Three commercially available TKIs are approved for the frontline treatment of CML: imatinib, dasatinib, and nilotinib. Available guidelines support all three as viable frontline options for the initial management of CP CML.
Prior to the development of targeted therapy, CML was treated with busulfan or hydroxyurea for many years, with a poor prognosis and inability to delay disease progression. The introduction of interferon-alfa (IFN-α) improved survival in CML and resulted in CCyRs in 5% to 25% of patients with CP CML.
Imatinib mesylate (STI-571 or Gleevec) is a selective and potent competitive inhibitor of the adenosine triphosphate (ATP)–binding site of the Bcr-Abl oncoprotein, as well as c-kit, PDGFRα and PDGFRβ, and abl-related gene (ARG) (12). It is taken orally with 98% bioavailability and a half-life of 13 to 16 hours. It was first used in CML patients who developed resistance or intolerance to IFN-α and resulted in a CCyR of 60% and an estimated 5-year OS of 76% (13).
Based on these results, the large International Randomized Study of Interferon and STI571 (IRIS) trial evaluated imatinib versus IFN-α and low-dose cytarabine as frontline therapy in patients with newly diagnosed CP CML. Patients were randomized to receive imatinib 400 mg/d or INF-α plus low-dose subcutaneous cytarabine, which was standard of care at the time (10). After a median follow-up of 19 months, planned outcome analyses were significantly better in almost all categories for patients receiving imatinib. The rates of CCyR (74% vs 9%; P < .001) and freedom from progression to AP or BP at 12 months (99% vs 93%; P < .001) were improved. There was a high crossover rate to imatinib. The responses to imatinib were durable, as outlined in an 8-year follow-up of the original study (14). Estimated event-free survival was 81%, and OS was 93% when only CML-related deaths were considered. With an annual mortality of 2%, the estimated median survival of a newly diagnosed patient with CML may be in the range of 20 to 30 years.
A phase I imatinib study in patients who had failed prior IFN-α therapy established a clear relationship between dose and response (15). No significant responses were observed at doses <300 mg daily. An arbitrary dose of 400 mg daily for CP was selected in phase II studies, despite the lack of dose-limiting toxicity at doses up to 1,000 mg daily (maximum-tolerated dose was not defined). The Rationale and Insight for Gleevec High-Dose Therapy (RIGHT) trial studied imatinib 400 mg twice a day as initial therapy in 115 patients with newly diagnosed CML (16). The rate of CCyR was 85% at 12 months and 83% at 18 months, with corresponding rates of MMR of 54% at 12 months and 63% at 18 months.
These results led to a randomized phase III open-label study, the Tyrosine Kinase Inhibitor Optimization and Selectivity Trial (TOPS), comparing 400 and 800 mg of imatinib in 476 patients. The trial showed significant superiority for the 800-mg dose in terms of MMR rate at 3 months (3% vs 12%), 6 months (17% vs 34%), and 9 months (33% vs 45%) but not at 12 months (40% vs 46%) (17). A final update of the trial showed no significant difference in MMR rates at 24 months (52% vs 50%) (18). Another European study also reported no benefit with imatinib 800 mg compared to 400 mg in high-risk CML (CCyR rates were 64% and 58% and MMR rates were and 40% and 33%, respectively) (19).
The French SPIRIT study evaluated the impact of adding IFN or cytarabine in a randomized study where 636 patients with untreated CP CML received one of the following: imatinib 400 mg daily alone, imatinib 400 mg daily with cytarabine (20 mg/m2/d on days 15-28 of each 28-day cycle) or pegylated IFN-α-2a (90 μg weekly), or imatinib 600 mg daily alone (20). The rates of cytogenetic response at 12 months were similar among the four groups, whereas the rate of molecular response (a decrease in the ratio of BCR-ABL1/ABL1 of ≤0.01%) was significantly higher in patients receiving imatinib and pegylated IFN-α-2a compared with imatinib 400 mg alone arm (30% vs 14%, respectively; P = .001). This rate was also significantly higher in patients treated for more than 12 months compared to treatment lasting ≤12 months. However, this high rate of early and deep responses did not translate into long-term improvement due to the poor tolerance of pegylated IFN.
Imatinib 400 mg daily is the regimen of choice for newly diagnosed patients with CP CML, with an emphasis on maintaining adequate dose intensity with minimal treatment interruptions or dose reductions for the best outcome.
