Cytogenetics is an advancement in which clinicians can look for specific genetic mutations of chromosomal DNA and use that information to determine patient prognosis and individualize therapy. In this presentation I cover what cytogenetics are, how they impact patient risk, what therapies to use based on risk, and how genetically targeted agents may be used in the future.
5. 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.
6. Cytogenetics
Examines abnormalities of chromosomes
Inversions, translocations, deletion, monosomy
http://cnx.org/content/m45467/latest/
Estey EH. Am J Hematol. 2013;88(4):318-27.
7. 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.
8. 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.
10. 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.
11. 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
c-KIT
overexpression
c-KIT mutation
Proliferation
and survival
Paschka P, Marcucci G, Ruppert AS et al.. J Clin Oncol. 2006;24(24):3904-11.
12. DNMT3A and IDH 1/2
Enzymes involved in epigenetic regulation
DNA (cytosine-5) methyltransferase 3 alpha
DNMT3Amut
Altered DNA
methylation
Abnormal
silencing and
activation of DNA
transcription
IDH 1/2 – Isocitrate Dehydrogenase 1 and 2
IDH1/2 mut
Neomorphic
Activity
Depletion of
cofactors for
epigenetic
machinery
Gaidzik VI, Schlenk RF, Paschka P et al. Blood. 2013;121(23):4769-77.
Rakheja D, Konoplev S, Medeiros LJ et al Hum Pathol. 2012;43(10):1541-51.
18. Better Risk (Best) Treatment
Better Risk
CBF AML [inv (16),
t(16;16) or t(8;21)]
NK with NPM1 mutation
and no FLT3-ITD
Consolidation
Induction
CBF with
7+3
(Cytarabine +
Daunorubicin)
c-KIT +?
NK with double mutated
CEBPA
Yes
Dasatinib in
clinical trial
Estey EH. Am J Hematol. 2013;88(4):318-27.
No
High Dose
Cytarabine
19. Intermediate 1 Treatment
Intermediate 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
Estey EH. Am J Hematol. 2013;88(4):318-27.
Matched
sibling donor
(MSD) HCT
High dose
Cytarabine
21. Intermediate 3 Treatment
Intermediate 3 Risk
Unfavorable cytogenetics
without monosomal
karyotype
Induction
Clinical Trial
Consolidation
Matched sibling
donor (MSD) or
matched unrelated
donor (MUD) HCT
Estey EH. Am J Hematol. 2013;88(4):318-27.
Clinical trial for nontransplant
candidates
HCT clinical trial
involving new
preparative
regimen or means
to prevent relapse
22. Poor Risk (Worst) Treatment
Poor Risk
Monosomal karyotype
Induction
Clinical Trial
Consolidation
Matched sibling
donor (MSD) or
matched unrelated
donor (MUD) HCT
Estey EH. Am J Hematol. 2013;88(4):318-27.
Clinical trial for nontransplant
candidates
HCT clinical trial
involving new
preparative
regimen or means
to prevent relapse
23. 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
7+3
Cytarabine at 1g/m2 BID daily x 6
Dasatinib in clinical trial if CBF with c-KIT
mutation
NK with double mutated CEBPA
Intermediate 1
Intermediate 3
7+3
HCT from matched sibling donor (MSD)
Cytogenetic abnormalities other
than best of unfavorable
Intermediate 2
NK w/o NPM mutation or FLT3-ITD
Clinical trial
Cytarabine as above or clinical trial if not HCT
candidate
FLT3-ITD+
Clinical trial
involving
FLT3
inhibitor
HCT from MSD or matched unrelated donor
(MUD); consider trial with FLT3 inhibitor
Clinical trial
HCT from MSD, MUD; consider trial involving
new prep regimen or means to prevent relapse
after HCT
Unfavorable cytogenetics
without monosomal karyotype
Cytarabine as above or clinical trial if not HCT
candidate
Clinical trial if not HCT candidate
Worst
Monosomal karyotype
Estey EH. Am J Hematol. 2013;88(4):318-27.
Clinical trial
As in intermediate 3
25. 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
26. 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
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
DLT – QT prolongation, myelosuppression
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.
27. 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.
28. 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):
Treatment group
Decitabine
TC
P-value
OS
7.7 months
5.0 months
0.108
CR
17.8%
7.8%
0.001
Stratification by IDH, TET2, or DNMT3A status?
Kantarjian HM, Thomas XG, Dmoszynska A et al. J Clin Oncol. 2012;30(21):2670-7.
30. 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
32. 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
33. 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?
34. 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.
35. 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):154151.
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.