In 2000, before imatinib was marketed, it was estimated that there would be 4400 new diagnoses of chronic myeloid leukemia (CML) and 2300 patients would die as a result of the disease in the United States.1 In 2009, the number of estimated new cases of CML increased to 5050, but the number of patients who were expected to succumb to the cancer decreased to 470 patients.2 The US Food and Drug Administration’s (FDA) approval of imatinib in 2001 was seen as a giant leap toward improving and prolonging the lives of patients diagnosed with CML. In the imatinib era, research in CML has focused on improving the utility of imatinib, developing more potent tyrosine kinase inhibitors (TKIs), and working to overcome drug resistance and intolerability.
The clinical course of CML is characterized by three phases: chronic phase (CP), accelerated phase (AP), and blast crisis (BC), with the majority of patients diagnosed in CP. Historically, patients progressed within 3 to 5 years to AP and BC, which are ultimately fatal if untreated.3 The improvements in treating CML are related to it being the first cancer defined by a specific karyotypic abnormality, specifically a reciprocal chromosomal translocation between chromosomes 9 and 22.4 This chromosomal translocation, referred to as the Philadelphia (Ph) chromosome, results in the production of the BCR-ABL tyrosine kinase protein. Imatinib inhibits the activity of the BCR-ABL protein with high selectivity. Based on results from the International Randomized Study of Interferon and STI571 published in 2003, imat inib has become the standard frontline therapy for Ph-positive (Ph+) CML.5,6
The 8-year follow-up results to this clinical trial, which recently became available, demonstrated an estimated event-free survival (EFS) of 81%, with freedom from progression to AP/BC at 92% in the imatinib arm.7 Most occurrences of progression to AP and BC occurred early, and the risk of progression decreased after 3 years of treatment. Also noted, imatinib’s adverse event profile did not change over time.
The FDA-approved dose of imatinib for first-line treatment of CP CML is 400 mg/day or 600 mg/day in AP or BC.8 For patients with disease progression or intolerance to imatinib, current TKI options include higher-dose imatinib, dasatinib, or nilotinib (Table). Allo - geneic stem-cell transplant (SCT) is also an option. In CP CML, increasing the dose of imatinib to 800 mg/day when the initial dose failed to achieve a complete cytogenetic re sponse (CCyR) has been evaluated. In this analysis, 13 (38%) of 34 patients achieved a CCyR with the higher dose.12
Recently, a phase 3 trial compared imatinib 400 mg/day with 800 mg/day as initial treatment in CP CML.13 The primary objective was major molecular response (MMR) at 12 months with several secondary objectives, including time to MMR and time to CCyR. No significant difference was observed for the primary objective, but MMR and CCyR occurred sooner at the higher dose. At 6 months, 17.2% of patients on the lower dose and 33.5% of patients on the higher dose had achieved an MMR. Adverse effects, including rash, edema, and gastrointestinal problems, occurred more often at the higher dose, but overall, both doses were considered well tolerated. Continued follow-up is still needed to determine whether earlier response affects survival.
Dasatinib is FDA-approved for adults with CML that is resistant or intolerant to prior therapy. The recommended dose is 100 mg/day for CP CML and 140 mg/day for patients in AP or BC CML.9 Dasatinib’s inhibition of unmutated BCR-ABL is 300 times more potent in vitro than imatinib’s and it has the ability to overcome mutations that lead to imatinib resistance, with the notable exception of the T315I mutation.
A randomized, open-label study found that patients resistant or intolerant to imatinib achieved a complete hematologic response (CHR) of 92%, a major cytogenetic response (MCyR) of 63%, and a CCyR of 50%, with 93% of patients who achieved a MCyR maintaining response for 18 months.9
Dasatinib was originally evaluated with twice-daily dosing but has since been shown to have comparable efficacy and less toxicity when given once daily. In CP CML, 3-year follow-up data showed that patients treated with 100 mg once daily had fewer drug-related pleural effusions and cytopenias than those who received other dosing regimens (70 mg twice daily, 140 mg daily, or 50 mg twice daily).14 In AP CML, 15- month median follow-up data evaluating dasatinib 140 mg once daily versus 70 mg twice daily have also become available. Efficacy results with the two regimens were similar, with a major hematologic response (MHR) of 66% versus 68%, MCyR of 39% versus 43%, and overall survival (OS) rates of 63% versus 72%, respectively. Patients who received once-daily dosing had significantly fewer pleural effusions at 20% versus 39% (P <.001).15
Preliminary results are currently available for an ongoing phase 2 trial evaluating dasatinib in the frontline setting of CML at 100 mg once daily or 50 mg twice daily.16 Of the 50 patients who had been evaluated for at least 3 months, 49 (98%) had achieved a CCyR, and 41 (82%) had achieved an MMR. No difference in efficacy was seen between the two arms, and 90% of patients achieved a CCyR within the first 6 months of treatment. As with the use of high-dose imatinib as frontline therapy, it is unclear whether the earlier response will translate into improved survival. The adverse effect profile has been similar to that in past trials containing high-dose imatinib. One side effect that had not been prominently reported in previous trials with dasatinib was peripheral neuropathy, which was seen in 31% of patients. Most events were grade 1 or 2 severity, but 5% were grade 3, requiring dose interruption and dose reduction. Toxicity with once- and twice-daily dosing was similar, with a trend toward more pleural effusions with twice-daily dosing.
