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T.P. Hughes et al.
Table 4. Efficacy of dasatinib by occurrence of drug-related pleural effusion in dasatinib-treated patients with CML-CP in DASISION and 034/Dose-optimization.
Dasatinib-treated patients, n (%)
034/Dose-optimization† (N=662)
(n=185) (n=73) (n=28) (n=45) (n=258) (n=442) (n=220) (n=86) (n=134) (n=662)
DASISION* (N=258)
NoPE WithPE 1PE >1PE Total NoPE WithPE 1PE >1PE Total
Best response to dasatinib‡ MMR
MR4.5 CCyR
Median MMR duration,
months (range)
138 60 24 36 198 162 117 37 80 279
(75) (82) (86) (80) (77) (37) (53) (43) (60) (42) 78 37 NA NA 115 57 40 NA NA 97
(42) (51) (45) (13) (18) (15) 155 71 NA NA 226 193 146 NA NA 339
(84) (97)
NA NA
(88) (44) (66)
(51)
42 43
39
(0-68)
45
(0-70)
48 NA
(0-70)
NA
34
(0-85)
(0-84)
(0-90)
*Both on-study and follow-up patients are included. †Only on-study patients are included. ‡All responses listed were those obtained at end of study. For DASISION, that was 60 months, and for 034/Dose-optimization, that was 84 months. CCyR: complete cytogenetic response; CML-CP: chronic myeloid leukemia in chronic phase; MMR: major molecular response, BCR-ABL1 transcripts ≤0.1% on the International Scale (IS) corresponding to a 3-log reduction from the standardized baseline; MR4.5: BCR-ABL1 transcripts ≤0.0032% (IS) corresponding to a 4.5-log reduction from the standardized baseline; NA: not applicable; PE: pleural effusion.
60 years; patients who did not develop pleural effusion had a median age of 53 years (Table 3). Advanced age was found to be a significant risk factor for pleural effusion in patients treated with 100 mg QD dasatinib in a multivari- ate model (OR 1.074; 95% CI 1.035-1.114; Figure 1B). In addition to age, a strong statistical correlation was observed between the depth of MR and the overall inci- dence of pleural effusion, for those treated with 100 mg QD dasatinib (OR 3.851; 95% CI 1.182-12.552) (Figure 1B). Both age and depth of MR were confirmed as risk fac- tors by a reduced model multivariate analysis.
Lymphocytosis was not found to be associated with the development of pleural effusion in a multivariate analysis of patients treated with 100 mg QD dasatinib (Figure 1B); overall, 17 (10%) patients had lymphocytosis before the onset of pleural effusion versus 0 after.
No other associations were found between pleural effu- sion and the remaining variables analyzed via multivariate analysis (Figure 1B).
Pooled DASISION and 034/Dose-optimization. To assess the relation between potential prognostic factors and pleural effusion in a larger population, patients treated with 100 mg QD dasatinib from both DASISION (n=258) and 034/Dose-optimization (n=165) were pooled (n=423), and a multivariate analysis was performed (Figure 1C). In this pooled population, patients in MMR (OR 2.482; 95% CI 1.191-5.174) and MR4.5 (OR 2.756; 95% CI 1.30-5.841) had a significantly increased risk of developing pleural effusion compared with patients not in MMR. Increased age also was found to be a significant risk factor (OR 1.069; 95% CI 1.048-1.091).
In the pooled DASISION and 034/Dose-optimization patient population, 40 (9%) patients had a history of lung disease, and 13 (3%) patients had a history of autoim- mune disease. When the relationship between pleural effusion and prior lung disease, autoimmune disease, or skin rash was assessed using a reduced model multivariate analysis, no association was found. Average daily dasa- tinib dose also was not found to be a risk factor using the reduced model.
In the reduced multivariate model, imatinib-intolerant
patients receiving second-line dasatinib had a significantly increased risk of developing pleural effusion compared with first-line patients (OR 0.232; 95% CI 0.086-0.623).
Efficacy of patients with pleural effusion
DASISION. Of 73 dasatinib-treated patients in the DASISION trial with drug-related pleural effusion, 97% achieved CCyR, 82% had MMR, and 51% had MR4.5 (Table 4). These results are comparable to those in patients who did not have drug-related pleural effusion, and reflec- tive of the overall responses for the entire study popula- tion.17 Duration of MMR was 39 months for those with 1 drug-related pleural effusion and 45 months for those with >1 (Table 4). Five-year progression-free survival (PFS) was similar for patients with or without drug-related pleural effusion (Online Supplementary Figure S1A). Of patients who experienced drug-related pleural effusion events, 5/73 (7%) progressed, whereas 21/185 (11%) patients who did not experience pleural effusion events pro- gressed. Overall survival (OS) was similar in patients who did or did not experience drug-related pleural effusion as well (Online Supplementary Figure S1B).
Many patients did achieve cytogenetic or molecular responses prior to the first occurrence of drug-related pleu- ral effusion, and these responses were often maintained or improved despite dose modifications required to manage the effusion (Online Supplementary Table S2). Sixty-five patients (89% of patients with a drug-related pleural effu- sion) had CCyR, 35 (48%) had MMR, and 12 (16%) had MR4.5 prior to experiencing their first pleural effusion event. Following the first pleural effusion, 55 patients maintained/improved to CCyR. Similarly, 19 patients maintained/improved to MMR, and 32 patients main- tained/improved to MR4.5. One patient went from MMR to BCR-ABL1 0.1-≤1% following their first pleural effu- sion event. No patient had BCR-ABL1 >10% or lost any cytogenetic response after their first event.
034/Dose-optimization. Of 220 dasatinib-treated patients in 034/Dose-optimization who had drug-related pleural effusion, 66% achieved CCyR, 53% had MMR, and 18% had MR4.5 (Table 4). As seen in the DASISION trial, molec-
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