About CML

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder (MPD) affecting 1 to 2 people per 100,000 annually. MPDs arise from genetic defects in haematopoietic stem cells, and are associated with an increased production of mature and immature blood cells, which affects one or all cell lineages.

Shared Features of MPDs

  • Excessive proliferation of blood elements (erythroid precursors, platelet precursors, myeloid precursors) in the bone marrow, peripheral blood, and, occasionally, in extramedullary organs, such as liver, spleen, or lymph nodes
  • Progression through clinical stages of increasing aggressiveness
  • Eventual transformation into a terminal stage of either blast phase (acute leukaemia-like) disease or marrow fibrosis (“burnt-out marrow”)

Non-CML MPDs

  • Polycythaemia vera (PV): A malignancy that affects erythrocytes
  • Essential thrombocythaemia (ET): A malignancy that affects megakaryocytes and platelets
  • Agnogenic myeloid metaplasia (AMM), also termed idiopathic myelofibrosis: A malignancy that affects the bone marrow microenvironment

 

Epidemiology and Aetiology of CML

Epidemiology

CML incidence is relatively consistent in all countries where adequate statistics are available. Occurring at about 1 to 2 per 100,000 population, CML is a rare disease in children, where it makes up no more than 5% of the leukaemias.


In adults, CML represents about 15% of all cases of leukaemia and is less common than acute myeloid leukaemia and myelodysplastic syndrome (AML/MDS) and chronic lymphocytic leukaemia (CLL).


The median age of onset is 45 to 55 years. Half of CML patients are older than 60 years.

Aetiology

The aetiology of CML (chronic myeloid leukaemia) is unknown. There is very little evidence linking hereditary factors to CML. The offspring of patients with CML do not have a higher incidence of CML than the general population, and there is no correlation in monozygotic twins. These observations strongly suggest that CML is an acquired (rather than hereditary) disorder.
There is some association between CML and exposure to radiation (such as in atomic bomb survivors in Japan). Whether exposure to radiation therapy causes CML is disputed. There is no known association with infectious agents. 

 

The Clinical Picture and Natural History of CML

CML typically progresses through three stages or “phases”. Most patients present in chronic phase, progress through an accelerated phase (although some patients skip this phase), and then die after entering a brief phase, blast crisis. The lengths of these phases have been somewhat altered by conventional chemotherapy, but not the clinical course.

 

 

Table 1. Clinical Criteria for the Phases of CML

 

Chronic

Accelerated

Blast Crisis

WBC

≥ 20 x 109/L

Blasts

<15%

15%-30%

>30%

Basophils

≥ 20%

-

Platelets

Normal or ↑

↑ / ↓

Marrow cellularity

Chromosome

Ph+

Ph+

Ph+

Accelerated phase criteria used in the Novartis clinical development programme.

Phase Specifics

  • Chronic phase CML is relatively straightforward to define. Patients have an elevated WBC, with granulocytes at all stages of maturation, and fewer than 15% of myeloblast cells in the peripheral blood and bone marrow.
  • Blast crisis is defined by the presence of 30% of blasts in the peripheral blood or bone marrow, and tissue infiltrates of leukaemic cells, which may involve lymph nodes, skin, subcutaneous tissues bone, or the central nervous system (sometimes referred to as chloromas).
  • It can be difficult to determine the lineage of blast crisis cells by microscopic appearance alone. Immunological studies have shown that most blast crisis patients have cells that resemble the myeloid blasts seen in AML (acute myeloid leukaemia). This is an important distinction, because the minority of patients whose cells resemble acute lymphocytic leukaemia (ALL) blasts respond to ALL therapy, and have a better prognosis than those in the other groups.
  • Based on immunological studies, about half of patients with blast crisis CML, have abnormal cells displaying markers consistent with a leukocyte lineage (e.g., AML). About a quarter of blast crisis CML patients have cells displaying immunological markers consistent with ALL. The remainder have cells that either have no specific cell antigens or display evidence of rare phenotypes (megakaryocytic, erythroid, basophilic). This distinction is important because the 25% of patients with ALL-type blastic transformation respond to ALL therapy, and have a better prognosis than those in the other groups.
  • Accelerated phase CML is a somewhat ill-defined transitional phase. Criteria used in common practice to define the accelerated phase of CML reflect evidence of increasing resistance to therapy and ongoing disease activity despite therapy.

 

The ill-defined nature of the accelerated phase may lead to conflicting trial results where some groups report better outcomes for patients in “accelerated phase” than other groups because other groups would consider these patients to be in chronic phase CML. The M.D. Anderson group uses more stringent criteria for the accelerated phase, which have been defined by multivariate analysis and are associated with a survival probability of ≤ 1.5 years. Another feature of disease acceleration is the appearance of additional evidence of chromosomal damage (so-called cytogenetic or clonal evolution).


Be prepared to recognise the Symptoms of CML.