Suspect acute leukaemia in patients with anaemia, neutropenia, thrombocytopenia and associated systemic symptoms such as infections and bleeding, particularly mucosal bleeding.
Advanced acute leukaemia is characterized by poor general condition of the patient, leucocytosis and immature blast cells in the blood.
The establishment of precise diagnosis and the initiation of urgent treatment take place in a specialized hospital. Post-treatment follow-up is carried out in the hospital outpatient clinic and later in the primary health care.
Definition
Acute leukaemias form a heterogeneous group of malignant haematological diseases where leukaemic blast cells accumulate in the bone marrow and, in most cases, in the blood. In some cases, the proportion of more mature (pathological) cells is significant.
Leukaemic cells will also invade other parts of the body.
Epidemiology
The annual incidence is about 4 new cases /100 000 individuals.
Up to the age of 40-50 years, the annual incidence is about 2/100 000. Thereafter the annual incidence increases up to 15-20/100 000 by the age of 75 years.
About 80% of adult patients have acute myeloid leukaemia (AML), and 20% have acute lymphoblastic leukaemia (ALL).
Aetiology
The cause can rarely be individually demonstrated.
Known risk factors include earlier treatment with alkylating cytotoxic drugs, etoposide or anthracyclines, as well as ionizing radiation and organic solvents (particularly benzene).
Secondary leukaemias (usually AML) are associated with other cancers and their treatment, and they comprise about 10-20% of all cases of acute leukaemia.
Acute leukaemia may also develop during the late stages of myeloproliferative diseases.
Some genetic syndromes are associated with an increased risk of acute leukaemia.
Diagnostic principles
A suspicion of acute leukaemia is usually raised by the examination of complete blood count.
The proportion of blasts among bone marrow nucleated cells is over 20%, or a chromosomal change characteristic of acute leukaemia is detected in the cells.
The diagnosis is based on cell count (complete automated blood count), morphology (peripheral blood smear, bone marrow aspiration and, as needed, biopsy, and any other biopsy material), as well as on immunophenotyping and chromosome and molecular biological studies of the malignant cells Tumours of Haematopoietic and Lymphoid Tissues: General Information.
Patients for whom active treatment is feasible are urgently referred to the haematological department of a specialized hospital for investigations and treatment.
Classification of acute leukaemias (WHO classification)
AML
AML with a specified genetic abnormality
AML with myelodysplasia-related genetic or morphologic changes
AML or myelodysplastic syndrome, related to earlier cytostatic or radiation therapy
AML not otherwise categorised
Myeloid sarcoma (tumour composed of AML cells)
AML related to Down's syndrome
AML related to changes in the germ line
Other rare subtypes
ALL
B-cell ALL
ALL with a specified genetic abnormality
ALL not otherwise categorised
T-cell ALL
With the help of molecular genetic studies and minimal residual disease analysis, the aim is to further improve the classification as a means for steering the treatment.
In AML, the proportion of blasts with myeloid immunophenotype in the bone marrow or blood is at least 20% or the blasts show a genetic change that is typical to AML.
ALL: AML, lymphoblastic lymphomas, large cell lymphomas, lymphatic blast phase of myeloid leukaemia, primitive plasma cell leukaemia, mononucleosis
B and T lymphoblastic lymphomas are different manifestations of the same disease as the corresponding forms of ALL. Lymphomas are characterised by significant extramedullary tumours and the infiltration rate of blasts in the bone marrow is less than 25%. However, in many cases it is difficult to make a distinction between lymphoma and leukaemia.
Clinical picture and laboratory findings
The growing leukaemic cell population adversely affects normal haematopoiesis in the bone marrow.
The clinical picture is characterised by anaemia, neutropenia, thrombocytopenia, and associated systemic symptoms such as infections and bleeding, particularly mucosal bleeding. See also picture 1.
Immature, abnormal cells (blasts) seen in a full blood count and peripheral blood smear are an important finding. Many patients also have leucocytosis. In the early phase, some patients have no blasts in the standard differential count.
The diagnosis of leukaemia can only be made on a representative bone marrow sample.
Other laboratory findings are non-specific, but they help in assessing the functional status of different organs, the complications caused by leukaemia and the possibilities to provide powerful treatments.
Disease progression and prognosis
An untreated disease will progress quickly in most cases and result in death within a few weeks.
In rare cases the disease progresses slowly, and the life expectancy without cytotoxic chemotherapy may, with additional supportive measures, be 12 months.
Post-treatment prognosis is dependent on the patient's ability to receive treatment and on his/her age, together with the disease burden, type of disease, the chromosome and gene changes of the leukaemic cells, the patient's sensitivity to drugs and the treatment administered.
