1. ASH review 2012 Acute leukemias
Tibor Kovacsovics
Center for Hematologic Malignancies
OHSU
I would like to thank you for the orgniazers for inviting me to this scientific session on ALL. The title of my presentation is misleading ; I am not going to present data on novel medications, but I will present you data on SCT based on the French LALA trials, to which the SAKK has participated since 1997.

3. 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

4. More gene mutations in AML?
Established genes:
- FLT3-ITD
- NPM1
- CEBPA
- cKIT
- Nras/Kras
New genes:
- TET, IDH, DMT3A, ASXL1

5. Clinical objectives of routine molecular work-up in AML
Risk stratification: distinguish high-risk from low-risk leukemias
- NPM1+, FLT3-ITD- AML: no transplant
- FLT3-ITD+ AML: transplant
Identification of drugable targets:
- FLT3-ITD+: FLT3 inhibitors (AC220, sorafenib)

6. NPM1+ and CEBPA + AML: RFS and OS in young patients
Schlenk N Engl J Med 2008

7. Consolidation therapy in young NPM1+ FLT3-ITD- AML
67% overall survival after consolidation with high-dose AraC
Thomas et al J Clin Oncol 2011
These patients can be consolidated like CBF leukemia [t(8;21) or inv(16)]

8. 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
>60
>60
>70
Becker et al J Clin Oncol 2010

9. 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

10. Current AML risk stratification

11. AML trials Cytarabine dosing Mylotarg ATRA in NPM1+ AML
FLT3 inhibitors: AC220
Vorinostat combination
What I would like to do is to review the SCT results of the LALA 94 trial in high-risk patients adn to show a meta-analysis of SCT in the 3 LALA trials.

12. 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
What I would like to do is to review the SCT results of the LALA 94 trial in high-risk patients adn to show a meta-analysis of SCT in the 3 LALA trials.

13. 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
What I would like to do is to review the SCT results of the LALA 94 trial in high-risk patients adn to show a meta-analysis of SCT in the 3 LALA trials.

14. 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
What I would like to do is to review the SCT results of the LALA 94 trial in high-risk patients adn to show a meta-analysis of SCT in the 3 LALA trials.

15. ALFA Fractionated Doses of Gemtuzumab Ozogamicin
Combined to Standard Chemotherapy
Improve Event-free and Overall Survival
In Newly-Diagnosed de novo AML Patients
Aged Years Old.
A Prospective Randomized Phase 3 Trial from the Acute Leukemia French Association (ALFA)
ALFA

16. 2nd course if BM blasts >10% at D15
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
1st CONSOLIDATION
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
2nd CONSOLIDATION 16

17. Induction results Induction cycles, N 139 1 102 (73%) 114 (82%) 2
Control
arm A
Experimental
arm B (GO)
P-value
Induction cycles, N
139 1
102 (73%)
114 (82%) 2
36 (26%)
25 (18%)
0.15
Response CR
99 (71%)
1.0
CRp
5 (4%)
14 (10%)
0.055
CR + CRp
104 (75%)
113 (81%)
0.25
Failure
29 (21%)
17 (13%)
0.075
Early death
6 (4%)
9 (6,5%)
0.60

18. Overall survival P= 0.046 by the log-rank test GO arm Control arm OS
A (control)
(n=139) B
(GO)
Deaths 71 59
Median
19.2 mo
34 mo
2-year
43.5%
53.1% HR
(95% CI) 1
0.70
( )
GO arm
Control arm
P= 0.046
by the log-rank test 18

19. Relapse-free survival (CR/CRp pts.)
RFS
A (control)
(n=104)
B (GO)
(n=113)
Events 69 50
Median
12.5 mo
28.1 mo
2-year
21.7%
50.8% HR 1
0.51
( )
GO arm P=
by the log-rank test
Control arm 19

20. OS according to cytogenetics risk-groups
Favorable/intermediate cytogenetics
Unfavorable cytogenetics
GO arm
Control arm
Control arm
GO arm

21. Effect of Mylotarg in CBF relapsed AML.2 .4 .6 .8 1 2 4 6 8 10
Overall survival %
Time (year)
GO+
GO-
p=.03 .2 .4 .6 .8 1 2 4 6 8 10
Overall survival %
Time (year)
GO+
GO-
p=.03
OS by Mylotarg exposure
Post-allo SCT survival
Hospital ASH 2011

22. 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
What I would like to do is to review the SCT results of the LALA 94 trial in high-risk patients adn to show a meta-analysis of SCT in the 3 LALA trials.

