Chronic Myeloid Leukemia: A Review of TKI Therapy

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Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22, t(9;22)(q34;q11.2) (the Philadelphia chromosome), resulting in the generation of the BCR-ABL1 fusion gene and its protein product, BCR-ABL tyrosine kinase. BCR-ABL is a constitutively active fusion kinase that confers proliferative and survival advantage to hematopoietic cells through activation of downstream pathways.

CML is divided into 3 phases based on the number of myeloblasts observed in the blood or bone marrow: chronic, accelerated, and blast. Most cases of CML are diagnosed in the chronic phase (CP), which is marked by proliferation of primarily the myeloid element.

The advent of tyrosine kinase inhibitors (TKIs), a class of small molecules targeting the tyrosine kinases, particularly the BCR-ABL tyrosine kinase, led to rapid changes in the management of CML and improved survival for patients. Patients diagnosed with CP-CML now a have life-expectancy that is similar to that of the general population, as long as they receive the appropriate TKI therapy and adhere to treatment. As such, it is crucial to identify patients with CML, ensure they receive a complete, appropriate diagnostic work-up, and select the best therapy for each individual patient. The diagnosis and work-up of CML are reviewed in a separate article; here, the selection of TKI therapy for a patient with newly diagnosed CP-CML is reviewed.

Case Presentation

A 53-year-old woman who recently was diagnosed with CML presents to review her treatment options. The diagnosis was made after she presented to her primary care physician with fatigue, early satiety, left upper quadrant abdominal pain, and an 8-lb unintentional weight loss over the prior month. On physical exam her spleen was palpated 8 cm below the left costal margin. Laboratory evaluation showed a total white blood cell (WBC) count of 124,000/μL with a left-shifted differential including 6% basophils, 3% eosinophils, and 3% blasts; hemoglobin and platelet count were 12.4 g/dL and 801 × 10³/µL, respectively. Fluorescent in-situ hybridization for BCR-ABL gene rearrangement using peripheral blood was positive in 87% of cells. Bone marrow biopsy and aspiration showed a 95% cellular bone marrow with granulocytic hyperplasia and 1% blasts. Cytogenetics were 46,XX,t(9;22)(q34;q11.2), and quantitative real-time polymerase chain reaction (RQ-PCR) to measure BCR-ABL1 transcripts in the peripheral blood showed a value of 98% international standard (IS). Her Sokal risk score was 1.42 (high risk). In addition, prior review of her past medical history revealed uncontrolled diabetes, coronary artery disease requiring placement of 3 cardiac stents 2 years prior, and chronic obstructive pulmonary disease (COPD) related to a 30-pack-year history of smoking.

What factors must be considered when selecting first-line therapy for this patient?

Selection of the most appropriate first-line TKI for newly diagnosed CP-CML patients requires incorporation of many patient-specific factors. These factors include baseline karyotype and confirmation of CP-CML through bone marrow biopsy, Sokal or EURO risk score, and a thorough patient history, including a clear understanding of the patient's comorbidities. In this case, the patient's high Sokal risk score along with her history of diabetes, coronary artery disease, and COPD are all factors that must be accounted for when choosing the most appropriate TKI. The adverse effect profile of all TKIs must be considered in conjunction with the patient's ongoing medical issues in order to decrease the likelihood of worsening her current symptoms or causing a severe complication from TKI therapy.

Imatinib

The management of CML was revolutionized by the development and ultimate regulatory approval of imatinib mesylate in 2001. Imatinib was the first small-molecule cancer therapy developed and approved. It acts by binding to the adenosine triphosphate (ATP) binding site in the catalytic domain of BCR-ABL, thus inhibiting the oncoprotein's tyrosine kinase activity.¹

The International Randomized Study of Interferon versus STI571 (IRIS) trial was a randomized phase 3 study that compared imatinib 400 mg daily to interferon α (IFNα) plus cytarabine. More than 1000 CP-CML patients were randomly assigned 1:1 to either imatinib or IFNα plus cytarabine and were assessed for event-free survival, hematologic and cytogenetic responses, freedom from progression to accelerated phase (AP) or blast phase (BP), and toxicity. Imatinib was superior to the prior standard of care for all these outcomes.² The long-term follow up of the IRIS trial reported an 83% estimated 10-year overall survival (OS) and 79% estimated event-free survival for patients on the imatinib arm of this study.³ The cumulative rate of complete cytogenetic response (CCyR) was 82.8%. Of the 204 imatinib-treated patients who could undergo a molecular response evaluation at 10 years, 93.1% had a major molecular response (MMR) and 63.2% had a molecular response 4.5 (MR4.5), suggesting durable, deep molecular responses for many patients (see Chronic Myeloid Leukemia: Evaluation and Diagnosis for discussion of the hematologic parameters, cytogenetic results, and molecular responses ussed in monitoring response to TKI therapy). The estimated 10-year rate of freedom from progression to AP or BP was 92.1%.

Higher doses of imatinib (600-800 mg daily) have been studied in an attempt to overcome resistance and improve cytogenetic and molecular response rates. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was a randomized phase 3 study that compared imatinib 800 mg daily to imatinib 400 mg daily. Although the 6-month assessments found increased rates of CCyR and a MMR in the higher-dose imatinib arm, these differences were no longer present at the 12-month assessment. Furthermore, the higher dose of imatinib led to a significantly higher incidence of grade 3/4 hematologic adverse events, and approximately 50% of patients on imatinib 800 mg daily required a dose reduction to less than 600 mg daily because of toxicity.⁴

The Therapeutic Intensification in De Novo Leukaemia (TIDEL) -II study used plasma trough levels of imatinib on day 22 of treatment with imatinib 600 mg daily to determine if patients should escalate the imatinib dose to 800 mg daily. In patients who did not meet molecular milestones at 3, 6, or 12 months, cohort 1 was dose escalated to imatinib 800 mg daily and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later, and cohort 2 was switched to nilotinib. At 2 years, 73% of patients achieved MMR and 34% achieved MR4.5, suggesting that initial treatment with higher-dose imatinib subsequently followed by a switch to nilotinib in those failing to achieve desired milestones could be an effective strategy for managing newly diagnosed CP-CML.⁵

Toxicity

Imatinib 400 mg is considered the standard starting dose in CP-CML patients. The safety profile of imatinib has been very well established. In the IRIS trial, the most common adverse events (all grades in decreasing order of frequency) were peripheral and periorbital edema (60%), nausea (50%), muscle cramps (49%), musculoskeletal pain (47%), diarrhea (45%), rash (40%), fatigue (39%), abdominal pain (37%), headache (37%), and joint pain (31%). Grade 3/4 liver enzyme elevation can occur in 5% of patients.⁶ In the event of severe liver toxicity or fluid retention, imatinib should be held until the event resolves. At that time, imatinib can be restarted if deemed appropriate, but this is dependent on the severity of the inciting event. Fluid retention can be managed by the use of supportive care, diuretics, imatinib dose reduction, dose interruption, or imatinib discontinuation if the fluid retention is severe. Muscle cramps can be managed by the use of a calcium supplements or tonic water. Management of rash can include topical or systemic steroids, or in some cases imatinib dose reduction, interruption, or discontinuation.⁷

Grade 3/4 imatinib-induced hematologic toxicity is not uncommon, with 17% of patients experiencing neutropenia, 9% thrombocytopenia, and 4% anemia. These adverse events occurred most commonly during the first year of therapy, and the frequency decreased over time.^3,6 Depending on the degree of cytopenias, imatinib dosing should be interrupted until recovery of the absolute neutrophil count or platelet count, and can often be resumed at 400 mg daily. However, if cytopenias recur, imatinib should be held and subsequently restarted at 300 mg daily.⁷

Dasatinib

Dasatinib is a second-generation TKI that has regulatory approval for treatment of adult patients with newly diagnosed CP-CML or CP-CML in patients with resistance or intolerance to prior TKIs. In addition to dasatinib's ability to inhibit ABL kinases, it is also known to be a potent inhibitor of Src family kinases. Dasatinib has shown efficacy in patients who have developed imatinib-resistant ABL kinase domain mutations.

