23rd July 2024

Leukaemia

There are four major types of leukaemia:

There are also other types of leukaemia, some of which shall be discussed briefly.

Acute myeloid leukaemia

Background of AML

AML occurs due to clonal proliferation of haematopoietic precursor cells of myeloid lineage in the bone marrow.

In adults, it is the most common acute leukaemia and the second most common leukaemia. The median age of diagnosis is 65 years, with a male predominance.

The exact aetiology is unknown, however there are numerous associated risk factors:

• Environmental exposure to radiation and benzene
• Pre-existing haematological pathology such as myelodysplastic syndrome or myeloproliferative neoplasm
• Previous treatment with chemotherapy, particularly alkylating agents and topoisomerase II inhibitors

Presentation and diagnosis of AML

The proliferation of precursor myeloid cells (blast cells) in the BM leads to BM failure, causing:

• Anaemia: pallor, palpitations, dyspnoea, fatigue
• Thrombocytopenia: bruising, excess bleeding
• Neutropenia: infections

Gum hypertrophy can also be a presenting feature, seen most commonly in the monocytic subtypes of AML.

Diagnosis is multi-faceted:

• Blood tests: FBC (cytopenias); can include a metabolic panel to screen for tumour lysis syndrome (high potassium, low calcium, high phosphate, high uric acid)
• Blood film: immature myeloid blasts with pathognomonic Auer rods (Figure 1), ≥20% blasts
• BM biopsy: diagnosis if ≥20% blasts; carry out immunophenotyping to differentiate AML from ALL (see acute lymphocytic leukaemia); cytogenetic and molecular analysis for prognostication and classification

Tumour lysis syndrome occurs due to the rapid breakdown of a large number of cancer cells. This occurs most commonly a few weeks after treatment initiation but can also occur spontaneously. A high phosphate is not seen as commonly in spontaneous tumour lysis syndrome, compared to post-treatment.

Image Source: Wikimedia Commons (2010). Myeloblast with Auer rod smear 2010-01-27, Licensed under a creative commons licence. Available for free at: https://en.wikipedia.org/wiki/Auer_rod#/media/File:Myeloblast_with_Auer_rod_smear_2010-01-27.JPG (Accessed: 16 January 2024)

Management and prognosis of AML

Full treatment for AML in medically fit and willing patients consists of two stages:

1. Remission induction: generally carried out with cytarabine and an anthracycline (e.g. daunorubicin)
2. Consolidation therapy: often carried out with high dose cytarabine

Allogeneic haematopoietic stem cell transplantation (SCT) can be used in patients with an intermediate or poor prognosis in addition to consolidation therapy, especially in patients <60 years old.

Less intensive chemotherapy options are available for patients not likely to tolerate high intensity regimes. These are less likely to induce complete remission and allow long-term disease control.

Maintenance chemotherapy is generally not used.

Various parameters are used for prognosis:

Acute promyelocytic leukaemia

Acute promyelocytic leukaemia (APL) is a subtype of AML. Peak incidence is in early adulthood. The vast majority of cases are caused by t(15;17) causing formation of the PML-RARα fusion gene.

APL is a medical emergency that warrants quick diagnosis and treatment as it can result in (and often presents with) disseminated intravascular coagulation or haemorrhage, which has high mortality.

Treatment is with all-trans-retinoic acid with an anthracycline for induction remission. Consolidation therapy uses the same combination of chemotherapy.

APL has a good prognosis with >80% cure rates.

Acute lymphoblastic leukaemia

Background of ALL

ALL occurs due to clonal proliferation of haematopoietic precursor cells of lymphoid lineage in the BM.

ALL is the most common malignancy in childhood. Peak incidence is between the ages of two and five, with further smaller peaks in the mid-30s and mid-80s. Incidence is higher in males than females.

Approximately 85% of ALL is of B-cell lineage and 15% is of T-cell lineage.

The exact cause is not known, but there are known associated contributing factors. These include genetic factors (higher likelihood of development between monozygotic twins than singleton siblings) and pre-existing genetic syndromes (e.g. Down syndrome, Klinefelter’s syndrome, ataxia-telangiectasia). Contributing environmental factors include radiation and smoking exposure.

