Abstract: Background In newly diagnosed acute myeloid leukemia (AML), the general recommendation is to start treatment immediately after the diagnosis has been made. This paradigm is based both on the observation that untreated acute leukemia has a poor prognosis and on retrospective analyses demonstrating a shorter survival in younger AML patients (pts) in whom treatment was delayed by more than 5 days (Sekeres et al., 2009). A more recent single-center analysis came to a different conclusion, showing no prognostic effect for the time from diagnosis to treatment (TDT; Bertoli et al., 2013). We explored the relationship between TDT and prognosis on a large set of real-world data from the AML registry of the Study Alliance Leukemia (SAL) and compared it to the published cohorts. Methods The SAL runs a transregional AML registry in 46 treatment centers across Germany (NCT03188874). All registered patients with an intensive induction treatment, a minimum follow-up time of 12 months and no acute promyelocytic leukemia were selected (n=2,200). Treatment start was defined by the first day of cytarabine, whereas single agent hydroxyurea (HU) was labeled as pretreatment. We analyzed the influence of TDT on complete remission (CR), early death (ED) and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0-5, 6-10, 11-15 and & gt;15 days of TDT, and by using the restricted cubic spline (RCS) method for data modelling. In order to adjust for the influence of established prognostic variables on the outcomes, we used multivariable regression models and propensity score weighting. The influence of HU pretreatment on outcomes was investigated by introducing an interaction term between TDT and the presence of HU pretreatment. Results The median age was 59 years (y) (IQR 50-68), the proportion of pts with favorable, intermediate and adverse genetic risk according to ELN was 27%, 53%, and 20%; & gt;95% of pts received induction treatment with standard 7+3. HU pretreatment was administered in 4% of pts. The median TDT was 3 days (IQR 2-6). Descriptive statistics after grouping of pts showed the highest median age and the lowest proportion of NPM1 mutated and favorable risk in the TDT group 11-15. Of all pts, 79% achieved a CR/CRi; unadjusted CR rates for the patient groups with TDT of 0-5, 6-10, 11-15 and & gt;15 days were 80%, 77%, 74% and 76%, respectively (p=0.317). In multivariable analysis accounting for the influence of ELN risk, age, WBC, LDH, de novo versus secondary AML and ECOG, the OR for each additional day of TDT was 0.99 (95%-CI, 0.97-1.00; p=0.124). Four percent of pts died within the first 30 days from treatment start. The respective rates in the four TDT categories were 4.0%, 3.8%, 5.1% and 4.1% (p=0.960). In multivariable analysis, the OR for TDT was 1.01 (95%-CI, 0.98-1.05; p=0.549). After a median follow-up of 40 months, the 2-y OS of all pts was 51%. The unadjusted 2-y OS rates stratified by TDT of 0-5, 6-10, 11-15, & gt;15 days were 52, 49, 46, and 51% (see Table 1 and Figure 1). The hazard ratio (HR) for each day of treatment delay was 1.00 (95%-CI; 0.99-1.01; p=0.317). In multivariable Cox regression analysis, the HR for TDT as continuous variable was 1.00 (95%-CI, 0.99-1.01; p=0.689). When OS was analyzed separately stratified for age ≤60 and & gt;60 ys and for high versus lower initial WBC defined by a threshold of 50 x 109/L, no significant differences between TDT groups were observed. Multivariable models using TDT as a grouped variable or with RCS did not provide evidence for a significant influence of TDT on outcomes. Propensity score matching of pts in the four TDT groups did not reveal an influence on outcomes. The use of HU was not associated with CR, ED nor OS. Conclusion Our study on 2,200 newly diagnosed registry pts receiving consistent intensive induction with standard-dose cytarabine plus daunorubicin (7+3) suggests that TDT is not related to response or survival, neither in younger nor in older pts. Despite multivariable analyses, a bias towards longer TDT intervals in pts judged to