Fast Facts: Acute Lymphoblastic Leukemia

By B. Wrench, A. Castleton and M. Austin

Acute lymphoblastic leukemia (ALL) is the most diagnosed childhood cancer worldwide. Although rare in adults, this aggressive cancer also shows a second smaller incidence peak in later middle age.

Modern genetic profiling techniques are providing a better understanding of the molecular biology of ALL, which, in turn, is leading to significant advances in diagnosis, prognostication and therapy selection. Ongoing refinement of risk-adapted frontline treatment protocols, use of novel targeted therapies and better supportive care are improving outcomes for patients with ALL.

Fast Facts: Acute Lymphoblastic Leukemia covers the epidemiology, etiology, diagnosis and classification of ALL as well as the measurement of minimal residual disease to determine prognosis. It provides guidance on frontline therapies and the treatment of relapsed and refractory ALL, including the use of newer targeted agents and the role of allogeneic stem-cell transplantation. Looking to the future, it also considers the approaches and refinements that are in development for ALL.Table of Contents:

• Epidemiology, pathophysiology and etiology
• Diagnosis
• Prognostic factors
• Treatment
• Relapsed or refractory ALL
• Future directions

• Language: English
• Publisher: S. Karger
• Release date: Jun 30, 2022
• ISBN: 9783318069785

Book preview

Introduction

Acute lymphoblastic leukemia (ALL) is the most commonly diagnosed childhood cancer worldwide. This leukemia is rare in adults, but shows a second smaller incidence peak in later middle age. Without treatment, ALL is aggressive and invariably fatal. With treatment, the overall prognosis in children is excellent; in adults however, prognosis is less favorable.

In recent years, modern genetic profiling techniques have provided a greater understanding of the molecular biology of ALL, which in turn is yielding significant advances in diagnosis, prognostication and the selection of therapy. With the ongoing refinement of risk-adapted frontline treatment protocols, the incorporation of novel targeted therapies and the introduction of improved supportive care measures, outcomes for ALL are improving all the time.

In Fast Facts: Acute Lymphoblastic Leukemia we discuss the epidemiology, etiology, diagnosis and classification of ALL, as well as the use of factors such as minimal residual disease measurement to determine prognosis. Further chapters provide guidance on frontline treatment and on the treatment of relapsed and refractory ALL, including the use of newer targeted agents and the role of allogeneic stem-cell transplantation. Looking to the future, we describe some of the approaches and refinements that are in development, such as the search for new prognostic and predictive biomarkers and innovations in therapeutic agents, which may ultimately yield further improvements in outcome for patients with ALL.

We hope this resource will be an easily accessible, yet comprehensive guide for all members of the multidisciplinary healthcare team that cares for patients with ALL, providing a thorough understanding of current and potential future approaches to treating this form of blood cancer.

1Epidemiology, pathophysiology and etiology

Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood worldwide, but in adults it is a rare disease. The American Cancer Society estimated approximately 5690 new cases of ALL diagnosed in adults and children in the USA in 2021, and about 1580 deaths.¹ Data from Cancer Research UK indicate that in the UK approximately 800 cases of ALL are diagnosed annually in adults and children combined, and about 250 patients die each year.²

Epidemiology

Incidence. The overall incidence of ALL is between 1–2 cases per 100 000 population per year. Pediatric cases account for around 50% of this total, with the majority concentrated in infants aged 0–4 years.²,³ Following the initial reduction in incidence after childhood, there is a second, albeit lower peak in the late middle ages (Figure 1.1). As well as age, the incidence of ALL varies by ethnicity and sex, with a higher preponderance among men and those of Hispanic ethnicity.³ Overall, the trend of ALL incidence is stable in the UK and Europe while slowly increasing in the USA.²,³

Survival. The prognosis for a child diagnosed with ALL will depend on a range of risk factors (see below), but overall prognosis is excellent, with more than 90% survival at 5 years.³ The main exceptions to this favorable prognosis are infants aged 0–12 months, who have a generally poor prognosis due to the association of infant ALL with an aggressive form of the disease linked to rearrangements of the KMT2A gene (discussed in Chapter 3). The prognosis for an adult newly diagnosed with ALL also depends on numerous factors, but is generally worse than in pediatric disease, with 5-year overall survival (OS) at approximately 40%.² Survival among patients with ALL has improved dramatically in the majority of age groups over the past five decades, with the largest gains seen in the pediatric and young adult cohorts (Figure 1.2).

Figure 1.1 Average number of new cases of ALL per year by age and sex, UK data 2015–2017. Based on a graphic created by Cancer Research UK.

Pathophysiology

ALL arises from bone marrow blood progenitor cells of the lymphoid lineage that have gone through a single or a series of leukemia-initiating events which result in failure to progress to a mature form. This, combined with increased proliferation, leads to the progressive accumulation of immature lymphoblasts in the bone marrow (Figure 1.3).

Figure 1.2 Overall survival among children with ALL who were enrolled in Medical Research Council UKALL clinical trials, 1972–2011. Adapted from Br J Haematol 2020;191:562–7.

Figure 1.3 The hematopoietic hierarchy and model of ALL development.

In broad terms, ALL is subdivided by the lymphoid lineage, either B cell or T cell. The B-ALL subtype is the most common, accounting for around 75% of cases.⁴ Egress of bone marrow lymphoblasts into the peripheral blood leads to the typical leukemic presentation with a high white blood cell (WBC) count.

The interaction of proliferating lymphoblasts and the bone marrow environment causes a rapidly progressive loss of normal blood cell production, which leads to a syndrome of ‘bone marrow failure’ characterized by fatigue, shortness of breath, bleeding and susceptibility to infection. Untreated, the rapidly progressing bone marrow failure of ALL is almost universally fatal.

Unlike the more common acute myeloid leukemia (AML), the high circulating WBC count seen in ALL rarely leads to symptoms related to leukostasis. However, the T-cell variant of ALL is associated in up to 50% of cases with a mediastinal mass that can lead to symptoms related to its physical size, ranging from cough and breathlessness to cardiac tamponade and superior vena cava obstruction.⁵

In a small subset of primarily T-ALL cases the malignant progenitor cells are found as a discrete extramedullary tumor without, or with minimal, involvement of the bone marrow. In this scenario the disease is referred to as lymphoblastic lymphoma (LBL), but it is still treated as ALL.

Etiology of pediatric ALL

In pediatric ALL, leukemogenesis is thought to be a multistep process involving an inherited genetic predisposition, environmental factors and additional acquired (non-inherited) genetic mutations (Table 1.1).⁶

Inherited genetic predisposition. Direct evidence for an inherited genetic predisposition to ALL (although responsible for fewer than 5% of ALL cases) is provided by the high risk of ALL development associated with Bloom syndrome, neurofibromatosis, ataxia telangiectasia and constitutional trisomy 21 (Down syndrome). Outside of these genetic syndromes, recent genome-wide association studies have identified multiple low-risk variants in genes directly involved in lymphocyte differentiation and development (for example, IKZF1) as well as a number of single nucleotide polymorphisms which are likely to contribute to disease risk (see Table 1.1).

TABLE 1.1

Predisposing factors for ALL