Acute leukaemias in adults

Essentials

  • 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.
  • Leukaemic cells may also invade other parts of the body, e.g. to the central nervous system, spleen, lymph nodes or skin.

Epidemiology

  • The annual incidence is about 5 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 chemotherapy, ionizing radiation and organic solvents (particularly benzene).
  • Secondary leukaemias associated with the treatment of a previous cancer tumour comprise about 10–20% of all cases of leukaemia. The vast majority of these are AML cases.
  • Myelodysplastic syndrome (Myelodysplastic syndromes (MDS)) is often the mechanism behind secondary leukaemia.
  • Acute leukaemia may also develop during the late stages of myeloproliferative diseases.
  • Some hereditary germline gene disorders 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 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 guidelines).
  • The proportion of blasts among bone marrow nucleated cells is over 20%, or a molecular genetic or chromosomal change characteristic of acute leukaemia is detected in the cells.
  • Patients for whom active treatment is feasible should beurgently referred to a specialized hospital for diagnostics and treatment planning. Starting the treatment is urgent especially in association with significant leukocytosis.

Differential diagnosis

  • AML: ALL, myelodysplastic syndromes (Myelodysplastic syndromes (MDS)), blast phase of chronic myeloid leukaemia (Chronic myelogenous leukaemia (CML)), chronic myelomonocytic leukaemia, bone marrow infiltration with cancer, tuberculosis-related monocytosis
    • 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 (Lymphomas), lymphatic blast phase of myeloid leukaemia (Chronic myelogenous leukaemia (CML)), primitive plasma cell leukaemia, mononucleosis (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.

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 (Skin tumour of leukaemia).
  • Immature, abnormal cells (blasts) seen in a full blood count and peripheral blood smear are an important finding. Many patients also have leucocytosis. Blasts are not found in all patients in the standard differential count. Responses of the differential count may come in stages, and responses of an incomplete examination should be checked.
  • 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 treatment possibilities.

Disease progression and prognosis

  • An untreated disease will progress quickly in many cases and may result in death within a few weeks.
  • Post-treatment prognosis is dependent on the patient’s ability to receive treatment, general condition, his/her age, the chromosome and gene changes of the leukaemic cells, and the treatment administered.
  • More than half of adults under 65 years of age can be cured permanently. In younger adults, treatment results are significantly better than this. Patients over 70–75 years of age also often achieve a good treatment response, but curative treatment is very rarely achieved.
  • After allogeneic stem cell transplantation in first remission, 60–70% of patients are permanently cured. The treatment is intensive and not suitable for all patients.

Treatment

  • Patients are most often treated with combined chemotherapy. Targeted therapies have become an increasingly important part of treatment. 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 leukaemia cells that are beyond the reach of cytostatic drugs (e.g. in the CNS) (large dose cytarabine and methotrexate intravenously, intrathecal therapy in ALL)
    • to prevent relapse (consolidation therapy after remission, possible maintenance treatment especially in ALL, allogeneic stem cell transplantation).
  • The most important drugs in the treatment of AML are cytarabine and anthracyclines (daunorubicin and idarubicin) and in elderly people azacitidine.
    • In several subgroups, chemotherapy can be combined with targeted therapy, such as tretinoin and arsenic trioxide in acute promyelocytic leukaemia, midostaurin or gilteritinib in FLT3-mutated AML and IDH inhibitors in IDH-mutated AML.
    • Elderly patients often receive a combination of azacitidine and venetoclax.
  • In ALL, the drug combinations include several drugs, such as an anthracycline, vincristine, glucocorticoid, methotrexate, cyclophosphamide, mercaptopurine, cytarabine, etoposide, and asparaginase. In Philadelphia-chromosome positive leukaemia, tyrosine kinase inhibitor such as dasatinib, imatinib or ponatinib is additionally given. Treatments that target the surface structures of leukaemia cells, such as blinatumomab or inotuzumab ozogamicin, can also be used.
  • 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 65–70 years, with the exception of patients with the most favourable prognosis, during the first remission using either a first-degree relative 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 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 treatment impossible.
  • Palliative treatment of patients with acute leukaemia can be managed by a general practitioner in accordance with guidelines issued by a haematologist.

Follow-up

  • 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.
  • 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 with differential leucocyte count once a month and bone marrow every 3 months
    • During the 2nd year: complete blood count with differential leucocyte count and bone marrow every 3 months
    • During the 3rd and 4th years: complete blood count with differential leucocyte 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

1. Gökbuget N, Boissel N, Chiaretti S, et al. Management of ALL in adults: 2024 ELN recommendations from a European expert panel. Blood 2024;143(19):1903-1930  [PMID:38306595]
2. Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 2022;140(12):1345-1377  [PMID:35797463]
3. Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J 2017;7(6):e577  [PMID:28665419]
4. Döhner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med 2015;373(12):1136-52  [PMID:26376137]
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