Present and Future Impact of Cytogenetics on Acute Myeloid Leukemia

Marti Larriva

PharmD Candidate 2014

September 11, 2013

Present and future impact of cytogenetics on AML treatment

Outline

Background AML Cytogenetics Molecular genetics

Current Practice Prognosis Treatment

Future Practice Novel therapeutics

Question

What areas of AML therapy are most fluid and subject to change?

BackgroundAML, Cytogenetics, Molecular Genetics

Acute Myeloid Leukemia

Excessive production of immature myeloblast cells Anemia Thrombocytopenia Neutropenia

Symptoms Fatigue Infection

Estey EH. Am J Hematol. 2012;87(1):89-99.

Cytogenetics

Examines abnormalities of chromosomes Inversions, translocations, deletion, monosomy

http://cnx.org/content/m45467/latest/


Molecular Genetics

Examines abnormalities of genes Most well studied:

NPM1 (27%) FLT3 (28%) CEBPA (6%) c-KIT(4%)

Less well studied: DNMT3A(26%) IDH 1 or 2 (20%)

Cancer Genome Atlas Research Network. N Engl J Med. 2013;368(22):2059-74.

NPM1

Nucleophosmin Shuttle between cytoplasm and nucleus NPMc+ = mutation Better outcomes

NPMc+

Loss of function

Oncogene

Paolo S. Pediatric Reports. 2011;3(s2):11-13.

FLT3

FMS-like tyrosine kinase 3 FLT3 – ITD = mutation Associated with poor outcomes

FLT3-ITD

Constitutive

Activation

Proliferation

Impaired Apoptosis

Leung AY, Man CH, Kwong YL. Leukemia. 2013;27(2):260-8.

CEBPA

CCAAT enhancer binding protein alpha Transcription factor essential for myeloid differentiation Double mutation (both chromosomes) = better outcomes

CEBPA Mutation

Lack of transcription factor binding

Missing elements for

myeloid differentiation

Pabst T, Mueller BU. Clin Cancer Res. 2009;15(17):5303-7.

c-KIT Receptor tyrosine kinase

Expressed on surface of hematopoietic progenitor cells More common in core binding factor (CBF) AML

inv (16) and t (8; 21) Poor outcomes

Proliferation and survival

c-KIT overexpressi

on

c-KIT mutation

Paschka P, Marcucci G, Ruppert AS et al.. J Clin Oncol. 2006;24(24):3904-11.

DNMT3A and IDH 1/2

Enzymes involved in epigenetic regulation

DNA (cytosine-5) methyltransferase 3 alpha

IDH 1/2 – Isocitrate Dehydrogenase 1 and 2

DNMT3Amut Altered DNA methylation

Abnormal silencing and activation of

DNA transcription

IDH1/2 mut Neomorphic Activity

Depletion of

cofactors for

epigenetic machinery

Rakheja D, Konoplev S, Medeiros LJ et al Hum Pathol. 2012;43(10):1541-51.

Gaidzik VI, Schlenk RF, Paschka P et al. Blood. 2013;121(23):4769-77.

Complex Heterogeneity

Patel JP, Gonen M, Figueroa ME et al. N Engl J Med. 2012;366(12):1079-89.

Making sense of it all

Current Impact of CytogeneticsPrognosis, Treatment

Risk stratification and PrognosisRisk Cytogenetics Molecular

Abnormalities5-year Survival

Better Risk Inv (16)t(16;16)t(8;21)t(15,17)

Normal cytogenetics: NPM1 w/o FLT3-ITD or isolated double mutation CEBPA

55-65%

Intermediate Risk

Normal cytogenetics+8 onlyt(9;11)

CBF [t(8;21), inv(16), t(16;16)] with c-KIT mutation

24-40%

Poor Risk Complex (≥3 abnormalities)-5, -7, 5q-, 7q-Abnormalities of 11q23 excluding t(9;11)Inversion 3t(3;3), t(6;9), t(9;22)

Normal cytogenetics: with FLT3-ITD mutation

5-14%

National Comprehensive Cancer Network. Acute Myeloid Leukemia (version 2.2013)

Treatment

Stratified based upon cytogenetics

Two stages Induction Consolidation

HSCT – CR1 vs. CR2

Better Risk (Best) TreatmentBetter Risk

CBF AML [inv (16), t(16;16) or t(8;21)]

NK with NPM1 mutation and no FLT3-ITD

NK with double mutated CEBPA

Induction

7+3 (Cytarabine

+ Daunorubicin

)

Consolidation

CBF with c-KIT +?

