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.
Authors: Cortes Jorge E. , Khoury H. Jean , Lipton Jeff H , Gambacorti-Passerini Carlo , Brümmendorf Tim H , Kim Dong-Wook , Leip Eric , Kelly Virginia , Besson Nadine , Turnbull Kathleen , Kantarjian Hagop M. 
Published: October 2019

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.