Dose Optimization in Elderly CML Patients Treated with Bosutinib after Intolerance or Failure of First-Line Tyrosine Kinase Inhibitors

• Published in: Blood 2019-11, Vol.134 (Supplement_1), p.496-496
• Main Authors: Castagnetti, Fausto, Gugliotta, Gabriele, Bocchia, Monica, Trawinska, Malgorzata Monika, Capodanno, Isabella, Bonifacio, Massimiliano, Rege Cambrin, Giovanna, Crugnola, Monica, Binotto, Gianni, Elena, Chiara, Lucchesi, Alessandro, Bergamaschi, Micaela, Albano, Francesco, Luciano, Luigiana, Sorà, Federica, Lunghi, Francesca, Stagno, Fabio, Pregno, Patrizia, Iurlo, Alessandra, Scortechini, Anna Rita, Cedrone, Michele, Spadano, Raffaele, Trabacchi, Elena, Lunghi, Monia, Spinosa, Giuseppina, Ferrero, Dario, Pini, Massimo, Rapezzi, Davide, Nocilli, Laura, Cavo, Michele, Saglio, Giuseppe, Pane, Fabrizio, Baccarani, Michele, Rosti, Gianantonio
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-127514

Background and Rationale. Bosutinib (BOS), dasatinib (DAS) and nilotinib (NIL) are 2nd generation TKIs with similar second-line efficacy. The use of DAS and NIL may be burdened by pulmonary, infectious, cardiovascular and metabolic complications; these complications are more frequent and more clinically relevant in the elderly. BOS could represent an important therapeutic option in elderly patients intolerant to or failing a first-line TKI, but the dose of 500 mg OAD may be higher than necessary. Aims. All TKIs have been tested at a fixed initial dose, with dose adjustment in case of toxicity or treatment failure. On the contrary, the aim of our study was to evaluate in elderly CML patients if second-line BOS was effective and better tolerated at doses lower than 500 mg OAD, beginning with 200 mg OAD, then increasing the dose to 300 OAD or 400 mg OAD according to the molecular response, to find the minimum effective dose. Methods. A prospective phase 2 single-arm multicenter study has been designed by the GIMEMA CML Working Party (NCT02810990). Study design: all patients started with 200 mg OAD for 2 weeks (“run-in” period), then the dose was increased to 300 mg OAD; after 3 months, patients with BCR-ABLIS transcript ≤ 1% continued 300 mg OAD, while in patients with transcript > 1% the dose is furtherly increased to 400 mg OAD. In responsive patients, BOS dose was maintained, 300 mg or 400 mg OAD. Key inclusion criteria: > 60 yrs old, chronic phase CML, intolerance or failure of any first-line TKI (2013 ELN criteria), absence of T315I or V299L mutation. Sixty-three patients have been enrolled. The primary endpoint was the proportion of patients in MR3 at 1 year. Definitions: MR3, BCR-ABLIS < 0.1%; MR4, BCR-ABLIS < 0.01% with > 10.000 copies; MR4.5, BCR-ABLIS < 0.0032% with > 32.000 copies. Results. Median age: 73 yrs (range 60-90). Age distribution: 60-69 yrs, 18 pts (29%); 70-79 yrs, 31 pts (49%); > 80 yrs, 14 pts (22%). Sokal score at diagnosis: low 19%, intermediate 49%, high 32%. Reasons for switching to BOS: intolerance 63%, resistance 37%. First-line TKI: imatinib 83%, DAS 11%, NIL 6% (same TKI distribution in intolerant and resistant patients). Median follow-up: 9 mos (range 1-30). Overall, 10/63 patients had a dose-increase to 400 mg OAD, 49/63 to 300 mg OAD, while 4/63 continued on BOS 200 mg OAD without any dose increase. At baseline, 13 patients were already in MR3. The MR3 rates by 3 and 6 months were 43% and 56%, respectively. The cumulative r