ASH review 2012
Acute leukemias
Tibor Kovacsovics
Center for Hematologic Malignancies
OHSU
Whole genome sequencing in acute
leukemia
• AML:
- IDH and DMT3A are prototypes of genes
identified by this approach
- goal is to sequence a total of 500 AMLs
- AML has an average of 3 mutated recurrent
mutations
Ley Nature 2008
Mardis New Engl J Med 2009
Ley N Engl J Med 2010
Welch ASH 2011
More gene mutations in AML?
• Established genes:
- FLT3-ITD
- NPM1
- CEBPA
- cKIT
- Nras/Kras
• New genes:
- TET, IDH, DMT3A, ASXL1
Clinical objectives of routine
molecular work-up in AML
• Risk stratification: distinguish high-risk from lowrisk leukemias
- NPM1+, FLT3-ITD- AML: no transplant
- FLT3-ITD+ AML: transplant
• Identification of drugable targets:
- FLT3-ITD+: FLT3 inhibitors (AC220, sorafenib)
NPM1+ and CEBPA + AML: RFS and OS
in young patients
Schlenk N Engl J Med 2008
Consolidation therapy in young
NPM1+ FLT3-ITD- AML
• 67% overall survival after consolidation with highdose AraC
Thomas et al J Clin Oncol 2011
• These patients can be consolidated like CBF
leukemia [t(8;21) or inv(16)]
OS in older NPM1+ AML after standard
therapy
• ~80% CR and
improved overall
survival rate in
patients >60
• These patients are
candidates for 7+3
and consolidation
Becker et al J Clin Oncol 2010
• >60
>60
>70
Current cytogenetic and molecular
work-up in AML
• Conventional cytogenetics and FISH panel
• PCR: FLT3-ITD, FLT3 variant, NPM1,
CEBPA, c-KIT in CBF leukemias
• Sequenom panel for gene mutations
Current AML risk stratification
AML trials
•
•
•
•
•
Cytarabine dosing
Mylotarg
ATRA in NPM1+ AML
FLT3 inhibitors: AC220
Vorinostat combination
Cytarabine dosing
• 3 randomized trials, with different designs
- 2 studies of high-dose AraC to multi-agent
consolidation
Thomas J Clin Oncol 2011; Miyazawi Blood 2011
- 1 study of high versus low cumulative doses
of AraC
Lowenberg N Engl J Med
Cytarabine dosing
• We probably give too much high-dose AraC
• High-dose AraC had best outcome in CBF
leukemia
• High-dose AraC was more toxic than
multiagent consolidation
• In a situation of AraC shortage, there are
alternative consolidation regimens in non-CBF
AML
Mylotarg
• Mylotarg has been removed by Pfizer in 2009
after increased toxicity was seen in a randomzied
SWOG trial
• Ironically, some benefit has been observed since
then in randomized clinical trials in CBF leukemias
• New positive studies were reported at ASH
Fractionated Doses of Gemtuzumab Ozogamicin
Combined to Standard Chemotherapy
Improve Event-free and Overall Survival
In Newly-Diagnosed de novo AML Patients
Aged 50-70 Years Old.
A Prospective Randomized Phase 3 Trial
from the Acute Leukemia French Association (ALFA)
