Abstract: Bosutinib (BOS) is an oral dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following TKI failure. Pts (n=118) aged ≥18 y with prior imatinib (IM) failure plus dasatinib (D) resistance (D-R; n=38) or intolerance (D-I; n=50), nilotinib (N) resistance (N-R; n=26), or N-I or D-R/I + N-R/I (n=4) received BOS starting at 500 mg/d. Median (range) age was 56 (20–79) y; time from CML diagnosis was 6.6 (0.6–18.3) y; follow-up duration was 33.1 (0.3–84.8) mo; BOS treatment duration was 8.5 (0.2–78.1) mo. Escalation to BOS 600 mg/d occurred in 21 (18%) pts. For the last enrolled pt, time from first dose was ≥36 mo; 19% are still receiving BOS. Confirmed complete hematologic response (CHR) was newly attained or maintained from baseline by 73% of pts (Table). Major cytogenetic response (MCyR) was attained/maintained by 40% of pts (32% with complete cytogenetic response [CCyR]). Kaplan-Meier probability of maintaining CHR or MCyR at 3 y was 65%.IM + D-R (n=38)IM + D-I (n=50)IM + N-R (n=26)IM + N-I or D-R/I + N-R/Ia (n=4)Total (n=118)Evaluable,b n3849254116Confirmed CHR, n (%)26 (68)37 (76)19 (76)3 (75)85 (73)Probability of maintaining CHR at 3 yc57%74%62%NR65%Evaluable,b n3645254110MCyR, n (%)14 (39)19 (42)9 (36)2 (50)44 (40)CCyR , n (%)8 (22)18 (40)7 (28)2 (50)35 (32)Probability of maintaining MCyR at 3 yc29%87%75%NR65%Treated, n3850264118PD/death at 3 yd26%16%35%NR25%OS at 2 yc80%83%92%NR84%D=dasatinib; I=intolerant; IM=imatinib; N=nilotinib; NR=not reported (small sample size); OS=overall survival; PD=progressive disease; R=resistant.aIncludes 3 pts with prior exposure to all 3 TKIs and 1 N-I pt.bReceived ≥1 BOS dose and had a valid baseline efficacy assessment for the respective endpoint.cBased on KM estimates.dBased on cumulative incidence adjusting for competing risk of treatment discontinuation without PD or death. Of 85 pts with known baseline mutation status, 19 unique BCR-ABL mutations occurred in 39 (46%) pts, including 7 (8%) with T315I. Responses were seen across mutations, but were low in pts with T315I (29% CHR; 14% MCyR). In pts with ≥1 mutation, excluding T315I, 75% had CHR and 40% had MCyR. 38 pts had known baseline and end of treatment mutation status; 8/38 had ≥1 new mutation (V299L, n=4; T315I, n=2; F359C, G250E, L248V, n=1 each); 7/8 discontinued BOS due to disease progression or lack of efficacy. Cumulative incidence of on-treatment transformation to accelerated-phase (AP) CML at 3 y was 4%; 77% discontinued without transformation. No pt transformed to blast-phase (BP); no transformations occurred after 2 y. Cumulative incidence of on-treatment progression (transformation to AP/BP CML, increasing white blood cell count [doubling over ≥1 mo with 2nd count 〉 20×109/L and confirmed ≥1 wk later], or loss of confirmed CHR or unconfirmed MCyR) or death at 3 y was 25%; 55% of pts discontinued without an event. Overall survival (OS) at 2 y was 84% (Table; 3-y OS estimates unreliable; pts followed for OS for only 2 y after BOS discontinuation] ). Overall, 96 (81%) pts discontinued treatment, the most common primary reasons were adverse event (AE; n=29 [25%]), disease progression (n=25 [21%] ), or unsatisfactory efficacy (n=23 [19%]). 26 (22%) deaths occurred on study, 5 within 30 d of last BOS dose. Most deaths were due to disease progression (n=11 [9%] ) or AE (n=11 [9%], including 1 death reported as treatment-related due to lower gastrointestinal bleeding). 