Acute Myeloid Leukemia
Peter M. Voorhees, M.D.
The University of North Carolina at Chapel Hill
Division of Hematology-Oncology
Lineberger Comprehensive Cancer Center
Outline
• Molecular
Pathogenesis
• Classification
• Prognosis
• Treatment
Molecular Pathology of AML
• Abnormal cell proliferation
– FLT3 mutations
– Ras mutations
– Others: c-KIT mutations
• Block in differentiation
– CBF AML (t(8;21) and inv(16))
– PML-RARα (t(15;17))
– MLL translocations (11q23)
– Hox gene translocations
– C/EBPα mutations
• Suppression of apoptosis
– Bcl-2 over-expression
• Capacity for indefinite self-
renewal
Proliferation: FLT3
• A receptor tyrosine
kinase expressed in 70 –
100% of AML cases.
• Activating mutations in
FLT3 are seen in ~30%
of AML cases.
– Tandem duplication of the
juxtamembrane region.
– Point mutation within the
activation loop of the
kinase domain.
• Activation of FLT3 leads
to deregulated
proliferation of AML cells.
Proliferation: Ras
• Small guanine nucleotide binding proteins that
play a role in several cell signaling pathways.
• Activating point mutations seen in ~25% of AML
cases.
– N-Ras: 10 – 25%
– K-Ras: 5 – 15%
– H-Ras: Rare
• Activation of Ras leads to deregulated cell
proliferation.
Differentiation: Core Binding Factor
(CBF)-α in M2 AML
• CBFs: heterodimeric
complexes (CBFα and CBFβ)
that regulate expression of
genes involved in
hematopoietic cell
differentiation.
• CBFα = AML1.
• t(8;21)(q22;q22): AML1-ETO
fusion gene.
• AML1-ETO is a transcriptional
repressor.
– recruits the nuclear co-
repressor complex and
histone deacetylases to CBF
sites
Differentiation: Core Binding
Factor-β
• CBFβ is located at 16q22.
• Inv(16)(p13q22) and t(16;16)(p13;q22):
CBFβ-MYH11 fusion gene that functions
as a dominant negative inhibitor of CBF.
• The result is the suppression of
transcription of genes crucial for
hematopoiesis / differentiation.
Differentiation: the Retinoic Acid
Receptor-α (RARα) in APL
• RARα: involved in transcription of genes necessary for
hematopoiesis / differentiation.
• t(15;17)(q22;q22): fusion gene PML-RARα.
– t(11;17): PLZF-RARα
– t(5;17): NPM-RARα
• PML-RARα is a transcriptional repressor
– recruits the nuclear co-repressor complex and histone deacetylases.
Differentiation: the Mixed Lineage
Leukemia (MLL) Gene
• MLL is a protein that
regulates Hox gene
expression.
• Hox family members play
critical roles in
transcription of genes
involved in
hematopoiesis.
• Normal MLL requires
cleavage by taspase into
its mature form →
dysregulated Hox gene
expression → block in
differentiation.
Pathogenesis: Summary
• Strategies that interfere with over-activation of
signaling pathways and the block in cellular
differentiation have the potential to improve
patient outcomes in AML.
The FAB Classification
The WHO Classification
Prognosis: Cytogenetics from the MRC
AML 10 trial in patients 7 days.
– Reduced incidence of fever
• 65% vs. 85% (p=0.001)
– Decreased microbiologically-documented infections.
– Decreased gram-negative and polymicrobial
bacteremia.
– No difference in overall mortality (3% vs. 5%) or
infection-related mortality (2% vs. 4%).
Supportive care after induction:
antifungal prophylaxis?
• Cornely et al.
– Phase 3 study of posaconazole vs. fluconazole.
– AML/MDS patients with expected ANC 7 days.
– Posaconazole decreased:
• Proven and probable fungal infections (2% vs. 8%).
• Invasive aspergillosis (1% vs. 7%).
