AML: How Molecular Biology is Influencing Clinical Care · Implication: Need to assess...
Transcript of AML: How Molecular Biology is Influencing Clinical Care · Implication: Need to assess...
AML: How Molecular Biology is Influencing Clinical Care
Aaron Schimmer, MD
How molecular biology is
impacting clinical care in AML
• Prognostic Markers
• Therapeutic targets
• Understanding of disease – impacting
future care
Molecular Biology and AML
• Prognostic markers -- Impact on patient
risk stratification
Survival of adults with newly diagnosed AML according to cytogenetic risk group (1984-2000)
Byrd et al. (CALGB 8461) Blood 2002; 100:4325-4336
Cytogenetic risk stratification in
Acute myeloid leukemia
Molecular mutations–
FLT3 and AML
• Flt3 receptor over-expressed in
AML
• 1996: Nakao et al., identified ITD
mutations
while sequencing the gene in AML
patients
• FLT3 ITD found in 25% of AML
Kottaridis P D et al. Blood 2001;98:1752-
1759
FLT3 ITD mutation status
risk stratifies AML
Molecular Mutations in Cytogenetically Normal AML
The Cancer Genome Atlas Research Network. N Engl J Med 2013;368:2059-2074
The Cancer Genome Atlas Research Network. N Engl J Med 2013;368:2059-2074
Molecular markers provide
prognostic information
How et al., Cancer, 2012
From: Association Between Mutation Clearance After Induction Therapy and Outcomes in Acute Myeloid
Leukemia JAMA. 2015;314(8):811-822. doi:10.1001/jama.2015.9643
Clearance of mutations on D30 predicts
relapse and survival for AML
The Princess Margaret Advanced
Genomics In LEukemia (AGILE)
Trial
Illumina TruSight Myeloid Panel
ABL1 DNMT3A KDM6A RUNX1
ASXL1 ETV6/TEL KIT SETBP1
ATRX EZH2 KMT2A SF3B1
BCOR FBXW7 KRAS SMC1A
BCORL1 FLT3 MPL SMC3
BRAF GATA1 MYD88 SRSF2
CALR GATA2 NOTCH1 STAG2
CBL GNAS NPM1 TET2
CBLB HRAS NRAS TP53
CBLC IDH1 PDGFRA U2AF1
CDKN2A IDH2 PHF6 WT1
CEBPA IKZF1 PTEN ZRSR2
CSF3R JAK2 PTPN11
CUX1 JAK3 RAD21
54 genes covered
Molecular Biology and AML
• Impact on therapy
Drugable targets in AML
The Cancer Genome Atlas Research Network. N Engl J Med 2013;368:2059-2074
The Cancer Genome Atlas Research Network. N Engl J Med 2013;368:2059-2074
Drugable mutations
FLT3
IDH2
IDH1
FLT3 inhibitors
Randomized phase II trial of
quizartinib/AC220 in
relapsed and refractory FLT3-ITD +
AML
EHA 2014
Phase I trial of the IDH2 inhibitor AG-221
in relapsed and refractory AML
IDH2
mutated
N = 158
Rate of response 41%
CR 18%
• Mutations in IDH2 found in 10-20% of AML
• Associated with a worse outcome
• Alters cell metabolism
Isocitrate
a-ketoglutarate
2-hydroxyglutarate
IDH2
IDH2 mut
Succinyl-CoA
• Oncometabolite
• Increased DNA methylation
AG-221
EHA 2015
Molecular Biology and AML
• Understanding disease – impacting future
therapy
– Clonal heterogeneity in AML
Paguirigan etl al, Single-cell genotyping demonstrates complex clonal diversity in acute myeloid leukemia. Sci Transl Med,
2015
AML is a Heterogeneous Disease
Ding et al., Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing, Nature, 2012
Models of relapse
• Dominant clone not eradicated and regrows
• Rare subclone emerges
• New clone emerges as acquires new mutations
Additional factors that influence/ complicate
heterogeneity
• Stem cells
• Preleukemic “normal” cells
Models of relapse
Implication: Need to assess heterogeneity in different
cellular populations
Conclusions
AML is leading the genomics era
of cancer
–Prognosis
–Therapy
–Biology
The Future?
• Match patients to therapies based on
genetic profile/mutations
• Proteomics – the next frontier?
• Tailored therapies for small subsets
• Oncologists will need to understand
genomics and proteomics