age*
1990-2010
100
Transplants, %
< 50 years
>= 50 years
80
80
60
60
40
40
20
20
0
<=20 yrs
21-40 yrs
41-50 yrs
51-60 yrs
>60 yrs
0
1990-1996 1997-2003 2004-2010 1990-1996
1997-2003 2006-2010
2004-2010
2001-2005
* Transplants for AML, ALL, NHL, Hodgkin Disease, Multiple Myeloma
200
Allogeneic Transplants for Age > 20yrs,
Registered with the CIBMTR, 1993-2010
14,000
13,000
12,000
Number of Transplants
11,000
- by Donor Type and Graft Source Related BM/PB
Unrelated BM
Unrelated PB
Unrelated CB
10,000
9,000
8,000
7,000
6,000
5,000
4,000
3,000
2,000
1,000
0
1993-94
1995-96
1997-98
1999-00
2001-02
2003-04
2005-06
2007-08
2009-10
Genetics and Transplantation
Overall Survival After Transplant
Blasts < 5% (n=42)
Blasts ≥ 5% (n=45)
p = 0.029
Bejar et al. ASH Meeting 2012. (in submission)
Other karyotype (n=59)
Complex karyotype (n=28)
p = 0.005
Genetics and Transplantation
72 patients with select mutations
Bejar et al. ASH Meeting 2012. (in submission)
TK Pathway = NRAS, KRAS, CBL, CBLB, JAK2, PTPN11, BRAF, MPL, KIT
Genetics and Transplantation
Overall Survival After Transplant
No Adverse Mutation (n=47)
TP53 Mutated (n=18)
No Complex Karyotype (n=59)
TET2 Mutated w/o TP53 mutation (n=10)
Complex and TP53 Mut Absent (n=12)
DNMT3A Mutated w/o TP53 or TET2 mutation (n=12)
Complex and TP53 Mut Present (n=16)
Genetic testing can better predict risk of transplantation
Identify patients that are unlikely to do well with standard approaches.
Find those that might do better than expected!
Immunologic Therapy
Killer T-cell
Tumor Cell
Chimeric Antigen Receptor
Plasma B-cell
Immunologic Therapy
Chimeric Antigen Receptor
Modified T-cell
Tumor Cell
Acknowledgements:
Bejar Lab - UCSD
Columbia University
Albert Perez
Azra Raza
Brigham and Women’s
MD Anderson Cancer Center
Ben Ebert
Allegra Lord
Ann Mullally
Anu Narla
Bennett Caughey
Bernd Boidol
Damien Wilpitz
Marie McConkey
Guillermo Garcia-Manero
Hagop Kantarjian
Sherry Pierce
Gautam Borthakur
DFCI / Broad
David Steensma
Donna Neuberg
Kristen Stevenson
Mike Makrigiorgos
Derek Murphy
Naomi Galili
Memorial Sloan-Kettering
Ross Levine
Omar Abdel-Wahab