Chronic Myeloid Leukemia (CML)

Pathophysiology:

· Myeloproliferative d/o with overproduction of myeloid cells and mature granulocytes (predominantly neutrophils, but also basophils and eosinophils) as well as megakaryocytes and erythroid cells

· BCR-ABL fusion (Philadelphia chromosome): chromosomal translocation for the BCR gene on chromosome 22 and fusion with ABL gene on chromosome 9, induces a constitutively active tyrosine kinase

· In the absence of treatment, CML has a triphasic or biphasic clinical course as it progresses from a chronic phase to an accelerated phase and on to a terminal blast crisis

· In the chronic phase, blasts are less than 2 percent, granulocytes are morphologically normal with no evidence of dysplasia

 

 

Epidemiology/Natural history

· Typically present in 5th or 6th decade of life, although can be a wide age range

· Prognosis in patients with CML is the stage of disease at the time of diagnosis: pts with chronic phase at the time of diagnosis can have years of disease control on treatment, while those in accelerated phase or blast crisis have a much poorer prognosis.

 

 

Clinical Findings

· Most pts are asymptomatic at diagnosis, leukocytosis is found incidentally

· Can develop fatigue, night sweats, weight loss and splenomegaly on exam

· The peripheral smear typically demonstrates a leukocytosis with a median white count of approximately 100,000

 

 

Diagnosis

· LAP score: leukocyte (or neutrophil) alkaline phosphatase (LAP, or NAP) score can be helpful in excluding a reactive leukocyotsis or leukemoid rxn (LAP score is elevated or normal) from a leukemic process (score is low) (not specific for CML)

· Hypercellular BM, with marked myeloid proliferation, initially have <10% blasts in circulating blood, with progressive disease can have up to 20% (accelerated phase) or >20% in blast crisis

· Diagnosis requires identification of the bcr-abl fusion gene

 

 

Treatment

· Imantinib (gleevec) is a tyrosine kinase inhibitor that induces remission in up to 70% of patients treated in the chronic phase and most of these remain in remission for >5 yrs

· dasantinib and nilotinib are 2 other TK inhibitors for pts with imantinib-resistant CML (previously HSCT was only treatment)

· accelerated and blast crisis typically have poorer responses to TKIs

· Hydroxyurea: Antimetabolite which halts the cell cycle at the G1/S phase and can be used for leukoreduction (also used in PV and ET) (In sickle cell anemia, hydroxyurea increases Hgb F and improved RBC deformability)

 

 

(Victoria Kelly MD, 4/25/11)