• 100-day all-cause mortality (14% vs. 21%). NNT = 14
patients.
– 2% vs. 5% fungal-specific death.
– Posaconazole increased SAEs probably or possibly
drug-related (6% vs. 2%).
Blood product support
• Leukoreduced products
– Reduced febrile infusion reactions
– Decreased platelet alloimmunization
– Decreased likelihood of transplkant rejection
– Decreased CMV exposure in seronegative patients
• Irradiated products
– Prevent GVHD.
• At UNC, all products are leukoreduced.
– Irradiation must be requested.
– Once requested, all subsequent products are
irradiated.
Treatment: Post-Remission
Chemotherapy
• Mayer et al. NEJM 331:
896, 1994.
– Phase III trial comparing 3
different consolidation
strategies for patients with
AML in CR (HIDAC, IDAC,
low-dose cytarabine).
– In patients 60, the DFS
was 16% or less for all
groups.
Post-Remission Chemotherapy: How many
cycles of consolidation should be given?
• 3-4 HIDACs are better than 1 in good risk patients
– Byrd et al. JCO 17: 3767, 1999. Byrd et al. JCO 22: 1087,
2004.
– 3-4 cycles of HIDAC vs. 1 cycle of HIDAC followed by 2 cycles of
combination chemotherapy.
– Subset analysis of t(8;21) and inv(16) / t(16;16) patients.
– RFS was better for both subtypes, although OS benefit was only
seen in the t(8;21) group.
• Are 4 HIDACs better than 3?
– Farag et al. JCO 23: 482, 2005. Comparison of patients treated
on different CALGB studies.
– Patients
50% in 70% of patients.
– > 50% reductions in bone marrow blast burden in 6 of
57 patients.
– Combination trials ongoing.
• Others
– MLN518
– SU11248
– CEP-701
Novel Therapies: Others
• Histone Deacetylase Inhibitors
• Proteasome Inhibitors
• AKT / mTor inhibitors
• Clofarabine
• Apoptotic agents
– Genasense
• MDR modulators
– Zosuquidar
Treatment of Relapsed and
Refractory AML: The EPI
• European Prognostic – Age at relapse
Index • ≤ 35: 0 points
• 36 to 45: 1 point
– Relapse-free interval
• > 45: 2 points
from first CR
• ≤ 6 months: 5 points
– Prior transplant
• 7 to 18 months: 3 points • No: 0 points
• > 18 months: 0 points • Yes: 2 points
– Original cytogenetics – 5-year overall survival
• Good: 0 points • 1 to 6 points: 22 to 46%
• Intermediate: 3 points • 7 to 9 points: 12 to 18%
• Bad: 5 points • 10 to 14 points: 4 to 6%
Treatment of Relapsed and
Refractory AML
• Transplant when possible
– 5 year OS in first relapse or second CR:
• First CR > 6 months: 35%.
• First CR < 6 months: 20%.
– Primary treatment failure: 15%
– Beyond second CR or refractory first relapse: 5%
• Clinical trials!!!
• Salvage chemotherapy
– MEC
– ME
– HIDAC
– HIDAC + L-asparaginase
– Gemtuzumab
AML Therapy in the Elderly
• Advanced age is a poor prognostic factor.
• Disease biology different.
– Frequent adverse cytogenetic profile.
– High levels of MDR1 (P-glycoprotein)
expression.
– Frequent antecedent hematologic disorder.
• These patients should be referred for a
clinical trial when possible.
AML Therapy in the Elderly
• Standard induction chemotherapy, esp. for
patients with intermediate or good risk
cytogenetics.
– A phase III trial comparing best supportive care and
induction chemotherapy with cytarabine,
daunorubicin, and vincristine demonstrated improved
survival (21 vs. 11 weeks) and no difference in days
hospitalized.
• Low-dose cytarabine.
– Similar overall response rate and less toxicity c/w
cytarabine and rubidazone.