Gourt Home::Gourt :: Chronic myelogenous leukemia
Chronic myelogenous leukemia or Chronic myeloid leukaemia (CML) is a form of chronic leukemia characterized by increased production of myeloid cells in the bone marrow. It is a type of myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia chromosome. It is traditionally treated with chemotherapy, interferon and bone marrow transplantation, although a specific inhibitor (imatinib mesylate) has radically changed the management.
Signs and symptoms
Patients are often asymptomatic at diagnosis, presenting incidentally with an elevated white blood count on a routine laboratory test. Symptoms may include: malaise, low grade fever, increased susceptibility to infections, anemia and thrombocytopenia with resultant bruising (although an increased platelet count, thrombocytosis, may be a feature). Splenomegaly may also be seen.
The disease may remain dormant for years, but a proportion proceed to accelerated phase (in which the disease progresses rapidly) or transform to overt blast crisis, which may have the symptoms and risks of acute myelogenous leukemia (AML) or Philadelphia chromosome positive acute lymphoblastic leukemia (ALL), depending on the hematopoietic lineage that is involved in the transformation.
Diagnosis
CML is often suspected on the basis on the full blood count, which shows increased granulocytes of all types (including basophils). When the index of suspicion is high, a bone marrow biopsy is required to distinguish CML from other diseases that feature the same symptoms.
Ultimately, CML is diagnosed by detecting the Philadelphia chromosome (a translocation between the 9th and 22nd chromosome leading to an aberrant protein that drives cell division). This translocation leads to bcr-abl fusion and activation of protein tyrosine kinase cascade.
Disease activity can be determined on the basis of the bone marrow examination, cytogenetics and by quantitative PCR.
Pathophysiology
CML was the first malignancy to be linked to a clear genetic abnormality, the chromosomal translocation named Philadelphia chromosome, in 1960. The fusion of two genes on chromosomes 9 and 22, termed abl and bcr respectively, leads to a protein that propels mitosis and causes genomic instability (leading to further mutations).
CML progresses to accelerated phase, and then blast crisis, when additional genetic abnormalities speed up the rate at which new malignant cells are produced in the bone marrow. A second Philadelphia chromosome may appear, as well as deletions of (parts of) chromosomes.
Epidemiology
CML occurs in all age groups, but most commonly in the middle-aged and elderly. Its annual incidence is about 1 per million.
Treatment
Chronic phase
Chronic phase CML is treated with Imatinib (marketed as Gleevec or Glivec; previously known as STI-571). In the past, hydroxyurea, alkylating agents (e.g. cytarabine), interferon alfa 2b and steroids were used, but this has been replaced by Imatinib. Imatinib is a new agent approved by the US FDA in 2001 which specifically targets the abnormality caused by the Philadelphia chromosome. It is better tolerated and more effective than previous therapies. Bone marrow transplants were also used as initial treatment for CML before Imatinib and can be curative.A new Drug, dasatinib (marketed as Sprycel; previously known as BMS-354825) was approved by the US FDA in June 2006 for use in patients with CML who are no longer responding to, or who can no longer tolerate, therapy with imatinib. *
Various combinations of the different treatment modalities are being explored.
In 2005, Bocchia et al reported favourable results of vaccination with the bcr-abl p210 fusion protein in patients with stable disease, with GM-CSF as an adjuvant.
Two other drugs, ceflatonin (homoharringtonine) and AMN 107 (nilotinib) are currently in active clinical trials in patients with Chronic Myeloid Leukemia (CML) who have developed resistance to Imatinib. **
Blast crisis
Blast crisis carries all the symptoms and characteristics of either acute myelogenous leukemia or acute lymphoblastic leukemia, and has a very high mortality rate. This stage can most effectively be treated by a bone marrow transplant after high-dose chemotherapy. In young patients in the accelerated phase, a transplant may also be an option. However the likelihood of relapse after a bone marrow transplant is higher in patients in blast crisis or in the accelerated phase as compared to patients in the chronic phase.Prognosis
The prognosis of CML depends on a number of different parameters. Two different scoring systems are in use: one by Sokal et al (1984) and one by Hasford et al (1998).
References
- Bocchia M, Gentili S, Abruzzese E, Fanelli A, Iuliano F, Tabilio A, Amabile M, Forconi F, Gozzetti A, Raspadori D, Amadori S, Lauria F. Effect of a p210 multipeptide vaccine associated with imatinib or interferon in patients with chronic myeloid leukaemia and persistent residual disease: a multicentre observational trial. Lancet 2005;365:657-62.
- Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in good risk chronic granulocytic leukemia. Blood 1984;63:789-799. PMID 6584184.
- Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, Alimena G, Steegmann JL, Ansari H. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. J Natl Cancer Inst 1998;90:850-858. PMID 9625174.
External links
For more information, see:
Chronische myeloische Leukämie | Leucémie myéloïde chronique | Kronisk myeloisk leukemi
"Chronic myelogenous leukemia"