Yes

Dasatinib in clinical trial

No

High Dose Cytarabine


Intermediate 1 TreatmentIntermediate 1 Risk

NK w/o NPM1 mutation or FLT3-ITD

Cytogenetic abnormalities other than best or

unfavorable

Induction

7+3 (Cytarabine + Daunorubicin)

Clinical Trial

Consolidation

Matched sibling donor (MSD) HCT

High dose Cytarabine



FLT3-ITD+

Induction

Clinical Trial involving

FLT3 inhibitor

Consolidation

Matched sibling donor (MSD) or

matched unrelated donor (MUD) HCT

High dose Cytarabine

Clinical trial involving FLT3

inhibitor



Unfavorable cytogenetics without monosomal

karyotype

Induction

Clinical Trial

Consolidation



Clinical trial for non-transplant

candidates

HCT clinical trial involving new preparative

regimen or means to prevent relapse


Poor Risk (Worst) TreatmentPoor Risk

Monosomal karyotype

Induction

Clinical Trial

Consolidation



Clinical trial for non-transplant

candidates

HCT clinical trial involving new preparative

regimen or means to prevent relapse


Treatment Summary

Prognostic Group

Subsets Induction Post-Remission

Best inv (16), t(16;16) or t(8;21) NK with NPM1 mutation and no FLT3-ITD

NK with double mutated CEBPA

7+3 Cytarabine at 1g/m2 BID daily x 6

Dasatinib in clinical trial if CBF with c-KIT mutation

Intermediate 1 NK w/o NPM mutation or FLT3-ITD

Cytogenetic abnormalities other than best of unfavorable

7+3

Clinical trial

HCT from matched sibling donor (MSD)

Cytarabine as above or clinical trial if not HCT candidate

Intermediate 2 FLT3-ITD+ Clinical trial involving FLT3 inhibitor

HCT from MSD or matched unrelated donor (MUD); consider trial with FLT3 inhibitor

Cytarabine as above or clinical trial if not HCT candidate

Intermediate 3 Unfavorable cytogenetics without monosomal karyotype

Clinical trial

HCT from MSD, MUD; consider trial involving new prep regimen or means to prevent relapse after HCT

Clinical trial if not HCT candidate

Worst Monosomal karyotype Clinical trial

As in intermediate 3Estey EH. Am J Hematol. 2013;88(4):318-27.

Future Impact of CytogeneticsFLT3 inhibitors, c-KIT inhibitors, Hypomethylating agents

Predicting the future…

“While theoretically and technically television may be feasible, commercially and financially I consider it an impossibility, a development of which we need waste little time dreaming.” – Lee DeForest, American radio pioneer, 1926.

“Well informed people know it is impossible to transmit the voice over wires, and that were it possible to do so, the thing would be of no practical value.” – Editorial in the Boston Post, 1865

FLT3 inhibition No FDA approval yet

Efficacy and resistance issues Ongoing trials

Several multi-TKI inhibitors exist – tandutinib, sorafenib, sunitinib, midostaurin, lestaurtinib

Oral FLT3 specific inhibitor – quizartinib Monotherapy for relapsed/refractory disease after 2nd line

chemotherapy or HSCT

DLT – QT prolongation, myelosuppression

Patient group FLT3-ITD + FLT3-ITD -

All patients CRc 44%OS 23.1 weeks

CRc 34%OS 25.6 weeks

≥ 70 years old CRc 53%OS 21.0 weeks

CRc 43%OS 19 weeks

Grunwald MR, Levis MJ. Int J Hematol. 2013;97(6):683-94.Levis MJ, Perl AE, Dombret H, Dohner H et al. Blood (ASH Annual Meeting Abstracts). 2012; 120:Abstract 673.

c-KIT inhibition

No clear clinical benefit, still in clinical trials c-KIT overexpression in CBF AML Case reports of success and failure

c-KIT inhibitors – midostaurin, dasatinib, imatinib, nilotinib Clinical trials evaluating:

monotherapy in relapsed/refractory disease combination with induction and salvage chemotherapy combination with low dose chemo for older patients

Smith CC, Shah NP. Am Soc Clin Oncol Educ Book. 2013;2013:313-8.

Hypomethylation

Use of azacitadine and decitabine increasing

Older adults ≥ 65 + intermediate/poor risk disease Phase III trial decitabine vs. Treatment of choice

(supportive care or low dose cytarabine):

Stratification by IDH, TET2, or DNMT3A status?

