Page 104 - 2019_01-Haematologica-web

T.P. Hughes et al.
Table 1. Summary of pleural effusion events in dasatinib-treated patients with CML-CP in DASISION and 034/Dose-optimization. Dasatinib-treated patients, n (%)
Patients with PE (any grade), n (%)
Patients with drug-related PE (any grade), n (%)
Grade 1 Grade 2 Grade 3 Grade4
Patients with >1 drug-related PE (any grade), n (%)
Median time to first drug-related PE (any grade), weeks (range)
Grade 1 Grade 2 Grade 3
Median duration of first drug-related PE (any grade), weeks (range) Grade 1
Grade 2
Grade 3
First occurrences of PE (any grade) by patients at risk, n/n at risk (%)*
Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7
DASISION (n=258)
74 (29)
73 (28)
21 (8) 45 (17) 7 (3)
034/Dose-optimization (n=662)
227 (34)
220 (33)
28 (4) 144 (22) 44 (7)
0 4(1)
45 (17)
114 (4-299)
132 (4-299)
114 (6-281)
175 (114-274) 4 (0-223)
7 (1-223)
3 (1-210)
4 (0-25)
20/258 (8) 13/209 (6) 11/184 (6) 14/160 (9) 12/141 (9) NA
NA
134 (20)
60 (1-371)
60 (2-369) 83 (1-371) 105 (3-350) 4 (0-235) 7 (0-80) 3 (0-235) 3 (0-96)
100/662 (15) 37/430 (9) 30/305 (10) 15/230 (7) 17/182 (9) 7/144 (5) 9/133 (7)
*Two patients in 034/Dose-optimization have not been categorized into any year due to missing PE onset date. CML-CP: chronic myeloid leukemia in chronic phase; NA: not applicable; PE: pleural effusion.
clinical practice, pleural effusion observed with dasatinib therapy remains a concern for both patients and pre- scribers.
Risk factors for pleural effusion in dasatinib-treated patients have been described in previous reports, including advanced age, advanced disease, heart disease, preexisting hypertension, hypercholesterolemia, autoimmune disease, rash, drug dose and schedule, and the presence of lympho- cytosis.10,12-14 A correlation with plasma trough level, drug exposure, treatment duration, and depth of response to treatment has been suggested, but not confirmed.15
Here, we present an analysis of the proportion of patients with pleural effusion by grade, and efficacy out- comes in these patients, in dasatinib clinical trials. Additionally, we report the results of multivariate analyses of dasatinib clinical trial data, exploring factors associated with the development of pleural effusion in dasatinib- treated patients.
Methods
Patient populations
DASISION (CA180-056). In the phase 3 dasatinib versus ima- tinib study in treatment-naive CML patients (DASISION [CA180- 056]; clinicaltrials.gov identifier 00481247), 519 patients with newly diagnosed CML-CP were randomized to receive either 100 mg QD dasatinib (n=259) or 400 mg QD imatinib (n=260).16-18 The pri-
mary endpoint was the proportion of patients with confirmed complete cytogenetic responses (CCyR) by 12 months. Patients included in this report had a minimum of 5 years of follow up.19
034/Dose-optimization (CA180-034). In the phase 3 dose-optimiza- tion study in imatinib-resistant or -intolerant CML-CP patients (CA180-034; clinicaltrials.gov identifier 00123474), 670 patients with CML-CP intolerant of or resistant to imatinib were randomized to receive dasatinib 100 mg QD (n=167), 140 mg QD (n=167), 50 mg twice daily (BID; n=168), or 70 mg BID (n=168).20-22 A subset of patients modified their dose over the course of the study; howev- er, analyses of data were performed according to each patient’s ini- tial randomization. The primary endpoint was the percentage of patients with major cytogenetic response (MCyR) after a mini- mum follow up of 6 months. Patients included in this report had a minimum of 7 years of follow up.23
Pooled population of patients with Ph+ leukemia. Patients (N=2712) with Ph+ leukemia who were treated with first- or second-line dasatinib15mgto240mgQDin1of11phase1,2,or3trials were included in these analyses (Online Supplementary Table S1).16,19,21,23-31 DASISION and 034/Dose-optimization were ana- lyzed separately and as part of the pooled population for this report. In total, 324 newly diagnosed patients treated with dasa- tinib 100 mg QD (DASISION [n=258], CA180-363 [n=66]), and 2388 patients with CML (CML-CP [n=1294], advanced phases of CML [n=958]) or Ph+ ALL (n=136) previously treated with ima- tinib were included. Previously treated patients received dasatinib at daily doses ranging from 15 mg to 240 mg administered once or in divided doses daily.
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