chronic myeloid leukemia ( cml ) accounts for approximately 15% of adult leukemias , with an estimated 6,660 new cases of cml diagnosed in the united states in 2015.1 ) although the median age of diagnosis is 67 years , cml may present at any age.2 ) the advent of tyrosine kinase inhibitor ( tki ) therapy has transformed cml from a fatal disease into a chronic disease for the majority of patients .
the 8-year survival improved from 42% to 65% from 1983 to 2000 with the use of interferon--based therapy and allogeneic hematopoietic stem cell transplant ( hsct ) therapy . with the introduction of tki therapy in 2001 ,
the 8-year survival is now 87% and continues to improve with the use of second- and third - generation tki therapy.3 ) given the dramatic decrease in the number of deaths in cml patients and the stable incidence , the prevalence of cml continues to increase .
the estimated prevalence of cml in the united states was approximately 70,000 in 2010 and is expected to increase to approximately 112,000 in 2020.4 )
cml is a clonal myeloproliferative disorder characterized by the presence of a balanced genetic translocation of chromosomes 22 and 9 , termed the philadelphia ( ph ) chromosome ( figure 1 ) .
the resulting breakpoint cluster region - abelson murine leukemia ( bcr - abl ) fusion oncogene is translated into the bcr - abl oncoprotein.5 ) bcr - abl is a constitutively active tyrosine kinase that activates a number of signal - transduction pathways that affect the growth and survival of hematopoietic cells.6 )
cml is classified into three different phases : chronic , accelerated , and blast ( table 1).789 ) the natural history of cml is a chronic phase for three to five years followed by rapid progression to the fatal blast phase . in two - thirds of patients ,
approximately 85% of patients with cml are diagnosed in the chronic phase.10 ) forty percent of patients with chronic phase cml are asymptomatic with the diagnosis made solely based on an abnormal blood count.6 ) among the patients who have symptoms , complaints are usually related to anemia and splenomegaly ; these include fatigue , weight loss , anorexia , early satiety , and left upper quadrant pain or fullness .
splenomegaly is the most common finding on physical exam and is present in over half of patients.11 )
unexplained leukocytosis with left shift ( immature myeloid cells including myelocytes , promyelocytes or blasts ) , basophilia , and splenomegaly are suggestive of cml ( figure 2 ) .
the differential diagnosis includes leukemoid reaction ( due to infection or inflammation ) , ph negative myeloproliferative disorder , chronic myelomonocytic leukemia , and proliferative myelodysplastic syndrome . on occasion
the diagnosis of cml may be confirmed with fluorescence in situ hybridization ( fish ) or reverse transcriptase polymerase chain reaction ( rt - pcr ) for bcr - abl performed on the peripheral blood .
however , bone marrow aspiration with cytogenetic analysis ( karyotype ) is required to appropriately stage as the chronic phase , accelerated phase , or blast phase and to identify chromosomal abnormalities that are not detectable with fish for bcr - abl ( figures 3 , 4).12 )
tki therapy has transformed the outcomes of patients with cml over the last 15 years .
tkis interfere with the interaction between the bcr - abl oncoprotein and adenosine triphosphate , thereby blocking proliferation of the malignant clone .
there are currently three tkis approved by the food and drug administration for the first - line treatment of chronic phase cml : imatinib , dasatinib , and nilotinib .
imatinib was the first tki to be approved in 2001 . in the landmark study comparing imatinib to combination interferon and cytarabine therapy , imatinib had superior tolerability , hematologic and cytogenetic responses , and decreased likelihood of progression to accelerated phase or blast phase cml.13 ) the choice of first - line therapy depends on the sokal or hasford risk stratification score , patient age , ability to tolerate therapy , and medical comorbidities .
the sokal score includes age , spleen size , platelet count , and blast percentage.14 ) the hasford score also incorporates the percent of eosinophils and basophils.15 ) compared to imatinib , dasatinib and nilotinib have improved efficacy and may be preferred in intermediate- and high - risk patients based on the sokal or hasford risk stratification scores.16171819 ) in patients who are refractory or intolerant to first - line tki therapy , second - line options include second - generation tkis , dasatinib , nilotinib , and bosutinib .
ponatinib is a third - generation tki and is the only tki that is effective in patients who harbor the threonine - to - isoleucine mutation at position 315 ( t315i ) .
