Chronic Myelogenous Leukemia

Etiology

There is an increased incidence of CML among atomic bomb survivors; however, the predisposing risk factors are unknown.[1]

Epidemiology

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 years. There is a slight male predominance. The median age of diagnosis is 56 years old.[2]

In the United States, the annual incidence rate between 2009 and 2013 was 1.4 and 2.2 per 100,000 for females and males, respectively.[3] Estimates for 2018 were 8490 new cases of CML and 1090 estimated deaths.[4]

Pathophysiology

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 has 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]

Histopathology

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]

History and Physical

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.

Evaluation

Initially, if CML is suspected, cytogenetic testing, fluorescent in situ hybridization (FISH), 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 three months after initiation of therapy. After BCR-ABL1 is less than or equal to 1% by international scale, quantitative PCR should continue for two years and then every 3 to 6 months after two 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 HLA 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]

Treatment / Management

There are 4 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]
(A1)

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](A1)

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](B3)

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.

Differential Diagnosis

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 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. Both 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]

Pertinent Studies and Ongoing Trials

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 include 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]

Treatment Planning

Any of the four FDA-approved tyrosine kinase inhibitors are highly effective in treating chronic phase CML. In selecting front-line therapy, a patient’s age, comorbidities, and tyrosine kinase toxicities must be taken into account.

For patients with chronic phase CML, the use of the Sokal or Hasford risk stratification scores helps predict outcomes and choose the first-line tyrosine-kinase inhibitor.[11][12][11] For chronic phase, CML with intermediate- or high-risk score, second-generation tyrosine kinase inhibitors (bosutinib, dasatinib, nilotinib) may have the additional benefit over imatinib in achieving response milestones.[15][16][17][28]

At baseline, all patients should undergo bone marrow examination and cytogenetic analysis to monitor treatment response. The patient should be monitored at 3, 6, and 12 months after starting therapy using cytogenetic and molecular studies such as PCR performed on peripheral blood.[29] The major goal in chronic phase CML treatment is achieving complete cytogenetic response by 12 months after the initiation of tyrosine kinase inhibitors. Response milestones include complete hematologic response, cytogenetic response, and major molecular response.[6] A complete hematologic response is defined as complete normalization of peripheral blood counts with a leukocyte count below 10 x 10^9/L and platelet count below 450 x 10^9/L, the absence of myelocytes, promyelocytes, and blasts, and absence of signs and symptoms of the disease, including the disappearance of a palpable spleen.[30] A complete cytogenetic response shows no Philadelphia-positive metaphases, and a major molecular response is defined as BCR-ABL1 transcripts of less than or equal to 0.1% on the international scale (IS).[31]

The European Leukemia Net (ELN) 2013 criteria can be a guide to monitor failure or suboptimal response to first-line therapy or second-line therapy. These criteria evaluate patients with chronic phase CML at 3 months, 6 months, and 12 months and then any subsequent follow-up; the optimal response is defined by PCR as BCR-ABL1 transcripts (IS) of less than or equal to 10%, less than 1%, and less than or equal to 0.1%, respectively. Alternatively, if quantitative PCR is not available, cytogenetics can determine levels of the Philadelphia chromosome but is not useful in cryptic BCR-ABL1. If the optimal response is not achieved, there is a warning response group and a failure response group. In the warning group, consideration of dose escalation of imatinib or changing tyrosine kinase inhibitors is warranted.[32] However, if an optimal response is not achieved at three months, studies show that most patients will achieve an optimal response at six months without changes in therapy with a similar prognosis.[33] Another consideration is patient compliance; poor adherence has been shown to be a significant contributor to treatment failure and loss of complete response.[34] In high-risk cases, at the time of diagnosis or in case of treatment failure despite good patient compliance, the tyrosine kinase inhibitor therapy should be changed. The patient should be evaluated for the possibility of allogeneic HSCT.[6]

In the event of tyrosine kinase inhibitor resistance, analysis of the BCR-ABL1 mutational profile may be useful in choosing second- or third-line therapy. The T315I mutation has been shown to confer resistance to imatinib and all second-generation tyrosine kinase inhibitors. In these patients, ponatinib should be considered.[18] In cases of Y253H, E255K/V, or F359C/V mutations, dasatinib or bosutinib may have better responses, and in cases of V299L and F317L mutations, nilotinib may have promising outcomes.[6]

For accelerated or blast phase CML, treatment considerations include evaluation for allogeneic HSCT, whether the advanced phase presented while the patient was on or off tyrosine kinase inhibitor therapy, comorbidities, age, prior therapy, and analysis of BCR-ABL1 mutation profile. Chemotherapy is often required in advanced CML to reduce disease burden and prepare for allogeneic HSCT.[19][20][32]

In patients who achieve a long-term deep molecular response to therapy, discontinuation of tyrosine kinase inhibitors may be considered. Treatment-free remission can be achieved in approximately 40% to 60% of the low risk to intermediate-risk patients. Characteristics that predict treatment-free remission include cases with low Sokal risk, no history of tyrosine kinase inhibitor resistance, and duration of tyrosine kinase inhibitor use greater than five years. Most relapses will occur within the first six months of discontinuation, and molecular monitoring should occur monthly for the first year post-discontinuation and every 6 to 12 weeks indefinitely. If molecular relapse occurs, the tyrosine kinase inhibitor therapy should be re-initiated.[35]

Toxicity and Adverse Effect Management

Most patients will develop mild to moderate adverse events early in tyrosine kinase inhibitor therapy, and most will resolve spontaneously or be well-controlled.

Adverse events and side effects divide into four grades based on severity.