ALFA
53rd ASH Annual Meeting ♦ San Diego, CA
ALFA
Treatment arms
Randomization
Arm A
Arm B
DNR 60 mg/m2 D1 to D3
AraC 200 mg/m2 D1 to D7
DNR 60 mg/m2 D1 to D3
AraC 200 mg/m2 D1 to D7
GO 3 mg/m2 D1, D4, D7
INDUCTION
2nd course if BM blasts >10% at D15
DNR 60 mg/m2 D1, D2
AraC 1g/m2/12h D1 to D3
CR or CRp
DNR 60 mg/m2 D1
AraC 1g/m2/12h D1 to D4
DNR 60 mg/m2 D1
AraC 1g/m2/12h D1 to D4
GO 3 mg/m2 D1
DNR 60mg/m2 D1,D2
AraC 1g/m2/12h D1 to D4
DNR60 mg/m2 D1,D2
AraC 1g/m2/12h D1 à D4
GO 3mg/m2 D1
53rd ASH Annual Meeting ♦ San Diego, CA
1st CONSOLIDATION
2nd CONSOLIDATION
ALFA
Induction results
Induction cycles, N
Control
arm A
Experimental
arm B (GO)
139
139
P-value
0
1
1
102 (73%)
114 (82%)
2
36 (26%)
25 (18%)
0.15
99 (71%)
99 (71%)
1.0
5 (4%)
14 (10%)
0.055
CR + CRp
104 (75%)
113 (81%)
0.25
Failure
29 (21%)
17 (13%)
0.075
6 (4%)
9 (6,5%)
0.60
Response
CR
CRp
Early death
53rd ASH Annual Meeting ♦ San Diego, CA
ALFA
Overall survival
OS
GO arm
A (control)
(n=139)
B
(GO)
(n=139)
Deaths
71
59
Median
19.2 mo
34 mo
2-year
43.5%
53.1%
1
0.70
(0.50-0.99)
HR
(95% CI)
Control arm
53rd ASH Annual Meeting ♦ San Diego, CA
P= 0.046
by the log-rank test
ALFA
Relapse-free survival (CR/CRp pts.)
RFS
GO arm
A (control)
(n=104)
B (GO)
(n=113)
Events
69
50
Median
12.5 mo
28.1 mo
2-year
21.7%
50.8%
1
0.51
(0.36-0.74)
HR
Control arm
53rd ASH Annual Meeting ♦ San Diego, CA
P= 0.00029
by the log-rank test
ALFA
OS according to cytogenetics risk-groups
Favorable/intermediate
cytogenetics
Unfavorable
cytogenetics
GO arm
Control arm
Control arm
GO arm
53rd ASH Annual Meeting ♦ San Diego, CA
ALFA
Effect of Mylotarg in
CBF relapsed AML
OS by Mylotarg exposure
Post-allo SCT survival
Hospital ASH 2011
Mylotarg
• Proof of principle of the benefit of
immmunotherapy in AML
• The administration of lower and fractionated
doses of Mylotarg may lead to more durable
responses and reduced toxicity
Myelodysplastic Syndromes and Acute Leukemia
clinicaloptions.com/oncology
All-Trans Retinoic Acid + Chemotherapy in
NPM-1 Mutant AML: AMLSG 07-04
Genetic profiling prior
to randomization
Patients
aged 18-60 yrs
with AML
(N = 1112)
Induction (two 28-day cycles)
Consolidation (three 28-day cycles)
ATRA 45 mg/m2 on Days 6-8,
15 mg/m2 on Days 9-21 +
Standard Chemotherapy*
(n = 550)
ATRA 15 mg/m2 on Days 6-28 +
Standard Chemotherapy*
Standard Chemotherapy*
(n = 562)
Standard Chemotherapy*
*Standard induction chemotherapy consisted of idarubicin/cytarabine/etoposide initiated on Day 1, with an
additional randomization ± valproic acid. Standard consolidation chemotherapy consisted of high-dose cytarabine
± valproic acid. Valproic acid included only from 2004-2006 (n = 374).