be clinically stable by the treating physician cannot be excluded entirely. As treatment stratification in intensive first-line treatment of AML evolves, the TDT data suggests that it may be a safe and reasonable approach to wait for genetic and other laboratory test results in order to assign clinically stable pts to the best available treatment option before the start of intensive treatment. Disclosures Krämer: Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; BMS: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hänel:Roche: Honoraria; Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board. Jost:Daiichi: Honoraria; Sanofi: Honoraria; Gilead: Other: travel grants; Jazz Pharmaceuticals: Honoraria. Brümmendorf:Merck: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; University Hospital of the RWTH Aachen: Employment; Ariad: Consultancy. Krause:Siemens: Research Funding; Takeda: Honoraria; MSD: Honoraria; Gilead: Other: travel; Celgene Corporation: Other: Travel. Scholl:Novartis: Other: Project funding; Pfizer: Other: Advisory boards; Gilead: Other: Project funding; Daiichi Sankyo: Other: Advisory boards; AbbVie: Other: Advisory boards. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Kiani:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Middeke:Sanofi: Research Funding, Speakers Bureau; Roche: Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Gilead: Consultancy; Janssen: Consultancy, Speakers Bureau; MSD: Consultancy. Thiede:AgenDix GmbH: Employment, Equity Ownership; Novartis: Research Funding, Speakers Bureau; Bayer: Research Funding; Daiichi-Sankyo: Speakers Bureau. Stoelzel:JAZZ Pharmaceuticals: Consultancy; Neovii: Other: Travel funding; Shire: Consultancy, Other: Travel funding. Platzbecker:Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, 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) 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: 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: Bosutinib (BOS) is an oral dual Src/Abl tyrosine kinase inhibitor (TKI). This long-term update of an ongoing open-label, phase 1/2 study evaluated the efficacy and safety of BOS as 3rd-line therapy in CP CML pts after prior TKI failure. Pts (n=119) were 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=5) and 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 31.1 (0.3–89.1) mo; and BOS treatment duration was 8.6 (0.2–87.7) mo. Escalation to BOS 600 mg/d occurred in 22 (19%) pts. For the last enrolled pt, time from first dose was ≥48 mo (24% still receiving BOS at 4 y). Major cytogenetic response (MCyR) was newly attained or maintained from baseline by 33% and 7% of pts, respectively (32% attained/maintained complete cytogenetic response [CCyR]) (Table). Kaplan-Meier probability of maintaining MCyR or CCyR at 4 y was 69% and 54%, respectively. At baseline, 95 pts had known mutation status. Twenty unique BCR-ABL mutations occurred in 39 (41%) pts, including 11 with 〉 1 mutation; common mutations were F317L (n=8), T315I (n=7), G250E, and Y253H (n=6 each). MCyR rate was similar in pts without mutations (37%) and pts with 1 mutation (38%); 27% of pts with 〉 1 mutation and 14% of pts with T315I had MCyR. Of 57 pts assessed for mutations at end of treatment, 13 had new mutations (V299L, n=6; T315I, n=3; G250E, n=2 [1 pt also had a new V299L mutation]; F359C, L248V, and L273M, n=1 each; 10 pts had prior mutation); 11/13 pts with new mutations discontinued BOS due to progressive disease (PD) or lack of efficacy. Cumulative incidence of on-treatment PD (ie, transformation to accelerated-/blast-phase [AP/BP] CML, increasing white blood cell count, loss of confirmed complete hematologic response or unconfirmed MCyR) or death* at 4 y was 24%; 52% of pts discontinued before 4 y without an event. Overall survival (OS) at 2 y was 84% (Table; pts followed for OS for only 2 y after BOS discontinuation] ). Cumulative incidence of on-treatment transformation* at 4 y was 4%; 71% discontinued before 4 y without transformation. No pt transformed to BP. There was limited follow-up of