Presentation on theme: "ASH review 2012 Acute leukemias"— Presentation transcript:
1ASH review 2012 Acute leukemias Tibor KovacsovicsCenter for Hematologic MalignanciesOHSUI 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.
3Whole 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 mutationsLey Nature 2008Mardis New Engl J Med 2009Ley N Engl J Med 2010Welch ASH 2011
4More gene mutations in AML? Established genes:- FLT3-ITD- NPM1- CEBPA- cKIT- Nras/KrasNew genes:- TET, IDH, DMT3A, ASXL1
5Clinical 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: transplantIdentification of drugable targets:- FLT3-ITD+: FLT3 inhibitors (AC220, sorafenib)
6NPM1+ and CEBPA + AML: RFS and OS in young patients Schlenk N Engl J Med 2008
7Consolidation therapy in young NPM1+ FLT3-ITD- AML 67% overall survival after consolidation with high-dose AraCThomas et al J Clin Oncol 2011These patients can be consolidated like CBF leukemia [t(8;21) or inv(16)]
8OS in older NPM1+ AML after standard therapy ~80% CR and improved overall survival rate in patients >60These patients are candidates for 7+3 and consolidation>60>60>70Becker et al J Clin Oncol 2010
9Current cytogenetic and molecular work-up in AML Conventional cytogenetics and FISH panelPCR: FLT3-ITD, FLT3 variant, NPM1, CEBPA, c-KIT in CBF leukemiasSequenom panel for gene mutations
11AML trials Cytarabine dosing Mylotarg ATRA in NPM1+ AML FLT3 inhibitors: AC220Vorinostat combinationWhat 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.
12Cytarabine dosing3 randomized trials, with different designs- 2 studies of high-dose AraC to multi-agent consolidationThomas J Clin Oncol 2011; Miyazawi Blood 2011- 1 study of high versus low cumulative doses of AraCLowenberg N Engl J MedWhat 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.
13Cytarabine dosing We probably give too much high-dose AraC High-dose AraC had best outcome in CBF leukemiaHigh-dose AraC was more toxic than multiagent consolidationIn a situation of AraC shortage, there are alternative consolidation regimens in non-CBF AMLWhat 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.
14MylotargMylotarg has been removed by Pfizer in 2009 after increased toxicity was seen in a randomzied SWOG trialIronically, some benefit has been observed since then in randomized clinical trials in CBF leukemiasNew positive studies were reported at ASHWhat 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.
15ALFA Fractionated Doses of Gemtuzumab Ozogamicin Combined to Standard ChemotherapyImprove Event-free and Overall SurvivalIn Newly-Diagnosed de novo AML PatientsAged Years Old.A Prospective Randomized Phase 3 Trial from the Acute Leukemia French Association (ALFA)ALFA
162nd course if BM blasts >10% at D15 Treatment armsRandomizationArm AArm BDNR 60 mg/m2 D1 to D3AraC 200 mg/m2 D1 to D7DNR 60 mg/m2 D1 to D3AraC 200 mg/m2 D1 to D7GO 3 mg/m2 D1, D4, D7INDUCTION2nd course if BM blasts >10% at D15DNR 60 mg/m2 D1, D2AraC 1g/m2/12h D1 to D3CR or CRpDNR 60 mg/m2 D1AraC 1g/m2/12h D1 to D4DNR 60 mg/m2 D1AraC 1g/m2/12h D1 to D4GO 3 mg/m2 D11st CONSOLIDATIONDNR 60mg/m2 D1,D2AraC 1g/m2/12h D1 to D4DNR60 mg/m2 D1,D2AraC 1g/m2/12h D1 à D4GO 3mg/m2 D12nd CONSOLIDATION16
18Overall survival P= 0.046 by the log-rank test GO arm Control arm OS A (control)(n=139)B(GO)Deaths7159Median19.2 mo34 mo2-year43.5%53.1%HR(95% CI)10.70( )GO armControl armP= 0.046by the log-rank test18
20OS according to cytogenetics risk-groups Favorable/intermediate cytogeneticsUnfavorable cytogeneticsGO armControl armControl armGO arm
21Effect of Mylotarg in CBF relapsed AML .188.8.131.52246810Overall survival %Time (year)GO+GO-p=.03.2.4.6.81246810Overall survival %Time (year)GO+GO-p=.03OS by Mylotarg exposurePost-allo SCT survivalHospital ASH 2011
22Mylotarg 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 toxicityWhat 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.
23All-Trans Retinoic Acid + Chemotherapy in NPM-1 Mutant AML: AMLSG 07-04 Genetic profiling prior to randomizationInduction (two 28-day cycles)Consolidation (three 28-day cycles)ATRA 45 mg/m2 on Days 6-8,15 mg/m2 on DaysStandard Chemotherapy*(n = 550)ATRA 15 mg/m2 on DaysStandard 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, OSSchlenk RF, et al. ASH Abstract 80.
