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T.P. Hughes et al.
those with a response. This supports a hypothesis that pleural effusion may be a marker for longevity of treat- ment: As patients do well on dasatinib and remain on treatment longer, they may be more likely to develop a pleural effusion. Further investigation into the relation between duration of treatment and pleural effusion is war- ranted.
Clinical data on molecular responses for patients who experienced pleural effusions during treatment with dasa- tinib are limited, though our observations indicate that patients who experienced pleural effusions while on dasa- tinib had similar responses to treatment as those who did not develop pleural effusion. A retrospective study exam- ining dasatinib-related pleural effusion in CML patients across 21 hematologic centers in Italy revealed that at the time of the first effusion, 28.6% were in MMR and 37.8% were in MR4.5.39
In summary, pleural effusion is an adverse event seen disproportionately in patients treated with dasatinib;
however, the management of pleural effusion by dose reductions does not negatively affect the response rate to dasatinib. Advanced age and longevity of treatment were found to be predictive risk factors for the development of pleural effusion.
Acknowledgments
The authors would like to thank the patients and families for making these Bristol-Myers Squibb-sponsored trials possible.
Funding
This analysis was supported by funding from Bristol-Myers Squibb. The Bristol-Myers Squibb policy on data sharing may be found at: https://www.bms.com/researchers-and- partners/independent-research/data-sharing-request- process.html. Professional medical writing and editorial assis- tance was provided by Samantha L. Dwyer, PhD, and Jessica Franciosi, PhD, of StemScientific, an Ashfield Company, part of UDG Healthcare plc, funded by Bristol-Myers Squibb.
References
1. Sprycel (dasatinib) [prescribing informa- tion]. Princeton, NJ: Bristol-Myers Squibb Company; 2017.
2. Kantarjian H, Cortes J, Kim DW, et al. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in acceler- ated phase resistant or intolerant to ima- tinib: 15-month median follow-up. Blood. 2009;113(25):6322-6329.
3. Lilly MB, Ottmann OG, Shah NP, et al. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: results from a phase 3 study. Am J Hematol. 2010;85(3):164-170.
4. Saglio G, Hochhaus A, Goh YT, et al. Dasatinib in imatinib-resistant or imatinib- intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 mil- ligrams twice daily. Cancer. 2010; 116(16):3852-3861.
5. Gleevec (imatinib) [prescribing informa- tion]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2017.
6. Tasigna (nilotinib) [prescribing informa- tion]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2017.
7. Porkka K, Khoury HJ, Paquette RL, Matloub Y, Sinha R, Cortes JE. Dasatinib 100 mg once daily minimizes the occur- rence of pleural effusion in patients with chronic myeloid leukemia in chronic phase and efficacy is unaffected in patients who develop pleural effusion. Cancer. 2010; 116(2):377-386.
8. Mustjoki S, Ekblom M, Arstila TP, et al. Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy. Leukemia. 2009;23(8):1398-1405.
9. Agrawal V, Doelken P, Sahn SA. Pleural fluid analysis in chylous pleural effusion. Chest. 2008;133(6):1436-1441.
10. Quintas-Cardama A, Kantarjian H, O'Brien S, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin
Oncol. 2007;25(25):3908-3914.
11. Buettner R, Mesa T, Vultur A, Lee F, Jove R.
Inhibition of Src family kinases with dasa- tinib blocks migration and invasion of human melanoma cells. Mol Cancer Res. 2008;6(11):1766-1774.
12. Wang X, Roy A, Hochhaus A, Kantarjian HM, Chen T-T, Shah NP. Differential effects of dosing regimen on the safety and efficacy of dasatinib: retrospective expo- sure–response analysis of a Phase III study. Clin Pharmacol. 2013;5:85-97.
13. Conchon M, Freitas CM, Rego MA, Braga Junior JW. Dasatinib—clinical trials and management of adverse events in imatinib resistant/intolerant chronic myeloid leukemia. Rev Bras Hematol Hemoter. 2011;33(2):131-139.
14. de Lavallade H, Punnialingam S, Milojkovic D, et al. Pleural effusions in patients with chronic myeloid leukaemia treated with dasatinib may have an immune-mediated pathogenesis. Br J Haematol. 2008; 141(5):745-747.
15. Wang X, Roy A, Hochhaus A, Kantarjian HM, Chen TT, Shah NP. Differential effects of dosing regimen on the safety and effica- cy of dasatinib: retrospective exposure- response analysis of phase III study. Clin Pharmacol. 2013;10(5):85-97.
16. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diag- nosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010; 362(24):2260-2270.
17. Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012; 119(5):1123-1129.
18. Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow- up from a randomized phase 3 trial (DASI- SION). Blood. 2014;123(4):494-500.
19. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results of DASISION: the Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin Oncol.
2016;34(20):2333-2340.
20. Shah NP, Guilhot F, Cortes JE, et al. Long-
term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood. 2014;123(15):2317-2324.
21. Shah NP, Kantarjian HM, Kim DW, et al. Intermittent target inhibition with dasa- tinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resis- tant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol. 2008;26(19):3204-3212.
22. Shah NP, Kim DW, Kantarjian H, et al. Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chron- ic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica. 2010;95(2):232-240.
23. Shah NP, Rousselot P, Schiffer CA, et al. Dasatinib in imatinib-resistant or -intoler- ant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA180-034. Am J Hematol. 2016; 91(9):869-874.
24. Saglio G, le Coutre P, Cortes J, et al. Safety and tolerability of dasatinib in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL): pooled analysis of over 2400 patients. Haematologica. 2014;99(suppl); abstr P884.
25. Guilhot F, Apperley J, Kim DW, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood. 2007;109(10):4143-4150.
26. Cortes J, Rousselot P, Kim DW, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood. 2007;109(8):3207-3213.
27. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematolog- ic and cytogenetic responses in chronic- phase chronic myeloid leukemia after fail-
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