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Chronic myelogenous leukemia (CML), BCR-ABL1-positive, is classified as a myeloproliferative neoplasm predominantly composed of proliferating granulocytes and determined to have the Philadelphia chromosome/translocation t(9;22)(q34;q11.2). CML affects both the peripheral blood and the bone marrow. There is an increased incidence of CML among atomic bomb survivors; however, the predisposing risk factors are unknown. This activity reviews the pathophysiology, evaluation, and management of CML and explains the role of the interprofessional team in caring for patients with this condition. Objectives: Describe the pathophysiology of chronic myelogenous leukemia. Explain the common laboratory findings associated with chronic myelogenous leukemia. Describe the management considerations for patients with chronic myelogenous leukemia. Outline the importance of collaboration and communication among interprofessional team members to enhance care delivery for patients affected by chronic myelogenous leukemia. Access free multiple choice questions on this topic.

Chronic myelogenous leukemia (CML), BCR-ABL1-positive, is classified as a myeloproliferative neoplasm predominantly composed of proliferating granulocytes and determined to have the Philadelphia chromosome/translocation t(9;22)(q34;q11.2). CML affects both the peripheral blood and the bone marrow.

CML has a worldwide annual incidence rate of 0.87 people per 100,000, increasing with age up to 1.52 in patients older than 70. There is a slight predominance in men, and the median age of diagnosis is 56.[2] In the United States, the annual incidence rate between 2009 and 2013 was 1.4 and 2.2 per 100,000 for women and men, respectively.[3] Estimates for 2018 were 8490 new cases of CML and 1090 estimated deaths.[4]

The fusion oncoprotein BCR-ABL1 defines CML. 90% to 95% of patients with CML have a shortened chromosome 22 because of a reciprocal translocation t(9;22) (q34;q11.2) called the Philadelphia chromosome. The ABL1 gene encodes a non-receptor tyrosine kinase on chromosome 9, and BCR is a breakpoint cluster region on chromosome 22. The translated oncoprotein, in most cases, is 210-kd and called p210 BCR-ABL1. Alternative splicing results in p190 and p230 BCR-ABL1, which may show different presentations. This oncoprotein acts as a constitutively expressed defective tyrosine kinase. The downstream pathways affected include JAK/STAT, PI3K/AKT, and RAS/MEK; they involve cell growth, cell survival, inhibition of apoptosis, and activation of transcription factors.[5] The remainder of patients have variant or complex translocations involving additional chromosomes detected by routine cytogenetics or a cryptic BCR-ABL1 translocation detected with fluorescent in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (PCR).[6]

Chronic Phase The peripheral blood smear will show a leukocytosis due to granulocytes in various stages of maturation. There will be a bimodal distribution with higher proportions of mature segmented neutrophils and myelocytes. Blast cells will account for less than 2% of the white blood cells. Increased basophils and eosinophils are common. Significant dysplasia affecting greater than 10% of the granulocyte population is absent. Monocytosis may be present; however, it is usually less than 3% of the white blood cells. Platelets usually range from the normal range to a significant increase; thrombocytopenia is an uncommon finding.[7] Bone marrow aspirate and biopsy will show hypercellularity with marked granulocytic proliferation and significantly increased myelocytes, although significant dysplasia should be absent (see Image. Chronic Myeloid Leukemia). Blasts are usually less than 5%. Erythroid precursors are decreased considerably, and there is an increased myeloid-to-erythroid ratio. Megakaryocytes may be reduced, normal, or increased. About half of the cases show a megakaryocytic proliferation. The megakaryocytes in CML show a small, hypo-lobate “dwarf” morphology. The biopsy will show immature granulocytes in a thickened band of 5 to 10 cells along bone trabeculae. Adjacent to bone trabeculae is the normal distribution site of immature granulocytes; however, it is usually 2 to 3 cells thick. The bone marrow may also show increased reticulin fibrosis.[8] Accelerated Phase The peripheral smear may or may not show increased blasts (10% to 19%). The bone marrow aspirate and biopsy will show similar changes to chronic phase CML with increased blasts (10% to 19%), possibly dysplastic changes in granulocytes, and increased reticulin and collagen fibrosis.[9] Blast Phase The peripheral smear and/or bone marrow aspirate will show greater than 20% blasts, or there will be an extramedullary proliferation of blasts. Most cases will show blasts with myeloid differentiation; however, other lineages or combinations may be present, including lymphoblasts. Extramedullary proliferation is most commonly seen in the skin, lymph nodes, bone, and the central nervous system (CNS).[10]