23. All-Trans Retinoic Acid + Chemotherapy in NPM-1 Mutant AML: AMLSG 07-04
Genetic profiling prior to randomization
Induction (two 28-day cycles)
Consolidation (three 28-day cycles)
ATRA 45 mg/m2 on Days 6-8,
15 mg/m2 on Days
Standard Chemotherapy*
(n = 550)
ATRA 15 mg/m2 on Days
Standard Chemotherapy*
Patients aged yrs with AML
(N = 1112)
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 (n = 374).
AML, acute myeloid leukemia; ATRA, all-trans retinoic acid; CR, complete response; EFS, event-free survival; OS, overall survival; RFS, relapse-free survival; SCT, stem cell transplantation.
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 Abstract 80.

24. CR to Induction Therapy (%)
AMLSG 07-04: Efficacy
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)
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)
ATRA + standard chemotherapy
Standard chemotherapy
100 90 90 84 80 69
69.5 70 60
CR to Induction Therapy (%) 50 40 30 20 10
AML, acute myeloid leukemia; ATRA, all-trans retinoic acid; CR, complete response; EFS, event-free survival; ITD, internal tandem duplication; OR, odds ratio; OS, overall survival
n =
142
141
345
351
NPM1-Mutated
AML
NPM1–Wild-
Type AML
Schlenk RF, et al. ASH Abstract 80.

25. David Lilienfeld,17 Eugen Leo,17 Mohit Trikha,17 and Mark Levis18
A Phase II, Open-Label, AC220 Monotherapy Efficacy (ACE) Study in Patients With Acute Myeloid Leukemia (AML) With FLT3-ITD Activating Mutations: Interim Results
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 1
Thank you. I will present today on behalf of my colleagues the results of a phase 1 study of AC220, a second generation FLT3 inhibitor.

26. Quizartinib: AC220-002 Trial Design
Study Design
Cohorts
Status
FLT3-ITD(+/-) AML subjects
Single-arm, 3-cohort
~100 sites WW
Coprimary endpoints
Composite CRc (CR+CRp+CRi) CR
Key secondary endpoints
Duration of response
Progression free survival
Overall survival
≥60 y old
FLT3 ITD+
1st relapse
~120 subjects
1st subjects dosed Nov 2009
Interim data analysis conducted on first 62 ITD+ subjects (53 evaluable for response)
≥18 y old
FLT3 ITD +
2nd relapse or post-HSCT
~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

27. 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)
Median survival for all 62 subjects = 24.6 weeks
Feb 22, 2011 data cut-off

30. AC220-002: Summary of Common (>25%) Adverse Events (Safety Population)
Preferred Term
Overall
(N=62)
N(%)
Treatment-related
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
21 (33.9)
Anorexia
Edema peripheral
17 (27.4)
6 (9.7)
Pyrexia
4 (6.5)
Dysgeusia
12 (19.4)
Hypokalemia
7 (11.3)
Feb 22, 2011 data cut-off

31. 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
What I would like to do is to review the SCT results of the LALA 94 trial in high-risk patients adn to show a meta-analysis of SCT in the 3 LALA trials.

32. 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
What I would like to do is to review the SCT results of the LALA 94 trial in high-risk patients adn to show a meta-analysis of SCT in the 3 LALA trials.

33. Vorinostat + Idarubicin/Cytarabine in Newly Diagnosed AML or Higher-Risk MDS
Single-arm phase II trial conducted in 75 patients aged 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)
IV idarubicin 8 mg/m2/day on Days 4-5
IV cytarabine 0.75 g/m2 on Days 4-6
Maintenance therapy: single-agent oral vorinostat 200 mg TID for 14 days every 28 days for up to 12 mos
AML, acute myeloid leukemia; IV, intravenous; MDS, myelodysplastic syndrome; q28d; every 28 days; tid, 3 times daily.
Garcia-Manero G, et al. ASH Abstract 763.