Imatinib is well tolerated, although adverse events not requiring treatment interruptions or decrease in dosing may occur in 30% to 40% of patients. A list of some of the most frequently encountered side effects and suggestions for management are included in Table 4-4. Any grade 3 or 4 toxicities related to imatinib require treatment interruption and resumption upon resolution of toxicity or its decrease to grade 1 or less. Subsequent dose should be reduced if recurring or long-lasting adverse effects are encountered, keeping in mind that doses below 300 mg daily are not recommended due to lack of adequate activity. Only 2% to 3% of patients exhibit true intolerance to imatinib and require permanent discontinuation. Early recognition and intervention targeting toxicities greatly reduce the need for unnecessary treatment interruptions and dose reductions.
Table 4-4Recommended Management of the Most Common Adverse Events Associated With Imatinib ||Download (.pdf) Table 4-4 Recommended Management of the Most Common Adverse Events Associated With Imatinib
|Adverse Events ||Management |
|Nausea/vomiting ||Take with food, fluids |
| ||Antiemetics |
|Diarrhea ||Loperamide |
| ||Diphenoxylate atropine |
|Peripheral edema ||Diuretics |
|Periorbital edema ||Steroid-containing cream |
|Skin rash ||Avoid sun exposure |
| ||Topical steroids |
| ||Systemic steroids |
| ||(Early intervention important) |
|Muscle cramps ||Tonic water or quinine |
| ||Electrolyte replacement as needed |
| ||Calcium gluconate |
|Arthralgia, bone pain ||Nonsteroidal anti-inflammatory agents |
|Elevated transaminases (uncommon) ||Hold therapy and monitor closely |
| ||Dose reduction upon resolution |
|Myelosuppression || |
|Anemia ||Treatment interruption/dose reduction usually not indicated |
| ||Erythropoietin or darbepoetin |
|Neutropenia ||Hold therapy if grade ≥3 (ie, ANC <1 × 109/L) |
| ||Restart at lower dose if recovery takes >2 weeks |
| ||Consider G-CSF if recurrent/persistent, or sepsis |
|Thrombocytopenia ||Hold therapy if grade ≥3 (ie, platelets <50 × 109/L) |
| ||Restart at lower dose if recovery takes >2 weeks |
| ||Consider IL-11 10 μg/kg 3-7 days/week |
Myelosuppression is common and frequently seen within the first 2 to 3 months of therapy. It is generally self-limited, and dose interruptions are not recommended unless grade 3 neutropenia or thrombocytopenia (ie, neutrophils <1 × 109/L, platelets <50 × 109/L) develops. Anemia alone usually does not require interruptions or dose adjustments. Treatment is restarted when counts recover above specified thresholds. Following treatment interruption, WBC should be monitored at least once weekly, and if recovery occurs within 2 weeks, treatment would be resumed with the same dose at which myelosuppression occurred. If recovery takes longer than 2 weeks, the dose could be reduced in increments (eg, from 800 to 600 mg, from 600 to 400 mg, or from 400 to 300 mg). Hematopoietic growth factors may be beneficial with recurrent or prolonged myelosuppression (eg, erythropoietin or darbepoetin and filgrastim).
Dasatinib (Sprycel) is an oral second-generation TKI that is a piperazinyl derivative. It has an excellent oral bioavailability and is 350 times more potent in vitro than imatinib (21,22) (in vitro sensitivity of different BCR-ABL1 mutants to different TKIs is presented in Table 4-5) (23). Dasatinib exhibits significant activity against most imatinib-resistant BCR-ABL1 mutations, with the exception of T315I, as well as a few others, including V299L and F317L (24). In contrast to imatinib, dasatinib binds to both the active and inactive conformations of BCR-ABL1 and also inhibits the Src family of kinases, which may be important in suppressing critical cell signaling pathways (25).
