Page 64 - Haematologica August 2018

C. Gambacorti-Passerini et al. Table 1. Treatment summary.*
Parameter
Median (range) duration of follow up,† mo
Median (range) time to first dose reduction due to AEs, d Any dose reduction
Reduction to 400 mg/d
Reduction to 300 mg/d
Median (range) cumulative duration of dose reduction due to AEs, d Any dose reduction
Reduction to 400 mg/d
Reduction to 300 mg/d
Discontinued treatment, n (%) Enrolled in extension study AE
PD
Patient request
Unsatisfactory response (efficacy)‡ Death
Investigator request Losttofollowup
Symptomatic deterioration Discontinuation of study by sponsor Other
IM-R (n=195)
46.8 (0.6–96.3)
27.6 (0.2–96.3)
133 (68) 8 (1–981) 24 (1–983)
89 (46)
48 (8–2166)
49 (8–1800) 194 (58–2166)
349 (3–2881) 238 (3–2667) 114 (3–1641)
195 (100) 61 (31) 32 (16) 43 (22) 12 (6) 19 (10) 5 (3)
7 (4) 4(2) 2 (1) 1 (1) 9 (5)
IM-I (n=89)
58.8 (0.6–93.2)
24.2 (0.3–84.3)
76 (85) 14 (1–280) 24 (1–429)
52 (58)
52 (7–1875) 55 (11–1875) 107 (29–1296)
285 (2–2368) 84 (1–2368) 168 (5–1473)
89 (100) 22 (25) 35 (39) 8 (9) 12 (13) 4 (4)
0 1(<1)
4 (4) 13 (5)
Median (range) duration of treatment,† mo
Total (n=284)
54.8 (0.6–96.3)
25.6 (0.2–96.3)
209 (74) 10 (1–981) 24 (1–983)
141 (50)
49 (7–2166)
52 (8–1875) 162 (29–2166)
346 (2–2881) 198 (1–2667) 116 (3–1641)
284 (100) 83 (29) 67 (24) 51 (18) 24 (8) 23 (8)
8 (3)
8 (3) 0 4(1) 0 2(1)
Patients with ≥1 dose interruption due to AEs, n (%)
Median (range) duration of events of dose interruptions, d Median (range) cumulative duration of dose interruptions, d
Patients with ≥1 dose reduction due to AEs, n (%)
3 (3) 1 (1)
1300
AE: adverse event; d: days; IM-I: imatinib-intolerant; IM-R: imatinib-resistant; n: number; mo: months; PD: progressive disease. *In both Parts 1 and 2, patients received treatment until PD, death, unacceptable toxicity, or withdrawal of consent. †One month is defined as 30.4 days. ‡Defined as failure to achieve an optimal response as determined by the investigator.
8%), and more likely to enroll in the extension study (32% vs. 19%) (Online Supplementary Table S3). Ninety-nine (35%) patients completed the 2-year follow up after treat- ment discontinuation (IM-R, n=60; IM-I, n=39). Thirty- two (11%) patients discontinued treatment after year 5, and 83 (29%) patients continued treatment in the exten- sion study.
Efficacy
Most cytogenetic responses to bosutinib occurred with- in two years of initiating treatment (Table 2). By week 12, the cumulative major cytogenetic response (MCyR) rate was 35% (n=93 of 262 evaluable patients), including 22% (n=57) who attained/maintained a CCyR. Of 246 evalu- able patients without a CCyR at baseline, 76 (31%) attained an MCyR and 45 (18%) attained a CCyR. The cumulative MCyR rate observed by year 2 was 58%, including 46% with a CCyR. Patients continued to attain a CCyR after two years, with 10 patients having initial on- treatment CCyR during years 3-5. By year 5, the cumula- tive MCyR CCyR rates were 60% (n=156 of 262 evaluable patients) and 50% (n=130), respectively; 57% (n=141 of 246 evaluable patients) newly-attained an MCyR and 47% (n=116) newly-attained a CCyR. The cumulative MMR rate was 42% (n=82 of 197 evaluable patients). Cytogenetic responses by both two and five years were similar in the IM-R and IM-I subgroups, whereas MMR rates were higher among IM-R patients at both time points (Table 2). Younger patients were more likely to
have at least an MCyR (61% vs. 54%); however, rates of CCyR were similar among patients aged under 65 years and 65 years or over (Online Supplementary Table S3).
Among responders, the Kaplan-Meier estimated proba- bility of maintaining a response was similar at years 5 and 2: 71% and 76%, respectively, for an MCyR; 69% and 78% for a CCyR; and 68% and 70% for MMR (Table 2 and Figure 1). Overall, 41 of 156 (26%) responders lost MCyR, 37 of 130 (28%) lost CCyR, and 25 of 82 (30%) lost MMR. Few patients lost response after year 2 (7 lost MCyR, 10 lost CCyR, and 2 lost MMR). At the last assess- ment prior to discontinuation, 81% (n=127) of all 156 responders had an MCyR and 68% (n=106) had a CCyR; of 141 responders without a baseline CCyR, 111 attained an MCyR and 93 attained a CCyR.
Among 132 patients (IM-R, n=81; IM-I, n=51) who required a dose reduction to 400 mg/day due to an AE, 81 (61%; IM-R, 63%; IM-I, 59%) had an MCyR, including 67 of 110 (61%) who did not have a CCyR at baseline (Online Supplementary Table S4). Fifty-seven (43%) patients first achieved an MCyR after dose reduction, 19 (14%) achieved an MCyR before and maintained it after dose reduction, and 5 (4%) lost their MCyR after dose reduc- tion. Among 50 patients (IM-R, n=32; IM-I, n=18) who had a dose reduction to 300 mg/day due to an AE, 29 (58%; IM-R, 69%; IM-I, 39%) had an MCyR, including 25 of 43 (58%) without a CCyR at baseline. Twenty (40%) patients achieved an MCyR before and maintained it after dose reduction, 8 (16%) first achieved MCyR after a dose
haematologica | 2018; 103(8)