Page 69 - Haematologica August 2018

Long-term second-line bosutinib for CP CML
year) were experienced by patients during year 1 (99.6%) of treatment, with rates somewhat lower in years 2 (74%), 3 (68%), 4 (52%), and 5 (57%) (Figure 4). Common AEs (in >5 patients) newly-occurring in year 3 were cough [5% (n=8)], increased blood creatinine [5% (n=7)], and pyrexia [4% (n=6)]; most events were grade 1/2. Common newly-occurring AEs in year 4 were increased blood crea- tinine [5% (n=6)] and pleural effusion [5% (n=7)]; 2 events (both grade 4 pleural effusion considered probably not related to bosutinib) resulted in hospitalization. No newly-occurring AEs were reported in more than 5 patients in year 5.
Adverse events led to treatment discontinuation in 69 (24%) patients throughout the study, including one who also discontinued due to PD and another who discontin- ued due to subject request as the primary reason. AEs resulting in treatment discontinuation in 2% or more of patients overall were thrombocytopenia [6% (n=17)], neu- tropenia [2% (n=6)], and alanine aminotransferase increased [2% (n=6)]. Of these 69 patients, 28 (41%) dis- continued treatment without attempting a dose reduction to less than 500 mg/day. The majority (86%) of discontin- uations due to AEs occurred during the first two years of treatment (Online Supplementary Table S2). AEs led to treat- ment discontinuation in 7 patients in years 3-5: coronary artery disease, scleroderma, and renal failure in year 3; ascites and serositis (same patient), increased blood creati- nine, and pulmonary hypertension in year 4; and throm- bocytopenia in year 5.
Although diarrhea was the most common AE [IM-R, 86% (n=167); IM-I, 85% (n=76)], in most instances this was grade 1 or 2 [IM-R, 76% (n=149); IM-I, 75% (n=67)] (Online Supplementary Table S6). Only 3 (2%) IM-R and one (1%) IM-I patient discontinued bosutinib treatment primarily because of diarrhea, all within the first two years. Diarrhea (any grade) occurred most frequently within year 1 (84%) with a median (range) time to first occurrence of 2 (1-1330) days; only 4 patients experienced diarrhea for the first time during years 2-5 (Figure 4).
Cardiac AEs occurred in 37 (13%) patients [IM-R, 13% (n=25); IM-I, 14% (n=12)], 12 (32%) of whom had a med- ical history of these events; maximum grade 3, 4, and 5 cardiac AEs occurred in 11 (4%), 5 (2%), and 2 (1%) patients, respectively (Online Supplementary Table S6). The most common cardiac AEs (occurring in ≥5 patients) were pericardial effusion [3% (grade 3/4, 1%)], congestive car- diac failure [2% (grade 3/4, 2%)], atrial fibrillation [2% (grade 3/4, 1%)], bradycardia [2% (grade 3/4, 1%)], and cardiac failure [2% (grade 3/4, 1%)]. Twelve (4%) patients [IM-R, 3% (n=6); IM-I, 7% (n=6)] experienced cardiac AEs considered by the investigator to be treatment-related, only 3 of whom experienced grade 3/4 events. The medi- an (range) time to first cardiac event was 184 (1-2563) days with the incidence of newly-occurring cardiac AEs decreasing after year 1 (Figure 4). Cardiac AEs led to treat- ment discontinuation in one patient (cardiac failure in year 2) and death in 2 patients (both congestive heart failure unrelated to bosutinib, occurring in years 3 and 7).
Twenty-two (8%) patients [IM-R, 7% (n=13); IM-I, 10% (n=9)] had vascular AEs including 8 (36%) who had a medical history of vascular events; 11 (4%) patients had grade 3/4 vascular AEs (Online Supplementary Table S6). In 4 (1%) patients [IM-R, 2% (n=3); IM-I, 1% (n=1)], vascular AEs were considered by the investigator to be treatment- related, only one of whom experienced a grade 3/4 vascu-
lar event. Most vascular AEs initially occurred within two years with a median (range) time to onset of 548 (47-2452) days. Only one patient discontinued treatment due to vas- cular AEs (coronary artery disease in year 3). No patients died because of vascular AEs. Twenty-six (9%) patients [IM-R, 10% (n=19); IM-I, 8% (n=7)] experienced hyper- tension-related AEs, 10 (38%) of whom had a history of vascular events. Events were of low severity in the major- ity of these patients (maximum grade 1/2, n=18; grade 3, n=8; no grade ≥4) and 5 (2%) experienced events consid- ered by the investigator to be related to treatment; how- ever, no patients discontinued due to hypertension-related AEs. As with vascular AEs, the incidence of newly-occur- ring hypertension-related AEs did not increase over time (Figure 4).
Renal AEs occurred in 37 (13%) patients [IM-R, 14% (n=27); IM-I, 11% (n=10)], 7 (19%) of whom had a med- ical history of renal events (Online Supplementary Table S6). Six (2%) patients had maximum grade 3/4 events and 14 (all grade; grade 3/4, n=1) had events considered by the investigator to be treatment related. The median (range) time to first renal AE was 673 (8-2695) days. Renal AEs led to treatment discontinuation in 3 patients (1 each in years 1, 2, and 3) and death in one patient (acute kidney injury in year 1 related to PD and unrelated to bosutinib).
Cross-intolerance
Eighty-nine patients were intolerant to prior imatinib (Online Supplementary Table S7). Of 85 patients with a spe- cific AE reported as the reason for discontinuation of ima- tinib, 52 (61%) experienced the same AE with bosutinib that led to imatinib discontinuation, most commonly hematologic AEs (thrombocytopenia, n=12; neutropenia, n=5; anemia, n=5) or gastrointestinal AEs (diarrhea, n=6; nausea, n=4); 14 (16%) had cross-intolerance (defined as having discontinued bosutinib due to the same AE that led to prior imatinib discontinuation). Twenty-five (29%) patients experienced the same grade 3/4 AE while on bosutinib. No patient receiving bosutinib died due to the same AE that led to intolerance to prior imatinib.
Discussion
After five years of follow up, the final results of this phase I/II study demonstrated durable efficacy and accept- able long-term safety for second-line bosutinib in patients with CP CML resistant or intolerant to imatinib. The esti- mated probabilities of responders maintaining an MCyR or CCyR at year 5 (71%, 69%) decreased modestly from the estimated probabilities at year 2 (76%, 78%). Resistance and intolerance to prior imatinib did not appear to result in differences in response durability, as rates observed at years 2 and 5 were similar for both IM-R and IM-I patients. Additionally, late disease progression was uncommon, supporting the observed response durability [although 38 (13%) patients discontinued after year 3, potentially biasing the interpretation of subsequent out- comes]. Cumulative response rates at years 5 and 2 were similar (year 5: MCyR, 60% and CCyR, 50%; year 2: MCyR, 58% and CCyR, 46%). However, it should be noted that results reported here are based on a finalized database resulting in slight differences from previously published data.10
The response rates achieved in this study are compara-
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