Table 4-5In Vitro Sensitivity of Different Bcr-Abl1 Mutants to Different Tyrosine Kinase Inhibitors ||Download (.pdf) Table 4-5 In Vitro Sensitivity of Different Bcr-Abl1 Mutants to Different Tyrosine Kinase Inhibitors
|BCR-ABL Mutant ||Ponatinib ||Imatinib ||Nilotinib ||Dasatinib ||Bosutinib |
|Native ||3 ||201 ||15 ||2 ||71 |
|M244V ||3 ||287 ||12 ||2 ||147 |
|L248R ||8 ||10000 ||549 ||6 ||874 |
|L248V ||4 ||586 ||26 ||5 ||182 |
|G250E ||5 ||1087 ||41 ||4 ||85 |
|Y253H ||5 ||4908 ||179 ||3 ||40 |
|E255K ||6 ||2487 ||127 ||9 ||181 |
|E255V ||16 ||8322 ||784 ||11 ||214 |
|V299L ||4 ||295 ||24 ||16 ||1228 |
|T315A ||4 ||476 ||50 ||59 ||122 |
|T315I ||6 ||9773 ||8091 ||10000 ||4338 |
|F317C ||3 ||324 ||16 ||45 ||165 |
|F317I ||7 ||266 ||25 ||40 ||232 |
|F317L ||4 ||675 ||21 ||10 ||82 |
|F317V ||10 ||1023 ||26 ||104 ||1280 |
|M351T ||4 ||404 ||15 ||2 ||97 |
|E355A ||7 ||441 ||18 ||3 ||74 |
|F359C ||6 ||728 ||47 ||2 ||70 |
|F359I ||11 ||324 ||64 ||3 ||76 |
|F359V ||4 ||346 ||41 ||2 ||59 |
|H396R ||4 ||395 ||23 ||2 ||60 |
|E459K ||5 ||612 ||38 ||4 ||127 |
|Criteria Used to Classify Drug Potency |
| ||Ponatinib ||Imatinib ||Nilotinib ||Dasatinib ||Bosutinib |
|Effective Cave at recommended dose ||28a ||444 ||131 ||11 ||159 |
|IC50 <75% of Cave ||<21 ||<333 ||<98 ||<8 ||<119 |
|IC50 75%-150% of Cave ||21-32 ||333-500 ||98-147 ||8-12 ||119-179 |
|IC50 150%-300% of Cave ||33-95 ||501-1499 ||148-442 ||13-37 ||180-537 |
|IC50 >300% of Cave ||>95 ||>1499 ||>442 ||>37 ||>537 |
Following evaluation in the salvage setting after imatinib failure, dasatinib was assessed in the frontline setting. The DASISION trial was a phase III randomized study that compared imatinib 400 mg once daily to dasatinib 100 mg once daily in 519 patients with newly diagnosed CP CML (26). The primary end point was confirmed CCyR at 12 months. The dasatinib arm resulted in higher confirmed CCyR at 12 months (77% vs 66%; P = .007). The rates of molecular response were significantly higher with dasatinib (MMR, 76% vs 64%, P = .002; molecular response with a 4.5-log reduction in BCR-ABL transcripts from baseline [MR4.5], 42% and 33%, P = .025). Dasatinib induced deeper responses at early time points (3, 6, or 12 months) compared to imatinib. The rate of transformation to AP or BP was lower in patients treated with dasatinib (4.6% and 7.3%, respectively). There was no progression-free survival (PFS) or OS difference at 5 years. Relevant toxicities included pleural effusion rate of 29% with dasatinib (mostly grade 1 or 2; 15 patients discontinued dasatinib due to pleural effusion). Arterial ischemic events were slightly higher with dasatinib (5% vs 2%, respectively). Pulmonary hypertension was reported in 14 dasatinib-treated patients, with 6 discontinuing the drug. Comparison of the phase III trials in the frontline treatment of CP CML with imatinib, dasatinib, and nilotinib is outlined in Table 4-6.
Table 4-6Comparison of the Phase Iii Trials in the Frontline Treatment of CP CML ||Download (.pdf) Table 4-6 Comparison of the Phase Iii Trials in the Frontline Treatment of CP CML
|Trial ||Treatment ||CCyR (%) ||MMR (%) ||BCR-ABL <10% at 3 Months (%) ||EFS/PFS (%) ||OS (%) ||Longest Follow-Up (years) |
| || ||At 6 years ||At 6 years |
|IRIS ||Imatinib (n = 304) ||83 ||86 ||NR ||81 ||85 ||8 |
| || ||At 2 years ||At 5 years || ||At 5 years || |
|DASISION ||Dasatinib (n = 259) ||86 ||76 ||84 ||85 ||91 ||5 |
| ||Imatinib (n = 260) ||82 ||64 ||64 ||86 ||90 || |
| || ||At 2 years ||At 5 years || ||At 5 years ||At 6 years || |
|ENESTnd ||Nilotinib 300 mg (n = 282) ||87 ||77 ||91 ||95 ||92 ||6 |
| ||Nilotinib 400 mg (n = 281) ||85 ||77 ||89 ||97 ||96 || |
| ||Imatinib (n = 283) ||77 ||60 ||67 ||93 ||91 || |
A randomized phase II trial compared dasatinib 100 mg daily with imatinib 400 mg daily in 253 patients with newly diagnosed CP CML. Higher rates of CCyR (84% vs 69%) and 12-month MMR (59% vs 44%; P = .059) were reported in patients receiving dasatinib. No difference in PFS or OS was reported. Grade 3 and 4 toxicities were most commonly hematologic, including thrombocytopenia, which was more common with dasatinib (18% vs 8%) (27).
