The European Medicines Agency Review of Bosutinib for the Treatment of Adult Patients With Chronic Myelogenous Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

Abstract

On March 27, 2013, a conditional marketing authorization valid throughout the European Union was issued for bosutinib (Bosulif) for the treatment of adult patients with chronic‐phase, accelerated‐phase, and blast‐phase Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) previously treated with one tyrosine kinase inhibitor or more and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options. Bosutinib is a kinase inhibitor that targets the BCR‐ABL kinase. The recommended dose is 500 mg of bosutinib once daily. The main evidence of efficacy for bosutinib was based on a CML subgroup analysis of study 3160A4‐200, a phase I/II study of bosutinib in Ph+ leukemia in imatinib‐resistant or intolerant CML. The subgroup was defined based on the presence of a BCR‐ABL kinase domain mutation that would be expected to confer resistance to dasatinib (F317, E255) or nilotinib (E255, Y253, F359) and expected to have sensitivity to bosutinib or based on the presence of medical conditions or prior toxicities that may predispose the patient to unacceptable risk in the setting of nilotinib or dasatinib therapy. A conditional marketing authorization was granted because of the limited evidence of efficacy and safety currently supporting this last‐line indication.

Practical management of toxicities associated with bosutinib in patients with Philadelphia chromosome-positive chronic myeloid leukemia

“…Eleven articles were excluded on the basis of the prespecified eligibility criteria and authors’ combined assessment of relevance (five pharmacokinetic studies in healthy volunteers [ 21–25 ], three studies in newly diagnosed patients [ 6 , 10 , 26 ], one retrospective analysis of fourth-line bosutinib as part of a compassionate use program [ 27 ], one study in patients with advanced leukemias [ 8 ], and one article summarizing the EU conditional marketing authorization for bosutinib [ 12 ]).…”

“…In the frontline setting, despite an improvement in several efficacy end points, bosutinib was not superior to imatinib for inducing cytogenetic response and was associated with increased hepatotoxicity and gastrointestinal toxicity compared with imatinib [ 10 , 11 ]. Thus, bosutinib is currently not indicated for patients newly diagnosed with CML [ 10 , 12 ]. However, recent results from another ongoing study of frontline bosutinib (BFORE trial) are positive, demonstrating the superiority of bosutinib over imatinib for the treatment of patients newly diagnosed with CP CML [ 13 ].…”

Expert Opinion on the Treatment of Refractory Chronic Phase Chronic Myeloid Leukaemia

“…In addition, bosutinib (Bosulif ® ; Pfizer, New York, US) received a conditional marketing authorisation in 2013 that is valid throughout the European Union (see Table 1), [8][9][10] for the treatment of adult chronic myeloid leukaemia (CML) patients in all phases. 11,12 Despite some good responses to second-line TKI therapy, approximately half of patients treated with dasatinib 100 mg daily or nilotinib 400 mg twice daily develop resistance or intolerance 8,13,14 and discontinue therapy.…”

Short overview on the current treatment of chronic myeloid leukemia in chronic phase

“…Bosutinib after imatinib failure demonstrated CCyR rates of 41–48% [20, 23] and MMR rates of 64%. Ponatinib data refer [24] to a highly pretreated population with 58% patients having received three and more TKIs prior to this ponatinib.…”