patients after treatment discontinuation. Overall, 90 (76%) pts discontinued treatment within 4 y, most commonly due to adverse event (AE; n=28 [24%]) as primary reason for treatment discontinuation. Twenty-six (22%) deaths occurred on study, 5 within 30 d of last BOS dose. Most deaths were due to disease progression (n=12) or AE (n=11; 1 related to BOS); 3 had unknown cause. Non-hematologic treatment-emergent AEs (TEAEs) commonly included (all grades; grade 3/4) diarrhea (83%; 9%), nausea (48%; 1%), and vomiting (38%; 1%); hematologic toxicities included thrombocytopenia (39%; 26%), neutropenia (21%; 16%), and anemia (20%; 7%). Cardiac events (MedDRA system organ classification of cardiac disorders) occurred in 18% of pts (8% grade 3/4). Overall incidence of newly occurring TEAEs for pts on treatment during specific years was 99% in year 1 (y1; n=118/119), 74% in y2 (n=37/50), 64% in y3 (n=25/39), and 72% in y4 (n=23/32). The most common TEAEs were diarrhea in y1 (n=98), pleural effusion in y2 (n=6), abdominal pain in y3 (n=5), and pleural effusion in y4 (n=5). TEAEs were managed primarily by dose delays (66%) and dose reductions (50%). Discontinuations due to AEs were most common in y1 (19% [n=23/119]); 2, 2, and 3 pts discontinued due to AEs in y2, y3, and y4, respectively. The most common reason for discontinuation due to AE was thrombocytopenia (6%). After ≥48 mo follow-up, third-line BOS therapy shows efficacy and manageable toxicity in CP CML pts. Table 1IM + D-R (n=38)IM + D-I (n=50)IM + N-R (n=26)IM + N-I orD-R/I+ N-R/I (n=5)Total (n=119)Evaluable,a n3645265112MCyR, n (%)14 (39)19 (42)10 (39)2 (40)45 (40)CCyR , n (%)8 (22)18 (40)8 (31)2 (40)36 (32)Probability of maintaining MCyR at 4 yb43%87%78%NR69%Probability of maintaining CCyR at 4 yb17%66%63%NR54%Treated, n3850265119PD/death at 4 yc24%16%35%NR24%OS at 2 yb80%83%92%NR84% NR=not reported (small sample size). 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 event. Disclosures Gambacorti-Passerini: Pfizer Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Kantarjian:Pfizer Inc: Research Funding. Lipton:Ariad: Equity Ownership, 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; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kim:Pfizer Inc: 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; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ILYANG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schafhausen:Ariad: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer Inc: Consultancy, Honoraria. Matczak:Pfizer Inc: Employment. Leip:Pfizer Inc: Employment. Noonan:Pfizer Inc: Employment. Brümmendorf:Ariad: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc: Consultancy, Honoraria; Patent on the use of imatinib and hypusination inhibitors: Patent on the use of imatinib and hypusination inhibitors Patents & Royalties. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer Inc: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Abstract: The dual Src/Abl tyrosine kinase inhibitor (TKI) bosutinib (BOS) is indicated for adults with Ph+ CML resistant/intolerant to prior therapy. This long-term update of an ongoing open-label, phase 1/2 study evaluated 2nd-line BOS in CP CML pts aged ≥18 y following imatinib resistance (IM-R) or intolerance (IM-I). This analysis included IM-R (n=195) or IM-I (n=89) CP CML pts receiving BOS 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 25.6 (0.2-94.9) mo; and follow-up duration was 45.1 (0.6–94.9) mo. BOS dose was escalated to 600 mg/d in 13% of pts. For the last enrolled pt, time from first BOS dose was ≥60 mo (41% of pts still receiving BOS at 5 y). Major cytogenetic responses (MCyR, including complete cytogenetic response [CCyR]) newly attained (54% of pts) or maintained from baseline (6%) are summarized (Table). In 224 pts assessed at baseline, 42 unique BCR-ABL mutations occurred in 78 (35%) pts, including 12 with 〉 1 mutation; common mutations were T315I and F359V (n=9 each), M351T (n=8), G250E and M244V (n=6 each). MCyR rate was similar in pts without mutations (58%) and with 1 single