• Grade 1 would require no change in tyrosine kinase inhibitor therapy; however, it may require specific treatment.
• Grade 2 will involve withholding therapy until severity decreases or continuing therapy if symptoms decrease in severity with monitoring. If a Grade 2 side effect is recurrent, dose reduction should be considered.
• Grade 3 should involve withholding therapy until severity decreases and then restarting at a lower dose or withholding till symptoms reach a grade 1 level or less and resume prior dosage. If there is no resolution or Grade 3 side effects are recurrent, the tyrosine kinase inhibitor should be changed.
• Grade 4 events should involve switching tyrosine kinase inhibitor therapy when possible.[36]

Vascular System: Ischemic heart disease, ischemic cerebrovascular events, and peripheral arterial occlusive disease have correlations with nilotinib and ponatinib. Higher dosing has been related to higher risks of these events. Cardiovascular risk should undergo evaluation before therapy begins with these agents and should be closely monitored during treatment. Risk assessment and monitoring should include hemoglobin A1C, lipid profile, and serum creatinine. These drugs should be used with caution in patients with a high risk for vascular disease.

Cardiac Function: Ponatinib has an associated incidence of heart failure. The monitoring of cardiac function should be mandatory for patients on ponatinib.

Cardiac Rhythm Alterations: Tyrosine kinase inhibitors have the potential to alter the QT interval. Nilotinib has the highest incidence of QT interval prolongation. Ponatinib is associated with QT interval shortening. Electrocardiogram at baseline and periodically in select patients who are on any tyrosine kinase inhibitor and have QT interval prolongation, and for those who are on ponatinib. Nilotinib should be avoided in patients with a high risk for arrhythmias or when other drugs that may alter the QT interval are being administered. Potassium and magnesium levels should be replete before initiation of tyrosine kinase inhibitor therapy in all cases.

Pulmonary System: Pleural effusions can occur with all tyrosine kinase inhibitors but most commonly occurs with dasatinib. Patients with pre-existing lung injuries, chronic lung disease, congestive heart failure, and hypertension are at the highest risk of developing pleural effusions. Caution is necessary if patients develop a cough, shortness of breath, or chest pain during therapy, and a chest X-ray must be obtained in such cases. Reports also exist of pulmonary hypertension with dasatinib use. If the development of pulmonary hypertension is suspected, dasatinib should be stopped immediately.

Hepatobiliary System: Hepatotoxicity is common in all tyrosine kinase inhibitors. Ponatinib has the highest risk for developing high-grade increases in transaminases. Substances that alter liver metabolism by cytochrome P450 and acetaminophen should be used with caution or avoided entirely—prompt treatment with glucocorticoids in severe cases of hepatotoxicity assists in hepatic recovery.

Hyperglycemia: Nilotinib has been shown to induce hyperglycemia in non-diabetic and diabetic patients. Fasting glucose and hemoglobin A1C require monitoring.

Hypercholesterolemia: Nilotinib shows correlations with increases in LDL-cholesterol. Hypertriglyceridemia has been reported with ponatinib. If persistent high-risk hypercholesterolemia develops, appropriate statin initiation may be warranted.

Other Endocrinopathies: Hypophosphatemia and hypocalcemia have been reported with imatinib, nilotinib, and dasatinib. Phosphate, calcium, and Vitamin D levels should be tested at baseline and monitored after that. Hypothyroidism may also develop and is treated effectively with hormone replacement.

Myelosuppression: Development is common with all tyrosine kinase inhibitors but is usually limited to the first few weeks to months of therapy. Leukocytes, erythrocytes, and platelets can all be affected; this necessitates close monitoring of blood counts and response to avoid infection and bleeding. Tyrosine kinase interruption, dose reduction, and supportive management with blood products are considerations based on levels of cytopenias, the specific tyrosine kinase inhibitor, and the phase of the disease. Any nutritional deficiencies should be corrected before the initiation of therapy.

Gastrointestinal System: Nausea, diarrhea, abdominal pain, and vomiting are frequent side effects related to tyrosine kinase inhibitors. Diarrhea is especially significant with bosutinib and often requires dose interruption and/or dose reduction. Patients can take their medication with meals to avoid nausea and vomiting. In severe cases, antiemetic and/or antidiarrheal medication can be administered, and close monitoring of hydration status should occur. Gastrointestinal bleeding has been reported with dasatinib. There are reports of increased lipase levels and pancreatitis with nilotinib and ponatinib.

Dermatologic System: Rash development is common with all tyrosine kinase inhibitors. Most cases are dose-related and self-limited. Management can comprise topical therapies, antihistamines, and/or short courses of systemic steroids. In severe cases, prednisone merit consideration with the gradual reintroduction of the offending tyrosine kinase inhibitor.

Kidney Injury: Monitoring for tumor lysis syndrome should be done from the outset of treatment with all tyrosine kinase inhibitors. Otherwise, the development of acute kidney injury may result from imatinib therapy. Dasatinib and bosutinib have also been associated with acute kidney injury but at lower incidence rates. Serum creatinine requires monitoring in these patients, and caution is necessary for patients with renal insufficiency.

Other commonly reported side effects include myalgia, bone pain, ophthalmological changes, and headache.[6][36]

Staging

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 one or more of the following criteria:

• Persistent or increasing high white blood cell count (greater than 10 x 10^9/L) unresponsive to therapy
• Persistent or increasing splenomegaly unresponsive to therapy
• Persistent thrombocytosis (greater than 1000 x 10^9/L) unresponsive to therapy
• Persistent thrombocytopenia (less than 100 x 10^9/L)
• Greater than or equal to 20% basophils in peripheral blood
• 10-19% 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]

Prognosis

Before introducing imatinib, most CML cases progressed to the blast phase, and death occurred in under five 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 ten-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 two 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

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