Primary endpoints: CR after induction therapy, EFS (patients with CR who received
allogeneic SCT censored at date of transplantation)

Secondary endpoints: RFS, OS
Schlenk RF, et al. ASH 2011. Abstract 80.
Myelodysplastic Syndromes and Acute Leukemia
clinicaloptions.com/oncology
AMLSG 07-04: Efficacy
CR to Induction Therapy (%)
ATRA + standard chemotherapy
Standard chemotherapy
100
90
80
70
60
50
40
30
20
10
0
90
84
69 69.5

Addition of ATRA to standard
chemotherapy
– Significantly improved odds of CR in
NPM1-mutated AML (OR: 2.29; P =
.05), but not NPM1–wild-type AML
(OR: 1.09;
P = .66) in multivariate analysis
– Benefit independent of FLT3
ITD status (OR: 0.70; P = .39)
n = 142 141
NPM1-Mutated
AML
345 351
NPM1–WildType AML
Schlenk RF, et al. ASH 2011. Abstract 80.
– Significantly improved EFS in
NPM1-mutated AML (P = .03), but
not NPM1–wild-type AML
(P = .78)
– Significantly improved OS in total
patient population (P = .03)
A Phase II, Open-Label, AC220
Monotherapy Efficacy (ACE) Study in
Patients With Acute Myeloid Leukemia
(AML) With FLT3-ITD Activating
Mutations: Interim Results
1
Jorge Cortes,1 Alexander Perl,2 Catherine Smith,3 Tibor Kovacsovics,4 Herve Dombret,5 Hartmut Dohner,6
Björn Steffen,7 Arnaud Pigneux,8 Philippe Rousselot,9 Jürgen Krauter,10 Giovanni Martinelli,11 Elihu Estey,12
Alan Burnett13, Anthony Ho14, Norbert Ifrah15, Theo de Witte16, Robert Corringham17, Joyce James17,
David Lilienfeld,17 Eugen Leo,17 Mohit Trikha,17 and Mark Levis18
Quizartinib:
AC220-002 Trial Design
Study Design
• FLT3-ITD(+/-) AML subjects
• Single-arm, 3-cohort
• ~100 sites WW
• Coprimary endpoints
• Composite CRc
(CR+CRp+CRi)
• CR
Cohorts
•
•
•
•
≥60 y old
Status
• 1st subjects dosed Nov 2009
FLT3 ITD+
1st relapse
~120 subjects
• ≥18 y old
• FLT3 ITD +
• 2nd relapse or
• Interim data analysis
conducted on first 62 ITD+
subjects (53 evaluable for
response)
post-HSCT
• Key secondary endpoints
• Duration of response
• Progression free survival
• Overall survival
• ~120 subjects
• ≥18 y old
• FLT3 ITD - cohorts 1
&2
• ~60 subjects
CR=complete remission; CRi=complete remission with incomplete hematologic recovery;
CRp=complete remission with incomplete platelet recovery; QD=once daily
AC220-002:
Preliminary Efficacy Analysis
Cohort
CRc: Composite
Complete
Response*
Median
Survival*
Transition
to HSCT**
≥18 years
2nd Relapse
48%
Not yet reached
22/31 alive
34%
≥60 years
1st Relapse
41%
24.1 weeks
10/22 alive
8%
Total
45%
24.7 weeks
32/53 alive
23%
*Based on efficacy evaluable population (N=53)
** Based on safety population (N=62)
Feb 22, 2011 data cut-off
AC220-002: Summary of Common (>25%)
Adverse Events (Safety Population)
Overall
(N=62)
N(%)
Treatment-related
(N=62)
N(%)
Any Adverse Event
62 (100.0)
55 (88.7)
Febrile neutropenia
30 (48.4)
14(22.6)
Nausea
29 (46.8)
22 (35.5)
Fatigue
28 (45.2)
16 (25.8)
Diarrhea
24 (38.7)
13 (21.0)
Vomiting
23 (37.1)
18 (29.0)
Electrocardiogram QT prolonged
22 (35.5)
21 (33.9)
Anorexia
21 (33.9)
13 (21.0)
Edema peripheral
17 (27.4)
6 (9.7)
Pyrexia
17 (27.4)
4 (6.5)
Dysgeusia
16 (25.8)
12 (19.4)
Hypokalemia
16 (25.8)
7 (11.3)
Preferred Term
Feb 22, 2011 data cut-off
AC220 (quizartinib) planned trials
• Monotherapy phase 3 trial in relapsed FLT3-ITD +
AML
• Combination phase 1 induction and consolidation
trial in newly diagnosed FLT3-ITD + AML
•
Maintenance phase 1 study in post-allogeneic stem
cell transplant
Other FLT3 inhibitors
• PKC412:
- enrollment in randomized upfront study
completed
• Sorafenib:
•
- several combination trials ongoing
Several new agents are being tested in phase 1-2
trials
Myelodysplastic Syndromes and Acute Leukemia
clinicaloptions.com/oncology
Vorinostat + Idarubicin/Cytarabine in Newly
Diagnosed AML or Higher-Risk MDS

Single-arm phase II trial conducted in 75 patients aged 19-65 yrs

Induction therapy (1 cycle)

