Chronic myelogenous leukemia (CML) is a form of chronic leukemia characterized by increased and unregulated clonal proliferation of predominantly myeloid cells in the bone marrow. CML is a clonal bone marrow stem cell disorder in which proliferation of mature granulocytes (neutrophils, eosinophils, and basophils) and their precursors is the main finding. It is a type of myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia chromosome. Historically, it has been treated with chemotherapy, interferon and bone marrow transplantation, although targeted therapies introduced at the beginning of the 21st century have radically changed the management of CML.
Signs and symptoms:
Patients are often asymptomatic at diagnosis, presenting incidentally with an elevated white blood cell count on a routine laboratory test. In this setting, CML must be distinguished from a leukemoid reaction, which can have a similar appearance on a blood smear. Symptoms of CML may include: malaise, low-grade fever, increased susceptibility to infections, anemia, and thrombocytopenia with easy bruising (although an increased platelet count (thrombocytosis) may also occur in CML). Splenomegaly may also be seen.
Treatment:
Chronic phase: Chronic phase CML is treated with inhibitors of tyrosine kinase , the first of which was imatinib mesylate (marketed as Gleevec® or Glivec®; previously known as STI-571). In the past, antimetabolites (e.g. cytarabine, hydroxyurea), alkylating agents, interferon alfa 2b, and steroids were used, but these drugs have been replaced by imatinib. Imatinib was approved by the US FDA in 2001 and specifically targets BCR/abl, the constitutively activated tyrosine kinase fusion protein caused by the Philadelphia chromosome translocation. It is better tolerated and more effective than previous therapies. Bone marrow transplantation was also used as initial treatment for CML in younger patients before the advent of imatinib, and while it can often be curative, there is a high rate of transplant-related mortality.
Another new drug, dasatinib (marketed as Sprycel; previously known as BMS-354825), which has a similar mechanism of action to imatinib but inhibiting a broader spectrum of tyrosine kinases, was approved by the U.S. 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. Pre-clinical research indicates that the anti-leukemic effect of dasatinib may be further enhanced by the addition of a small molecular inhibitor known as PD184352
Various combinations of the different treatment modalities are being explored.
In 2005 favourable results of vaccination were reported with the BCR/abl p210 fusion protein in patients with stable disease, with GM-CSF as an adjuvant.
Two other drugs, ceflatonin (homoharringtonine) and nilotinib (AMN 107) are currently in active clinical trials in patients with 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.