4 deaths had unknown cause 33–615 d after the last BOS dose. Non-hematologic treatment-emergent AEs in ≥20% of pts (all grades; grade 3/4) were diarrhea (83%; 9%), nausea (48%; 1%), vomiting (38%; 1%), rash (27%; 3%), headache (26%; 3%), fatigue (23%; 2%), and abdominal pain (24%; 1%); common hematologic toxicities included thrombocytopenia (38%; 26%), neutropenia (20%; 15%), and anemia (19%; 7%). Cardiac events occurred in 15% of pts (8% grade 3/4). Grade 3/4 laboratory abnormalities in ≥10% of pts were thrombocytopenia (26%), neutropenia (20%), lymphopenia (16%), and hypermagnesemia (12%). 78 (66%) pts had ≥1 dose delay; 59 (50%) had ≥1 dose reduction. 31 (26%) pts discontinued BOS due to AE, most commonly thrombocytopenia (7%). BOS continues to demonstrate durable efficacy and manageable toxicity after ≥36 mo follow-up in CP-CML pts following resistance or intolerance to multiple TKIs. Disclosures: Cortes: Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Bristol Myer Squibb: Research Funding; Teva: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kantarjian:Pfizer Inc: Research Funding. Lipton:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squib: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kim:Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Conlan:Pfizer Inc: Employment. Leip:Pfizer Inc: Employment. Turnbull:Pfizer Inc: Employment. Brümmendorf:Ariad: Consultancy; Patent on the use of imatinib and hypusination inhibitors: Patents & Royalties; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria. Gambacorti-Passerini:Bristol Myer Squibb: Consultancy; Pfizer Inc: Consultancy, Research Funding; Novartis: Consultancy.

Abstract: Vascular and cardiac safety during tyrosine kinase inhibitor (TKI) therapy is an emerging issue. We evaluated vascular/cardiac toxicities associated with long‐term bosutinib treatment for Philadelphia chromosome‐positive (Ph+) leukemia based on treatment‐emergent adverse events (TEAEs) and changes in QTc intervals and ejection fraction in two studies: a phase 1/2 study of second‐/third‐/fourth‐line bosutinib for Ph+ leukemia resistant/intolerant to prior TKIs ( N  = 570) and a phase 3 study of first‐line bosutinib ( n  = 248) versus imatinib ( n  = 251) in chronic phase chronic myeloid leukemia. Follow‐up time was ≥48 months (both studies). Incidences of vascular/cardiac TEAEs in bosutinib‐treated patients were 7%/10% overall with similar incidences observed with first‐line bosutinib (5%/8%) and imatinib (4%/6%). Few patients had grade ≥3 vascular/cardiac events (4%/4%) and no individual TEAE occurred in 〉 2% of bosutinib patients. Exposure‐adjusted vascular/cardiac TEAE rates (patients with events/patient‐year) were low for second‐line or later bosutinib (0.037/0.050) and not significantly different between first‐line bosutinib (0.015/0.024) and imatinib (0.011/0.017; P  ≥ 0.267). Vascular/cardiac events were managed mainly with concomitant medications (39%/44%), bosutinib treatment interruptions (18%/21%), or dose reductions (4%/8%); discontinuations due to these events were rare (0.7%/1.0%). Based on logistic regression modelling, performance status 〉 0 and history of vascular or cardiac disorders were prognostic of vascular/cardiac events in relapsed/refractory patients; hyperlipidemia/hypercholesterolemia and older age were prognostic of cardiac events. In newly diagnosed patients, older age was prognostic of vascular/cardiac events; history of diabetes was prognostic of vascular events. Incidences of vascular and cardiac events were low with bosutinib in the first‐line and relapsed/refractory settings following long‐term treatment in patients with Ph+ leukemia. Am. J. Hematol. 91:606–616, 2016. © 2016 Wiley Periodicals, Inc.

