AML is an aggressive, fast-growing, molecularly and clinically heterogeneous disease characterized by the rapid proliferation and accumulation of abnormal, immature myeloid blasts in the peripheral blood, bone marrow, and/or other tissues that can result in the suppression of normal hematopoiesis.^4-6 Highly expressed BCL-2 proteins in AML cells act as gate-keepers to prevent cell death.¹⁸

AML is a clonal malignancy that can develop de novo, as a secondary malignancy (therapy-related- or t-AML) following cytotoxic therapy (including alkylating agents, topoisomerase inhibitors, and antimetabolites, and/or myeloablative radio-chemotherapy), or secondary to myelodysplastic syndromes (MDS).^4,7

• Both de novo and secondary AML develop through a multistep process that involves the acquisition of a variety of genetic alterations, which may induce:^6,8
  • a block in cell differentiation
  • increased cell proliferation
  • an adverse impact on epigenetic control
• More specifically, genetic alterations and abnormalities contribute to AML pathogenesis due to their effects on tumor suppressor genes and the dysregulation of intracellular signaling pathways, apoptosis, epigenetic mechanisms, and mitochondrial metabolism.^6,8,9

A diagnosis of AML is made based on the presence of 20% or more blasts in the bone marrow or peripheral blood and is further defined by cytogenetic and molecular genetic changes.⁴

AML is a highly heterogenous disease and expanded understanding of the molecular pathogenesis of AML has led to the identification of diagnostic and prognostic markers.^4,10

Favorable

• Abnormalities of chromosome 16 at bands p13 and q22 [t(16;16)(p13;q22) or inv(16)(p13q22)]; CBFB-MYH11 fusion
• Translocation between chromosomes 8 and 21 [t(8;21)]; RUNX1-RUNX1T1 rearrangement
• Biallelic mutated CEBPA
• Mutations in the NPM1 w/o FLT3-ITD or w/FLT3-ITD^low*

Intermediate

• Mutated NPM1 and FLT3-ITD^high†
• Wild-type NPM1 w/o FLT3-ITD or w/FLT3-ITD^low† (w/o adverse risk lesions)
• Translocation between chromosomes 9 and 11 [t(9;11)] with otherwise normal chromosomes; MLLT3-KMT2A fusion
• Cytogenetic abnormalities not classified as favorable or adverse

Poor/Adverse

• Translocation between chromosomes 6 and 9 [t(6;9)]; DEK-NUP214 fusion
• Abnormalities of chromosome 11 at band q23 [t(v11q23.3); KMT2A rearranged]
• Translocation between chromosomes 9 and 22 [t(9;22)]; BCR-ABL1 fusion
• Changes to chromosome 3 at band q26 [inv(3) (q21q26.2) or t(3;3)(q21;q26.2)]
• Deletion of all or part of chromosomes 5 or 7
• Complex or monosomal karyotype
• Wild-type NPM1 and FLT3-ITD^high*
• Mutated RUNX1, ASXL1, TP53

*Low: low allelic ratio (<0.5); high: high allelic ratio (≥0.5)

Patients are stratified according to risk category by multiple factors in order to determine ability to receive intensive induction therapy.¹⁹

The standard therapy for AML patients eligible for intensive induction therapy has not changed significantly in the past 40 years.^6,8

• Induction therapy with 7+3 combination chemotherapy (7 days of cytarabine and 3 days of an anthracycline)
• Followed by consolidation therapy to maintain remission (high-dose chemotherapy)
• Some eligible patients with intermediate/poor risk disease may also receive a stem cell transplant along with consolidation therapy

Outcomes remain poor, with high rates of relapse for most patients. Older patients pose a difficult therapeutic challenge due to comorbidities and poor performance status, which may make them ineligible for intensive therapy.¹⁴ Survival in older patients who are unable to receive intensive treatment is 5-10 months.²²

An increased understanding of the pathophysiology of AML has facilitated the development of novel, molecularly targeted therapies. However, these recent additions may only benefit certain patients due to the heterogeneity of the disease.

Dramatic advances in the understanding of AML biology and genetics are being translated into strategies for targeting mutated proteins and dysregulated pathways. While these therapies address a number of areas of unmet need in AML, much clinical research and biomarker analysis remains to be done in order to expand and optimally implement these agents.²⁴

The BCL-2 protein is overexpressed in up to 70% of AML cases; elevated levels of BCL-2 correlate with poor prognosis and chemoresistance.^15,23