Introduction

Acute myeloid leukaemia (AML) is a rare type of blood cancer that affects certain blood cells called haematopoietic stem cells.¹ The disease is caused by genetic alterations or disruptions that impact the control of stem cell production, resulting in an increase of cells called neoplastic clonal myeloid stem cells.¹ When immature blood cells (myeloblasts) accumulate in the bone marrow, they disrupt hematopoietic stem cell development, leading to fewer red blood cells (RBCs), platelets, and white blood cells.^1,2 

The onset of AML can be rapid, with many patients showing symptoms or some only having their underlying disease identified by routine blood work. The disease mostly affects older patients (ages 60 and over). Symptoms can be categorised as specific and general and include:²

General symptoms

• Fatigue
• Loss of appetite
• Breathlessness
• Fever

Specific symptoms

• Monocytosis (abnromal moncyte count)
• Frequent, unusual bleeding
• Disseminated intravascular coagulation (DIC)
• Bone marrow failure (BMF)

AML is the most common form of acute leukaemia in adults, with around 3000 new cases every year in the UK.² Diagnosis involves detecting myeloblasts in the bone marrow and blood, along with immunophenotyping and cytogenetic characterisation.² 

Monocytes are essential to the immune system and play a role in identifying and engulfing foreign particles, such as antigens, thereby triggering an inflammatory response.³ 

Monocytes also help other immune cells, such as lymphocytes, by becoming dendritic cells that present antigens to lymphocytes, thereby controlling the immune response. A normal monocyte count is between 0.2 and 0.8 x 10⁹/L, compared to levels in pro-inflammatory responses, where monocyte levels increase dramatically. A level above 1 x 109/L for more than 3 months is clinically defined as monocytosis.³ It is essential to monitor monocytosis in patients since it is commonly present in those patients with monocytic acute leukaemias, a specific type of AML.³ New advances in the younger AML population (below 60 years) have improved patient outcomes, but there seems to be some stagnation in the survival rates for the older AML patients, indicating an immediate need for new AML therapeutics.

Pathophysiology of AML

AML can be classified into three groups: favourable, intermediate, and high-risk groups. These groups are assigned based on survival rates and specific genetic changes that may result in a more aggressive form of AML. Favourable cases have the highest five-year survival rate (64%), intermediate cases have a survival rate of 41%, and high-risk cases have a survival rate of 11%.¹

Genetic changes in the favourable group include chromosomal translocations in specific regions, the CEBPA in-frame mutation, and a lack of FLT3-ITD (internal tandem duplication) mutations.⁴ The intermediate group normally contains the FLT3-ITD mutations or specific rearrangements such as p21.3.^1,4 The most aggressive form of AML is classified under the high-risk group, which most notably includes the monosomy deletions and mutations with TP53, SRSF2, EZH2, and ASXL1.⁴ Mutations of TP53 are most commonly associated with poor outcomes and increased resistance to chemotherapy. Some genetic abnormalities cause resistance to standard AML care, such as the Runt-related transcription factor (RUNX1), a major driver of normal hematopoiesis and an important AML1-binding protein that is frequently translocated in 12% of AML cases.⁴

Monocytosis in AML

Monocytosis is related to AML since it can be a major disease symptom, especially in younger patients. Some subtypes of classical AML include acute monoblastic / monocytic leukaemia (AMoL), which makes up around 15-24% of AMLs within children.⁵ AMoL is diagnosed when 20% of immature (blast) cells are found within the bone marrow or blood, with at least 80% of these blast cells coming from monocyte cell lines.⁵

Diagnostic significance

Monocytosis is defined as elevated monocyte counts above 1 x 109/L for more than 3 months, indicating systemic inflammation. One of the first methods for diagnosing patients with suspected monocytosis is to screen for infectious diseases and perform a physical exam.³

Diagnostic procedures for monocytosis:

• When monocytosis is suspected, a complete blood count (CBC) is used to measure the amount of red blood cells (RBCs) and white blood cells (WBCs) 
• A peripheral blood smear is used to assess the phenotypic characteristics of blood cells under a microscope to further differentiate between monocytosis and other conditions
• The morphology of monocytes should be investigated on a peripheral smear for dysplasia
• An absolute monocyte count measures the number of monocytes in your blood, determining whether further testing is needed 
• For persistent monocytosis, a monocyte compartment flow cytometry can be used to distinguish between rheumatological or infectious diseases³