mutation (61%); 45% of pts with 〉 1 mutation and 22% of pts with T315I had MCyR. During therapy, of 92 pts evaluable for mutations, 20 acquired a new BCR-ABL mutation (T315I, n=9; V299L, n=4; E255V, E450A, E450G, G250E, K378E, L273M, and M244V, n=1 each [all in different pts]; 11 of these 20 pts had baseline mutations); 19 of these 20 pts discontinued due to either progressive disease (PD; n=12), lack of efficacy (n=6), or death (n=1). Cumulative incidence of on-treatment PD (ie, transformation to accelerated-/blast-phase [AP/BP] CML, increasing white blood cell count, loss of confirmed complete hematologic response or unconfirmed MCyR) or death* at 5 y was 19% (Table); 40% of pts discontinued BOS prior to 5 y without an event. Kaplan-Meier (KM)–estimated overall survival (OS) at 2 y was 91% (Table; per protocol, pts were followed for OS for only 2 y after BOS discontinuation). Cumulative incidence of on-treatment transformation to AP/BP CML* at 5 y was 4%; 55% of pts discontinued BOS prior to 5 y without transformation. In 12 pts with transformations, 6 were to AP and 6 were to BP. There was limited follow-up of patients after treatment discontinuation. Overall, 168 (59%) pts discontinued BOS within 5 y, commonly due to adverse event (AE; n=64 [23%]) or disease progression (n=47 [17%] ) as primary reason for discontinuation. Forty-four (16%) deaths occurred on study, 10 within 30 d of last BOS dose. Most deaths were due to disease progression (n=26; IM-R: 23 pts; IM-I: 3 pts) or AE unrelated to BOS (n=16; IM-R: 14 pts; IM-I: 2 pts); 2 were due to unknown causes. No deaths were reported as BOS-related. The most frequent (≥30%) hematologic treatment-emergent AE (TEAE; all grade/grade 3/4) was thrombocytopenia (42%/26%); common non-hematologic TEAEs were diarrhea (86%/10%), nausea (47%/1%), vomiting (37%/4%), and rash (36%/9%). Cardiac events (MedDRA system organ classification of cardiac disorders) occurred in 17% of pts (8% grade 3/4). Toxicities were managed by ≥1 dose delay in 73% of pts (IM-R: 67%; IM-I: 85%) and by ≥1 dose reduction in 50% of pts (IM-R: 46%; IM-I: 58%). AEs led to BOS discontinuation in 68 (24%) pts (IM-R: n=32 [16%]; IM-I: n=36 [40%] ); the most common reason was thrombocytopenia, in 16 (6%) pts (IM-R: n=6 [3%]; IM-I: n=10 [11%] ). Overall incidence of newly occurring TEAEs for pts on treatment during specific years was 100% (n=283/284) in year 1 (y1), 74% (n=139/189) in y2, 68% (n=100/148) in y3, 52% (n=68/130) in y4, and 57% (n=70/124) in y5. Discontinuations due to AEs were most common in y1 (18% [n=50/284]); 8, 3, 3, and 1 pts discontinued due to AEs in y2, y3, y4, and y5. After ≥60 mo of follow-up, BOS shows efficacy and manageable toxicity in CP CML pts following IM-R or IM-I. Table IM-R (n=195) IM-I (n=89) Total (n=284) Evaluable,a n 182 80 262 MCyR, n (%) 107 (59) 49 (61) 156 (60) CCyR , n (%) 88 (48) 42 (53) 130 (50) Probability of maintaining MCyR at 5 yb 67% 80% 71% Probability of maintaining CCyR at 5 yb 72% 68% 71% Treated, n 195 89 284 PD/death at 5 yc 23% 10% 19% OS at 2 yb 88% 98% 91% aReceived ≥1 BOS dose and had a valid baseline efficacy assessment for the respective endpoint; responses newly attained or maintained from baseline. bBased on KM estimates. cBased on cumulative incidence, *adjusting for competing risk of treatment discontinuation without event. Disclosures Brümmendorf: Patent on the use of imatinib and hypusination inhibitors: Patent on the use of imatinib and hypusination inhibitors Patents & Royalties; Pfizer Inc: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Cortes:Ariad: Consultancy, Research Funding; Pfizer Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Kantarjian:Pfizer Inc: Research Funding. Kim:Pfizer Inc: 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; ILYANG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schafhausen:Pfizer Inc: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Zeremski:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment. Leip:Pfizer Inc: Employment. Gambacorti-Passerini:Bristol-Myers Squibb: Consultancy; Pfizer Inc: Consultancy, Research Funding. Lipton: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; Pfizer Inc: 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: Objectives: Bosutinib (BOS), an oral dual Src/Abl tyrosine kinase inhibitor for adult patients with Philadelphia chromosome−positive chronic myeloid leukemia (Ph+ CML), has a recommended starting dose of 500 mg/d. This analysis evaluates efficacy and safety following BOS dose reduction due to intolerance in patients with Ph+ CML. Methods: Data from 2 studies were analyzed: a phase 1/2 study (NCT00261846) that included patients with chronic phase (CP) CML following resistance/intolerance to imatinib (IM; CP2L) or to IM plus dasatinib and/or nilotinib (CP3L), and those with accelerated/blast phase CML or acute lymphoblastic leukemia after at least IM (advanced [ADV]); and a phase 3 study (NCT00574873) in CP CML patients treated with BOS or IM as first-line therapy (CP1L). Results: Of 570 CP2L/CP3L/ADV patients receiving BOS (median treatment duration 11 months [range: 0.03−96]), 257 (45%) experienced ≥1 dose reduction (236 patients to 400 mg/d and 95 to 300 mg/d). Median time to dose reduction to 400 and 300 mg/d was 54.5 (range: 4-1875) and 146 days (8-2166), respectively; median duration of dose reduction was 3.6 (0.03-87.7) and 4.2 months (0.03-60.5), respectively. In CP1L, 248 patients received BOS (median treatment duration: 55.4 months [0.03−76] ), of whom 111 (45%) experienced ≥1 dose reduction (103 to 400 mg/d and 56 to 300 mg/d). Median time to dose reduction to 400 and 300 mg/d was 64.0 (2-1714) and 139 days (20-1778), respectively; median duration of dose reduction was 2.6 (0.03-66.1) and 8.9 months (0.03-71.2), respectively. Patients achieved anew or maintained a previously achieved complete cytogenetic response following BOS dose reduction to 400 mg/d (achieved: 29% [CP2L/CP3L/ADV], 40% [CP1L] ; maintained: 13% [CP2L/CP3L/ADV], 26% [CP1L] ) and to 300 mg/d (achieved: 14% [CP2L/CP3L/ADV], 18% [CP1L] ; maintained: 24% [CP2L/CP3L/ADV], 45% [CP1L] ; Table 1). Treatment-emergent adverse events (TEAEs) were generally similar in incidence, type, and severity before vs after BOS dose reduction. However, incidences of certain gastrointestinal TEAEs were lower and of similar severity following BOS dose reduction to 400 mg/d (diarrhea: 84% vs 50% [CP2L/CP3L/ADV], 70% vs 41% [CP1L] ; nausea: 45% vs 23% [CP2L/CP3L/ADV], 34% vs 21% [CP1L] ; vomiting: 33% vs 21% [CP2L/CP3L/ADV], 28% vs 22% [CP1L] ) or to 300 mg/d (diarrhea: 85% vs 31% [CP2L/CP3L/ADV], 75% vs 38% [CP1L] ; nausea: 43% vs 14% [CP2L/CP3L/ADV], 43% vs 21% [CP1L] ; vomiting: 34% vs 11% [CP2L/CP3L/ADV], 34% vs 18% [CP1L] ). Conclusions: CP2L/CP3L/ADV and CP1L CML patients who required BOS dose reduction due to AEs were still able to achieve or maintain cytogenetic responses and appeared to experience fewer gastrointestinal AEs. Disclosures Kota: Incyte: Membership on an entity's Board of Directors or advisory committees; Ariad Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Brümmendorf:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Patent on the use of imatinib and hypusination inhibitors: Patents & Royalties. Gambacorti-Passerini:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Lipton:Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Kantarjian:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. An:Pfizer Inc: Employment. Leip:Pfizer Inc: Employment. Crescenzo:Pfizer Inc: Employment. Woloj:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment, Equity Ownership. Khoury:Pfizer Inc: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction: Mutations (muts) in JAK2, MPL, and CALR are genetic hallmarks in myeloproliferative neoplasms such as myelofibrosis (MF). Prognostication in MF is predominantly based on clinical parameters according to the Dynamic International Prognostic Scoring System (DIPSS). However, gene mutations become increasingly important allowing for a more precised assessment of prognosis. For instance, CALR mutated MF is associated