Nilotinib is FDA-approved for treatment of CP and AP Ph+ CML in adult patients resistant or intolerant to prior therapy that included imatinib.10 Nilotinib has been shown to prolong the QT interval, and five sudden deaths have been reported in patients receiving nilotinib, prompting a black-box warning. It is recommended that patients initiated on this drug obtain electrocardiograms at baseline, after week 1, and then periodically thereafter or with any dose adjustment.10 Nilotinib is a 25 times more potent inhibitor of BCR-ABL than imatinib, with the ability to overcome imatinib resistance related to multiple mutations, with the exception of T315I. Data are available after a minimum of 19 months of followup in patients with CP CML treated with nilotinib following imatinib failure.17 At a dose of 400 mg twice daily, nilotinib induced a CHR of 94%, with 59% of patients achieving an MCyR at a median of 2.8 months. At 24 months, 78% of patients maintained an MCyR, with an estimated OS rate of 88%. Nilotinib was well tolerated; pleural or pericardial effusions (grade 3/4) were uncommon (<1%), which distinguishes it from dasatinib. The grade 3/4 adverse events that were most often reported included asymptomatic laboratory abnormalities and hematologic toxicities. To date, this ongoing study has provided no further update with regard to QT prolongation.
Follow-up data after a minimum of 11 months of treatment with nilotinib in AP CML are available.18 At a median time to first hematologic response (HR) of 1 month, 56% of patients had a confirmed HR, with 31% achieving a CHR. At 24 months, 54% of these patients had maintained their HR. An MCyR was achieved in 32% of patients and a CCyR in 20% of patients. This response was long lasting, with 70% of these patients maintaining their MCyR at 24 months and 83% maintaining their CCyR at 12 months. The estimated OS at 24 months was 67%, with a similar side-effect profile as reported for CP treatment.
Data evaluating nilotinib in the frontline setting are now available from a phase 2 clinical trial that used the approved dose of 400 mg twice daily administered on an empty stomach and provided information on 51 patients with a median follow-up of 3 months.19 Of those evaluated, 50 (98%) had achieved a CCyR, and 39 (76%) had achieved an MMR. Responses occurred more quickly than historically reported with standard-dose imatinib, with 90% of patients achieving CCyR by 3 months and 96% achieving CCyR by 6 months. Grade 3 or 4 toxicities did occur but were rare and were similar to those previously reported. There were two reported incidences each of hypertension and QT prolongation, but none were grade 3 or 4. Prospective clinical trials are ongoing to determine whether nilotinib will be superior to imatinib with regard to EFS and OS in newly diagnosed patients.
Ensuring patient adherence is pivotal to optimizing expected outcomes with drug therapy in CML. Healthcare providers can provide education to enable patients to achieve the best outcome on these oral therapies. Patient adherence to imatinib was measured in 87 consecutive patients with CP CML over 3 months. All patients had received imatinib 400 mg/day as firstline therapy for a median of 59.7 months before enrollment.20 Several prognostic factors and imatinib plasma levels were also evaluated. Although the median adherence rate was 97.6%, 23 (26.4%) patients had an adherence rate of 90%, and in 12 patients, 80%. Adherence was found to be the sole independent factor for complete molecular response (CMR) and one of two predictors for MMR. None of the patients with a 90% adherence rate achieved CMR at 6 years, and only 28.4% achieved MMR (Figure). Patients who had been prescribed an increased dose of imatinib had worse adherence rates, reported at a median of 86.4%. This study concluded that patient adher-ence to therapy was the major determinant of response to imatinib.
