Leukaemias may be lymphoid, myeloid, monocytic or megakaryocytic in origin (Fig. 1). The cells may retain some of their original characteristics; however, some are poorly differentiated and the precise lineage can be difficult to identify by morphology alone. This chapter focuses on lymphoblastic leukaemias – both acute lymphoblastic leukaemia (ALL) and chronic lymphocytic leukaemia (CLL); readers are referred to the Essentials of Haematology edition for details on other leukaemias.
Fig1. Malignant counterparts at each step in the leucocyte differentiation pathway. B, B cell; LPCC, lymphoplasma cytoid cell; T, T cell; Tc, T cytotoxic cell; TH, T helper cell.
Acute lymphoblastic leukaemia
ALL is largely a disease of children and young people; it is less common over the age of 20 years (Fig. 2). It is five times more common than acute myeloid leukaemia (AML). Patients with ALL often present with complications of bone marrow failure, including bleeding, infection and anaemia. Other signs/symptoms include sweats and meningeal irritation. Patients may have palpable lymphadenopathy and a small proportion (10%) have a mediastinal mass apparent on chest X- ray. Over 80% of patients are thrombocytopenic and in some this is severe and results in petechiae. Many (60%) have low haemoglobin levels below 80 g/L. The white cell count is usually low (leucopenia), but a minority of patients present with an apparently high white cell count due to circulating blasts and this indicates a poorer prognosis.
Fig2. Decade of onset in acute lymphoblastic leukaemia (ALL; yellow line) and chronic lymphocytic leukaemia (CLL; green line).
The diagnosis of leukaemia is confirmed by performing a bone marrow aspirate and trephine biopsy and finding that >20% of cells are leukaemic blast cells. The blasts in the marrow and peripheral blood are immunophenotyped using flow cytometry (Table 1) and immunohistology.
Table1. Panel of antibodies for the diagnosis of acute leukaemias
ALL may be of B- or T- cell origin. In B- ALL, the malignant cells have the B- cell surface markers, CD10+, CD19+, CD24+ and cytoplasmic CD79+, as well as terminal deoxynucleotidyl transferase (TdT). There is variable expression of lymphoid line age CD45, and confusingly some cells may have aberrant expression of myeloid lineage surface markers such as CD13 and CD33.
The malignant cells in T- ALL express T- cell markers such as CD2, CD3, CD4, CD5, CD7 and CD8, reflecting transformation of intrathymic T- cell development (Fig. 3).
Fig3. Markers of various forms of acute lymphoblastic leukaemia (ALL). See Fig. 1 for abbreviations.
In addition to flow cytometry and histology, cytogenetic studies are performed to identify genetic mutations that correlate with prognosis. For example, in B- ALL, poor prognostic indicators include presence of the BCR- ABL fusion protein caused by the t (9;22) translocation and rearrangements of the MLL gene. The TEL- AML1 or t (12;21) translocation is associated with a good prognosis. Chromosomal translocations involving T- cell receptors are seen in about a third of T- ALL cases; these include NOTCH1, FBW7, MYB, LMO1/2 and CALM- AF10, as well as TCR γ/δ. Better prognosis in T- ALL patients occurs with some HOX rearrangements and some TAL1/SCL mutations.
Other factors used as prognostic criteria in ALL include the white cell count and age at presentation. Children under 1 year old or over 10 years and those with a high blast cell count at presentation (>50 × 109/L) are considered high risk.
Complications of ALL include anaemia and thrombocytopenia, resulting in bleeding due to marrow infiltration (Table 2). Concentrated red cells are given to correct anaemia, and platelet concentrates to prevent and treat bleeding. Infection is a common complication of ALL and preventive measures, such as barrier nursing and prophylactic antifungal and antiviral agents, are important.
Table2. Complications of acute lymphoblastic leukaemia associated with disease or its treatment with chemotherapy and human stem cell transplantation
ALL is a fatal condition if untreated, but aggressive chemotherapy may eliminate the clone of malignant cells and induce a cure (see Box 1). B- ALL has an excellent outcome in children. A complete remission is achieved with initial high- dose ‘induction’ chemotherapy in around 95% of children and 60–85% of adults. Further treatment is then required to ‘consolidate’ and ‘maintain’ the remission. The intensity of the consolidation therapy depends on prognostic factors at presentation and on the initial response to chemotherapy, in particular whether there is any residual disease following induction chemotherapy. For higher- risk patients, an allogeneic human stem cell transplant (HSCT) may be performed if a suitably matched donor is identified. A recent major advance in the treatment of end- stage B- ALL refractory to conventional chemotherapy is the use of autologous chimeric antigen receptor T- cell (CAR- T) therapy targeting B- cell antigens such as CD19 (tisagenlecleucel). This is licensed for the treatment of children and young adults with B- ALL and adults with refractory diffuse large B- cell lymphoma. Because of its mode of action, CD- 19- directed CAR- T cell therapy causes unavoidable B- cell aplasia associated with hypogammaglobulinaemia. Immunoglobulin replacement therapy in the medium term is, therefore, required until B- cell reconstitution occurs.