Presentation and diagnosis of ALL

The presenting signs and symptoms are from BM failure (see acute myeloid leukaemia).

In addition, children can often present with hepatomegaly and/or splenomegaly and lymphadenopathy.

As with AML, diagnosis requires blood tests, blood film and BM biopsy (for immunophenotyping, cytogenetics and molecular analysis).

Image Source: Wikimedia Commons (2007). Acute leukemia-ALL, Licensed under a creative commons licence. Available for free at: https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia#/media/File:Acute_leukemia-ALL.jpg (Accessed: 16 January 2024).

Differentiating between AML and ALL

Management and prognosis of ALL

Treatment of ALL consists of four main stages:

1. Remission induction: generally a four drug regimen.
2. Consolidation therapy: several combinations, aiming to use drugs that differ in mechanism of action to those used for induction.
3. CNS prophylaxis (or treatment if there is CNS involvement): intrathecal CNS prophylaxis is given alongside all stages of treatment to reduce risk of relapse with leukaemic meningitis.
4. Stem cell transplant/maintenance therapy: SCT is preferred in patients after consolidation therapy who are at high risk of relapse. Maintenance therapy is recommended in patients who are high risk, but ineligible for SCT, or who are at standard risk for relapse.

Prognosis is significantly worse in adults than in children. Cure rates in children are high at around 80%, whereas 35-40% of adults treated with intensive chemotherapy survive two years. Prognostic factors include:

Chronic myeloid leukaemia

Background of CML

CML is a myeloproliferative disorder caused by clonal proliferation of mature and maturing granulocytes, predominantly neutrophils. Cell differentiation is relatively preserved, in contrast to AML. CML accounts for 15-20% of adult leukaemias. Median age of presentation is 50 years and it has a slight male predominance.

Ionising radiation is the only known risk factor.

Translocation between chromosomes 9 and 22, t(9;22)(q34;q11), causes formation of an abnormal chromosome 22, called the Philadelphia chromosome. This is pathognomonic for CML. The translocation results in formation of the BCR-ABL1 fusion gene, an oncogene that produces the BCR-ABL1 protein, a dysregulated and constitutively active tyrosine kinase.

Presentation and diagnosis of CML

CML is a triphasic or biphasic disease:

• Chronic phase: <10% blasts in BM
• Accelerated phase: 10-19% blasts in BM (some patients go straight from the chronic phase to a blast crisis)
• Blast crisis: ≥20% blasts in BM, resembles an acute leukaemia

Signs and symptoms depend on which phase patients present in. Around 85% of patients present in the chronic phase. As a result, up to half of patients are asymptomatic on presentation, being picked up incidentally on an FBC.

Splenomegaly, present in ~75% of patients, can cause abdominal pain or early satiety. Patients can also present with constitutional symptoms of fatigue, weight loss and sweats. Patients in a blast crisis can present with BM failure.

Diagnostic workup includes:

• Blood tests: FBC (raised WCC)
• Blood film: mature/maturing myeloid cells
• BM biopsy: to confirm disease phase

Definitive diagnosis is made by cytogenetic confirmation of the presence of the Philadelphia chromosome, and hence the BCR-ABL1 fusion gene, by fluorescent in situ hybridisation or quantitative reverse transcription polymerase chain reaction.

Image Source: Wikimedia Commons (2009). Chronic Myeloid Leukemia smear 2009-04-09, Licensed under a creative commons licence. Available for free at: https://en.wikipedia.org/wiki/Chronic_myelogenous_leukemia#/media/File:Chronic_Myeloid_Leukemia_smear_2009-04-09.JPG (Accessed: 16 January 2024).

Management and prognosis of CML

Management options for CML include:

1. Tyrosine kinase inhibitors (TKI): first line TKIs include the first-generation imatinib and second-generation medications dasatinib and nilotinib. TKIs are generally continued indefinitely as long as they are working, and they provide good disease control long-term.
2. Allogeneic SCT: can be considered in any patient not responding to initial therapy or with relapse.
3. Hydroxycarbamide: can be used for symptom control while awaiting a diagnosis for patients with significant leucocytosis, systemic symptoms or symptomatic splenomegaly. It has no bearing on survival.