The results of the SPIRIT-2 trial were recently reported (28). More than 800 patients with newly diagnosed CML were treated in a phase III trial and were randomized to either dasatinib 100 mg daily or imatinib 400 mg daily (28). The 12-month CCyR and MMR rates were higher with dasatinib (CCyR: 51% vs 40%, P = .002; MMR: 58% vs 43%, P < .001). Among 40 patients who discontinued therapy due to suboptimal response, only three patients (1%) received dasatinib. The PFS and OS were not significantly different. The rate of grade 3 or 4 thrombocytopenia was higher with dasatinib (13% vs 4%). Pleural effusions were observed in 78 patients (19%) treated with dasatinib (13 required drainage). The rate of cardiovascular events was slightly higher with dasatinib (2% vs 0.5%).
Dasatinib is otherwise well tolerated. Myelosuppression occurs frequently, with grade 3 or 4 neutropenia or thrombocytopenia in 20% of patients. The most common nonhematologic grade 3 or 4 toxicities at the same dose were pleural effusion (9%), dyspnea (6%), bleeding (4%), diarrhea (3%), and fatigue (3%).
Nilotinib (Tasigna) is a structural analog of imatinib with 50 times more potent affinity for the ATP-binding site in vitro (29) and more selective activity against unmutated and most mutated forms of BCR-ABL1 (29,30). It is approved at a dose of 400 mg twice daily for patients with CP or AP CML who have resistance or intolerance to imatinib.
After approval for patients who failed imatinib therapy, nilotinib was evaluated in newly diagnosed CML in CP. The ENESTnd study was a randomized phase III trial comparing two different dose schedules of nilotinib (300 and 400 mg twice daily) to imatinib 400 mg once daily as initial therapy for patients with early CP CML (31). The primary end point was the rate of MMR at 12 months, which was higher with both doses of nilotinib compared to imatinib (44% and 43% vs 22%; P < .001). The rate of transformation to AP or BP by 12 months of therapy was significantly lower with nilotinib (<1%) compared to imatinib (4%). The adverse effect profiles showed a higher rate of cardiovascular events with nilotinib (10% with nilotinib 300 mg twice a day; 16% with nilotinib 400 mg twice a day; and 2% with imatinib). The 6-year follow-up continues to demonstrate higher rates of early and deeper sustained molecular response with nilotinib, a reduced risk of progression to AP and BP, and an acceptable safety profile (32). Nilotinib is well tolerated, with grade 3 or 4 myelosuppression as the most common adverse event (neutropenia or thrombocytopenia observed in 10%-20% of patients). Nonhematologic toxicity includes liver function abnormalities in 10% to 15% of patients and asymptomatic elevation of lipase and amylase in 10% to 15% of patients. Vascular adverse events were reported at an cumulative rate of 10% over 6 years. Rare cases (<1%) of pancreatitis have been reported. Nilotinib has the potential for QTc prolongation, and a baseline electrocardiogram is required prior to the start of therapy. Diabetes may be exacerbated with nilotinib.
Selecting a Frontline Therapy
With multiple TKIs available for newly diagnosed CP CML, there are several considerations when choosing a starting agent, such as efficacy, patient status (eg, age; comorbidities; history of diabetes, hypertension, pancreatitis, chronic lung disease, pulmonary hypertension, cardiac history), and treatment value. The high prices of TKIs are of concern, given that patients can now remain on TKIs and expect to live normal lives (33). The prices for the second-generation dasatinib and nilotinib are comparable, both costing more than $100,000 annually. Once imatinib becomes available as a generic drug, the choice of TKIs in relation to value (benefit-to-price) needs to be considered, particularly in patients with low-risk disease.
For patients with baseline cardiopulmonary comorbidities such as chronic obstructive pulmonary disease, congestive heart failure, or uncontrolled hypertension or pulmonary arterial hypertension, a TKI other than dasatinib may be favored, given the risk of pleural effusions. Dasatinib also impairs platelet function, and patients on concomitant anticoagulants may be at an increased risk for hemorrhagic complications (34).
Nilotinib has been linked with hyperglycemia and QT interval prolongation, and should be used with caution in uncontrolled diabetics and in patients with baseline QT prolongation (routine monitoring of the QT interval is essential). Potassium and magnesium should be repleted to optimal serum levels prior to starting nilotinib, and the drug should be taken on an empty stomach twice daily. Recently, nilotinib has been associated with a low but significant incidence of peripheral artery disease, cerebrovascular accidents, and cardiovascular syndromes (35). Therefore, it is reasonable to choose other TKIs for patients with cardiovascular morbidities. Nilotinib rarely causes pancreatitis and should be avoided in patients with prior history of pancreatic inflammations. Imatinib is associated with the development of peripheral edema as one of its major side effects. Among patients with significant baseline peripheral edema, nilotinib or dasatinib may be favored as first options; close monitoring and intermittent use of loop diuretics might mitigate the effects of fluid retention.