Dasatinib was initially approved as second-line therapy in patients with resistance or intolerance to imatinib. This indication was based on the results of the phase 3 CA180-034 trial which ultimately identified dasatinib 100 mg daily as the optimal dose. In this trial, 74% of patients enrolled had resistance to imatinib and the remainder were intolerant. The 7-year follow-up of patients randomized to dasatinib 100 mg (n = 167) daily indicated that 46% achieved MMR while on study. Of the 124 imatinib-resistant patients on dasatinib 100 mg daily, the 7-year progression-free survival (PFS) was 39% and OS was 63%. In the 43 imatinib-intolerant patients, the 7-year PFS was 51% and OS was 70%.⁸

Dasatinib 100 mg daily was compared to imatinib 400 mg daily in newly diagnosed CP-CML patients in the randomized phase 3 DASISION trial. More patients on the dasatinib arm achieved an early molecular response of BCR-ABL1 transcripts ≤10% IS after 3 months on treatment compared to imatinib (84% versus 64%). Furthermore, the 5-year follow-up reports that the cumulative incidence of MMR and MR4.5 in dasatinib-treated patients was 76% and 42%, and was 64% and 33%, with imatinib (P = 0.0022 and P = 0.0251, respectively). Fewer patients treated with dasatinib progressed to AP or BP (4.6%) compared to imatinib (7.3%), but the estimated 5-year OS was similar between the 2 arms (91% for dasatinib versus 90% for imatinib).⁹ Regulatory approval for dasatinib as first-line therapy in newly diagnosed CML patients was based on results of the DASISION trial.

Toxicity

Most dasatinib-related toxicities are reported as grade 1 or grade 2, but grade 3/4 hematologic adverse events are fairly common. In the DASISION trial, grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 29%, 13%, and 22% of dasatinib-treated patients, respectively. Cytopenias can generally be managed with temporary dose interruptions or dose reductions.

During the 5-year follow-up of the DASISION trial, pleural effusions were reported in 28% of patients, most of which were grade 1/2. This occurred at a rate of approximately ≤ 8% per year, suggesting a stable incidence over time, and the effusions appear to be dose-dependent.⁹ Depending on the severity of the effusion, this may be treated with diuretics, dose interruption, and in some instances, steroids or a thoracentesis. Typically, dasatinib can be restarted at 1 dose level lower than the previous dose once the effusion has resolved.⁷ Other, less common side effects of dasatinib include pulmonary hypertension (5% of patients), as well as abdominal pain, fluid retention, headaches, fatigue, musculoskeletal pain, rash, nausea, and diarrhea. Pulmonary hypertension is typically reversible after cessation of dasatinib, and thus dasatinib should be permanently discontinued once the diagnosis is confirmed. Fluid retention is often treated with diuretics and supportive care. Nausea and diarrhea are generally manageable and occur less frequently when dasatinib is taken with food and a large glass of water. Antiemetics and antidiarrheals can be used as needed. Troublesome rash can be best managed with topical or systemic steroids as well as possible dose reduction or dose interruption.^7,9 In the DASISION trial, adverse events led to therapy discontinuation more often in the dasatinib group than in the imatinib group (16% versus 7%).⁹ Bleeding, particularly in the setting of thrombocytopenia, has been reported in patients being treated with dasatinib as a result of the drug-induced reversible inhibition of platelet aggregation.¹⁰

Nilotinib

The structure of nilotinib is similar to that of imatinib; however, it has a markedly increased affinity for the ATP‐binding site on the BCR-ABL1 protein. It was initially given regulatory approval in the setting of imatinib failure. Nilotinib was studied at a dose of 400 mg twice daily in 321 patients who were imatinib-resistant or -intolerant. It proved to be highly effective at inducing cytogenetic remissions in the second-line setting, with 59% of patients achieving a major cytogenetic response (MCyR) and 45% achieving CCyR. With a median follow-up time of 4 years, the OS was 78%.¹¹

Nilotinib gained regulatory approval for use as a first-line TKI after completion of the randomized phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial. ENESTnd was a 3-arm study comparing nilotinib 300 mg twice daily versus nilotinib 400 mg twice daily versus imatinib 400 mg daily in newly diagnosed, previously untreated patients diagnosed with CP-CML. The primary endpoint of this clinical trial was rate of MMR at 12 months.¹² Nilotinib surpassed imatinib in this regard, with 44% of patients on nilotinib 300 mg twice daily achieving MMR at 12 months versus 43% of nilotinib 400 mg twice daily patients versus 22% of the imatinib-treated patients (P < 0.001 for both comparisons). Furthermore, the rate of CCyR by 12 months was significantly higher for both nilotinib arms compared with imatinib (80% for nilotinib 300 mg, 78% for nilotinib 400 mg, and 65% for imatinib) (P < 0.001).¹² Based on this data, nilotinib 300 mg twice daily was chosen as the standard dose of nilotinib in the first-line setting. After 5 years of follow-up on the ENESTnd study, there were fewer progressions to AP/BP CML in nilotinib-treated patients compared with imatinib. MMR was achieved in 77% of nilotinib 300 mg patients compared with 60.4% of patients on the imatinib arm. MR4.5 was also more common in patients treated with nilotinib 300 mg twice daily, with a rate of 53.5% at 5 years versus 31.4% in the imatinib arm.¹³ In spite of the deeper cytogenetic and molecular responses achieved with nilotinib, this did not translate into a significant improvement in OS. The 5-year OS rate was 93.7% in nilotinib 300 mg patients versus 91.7% in imatinib-treated patients, and this difference lacked statistical significance.¹³

Toxicity

Although some similarities exist between the toxicity profiles of nilotinib and imatinib, each drug has some distinct adverse events. On the ENESTnd trial, the rate of any grade 3/4 non-hematologic adverse event was fairly low; however, lower-grade toxicities were not uncommon. Patients treated with nilotinib 300 mg twice daily experienced rash (31%), headache (14%), pruritis (15%), and fatigue (11%) most commonly. The most frequently reported laboratory abnormalities included increased total bilirubin (53%), hypophosphatemia (32%), hyperglycemia (36%), elevated lipase (24%), increased alanine aminotransferase (ALT; 66%), and increased aspartate aminotransferase (AST; 40%). Any grade of neutropenia, thrombocytopenia, or anemia occurred at rates of 43%, 48%, and 38%, respectively.¹² Although nilotinib has a Black Box Warning from the US Food and Drug Administration for QT interval prolongation, no patients on the ENESTnd trial experienced a QT interval corrected for heart rate greater than 500 msec.¹²

