The second generation tyrosine kinase inhibitor (TKI) nilotinib has proven efficacy in treatment of chronic and accelerated phase CML.
CHRONIC PHASE (CP)
Saglio and colleagues published the results of their phase 3 trial of nilotinib vs imatinib in newly diagnosed chronic myeloid leukemia (CML) in 2010.r In this randomised, open-label, multicentre study, patients with chronic phase Ph+ CML (n=846) were assigned in a 1:1:1 ratio to receive nilotinib (at a dose of either 300 mg or 400 mg twice daily) or imatinib (at 400 mg daily) – the ENESTnd trial. Patients with impaired cardiac function were excluded. The use of therapeutic coumarin derivatives, drugs that block or stimulate cytochrome enzyme CYP3A4, or any medication with potential to prolong QT interval was prohibited.
Primary end point was rate of major molecular response (MMR) at 12 months. MMR was defined as a bcr-abl transcript level of 0.1% or less on the International Scale in peripheral blood on RQ-PCR (equivalent to 3 log reduction compared with the standardised baseline established in the IRIS trial). Secondary end points include MMR at 24 months, complete cytogenetic remission (CCyR) at 12 months and progression to accelerated phase (AP) or blast crisis (BC). Minimal follow up was 12 months after the date of randomisation. Median duration of treatment was approximately 14 months in all study groups. Sokal risk and race or ethnic groups were well matched between the study groups. 45 patients in the imatinib group had a dose escalation to 800 mg per day.
At 12 months the rates of MMR for nilotinib (44% for 300 mg dose and 43% for 400 mg dose) were nearly twice that for imatinib (22%) (p<0.001 for both comparisons)r (see figure below).
© NEJM 2010
Median time to MMR was 8.6 months for the 300 mg nilotinib group, 11.0 months for the 400 mg nilotinib group, whereas the median was not reached in those receiving imatinib. Among patients with a high Sokal risk, rates of MMR at 12 months were 41% for patients receiving 300 mg of nilotinib, 32% for those receiving 400 mg of nilotinib, and 17% for those receiving imatinib.
The rates of CCyR by 12 months, and time to progression to AP or BC also significantly favoured nilotinib (at both dose levels). Among patients with a high Sokal risk, rates of CCyR by 12 months were: 74% in the 300 mg nilotinib group, 63% in the 400 mg nilotinib group, and 49% among those receiving imatinib.
By the data cutoff date, progression to AP or BC had occurred in 14 patients: 11 patients (4%) receiving imatinib, 2 patients (<1%) receiving 300 mg of nilotinib and 1 patient (<1%) receiving 400 mg of nilotinib. Both doses of nilotinib were also significantly better than imatinib in time progression to AP and BC. Of note, there was no progression observed in patients who achieved an MMR.
Summarising the data from this trial:
Nilotinib at both doses:
- led to significantly higher rates of both MMR and CCyR than did imatinib,
- was associated with fewer suboptimal responses or treatment failures,
- the 300 mg dose of nilotinib had lowest rates of discontinuation because of adverse events or laboratory abnormalities among the three study groups.
The 5 year follow up of the ENESTnd trial was published in 2016r showed a persisting benefit in terms of achievement of MMR for the patients on nilotinib. By 5 years, more than half the patients assigned nilotinib (54% on 300mg BD, 52% on 400mg BD) had achieved MR4.5 (BCRABL=0.0032%) compared with 31% on imatinib (see figures below).
© Leukemia 2016
No new progressions to AP or BC occurred on core treatment after the 2-year analysis.r Overall, progressions on study were lower in both nilotinib groups than in the imatinib group. At the 5 year analysis both progression free and overall survival was significantly lower in the nilotinib 400 mg BD group than the other two cohorts (p=0.026).r It should be noted, however, that this is not the currently approved dose for CML-CP.
A subanalysis of the ENEST-First line treatment study showed that age did not have a significant impact on the deep molecular response rates of nilotinib therapy in newly diagnosed CML.r
The phase 2 ENESTfreedom trial evaluated the potential for treatment-free remission (TFR) in patients with Philadelphia chromosome-positive CML-CP with MR4.5 (BCR-ABL1 ⩽0.0032% on the International Scale (BCR-ABL1IS)) following ⩾ 2 years of frontline nilotinib treatment. 215 patients received nilotinib consolidation treatment for 12 months and had to sustain deep molecular response during this phase to be eligible to stop treatment and enter the TFR phase. 51.6% (95% CI, 44.2–58.9) of patients remained in remission at 48 weeks after stopping nilotinib. The majority of patients lost MMR response within 6 months of stopping nilotinib, which highlighted the need for frequent monitoring of patients who stop TKI therapy to ensure timely retreatment. Patients who reinitiated nilotinib after loss of MMR rapidly regained MMR (98.8%) and MR4.5 (88.4%). No patients progressed to AP/BC and no new safety signals were identified during treatment. Stopping frontline nilotinib was deemed safe in the ENESTfreedom trial.r
ACCELERATED PHASE (AP)
Patients can present with CML in accelerated phase (CML-AP). Alternatively, CML patients treated with a TKI such as imatinib can develop resistance and may then satisfy the definition of accelerated phase. In either case, treatment to return the patient to chronic phase is the desired goal, whether the definitive treatment eventually is a stem cell transplant.
