Bosutinib in the Real-Life Treatment of Chronic Phase Chronic Myeloid Leukemia (CML) Patients Aged > 65 Years Resistant/Intolerant to Frontline Tyrosine-Kynase Inhibitors

Background Bosutinib is a 2^nd generation tyrosine-kinase inhibitor (TKI) active in Chronic Myeloid Leukemia (CML) patients resistant or intolerant to frontline imatinib, dasatinib or nilotinib; the favourable toxicity profile makes bosutinib potentially useful in elderly patients, but at present there are no data in unselected cohorts of these subjects.

Aim To highlight this issue, a real-life cohort of 91 patients followed in 21 Italian Centers and treated with bosutinib when aged > 65 years was retrospectively evaluated.

Patients The main clinical features of the whole cohort at diagnosis and at baseline of bosutinib treatment are reported in the Table; all patients were in CP when bosutinib was started. Median interval from diagnosis to bosutinib treatment was 49.7 months [interquartile range (IQR) 14.2 - 117.5].

Results Starting dose of bosutinib was 500 mg/day in 20 patients (22.0%), 400 mg/day in 7 patients (7.7%), 300 mg/day in 28 patients (30.8%), 200 mg/day in 34 patients (37.3%) and 100 mg/day in 2 patients (2.2%), respectively. After a median period of treatment of 18.1 months (IQR 9.4 - 27.7) all patients were evaluable for toxicity; on the whole, all grade hematological and extra-hematological toxicities were reported in 12/91 (13.1%) and 45/91 (49.4%) patients, respectively. A grade 3 - 4 hematological toxicity occurred in 5/91 patients (5.4%); a grade 3 - 4 extra-hematological toxicity occurred in 16/91 patients (17.5%). Overall, 46 patients (50.5%) never discontinued bosutinib: a temporary discontinuation < 6 weeks was needed in 19 patients (20.9%) and a temporary discontinuation > 6 weeks in 2 patients (2.2%). A permanent bosutinib discontinuation was needed in the remaining 24 patients (26.4%): in particular, 11 patients (12.1%) permanently discontinued bosutinib due to toxicity (skin rash in 3 cases, gastro-intestinal toxicity in 3 cases, pleural effusion in 2 cases, transaminitis, QTc prolongation and myalgia in 1 case each), 6 patients (6.6%) due to resistance and 7 patients (7.7%) due to other reasons (unrelated death in 6 cases and patient decision in 1 case). As to response, 5 patients (5.5%) were considered too early for assessment (< 3 months of treatment); among the 86 patients evaluable for response, 11 patients (12.7%) did not have any response (including 6 patients who discontinued bosutinib for early toxicity), 4 (4.6%) achieved hematological response only, and 71 (82.5%) achieved Cytogenetic Response (CyR) (Major CyR in 4, Complete CyR in 67). Among the 67 patients in Complete CyR, 58 (67.4% of all 86 evaluable patients) also achieved Molecular Response (MR) [Major MR (MR 3.0) in 19 (22.1%), Deep MR (MR 4.0/4.5) in 39 (45.3%)]. The 3-year Overall Survival and Event-Free Survival of the whole cohort of patients from bosutinib start were 83.0% (CI95% 71.6 - 94.4) (Figure 1) and 59.5% (CI95% 39.9 - 72.1), respectively.

Conclusions Our real-life data show that bosutinib is effective, even if initial doses in many cases were lower than recommended, with a favourable safety profile also in elderly patients with important comorbidities resistant/intolerant to previous TKI treatments,: as a consequence, it could play a significant role in the current clinical practise for these frail patients.

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