More recent concerns have emerged regarding the potential for cardiovascular toxicity after long-term use of nilotinib. The 5-year update of ENESTnd reports cardiovascular events, including ischemic heart disease, ischemic cerebrovascular events, or peripheral arterial disease occurring in 7.5% of patients treated with nilotinib 300 mg twice daily compared with a rate of 2.1% in imatinib-treated patients. The frequency of these cardiovascular events increased linearly over time in both arms. Elevations in total cholesterol from baseline occurred in 27.6% of nilotinib patients compared with 3.9% of imatinib patients. Furthermore, clinically meaningful increases in low-density lipoprotein cholesterol and glycated hemoglobin occurred more frequently with nilotinib therapy.¹²

Nilotinib should be taken on an empty stomach; therefore, patients should be made aware of the need to fast for 2 hours prior to each dose and 1 hour after each dose. Given the potential risk of QT interval prolongation, a baseline electrocardiogram (ECG) is recommended prior to initiating treatment to ensure the QT interval is within a normal range. A repeat ECG should be done approximately 7 days after nilotinib initiation to ensure no prolongation of the QT interval after starting. Close monitoring of potassium and magnesium levels is important to decrease the risk of cardiac arrhythmias, and concomitant use of drugs considered strong CYP3A4 inhibitors should be avoided.⁷

If the patient experiences any grade 3 or higher laboratory abnormalities, nilotinib should be held until resolution of the toxicity, and then restarted at a lower dose. Similarly, if patients develop significant neutropenia or thrombocytopenia, nilotinib doses should be interrupted until resolution of the cytopenias. At that point, nilotinib can be reinitiated at either the same or a lower dose. Rash can be managed by the use of topical or systemic steroids as well as potential dose reduction, interruption, or discontinuation.

Given the concerns for potential cardiovascular events with long-term use of nilotinib, caution is advised when prescribing it to any patient with a history of cardiovascular disease or peripheral arterial occlusive disease. At the first sign of new occlusive disease, nilotinib should be discontinued.⁷

Bosutinib

Bosutinib is a second-generation BCR-ABL1 TKI with activity against the Src family of kinases that was initially approved to treat patients with CP-, AP-, or BP-CML after resistance or intolerance to imatinib. Long-term data has been reported from the phase 1/2 trial of bosutinib therapy in patients with CP-CML who developed resistance or intolerance to imatinib plus dasatinib and/or nilotinib. A total of 119 patients were included in the 4-year follow-up; 38 were resistant/intolerant to imatinib and resistant to dasatinib, 50 were resistant/intolerant to imatinib and intolerant to dasatinib, 26 were resistant/intolerant to imatinib and resistant to nilotinib, and 5 were resistant/intolerant to imatinib and intolerant to nilotinib or resistant/intolerant to dasatinib and nilotinib. Bosutinib 400 mg daily was studied in this setting. Of the 38 patients with imatinib resistance/intolerance and dasatinib resistance, 39% achieved MCyR, 22% achieved CCyR, and the OS was 67%. Of the 50 patients with imatinib resistance/intolerance and dasatinib intolerance, 42% achieved MCyR, 40% achieved CCyR, and the OS was 80%. Finally, in the 26 patients with imatinib resistance/intolerance and nilotinib resistance, 38% achieved MCyR, 31% achieved CcyR, and the OS was 87%.¹⁴

Five-year follow-up from the phase 1/2 clinical trial which studied bosutinib 500 mg daily in CP-CML patients after imatinib failure reported data on 284 patients. By 5 years on study, 60% of patients had achieved MCyR and 50% achieved CCyR with a 71% and 69% probability, respectively, of maintaining these responses at 5 years. The 5-year OS was 84%.¹⁵ These data led to the regulatory approval of bosutinib 500 mg daily as second-line or later therapy.

Bosutinib was initially studied in the first-line setting in the randomized phase 3 BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial. This trial compared bosutinib 500 mg daily to imatinib 400 mg daily in newly diagnosed, previously untreated CP-CML patients. This trial failed to meet its primary endpoint of increased rate of CCyR at 12 months, with 70% of bosutinib patients achieving this response compared to 68% of imatinib-treated patients (P = 0.601). In spite of this, the rate of MMR at 12 months was significantly higher in the bosutinib arm (41%) compared to the imatinib arm (27%; P = 0.001).¹⁶

A second phase 3 trial (BFORE) was designed to study bosutinib 400 mg daily versus imatinib in newly diagnosed, previously untreated CP-CML patients. This study enrolled 536 patients who were randomly assigned 1:1 to bosutinib versus imatinib. The primary endpoint of this trial was rate of MMR at 12 months. A significantly higher number of bosutinib-treated patients achieved this response (47.2%) compared with imatinib-treated patients (36.9%, P = 0.02). Furthermore, by 12 months 77.2% of patients on the bosutinib arm had achieved CCyR compared with 66.4% on the imatinib arm, and this difference did meet statistical significance (P = 0.0075). A lower rate of progression to AP- or BP-CML was noted in bosutinib-treated patients as well (1.6% versus 2.5%). Based on this data, bosutinib gained regulatory approval for first-line therapy in CP-CML at a dose of 400 mg daily.¹⁷

Toxicity

On the BFORE trial, the most common treatment-emergent adverse events of any grade reported in the bosutinib-treated patients were diarrhea (70.1%), nausea (35.1%), increased ALT (30.6%), and increased AST (22.8%). Musculoskeletal pain or spasms occurred in 29.5% of patients, rash in 19.8%, fatigue in 19.4%, and headache in 18.7%. Hematologic toxicity was also reported, but most was grade 1/2. Thrombocytopenia was reported in 35.1%, anemia in 18.7%, and neutropenia in 11.2%.¹⁷

Cardiovascular events occurred in 5.2% of patients on the bosutinib arm of the BFORE trial, which was similar to the rate observed in imatinib patients. The most common cardiovascular event was QT interval prolongation, which occurred in 1.5% of patients. Pleural effusions were reported in 1.9% of patients treated with bosutinib, and none were grade 3 or higher.¹⁷

If liver enzyme elevation occurs at a value greater than 5 times the institutional upper limit of normal, bosutinib should be held until the level recovers to ≤2.5 times the upper limit of normal, at which point bosutinib can be restarted at a lower dose. If recovery takes longer than 4 weeks, bosutinib should be permanently discontinued. Liver enzymes elevated greater than 3 times the institutional upper limit of normal and a concurrent elevation in total bilirubin to 2 times the upper limit of normal is consistent with Hy's law, and bosutinib should be discontinued. Although diarrhea is the most common toxicity associated with bosutinib, it is commonly low grade and transient. Diarrhea occurs most frequently in the first few days after initiating bosutinib. It can often be managed with over-the-counter antidiarrheal medications, but if the diarrhea is grade or higher, bosutinib should be held until recovery to grade 1 or lower. Gastrointestinal side effects may be improved by taking bosutinib with a meal and a large glass of water. Fluid retention can be managed with diuretics and supportive care. Finally, if rash occurs, this can be addressed with topical or systemic steroids as well as bosutinib dose reduction, interruption, or discontinuation.⁷

