Acute lymphoblastic leukemia: an overview of etiology, epidemiology, pathophysiology, diagnosis, and treatment

Acute lymphoblastic leukemia (ALL) is a malignant neoplasm clinically characterized by uncontrolled proliferation of abnormal, immature lymphoid cells resulting in clonal accumulation in the bone marrow, blood, and extramedullary sites. Despite occurring in both children and adults, it is more frequent in children, with a peak incidence in those aged 1–4 years and the lowest incidence in those aged 25–45 years. The two main types of ALL are B-cell ALL (B-ALL) and T-cell ALL (T-ALL).^1-3

Etiology

The etiology of ALL is currently unknown²; however, there are various environmental risk factors and several genetic syndromes that predispose some individuals to ALL (Figure 1)¹:

Genetic susceptibility²

• Congenital syndromes include Down’s syndrome, Fanconi anaemia, ataxia telangiectasia, Bloom syndrome, Nijmegen breakage syndrome;
• Inherited gene variants include, ARID5B, IKZF1, CEBPE, CDKN2A or CDKN2B, PIP4K2A, ETV6;
• constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10);
• single nucleotide polymorphisms such as rs12402181 in miR-3117 and rs62571442 in miR-3689d2; and
• rare germline mutations in PAX5, ETV6 and p53.

Environmental risk factors^1-3

• Environmental risk factors include exposure to benzene, ionising radiation, or previous exposure to chemotherapy or radiotherapy
• Pesticide exposure and certain solvents or infections, such as Epstein-Barr virus and human immunodeficiencies

Epidemiology

Pathophysiology

B-ALL

B-ALL results from a series of genetic mutations followed by clonal expansion, differentiation, cell proliferation, and dysregulated cell apoptosis. The molecular pathways involved in B-ALL pathogenesis are detailed in Figure 3.⁷

T-ALL

The pathogenesis of T-ALL is characterized by the accumulation of multiple genetic mutations altering cell growth, differentiation, proliferation, and survival; these include deregulation of oncogenic NOTCH1 signaling, cell cycle, increased activation of kinase signaling, transcriptional alterations of oncogenes or tumor-suppressor genes, alterations in ribosomal function and translation, and deregulation of epigenetic regulators (Figure 4).⁸

Signs and Symptoms²

^{The signs and symptoms of ALL are summarized below in Figure 5.}

Diagnosis

Diagnosis of ALL is defined by the presence of ≥20% lymphoblasts in the bone marrow or peripheral blood.³ Infiltration of the peripheral blood or bone marrow with lymphoblasts is identified by morphological assessment; immunophenotyping is used to distinguish B- and T-cell lineage and for risk stratification.¹ According to the 2008 World Health Organization classification, the current diagnostic approach for ALL relies on a combination of morphological, immunological, and genetic/cytogenetic-based assessments.⁹  

Key tests

Diagnostic tests for ALL include a complete blood count, a peripheral blood smear, and a bone marrow biopsy. Laboratory tests include histochemical studies, cytogenetic testing, immunophenotyping, and specific molecular and genetic tests. Lumbar punctures are performed to investigate central nervous system (CNS) involvement. Imaging assessments, such as X-ray, computed tomography, magnetic resonance imaging and ultrasound, may also be performed during diagnosis.^10,11  The diagnostic journey for patients with ALL is outlined below (Figure 6).

Diagnostic criteria for B-ALL

The markers for differential classification of B-ALL are CD19, CD20, CD22, CD24 and CD79a.⁹  The main genetic subtypes of B-ALL are described in the table below.

Diagnosis criteria for T-ALL

Through immunophenotyping, CD1a, CD2, cytoplasmic and membrane/surface CD3, CD4, CD5, CD7, and CD8 have been identified as T-cell specific markers. Positive expression of cytoplasmic CD3 and CD7 is commonly seen, with variable expression of the others. In up to 25% of T-ALL cases, CD10 antigens are observed in a non-specific manner with expression of CD34, alongside myeloid markers CD33 and/or CD13.⁹

T-ALL subtypes associated with thymocyte differentiation stages include pro, pre, cortical, mature, and more recent early T-precursor. Each of these subtypes can be identified based on unique immunological features.⁹

Guidance on diagnosis may vary between countries. Below, we summarize key guidelines and further information.

Prognostic factors

Identification of prognostic factors and accurate risk stratification is important for treatment planning.¹ Some favorable and adverse risk factors for ALL are summarized below.

Treatment

There are four phases in the first-line treatment of patients with ALL,

• initial induction, to eradicate disease burden and achieve complete remission;
• consolidation, to eradicate any remaining leukemia cells in the body that have not been identified by common blood and bone marrow tests;
• intensification, to prevent the return or re-growth of cancer cells in the body; and
• long-term maintenance, aiming to prevent disease relapse.

The phases of first-line treatment and key chemotherapy regimens are summarized in Figure 9.¹

Additionally, CNS-directed therapy is administered to prevent CNS relapse. Treatment strategies include intensive intrathecal chemotherapy with methotrexate alone, or methotrexate, cytarabine, and hydrocortisone in conjunction with high-dose intravenous methotrexate and cytarabine. Allogeneic hematopoietic stem cell transplantation is a consolidation treatment primarily undertaken by high-risk patients or those with persistent minimal residual disease. Patients with Philadelphia-chromosome positive ALL are given tyrosine kinase inhibitors.¹

Although disease-risk stratification and intensive chemotherapy regimens have significantly improved survival rates, there is a lack of treatments in some low- and middle-income countries, leading to disparities in survival rates.¹

There are now several targeted therapies being utilized and developed for ALL. A summary of the targeted therapies, cellular targets, and associated toxicities is provided in Figure 10.¹ A summary of targeted therapies for B-ALL and T-ALL is provided in Figure 11.  

Guidance on treatment may vary between countries. Please read the section below on key guidelines for further information.

Key Guidelines and organizations

• Genetic heterogeneity, incidence, and prognosis of T-ALL
• Diagnostic approaches and risk stratification in T-ALL
• ESMO clinical practice guidelines for the diagnosis and treatment of adult ALL
• Patient Organizations: American Cancer Society and Cancer Research UK