Abstract
Bosutinib is a second-generation tyrosine kinase inhibitor (2GTKI) approved at 400 mg once daily (QD) as first-line therapy in patients with chronic myeloid leukemia (CML) patients and at 500 mg QD in patients who are resistant to or intolerant of prior therapy. In clinical practice, bosutinib is often given to patients who have failed imatinib, nilotinib, and dasatinib (i.e., as fourth-line treatment), despite the limited data on its clinical benefit in this setting. We have retrospectively evaluated the results of bosutinib in a series of 62 CML patients who have failed to prior treatment with all three, imatinib, nilotinib, and dasatinib. Median time on TKI treatment before bosutinib start was 105 (9–163) months, and median duration on bosutinib was 9 months (1–30). Overall, probabilities to achieve complete cytogenetic response (CCyR) and major molecular response (MMR) were 25% and 24% respectively. After a median follow-up period of 14 months, the event-free survival and progression-free survival were 68 and 85%, respectively. Sixty-four percent of patients in CCyR at the time of bosutinib start were able to achieve MMR. In contrast, patients without CCyR, probabilities to obtain CCyR and MMR were 25% and 14%. Bosutinib was well tolerated in this heavily pretreated patients’ cohort. Pleural effusions and diarrhea were the most frequent grade II–IV side effects, leading to treatment discontinuation in 16% of patients. Bosutinib is an effective treatment option for patients who have failed previous 2GTKIs due to intolerance. However, efficacy seems to be related to the molecular response that the patient achieved prior to bosutinib.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, Cervantes F, Clark RE, Cortes JE, Guilhot F, Hjorth-Hansen H, Hughes TP, Kantarjian HM, Kim DW, Larson RA, Lipton JH, Mahon FX, Martinelli G, Mayer J, Muller MC, Niederwieser D, Pane F, Radich JP, Rousselot P, Saglio G, Saussele S, Schiffer C, Silver R, Simonsson B, Steegmann JL, Goldman JM, Hehlmann R (2013) European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 122:872–884
Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqué C, Shah NP, Chuah C, Casanova L, Bradley-Garelik B, Manos G, Hochhaus A (2016) Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial. J Clin Oncol 34:2333–2340
Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, le Coutre PD, Etienne G, Dorlhiac-Llacer PE, Clark RE, Flinn IW, Nakamae H, Donohue B, Deng W, Dalal D, Menssen HD, Kantarjian HM (2016) Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia 30:1044–1054
Giles FJ, le Coutre PD, Pinilla-Ibarz J, Larson RA, Gattermann N, Ottmann OG, Hochhaus A, Radich JP, Saglio G, Hughes TP, Martinelli G, Kim DW, Novick S, Gillis K, Fan X, Cortes J, Baccarani M, Kantarjian HM (2013) Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia 27:107–112
Shah NP, Guilhot F, Cortes JE, Schiffer CA, le Coutre P, Brummendorf TH, Kantarjian HM, Hochhaus A, Rousselot P, Mohamed H, Healey D, Cunningham M, Saglio G (2014) Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood 123:2317–2324
Jabbour E, Kantarjian H, Cortes J (2015) Use of second- and third-generation tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia: an evolving treatment paradigm. Clin Lymphoma Myeloma Leuk 15:323–334
Syed YY, McCormack PL, Plosker GL (2014) Bosutinib: a review of its use in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. BioDrugs 28:107–120
Cortes JE, Khoury HJ, Kantarjian HM, Lipton JH, Kim DW, Schafhausen P, Matczak E, Leip E, Noonan K, Brümmendorf TH, Gambacorti-Passerini C (2016) Long-term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib. Am J Hematol 91:1206–1214
Gambacorti-Passerini C, Cortes JE, Lipton JH, Kantarjian HM, Kim DW, Schafhausen P, Crescenzo R, Bardy-Bouxin N, Shapiro M, Noonan K, Leip E, DeAnnuntis L, Brümmendorf TH, Khoury HJ (2018) Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study. Haematologica 103:1298–1307
Poch Martell M, Sibai H, Deotare U, Lipton JH (2016) Ponatinib in the therapy of chronic myeloid leukemia. Expert Rev Hematol 9:923–932
Redaelli S, Piazza R, Rostagno R, Magistroni V, Perini P, Marega M, Gambacorti-Passerini C, Boschelli F (2009) Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol 27:469–471
