1. Targeted Therapy in Acute Myeloid Leukemia
Ross L. Levine M.D.
Human Oncology and Pathogenesis Program
Leukemia Service, Department of Medicine
Memorial Sloan Kettering Cancer Center
Weill Cornell School of Medicine

2. Acute Myeloid Leukemia Remains Associated with Poor Overall Survival
Note from NCCN: changed -> into arrow symbol ().
Even with intensive induction chemotherapy/transplantation most patients die of their disease new insights are needed
Issa, Kantarjian et al, Cancer 2008

3. Mutational Analysis of AML Has Identified Many New Classes of Mutations
DNA
Methylation
Chromatin
State
TCGA AML NEJM 2013

4. IDH1 Mutations in AML*
Whole genome sequencing identified somatic IDH1 mutation->seen in 8% of 187 additional samples
*Mardis et al NEJM 2009

5. IDH1 mutations acquire a novel enzymatic function
Metabolomic profiling found that IDH1 mutant allele expression resulted in production of 2-hydroxyglutarate, an aberrant metabolite
IDH1 mutant cancers produce a vast excess of 2HG
Leukemias
Brain Tumors
Pancreatic Cancer
Sarcomas
Many others
Dang et al. Nature 2009

6. IDH2 mutations in AML
Elevated 2-HG levels in IDH1-wildtype patients led to discovery of IDH2 mutations in AML in patients from ECOG and Alliance Cooperative Group Trials
The overall incidence of IDH1/2 mutations is 15-30%, most common in older patients, normal karyotype
However, it was not known HOW these mutations contribute to AML or other cancers
Ward et al. Cancer Cell 2010
Marcucci et al JCO 2010
Gross et al. J Ex Med 2010

7. Human genetics is always right: using mutational studies to elucidate AML pathogenesis
By profiling primary patient samples we can improve our understanding of AML biology
We hypothesized that we could elucidate the function of IDH mutations in AML by identifying mutations exclusive of IDH mutations of AML
We wanted to look at this idea of mutational complementation groups in AML. “say genes”

8. ECOG 1900 Cohort: IDH1/2 mutations mutually exclusive of TET2 mutations
We had found that IDH1/2 and TET2 are mutually exclusive in this cohort and in a colloborative effort we also investigated this functionally with the labs of Craig Thompson and Ari Melnick.
Figueroa, Abdel-Wahab, Lu et al, Cancer Cell 2010

9. Can these mutations be therapeutically targeted?
Mutations in IDH1/2 and TET2 lead to impaired DNA Hydroxymethylation and Increased DNA Methylation
Can these mutations be therapeutically targeted?
Figueroa, Abdel-Wahab, Lu et al, Cancer Cell 2010

10. Development of Specific inhibitors of IDH1/2*
Small molecule inhibitors of IDH2 and IDH1 have been developed with potent, specific on target effects
In vitro and in vivo assays in mouse models and patient samples show significant efficacy alone and in combination with other AML therapies
Led to first-in-man clinical trials of AG-221, IDH2-specific inhibitor in relapsed/refractory IDH2-mutant AML (Eytan Stein, PI)
*Kate Yen/Agios, Alan Shih

11. Efficacy of IDH2 Inhibitor AG-221 in Relapsed/Refractory AMLCR
Transplant
30 mg
BID
CRp
Bone Fracture, Death Unrelated CR PR
On Study
CR*
Off Study CR
Response
50 mg
BID PR
Bone Marrow
CRi
CR**
75 mg
BID
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Significant clinical activity in AML patients with IDH2 mutations (required for enrollment)
PD studies show target inhibition at doses which show efficacy
Evidence of differentiation in vivo with neutrophil expansion followed by clinical response PR
100 mg QD CR
100 mg
BID
CRp PR
150 mg QD PR
Stein et al. AACR, 2014; Agresta et al. EHA, Milan, 2014

12. Conclusions
Genome sequencing of AML patients can identify novel, clinically important mutations
Can use these data to improve our understanding of AML biology
Can lead to the development of novel, molecularly targeted therapies

13. Acknowledgements Levine Lab Alan Shih Kaitlyn Shank Jay Patel MSKCC
Craig Thompson
Eytan Stein
Kristina Knapp
Omar Abdel-Wahab
Scott Armstrong
Marty Tallman
Scott Lowe
NYU
Iannis Aifantis
Chicago
Chuan He
Lucy Godley
Einstein
Uli Steidl
Laura Barreyo
Ileana-Antony Debre
ECOG
Elisabeth Paietta
Robert Comis
Cornell
Ari Melnick
Chris Mason
Agios
Kate Yen
Sam Agresta
David Scheikein
Michigan
Ken Figueroa
Funded by National Cancer Institute