24CR to Induction Therapy (%) AMLSG 07-04: EfficacyAddition of ATRA to standard chemotherapySignificantly 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 analysisBenefit 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 chemotherapyStandard chemotherapy100909084806969.57060CR to Induction Therapy (%)5040302010AML, acute myeloid leukemia; ATRA, all-trans retinoic acid; CR, complete response; EFS, event-free survival; ITD, internal tandem duplication; OR, odds ratio; OS, overall survivaln =142141345351NPM1-MutatedAMLNPM1–Wild-Type AMLSchlenk RF, et al. ASH Abstract 80.
25David 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 ResultsJorge Cortes,1 Alexander Perl,2 Catherine Smith,3 Tibor Kovacsovics,4 Herve Dombret,5 Hartmut Dohner,6Björn Steffen,7 Arnaud Pigneux,8 Philippe Rousselot,9 Jürgen Krauter,10 Giovanni Martinelli,11 Elihu Estey,12Alan Burnett13, Anthony Ho14, Norbert Ifrah15, Theo de Witte16, Robert Corringham17, Joyce James17,David Lilienfeld,17 Eugen Leo,17 Mohit Trikha,17 and Mark Levis181Thank you. I will present today on behalf of my colleagues the results of a phase 1 study of AC220, a second generation FLT3 inhibitor.
26Quizartinib: AC220-002 Trial Design Study DesignCohortsStatusFLT3-ITD(+/-) AML subjectsSingle-arm, 3-cohort~100 sites WWCoprimary endpointsComposite CRc (CR+CRp+CRi)CRKey secondary endpointsDuration of responseProgression free survivalOverall survival≥60 y oldFLT3 ITD+1st relapse~120 subjects1st subjects dosed Nov 2009Interim data analysis conducted on first 62 ITD+ subjects (53 evaluable for response)≥18 y oldFLT3 ITD +2nd relapse or post-HSCT~120 subjects≥18 y oldFLT3 ITD - cohorts 1 & 2~60 subjectsCR=complete remission; CRi=complete remission with incomplete hematologic recovery; CRp=complete remission with incomplete platelet recovery; QD=once daily
27AC220-002: Preliminary Efficacy Analysis CohortCRc: Composite Complete Response*MedianSurvival*Transition to HSCT**≥18 years2nd Relapse48%Not yet reached22/31 alive34%≥60 years1st Relapse41%24.1 weeks10/22 alive8%Total45%24.7 weeks32/53 alive23%*Based on efficacy evaluable population (N=53)** Based on safety population (N=62)Median survival for all 62 subjects = 24.6 weeksFeb 22, 2011 data cut-off
31AC220 (quizartinib) planned trials Monotherapy phase 3 trial in relapsed FLT3-ITD + AMLCombination phase 1 induction and consolidation trial in newly diagnosed FLT3-ITD + AMLMaintenance phase 1 study in post-allogeneic stem cell transplantWhat 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.
32Other FLT3 inhibitors PKC412: - enrollment in randomized upfront study completedSorafenib:- several combination trials ongoingSeveral new agents are being tested in phase 1-2 trialsWhat 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.
33Vorinostat + Idarubicin/Cytarabine in Newly Diagnosed AML or Higher-Risk MDS Single-arm phase II trial conducted in 75 patients aged yrsInduction therapy (1 cycle)Oral vorinostat 500 mg TID on Days 1-3IV idarubicin 12 mg/m2/day on Days 4-6IV cytarabine 1.5 g/m2 as continuous infusion daily for 3-4 days on Days 4-7Consolidation therapy (5 cycles)IV idarubicin 8 mg/m2/day on Days 4-5IV cytarabine 0.75 g/m2 on Days 4-6Maintenance therapy: single-agent oral vorinostat 200 mg TID for 14 days every 28 days for up to 12 mosAML, acute myeloid leukemia; IV, intravenous; MDS, myelodysplastic syndrome; q28d; every 28 days; tid, 3 times daily.Garcia-Manero G, et al. ASH Abstract 763.
34First-line Vorinostat/Idarubicin/Cytarabine in AML/Higher-Risk MDS: Efficacy Patient GroupORR, %Median EFS, Wks (Range)Median OS, Wks (Range)All patients8547 (3-134)82 (3-134)SubgroupsDiploid cytogenetics9368 (5-134)105 (5-134)-5 or -75914 (3-92)34 (3-92)FLT3 ITD10066 (6-134)91 (6-134)An unmatched comparison with historical data showed that response to vorinostat/ idarubicin/cytarabine markedly higher than with standard idarubicin/ cytarabine85% 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.