Similar to other TKIs, if bosutinib-induced cytopenias occur, treatment should be held and restarted at the same or a lower dose upon blood count recovery.⁷

Ponatinib

The most common cause of TKI resistance in CP-CML is the development of ABL kinase domain mutations. The majority of imatinib-resistant mutations can be overcome by the use of second-generation TKIs including dasatinib, nilotinib, or bosutinib. However, ponatinib is the only BCR-ABL1 TKI able to overcome a T315I mutation. The phase 2 PACE (Ponatinib Ph-positive ALL and CML Evaluation) trial enrolled patients with CP-, AP-, or BP-CML as well as patients with Ph-positive acute lymphoblastic leukemia who were resistant or intolerant to nilotinib or dasatinib, or who had evidence of a T315I mutation. The starting dose of ponatinib on this trial was 45 mg daily.¹⁸ The PACE trial enrolled 267 patients with CP-CML: 203 with resistance or intolerance to nilotinib or dasatinib, and 64 with a T315I mutation. The primary endpoint in the CP cohort was rate of MCyR at any time within 12 months of starting ponatinib. The overall rate of MCyR by 12 months in the CP-CML patients was 56%. In those with a T315I mutation, 70% achieved MCyR, which compared favorably with those with resistance or intolerance to nilotinib or dasatinib, 51% of whom achieved MCyR. CCyR was achieved in 46% of CP-CML patients (40% in the resistant/intolerant cohort and 66% in the T315I cohort). In general, patients with T315I mutations received fewer prior therapies than those in the resistant/intolerant cohort, which likely contributed to the higher response rates in the T315I patients. MR4.5 was achieved in 15% of CP-CML patients by 12 months on the PACE trial.¹⁸ The 5-year update to this study reported that 60%, 40%, and 24% of CP-CML patients achieved MCyR, MMR, and MR4.5, respectively. In the patients who achieved MCyR, the probability of maintaining this response for 5 years was 82% and the estimated 5-year OS was 73%.¹⁹

Toxicity

In 2013, after the regulatory approval of ponatinib, reports became available that the drug can cause an increase in arterial occlusive events including fatal myocardial infarctions and cerebral vascular accidents. For this reason, dose reductions were implemented in patients who were deriving clinical benefit from ponatinib. In spite of these dose reductions, ≥90% of responders maintained their response for up to 40 months.¹⁹ Although the likelihood of developing an arterial occlusive event appears higher in the first year after starting ponatinib than in later years, the cumulative incidence of events continues to increase. The 5-year follow-up to the PACE trial reports 31% of patients experiencing any grade of arterial occlusive event while on ponatinib. Aside from these events, the most common treatment-emergent adverse events in ponatinib-treated patients on the PACE trial included rash (47%), abdominal pain (46%), headache (43%), dry skin (42%), constipation (41%), and hypertension (37%). Hematologic toxicity was also common, with 46% of patients experiencing any grade of thrombocytopenia, 20% experiencing neutropenia, and 20% anemia.¹⁹

Patients receiving ponatinib therapy should be monitored closely for any evidence of arterial or venous thrombosis. In the event of an occlusive event, ponatinib should be discontinued. Similarly, in the setting of any new or worsening heart failure symptoms, ponatinib should be promptly discontinued. Management of any underlying cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, or smoking history is recommended, and these patients should be referred to a cardiologist for a full evaluation. In the absence of any contraindications to aspirin, low-dose aspirin should be considered as a means of decreasing cardiovascular risks associated with ponatinib. In patients with known risk factors, a ponatinib starting dose of 30 mg daily rather than the standard 45 mg daily may be a safer option resulting in fewer arterial occlusive events, although the efficacy of this dose is still being studied in comparison to 45 mg daily.⁷

In the event of ponatinib-induced transaminitis greater than 3 times the upper limit of normal, ponatinib should be held until resolution to less than 3 times the upper limit of normal, at which point it should be resumed at a lower dose. Similarly, in the setting of elevated serum lipase or symptomatic pancreatitis, ponatinib should be held and restarted at a lower dose after resolution of symptoms.⁷

In the event of neutropenia or thrombocytopenia, ponatinib should be held until blood count recovery and then restarted at the same dose. If cytopenias occur for a second time, the dose of ponatinib should be lowered at the time of treatment reinitiation. If rash occurs, it can be addressed with topical or systemic steroids as well as dose reduction, interruption, or discontinuation.⁷

Case Conclusion

Given the patient's high-risk Sokal score, ideal first-line treatment is a second-generation TKI in order to increase the likelihood of achieving the desired treatment milestones and improving long-term outcomes. Her history of uncontrolled diabetes and coronary artery disease raises concerns for using nilotinib. Furthermore, her history of COPD makes dasatinib suboptimal because she would have little pulmonary reserve if she were to develop a pleural effusion. For this reason, bosutinib 400 mg daily is chosen as her first-line TKI. Shortly after starting bosutinib, she experiences diarrhea that occurs approximately 3 or 4 times daily during the first week on treatment. She is able to manage this with over-the-counter loperamide and the diarrhea resolves shortly thereafter.

After 3 months of bosutinib therapy, quantitative real-time PCR (RQ-PCR) assay on peripheral blood is done to measure BCR-ABL1 transcripts, and the result is reported at 1.2% IS. This indicates that the patient has achieved an early molecular response, which is defined as a RQ-PCR value of ≤10% IS. She undergoes RQ-PCR monitoring every 3 months, and at 12 months her results indicate a value of 0.07% IS, suggesting she has achieved a MMR.

Conclusion

With the development of imatinib and the subsequent TKIs, dasatinib, nilotinib, bosutinib, and ponatinib, CP-CML has become a chronic disease with a life-expectancy that is similar to the general population. Given the successful treatments available for these patients, it is crucial to identify patients with this diagnosis, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated. This is the only way to be certain patients are achieving the desired treatment milestones that correlate with the favorable long-term outcomes that have been observed with TKI-based treatment of CP-CML.

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17. Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol. 2018;36:231-237.

18. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369:1783-1796.

19. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132:393-404.

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Hospital Physician: Hematology/Oncology - 14(1)

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Hospital Physician: Hematology/Oncology

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Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22, t(9;22)(q34;q11.2) (the Philadelphia chromosome), resulting in the generation of the BCR-ABL1 fusion gene and its protein product, BCR-ABL tyrosine kinase. BCR-ABL is a constitutively active fusion kinase that confers proliferative and survival advantage to hematopoietic cells through activation of downstream pathways.

CML is divided into 3 phases based on the number of myeloblasts observed in the blood or bone marrow: chronic, accelerated, and blast. Most cases of CML are diagnosed in the chronic phase (CP), which is marked by proliferation of primarily the myeloid element.

The advent of tyrosine kinase inhibitors (TKIs), a class of small molecules targeting the tyrosine kinases, particularly the BCR-ABL tyrosine kinase, led to rapid changes in the management of CML and improved survival for patients. Patients diagnosed with CP-CML now a have life-expectancy that is similar to that of the general population, as long as they receive the appropriate TKI therapy and adhere to treatment. As such, it is crucial to identify patients with CML, ensure they receive a complete, appropriate diagnostic work-up, and select the best therapy for each individual patient. The diagnosis and work-up of CML are reviewed in a separate article; here, the selection of TKI therapy for a patient with newly diagnosed CP-CML is reviewed.