previously , ponatinib was considered a third - line treatment option . however , due to the associated risk of arterial and venous thromboembolism , its use is generally reserved for patients harboring the t315i mutation.2021 ) all tki agents are administered orally .
the initial dosing and common and notable adverse effects are summarized in table 2.2223 ) the management of toxicities associated with tki therapy is discussed elsewhere.1224 ) patients with chronic phase cml are continued on tki therapy indefinitely .
although discontinuation of tki therapy with close molecular monitoring may be possible in selected patients , the discontinuation of tki therapy should only been considered in the context of a clinical trial.122526 ) the response to therapy is classified based on hematological , cytogenetic , and molecular responses ( table 3).12 ) optimal responses to first - line tki therapy include complete hematologic response with bcr - abl1 transcript 10% ( rt - pcr ) and/or ph positive cells 35% ( bone marrow cytogenetics ) at 3 months , bcr - abl1 transcript < 1% and/or no detectable ph positive cells at 6 months , and bcr - abl1 transcript 0.1% at 12 months .
failure of first - line tki therapy is defined as failure to achieve a complete hematologic response and/or ph positive cells > 95% at 3 months , bcr - abl1 transcript > 10% and/or ph positive cells >
loss of complete hematologic response , complete cytogenetic response , or major molecular response or presence of mutations or clonal evolution are also considered as treatment failure.8 ) administration of the protein synthesis inhibitor omacetaxine is a treatment option for patients who have failure or intolerance to two or more tkis , including patients who harbor the t315i mutation.2728 ) the accelerated or blast phases may be treated with an alternative tki as a bridge to hsct .
hsct is a potentially curative treatment in patients with cml , and hsct evaluation is recommended for patients with the t315i mutation , failure or intolerance to two or more tkis , or those with accelerated or blast phase cml.12 )
although most pregnancy outcomes are normal in patients exposed to imatinib , there is still a risk for serious fetal malformation with imatinib exposure.29 ) for this reason , discontinuation of tki therapy is generally advised during pregnancy.12 ) for women who desire pregnancy , a planned pregnancy is preferred .
once a woman is in at least a major molecular response , then a two to three month washout period of tki therapy is advised prior to conception .
tki therapy should be held during pregnancy and resumed immediately after birth . when treatment is needed during pregnancy due to a very high white blood cell ( wbc ) count , leukapheresis is preferred.30 ) interferon may be used safely in pregnancy
. however , its use is limited by toxicity and slow time to response.313233 ) the use of hydroxyurea also appears to be safe in pregnancy , but its use is typically reserved for pulse dosing to control very high wbc counts.30343536373839 ) although the use of tki appears to be safe in men fathering a child , patients should be advised that the data in this setting is limited.404142 )
primary care physicians may be the first to detect cml since 40% patients present only with an abnormal blood count.6 ) thus , it is important for primary care physicians to be aware of the appropriate initial evaluation of patients with suspected cml . during the routine follow - up of other medical comorbidities , the primary care physician may be the first to detect new adverse effects to tki therapy , treatment failure , or progression of disease . with recognition of the common and serious adverse effects of tki therapy , the primary care physician may provide appropriate counseling or arrange for earlier follow - up with the patient 's hematologist / oncologist for management . with the recognition of possible treatment failure or progression of disease from the chronic phase to the accelerated or blast phases ( i.e. , increasing wbc count ) , the primary care physician should arrange for the patient to been seen by his / her hematologist / oncologist promptly for further evaluation .
 chronic myeloid leukemia ( cml ) accounts for approximately 15% of adult leukemias . 
 forty percent of patients with cml are asymptomatic , in whom the disease is detected solely based on laboratory abnormalities . since the introduction of tyrosine kinase inhibitor therapy in 2001 , cml has become a chronic disease for the majority of patients . 
 primary care physicians may be the first to recognize a new diagnosis of cml . in patients with known cml 
 , the primary care physician may be the first to detect disease progression or adverse effects to therapy . 
 this article provides an overview of the clinical presentation , diagnostic approach , and treatment considerations of cml . 
INTRODUCTION
PATHOGENESIS
CLINICAL MANIFESTATIONS AND STAGING
DIAGNOSIS
TREATMENT
PREGNANCY
ROLE OF THE PRIMARY CARE PHYSICIAN