By Lynda Williams, Senior medwireNews Reporter
Four-year results for an ongoing study of second-line bosutinib indicate that the tyrosine kinase inhibitor (TKI) offers long-term efficacy with manageable side effects for patients with chronic phase chronic myeloid leukaemia (CP CML).
“Overall, these findings highlight the therapeutic potential of bosutinib as second-line therapy in IM-R [imatinib resistant] or IM-I [imatinib intolerant] CP CML patients”, say Tim Brümmendorf (Universitätsklinikum der RWTH Aachen, Germany) and co-investigators.
In the phase I/II trial, bosutinib 500 mg/day was given for a median of 24.8 months to 196 IM-R and 90 IM-I patients; 59% of 264 evaluable patients achieved or maintained a major cytogenetic response (MCyR) for at least 4 weeks, including 59% of the IM-R and 61% of the IM-I groups.
Of the 248 patients without a complete cytogenetic response (CCyR) at baseline, 57% achieved a MCyR and 47% a CCyR during bosutinib therapy. And 14 of the 16 patients with a baseline CCyR maintained this response for between 12 and 288 weeks; two discontinued bosutinib because of adverse events (AEs) and were not reassessed.
The median times to MCyR and CCyR were 12.3 and 24.0 weeks, respectively.
The 4-year cumulative incidences of MCyR and CCyR, at 59% and 49%, respectively, were similar to the previously reported 2-year figures of 59% and 48%, prompting the authors to suggest that “most initial responses occur within 2 years from bosutinib treatment initiation.”
The rate of cumulative progression or death during treatment was an estimated 19% at 4 years.
The Kaplan–Meier-estimated probability of maintaining MCyR at 4 years was found to be high for the whole population and the IM-R and IM-I groups, at 74.5%, 69.3% and 86.3%, respectively, and the median duration of this response had not yet been reached.
Analysis identified characteristics at baseline that significantly predicted patient outcomes. For instance, younger age was significantly associated with the likelihood of MCyR at 3 months; male gender was significantly linked to achievement of MCyR at any time point and CCyR at 3 or 6 months; and prior response to imatinib and receipt of interferon-alpha were both significantly associated with MCyR and CCyR at 3 months, 6 months and anytime during treatment.
In addition, overall survival was significantly lower in patients who had bosutinib-insensitive BCR–ABL1 mutations than those who did not (hazard ratio [HR]=3.35), whereas a baseline Philadelphia-positive ratio of 95% or above was associated with a significantly lower chance of progression-free survival than a ratio of 35% or less (HR=7.94).
Treatment was discontinued because of AEs by 16% of IM-R and 39% of IM-I patients, after a median of 162 and 115 days, respectively.
Diarrhoea was the most common AE reported, affecting 86% of patients, although few discontinued treatment for this symptom. And grade 3 or 4 diarrhoea was significantly linked to the presence of bosutinib-sensitive BCR-ABL1 mutations at baseline, with a HR of 3.25 compared with no such mutations.
The most common haematological AEs were thrombocytopenia (42%), anaemia (27%) and neutropenia (16%) and these were managed by dose interruptions, reductions or medication.
Drug-related cardiac AEs were reported in 5% of patients, most commonly angina pectoris, pericardial effusion and palpitation. Comparing patients aged less than 65 years with older patients showed differences with regard to any grade of bradycardia (0.9 vs 6.3%), congestive cardiac failure (0.9 vs 6.3%) and cardiac failure (0.0 vs 6.3%).
“In conclusion, bosutinib continues to demonstrate durable efficacy and manageable toxicity in CP CML patients following IM-R or IM-I after ≥48 months of follow-up”, the authors write in the British Journal of Haematology.
“The baseline factors predictive of long-term patient outcomes identified here may allow identification of patient subgroups with [Philadelphia chromosome positive] CML who might benefit optimally from bosutinib treatment.”
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