Case Presentation

A 53-year-old woman who recently was diagnosed with CML presents to review her treatment options. The diagnosis was made after she presented to her primary care physician with fatigue, early satiety, left upper quadrant abdominal pain, and an 8-lb unintentional weight loss over the prior month. On physical exam her spleen was palpated 8 cm below the left costal margin. Laboratory evaluation showed a total white blood cell (WBC) count of 124,000/μL with a left-shifted differential including 6% basophils, 3% eosinophils, and 3% blasts; hemoglobin and platelet count were 12.4 g/dL and 801 × 10³/µL, respectively. Fluorescent in-situ hybridization for BCR-ABL gene rearrangement using peripheral blood was positive in 87% of cells. Bone marrow biopsy and aspiration showed a 95% cellular bone marrow with granulocytic hyperplasia and 1% blasts. Cytogenetics were 46,XX,t(9;22)(q34;q11.2), and quantitative real-time polymerase chain reaction (RQ-PCR) to measure BCR-ABL1 transcripts in the peripheral blood showed a value of 98% international standard (IS). Her Sokal risk score was 1.42 (high risk). In addition, prior review of her past medical history revealed uncontrolled diabetes, coronary artery disease requiring placement of 3 cardiac stents 2 years prior, and chronic obstructive pulmonary disease (COPD) related to a 30-pack-year history of smoking.

What factors must be considered when selecting first-line therapy for this patient?

Selection of the most appropriate first-line TKI for newly diagnosed CP-CML patients requires incorporation of many patient-specific factors. These factors include baseline karyotype and confirmation of CP-CML through bone marrow biopsy, Sokal or EURO risk score, and a thorough patient history, including a clear understanding of the patient's comorbidities. In this case, the patient's high Sokal risk score along with her history of diabetes, coronary artery disease, and COPD are all factors that must be accounted for when choosing the most appropriate TKI. The adverse effect profile of all TKIs must be considered in conjunction with the patient's ongoing medical issues in order to decrease the likelihood of worsening her current symptoms or causing a severe complication from TKI therapy.

Imatinib

The management of CML was revolutionized by the development and ultimate regulatory approval of imatinib mesylate in 2001. Imatinib was the first small-molecule cancer therapy developed and approved. It acts by binding to the adenosine triphosphate (ATP) binding site in the catalytic domain of BCR-ABL, thus inhibiting the oncoprotein's tyrosine kinase activity.¹

The International Randomized Study of Interferon versus STI571 (IRIS) trial was a randomized phase 3 study that compared imatinib 400 mg daily to interferon α (IFNα) plus cytarabine. More than 1000 CP-CML patients were randomly assigned 1:1 to either imatinib or IFNα plus cytarabine and were assessed for event-free survival, hematologic and cytogenetic responses, freedom from progression to accelerated phase (AP) or blast phase (BP), and toxicity. Imatinib was superior to the prior standard of care for all these outcomes.² The long-term follow up of the IRIS trial reported an 83% estimated 10-year overall survival (OS) and 79% estimated event-free survival for patients on the imatinib arm of this study.³ The cumulative rate of complete cytogenetic response (CCyR) was 82.8%. Of the 204 imatinib-treated patients who could undergo a molecular response evaluation at 10 years, 93.1% had a major molecular response (MMR) and 63.2% had a molecular response 4.5 (MR4.5), suggesting durable, deep molecular responses for many patients (see Chronic Myeloid Leukemia: Evaluation and Diagnosis for discussion of the hematologic parameters, cytogenetic results, and molecular responses ussed in monitoring response to TKI therapy). The estimated 10-year rate of freedom from progression to AP or BP was 92.1%.

Higher doses of imatinib (600-800 mg daily) have been studied in an attempt to overcome resistance and improve cytogenetic and molecular response rates. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was a randomized phase 3 study that compared imatinib 800 mg daily to imatinib 400 mg daily. Although the 6-month assessments found increased rates of CCyR and a MMR in the higher-dose imatinib arm, these differences were no longer present at the 12-month assessment. Furthermore, the higher dose of imatinib led to a significantly higher incidence of grade 3/4 hematologic adverse events, and approximately 50% of patients on imatinib 800 mg daily required a dose reduction to less than 600 mg daily because of toxicity.⁴

The Therapeutic Intensification in De Novo Leukaemia (TIDEL) -II study used plasma trough levels of imatinib on day 22 of treatment with imatinib 600 mg daily to determine if patients should escalate the imatinib dose to 800 mg daily. In patients who did not meet molecular milestones at 3, 6, or 12 months, cohort 1 was dose escalated to imatinib 800 mg daily and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later, and cohort 2 was switched to nilotinib. At 2 years, 73% of patients achieved MMR and 34% achieved MR4.5, suggesting that initial treatment with higher-dose imatinib subsequently followed by a switch to nilotinib in those failing to achieve desired milestones could be an effective strategy for managing newly diagnosed CP-CML.⁵

Toxicity

Imatinib 400 mg is considered the standard starting dose in CP-CML patients. The safety profile of imatinib has been very well established. In the IRIS trial, the most common adverse events (all grades in decreasing order of frequency) were peripheral and periorbital edema (60%), nausea (50%), muscle cramps (49%), musculoskeletal pain (47%), diarrhea (45%), rash (40%), fatigue (39%), abdominal pain (37%), headache (37%), and joint pain (31%). Grade 3/4 liver enzyme elevation can occur in 5% of patients.⁶ In the event of severe liver toxicity or fluid retention, imatinib should be held until the event resolves. At that time, imatinib can be restarted if deemed appropriate, but this is dependent on the severity of the inciting event. Fluid retention can be managed by the use of supportive care, diuretics, imatinib dose reduction, dose interruption, or imatinib discontinuation if the fluid retention is severe. Muscle cramps can be managed by the use of a calcium supplements or tonic water. Management of rash can include topical or systemic steroids, or in some cases imatinib dose reduction, interruption, or discontinuation.⁷

Grade 3/4 imatinib-induced hematologic toxicity is not uncommon, with 17% of patients experiencing neutropenia, 9% thrombocytopenia, and 4% anemia. These adverse events occurred most commonly during the first year of therapy, and the frequency decreased over time.^3,6 Depending on the degree of cytopenias, imatinib dosing should be interrupted until recovery of the absolute neutrophil count or platelet count, and can often be resumed at 400 mg daily. However, if cytopenias recur, imatinib should be held and subsequently restarted at 300 mg daily.⁷

Dasatinib

Dasatinib is a second-generation TKI that has regulatory approval for treatment of adult patients with newly diagnosed CP-CML or CP-CML in patients with resistance or intolerance to prior TKIs. In addition to dasatinib's ability to inhibit ABL kinases, it is also known to be a potent inhibitor of Src family kinases. Dasatinib has shown efficacy in patients who have developed imatinib-resistant ABL kinase domain mutations.