with favorable prognosis, while mutations in distinct high molecular-risk (HMR) genes are considered adverse. Our multicenter phase-Ib/II MPNSG-0212 trial (NCT01644110) investigating ruxolitinib plus pomalidomide in a total cohort of 92 patients with advanced MF and anemia provides an ideal basis for investigating the genomic landscape and molecular risk in a well-defined study population. Aims & Methods: To assess the genomic landscape in MF patients treated within the MPNSG-0212 trial and to correlate the results with clinical parameters and overall survival (OS). So far, targeted next generation sequencing (NGS) of 269 candidate genes was performed in peripheral blood or bone marrow from 81/92 patients using libraries prepared with SureSelectXT HS (Agilent, Santa Clara, USA). NGS was carried out on a NextSeq550 (Illumina, San Diego, USA). Results: At study entry, median age of the 81 patients was 71 years (range 52-86), median Hb 8.6 g/dL (range 5.4-11.7 g/dl); 30% of patients were RBC transfusion-dependent; 67% had primary MF (PMF) and 33% secondary MF (SMF), respectively. According to DIPSS, the vast majority of the patients were categorized as intermediate-2 (63%) or high-risk (26%) MF; 11% were low- and intermediate-1 risk patients. Overall, 315 muts were identified in 80/81 (99%) patients with a median of 3 muts/patient (range 0-9). Recurrent muts (≥5%) were identified in JAK2 (60%), ASXL1 (30%), SRSF2 (21%), CALR (20%; type-1: 75% [n=12], type-2 and non-type-1/2: 12.5% [n=2] each), MPL (19%), SF3B1 (19%), TET2 (16%), U2AF1 (15%), CBL and EZH2 (10% each), IDH2 and DNMT3A (7% each), PHF6, ZRSR2, and CUX1 (5% each). The majority of the patients (95%) was characterized by the presence of a driver mut in JAK2, CALR, or MPL; 4/81 patients (5%) were triple negative (Figure 1). JAK2mut was associated with TET2mut (p=.047), whereas muts in CALR and TET2 were mutually exclusive (p=.05). CALRmut patients had less co-muts than patients with JAK2/MPL muts (mean 2.5 vs. 4.1, p=.007) and were mutually exclusive with muts in the spliceosome regulating genes SRSF2, SF3B1, U2AF1, and ZRSR2 (p=.009). Compared to MF with mutated JAK2 or MPL, MF patients with mutated CALR had a longer median OS (not reached vs. 3.1 years; p=.04). With regard to high molecular risk (HMR) muts, n=56 were detected in 38 patients (47%), with 40% (15/38) of the patients harboring ≥2 HMR muts. The most commonly mutated HMR genes were ASXL1 (43%; 24/56), followed by SRSF2 (30%), EZH2 (14%), IDH2 (11%), and IDH1 (2%). MPLmut but not JAK2mut or CALRmut were significantly associated with HMR mut (p=.023). HMR mut patients harbored more co-muts than HMR wt patients (median 5 vs. 3; p & lt;.0001). There were no significant differences in the variables age, sex, WBC, Hb, PLT, or LDH level between patients with HMR mut and HMR wt MF. In univariate analysis, patients with HMR mut MF had shorter median OS (2.3 vs 3.7 years, p=.007). In multivariate analysis (HMR mut, age, DIPSS-category, SMF vs. PMF) a higher DIPSS-score (HR, 3.2; 95% CI, 1.5-7.0; p=.004) and muts in HMR genes (HR, 3.5; 95% CI, 1.5-8.1; p=.003) were significant adverse prognostic factors for OS. Conclusions: Our NGS data underline the genomic complexity of advanced MF. CALR mutations were only found in 20% of the patients that were characterized by less co-mutations, mutual exclusivity with spliceosome mutations, and with more favorable outcome suggesting a distinct disease biology. Almost 50% of patients showed mutations in HMR genes which were associated with an inferior OS in univariate and multivariate analyses. §Frank Stegelmann and Konstanze Döhner contributed equally to this work. Figure 1 Figure 1. Disclosures Koschmieder: Shire: Honoraria, Other; Alexion: Other: Travel support; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Geron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; AOP Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Baxalta: Membership on an entity's Board of Directors or advisory committees, Other; Abbvie: Other: Travel support; CTI: Membership