Patients in the chronic phase are treated with a TKI with a generally very good response.

Patients in the accelerated phase or blast crisis are treated with the same TKIs but have a lower likelihood of response and higher risk of relapse. As such, allogeneic SCT is more likely to be required and considered earlier.

TKIs allow patients with CML to have a near normal life expectancy. Stage of disease at presentation has the strongest impact on outcome.

Chronic lymphocytic leukaemia

Background of CLL

CLL (known as small lymphocytic lymphoma, SLL, if the disease is predominantly in the lymph nodes) is an indolent lymphoproliferative disorder of mature monoclonal B-cells. CLL is the most common leukaemia in Western adults. Median age of diagnosis is 70 years with a male predominance.

There appears to be a genetic predisposition to CLL. No environmental risk factors have been identified.

Presentation and diagnosis of CLL

The majority of patients are asymptomatic at diagnosis, usually identified on a routine FBC.

If symptomatic, patients may present with lymphadenopathy, splenomegaly, hepatomegaly, signs of BM failure (as discussed in the section on AML) or with ‘B’ symptoms of lymphoma (fever, fatigue, weight loss, night sweats).

Cytopenias can also occur as a result of autoimmune haemolytic anaemia (AIHA; in ~10% of patients) and immune thrombocytopenia (ITP; in ~1-2%).

Diagnosis usually involves:

• Blood tests: FBC with absolute lymphocytosis (>5 x109/L); there may be anaemia or thrombocytopenia
• Blood film: lymphocytosis with ‘smudge’ or ‘smear’ cells
• Immunophenotyping with flow cytometry: positive for CD5, CD19, CD20, CD23, kappa or lambda immunoglobulin light chain

BM biopsy is usually not required.

Image Source: Wikimedia Commons (2014). Smear cells, Licensed under a creative commons licence. Available for free at: https://en.wikipedia.org/wiki/Chronic_lymphocytic_leukemia#/media/File:Smear_cells.jpg (Accessed: 16 January 2024).

Management and prognosis of CLL

CLL is staged using cell counts, lymphadenopathy and hepatosplenomegaly.

Early stage asymptomatic disease is managed with observation. Indications to initiate treatment include:

• Progressive bone marrow failure
• AIHA/ITP unresponsive to steroids
• Massive (≥6 cm below costal margin) or progressive splenomegaly
• Massive (≥10 cm) or progressive lymphadenopathy
• Progressive lymphocytosis with >50% increase in 2 months or doubling time <6 months
• Significant constitutional symptoms (weight loss ≥10% in 6 months, fevers >2 weeks without infection, night sweats without infection, significant fatigue)

If the decision is made to begin chemotherapy, factors such as age, performance status, comorbidities and severity of symptoms can be used to decide between a palliative approach, minimising toxicity, and an approach aiming for complete remission. Chemotherapy choice is guided by cytogenetic analysis.

If treatment is required, first-line chemotherapy can achieve 25-50% remission rates. However, there is a high risk of relapse, with most patients requiring further treatment after 2-3 years.

Hairy cell leukaemia

Hairy cell leukaemia (HCL) is an uncommon B-cell lymphoproliferative malignancy, which is distinct from CLL.

Median age of presentation of 50-55 years and there is a strong male predominance.

Patients generally present with symptoms related to BM failure or splenomegaly.

Diagnosis usually requires blood tests, blood film and immunophenotyping (CD19, CD20 and CD22 positive). BM biopsy is usually not possible due to increased BM fibrosis from HCL invasion.

Image Source: Wikimedia Commons (2015). Hairy Cell Leukaemia, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Hairy_Cell_Leukaemia.jpg (Accessed: 16 January 2024).

As with CLL, asymptomatic patients are managed with observation and can be observed for months or years. Symptomatic patients (significant cytopenia, symptomatic splenomegaly or lymphadenopathy or significant constitutional symptoms) are treated with purine analogues first line. These have a very high response rate and most patients with HCL survive >10 years after diagnosis.

References

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