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ASH review 2012 Acute leukemias

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

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ASH review 2012 Acute leukemias

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  1. ASH review 2012Acute leukemias Tibor Kovacsovics Center for Hematologic Malignancies OHSU

  2. Whole genome sequencing in acute leukemia • AML: - IDH and DMT3A are prototypes of genesidentified by thisapproach - goal is to sequence a total of 500 AMLs - AML has an average of 3 mutatedrecurrentmutations Ley Nature 2008 Mardis New Engl J Med 2009 Ley N Engl J Med 2010 Welch ASH 2011

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

  4. 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)

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

  6. Consolidation therapy in youngNPM1+ FLT3-ITD- AML • 67% overall survival after consolidation with high-dose AraC Thomas et al J ClinOncol 2011 • These patients can be consolidated like CBF leukemia [t(8;21) or inv(16)]

  7. 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

  8. 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

  9. Current AML risk stratification

  10. AML trials • Cytarabine dosing • Mylotarg • ATRA in NPM1+ AML • FLT3 inhibitors: AC220 • Vorinostatcombination

  11. Cytarabine dosing • 3 randomized trials, withdifferent designs - 2 studies of high-doseAraC 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

  12. Cytarabine dosing • Weprobablygivetoomuchhigh-doseAraC • High-doseAraChad best outcome in CBF leukemia • High-doseAraCwas more toxicthanmultiagent consolidation • In a situation of AraCshortage, there are alternative consolidation regimens in non-CBF AML

  13. Mylotarg • Mylotarg has been removed by Pfizer in 2009 afterincreasedtoxicitywasseen in a randomzied SWOG trial • Ironically, somebenefit has been observedsincethen in randomizedclinical trials in CBF leukemias • New positive studieswerereportedat ASH

  14. A Prospective Randomized Phase 3 Trialfrom the Acute Leukemia French Association (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. ALFA

  15. 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

  17. Overall survival GO arm P= 0.046 by the log-rank test Control arm

  18. Relapse-free survival (CR/CRp pts.) GO arm P= 0.00029 by the log-rank test Control arm

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

  20. Overall survival % Overall survival % GO+ GO+ 1 1 .8 .8 .6 .6 GO- GO- .4 .4 .2 .2 p=.03 p=.03 0 0 0 0 2 2 4 4 6 6 8 8 10 10 Time (year) Time (year) Effect of Mylotarg in CBF relapsed AML OS by Mylotarg exposure Post-allo SCT survival Hospital ASH 2011

  21. Mylotarg • Proof of principle of the benefitof immmunotherapy in AML • The administration of lower and fractionated doses of Mylotargmaylead to more durable responses and reducedtoxicity

  22. All-Trans Retinoic Acid + Chemotherapy in NPM-1 Mutant AML: AMLSG 07-04 • Primary endpoints: CR after induction therapy, EFS (patients with CR who received allogeneic SCT censored at date of transplantation) • Secondary endpoints: RFS, OS 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). Schlenk RF, et al. ASH 2011. Abstract 80.

  23. 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 69.5 69 70 60 CR to Induction Therapy (%) 50 40 30 20 10 n = 142 141 345 351 0 NPM1-Mutated AML NPM1–Wild- Type AML Schlenk RF, et al. ASH 2011. Abstract 80.

  24. 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,3Tibor Kovacsovics,4Herve Dombret,5Hartmut Dohner,6 Björn Steffen,7 Arnaud Pigneux,8 Philippe Rousselot,9Jürgen Krauter,10 Giovanni Martinelli,11Elihu 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

  25. Quizartinib:AC220-002 Trial Design Study Design Status Cohorts • FLT3-ITD(+/-) AML subjects • Single-arm, 3-cohort • ~100 sites WW • Coprimaryendpoints • 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

  26. AC220-002:Preliminary Efficacy Analysis *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

  27. AC220-002: Summary of Common (>25%) Adverse Events (Safety Population) Feb 22, 2011 data cut-off

  28. 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

  29. 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

  30. 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 therapy: single-agent oral vorinostat 200 mg TID for 14 days every 28 days for up to 12 mos Garcia-Manero G, et al. ASH 2011. Abstract 763.

  31. First-line Vorinostat/Idarubicin/Cytarabine in AML/Higher-Risk MDS: Efficacy • 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.

  32. First-line Vorinostat/Idarubicin/Cytarabine in AML/Higher-Risk MDS: Safety *Mucositis, typhlitis, colitis. Garcia-Manero G, et al. ASH 2011. Abstract 763.

  33. ALL • Ph+ ALL: single agent Dasatinib • Monoclonal antibodies

  34. Ph+ ALL: single agent dasatinib • N= 53 • Medianage 53 (23-78) • Dasatinib dose 140mg qdwith 30 daysteroid • post-remissionregimen free after 84d • responses: - hematologic : 100% CR, medianday 23 - median OS 30.8 months (unknown in patients on Dasatinib maintenance) Foá Blood epub 2011

  35. 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 • prognosticrole of BCR-ABL reduction >3 logs Foá Blood epub 2011

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

  37. Phase II Study of Dasatinib + Chemo in Older Patients With Ph+ ALL *Dose reduction in patients older than 70 yrs of age. Rousselot P, et al. ASH 2010. Abstract 172.

  38. Response and Survival With Dasatinib Plus Chemotherapy 100 Postinduction (MRD1) • 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 90 During consolidation (MRD2) 80 71 70 56 60 Patients With Molecular Response (%) 50 40 28 30 23 20 10 0 BCR-ABL/ABL ≤ .1% MRD negative* Response Type *Sensitivity 10-4.5 Rousselot P, et al. ASH 2010. Abstract 172.

  39. Inotuzumab Ozogamicin in Patients With Relapsed/Refractory ALL • Inotuzumabozogamicin: 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.

  40. Inotuzumab Ozogamicin in Relapsed/Refractory ALL: Efficacy • 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 O’Brien S, et al. ASH 2011. Abstract 875.

  41. 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.

  42. 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 O’Brien S, et al. ASH 2011. Abstract 875.

  43. Immunotherapy in ALL • Various monoclonal antibodies are being developed in ALL - anti-CD 22 (Inotuzomab) - anti-CD19 (Seattle Genetics) - BITE technology

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