Treatment group

Decitabine TC P-value

OS 7.7 months 5.0 months 0.108

CR 17.8% 7.8% 0.001

Kantarjian HM, Thomas XG, Dmoszynska A et al. J Clin Oncol. 2012;30(21):2670-7.

Combination Regimens

AML Heterogeneity

Multiple mechanisms of therapy

AML Clinical trials at Mayo

c-KIT overexpression: Nilotinib and 7+3 (DATA) – Phase II

Hypomethylation Clofarabine OR 7+3 followed by decitabine OR Observation (Older

patients with newly diagnosed AML) SGI-110 in intermediate or poor risk MDS or AML- Phase I/II

FLT3-ITD Midostaurin + SOC vs. SOC post HSCT to prevent relapse- Phase II Bortezomib + Sorafenib for De Novo AML with high allelic ratio

FLT3-ITD – Phase III

http://www.mayo.edu/research/clinical-trials/search-results?keyword=acute%20myeloid%20leukemia

Summary & ConclusionsTried and true vs. room for something new

Summary

FLT3-ITD and c-KIT Bad prognostic markers Alternative therapies, HSCT in CR1 Maybe future drug targets

NPM1, double CEBPA Better prognostic markers Standard therapy is an option, HSCT in CR2

Summary & Conclusions

Tried & true

7+3 induction for better risk disease and HiDAC consolidation

HSCT for worst risk disease after first CR

Something new?

Molecular targeted therapies (FLT3, c-KIT) Combination regimens Bridge to HSCT

Hypomethylating agents Particularly in elderly

population Characterization of

epigenetics for prognosis?

References

1. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059-74.

2. Dohner H, Estey EH, Amadori S et al. Diagnosis and management of acute myeloid leukemia in adults: Recommendations from an international expert panel, on behalf of the european LeukemiaNet. Blood. 2010;115(3):453-74.

3. Estey EH. Acute myeloid leukemia: 2013 update on risk-stratification and management. Am J Hematol. 2013;88(4):318-27.

4. Estey EH. Acute myeloid leukemia: 2012 update on diagnosis, risk stratification, and management. Am J Hematol. 2012;87(1):89-99.

5. Ferrara F, Schiffer CA. Acute myeloid leukaemia in adults. Lancet. 2013;381(9865):484-95.

6. Gaidzik VI, Schlenk RF, Paschka P et al. Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: Results of the AML study group (AMLSG). Blood. 2013;121(23):4769-77.

7. Grunwald MR, Levis MJ. FLT3 inhibitors for acute myeloid leukemia: A review of their efficacy and mechanisms of resistance. Int J Hematol. 2013;97(6):683-94.

8. Kantarjian HM, Thomas XG, Dmoszynska A et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30(21):2670-7.

9. Leung AY, Man CH, Kwong YL. FLT3 inhibition: A moving and evolving target in acute myeloid leukaemia. Leukemia. 2013;27(2):260-8.

10. Levis MJ, Perl AE, Dombret H, Dohner H et al. Blood (ASH Annual Meeting Abstracts). 2012; 120:Abstract 673.

References

11. Magenau J, Couriel DR. Hematopoietic stem cell transplantation for acute myeloid leukemia: To whom, when, and how. Curr Oncol Rep. 2013.

12. Mrozek K, Marcucci G, Nicolet D et al. Prognostic significance of the european LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J Clin Oncol. 2012;30(36):4515-23.

13. National Comprehensive Cancer Network. Acute Myeloid Leukemia (version 2.2013). Accessed 9/8/13. http://www.nccn.org/professionals/physician_gls/pdf/aml.pdf

14. Pabst T, Mueller BU. Complexity of CEBPA dysregulation in human acute myeloid leukemia. Clin Cancer Res. 2009;15(17):5303-7.

15. Paolo S. How does the NPM1 mutant induce leukemia? Pediatric Reports. 2011;3(s2):11-13.

16. Paschka P, Marcucci G, Ruppert AS et al. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): A cancer and leukemia group B study. J Clin Oncol. 2006;24(24):3904-11.

17. Patel JP, Gonen M, Figueroa ME et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079-89.

18. Rakheja D, Konoplev S, Medeiros LJ et al. IDH mutations in acute myeloid leukemia. Hum Pathol. 2012;43(10):1541-51.

19. Smith CC, Shah NP. The role of kinase inhibitors in the treatment of patients with acute myeloid leukemia. Am Soc Clin Oncol Educ Book. 2013;2013:313-8.

Questions?

Health & Medicine

Present and Future Impact of Cytogenetics on Acute Myeloid Leukemia