New drugs in Acute Leukemia Cristina Papayannidis, MD, PhD University of Bologna
Challenges to targeted therapy in AML Multiple subtypes based upon mutations/cytogenetic aberrations No known uniform genomic aberration or dominant driving pathway to pathogenesis as in other leukemia subtypes Two driving mechanisms: 1) block of differentiation 2) enhance of survival/proliferation.do we have to target both?
Molecular alterations in AML Gene Symbol Gene Location Prognostic Impact Frequency MLL-PTD 11q23 Adverse-Neutral 5-10% FLT3-ITD 13q12 Adverse 30-35% FLT3-TKD 13q12? Adverse 10% CEBPA mutations 19q13.1 Favorable 10-20% NPM1 mutations 5q35 Favorable 55-65% WT-1 mutations 11p13 Adverse 6-12% IDH mutations (IDH1-IDH2) 2q33.3 &15q26.1 +/-Adverse 25-35% RUNX1 mutations 21q22.12 Adverse 8-16% TET2 mutations 4q24 +/- Adverse 18-30% ASXL1 mutations 20q11.21 Adverse 4-16% DNMT3A mutations 2p23.3 Adverse 35%
IDH1-IDH2 ONCOMETABOLITE
TET2 INHIBITION PROMOTER METHYLATION EPIGENETIC REPROGRAMMING
IDH mutations in cancer
IDH2 mutations Are much more common in adult than pediatric AML, representing approximately 10% of all patients Occurr more frequently as adult age increases Are more commonly associated with normal or intermediate risk Occurr at 2 hotspots: IDH2 R140 (80%): associated with normal cytogenetics, NPM1 mutated and FLT3 ITD IDH2 R172 (20%): associated with older age, lower WBC, higher PLT, infrequent other mutations, resistance to induction chemotherapy, shorter EFS and OS
IDH1 and IDH2 mutations confer adverse prognosis in NPM1+, FLT3 ITD neg AML NPM1+, FLT3 ITDwild type IDH wild type IDH Paschka P. et al, JCO 2010
Take home messages (I) Two variants of IDH2 mutations have different clinical features in adult AML Presence of IDH2 mutation can be monitored by 2-HG levels and this decreases with successful induction therapy Negative Clinical impact has been shown in FLT3 ITD neg, NPM1 pos AML patients Can mutant IDH2 be targetable?
Clinical safety and activity in a Phase I trial of AG-221, a first in class, potent inhibitor of the IDH2 mutant protein, in patients with IDH2 mutant positive advanced hematologic malignancies E M. Stein, M. S. Tallman et al, MSKCC, New York
AG-221: selective oral inhibitor of IDH2 mutant enzyme Significantly decreases 2-HG plasma levels in murine models of IDH2 mutated AML In vivo activity in a murine mouse model of IDH2R140Q mutated AML Reverses histone hypermethylation and induces differentiation in IDH2R140Q leukemiacell model
AG-221 reverses differentiation block in primary patient samples AML M1 patient: citology following treatment with AG-221
Demographics, Efficacy Evaluable Cohorts 1 and 2 Population N 10 Median Age, years (range) 62.5 (53-74) ECOG Performance Status, n 0 1 2 Prior regimens (range) Prior BMT Secondary AML IDH2 Mutations, n R140 R172 Median Cycles of AG-221 Completed (range) 8 2 0 2 (1-4) 1 0 10 8 2 2 (<1-4+)
Prior therapies
Safety and adverse events
Best Response Efficacy evaluation Cohort 1 and 2
CR CR CR CRp CRp PR
Differentiation effects in the bone marrow
Take home messages (II) AG-221 safe and well tolerated to date Consistent with preclinical models, IDH2 inhibitions leads to a profound differentiation effect Dose escalation continues, expansion cohorts to begin in late 2014 These data provide early validation of mutant IDH2 as a therapeutic target in cancer Explore combinations therapy