Abstract: Abstract 2793 Bosutinib (BOS) is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated the activity and tolerability of BOS 500 mg/d in Philadelphia chromosome–positive (Ph+) leukemia following prior TKI exposure. The current analysis investigated baseline characteristics as predictors of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR), and 2-year Kaplan- Meier–estimated progression-free survival (PFS) and overall survival (OS). All included patients had chronic phase (CP) chronic myeloid leukemia (CML), had developed resistance/intolerance to prior imatinib, and were also either dasatinib resistant (n = 38), dasatinib intolerant (n = 50), nilotinib resistant (n = 27), nilotinib intolerant (n = 1), or resistant/intolerant to dasatinib and nilotinib (n = 3). Median follow-up was 31.4 mo (range, 0.3–66.0 mo). A summary of results is provided in the Table. Longer time since CML diagnosis versus shorter time (median time 6.61 years) was associated with greater OS (2-y probability, 90% vs 79%; log-rank P= 0.0435); however, no association with MCyR, CCyR, or PFS was observed. A lower percentage of Ph+ cells ( 〈 95% Ph+ cells vs ≥95% Ph+ cells) at baseline was significantly associated with a higher rate of MCyR (76% vs 23%; P 〈 0.001) and CCyR (65% vs 14%; P 〈 0.001), as well as PFS (2-y probability, 83% vs 68%; log-rank P = 0.0181); no association with OS was observed. Resistance versus no resistance (ie, only intolerance) to prior TKIs was not significantly associated with response or survival, although a numeric trend toward lower rates of MCyR (39% vs 50%) and CCyR (28% vs 50%), as well as 2-y probabilities of PFS (72% vs 89%) and OS (82% vs 91%) among resistant patients was observed. Prior response of at least a minor cytogenetic response (MiCyR) versus no response to first-line imatinib was associated with a higher rate of MCyR (49% vs 28%; P= 0.0375) and a numeric trend toward a higher rate of CCyR (39% vs 20%) on BOS; no trend for PFS or OS was observed. Prior response of at least MiCyR versus no response to second-line dasatinib/nilotinib was associated with higher rates of MCyR (56% vs 19%; P 〈 0.001) and CCyR (48% vs 7%; P 〈 0.001), as well as PFS (2-y probability, 80% vs 64%; log-rank P= 0.0180) and OS (2-y probability, 89% vs 77%; log-rank P= 0.0285) on BOS. While baseline demographic characteristics showed a numerical trend toward lower response and/or survival rates with age ≥65 y and female gender, no trends were statistically significant. There was also no predictive effect for presence of a Bcr-Abl kinase domain mutation at baseline or CP status at onset of imatinib therapy. In conclusion, most evaluated baseline characteristics appeared not to be predictive of response and/or survival on BOS in patients with CP CML and resistance/intolerance to multiple prior TKIs, although at least MiCyR to prior dasatinib/nilotinib and lower percentage of Ph+ cells at baseline were found to be consistently predictive of better outcomes on BOS. n/n evaluable (%) Kaplan-Meier estimate, % n MCyRa CCyRa PFS at 2 years OS at 2 years Age ≥65 y 26 7/22 (32) 5/22 (23) 70 80 〈 65 y 93 38/88 (43) 30/88 (34) 76 85 Sex Female 66 23/61 (38) 17/61 (28) 77 83 Male 53 22/49 (45) 18/49 (37) 73 86 Time since CML diagnosis * ≥6.61 y 60 23/57 (40) 17/57 (30) 79 90 〈 6.61 y 59 22/53 (42) 18/53 (34) 71 79 Status at onset of imatinibb Early CP 44 17/39 (44) 15/39 (39) 71 78 Late CP 75 28/71 (39) 20/71 (28) 77 88 Percentage of Ph+ cells at baseline ** ** * ≥95% Ph+ cells 66 15/66 (23) 9/66 (14) 68 83 〈 95% Ph+ cells 43 28/37 (76) 24/37 (65) 83 85 Baseline Bcr-Abl mutation No 46 18/45 (40) 15/45 (33) 80 88 Yes 40 14/37 (38) 8/37 (22) 77 80 Prior response to imatinib * No response 44 11/40 (28) 8/40 (20) 76 88 At least MiCyRc 60 28/57 (49) 22/57 (39) 78 87 Prior response to dasatinib/nilotinib ** ** * * No response 33 6/31 (19) 2/31 (7) 64 77 At least MiCyRc 67 35/63 (56) 30/63 (48) 80 89 Resistance to prior TKI No 23 10/20 (50) 10/20 (50) 89 91 Yes 96 35/90 (39) 25/90 (28) 72 82 a Cumulative response rates. b Patients were considered to be in late CP at the moment of starting imatinib if they had commenced imatinib ≥6 mo after diagnosis or had received prior interferon therapy; other patients were considered to be in early CP. c Defined as 〈 15% blasts in bone marrow and blood, 〈 30% blasts + promyelocytes in bone marrow and blood, and 〈 20% basophils in peripheral blood with no extramedullary disease other than spleen and liver. * P value 〈 0.05; ** P value 〈 0.001. Disclosures: Cortes: Novartis, Bristo Myer Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding. Gambacorti-Passerini:Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Brümmendorf:Bristol Myer Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Patent on the use of imatinib and hypusination: Patents & Royalties. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Besson:Pfizer Inc: Employment. Turnbull:Pfizer Inc, l3/Inventiv Clinical Solutions: Employment. Kantarjian:Pfizer Inc: Research Funding.

