Page 65 - Haematologica August 2018

Long-term second-line bosutinib for CP CML
Table 2. Efficacy outcomes at two and five years. Parameter
Response,*† n. of evaluable patients (%) [95% CIs] Cumulative MCyR
Cumulative CCyR Cumulative MMR
Probability of maintaining
MCyR, % (95% CI)‡
Probability of maintaining CCyR, % (95% CI)‡
Probability of maintaining
MMR, % (95% CI)‡
Cumulative incidence of progression or death,§
% (95% CI) ǁ Cumulative incidence of transformation to AP/BP CML,
% (95% CI) OS,‡,# % (95% CI)
IM-R (n=195)
IM-I (n=89)
Total (n=284)
Year 2
102/182 (56) [48.5‒63.4] 79/182 (43) [36.1‒50.9] 42/127 (33) [25.0‒42.0]
72.0
(62.1−79.8)
77.3 (66.8−84.9)
62.9
(48.5−74.2)
19.0 (14.2–25.4)
5.6
(3.2–10.0) 88.2
(82.7–92.1)
Year 5
107/182 (59) [51.3‒66.0] 88/182 (48) [40.9‒55.9] 57/127 (45) [36.1‒54.0]
67.2
(56.8−75.6)
69.6 (57.9−78.6)
62.9
(48.5−74.2)
23.1 (17.9–29.8)
6.2
(3.6–10.6) 80.8
(73.8–86.0)
Year 2
49/80 (61) [49.7‒71.9] 41/80 (51) [39.8‒62.6] 20/70 (29) [18.4‒40.6]
86.3
(72.0−93.6)
78.9 (62.2−88.9)
87.2
(65.3−95.7)
6.7 (3.1–14.6)
2.2
(0.6–8.8) 97.7
(91.0–99.4)
Year 5
49/80 (61) [49.7‒71.9] 42/80 (53) [41.0‒63.8] 25/70 (36) [24.6‒48.1]
79.8
(63.1−89.5)
68.2 (49.5−81.3)
81.4
(57.1−92.7)
10.1 (5.4–18.8)
2.2
(0.6–8.8) 89.6
(79.1–95.0)
Year 2
151/262 (58) [51.4‒63.7] 120/262 (46) [39.7‒52.0] 62/197 (31) [25.1‒38.5]
76.4
(68.5−82.5)
77.8 (69.2−84.2)
70.0
(58.4−79.0)
15.1 (11.5–19.9)
4.6
(2.7–7.8) 91.2
(87.1–94.0)
Year 5
156/262 (60) [53.3‒65.5] 130/262 (50) [43.4‒55.8] 82/197 (42) [34.7‒48.8]
71.1
(62.6−78.0)
69.3 (59.7−77.0)
68.3
(56.4−77.5)
19.0 (15.0–24.2)
4.9
(3.0–8.2) 83.5
(78.1–87.7)
n: number; MCyR: major cytogenetic response (complete + partial); CCyR: complete cytogenetic response; MMR: major molecular response; CI: Confidence Interval; AP: accel- erated phase; BP: blast phase; CML: chronic myeloid leukemia; IM-I: imatinib intolerant; IM-R: imatinib-resistant; OS: overall survival. *To be considered a responder for MCyR or CCyR,the patient must have improved from their baseline assessment or maintained their baseline response.To be considered a responder for MMR,a patient must have had a ≥3-log reduction from standardized baseline, a detectable BCR-ABL1 transcript at baseline or postbaseline, and must have maintained or attained a CCyR. Patients from sites in China,India,Russia and South Africa were not assessed for molecular response.Three patients achieved their initial MMR after year 5.†Evaluable patients had received ≥1 bosu- tinib dose and had a valid baseline cytogenetic assessment.‡Based on Kaplan-Meier estimates.Results for MCyR and CCyR are based on both maintained and achieved respons- es. §Based on cumulative incidence adjusting for competing risk of treatment discontinuation without progressive disease or death; progressive disease was defined as transfor- mation to accelerated or blast phase CML, increasing white blood cell count (doubling over ≥1 month with second count >20×109/L and confirmed ≥1 week later), or loss of confirmed complete hematologic response or unconfirmed MCyR.ǁBased on cumulative incidence adjusting for competing risk of treatment discontinuation without transfor- mation.#Per protocol,patients were followed for OS for two years after treatment discontinuation.Analysis includes data from long-term extension study.
reduction to 300 mg/day, and one (2%) patient lost MCyR. Among patients who achieved an MCyR after a dose reduction, median duration of response (non-Kaplan- Meier) was longer for patients receiving 400 mg/day versus 300 mg/day (167 days vs. 17 days); median MCyR dura- tions (non-Kaplan-Meier) were similar in patients who had a response before and after dose reduction (283 days vs. 260 days) (Online Supplementary Table S4).
Of the 224 (79%) patients with a known baseline muta- tion status, 79 (35%) had at least one mutation in the BCR-ABL1 kinase domain, most of whom were in the IM- R cohort [IM-R, n=73 of 156 (47%); IM-I, n=6 of 68 (9%)] (Online Supplementary Table S5). Thirteen patients had multiple mutations, all of whom were IM-R. A total of 43 unique BCR-ABL1 mutations were evident, most com- monly F359V (n=9), M351T (n=8), M244V (n=6), G250E (n=6), and T315I (n=9). Among evaluable patients with a mutation other than T315I, most (44 of 69, 64%) attained/maintained an MCyR; response rates were simi- lar among patients without a mutation (75 of 130, 58%) and appeared lower among those with multiple mutations (6 of 12; 50%). Among evaluable patients with mutations that are sensitive (n=30), moderately resistant (n=12), and highly resistant (n=12) to bosutinib (see Figure 2 legend for definitions), the cumulative MCyR rates were 67%, 58%, and 33%, respectively, with corresponding CCyR rates of 57%, 42%, and 33%. Among evaluable patients with mutations of unknown sensitivity (n=24) and patients for whom mutation status was unknown (n=54), the MCyR
rates were 63% and 65%, respectively, with correspon- ding CCyR rates of 50% and 57%.
Of 104 (37%) patients evaluated for BCR-ABL1 kinase domain mutations before and during bosutinib therapy, 26 had at least one newly-emerging mutation; this was most commonly T315I (n=9), V299L (n=5), and M244V (n=2). Fourteen of the 26 patients with newly-emerging muta- tions also had at least one BCR-ABL1 mutation present at baseline. Four patients were enrolled in the extension study; the remaining 22 discontinued because of PD (n=12), unsatisfactory response (n=6), AE (grade 2 liver toxicity; n=1), death (sepsis unrelated to bosutinib; n=1), and other (n=2). Four patients achieved a best response of partial cytogenetic response (PCyR) and 8 achieved a CCyR; 12 patients achieved only a CHR as a best response, and 2 patients had no response.
Transformations and survival outcomes
On-treatment transformation to AP/BP CML occurred in 15 (IM-R, n=13; IM-I, n=2) patients overall, with 9 patients transforming to AP (IM-R, n=7; IM-I, n=2), and 6 patients transforming to BP (all IM-R). The cumulative incidence at year 5 was 5% overall (IM-R, 6%; IM-I, 2%); 95% of patients discontinued treatment without transfor- mation. Among the baseline and on-treatment factors examined, only higher baseline peripheral blood blasts was predictive of on-treatment transformation (P=0.0011).
Despite being initially classified as having progressed to AP, 2 patients did well on bosutinib therapy for two years
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