AML
Remission is obtained in 50-80% of patients. The prognosis is worsened by advanced age: remission is obtained in about 80-90% of patients less than 65 years of age, but in only 30-70% of patients above the age of 65.
Cytotoxic drugs will lead to total cure in about 45-50% of all patients less than 65 years. After cytotoxic treatment and stem cell transplantation, 50-70% of patients will be cured. The long-term prognosis of older patients is worse.
In the cases where AML has the most favourable prognosis, 60-80% of the patients will be permanently cured with chemotherapy (e.g. acute promyelocytic leukaemia, certain other gene and chromosomal changes). In the disease types where the prognosis is the least favourable, very few patients can be permanently cured (e.g. chaotic chromosomal changes, high disease burden).
ALL
Remission is obtained in 80-90% of patients. Cytotoxic drugs will lead to total cure in about 45-50% of adult patients, and after allogeneic stem cell transplantation performed during first remission 50-70% will be cured.
Complications
Infections
Bleeding
Involvement of CNS with leukaemic cells (neuroleukaemia)
Complications associated with chemotherapy
Treatment and follow-up
Most patients are treated with intensive combined chemotherapy. The therapy is tailored according to the expected treatment response as well as to the risk of relapse and mortality related to each case. The goals of the therapy are:
to destroy leukaemic cells and rapidly restore normal haematopoiesis (remission induction therapy)
to eliminate pockets (e.g. in the CNS) harbouring leukaemic cells (large dose cytarabine and methotrexate intravenously, intrathecal therapy in ALL)
to prevent relapse (consolidation therapy after remission, maintenance treatment in ALL, allogeneic stem cell transplantation).
The most important drugs in the treatment of AML are cytarabine and anthracyclines (daunorubicin and idarubicin). More specific therapy is available for some subgroups, such as tretinoin and arsenic trioxide in acute promyelocytic leukaemia, midostaurin or gilteritinib in FLT3-mutated and IDH inhibitors in IDH-mutated AML. Elderly patients in poor health often receive treatment containing azacitidine.
Cytotoxic drugs are administered as a course of treatment, which induces a period of cytopenias. Early detection and treatment of infections, as well as blood cell replacement therapy, is of the utmost importance during this period.
Treatment success is monitored by bone marrow samples taken between and after periods of therapy (morphology, genetic or immunophenotypic change suitable for monitoring minimal residual disease).
Allogeneic stem cell transplantation is attempted in AML patients aged less than 65 years, with the exception of patients with the most favourable prognosis, during the first remission using either a sibling donor or a donor chosen from a donor register. In ALL, a stem cell transplantation is carried out during remission in patients who have the worst prognosis and in patients in whom a minimal residual disease is detected during consolidation therapy.
Treatment that aims to achieve remission and permanent cure is carried out in specialised centres. A lighter therapy option may be indicated if the patient's comorbidities or very advanced age render powerful cytotoxic treatment impossible.
The risk of relapse is highest during the first 3 years, but in some cases the disease recurs later. In order to catch a possible relapse the patient is followed up by monitoring the full blood count and during the first post-treatment years also by morphology of bone marrow aspirates and with the help of sensitive molecular genetic or immunophenotypic markers of residual disease.
A new remission may be achieved in some of the patients with relapse by performing a new remission induction therapy.
Palliative treatment of patients with acute leukaemia can be managed by a general practitioner in accordance with guidelines issued by a haematologist. Hospitalisation is often needed at some stage even for good palliative care due to infections and for blood transfusions.
For patients in remission, regular follow-up by the patient's own doctor is warranted for up to 5 years in case the disease relapses. In particular, susceptibility to infection or to bleeding, worsening of the patient's general condition, as well as anaemia, neutropenia, thrombocytopenia or appearance of blast cells in the blood require further investigations.
In a trouble-free situation laboratory tests are performed according to the following scheme:
During the 1st year: complete blood count once a month and bone marrow every 3 months
During the 2nd year: complete blood count and bone marrow every 3 months
During the 3rd and 4th years: complete blood count every 4-6 months and bone marrow if the blood values change.
It is important that the patient has a low threshold possibility to contact an assigned follow-up centre, should any suspicious symptoms possibly related to potential treatment-related late complications emerge.
References
Döhner H, Estey E, Grimwade D ym. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017;129(4):424-447. [PubMed]
Hoelzer D, Bassan R, Dombret H ym. Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016;27(suppl 5):v69-v82. [PubMed]
Estey EH. Acute myeloid leukemia: 2019 update on risk-stratification and management. Am J Hematol 2018;93(10):1267-1291. [PubMed]