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