Approximately half of the patients with CML are asymptomatic and are diagnosed on routine complete blood count. Most patients are in the chronic phase of CML. CML, in the chronic phase, most often presents with symptoms related to anemia and splenomegaly. Symptomatic anemia includes symptoms such as fatigue and malaise. Splenomegaly may cause a mass effect resulting in early satiety, left upper quadrant fullness, or pain. CML may also cause thrombocytopenia or platelet dysfunction resulting in bleeding, thrombocytosis resulting in thrombosis or priapism, basophilia resulting in histamine release, and upper gastrointestinal ulcers. As CML progresses into the accelerated phase or blast phase, symptoms such as headaches, bone pain, fever, joint pain, bleeding, infections, and lymphadenopathy become more common.[6] The physical exam should include assessing the spleen size by palpation, measured in centimeters below the costal margin.[11][12] Splenomegaly is the most common physical exam finding in patients suffering from CML. In more than half of the patients, the spleen size extends beyond 5 cm below the left costal margin at the time of diagnosis. A very large spleen is usually a herald sign of the transformation into an acute blast crisis from the disease. Hepatomegaly may also be found as it is a part of the extramedullary hematopoiesis occurring in the spleen. Physical exam findings may also include the signs of hyperviscosity. On fundoscopy, the retina may reveal papilledema, venous obstruction, and hemorrhages.

Initially, if CML is suspected, cytogenetic testing, fluorescent in situ hybridization, and/or reverse transcriptase-polymerase chain reaction (PCR) to determine the Philadelphia chromosome, or BCR-ABL1 oncoprotein presence can be performed on peripheral blood. At the time of diagnosis, laboratory blood testing should include a complete blood count with differential, chemistry panel, hepatitis panel, and a quantitative PCR for BCR-ABL1. A baseline bone marrow aspirate and biopsy should be performed with cytogenetics. Quantitative PCR should be repeated every 3 months after initiation of therapy. After BCR-ABL1 is less than or equal to 1% (international scale), quantitative PCR should continue for 2 years and then every 3 to 6 months after 2 years. If chronic phase CML is established, additional evaluation includes determining the risk score using Sokal et al or Hasford et al risk calculations before determining first-line therapy.[6] Sokal risk calculation uses age, spleen size, platelet count, and percentage of myeloblasts in peripheral blood to determine the risk group [11] Hasford risk calculation uses age, spleen size, platelet count, and percentage of blasts, eosinophils, and basophils in the peripheral blood to determine the risk group [12] If accelerated or blast phase CML is diagnosed or progresses from chronic phase CML, additional testing should include flow cytometry to determine lineage, mutational analysis, and histocompatibility testing if allogeneic hematopoietic stem cell transplant (HCT) is being considered. Additional bone marrow cytogenetics and mutational analysis should be considered when there is a failure to reach response milestones or any sign of hematologic or cytogenetic relapse.[6]

There are 4 United States Food and Drug Administration (FDA)-approved, first-line treatments for chronic phase CML that are commercially available tyrosine kinase inhibitors, including first-generation imatinib and second-generation dasatinib, nilotinib, and bosutinib. Dosing Imatinib: 400 mg daily [13][14] Bosutinib: 500 mg daily [15] Dasatinib: 100 mg daily [16] Nilotinib: 300 mg twice a day [17] For chronic phase, CML with intermediate- or high-risk score, second-generation tyrosine kinase inhibitors (bosutinib, dasatinib, nilotinib) as first-line therapy may have an additional benefit over imatinib.[15][16][17] Ponatinib, a third-generation tyrosine kinase inhibitor, dosed at 45 mg daily, is a third-line treatment option in chronic phase CML for patients who have failed to respond to multiple tyrosine kinase inhibitors and for individuals who have the T315I mutation.[18] Advanced CML (accelerated or blast phase) has additional therapeutic considerations. Second- or third-generation tyrosine kinase inhibitor therapy should be initiated to reduce the CML burden and be considered for early allogeneic hematopoietic stem cell transplant (HSCT).[6] Omacetaxine is a chemotherapeutic agent that is an additional treatment option in cases refractory to tyrosine kinase inhibitor therapy that advanced from chronic phase CML.[19] Allogenic HSCT should be considered in patients resistant to tyrosine kinase inhibitor therapy in chronic phase CML and cases of advanced CML.[6][20] Clinical trial participation should be considered for all patients.