36ALLPh+ ALL: single agent DasatinibMonoclonal antibodies
37Ph+ ALL: single agent dasatinib Median age 53 (23-78)Dasatinib dose 140mg qd with 30 day steroidpost-remission regimen free after 84dresponses:- hematologic : 100% CR, median day 23- median OS 30.8 months (unknown in patients on Dasatinib maintenance)Foá Blood epub 2011The 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
38Ph+ ALL: single agent dasatinib relapse: at 20 months 20% free of relapsemedian time to relapse 5.9 monthsrelapse occured in 14/19 patients on TKI alone, in 5/14 on TKI +chemo, in 2/16 allo patientsprognostic role of BCR-ABL reduction >3 logsFoá Blood epub 2011The 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
39Older Ph+ ALL: single agent dasatinib Foá Blood epub 2011
40Phase II Study of Dasatinib + Chemo in Older Patients With Ph+ ALL Treatment PhaseTreatmentSchedulePrephaseDexamethasone 10 mg/m2Days -7 to -3Induction(Wks 1-8)Dasatinib 140 mg*Vincristine 1 mgDexamethasone 40 mgDaily for 8 wksDays 1 and 2 repeated weekly for 4 wksConsolidation(Wks 8-16)Dasatinib 100 mgMethotrexate 1000 mg/m2*L-asparaginase 10,000 IU/m2*Cytarabine 1000 mg/m2/12 hr*Daily for 6 cyclesDay 1 of cycles 1, 3, 5Day 2 of cycles 1, 3, 5Days 1, 3, and 5 of cycles 2, 4, 6Maintenance(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 mosALL, acute lymphocytic leukemia; Ph+, Philadelphia chromosome positive*Dose reduction in patients older than 70 yrs of age.Rousselot P, et al. ASH Abstract 172.
41Response and Survival With Dasatinib Plus Chemotherapy Median follow-up: 20 mosCR: 63 of 71 patients (88.7%)Median OS: 27 mosMedian RFS: 25 mosAdditional chromosomal abnormalities (P = .009) and lack of molecular response during consolidation (P < .0001) associated with lower RFS rate19 patients (27%) relapsed after a median of 4.8 mosMajority had T315I BCR-ABL mutation100Postinduction (MRD1)90During consolidation (MRD2)8071706056Patients With Molecular Response (%)50402830232010CR, complete response; MRD, minimal residual disease; OS, overall survival; RFS, relapse-free survival.BCR-ABL/ABL ≤ .1%MRD negative*Response Type*SensitivityRousselot P, et al. ASH Abstract 172.
42Inotuzumab Ozogamicin in Patients With Relapsed/Refractory ALL Inotuzumab ozogamicin: monoclonal anti-CD22 antibody conjugated with calicheamicinPhase I dose-escalation study conducted in 49 patientsPatient eligibility16 yrs of age or older in first 10 patients; children subsequently eligibleRelapsed/refractory, CD22-positive ALLUp to 8 treatment cycles administeredInotuzumab 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 wksIf 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 diseaseO’Brien S, et al. ASH Abstract 875.
43Inotuzumab Ozogamicin in Relapsed/Refractory ALL: Efficacy CyclesCR, nCRp, nCRi, nTotal Response Rate, n (%)All cycles914528 (57)Cycle 1816 (33)Cycle 216411 (22)≥ Cycle 31 (2)Median response duration: 5.0 mosNo clear correlations between response and baseline patient/disease characteristics except regarding karyotypeLower 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 responseUndetectable MRD attained in 63% of 27 evaluable patients with responseALL, 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 positiveO’Brien S, et al. ASH Abstract 875.
44Inotuzumab 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 toleratedTreatment-associated fever (Days 1-2: 90%) and hypotension (Days 1-2: 26%) generally occurred during first cycle only and transientLiver function abnormalities also associated with inotuzumab, but reversible and typically mild22 patients underwent allogeneic SCT after inotuzumab (second transplantation for 5 patients)5 patients developed suspected veno-occlusive disease after transplantationALL, acute lymphoblastic leukemia; IV, intravenous; SD, stable diseaseO’Brien S, et al. ASH Abstract 875.
45Inotuzumab Ozogamicin in Relapsed/ Refractory ALL: Conclusions Inotuzumab yielded very high response rates in patients with relapsed/refractory ALL when administered as single agentORR: 57%Response correlated with inotuzumab plasma levels after dosingInotuzumab generally well tolerated, with major toxicities including thrombocytopenia and abnormal liver function testsPlans under way to further investigate inotuzumab in ALLWeekly scheduleIn combination with chemotherapyORR, overall response rateO’Brien S, et al. ASH Abstract 875.
46Immunotherapy in ALLVarious monoclonal antibodies are being developed in ALL- anti-CD 22 (Inotuzomab)- anti-CD19 (Seattle Genetics)- BITE technologyWhat 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.