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Chronic Myelogenous Leukaemia (CML)

Essentials

  • CML is a slowly progressing haematological disorder characterised by an increase in the number of mature and immature granulocytes in the blood. The number of blood platelets is often also increased.
  • The problem in differential diagnosis is to recognize the rare CML among the numerous other more common causes of neutrophilia.
  • The diagnosis is based on detecting the BCR-ABL1 fusion gene in blood sample and/or Philadelphia (Ph) chromosome in bone marrow.

Epidemiology

  • About 1 new case / 100 000 adults / year
  • Accounts for 20% of all leukaemias
  • There are no gender differences in the incidence of CML.
  • The majority of patients are 40-70 years old, the incidence peak being around the age of 55 years. Also occurs rarely in children.

Aetiology

  • Remains unknown in individual patients.

Diagnostic criteria

  • Detection of the BCR-ABL1 fusion gene by a molecular genetic method (PCR). Philadelphia chromosome (abnormal chromosome 22 due to translocation t(9;22)) in chromosome study is a sign of this in 95% of these patients.

Differential diagnostics

  • Other disorders associated with myeloid leucocytosis (infections, tissue necrosis, neoplasms, other myeloproliferative diseases, such as myelofibrosis Myelofibrosis (Mf))

Clinical picture and laboratory findings

  • Asymptomatic in a large share of patients; suspicion of the diagnosis arises when the blood picture is examined for some other reason.
  • Slowly increasing neutrophilic leucocytosis, immature cells found in differential count
  • Often thrombocytosis
  • Anaemia is possible as a later phenomenon.
  • Sometimes splenomegaly, causing pain and the feeling of pressure in the left costal arch
  • Sometimes symptoms and signs associated with hypermetabolism, such as night sweats, mild fever, tiredness and weight loss
  • In more than 90% of patients the disease is diagnosed during the stable chronic phase. A few patients are in the accelerated phase at the time of diagnosis, and some of them are already in a blast crisis that resembles acute leukaemia.

Laboratory findings

  • Represent the phase of the disease.
  • Leucocytosis in the blood, abundant mature gralunocytes, usually also granulocyte precursors, such as blasts, promyelocytes, metamyelocytes and myelocytes.
  • During blast crisis, > 20% of the leucocytes are blasts.

Basic investigations

  • Complete blood count with differential count, which often provides a rather certain diagnosis
  • If CML is suspected, a haematologist should be consulted. There is rarely need for emergency treatment if the patient is asymptomatic.
  • A specific diagnosis is obtained by fusion gene and/ or chromosome analysis.
  • PCR test of blood to detect BCR-ABL1 fusion gene
  • Bone marrow examination with morphological examination and G band analysis (Philadelphia chromosome)
  • Upper abdominal ultrasonography (spleen size)
  • Plasma urate (sometimes hyperuricaemia and also symptoms of gout), lactate dehydrogenase (reflects the burden of disease quite well) and creatinine

Complications

  • Bleeding (rare)
  • Thrombosis and infarctions resulting from leucostasis are rare, but they should be remembered in the context of sudden deafness and problems with vision.
  • Without treatment, proceeds within months/a few years to blast crisis resembling acute leukaemia.

Course of the disease and prognosis

  • As the cells typical for the disease keep proliferating, the possibility of new genetic abnormalities increases. These accelerate cell production further, increasing the number of blasts. A significant reduction in disease burden, possible for most patients with current treatment, will prevent this development.
  • When the treatment effect is in accordance with the objectives, the prognosis of these patients will not differ significantly from that of the general population. Clearly inadequate treatment effect and a disease form that has progressed to the blast crisis phase significantly impair the prognosis.

Treatment and follow-up

  • The lines of treatment are defined by a haematologist, who should be consulted if CML is suspected to make sure that diagnostic examinations proceed flexibly.
  • An asymptomatic patient, in whom suspicion of the disease has arisen due to an incidental finding, does not need emergency examinations or treatment.
  • Hydroxyurea, a traditional cytostatic drug in oral (tablet) form, can be used at first to lower leucocyte and thrombocyte levels. Allopurinol and sufficient fluid intake prevent renal problems during early stages of treatment.
  • The first-line treatment in all patients with chronic or accelerated phase disease is a tyrosine kinase inhibitor (imatinib, nilotinib). Second-line and further line treatment options also include dasatinib, bosutinib and ponatinib. In patients in blast crisis, induction therapy with cytostatic drugs as in acute leukaemia is often used in addition to tyrosine kinase inhibitors.
  • In the currently rare cases when leucostasis, i.e. a high leucocyte count (> 300 × 109 /l) slowing down circulation (in the brain, lungs, heart), becomes life-threatening, treatment may be started by leucapheresis, i.e. removing leucocytes from the blood by passing it through a separator outside the body.
  • The possibility for an allogeneic blood stem cell transplantation should always be assessed for patients in blast crisis and for those in other phases if the response to tyrosine kinase inhibitors is insufficient or if such treatment cannot be effectively used due to adverse effects.