This discussion is confined to the role of nilotinib in the treatment of CML-AP in patients receiving imatinib.
Le Coutrer reported a phase 2 study of 119 patients with CML-AP and imatinib resistance (81%) or intolerance. Nilotinib was administered at 400 mg BD, with escalation to 600 mg BD for inadequate response. Primary and key secondary endpoints were rate of confirmed haematologic response (HR) and major cytogenetic response (MCyR) respectively. These results were subsequently updated in 2008,r when a total of 136 patients were analysed (patient had to have received at least 1 dose of nilotinib). Median age was 58, median dose achieved was 781 mg/day, and median treatment duration was 210 days. Confirmed HR occurred in 69/129 patients (54%); 34 (26%) had complete HR. Of imatinib-resistant patients, 55/104 (53%) patients had a confirmed HR, whereas 14/25 (56%) imatinib-intolerant patients had a confirmed HR. 82% of responding patients maintained HR for at least 12 months. MCyR occurred in 40/129 patients (31%) – 30/104 imatinib-resistant patients and 10/25 imatinib-intolerant patients and a total of 24/129 (19%) patients had CCyR. Time to first HR and MCyR was 1 and 2.8 months respectively. At 12 months, it is estimated that 57% of patients were without progression, and the estimated overall survival rate was 81%. On further follow up at 24 months,r 66% of patients who achieved a MCyR maintained this response, and the overall and progression free survival rates were 70 and 33% respectively.
In the initial report of ENESTnd,r at the time of data cutoff, the proportions of patients receiving a study drug were 84% in the 300 mg nilotinib group, 82% in the 400 mg nilotinib group and 79% in the imatinib group. Adverse events and newly occurring or worsening haematologic or biochemical abnormalities reported in the safety monitoring group are displayed in the following table:
© NEJM 2010
In general, gastrointestinal and fluid retention events were more frequent among patients receiving imatinib, whereas dermatologic events and headaches were more frequent in those receiving nilotinib. Discontinuation due to aminotransferase and bilirubin elevations were low in all three study groups.
Grade 3/4 neutropenia and anaemia were more frequent in the imatinib group, whereas thrombocytopenia tended to be more frequent in both nilotinib groups. All newly occurring grade 3/4 haematologic laboratory abnormalities occurred within the first two months of therapy in all three study groups.
Median cumulative durations of dose interruptions because of adverse events or laboratory abnormalities were 19 days in the 300 mg nilotinib group, 22 days in the 400 mg nilotinib group and 15 days among patients receiving imatinib. Correspondingly, dose reductions or interruptions occurred in 59%, 66% and 52% respectively. 12.2% and 19.1% of patients on nilotinib 300 mg BD and 400 mg BD, respectively, discontinued treatment prior to the 24 month mark, compared with 13.9% on the imatinib arm.r
Patients were closely monitored for QT prolongation and changes in the left ventricular ejection fraction (LVEF). No patient in any of the study groups had a QTc of >500msec. No decrease from baseline in the mean LVEF was observed at any time during the study. A total of 11 patients from all three study groups had an ischaemic heart disease event, with one resulting in treatment discontinuation.
In the 5 year follow up reportr the safety results were consistent with the previous reports. Of note, some adverse events were more common in the nilotinib 400mg BD arm than the 300mg BD arm. The most significant observation was the increased rate of cardiovascular events (CVE) in patients on nilotinib compared with those on imatinib. The incidence was 7.5% in patients receiving nilotinib 300mg BD, 13.4% nilotinib 400mg BD and 2.1% imatinib (see figure 5 below). Blood cholesterol and glucose levels were also more frequently elevated in patients on nilotinib.
© Leukemia 2016
In the ENESTfreedom trial, the most common adverse events during the consolidation and TFR phases were nasopharyngitis (11.1%) and arthralgia (12.1%). Elevations in glucose, alanine aminotransferase, aspartate aminotransferase, bilirubin and lipase were less common in the TFR phase than in the consolidation phase. 24.7% of patients experienced musculoskeletal pain related adverse events with most reports occurring within 24 weeks of stopping nilotinibr