Abstract: Bosutinib (BOS) is an oral dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated BOS in patients (pts) aged ≥18 y with chronic-phase (CP) chronic myeloid leukemia (CML) following imatinib resistance (IM-R) or intolerance (IM-I). IM-R (n=196) or IM-I (n=90) CP-CML pts received BOS as 2nd-line TKI therapy starting at 500 mg/d. Median (range) age was 53 (18–91) y; time from CML diagnosis was 3.7 (0.1–15.1) y. Treatment duration was 24.8 (0.2-83.4) mo and follow-up duration 47.3 (0.6–90.6) mo. BOS dose was escalated to 600 mg/d in 13% of pts. For the last enrolled pt, time from first BOS dose was ≥48 mo; 40% of pts are still receiving BOS. Confirmed complete hematologic responses (CHR) and major cytogenetic responses (MCyR, including complete cytogenetic response [CCyR]) newly attained or maintained from baseline are summarized (Table).TableIM-R (n=196)IM-I (n=90)Total (n=286)Evaluable,a n19590285Confirmed CHR, n (%)168 (86)76 (84)244 (86)Probability of maintaining CHR at 4 yb64%79%68%Evaluable,a n18381264MCyR, n (%)107 (58)49 (60)156 (59)CCyR , n (%)88 (48)42 (52)130 (49)Probability of maintaining MCyR at 4 yb69%86%75%Treated, n19690286 PD/death at 4 yc22%10%19% OS at 2 yb88%98%91%I=intolerant; PD=progressive disease; R=resistant.aReceived ≥1 BOS dose and had a valid baseline efficacy assessment for the respective endpoint.bBased on KM estimates.cBased on cumulative incidence adjusting for competing risk of treatment discontinuation without PD or death. Of 210 pts with known mutation status at baseline, 79 (38%) had ≥1 BCR-ABL kinase domain mutation (n=42 unique), most commonly T315I (n=9), M351T (n=9), F359V (n=8), G250E (n=6), M244V (n=6), and L248V (n=5). Among pts with T315I, CHR and MCyR rates were low (22% each). Of 67 pts evaluated for mutations before and during therapy, 18 had ≥1 new BCR-ABL mutation (T315I, n=8; V299L, n=3; and E255V, E450A, E450G, G250E, K378E, L273M, and M244V, n=1 each); 17 of these 18 pts discontinued due to disease progression (n=12), lack of efficacy (n=4), or death (n=1). The cumulative incidence of on-treatment progression (transformation to accelerated phase [AP] or blast phase [BP] CML, increasing white blood cell count [doubling over ≥1 mo with second count 〉 20×109/L and confirmed ≥1 wk later], or loss of confirmed CHR or unconfirmed MCyR) or death at 4 y was 22% for IM-R and 10% for IM-I pts; 40% of pts discontinued BOS without an event. Kaplan-Meier (KM)–estimated overall survival (OS) at 2 y was 88% for IM-R and 98% for IM-I pts (4-y OS not reliable; pts were followed for OS for only 2 y after BOS discontinuation). The cumulative incidence of on-treatment transformation to AP/BP CML at 4 y was 4%; 57% of pts discontinued treatment without transformation. No new transformations occurred after 2 y. Overall, 173 (60%) pts discontinued BOS, most common primary reasons were adverse event (AE; n=64 [22%] ) and disease progression (n=51 [18%]). Forty (14%) deaths occurred on study, 7 within 30 d of last BOS dose. Most deaths were due to disease progression (n=24 [8%; 22 and 2 in IM-R and IM-I pts, respectively] ) or AE unrelated to BOS (n=13 [5%; 11 and 2]). 3 deaths occurring ≥99 d after last BOS dose were due to unknown causes; no deaths were assessed as BOS-related. The most frequent hematologic treatment-emergent AEs (TEAEs; all grades/grade 3/4) were thrombocytopenia (42%/26%) and anemia (27%/11%); the most frequent non-hematologic TEAEs were diarrhea (86%/10%), nausea (46%/1%), vomiting (37%/4%), rash (36%/9%), abdominal pain (26%/2%), fatigue (26%/1%), pyrexia (26%/1%), increased alanine aminotransferase (ALT; 22%/9%), cough (22%/0), and upper abdominal pain (20%/ 〈 1%). Cardiac events occurred in 16% of pts (7% grade 3/4). Grade 3/4 on-treatment hematologic and non-hematologic laboratory abnormalities in ≥10% of pts included thrombocytopenia (25%), neutropenia (17%), lymphopenia (15%), anemia (14%), alanine transaminase elevation (11%), and hypermagnesemia (11%). Toxicities were managed by ≥1 BOS dose reduction in 44% of IM-R and 58% of IM-I pts and by ≥1 dose delay