Chronic Myelogenous Leukemia (CML)
last authored:
last reviewed:
Introduction
CML is a myeloproliferative disorder primarily affects adults between 25 and 60 years, with peak onset between 40 and 60.
Incidence of 1-2 / 100,000.
CML accounts for 15-20% of all leukemias.
The Case of...
a simple case introducing clincial presentation and calling for a differential diagnosis to get students thinking.
Causes and Risk Factors
CML is idiopathic in most cases.
Ionizing radiation appears to increase risk.
Pathophysiology
CML is distinguished by the presence of the BCR-ABL fusion protein, following translocation of chromosomes 9 and 22. BCR-ABL is a constitutively active tyrosine kinase capable of autophosphorylation and activation of downstream pathways. These drive the cell into cell division while inhibiting apoptosis.
Multiple myeloid lineages, B lymphocytes, and possibly T lymphocytes express the BCR-ABL fusion protein, suggesting the translocation has occurred in a pluripotent stem cell. For unknown reasons, its transformative effects are present only in granulocytic progenitors and to a lesser extent in megakaryocytic progenitors.
Signs and Symptoms
- history
- physical exam
History
Mild or moderate anemia and hypermetabolism (fatigue, weakness, anorexia, night sweats due to increased cell turnover) can occur early in the disease.
- asymptomatic leukocytosis
- fatigue, malaise, weight loss
- splenomegaly
- usually asymptomatic
- feeling of fullness in the left upper quadrant
- early satiety
- splenic infarction can lead to acute pain
hyperleukocytosis can lead to:
- neurologic symptoms: headache, confusion, stroke
- pulmonary symptoms: dyspnea, chest pain
Physical Exam
Neoplastic extramedullary hematopoiesis produces marked splenomegaly, often with splenic infarction. Hepatomegaly and mild lymphadenopathy can also occur.
Investigations
- lab investigations
- diagnostic imaging
Lab Investigations
Complete blood count
- increased WBC count, especially neutrophils and myelocytes
- normocytic, normochromic anemia
- normal-appearing WBC
- thrombocytosis or thrombocytopenia
- eosinophilia, basophilia
- myeloblasts <10%
In more than 90% of CML cases, the Philadelphia chromosome can be detected by karyotyping. In 5-10% of cases, the rearrangement is complex or cryptic, necessitating FISH or RT-PCR for its detection.
Marrow
In contrast to normal marrow, which is 50% cellular and 50% fat, CML marrow is alomst 100% cellular. Maturing granulocytes make up most of the increase. Megarkaryocyte number can be increased, and erythroid progenitors can be normal or decreased.
Sea-blue histocytes are characteristic.
Increased reticulin deposition is typical, but fibrosis is rare.
Peripheral blood
Marked leukocytosis is present, often exceeding 100 x109 / L. These cells are primarily neutrophils, metamyelocytes, and myelocytes, with less than 10% blasts.
Low leukocyte alkaline phosphatase (LAP) score
Diagnostic Imaging
Differential Diagnosis
Treatments
Counts can be controlled by hydroxyurea or by leukopheresis.
CML responds very well to Gleevec (imatinib), a small molecule inhibitor of BCR-ABL. In patients who receive imatinib from time of diagnosis, overall survival rate was 89% by 60 months, and freedom from accelerated phase or blast crisis was 93% (Druker et al, 2006). Failures peak in the second year, with only 1% by the fifth year.
Desipte its success, imatinib supresses, rather than extinguish, neoplastic clones, and residual leukemia is usually detectable by qRT-PCR. As a result, imatinib does not cure patients. There is evidence, though not from RCTs, that high-dose imatinib (800 mg daily) produces superior disease-free survival, compared with standard 400 mg daily.
Patients in the accelerated phase or blast crisis rapidly become refractory to Gleevec. Acquired point mutations in the kinase domain appear responsible in many cases. However, new drugs, such as dasatinib and nilotinib, are emerging as second-line therapies, and multi-inhibitor therapies appear efficacious in patients with AP or BC.
Allogenic bone marrow transplantation is most effective when performed in the chronic phaise of CML. In people with suitable donors, up to 75% are considered cured.
Cyterabin a
Consequences and Course
Chronic phase
CML has a slow onset and progression. Even without treatment, people with CML survive a median of 3 years.
Accelerated phase
After a variable period averaging 3 years, 50% of people enter an accelerated phase, often accompanied by marked anemia and thrombocytopenia, as well as striking peripheral basophilia.
Additional abnormalities, including trisomy 8, isochromosome 17q, or Ph duplication, can appear. The accelerated phase terminates within 6-18 months with the 'blast crisis'.
Blast crisis
In the remaining 50%, blast crisis occurs abruptly, without an accelerated phase.
In 70% of blast crises, blasts resemble myeloblasts, while in the remainder resemble early B- or T-cells.
A blast crisis lasts an average of three months before death.
Resources and References
Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408- 2417.
Topic Development
authors:
reviewers:
 |