on an entity's Board of Directors or advisory committees, Other; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Image Biosciences: Other: Travel support; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karthos: Other: Travel support. Heidel: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hebart: AbbVie: Honoraria; AstraZeneca: Honoraria; BMS: Honoraria; Janssen: Honoraria; Roche: Honoraria. Isfort: Alexion: Other: Travel reimbursement; Roche: Other: Travel reimbursement; Amgen: Other: Travel reimbursement; Mundipharma: Other: Travel reimbursement; Hexal: Other: Travel reimbursement; BMS: Honoraria; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement. Reiter: AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Deciphera: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding. Waller: Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Mylan: Consultancy; Alvotech: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Lilly: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Chugai: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Amgen: Membership on an entity's Board of Directors or advisory committees; IPSEN: Other: travel grant. Scheid: 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. Goethert: Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel support; Incyte: Consultancy, Honoraria, Other: Travel support; zr pharma & : Honoraria; BMS: Consultancy, Honoraria, Other: Travel support; AOP Orphan Pharmaceuticals: Honoraria, Other: travel support; Proteros Biostructures: Consultancy. Schafhausen: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Swedish Orphan Biovitrum AB: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees. Radsak: Otsuka: Consultancy, Honoraria; Abbvie: Other: e.g. travel support; Astellas: Other: e.g. travel support; TEVA: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: e.g. travel support; Daiichi Sankyo: Consultancy, Honoraria, Other: e.g. travel support; Celgene/BMS: Consultancy, Honoraria, Other: e.g. travel support; Amgen: Other: e.g. travel support; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Corat: Consultancy, Honoraria; Cogent Biosciences: Consultancy, Honoraria; JAZZ: Other: e.g. travel support. Gattermann: Takeda: Research Funding; Novartis: Honoraria; Celgene: Honoraria. von Bubnoff: Novartis: Honoraria; Takeda: Honoraria. Brümmendorf: Bristol Myers: Research Funding; Janssen: Honoraria; Novartis: Honoraria, Patents & Royalties, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Repeat Diagnostics: Research Funding; Takepart Media: Honoraria. Döhner: Celgene: Honoraria, Research Funding; Agios: Honoraria, Research Funding; GEMoaB: Honoraria; Astex Pharmaceuticals: Honoraria; Astellas: Honoraria, Research Funding; Oxford Biomedica: Honoraria; Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Janssen: Honoraria; Helsinn: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Berlin-Chemie: Honoraria; Roche: Honoraria; Pfizer: Research Funding. Griesshammer: Amgen: Consultancy, Honoraria; AOP Orphan: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria. Stegelmann: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Döhner: Abbvie: Consultancy, Honoraria; Janssen: Honoraria, Other: Advisory Board; Jazz Roche: Consultancy, Honoraria; Daiichi Sankyo: Honoraria, Other: Advisory Board; Astellas: Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Agios and Astex: Research Funding. OffLabel Disclosure: Pomalidomide was shown to be active in patients with myelofibrosis in particular in the treatment of anemia (Tefferi et al 2009, Begna et al 2011, Mesa et al 2010)

Abstract: Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n = 200) or imatinibintolerant (n = 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%. Responses were seen across Bcr-Abl mutants, except T315I. Bosutinib exhibited an acceptable safety profile; the most common treatment-emergent adverse event was mild/moderate, typically self-limiting diarrhea. Grade 3/4 nonhematologic adverse events ( 〉 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846.