Dasatinib was initially approved as second-line therapy in patients with resistance or intolerance to imatinib. This indication was based on the results of the phase 3 CA180-034 trial which ultimately identified dasatinib 100 mg daily as the optimal dose. In this trial, 74% of patients enrolled had resistance to imatinib and the remainder were intolerant. The 7-year follow-up of patients randomized to dasatinib 100 mg (n = 167) daily indicated that 46% achieved MMR while on study. Of the 124 imatinib-resistant patients on dasatinib 100 mg daily, the 7-year progression-free survival (PFS) was 39% and OS was 63%. In the 43 imatinib-intolerant patients, the 7-year PFS was 51% and OS was 70%.⁸

Dasatinib 100 mg daily was compared to imatinib 400 mg daily in newly diagnosed CP-CML patients in the randomized phase 3 DASISION trial. More patients on the dasatinib arm achieved an early molecular response of BCR-ABL1 transcripts ≤10% IS after 3 months on treatment compared to imatinib (84% versus 64%). Furthermore, the 5-year follow-up reports that the cumulative incidence of MMR and MR4.5 in dasatinib-treated patients was 76% and 42%, and was 64% and 33%, with imatinib (P = 0.0022 and P = 0.0251, respectively). Fewer patients treated with dasatinib progressed to AP or BP (4.6%) compared to imatinib (7.3%), but the estimated 5-year OS was similar between the 2 arms (91% for dasatinib versus 90% for imatinib).⁹ Regulatory approval for dasatinib as first-line therapy in newly diagnosed CML patients was based on results of the DASISION trial.

Toxicity

Most dasatinib-related toxicities are reported as grade 1 or grade 2, but grade 3/4 hematologic adverse events are fairly common. In the DASISION trial, grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 29%, 13%, and 22% of dasatinib-treated patients, respectively. Cytopenias can generally be managed with temporary dose interruptions or dose reductions.

During the 5-year follow-up of the DASISION trial, pleural effusions were reported in 28% of patients, most of which were grade 1/2. This occurred at a rate of approximately ≤ 8% per year, suggesting a stable incidence over time, and the effusions appear to be dose-dependent.⁹ Depending on the severity of the effusion, this may be treated with diuretics, dose interruption, and in some instances, steroids or a thoracentesis. Typically, dasatinib can be restarted at 1 dose level lower than the previous dose once the effusion has resolved.⁷ Other, less common side effects of dasatinib include pulmonary hypertension (5% of patients), as well as abdominal pain, fluid retention, headaches, fatigue, musculoskeletal pain, rash, nausea, and diarrhea. Pulmonary hypertension is typically reversible after cessation of dasatinib, and thus dasatinib should be permanently discontinued once the diagnosis is confirmed. Fluid retention is often treated with diuretics and supportive care. Nausea and diarrhea are generally manageable and occur less frequently when dasatinib is taken with food and a large glass of water. Antiemetics and antidiarrheals can be used as needed. Troublesome rash can be best managed with topical or systemic steroids as well as possible dose reduction or dose interruption.^7,9 In the DASISION trial, adverse events led to therapy discontinuation more often in the dasatinib group than in the imatinib group (16% versus 7%).⁹ Bleeding, particularly in the setting of thrombocytopenia, has been reported in patients being treated with dasatinib as a result of the drug-induced reversible inhibition of platelet aggregation.¹⁰

Nilotinib

The structure of nilotinib is similar to that of imatinib; however, it has a markedly increased affinity for the ATP‐binding site on the BCR-ABL1 protein. It was initially given regulatory approval in the setting of imatinib failure. Nilotinib was studied at a dose of 400 mg twice daily in 321 patients who were imatinib-resistant or -intolerant. It proved to be highly effective at inducing cytogenetic remissions in the second-line setting, with 59% of patients achieving a major cytogenetic response (MCyR) and 45% achieving CCyR. With a median follow-up time of 4 years, the OS was 78%.¹¹

Nilotinib gained regulatory approval for use as a first-line TKI after completion of the randomized phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial. ENESTnd was a 3-arm study comparing nilotinib 300 mg twice daily versus nilotinib 400 mg twice daily versus imatinib 400 mg daily in newly diagnosed, previously untreated patients diagnosed with CP-CML. The primary endpoint of this clinical trial was rate of MMR at 12 months.¹² Nilotinib surpassed imatinib in this regard, with 44% of patients on nilotinib 300 mg twice daily achieving MMR at 12 months versus 43% of nilotinib 400 mg twice daily patients versus 22% of the imatinib-treated patients (P < 0.001 for both comparisons). Furthermore, the rate of CCyR by 12 months was significantly higher for both nilotinib arms compared with imatinib (80% for nilotinib 300 mg, 78% for nilotinib 400 mg, and 65% for imatinib) (P < 0.001).¹² Based on this data, nilotinib 300 mg twice daily was chosen as the standard dose of nilotinib in the first-line setting. After 5 years of follow-up on the ENESTnd study, there were fewer progressions to AP/BP CML in nilotinib-treated patients compared with imatinib. MMR was achieved in 77% of nilotinib 300 mg patients compared with 60.4% of patients on the imatinib arm. MR4.5 was also more common in patients treated with nilotinib 300 mg twice daily, with a rate of 53.5% at 5 years versus 31.4% in the imatinib arm.¹³ In spite of the deeper cytogenetic and molecular responses achieved with nilotinib, this did not translate into a significant improvement in OS. The 5-year OS rate was 93.7% in nilotinib 300 mg patients versus 91.7% in imatinib-treated patients, and this difference lacked statistical significance.¹³

Toxicity

Although some similarities exist between the toxicity profiles of nilotinib and imatinib, each drug has some distinct adverse events. On the ENESTnd trial, the rate of any grade 3/4 non-hematologic adverse event was fairly low; however, lower-grade toxicities were not uncommon. Patients treated with nilotinib 300 mg twice daily experienced rash (31%), headache (14%), pruritis (15%), and fatigue (11%) most commonly. The most frequently reported laboratory abnormalities included increased total bilirubin (53%), hypophosphatemia (32%), hyperglycemia (36%), elevated lipase (24%), increased alanine aminotransferase (ALT; 66%), and increased aspartate aminotransferase (AST; 40%). Any grade of neutropenia, thrombocytopenia, or anemia occurred at rates of 43%, 48%, and 38%, respectively.¹² Although nilotinib has a Black Box Warning from the US Food and Drug Administration for QT interval prolongation, no patients on the ENESTnd trial experienced a QT interval corrected for heart rate greater than 500 msec.¹²

More recent concerns have emerged regarding the potential for cardiovascular toxicity after long-term use of nilotinib. The 5-year update of ENESTnd reports cardiovascular events, including ischemic heart disease, ischemic cerebrovascular events, or peripheral arterial disease occurring in 7.5% of patients treated with nilotinib 300 mg twice daily compared with a rate of 2.1% in imatinib-treated patients. The frequency of these cardiovascular events increased linearly over time in both arms. Elevations in total cholesterol from baseline occurred in 27.6% of nilotinib patients compared with 3.9% of imatinib patients. Furthermore, clinically meaningful increases in low-density lipoprotein cholesterol and glycated hemoglobin occurred more frequently with nilotinib therapy.¹²

Nilotinib should be taken on an empty stomach; therefore, patients should be made aware of the need to fast for 2 hours prior to each dose and 1 hour after each dose. Given the potential risk of QT interval prolongation, a baseline electrocardiogram (ECG) is recommended prior to initiating treatment to ensure the QT interval is within a normal range. A repeat ECG should be done approximately 7 days after nilotinib initiation to ensure no prolongation of the QT interval after starting. Close monitoring of potassium and magnesium levels is important to decrease the risk of cardiac arrhythmias, and concomitant use of drugs considered strong CYP3A4 inhibitors should be avoided.⁷

If the patient experiences any grade 3 or higher laboratory abnormalities, nilotinib should be held until resolution of the toxicity, and then restarted at a lower dose. Similarly, if patients develop significant neutropenia or thrombocytopenia, nilotinib doses should be interrupted until resolution of the cytopenias. At that point, nilotinib can be reinitiated at either the same or a lower dose. Rash can be managed by the use of topical or systemic steroids as well as potential dose reduction, interruption, or discontinuation.