Differentiating CML from other causes of granulocytic leukocytoses, such as infections or drugs, is necessary. Most causes of reactive leukocytosis have a white blood cell count of less than 50 x 10/L and show toxic changes such as toxic granulation and Dohle bodies. There will also be an absence of basophilia. Other myeloproliferative disorders such as chronic neutrophilic leukemia (CNL) and polycythemia vera (PV) may present with leukocytosis and thrombocytosis. CNL and PV will lack the BCR-ABL1 fusion gene. CNL is rare and presents with mature segmented neutrophilia and lacks a bimodal leukocytosis with myelocytes.[6]

A search of ClinicalTrials.gov shows there are 221 active, interventional CML trials with 125 recruiting. These trials are widely variable, with study topics covering novel drugs, treatment optimization of current treatment modalities, potential drug treatment combination regimens, the efficacy of treatment discontinuation, and immunotherapy. Ongoing trials of note include the randomized international phase 3 study Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd)[17], and the phase 3 study Results of Efficacy and Safety of Radotinib Compared with Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia (RERISE).[21] Other pertinent studies include trials that supported the first-line treatment with imatinib and dosing including the CML Study IV,[13] the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study,[14] and the International Randomized Study of Interferon and STI571 trial (IRIS).[22] Important trials concerning the efficacy and dosing of the second generation FDA-approved tyrosine kinase inhibitors include Bosutinib Efficacy and Safety in Newly Diagnosed CML trial (BELA),[15] Bosutinib Versus Imatinib in Adult Patients With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia trial (BFORE),[23] Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients trial (DASISION),[16] and the ENESTnd study.[17] Pertinent studies and ongoing trials assessing tyrosine kinase inhibitor therapy discontinuation efficacy and candidate recommendations include the imatinib discontinuation study (STIM1),[24] Evaluating Nilotinib Efficacy and Safety in Clinical Trials: Treatment-Free Remission study (ENESTfreedom),[25] Imatinib Suspension and Validation study (ISAV),[26] and Discontinuation of Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukaemia trial (EURO-SKI).[27]

CML staging is determined by the phase of the disease, which includes a chronic phase, accelerated phase, and blast phase. The chronic phase has less than 10% blasts, asymptomatic to mild symptoms, and responds to tyrosine kinase inhibitor therapy. The World Health Organization (WHO) defines accelerated phase CML as having 1 or more of the following criteria: Persistent or increasing high white blood cell count (greater than 10 x 109/L) unresponsive to therapy Persistent or increasing splenomegaly unresponsive to therapy Persistent thrombocytosis (greater than 1000 x 109/L) unresponsive to therapy Persistent thrombocytopenia (less than 100 x 109/L) Greater than or equal to 20% basophils in peripheral blood 10% to 19% blasts in peripheral blood or bone marrow (without extramedullary blast proliferation) Additional chromosomal abnormalities in Philadelphia chromosome-positive cells at diagnosis Any new clonal chromosomal abnormality in Philadelphia chromosome-positive cells during therapy The WHO also considers resistance to tyrosine kinase inhibitors as provisional criteria for determining accelerated phase CML. Blast phase CML is defined by greater than or equal to 20% blasts in the peripheral blood and/or bone marrow or extramedullary blast proliferation.[9]

