Page 68 - Haematologica August 2018

C. Gambacorti-Passerini et al.
vs. 77%) (Online Supplementary Table S3). Causes of death were PD [n=26 (58%); IM-R: n=23; IM-I: n=3], AE unrelat- ed to bosutinib [n=16 (36%); IM-R: n=14; IM-I: n=2], and unknown cause [n=3 (7%); all IM-I]. None of the 45 deaths were assessed as treatment-related. Four deaths occurred within 30 days of the last bosutinib dose through year 2 (all IM-R) and 4 occurred during years 3-5 (2 IM-R and 2 IM-I patients).
Predictors of response duration, PFS, and OS
Significant (P<0.05) baseline factors predictive of MCyR or CCyR loss were Ph+ ratio ≥95% versus ≤35% and late versus early disease stage (Figure 2). No on-treatment factors were predictive of MCyR duration; however, experiencing treatment-emergent thrombocytopenia was predictive of loss of CCyR (P=0.0471). Several baseline factors predictive of decreased OS were identified: age ≥65 years versus <65 years, Ph+ ratio ≥95% versus ≤35%, lack of an MCyR by week 12, higher baseline peripheral blood blasts, and hav- ing a BCR-ABL1 mutation at baseline that is either sensi- tive or highly resistant to bosutinib. Among on-treatment
factors examined, experiencing an abnormal liver function test (LFT) was predictive of increased OS. Notably, prior response or resistance to imatinib did not predict duration of cytogenetic response or long-term survival outcomes.
Factors predictive of decreased PFS were Ph+ ratio ≥95% versus ≤35%, lack of MCyR by week 12, and higher base- line peripheral blood blasts (Figure 2). The on-treatment factor of receiving a bosutinib dose reduction to 400 mg due to AEs was predictive of increased PFS.
Safety and tolerability
The most common any grade hematologic treatment- emergent AEs (TEAEs) were thrombocytopenia [42% (Grade 3/4, 25%)], anemia [29% (Grade 3/4, 13%)], and neutropenia [16% (Grade 3/4, 10%)] (Online Supple- mentary Table S6). The most common non-hematologic TEAEs were diarrhea [86% (Grade 3/4, 10%)], nausea [46% (Grade 3/4, 2%)], vomiting [37% (Grade 3/4, 4%)], and rash [36% (Grade 3/4, 9%)]. Most newly-occurring AEs (MedDRA preferred terms not reported for the same patient previously for those on treatment during a given
Figure 4. Incidence of newly-occurring adverse events (AEs) over time.
Denominators are the number of patients on treatment during the indicated years (NB: incidences of certain AEs appear higher in later years compared with previous years due to a lower number of patients on treatment). Newly-occur- ring AEs were those not experienced by the same patient previously among patients on treatment during a given year (1 year = 365.25 days). *Includes the high-level group terms (HLGTs) cardiac arrhythmias, pericardial disorders, and heart failures under the cardiac disorders system organ class (SOC); relevant preferred terms (PTs) (cardiac death, sudden cardiac death, sudden death) under the general disorders and administration site SOC conditions; relevant PTs (decreased ejection fraction, abnormal electrocardiogram QT interval, pro- longed electrocardiogram QT, long QT syndrome, congenital long QT syndrome, Torsade de pointes, ventricular tachycardia) under the SOC investigations. †HLGTs included: coronary artery disorders, atherosclerosis, stenosis, vascular insufficiency and necrosis, embolism and thrombosis; high-level terms (HLTs) included arterial therapeutic procedures (excluding aortic), central nervous sys- tem hemorrhages and cerebrovascular accidents, central nervous system vas- cular disorders not elsewhere classified (NEC), non-site specific vascular disor- ders NEC, peripheral vascular disorders NEC (excluding the PTs flushing and hot flash), transient cerebrovascular events, vascular imaging procedures NEC, and vascular therapeutic procedures NEC and all subordinate terms. ‡HLGTs includ- ed: vascular hypertensive disorders and cardiac and vascular investigations (excluding enzyme tests), the HLT vascular tests NEC (including blood pressure); PTs included: abnormal blood pressure, abnormal ambulatory blood pressure, increased ambulatory blood pressure, abnormal diastolic blood pressure, increased diastolic blood pressure, increased blood pressure, abnormal systolic blood pressure, and increased systolic blood pressure. §HLT included: renal fail- ure and impairment; PTs included: blood creatinine abnormal, blood creatinine increased, creatinine renal clearance abnormal, creatinine renal clearance decreased, glomerular filtration rate abnormal, glomerular filtration rate decreased. ALT: alanine aminotransferase; AST: aspartate aminotransferase; URTI: upper respiratory tract infection; UTI: urinary tract infection; n: number.
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