34. First-line Vorinostat/Idarubicin/Cytarabine in AML/Higher-Risk MDS: Efficacy
Patient Group
ORR, %
Median EFS, Wks (Range)
Median OS, Wks (Range)
All patients 85
47 (3-134)
82 (3-134)
Subgroups
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)
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)
AML, acute myeloid leukemia; EFS, event-free survival; ITD, internal tandem duplication; MDS, myelodysplastic syndrome; ORR, overall response rate; OS, overall survival.
Garcia-Manero G, et al. ASH Abstract 763.

35. 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)
Rash, cellulitis, hand-foot reaction 25 3
28 (38)
Hepatic events 6
14 (19)
Hemorrhage/bleeding 5
13 (18)
Cardiac events 4 7
11 (15)
Renal events 2
5 (7)
Edema/swelling
4 (5)
AML, acute myeloid leukemia; GI, gastrointestinal; MDS, myelodysplastic syndrome.
*Mucositis, typhlitis, colitis.
Garcia-Manero G, et al. ASH Abstract 763.

36. ALL
Ph+ ALL: single agent Dasatinib
Monoclonal antibodies

37. Ph+ ALL: single agent dasatinib
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
The data showed limued avd very short activity. The next questionwas obviously to associate imatinib with chemotherapy. Because of the hematological and non-hematological toxicity of imatinib, there was obviously some concern in giving it in combination with chemotherapy. As you will see, it tutned out not

38. 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
The data showed limued avd very short activity. The next questionwas obviously to associate imatinib with chemotherapy. Because of the hematological and non-hematological toxicity of imatinib, there was obviously some concern in giving it in combination with chemotherapy. As you will see, it tutned out not

39. Older Ph+ ALL: single agent dasatinib
Foá Blood epub 2011

40. 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
Consolidation
(Wks 8-16)
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
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
ALL, acute lymphocytic leukemia; Ph+, Philadelphia chromosome positive
*Dose reduction in patients older than 70 yrs of age.
Rousselot P, et al. ASH Abstract 172.

41. Response and Survival With Dasatinib Plus Chemotherapy
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
100
Postinduction (MRD1) 90
During consolidation (MRD2) 80 71 70 60 56
Patients With Molecular Response (%) 50 40 28 30 23 20 10
CR, complete response; MRD, minimal residual disease; OS, overall survival; RFS, relapse-free survival.
BCR-ABL/ABL ≤ .1%
MRD negative*
Response Type
*Sensitivity
Rousselot P, et al. ASH Abstract 172.

42. 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 mg/m2 on Day 1 of subsequent cycles (inotuzumab on Day 2)
ALL, acute lymphoblastic leukemia; IV, intravenous; SD, stable disease
O’Brien S, et al. ASH Abstract 875.

43. Inotuzumab Ozogamicin in Relapsed/Refractory ALL: Efficacy
Cycles
CR, n
CRp, n
CRi, n
Total Response Rate, n (%)
All cycles 9 14 5
28 (57)
Cycle 1 8
16 (33)
Cycle 2 1 6 4
11 (22)
≥ Cycle 3
1 (2)
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
Undetectable MRD attained in 63% of 27 evaluable patients with response
ALL, acute lymphoblastic leukemia; CCyR, complete cytogenetic response; CR, complete response; CRi, marrow complete response without recovery of neutrophils or platelet counts; CRp, complete response except platelets < 100,000 cells/mm3; MRD, minimal residual disease; Ph+, Philadelphia-chromosome positive
O’Brien S, et al. ASH Abstract 875.

44. 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
ALL, acute lymphoblastic leukemia; IV, intravenous; SD, stable disease
O’Brien S, et al. ASH Abstract 875.

45. 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
In combination with chemotherapy
ORR, overall response rate
O’Brien S, et al. ASH Abstract 875.

46. Immunotherapy in ALL
Various monoclonal antibodies are being developed in ALL
- anti-CD 22 (Inotuzomab)
- anti-CD19 (Seattle Genetics)
- BITE technology
What I would like to do is to review the SCT results of the LALA 94 trial in high-risk patients adn to show a meta-analysis of SCT in the 3 LALA trials.