Puttini M, Coluccia AM, Boschelli F et al (2006) In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res 66:11314–11322
Apperley JF (2015) Chronic myeloid leukaemia. Lancet 385:1447–1459
Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim DW, Dyagil I, Glushko N, Milojkovic D, le Coutre P, Garcia-Gutierrez V, Reilly L, Jeynes-Ellis A, Leip E, Bardy-Bouxin N, Hochhaus A, Brümmendorf TH (2018) Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol 36:231–237
Garcia-Gutierrez V, Martinez-Trillos A, Lopez Lorenzo JL et al (2015) Bosutinib shows low cross intolerance, in chronic myeloid leukemia patients treated in fourth line. Results of the Spanish compassionate use program. Am J Hematol 90:429–433
Khoury HJ, Gambacorti-Passerini C, Brummendorf TH (2018) Practical management of toxicities associated with bosutinib in patients with Philadelphia chromosome-positive chronic myeloid leukemia. Ann Oncol 29:578–587
Gambacorti-Passerini C, Lipton J, Hochhaus A et al (2018) Cross-intolerance with bosutinib after prior tyrosine kinase inhibitors (TKIs) in patients (pts) with Philadelphia chromosome–positive (Ph+) leukemia: phase 1/2 study update. J Clin Oncol 36(15_suppl):7062–7062
Cortes JE, Gambacorti-Passerini C, Kim DW et al (2017) Effects of bosutinib treatment on renal function in patients with Philadelphia chromosome-positive leukemias. Clin Lymphoma Myeloma Leuk 17:684–695 e686
Kantarjian HM, Mamolo CM, Gambacorti-Passerini C, Cortes JE, Brümmendorf TH, Su Y, Reisman AL, Shapiro M, Lipton JH (2018) Long-term patient-reported outcomes from an open-label safety and efficacy study of bosutinib in Philadelphia chromosome-positive chronic myeloid leukemia patients resistant or intolerant to prior therapy. Cancer 124:587–595
Levy MY, McGarry LJ, Huang H et al (2018) Benefits and risks of ponatinib versus bosutinib following treatment failure of two prior tyrosine kinase inhibitors in patients with chronic phase chronic myeloid leukemia: a matching-adjusted indirect comparison. Curr Med Res Opin:1–17
Hochhaus A, Baccarani M, Deininger M, Apperley JF, Lipton JH, Goldberg SL, Corm S, Shah NP, Cervantes F, Silver RT, Niederwieser D, Stone RM, Dombret H, Larson RA, Roy L, Hughes T, Müller MC, Ezzeddine R, Countouriotis AM, Kantarjian HM (2008) Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 22:1200–1206
Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM, ENESTnd Investigators (2010) Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362:2251–2259
Dorer DJ, Knickerbocker RK, Baccarani M, Cortes JE, Hochhaus A, Talpaz M, Haluska FG (2016) Impact of dose intensity of ponatinib on selected adverse events: multivariate analyses from a pooled population of clinical trial patients. Leuk Res 48:84–91
Author information
Authors and Affiliations
Consortia
Contributions
VGG and JLS designed the study, coordinated the group, and wrote the manuscript. DM and JHB contributed to clinical data collection and wrote the manuscript. The other authors contributed to clinical data collection and reviewed the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
VGG: Novartis: Speaker Honoraria, advisory committees; BMS: Speaker Honoraria, advisory committees; Pfizer: Speaker Honoraria, advisory committees. Incyte: Advisory committees; JLS: Novartis: Consultancy, Speaker Honoraria, advisory committees; research grants; BMS: Consultancy, Speaker Honoraria, advisory committees; research grants; Pfizer: Consultancy, Speaker Honoraria, advisory committees; research grants: Incyte: Advisory committees. FC: Novartis: Consultancy, Speaker Honoraria, advisory committees; research grants; BMS: Consultancy, Speaker Honoraria, advisory committees; research grants; Pfizer: Consultancy, Speaker Honoraria, advisory committees; research grants: Incyte: Advisory committees. The rest of authors declare no conflict of interest.
Electronic supplementary material
ESM 1
(DOC 146 kb)
Rights and permissions
About this article
Cite this article
García-Gutiérrez, V., Milojkovic, D., Hernandez-Boluda, J.C. et al. Safety and efficacy of bosutinib in fourth-line therapy of chronic myeloid leukemia patients. Ann Hematol 98, 321–330 (2019). https://doi.org/10.1007/s00277-018-3507-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-018-3507-2