Before introducing imatinib, most CML cases progressed to the blast phase, and death occurred in under 5 years. Since tyrosine kinase inhibitors have been the first-line therapy for CML, the 5-year survival has risen from 33% to over 90%. The 10-year survival has risen from 11% to 84%, and complete cytogenetic response occurs in 70% to 90% of patients. Individuals diagnosed with chronic phase CML are expected to reach normal or near-normal life expectancy.[28] Cytogenetic analysis for additional abnormalities, in addition to the classic translocation, may be important for prognostic information. Previously, any additional chromosomal abnormalities were considered a risk for disease progression, tyrosine kinase inhibitor resistance, and worse prognosis. However, studies have shown that single additional chromosomal abnormalities, including trisomy 8, loss of Y, and an extra copy of the Philadelphia chromosome, do not impact survival. The presence of 2 or more additional chromosomal abnormalities or a single additional chromosomal abnormality involving i(17)(q10), the loss of 7 or deletion of 7q, and 3q26.2 rearrangements are poor prognostic indicators.[37] The BCR-ABL1 mutational analysis may also impact prognosis. The T315I mutation was the first mutation discovered in association with the development of tyrosine kinase inhibitor resistance. Over 100 point mutations in the BCR-ABL1 oncogene have been isolated in imatinib-resistant patients. These mutations may have an influence over treatment planning in first-line tyrosine kinase-resistant patients.[38] The future prognostic evaluation may include sequencing for mutations involving known cancer genes, such as IKZF1, RUNX1, ASXL1, BCORL1, and IDH1. These mutations were found in patients who underwent sequencing during blast-phase CML.[39]

Complications of CML can include: Hepatomegaly and/or splenomegaly Worsening anemia Changes in platelet count changes resulting in clotting or bleeding complications Recurrent infections Bone pain Fever

The interprofessional team should involve hematology/oncology, hematopathology, and other specialties already involved with patient comorbidities. If complications or adverse events develop, transfusion medicine, cardiology, endocrinology, gastroenterology, and infectious disease, consultations should be considered in select circumstances.

Patients need to understand the testing needed following CML diagnosis to check for metastatic disease and determine what phase the disease has achieved. Chronic myelogenous leukemia has 3 phases chronic, acute, and blastic. The phase will dictate the treatment. They must also understand that CML relapse is possible following treatment. Last, they need to be counseled on what to expect and their prognosis. Prognosis is affected by several factors, including: Patient age The disease phase The number of blasts in the blood or bone marrow. Spleen size Overall patient health They must also understand the ramifications and side effects of their therapy.

Pearls and other important information on CML include the following: Most patients with CML are asymptomatic in the chronic phase and are found by routine complete blood count showing leukocytosis with bimodal increases in myelocytes and mature segmented neutrophils. The diagnosis of CML requires the BCR-ABL1 translocation. A traditional karyotype can detect most cases; however, a small subset of cases are cryptic and require FISH. CML is divided into 3 phases: chronic, accelerated, and blast phase. The BCR-ABL1 oncoprotein acts as a constitutively active tyrosine kinase. The mainstay of treatment in CML is tyrosine kinase inhibitors. Risk stratification scores are useful in determining first-line therapy choices. The mutational analysis may be important in cases with resistance to tyrosine kinase inhibitor therapy. Ponatinib is a tyrosine kinase inhibitor especially useful for those with a T315I BCR-ABL1 mutation. Allogenic HSCT is an important consideration for resistant chronic phase and advanced phases of CML.

CML is a common leukemia found in adults, and the advancement of tyrosine kinase inhibitor treatment has a good prognosis. However, identifying patients with CML can be challenging in instances of cryptic translocations and presentations in advanced phases. The World Health Organization and the European LeukemiaNet provide evidence-based guidance on evaluation, diagnosis, treatment, and milestones for CML. To avoid misdiagnosis and delayed treatment, a bone marrow aspirate and collaboration with pathology are necessary in suspected cases to ensure adequate sampling to identify the BCR-ABL1 translocation.[32] Interprofessional teamwork and decision-making with the patient are vitally important, and side effects that may hinder treatment adherence should be discussed directly with the patient. Tyrosine kinase inhibitors are effective in most cases; however, the patient's non-compliance is a prominent cause of failure. The pharmacist must verify all chemotherapeutic agent dosing and compatibility, check for drug interactions, and educate the team on adverse effects. The healthcare team needs to identify side effects early, make patient concerns a priority, and combat any challenges as soon as possible.[34]  A coordinated interprofessional team approach involving nurses, primary care providers, pharmacists, and specialists will result in the most successful care of patients with CML.