in 66% of IM-R and 83% of IM-I pts. AEs led to BOS discontinuation in 32 (16%) IM-R and 35 (39%) IM-I pts; the most common reason was thrombocytopenia (3% of IM-R and 12% of IM-I pts). In conclusion, BOS demonstrates durable efficacy and manageable toxicity in CP-CML pts following IM-R or IM-I after ≥48 mo of follow-up, highlighting the therapeutic potential of BOS in these pts. Disclosures: Brümmendorf: Patent on the use of imatinib and hypusination inhibitors: Patents & Royalties; Ariad: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myer Squibb: Consultancy, Honoraria; Pfizer Inc: Consultancy, Honoraria. Cortes:Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Ariad: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Bristol Myer Squibb: Research Funding. Kantarjian:Pfizer Inc: Research Funding. Kim:BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Conlan:Pfizer Inc: Employment. Leip:Pfizer Inc: Employment. Turnbull:Pfizer Inc: Employment. Gambacorti-Passerini:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer Inc: Consultancy, Research Funding. Lipton:Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract: Introduction: Bosutinib, an oral dual Src/Abl tyrosine kinase inhibitor (TKI) is approved for patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML), at a starting dose of 400 once daily (QD) in newly diagnosed patients in chronic phase (CP). Approval of first-line bosutinib was based on results from the phase 3 BFORE trial, which showed improved efficacy outcomes with bosutinib vs imatinib in this patient population. This analysis evaluated efficacy and safety of bosutinib and imatinib following dose reductions in adult patients with newly diagnosed CP CML. Methods: This retrospective analysis included data (≥24-month follow-up) from the ongoing, open-label, phase 3 BFORE trial (NCT02130557). In all, 536 patients were randomized 1:1 to bosutinib or imatinib at a starting dose of 400 mg QD. Doses could be reduced in 100 mg decrements for toxicity; dose reductions to 〈 200 mg QD bosutinib and 〈 300 mg QD imatinib were not permitted. Efficacy and safety were assessed in patients who underwent dose reductions to 300 mg QD (without further reduction to 200 mg QD) or to 200 mg QD (bosutinib arm only) due to treatment-emergent adverse events (TEAEs). TEAEs were defined as adverse events that first occurred or worsened in severity, between the first administration of the study drug and 28 days after the last dose. Results: Of the 268 patients in the bosutinib arm, 80 dose-reduced to 300 mg only and 23 dose-reduced to 200 mg. The median (range) overall duration of bosutinib treatment for patients dose reduced to 300 mg was 24.3 months (1.4-33.5) and to 200 mg was 8.3 months (1.0-32.9) vs. 25.1 months (range: 0.26-33.2) for patients who remained on the 400 mg starting dose. Median (range) time to bosutinib dose reduction to 300 mg was 83 days (18-793) and to 200 mg was 121 days (29-882); respective median (range) duration on reduced dose was 138.5 days (1-957) and 28 days (3-463). Of the 268 (3 untreated) patients in the imatinib arm, 44 dose-reduced to 300 mg. The median duration of imatinib treatment for patients dose reduced to 300 mg was 22.4 months (range: 1.2-33.0) vs. 24.8 months (range: 0.7-33.4) for patients who remained on 400 mg. Median time to imatinib dose reduction to 300 mg was 85.0 days (range: 15-687); median duration on reduced dose was 99.0 days (range: 2-787). TEAEs leading to dose reduction in ≥10 patients were alanine aminotransferase increased and/or aspartate aminotransferase increased (n=21), thrombocytopenia (n=19), lipase increased (n=15) and diarrhea (n=11) with bosutinib, and neutropenia (n=11) with imatinib. The most common reason for treatment discontinuation in patients who dose-reduced was a TEAE related to bosutinib (300 mg: 22.5%; 200 mg: 52.2%) or imatinib (300 mg: 27.3%). Among patients who dose-reduced to 300 mg, 16 (20%) had a major molecular response (MMR) with bosutinib before and after reduction; an additional 36 (45%) achieved MMR for the first time after dose reduction. In the imatinib arm, 7 (15.9%) had an MMR before and after reduction; an additional 22 (50%) achieved MMR for the first time after dose reduction (Table 1). 