Haematological Malignancies and Leukaemia

Cellular Origins of CML

Throughout life, the bone marrow continuously produces a variety of blood cell lineages in a tightly controlled, yet flexible process termed haematopoiesis⁹. The 2 main groups of mature blood cells are red blood cells (RBCs) and white blood cells (WBCs), or leukocytes.

WBCs are subdivided into:

• Lymphoid lineages, which constitute the specific immune system (eg, B cells, T cells, natural killer cells, dendritic cells)
• Myeloid lineages, which are involved in innate and immediate host defence and inflammation (eg, monocytes, macrophages, dendritic cells, granulocytes)

Myeloid cells scavenge dead host cells and foreign substances, eliminating them directly or presenting them to lymphocytes to stimulate an immune response. The granulocytes-neutrophils, eosinophils, and basophils, named because of their differentially staining intracellular granules-are the most prevalent myeloid lineage in the normal circulation. The granulocyte series of cells, from the least to the most mature stages, are the cells that are massively expanded in CML.

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All mature blood cells originate from a small number of haematopoietic stem cells in the bone marrow. Haematopoietic stem cells are capable of self-renewal or differentiation, the process that leads down lineage pathways towards various mature cell types. Haematological malignancies are defined as neoplastic growths or cancers of blood cells. Malignant transformation in haematological malignancies, as in all cancers, occurs by a multistep process by which a single cell acquires a growth or survival advantage. This advantage leads to the uncontrolled growth of this cell and its progeny, resulting in the expansion of an identical, or clonal, population of cells. When this process of malignant transformation and uncontrolled growth occurs in any of the leukocyte cell lineages, the cancer that results is called leukaemia.

Types of Leukaemia

Most common forms of leukaemia are classified according to cell lineage (myeloid or lymphoid) and degree of terminal cellular differentiation, which relates to the clinical course of the disease. Acute leukaemias arise from neoplastic transformation of a primitive progenitor cell limited in its capacity for further maturation. Acute forms of the disease-acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL)-evolve rapidly and require prompt intervention. Chronic leukaemia arises from neoplastic transformation of a primitive progenitor cell that retains the ability to further differentiate and mature. Chronic forms of the disease-CML and chronic lymphoblastic leukaemia (CLL)-generally progress in an indolent manner, consistent with the slower proliferative capacity of more mature cells. CML is a myeloproliferative disease characterised by the presence of the Philadelphia chromosome (Ph) or the BCR-ABL fusion oncogene¹⁰.

Leukaemias account for 300,000 new cases (~3% of all new cancer cases) each year and 220,000 deaths worldwide¹¹. CML accounts for about 15%-20% of all adult leukaemias and occurs slightly more frequently in men than in women (incidence ratio: 1.4 to 2.2:1)^12-15. CML is rare in persons aged 19 years or younger, with only 10% of cases occurring in this younger age group. The disease is most often diagnosed in middle age¹⁵. The Ph chromosome, which predominates in CML, is also present in a small subset of patients with ALL and is associated with a worse prognosis¹⁶.

Chronic myeloid leukemia typically progresses through 3 stages or phases. Most patients present in chronic phase, deteriorate during the subsequent accelerated phase, and finally progress to a brief terminal phase, blast crisis. Although the lengths of the phases were altered by previous therapies, the clinical course and natural history of CML had not been changed before the molecular era. Glivec is expected to have a marked effect on the natural history of CML^8,15, based on clinical studies demonstrating 89% overall survival at 5-year follow-up and low overall risk for progression to advanced phase disease^5,6.

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Philadelphia chromosome-positive (Ph+) CML progresses through 3 phases of shortening duration, characterised by worsening clinical features and laboratory findings and by increasing resistance to therapy: chronic phase (CP), accelerated phase (AP) and blast crisis (BC) (Table 1).

Phase Specifics

• The chronic phase of CML is defined by an elevated WBC count at presentation (≥20 × 10⁹/L) and a relative lack of blasts (<10%) in peripheral blood and bone marrow (BM)²⁰. This phase could last 5-6 years in the pre-Glivec era. Glivec is expected to have a marked effect on the natural history of CML^8,15, based on clinical studies demonstrating 89% overall survival at 5-year follow-up and low overall risk for progression to advanced phase disease^5,6.
• The accelerated phase of CML is the second and intermediate phase in the natural history of the disease²⁰. Although diagnosis may be made on the basis of the presence of any of the typical laboratory findings, the defining criterion is the presence of 10%-19% of blast cells in peripheral blood or BM^18,19.
• A panel of experts has outlined recommendations suggesting that accelerated-phase criteria be defined by 15%-29% blast cells in blood or BM (blast cells plus promyelocytes in blood or BM >30%, with <30% blasts present in blood or marrow)⁸.
• The onset of the accelerated phase may be marked by thrombocytopaenia and progressive anaemia^10,20. Symptoms in accelerated phase may worsen and include unexplained fever, bone pain, splenomegaly, and hepatomegaly. Basophilia and decreased platelet counts may be observed. This phase may last 6-9 months¹⁵.
• The blast-crisis phase of CML is marked by an increase in the percentage of blast cells in blood or BM (20%-30%) and increased symptomatology, including anaemia, infection, lymphadenopathy, and bleeding. Of those in blast crisis, 50% have myeloid blast crisis, 25% have lymphoid blast crisis, and 25% are mixed. This phase is associated with a poor prognosis and median survival of 3-6 months²¹. Several factors, including the cell lineage expanded in the blastic phase and type of therapy, may alter the range of median survival seen in blast crisis¹⁵.

The introduction of new treatments could change the boundaries between chronic phase, accelerated phase, and blast crisis and slightly modify the subdivision of CML in 3 phases⁸. CML in its chronic and advanced phases is diagnosed on the basis of symptoms, signs, and laboratory findings.

Be prepared to recognise the Symptoms of CML.