–
Oral vorinostat 500 mg TID on Days 1-3
–
IV idarubicin 12 mg/m2/day on Days 4-6
–
IV cytarabine 1.5 g/m2 as continuous infusion daily for 3-4 days on Days 4-7
Consolidation therapy (5 cycles)
–
Oral vorinostat 500 mg TID on Days 1-3
–
IV idarubicin 8 mg/m2/day on Days 4-5
–
IV cytarabine 0.75 g/m2 on Days 4-6
 Maintenance
single-agent
oral vorinostat 200 mg TID for 14 days every 28 days for up to 12
Garcia-Manero
G, et therapy:
al. ASH 2011.
Abstract 763.
mos
Myelodysplastic Syndromes and Acute Leukemia
clinicaloptions.com/oncology
First-line Vorinostat/Idarubicin/Cytarabine
in AML/Higher-Risk MDS: Efficacy
Patient Group
ORR, %
Median EFS,
Wks (Range)
Median OS,
Wks (Range)
85
47 (3-134)
82 (3-134)
 Diploid cytogenetics
93
68 (5-134)
105 (5-134)
 -5 or -7
59
14 (3-92)
34 (3-92)
 FLT3 ITD
100
66 (6-134)
91 (6-134)
All patients
Subgroups
 An unmatched comparison with historical data showed that response
to vorinostat/ idarubicin/cytarabine markedly higher than with
standard idarubicin/ cytarabine
– 85% vs 72% (P = .01)
Garcia-Manero G, et al. ASH 2011. Abstract 763.
Myelodysplastic Syndromes and Acute Leukemia
clinicaloptions.com/oncology
First-line Vorinostat/Idarubicin/Cytarabine
in AML/Higher-Risk MDS: Safety
Adverse Events Observed During
Induction Therapy (Incidence ≥
5%)
Grade 1/2 Events, n
Grade 3/4 Events, n
Total Events, n (%)
Diarrhea
26
27
53 (72)
Nausea/vomiting
40
8
48 (65)
Other GI events*
18
11
29 (39)
25
3
28 (38)
Hepatic events
6
8
14 (19)
Hemorrhage/bleeding
8
5
13 (18)
Cardiac events
4
7
11 (15)
Renal events
3
2
5 (7)
Edema/swelling
4
0
4 (5)
Rash, cellulitis, hand-foot reaction
*Mucositis, typhlitis, colitis.
Garcia-Manero G, et al. ASH 2011. Abstract 763.
ALL
• Ph+ ALL: single agent Dasatinib
• Monoclonal antibodies
•
•
•
•
•
Ph+ ALL:
single agent dasatinib
N= 53
Median age 53 (23-78)
Dasatinib dose 140mg qd with 30 day steroid
post-remission regimen free after 84d
responses:
- hematologic : 100% CR, median day 23
- median OS 30.8 months (unknown in patients on
Dasatinib maintenance)
Foá Blood epub 2011
Ph+ ALL: single agent dasatinib
• relapse: at 20 months 20% free of relapse
• median time to relapse 5.9 months
• relapse occured in 14/19 patients on TKI
alone, in 5/14 on TKI +chemo, in 2/16 allo
patients
• prognostic role of BCR-ABL reduction >3 logs
Foá Blood epub 2011
Older Ph+ ALL:
single agent dasatinib
Foá Blood epub 2011
Phase II Study of Dasatinib + Chemo
in Older Patients With Ph+ ALL
Treatment Phase
Treatment
Schedule
Prephase
Dexamethasone 10 mg/m2
Days -7 to -3
Induction
(Wks 1-8)
Dasatinib 140 mg*
Vincristine 1 mg
Dexamethasone 40 mg
Daily for 8 wks
Days 1 and 2 repeated weekly
for 4 wks
Dasatinib 100 mg
Methotrexate 1000 mg/m2*
L-asparaginase 10,000 IU/m2*
Cytarabine 1000 mg/m2/12 hr*
Daily for 6 cycles
Day 1 of cycles 1, 3, 5
Day 2 of cycles 1, 3, 5
Days 1, 3, and 5 of cycles 2, 4, 6
Consolidation
(Wks 8-16)
Maintenance
(Wks 32-40)
Dasatinib 100 mg/day alternating with 6-mercaptopurine and methotrexate every other mo
and dasatinib/vincristine once every 2 mos for ≤ 24 mos
*Dose reduction in patients older than 70 yrs of age.
Rousselot P, et al. ASH 2010. Abstract 172.
•
Median follow-up: 20 mos
•
CR: 63 of 71 patients (88.7%)
•
Median OS: 27 mos
•
Median RFS: 25 mos
– Additional chromosomal
abnormalities (P = .009) and lack
of molecular response during
consolidation (P < .0001)
associated with lower RFS rate
•
19 patients (27%) relapsed after
a median of 4.8 mos
– Majority had T315I BCR-ABL
mutation
Rousselot P, et al. ASH 2010. Abstract 172.
Patients With Molecular Response
(%)
Response and Survival With
Dasatinib Plus Chemotherapy
100
90
80
70
60
50
40
30
20
10
0
Postinduction (MRD1)
During consolidation (MRD2)
71
56
23
28
BCR-ABL/ABL
MRD negative*
≤ .1%
Response Type
*Sensitivity 10-4.5
Myelodysplastic Syndromes and Acute Leukemia
clinicaloptions.com/oncology
Inotuzumab Ozogamicin in Patients With
Relapsed/Refractory ALL