Box1. Objectives of treatment in acute lymphoblastic leukaemia
There are complications associated with therapy, both with initial chemotherapy and HSCT (Table 2). Severe infection secondary to the profound neutropenia that results from intensive therapy is the major cause of mortality and morbidity in ALL. Barrier nursing and prompt and aggressive treatment of neutropenic fever according to standardized protocols can reduce the risk of death from sepsis in neutropenic patients, similar to the protocols used after HSCT for primary immunodeficiencies.
Graft- versus- host disease (GvHD) may occur after allogeneic stem cell transplantation, although some graft- versus- leukaemia effect is helpful for the antileukaemic effect. Long- term complications of survivors such as organ damage, infertility and psychological issues must also be considered.
Chronic lymphocytic leukaemia
CLL is a relatively common disease of elderly patients (20 per 105 prevalence in those >60 years old). It is uncommon in people under 50 years of age (see Fig. 2) and usually runs a relatively benign course, although speed of progression varies enormously. Excessive numbers of small lymphocytes are found in the peripheral blood (Fig. 4); in over 90% of cases of CLL, the neoplastic cells are B cells (Fig. 5). They have the characteristic cell- surface markers of circulating B cells (Table 3). The cells represent a malignant proliferation of a single clone of a B cell and are therefore, as in acute leukaemias, ‘monoclonal’. Normally ‘reactive’ lymphocytic proliferation is polyclonal and therefore the ratio of cells with κ or λ is 3 : 2. In contrast, in a monoclonal B- cell proliferation, this ratio is changed in favour of the malignant clone, as all the malignant cells express the same light- chain type. These cells accumulate progressively in the blood, lymph nodes, spleen, liver and bone marrow.
Fig4. Chronic lymphocytic leukaemia (CLL) blood film. Source: Axford J & O′Callaghan C (Eds) Medicine, 2nd Ed (2004). Reproduced with permission of John Wiley & Sons Ltd.
Fig5. Origins of various forms of chronic leukaemia. See Fig. 1 for abbreviations.
Table3. Immunophenotyping in differential diagnosis of chronic lymphocytic leukaemias
Although most elderly patients with CLL usually have a relatively benign illness and survive for over 8–10 years, the prognosis is variable. A combination of genomic, cytogenetic and cellular changes provides useful prognostic information. Chromosomal deletion at 17p and/or TP53 mutations predict poor responses to treatment. Chemotherapy is not necessary in the early stages, although some untreated CLL patients have severe recurrent bacterial infections due to low serum immunoglobulin levels and reduced antibodies. In these cases, immunoglobulin replacement therapy should be considered. Treatment with cytotoxic chemotherapy is considered when a patient becomes symptomatic either because of splenomegaly or constitutional symptoms such as sweats and weight loss, or if autoimmune complications develop such as auto immune thrombocytopenia or haemolytic anaemia. The most common chemotherapy regimen used in the UK com bines fludarabine (an adenosine deaminase inhibitor), cyclophosphamide (an alkylating agent) and rituximab (a monoclonal antibody to the B- cell marker CD20). Newer therapies include ofatumumab, a humanized monoclonal antibody to another part of the CD20 antigen that appears to be expressed more on malignant B cells than normal B cells. Upregulation of Bruton tyrosine kinase (BTK) on malignant B cells has led to BTK inhibitors such as ibrutinib being successfully adopted as a licensed therapy in CLL.
Other chronic lymphoid leukaemias
Sézary syndrome is part of a spectrum of T- cell malignancies that often involve the skin. The skin is infiltrated with the large, cleaved, mononuclear cells diagnostic of the condition. Immunological markers on peripheral blood have shown these cells to be CD4+ T cells in origin (see Table 3 ). Many patients die within 10 years of diagnosis, often as a result of infections.
Other T- cell malignancies include adult T- cell leukaemia/ lymphoma (ATL), which occurs in geographical clusters, particularly in Japan and the Caribbean, where the associated retrovirus (HTLV- I) is endemic. ATL is an aggressive systemic disorder, often with skin and neurological involvement.
Hairy cell leukaemia is a malignancy of late- stage B cells. It is a rare condition of middle- aged males, which although termed a ‘leukaemia’ is not necessarily associated with a high number of leukaemic cells circulating in the peripheral blood and is actually part of the World Health Organization (WHO) classification of lymphomas. Pancytopenia, leading to an increased risk of infection, is common. Two- thirds of the patients have splenomegaly. The abnormal cells are often diagnosed as ‘atypical lymphocytes’ as they do have a peripheral fringe of spiky projections; close inspection and the use of enzymatic and immunological markers confirm the diagnosis (see Table 3). The identity of the ‘hairy cell’ as a late- stage B cell can be confirmed by flow cytometry using monoclonal antibodies to B- cell- restricted antigens, as well as the integrin CD11c. Interferon (IFN) and cladribine induce remission in a high proportion of patients, with 75% achieving complete remission for >5 years. Splenectomy may be consid ered in those with large splenomegaly causing discomfort or severe cytopenias. Visit the website at www.wiley.com/go/ misbah/immunology to read case studies on Sézary syndrome and hairy cell leukaemia.
