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.

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 low-risk 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 high-dose 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 >60 >60 >70 Becker et al J Clin Oncol 2010

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 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.

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.

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.

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.

ALFA 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

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

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

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 (0.50-0.99) GO arm Control arm P= 0.046 by the log-rank test 18

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 (0.36-0.74) GO arm P= 0.00029 by the log-rank test Control arm 19

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

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

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.

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 9-21 + Standard Chemotherapy* (n = 550) ATRA 15 mg/m2 on Days 6-28 + Standard Chemotherapy* Patients aged 18-60 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 2004-2006 (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 2011. Abstract 80.

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 2011. Abstract 80.

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.

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

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

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

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.

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.

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) 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 2011. Abstract 763.

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 2011. Abstract 763.

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 2011. Abstract 763.

ALL Ph+ ALL: single agent Dasatinib Monoclonal antibodies

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

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

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 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 2010. Abstract 172.

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 10-4.5 Rousselot P, et al. ASH 2010. Abstract 172.

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) ALL, acute lymphoblastic leukemia; IV, intravenous; SD, stable disease O’Brien S, et al. ASH 2011. Abstract 875.

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 2011. Abstract 875.

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 2011. Abstract 875.

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 2011. Abstract 875.

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.