Second-line therapy after imatinib
There are no prospective, comparative clinical trials to delineate a secondline therapy when standard-dose imat - inib achieves a suboptimal response or when a patient is not able to tolerate the drug. A recent retrospective analysis evaluated the adverse events experienced by patients who either had their imatinib dose increased after suboptimal response or were switched to dasatinib after initial imatinib failure. Four hundred seventy-four patients had their dose of imatinib increased at some point to >400 mg/day, whereas 175 patients were switched to dasatinib. The study did not record the dosing schedule of dasatinib.21 Patients who switched treatments experienced a significantly higher risk of adverse effects, including fluid retention, pleural effusion, thrombocytopenia, neutropenia, dyspnea, constipation, nausea, vomiting, and congestive heart failure.
A previously published phase 2 trial evaluated imatinib 400 mg twice daily versus dasatinib 70 mg twice daily in patients who failed first-line imatinib. In this trial, more grade 3 and 4 pleural effusions and dyspnea occurred with dasatinib than with high-dose imatinib. The incidence of grade 3 and 4 diarrhea, fatigue, and headache was similar with high-dose imatinib and dasatinib.22 It is important to note that the recommended starting dose of dasatinib was changed to 100 mg once daily after it was shown that 100 mg once daily was equally efficacious as 70 mg twice daily with significantly fewer adverse events.
The presence of the T315I mutation precludes treatment with any of the commercially available TKIs indicated for CML and, consequently, these patients have a poor prognosis. Outside of a clinical trial, allogeneic SCT is the recommended option for patients harboring this mutation if a suitable donor is available.6 Prior treatment with TKIs has not been shown to adversely impact outcome for patients undergoing allogeneic SCT.6 In a retrospective review, the impact of the T315I mutation on transplant outcome was evaluated.23 Of the 33 patients meeting study criteria, 26 patients were in CP, one patient was in AP, and two patients were in BC. The remaining patients were being treated for Ph+ acute lymphoblastic leukemia. The 1- year OS rates following transplant were 69% for CP, 71% for AP, and 16% for BC CML. The OS remained similar at 3 years for CP and AP, but no patients were still alive who were in BC at transplantation.
Lack of a suitable donor and/or medical comorbidities preclude the wide application of allogeneic SCT in CML. Intensive research is centered on the development of novel compounds that are active in this disease. Three such compounds show promise. Bosutinib is an oral TKI with dual inhibition of SRCABL and has shown activity in patients with CP CML who failed prior imatinib or other TKI therapy.24 This drug is currently being compared with imatinib in a phase 3 trial for initial treatment in newly diagnosed CP CML.25
Omacetaxine is a first-in-class taxine and does not depend on tyrosine kinase inhibition for activity.26 The safety and efficacy of this compound was evaluated in a phase 2/3 clinical trial in patients who were considered imatinib-resistant and positive for the T315I mutation. The drug was administered with an induction and maintenance schedule. The induction schedule was 1.25 mg/m2 subcutaneously (SC) twice daily for 14 days every 28 days until HR. After an HR was achieved, the dose was adjusted to 1.2 mg/m2 SC twice daily for 7 days every 28 days. At the time of publication of the abstract, data were available for 66 patients, with 40 patients in CP, 16 patients in AP, and 10 patients in BC. The most promising results were in patients who initiated treatment in CP, with an overall CHR rate of 85% with a median duration of 7.7+ months. The MCyR was 15%, with a median duration of 6+ months. An MMR occurred in 15% of patients, with a reduction of baseline T315I mutated clone in 56.7% of CP patients. The median OS is not yet available for CP patients. The most commonly reported grade 3/4 toxicities were thrombocytopenia, anemia, and neutropenia. Grade 3/4 nonhematologic toxicities were uncommon.
The final agent with data reported in this patient population is another oral TKI. This agent, AP24534, was evaluated in a phase 1 clinical trial in patients refractory to other available options.27 At the time of the abstract release, 12 enrolled patients had the T315I mutation, and nine of these patients remained on study without progression. Patients in CP had the greatest HR, with a CHR in 83%. Patients in AP achieved an MHR, and one patient in BC had resolution of extramedullary symptoms. At abstract submission, two patients had achieved a CCyR after 2 and 5 months. The dose of 30 mg administered orally once daily produced no dose-limiting toxicities and achieved blood levels that allowed in vitro inhibition of the T315I mutation. This drug was considered generally well tolerated, with side effects including myelosuppression, QT prolongation, and dry eye.
Progress in treating CML continues at a rapid pace. Within a 10-year period, three new highly effective drugs became available, which have greatly improved and prolonged the lives of patients diagnosed with CML. The healthcare team’s ability to work together in assisting patients in acquiring the appropriate drug, educating patients on the management of side effects, and encouraging medication adherence provides the best chance for successful treatment and survival. !
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