Optimizing tolerability of TKI therapy in CML

In this issue of Blood, Kantarjian and colleagues evaluate the safety and tolerability of bosutinib, a new second-generation tyrosine kinase inhibitor (TKI) for treatment of chronic myeloid leukemia (CML) patients in all phases of the disease after failure of initial therapy. The authors propose various measures to avoid and manage side effects associated with the use of the drug.¹ 

Bosutinib is a dual SRC and ABL1 inhibitor with a unique binding mode that accommodates several BCR-ABL1 mutations that confer TKI resistance to imatinib, nilotinib, or dasatinib. In distinction to other inhibitors, bosutinib does not inhibit the platelet-derived growth factor (PDGF) receptors or KIT which might be associated with an individual safety profile.² 

The design of the bosutinib phase 1/2 study was complicated by the need to investigate the drug in a population of patients who had failed 2 or 3 prior lines of therapy. However, based on the favorable data presented by Cortes et al and Khoury et al in this journal, bosutinib (500 mg once daily) has been approved by the US Food and Drug Administration and the European Medicines Agency for patients resistant or intolerant to prior therapy. The exact wording of the indication might show some minor differences between the United States and Europe, but there is a new treatment choice available for patients after resistance to initial treatment.^3,4 

Generally, bosutinib demonstrated acceptable tolerability in patients with Ph⁺ CML and acute lymphoblastic leukemia, with an adverse event profile distinct from that of imatinib, nilotinib, and dasatinib. Mild or moderate gastrointestinal events and rash were the most common side effects. Cytopenias are usually observed during the initial phase of TKI therapy for Ph⁺ leukemias. Toxicities observed with bosutinib were manageable with treatment modification and/or concomitant medication.¹ 

However, in the Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia pivotal phase 3 study (BELA trial), testing bosutinib 500 mg once daily vs imatinib 400 mg once daily in first-line use, bosutinib failed to meet the primary end point: the improvement of the rate of complete cytogenetic remission after 12 months of therapy. Many patients were taken off therapy rather early because of toxicity and were not assessed for cytogenetic response. Despite these observations, bosutinib was associated with a superior major molecular response rate after 1 year of therapy (41% vs 27%). Furthermore, rates of transformations, treatment failures, and deaths were all significantly lower in the bosutinib arm.⁵ 

Bosutinib has been registered with an initial dose of 500 mg per day with the option to increase the dose to 600 mg per day in case of suboptimal response. This recommended dose was derived from a small phase 1 part of the study in patients after imatinib failure. As in other TKI developments, long-term safety data were not available when phase 2 and 3 studies started.⁶ 

For chronic-phase CML patients, a similar situation happened with nilotinib: the recommended second-line dose is 400 mg twice daily but 300 mg twice daily demonstrated better tolerability in first-line use.⁷  With dasatinib, the initial second-line dose was 70 mg twice daily, but dose optimization trials showed the advantage of 100 mg once daily.⁸  Most recently, with ponatinib, the daily dose of 45 mg was associated with a high rate of arterial and venous thrombotic events and a dose reduction has been proposed and will be evaluated systematically.⁹ 

The only exception for dose adjustments is imatinib: the large randomized German CML IV study demonstrated an improved efficacy of tolerability adapted high-dose therapy in first-line use.¹⁰  Initial second-line studies had been performed after failure of interferon α. Such patients, however, do not carry major clones harboring BCR-ABL1 mutations which may require higher doses of imatinib.

All of these observations are based on the different biology of leukemia at diagnosis vs after TKI resistance. The evolution of the disease, in particular, the clonal selection of BCR-ABL1 mutated cells, demands an optimal inhibitory power of the TKI. Thus, in second-line use, acute and chronic side effects might be tolerated and managed with individual measures to achieve best responses. In first-line use, dose should be adapted to reduce or avoid side effects by keeping the best efficacy.

For patients failing imatinib, all 3 second-generation TKIs, including bosutinib, are useful, with ∼40% of patients achieving durable complete cytogenetic remission.⁶  Hence, the analysis and the proposed management recommendations will be of crucial importance for the further use of bosutinib, not only after failure of other TKI, but also for first-line use. Data support the continued clinical development of bosutinib as monotherapy for the treatment of Ph⁺ CML patients. New studies may reveal an optimized daily dose of the drug reducing the incidence and the grading of side effects. Additional experience with bosutinib will further improve the management of toxicities.