Diagnostics for AML:

• Cytomorphology evaluation is the first step in diagnosing AMoL, which uses both peripheral blood and bone marrow smears to identify monocytic lineage cells and blast cells, but there is a great overlap between the morphology of these cells
• Multiparametric flow cytometry is essential for differentiating reactivity from dysplastic and the leukemic origin of affected monocytes
• Intense non-specific esterase activity (NSE), naphthol AS-D acetate esterase (CAE), and alpha-naphthyl butyrate esterase activity are major hallmarks within cytochemical staining for monocytic lineage leukaemia 
• NSE can be used to distinguish between myeloid cells and monocytes.
• In AMoL, promonocytes are amplified in bone marrow, but mature monocytes are common immune cells in peripheral blood
• Immunophenotyping can make use of fluorochrome-stained antibodies, which can distinguish between monocytic precursors and monocytic-lineage blasts from myeloid cells⁵

Clinical implications

There are many subtypes of AML which require unique treatment and management approaches based on their presentation. For example, AMoL, one of the most common forms of AML, can affect disease presentation and management depending on its classification and the genetic mutations involved.⁵ Mutations in the nucleophosmin gene 1 (NPM1), which account for 6.5% of AML cases, can present with various cell shape changes that reflect FAB-M4 and M5 subtypes, especially if these mutations occur with FLT3/ITD mutations.⁵

Management and treatment

For patients below 70 years who score well on the ECOG performance test (between 0-1,indicating good general fitness) and have newly diagnosed AML without complex genetic abnormalities, a continuous infusion of cytarabine can be used to increase long-term survival.⁴ 

On the other hand, for patients with complex abnormalities, high-risk cytogenetics, or secondary AML (caused by prior treatments), the FLAG-based regimen is used, which incorporates fludarabine, cytarabine, and granulocyte colony-stimulating factor (G-CSF). Standard therapy for patients with FLT3-ITD mutations is altered to include quizartinib. Those patients who are fit and older than 70 years receive hypomethylating agents such as azacitidine and decitabine, along with Bcl-2 inhibitors.⁴ Finally, allogeneic stem cell transplantation is the only curative treatment for AML, but has significant risks and complications such as graft vs host disease (GvHD).

Prognosis and outcomes

The prognosis for AML patients depends on their cytogenetic tests and molecular characterisation, as favourable-risk AML patients have a higher survivial rate based on their genetic mutations (chromosomal translocations).⁴ Patients with mutations in ASXL1 and U2AF1 have a worse prognosis, which is also exacerbated with age and WBC counts that are more than 100,000 upon diagnosis.⁴ The presence of leukemic cells and therapy-related AML also increases the aggressiveness of the disease. PCR and flow cytometry methods can now detect residual AML disease in patients who show complete remission. 

FAQs

Can I prevent monocytosis? 

Monocytosis results from an underlying condition driving an inflammatory response. As monocytosis is linked to dysfunctional immune systems and autoimmunity, the best way to avoid this is to maintain a strong immune system. This can be achieved by: 

• Maintaining a well-balanced diet 
• Regular exercise 
• Stopping smoking 
• Reducing chronic stress 
• Maintaining a healthy sleep pattern

Summary 

Acute myeloid leukaemia (AML) is a rare malignancy of hematopoietic stem cells characterised by genetic alterations that promote the increase of immature myeloid cells (myeloblasts), reducing red blood cells, white blood cells, and platelets. AML is commonly seen in older patients and can present with symptoms such as infections, bleeding, and anaemia.

Diagnosis involves detecting myeloblasts in bone marrow and peripheral blood via biopsies, immunophenotyping, and cytogenetic analysis. Monocytosis is commonly associated with AML and its subtypes, characterised by an increase in monocyte counts (above 0.8 x 10^9/L) for longer than 3 months. 

Treatment varies by patient age, cytogenetic analysis, and ECOG tests, with options ranging from cytarabine infusion to FLAG-based therapy, allogeneic stem cell transplantation, and hypomethylating agents. Early detection is essential to long-term survival and correct disease classification. Distinguishing between monocyte maturity is paramount to prognosis and treatment tailoring.