chronic myelogenous leukemia

chronic myelogenous leukemia
Name	Chronic myelogenous leukemia
Synonyms	Chronic myeloid leukemia, CML
Caption	A karyotype showing the Philadelphia chromosome (arrow), the genetic hallmark of the disease.
Field	Hematology, Oncology
Symptoms	Often asymptomatic initially; may include fatigue, abdominal pain, early satiety, night sweats, unintentional weight loss
Complications	Blast crisis, splenic rupture, tumor lysis syndrome
Onset	Typically adults, median age at diagnosis ~65 years
Duration	Chronic
Types	Chronic phase, accelerated phase, blast phase
Causes	Acquisition of the Philadelphia chromosome (t(9;22)(q34;q11))
Risks	Ionizing radiation exposure (e.g., atomic bomb survivors)
Diagnosis	Complete blood count, peripheral blood smear, bone marrow biopsy, cytogenetic analysis, FISH, PCR
Differential	Leukemoid reaction, myelofibrosis, atypical chronic myeloid leukemia
Treatment	Tyrosine kinase inhibitors (e.g., imatinib, dasatinib, nilotinib), allogeneic stem cell transplantation
Prognosis	Varies by phase; excellent long-term survival with modern treatment in chronic phase
Frequency	1–2 cases per 100,000 adults annually

chronic myelogenous leukemia is a myeloproliferative neoplasm characterized by the uncontrolled proliferation of mature granulocytes and their precursors. It is defined by a specific genetic abnormality, the Philadelphia chromosome, which results from a reciprocal translocation between chromosome 9 and chromosome 22. The disease typically progresses through distinct clinical phases, from a relatively indolent chronic phase to more aggressive accelerated and blast phases. The advent of targeted tyrosine kinase inhibitor therapy, beginning with imatinib, has dramatically transformed its prognosis and management.

Signs and symptoms

Many patients are diagnosed incidentally during routine blood tests while in the chronic phase and are asymptomatic. When symptoms occur, they are often nonspecific and may include profound fatigue, unintentional weight loss, night sweats, and low-grade fever—a constellation sometimes termed "B symptoms." Physical findings can include splenomegaly, leading to abdominal pain or early satiety, and less commonly hepatomegaly. Symptoms of leukostasis, such as priapism, retinal hemorrhage, or tinnitus, are rare in the chronic phase but become more common as the disease advances towards blast crisis.

Pathophysiology

The molecular pathogenesis is driven by the Philadelphia chromosome, formed by a translocation between the ABL1 gene on chromosome 9 and the BCR gene on chromosome 22. This creates a novel fusion gene, BCR-ABL1, which encodes a constitutively active tyrosine kinase protein. This aberrant kinase drives uncontrolled cell proliferation and inhibits apoptosis primarily within the myeloid lineage. The disease originates in a pluripotent hematopoietic stem cell, explaining why lymphoid blast crisis can also occur. The progression from chronic phase to blast crisis is associated with the accumulation of additional genetic mutations in genes such as TP53, RB1, and MYC.

Diagnosis

Diagnosis is typically suspected from a complete blood count showing marked leukocytosis with a full spectrum of myeloid cells, including myelocytes and basophilia. Examination of the peripheral blood smear is crucial. Confirmatory testing requires demonstration of the Philadelphia chromosome or the BCR-ABL1 fusion gene. This is achieved through cytogenetic analysis (karyotyping) of a bone marrow biopsy specimen, FISH, or highly sensitive PCR testing on blood or marrow. The World Health Organization classification system is used for definitive diagnosis and phase classification.

Treatment

The standard first-line therapy is a tyrosine kinase inhibitor targeting the BCR-ABL1 protein. The prototype drug, imatinib (marketed as Gleevec by Novartis), revolutionized management. Second-generation inhibitors like dasatinib, nilotinib, and bosutinib are used for initial therapy or for patients with intolerance or resistance to imatinib. Treatment response is monitored via quantitative PCR to measure BCR-ABL1 transcript levels, with goals of achieving major molecular response. Allogeneic stem cell transplantation remains a curative option but is typically reserved for patients with advanced phases or those failing multiple TKIs. Management of blast crisis resembles therapy for acute leukemia.

Prognosis

The prognosis has improved dramatically since the introduction of imatinib. For patients diagnosed in the chronic phase and responding to TKI therapy, life expectancy now approaches that of the general population. Prognosis is stratified by phases defined by criteria such as the percentage of blasts in blood or marrow; the chronic phase carries the best outlook. The Sokal score and EUTOS score are prognostic tools used at diagnosis. Survival is significantly worse for patients diagnosed in or who progress to accelerated phase or blast crisis.

Epidemiology

The disease accounts for approximately 15% of all adult leukemia cases in the Western world, with an incidence of 1–2 cases per 100,000 adults per year. The median age at diagnosis is around 65 years, and it is slightly more common in males than females. The only well-established environmental risk factor is exposure to high-dose ionizing radiation, as evidenced by studies of atomic bomb survivors from Hiroshima and Nagasaki. There is no known hereditary predisposition, and the Philadelphia chromosome is an acquired somatic mutation.

Category:Myeloproliferative neoplasms Category:Types of leukemia