1 (1.3%) patient lost a previously attained MMR following bosutinib dose reduction to 300 mg. Among patients who dose-reduced to 200 mg bosutinib, 4 (17.4%) had an MMR before and after reduction, and an additional 4 (17.4%) achieved MMR for the first time after dose reduction. Similar trends were seen for complete cytogenetic response (CCyR) before and after dose reduction (Table 1). Among patients who remained on 400 mg, 123/165 (74.5%) had a MMR with bosutinib; 131/152 (86.2%) achieved CCyR. In the imatinib arm, 130/219 (59.4%) had a MMR and 159/198 (80.3%) achieved CCyR. The majority of TEAEs decreased in incidence with dose reduction (Table 2). Following bosutinib dose reduction to 300 mg or to 200 mg decreases 〉 10% were seen in the incidence of diarrhea and nausea; with a decrease for rash following dose reduction to bosutinib 200 mg. Decreases ( 〉 10%) were noted for nausea following dose reduction to 300 mg imatinib. Conclusions: Management of TEAEs through bosutinib dose reduction to 300 mg or 200 mg improved tolerability in patients with newly diagnosed CP CML. These reductions in TEAEs enabled patients to continue bosutinib treatment, with a substantial number of patients achieving MMR and CCyR for the first time after dose reduction. Findings were similar for patients who dose-reduced to 300 mg imatinib. Disclosures Brummendorf: Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy; Merck: Consultancy; Janssen: Consultancy. Gambacorti-Passerini:BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Incyte: Research Funding. Lipton:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Kota:Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria; Xcenda: Honoraria; Novartis: Honoraria. Deininger:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy. Leip:Pfizer: Employment, Equity Ownership. Viqueira:Pfizer: Employment, Equity Ownership. Ferdinand:Pfizer: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.

Abstract: Bosutinib, an orally active, Src/Abl tyrosine kinase inhibitor, has demonstrated clinical activity and acceptable tolerability in chronic phase chronic myeloid leukemia (CP CML). This updated analysis of the BELA trial assessed the safety profile and management of toxicities of bosutinib versus imatinib in adults with newly diagnosed (≤6 months) CP CML after 〉 30 months from accrual completion. Among patients randomized to bosutinib 500 mg/d ( n  = 250) or imatinib 400 mg/d ( n  = 252), 248 and 251, respectively, received ≥1 dose of study treatment. Adverse events (AEs; any grade) with bosutinib versus imatinib were significantly more common for certain gastrointestinal events (diarrhea, 70% vs. 26%; P   〈  0.001; vomiting, 33% vs. 16%; P   〈  0.001), alanine aminotransferase (33% vs. 9%; P   〈  0.001) and aspartate aminotransferase (28% vs. 10%; P   〈  0.001) elevations, and pyrexia (19% vs. 12%; P  = 0.046). AEs significantly less common with bosutinib included edema (periorbital, 2% vs. 14%; P   〈  0.001; peripheral, 5% vs. 12%; P  = 0.006), musculoskeletal (myalgia, 5% vs. 12%; P  = 0.010; muscle cramps, 5% vs. 22%; P   〈  0.001; bone pain, 4% vs. 11%; P  = 0.003), increased creatine phosphokinase (8% vs. 20%; P   〈  0.001), neutropenia (13% vs. 30%; P   〈  0.001), and leukopenia (9% vs. 22%; P   〈  0.001). Between‐group differences in the incidence of cardiac and vascular AEs were not significant. Diarrhea was typically transient, mostly Grade 1/2, occurring early during treatment, and was manageable with antidiarrheal medication. Despite higher rates of aminotransferase elevation with bosutinib, events were managed in most patients with dose modification and/or concomitant medication. Bosutinib had a manageable safety profile distinct from that of imatinib in patients with newly diagnosed CP CML. Am. J. Hematol. 89:947–953, 2014. © 2014 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.

Abstract: Not available.