Inotuzumab ozogamicin: monoclonal anti-CD22 antibody conjugated with calicheamicin

Phase I dose-escalation study conducted in 49 patients

Patient eligibility
– 16 yrs of age or older in first 10 patients; children subsequently eligible
– Relapsed/refractory, CD22-positive ALL

Up to 8 treatment cycles administered
– Inotuzumab initiated in first 3 adults and 3 children at 1.3 mg/m2 IV, subsequently
increased to 1.8 mg/m2 IV over 1 hr every 3-4 wks
– If SD or no response after 2 courses, patients could also receive rituximab 375
mg/m2 on Day 1 of subsequent cycles (inotuzumab on Day 2)
O’Brien S, et al. ASH 2011. Abstract 875.
Myelodysplastic Syndromes and Acute Leukemia
clinicaloptions.com/oncology
Inotuzumab Ozogamicin in
Relapsed/Refractory ALL: Efficacy
Cycles
CR, n
CRp, n
CRi, n
Total Response Rate, n
(%)
9
14
5
28 (57)
 Cycle 1
8
8
0
16 (33)
 Cycle 2
1
6
4
11 (22)
 ≥ Cycle 3
0
0
1
1 (2)
All cycles

Median response duration: 5.0 mos

No clear correlations between response and baseline patient/disease characteristics except
regarding karyotype

–
Lower response rate in patients with Ph+ ALL: 3 of 7 (43%)
–
Lower response rate in patients with ALL with t(4;11): 1 of 5 (20%)
CCyR attained in 89% of 18 evaluable patients with response
O’Brien
S, et al. ASH MRD
2011. Abstract
 Undetectable
attained875.
in 63% of 27 evaluable patients with response
Myelodysplastic Syndromes and Acute Leukemia
clinicaloptions.com/oncology
Inotuzumab Ozogamicin in Relapsed/
Refractory ALL: Other Outcomes

Inotuzumab concentration in blood at 3 hrs postdose significantly associated with
response among 23 patients with evaluable PK data (P = .008)

Inotuzumab generally well tolerated
– Treatment-associated fever (Days 1-2: 90%) and hypotension (Days 1-2: 26%)
generally occurred during first cycle only and transient
– Liver function abnormalities also associated with inotuzumab, but reversible and
typically mild

22 patients underwent allogeneic SCT after inotuzumab (second transplantation for 5
patients)
– 5 patients developed suspected veno-occlusive disease after transplantation
O’Brien S, et al. ASH 2011. Abstract 875.
Myelodysplastic Syndromes and Acute Leukemia
clinicaloptions.com/oncology
Inotuzumab Ozogamicin in Relapsed/
Refractory ALL: Conclusions
 Inotuzumab yielded very high response rates in patients with
relapsed/refractory ALL when administered as single agent
– ORR: 57%
– Response correlated with inotuzumab plasma levels after dosing
 Inotuzumab generally well tolerated, with major toxicities
including thrombocytopenia and abnormal liver function tests
 Plans under way to further investigate inotuzumab in ALL
– Weekly schedule
Inal.combination
O’Brien–S, et
ASH 2011. Abstractwith
875.
chemotherapy
Immunotherapy in ALL
• Various monoclonal antibodies are being
developed in ALL
- anti-CD 22 (Inotuzomab)
- anti-CD19 (Seattle Genetics)
- BITE technology