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

According to WHO 2016, 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

The WHO was updated in 2022 and a new International Consensus Consortium (ICC) classification system was released in 2022 which employs different blast thresholds to define AML in certain situations. While there is no minimum threshold in the WHO criteria for AML with defining genetic abnormalities (with the exception of 20% required for AML with BCR::ABL1 and AML with CEBPA bZIP mutation), the ICC requires at least 10% blasts in the bone marrow or peripheral blood for defining AML with recurrent genetic abnormalities. For all other AML subgroups, the 20% blasts threshold was retained by the WHO. However, the ICC introduced a new category of MDS/AML with 10%–19% blasts in the bone marrow or peripheral blood, in recognition of the similarities in biology and prognosis between these patients and those with ≥20% myeloblasts.^27,28

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

A new European leukemia network (ELN) 2022 guidelines which include an update to the 2017 risk classification was recently published. The new 2022 risk classification integrates knowledge from novel molecular findings and recent trial results, as well as emphasizes dynamic risk based on response assessment, such as measurable residual disease (MRD) negativity. However, the guidelines are largely based on intensively treated patients, so future adjustments may be needed for patients who are treated with less-intensive therapies.¹⁹

In an analysis of 513 patients from the multicenter Beat AML cohort, the median overall survival across ELN 2022 favorable–, intermediate–, and adverse–risk groups was not reached, 16.8, and 9.7 months, respectively. The ELN 2022 guidelines more accurately stratified survival between patients with intermediate- or adverse-risk AML treated with induction chemotherapy compared with ELN 2017 guidelines.²⁶

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

5-Year Survival by Year of Diagnosis (2000-2018)²

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