Baseline Predictors of Response to Bosutinib in Patients with Chronic Phase Chronic Myeloid Leukemia Following Resistance or Intolerance to Imatinib Plus Dasatinib and/or Nilotinib.

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AbstractAbstract 2793Bosutinib (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, %nMCyRaCCyRaPFS at 2 yearsOS at 2 yearsAge≥65 y267/22 (32)5/22 (23)7080<65 y9338/88 (43)30/88 (34)7685SexFemale6623/61 (38)17/61 (28)7783Male5322/49 (45)18/49 (37)7386Time since CML diagnosis*≥6.61 y6023/57 (40)17/57 (30)7990<6.61 y5922/53 (42)18/53 (34)7179Status at onset of imatinibbEarly CP4417/39 (44)15/39 (39)7178Late CP7528/71 (39)20/71 (28)7788Percentage of Ph+ cells at baseline*****≥95% Ph+ cells6615/66 (23)9/66 (14)6883<95% Ph+ cells4328/37 (76)24/37 (65)8385Baseline Bcr-Abl mutationNo4618/45 (40)15/45 (33)8088Yes4014/37 (38)8/37 (22)7780Prior response to imatinib*No response4411/40 (28)8/40 (20)7688At least MiCyRc6028/57 (49)22/57 (39)7887Prior response to dasatinib/nilotinib******No response336/31 (19)2/31 (7)6477At least MiCyRc6735/63 (56)30/63 (48)8089Resistance to prior TKINo2310/20 (50)10/20 (50)8991Yes9635/90 (39)25/90 (28)7282aCumulative response rates.bPatients 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.cDefined 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.