Chronic Myeloid Leukemia (CML)

The Philadelphia (Ph) chromosome is present in 90 to 95% of cases of chronic myeloid leukemia. The Ph chromosome is the product of a reciprocal translocation between chromosomes 9 and chromosome 22, t(9;22). During this translocation, a piece of chromosome 9 containing the oncogene ABL is translocated to chromosome 22 and fused to the BCR gene. The chimeric fusion gene BCR-ABL is responsible for production of the oncoprotein bcr-abl tyrosine kinase.

The bcr-abl oncoprotein has uncontrolled tyrosine kinase activity, which deregulates cellular proliferation, decreases adherence of leukemia cells to the bone marrow stroma, and protects leukemic cells from normal programmed cell death (apoptosis).

CML ensues when an abnormal pluripotent hematopoietic progenitor cell initiates excessive production of all myeloid lineage cells, primarily in the bone marrow but also in extramedullary sites (eg, spleen, liver). Although granulocyte production predominates, the neoplastic clone includes red blood cells, megakaryocytes, monocytes, and even some T cells and B cells. Normal stem cells are retained and can emerge after drug suppression of the CML clone.

Untreated, CML undergoes 3 phases:

• Chronic phase: An initial indolent period that may last 5 to 6 years

• Accelerated phase: Treatment failure, worsening anemia, progressive thrombocytopenia or thrombocytosis, persistent or worsening splenomegaly, clonal evolution, increasing blood basophils, and increasing marrow or blood blasts (up to 19%)

• Blast phase: Accumulation of blasts in extramedullary sites (eg, bone, central nervous system, lymph nodes, skin); blasts in blood or marrow increase to ≥ 20%

The blast phase leads to fulminant complications resembling those of acute leukemia, including sepsis and bleeding. Some patients progress directly from the chronic to the blast phase.

About 85% of patients with CML present in the chronic phase. Patients are often asymptomatic early on, with insidious onset of nonspecific symptoms (eg, fatigue, weakness, anorexia, weight loss, night sweats, a sense of abdominal fullness particularly in left upper quadrant, gouty arthritis, symptoms of leukostasis such as tinnitus, stupor, and urticaria), which may prompt evaluation.

Initially, pallor, bleeding, easy bruising, and lymphadenopathy are unusual, but moderate or occasionally extreme splenomegaly is common (60 to 70% of cases). With disease progression, splenomegaly may increase, and pallor and bleeding occur. Fever, marked lymphadenopathy, and maculopapular skin involvement are ominous developments.

• Complete blood count (CBC)

• Bone marrow examination

• Cytogenetic studies (Ph chromosome)

Chronic myeloid leukemia is most frequently suspected based on an abnormal CBC obtained incidentally or during evaluation of splenomegaly. The granulocyte count is elevated, usually < 50,000/mcL (≤ 50 × 10⁹/L) in asymptomatic patients and 200,000/mcL (200 × 10⁹/L) to 1,000,000/mcL (1,000 × 10⁹/L) in symptomatic patients. Neutrophilia (a left-shifted white blood cell differential), basophilia, and eosinophilia are common. The platelet count is normal or moderately increased, and in some patients, thrombocytosis is the presenting manifestation. The hemoglobin level is usually > 10 g/dL (> 100 g/L).

Peripheral smear review may help differentiate CML from leukocytosis of other etiology. In CML, the peripheral smear frequently shows immature granulocytes as well as absolute eosinophilia and basophilia. However, in some patients with white blood cell counts ≤ 50,000/mcL (≤ 50 × 10⁹/L) and even in some with higher white blood cell counts, immature granulocytes may not be seen.

Bone marrow examination should be done to evaluate the karyotype as well as cellularity and extent of myelofibrosis.

Diagnosis is confirmed by finding the Ph chromosome in samples examined with cytogenetic or molecular studies. The classic Ph cytogenetic abnormality is absent in 5% of patients, but the use of fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR) can confirm the diagnosis.

During the accelerated phase of CML, anemia and thrombocytopenia usually develop. Basophils may increase, and granulocyte maturation may be defective. The proportion of immature myeloid cells may increase. In the bone marrow, myelofibrosis may develop and ringed sideroblasts may be present as may red cell aplasia, which can be missed due to the increased marrow cellularity. Evolution of the neoplastic clone may be associated with development of new abnormal karyotypes, often an extra chromosome 8, isochromosome 17q [i(17q)], or reduplication of BCR-ABL1.

Further evolution may lead to a blast phase with myeloblasts (60% of patients), lymphoblasts (30%), megakaryoblasts (10%) and, rarely, erythroblasts. In 80% of these patients, additional chromosomal abnormalities occur.

• Tyrosine kinase inhibitors

• Sometimes, allogeneic stem cell transplantation

stem cell transplantation is reserved for patients with accelerated or blast phase CML or those with disease resistant to the available tyrosine kinase inhibitors.

Except when stem cell transplantation is successful, treatment is not proven to be curative. However, tyrosine kinase inhibitors prolong survival. Some patients may be able to discontinue tryrosine kinase inhibitors and remain in remission. The durability of these remissions is not yet known.

Tyrosine kinase inhibitors inhibit the BCR-ABL

The response to TKI therapy is the most important prognostic factor for patients with CML. Patient's response is measured at baseline and then at 3 months, 6 months, and 1 year. The response can be assessed with either a molecular test (measurement of BCR-ABL protein) or a cytogenetic test (measurement of Ph+ chromosome cells), but both are recommended whenever possible. A major molecular response is defined as blood BCR-ABL < 1/1000th (or less) of the expected value for untreated CML. If, after 12 months, a major molecular response is achieved, the response can be monitored every 3 to 6 months by real time quantitative polymerase chain reaction of BCR-ABL protein and cytogenetic testing.

Allogeneic stem cell transplantation, because of its toxicity and because of the efficacy of tyrosine kinase inhibitors, is used selectively. Transplantation is reserved for patients with accelerated- or blast-phase CML resistant to BCR-ABL inhibitors. Transplantation can be curative.

With use of tyrosine kinase inhibitors, survival is now > 90% at 5 years after diagnosis for chronic phase CML. Before tyrosine kinase inhibitors were used, even with treatment, 5 to 10% of patients died within 2 years of diagnosis; 10 to 15% died each year thereafter. Median survival was 4 to 7 years. Most (90%) deaths followed a blast phase or an accelerated phase of the disease. Median survival after blast crisis was about 3 to 6 months or longer if remission was achieved.

The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

1. Leukemia and Lymphoma Society: Resources for Healthcare Professionals: Provides information on research and clinical trials and resources for referrals to specialty care