Given the concerns for potential cardiovascular events with long-term use of nilotinib, caution is advised when prescribing it to any patient with a history of cardiovascular disease or peripheral arterial occlusive disease. At the first sign of new occlusive disease, nilotinib should be discontinued.⁷

Bosutinib

Bosutinib is a second-generation BCR-ABL1 TKI with activity against the Src family of kinases that was initially approved to treat patients with CP-, AP-, or BP-CML after resistance or intolerance to imatinib. Long-term data has been reported from the phase 1/2 trial of bosutinib therapy in patients with CP-CML who developed resistance or intolerance to imatinib plus dasatinib and/or nilotinib. A total of 119 patients were included in the 4-year follow-up; 38 were resistant/intolerant to imatinib and resistant to dasatinib, 50 were resistant/intolerant to imatinib and intolerant to dasatinib, 26 were resistant/intolerant to imatinib and resistant to nilotinib, and 5 were resistant/intolerant to imatinib and intolerant to nilotinib or resistant/intolerant to dasatinib and nilotinib. Bosutinib 400 mg daily was studied in this setting. Of the 38 patients with imatinib resistance/intolerance and dasatinib resistance, 39% achieved MCyR, 22% achieved CCyR, and the OS was 67%. Of the 50 patients with imatinib resistance/intolerance and dasatinib intolerance, 42% achieved MCyR, 40% achieved CCyR, and the OS was 80%. Finally, in the 26 patients with imatinib resistance/intolerance and nilotinib resistance, 38% achieved MCyR, 31% achieved CcyR, and the OS was 87%.¹⁴

Five-year follow-up from the phase 1/2 clinical trial which studied bosutinib 500 mg daily in CP-CML patients after imatinib failure reported data on 284 patients. By 5 years on study, 60% of patients had achieved MCyR and 50% achieved CCyR with a 71% and 69% probability, respectively, of maintaining these responses at 5 years. The 5-year OS was 84%.¹⁵ These data led to the regulatory approval of bosutinib 500 mg daily as second-line or later therapy.

Bosutinib was initially studied in the first-line setting in the randomized phase 3 BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial. This trial compared bosutinib 500 mg daily to imatinib 400 mg daily in newly diagnosed, previously untreated CP-CML patients. This trial failed to meet its primary endpoint of increased rate of CCyR at 12 months, with 70% of bosutinib patients achieving this response compared to 68% of imatinib-treated patients (P = 0.601). In spite of this, the rate of MMR at 12 months was significantly higher in the bosutinib arm (41%) compared to the imatinib arm (27%; P = 0.001).¹⁶

A second phase 3 trial (BFORE) was designed to study bosutinib 400 mg daily versus imatinib in newly diagnosed, previously untreated CP-CML patients. This study enrolled 536 patients who were randomly assigned 1:1 to bosutinib versus imatinib. The primary endpoint of this trial was rate of MMR at 12 months. A significantly higher number of bosutinib-treated patients achieved this response (47.2%) compared with imatinib-treated patients (36.9%, P = 0.02). Furthermore, by 12 months 77.2% of patients on the bosutinib arm had achieved CCyR compared with 66.4% on the imatinib arm, and this difference did meet statistical significance (P = 0.0075). A lower rate of progression to AP- or BP-CML was noted in bosutinib-treated patients as well (1.6% versus 2.5%). Based on this data, bosutinib gained regulatory approval for first-line therapy in CP-CML at a dose of 400 mg daily.¹⁷

Toxicity

On the BFORE trial, the most common treatment-emergent adverse events of any grade reported in the bosutinib-treated patients were diarrhea (70.1%), nausea (35.1%), increased ALT (30.6%), and increased AST (22.8%). Musculoskeletal pain or spasms occurred in 29.5% of patients, rash in 19.8%, fatigue in 19.4%, and headache in 18.7%. Hematologic toxicity was also reported, but most was grade 1/2. Thrombocytopenia was reported in 35.1%, anemia in 18.7%, and neutropenia in 11.2%.¹⁷

Cardiovascular events occurred in 5.2% of patients on the bosutinib arm of the BFORE trial, which was similar to the rate observed in imatinib patients. The most common cardiovascular event was QT interval prolongation, which occurred in 1.5% of patients. Pleural effusions were reported in 1.9% of patients treated with bosutinib, and none were grade 3 or higher.¹⁷

If liver enzyme elevation occurs at a value greater than 5 times the institutional upper limit of normal, bosutinib should be held until the level recovers to ≤2.5 times the upper limit of normal, at which point bosutinib can be restarted at a lower dose. If recovery takes longer than 4 weeks, bosutinib should be permanently discontinued. Liver enzymes elevated greater than 3 times the institutional upper limit of normal and a concurrent elevation in total bilirubin to 2 times the upper limit of normal is consistent with Hy's law, and bosutinib should be discontinued. Although diarrhea is the most common toxicity associated with bosutinib, it is commonly low grade and transient. Diarrhea occurs most frequently in the first few days after initiating bosutinib. It can often be managed with over-the-counter antidiarrheal medications, but if the diarrhea is grade or higher, bosutinib should be held until recovery to grade 1 or lower. Gastrointestinal side effects may be improved by taking bosutinib with a meal and a large glass of water. Fluid retention can be managed with diuretics and supportive care. Finally, if rash occurs, this can be addressed with topical or systemic steroids as well as bosutinib dose reduction, interruption, or discontinuation.⁷

Similar to other TKIs, if bosutinib-induced cytopenias occur, treatment should be held and restarted at the same or a lower dose upon blood count recovery.⁷

Ponatinib

The most common cause of TKI resistance in CP-CML is the development of ABL kinase domain mutations. The majority of imatinib-resistant mutations can be overcome by the use of second-generation TKIs including dasatinib, nilotinib, or bosutinib. However, ponatinib is the only BCR-ABL1 TKI able to overcome a T315I mutation. The phase 2 PACE (Ponatinib Ph-positive ALL and CML Evaluation) trial enrolled patients with CP-, AP-, or BP-CML as well as patients with Ph-positive acute lymphoblastic leukemia who were resistant or intolerant to nilotinib or dasatinib, or who had evidence of a T315I mutation. The starting dose of ponatinib on this trial was 45 mg daily.¹⁸ The PACE trial enrolled 267 patients with CP-CML: 203 with resistance or intolerance to nilotinib or dasatinib, and 64 with a T315I mutation. The primary endpoint in the CP cohort was rate of MCyR at any time within 12 months of starting ponatinib. The overall rate of MCyR by 12 months in the CP-CML patients was 56%. In those with a T315I mutation, 70% achieved MCyR, which compared favorably with those with resistance or intolerance to nilotinib or dasatinib, 51% of whom achieved MCyR. CCyR was achieved in 46% of CP-CML patients (40% in the resistant/intolerant cohort and 66% in the T315I cohort). In general, patients with T315I mutations received fewer prior therapies than those in the resistant/intolerant cohort, which likely contributed to the higher response rates in the T315I patients. MR4.5 was achieved in 15% of CP-CML patients by 12 months on the PACE trial.¹⁸ The 5-year update to this study reported that 60%, 40%, and 24% of CP-CML patients achieved MCyR, MMR, and MR4.5, respectively. In the patients who achieved MCyR, the probability of maintaining this response for 5 years was 82% and the estimated 5-year OS was 73%.¹⁹

Toxicity

In 2013, after the regulatory approval of ponatinib, reports became available that the drug can cause an increase in arterial occlusive events including fatal myocardial infarctions and cerebral vascular accidents. For this reason, dose reductions were implemented in patients who were deriving clinical benefit from ponatinib. In spite of these dose reductions, ≥90% of responders maintained their response for up to 40 months.¹⁹ Although the likelihood of developing an arterial occlusive event appears higher in the first year after starting ponatinib than in later years, the cumulative incidence of events continues to increase. The 5-year follow-up to the PACE trial reports 31% of patients experiencing any grade of arterial occlusive event while on ponatinib. Aside from these events, the most common treatment-emergent adverse events in ponatinib-treated patients on the PACE trial included rash (47%), abdominal pain (46%), headache (43%), dry skin (42%), constipation (41%), and hypertension (37%). Hematologic toxicity was also common, with 46% of patients experiencing any grade of thrombocytopenia, 20% experiencing neutropenia, and 20% anemia.¹⁹

Patients receiving ponatinib therapy should be monitored closely for any evidence of arterial or venous thrombosis. In the event of an occlusive event, ponatinib should be discontinued. Similarly, in the setting of any new or worsening heart failure symptoms, ponatinib should be promptly discontinued. Management of any underlying cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, or smoking history is recommended, and these patients should be referred to a cardiologist for a full evaluation. In the absence of any contraindications to aspirin, low-dose aspirin should be considered as a means of decreasing cardiovascular risks associated with ponatinib. In patients with known risk factors, a ponatinib starting dose of 30 mg daily rather than the standard 45 mg daily may be a safer option resulting in fewer arterial occlusive events, although the efficacy of this dose is still being studied in comparison to 45 mg daily.⁷

In the event of ponatinib-induced transaminitis greater than 3 times the upper limit of normal, ponatinib should be held until resolution to less than 3 times the upper limit of normal, at which point it should be resumed at a lower dose. Similarly, in the setting of elevated serum lipase or symptomatic pancreatitis, ponatinib should be held and restarted at a lower dose after resolution of symptoms.⁷

In the event of neutropenia or thrombocytopenia, ponatinib should be held until blood count recovery and then restarted at the same dose. If cytopenias occur for a second time, the dose of ponatinib should be lowered at the time of treatment reinitiation. If rash occurs, it can be addressed with topical or systemic steroids as well as dose reduction, interruption, or discontinuation.⁷

Case Conclusion

Given the patient's high-risk Sokal score, ideal first-line treatment is a second-generation TKI in order to increase the likelihood of achieving the desired treatment milestones and improving long-term outcomes. Her history of uncontrolled diabetes and coronary artery disease raises concerns for using nilotinib. Furthermore, her history of COPD makes dasatinib suboptimal because she would have little pulmonary reserve if she were to develop a pleural effusion. For this reason, bosutinib 400 mg daily is chosen as her first-line TKI. Shortly after starting bosutinib, she experiences diarrhea that occurs approximately 3 or 4 times daily during the first week on treatment. She is able to manage this with over-the-counter loperamide and the diarrhea resolves shortly thereafter.

After 3 months of bosutinib therapy, quantitative real-time PCR (RQ-PCR) assay on peripheral blood is done to measure BCR-ABL1 transcripts, and the result is reported at 1.2% IS. This indicates that the patient has achieved an early molecular response, which is defined as a RQ-PCR value of ≤10% IS. She undergoes RQ-PCR monitoring every 3 months, and at 12 months her results indicate a value of 0.07% IS, suggesting she has achieved a MMR.

Conclusion

With the development of imatinib and the subsequent TKIs, dasatinib, nilotinib, bosutinib, and ponatinib, CP-CML has become a chronic disease with a life-expectancy that is similar to the general population. Given the successful treatments available for these patients, it is crucial to identify patients with this diagnosis, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated. This is the only way to be certain patients are achieving the desired treatment milestones that correlate with the favorable long-term outcomes that have been observed with TKI-based treatment of CP-CML.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22, t(9;22)(q34;q11.2) (the Philadelphia chromosome), resulting in the generation of the BCR-ABL1 fusion gene and its protein product, BCR-ABL tyrosine kinase. BCR-ABL is a constitutively active fusion kinase that confers proliferative and survival advantage to hematopoietic cells through activation of downstream pathways.

CML is divided into 3 phases based on the number of myeloblasts observed in the blood or bone marrow: chronic, accelerated, and blast. Most cases of CML are diagnosed in the chronic phase (CP), which is marked by proliferation of primarily the myeloid element.

The advent of tyrosine kinase inhibitors (TKIs), a class of small molecules targeting the tyrosine kinases, particularly the BCR-ABL tyrosine kinase, led to rapid changes in the management of CML and improved survival for patients. Patients diagnosed with CP-CML now a have life-expectancy that is similar to that of the general population, as long as they receive the appropriate TKI therapy and adhere to treatment. As such, it is crucial to identify patients with CML, ensure they receive a complete, appropriate diagnostic work-up, and select the best therapy for each individual patient. The diagnosis and work-up of CML are reviewed in a separate article; here, the selection of TKI therapy for a patient with newly diagnosed CP-CML is reviewed.

Case Presentation

A 53-year-old woman who recently was diagnosed with CML presents to review her treatment options. The diagnosis was made after she presented to her primary care physician with fatigue, early satiety, left upper quadrant abdominal pain, and an 8-lb unintentional weight loss over the prior month. On physical exam her spleen was palpated 8 cm below the left costal margin. Laboratory evaluation showed a total white blood cell (WBC) count of 124,000/μL with a left-shifted differential including 6% basophils, 3% eosinophils, and 3% blasts; hemoglobin and platelet count were 12.4 g/dL and 801 × 10³/µL, respectively. Fluorescent in-situ hybridization for BCR-ABL gene rearrangement using peripheral blood was positive in 87% of cells. Bone marrow biopsy and aspiration showed a 95% cellular bone marrow with granulocytic hyperplasia and 1% blasts. Cytogenetics were 46,XX,t(9;22)(q34;q11.2), and quantitative real-time polymerase chain reaction (RQ-PCR) to measure BCR-ABL1 transcripts in the peripheral blood showed a value of 98% international standard (IS). Her Sokal risk score was 1.42 (high risk). In addition, prior review of her past medical history revealed uncontrolled diabetes, coronary artery disease requiring placement of 3 cardiac stents 2 years prior, and chronic obstructive pulmonary disease (COPD) related to a 30-pack-year history of smoking.

What factors must be considered when selecting first-line therapy for this patient?