In Vivo Response to Sequential Tyrosine Kinase Inhibitors (TKI) in Chronic Myeloid Leukemia (CML) Modeled Based on In Vitro Properties of Particular BCR-ABL Kinase Domain (KD) Mutations.
Authors: Jabbour Elias , Kantarjian Hagop , Jones Dan , O’Brien Susan , Faderl Stefan , Estrov Zeev , Ravandi Farhad , Cortes Jorge 
Published: April 2020

Abstract
Background: 2ndgeneration TKI have shown preclinical activity against imatinib resistant BCR-ABL mutations with the exception of T315I. Relative sensitivities of different mutations to various TKI differ. The clinical response of BCR-ABL with particular mutations has been modeled by classifying each mutation based on the in vitro IC50 for each drug against kinase activity for BCR-ABL with that mutation into high, intermediate, and low sensitivity groups.
Study Aims: We investigated how patients (pts) with tumors with particular intermediate sensitivity BCR-ABL KD mutations against one TKI responded before and after shift to an alternative TKI that would be predicted to have more potency.
Methods: Mutation sensitivity was defined by the IC50 for each specific drug(O’Hare, Can Res2005;65:4500; Bradeen, Blood2006;108:2332). Mutations with intermediate sensitivity to dasatinib (D) and nilotinib (N) were defined as those with an IC50 of 2–20 nM and 200–450 nM.
Results: We identified 30 pts who developed intermediate sensitivity mutations to N or D, with median age of 54 years (36–96) followed for 24 months (mo) (6–38) from the start of therapy with 2nd generation TKI. 24 pts had such mutations at the start of 2nd line therapy, with N (n=15: 4 CP,6 AP,5 BP), or D (n=9: 6 CP,3 AP). 7/15 (47%) responded to N (best responses: 1 CMR, 1 MMR, 1 CCyR,1 MiCyR, 3 CHR) for a median of 18 mo (3–33). 3 have ongoing responses: 2 with F317L have CMR and PCyR at 17 and 29 mo, and 1 (F359C) a CCyR at 33 mo. 8/11 (89%) responded to D (3 CCyR, 4 CHR, 1 PHR) for a median of 16 mo (4–29); 2 (both Y253H) have an ongoing CCyR at 24 and 29 mo (Table 1).14 received 3rd line TKI [2 N (2 CP), 9 D (2 CP, 4 AP, 3 BP), 3 bosutinib (3 CP), 1 INNO-406 (1 CP)], and 3 pts 4th line TKI [1 N (1 CP), 2 INNO-406 (1 AP, 1 CP)]. 7/9 pts responded to D as 3rd line for a median of 11 mo (3–22) with 1 ongoing CCyR at 22 mo (F359V). 1/2 pts with F317L who failed D responded to N (ongoing CCyR at 3 mo) (Table 2). Three pts in CP (2 F317L, 1 V299L) received bosutinib as 3rd line: 2 (both F317L) had a transient CHR (6 and 9 mo). INNO-406 was used as 3rd line in 1 in CP (Y253H) and 4th line in 2 [CP (F317L), AP (V299L)] with no response.
Conclusion: Clinical efficacy of 2nd generation TKI correlates with in vitro sensitivity of KD-mutations. In pts failing a TKI in whom a mutation with intermediate in vitro sensitivity to this agent is detected, change to an agent with better in vitro potency against such mutation may improve the response.
Table 1. Dasatinib Nilotinib Best response (%) Best response (%) Cytogenetic Cytogenetic Mutation CHR Any CCyR CHR Any CCyR Intermediate sensitivity to N Y253F/H 1/3 (33) 2/3 (66) 2/3 (66) 0 1/3 (33) 0 E255G/K/V 1/1 (100) 0 0 2/6 (33) 0 0 F359C/V 1/2 (50) 0 0 0 1/2 (50) 1/2 (50) Intermediate sensitivity to D F317L 2/3 (66) 0 0 1/4 (25) 2/4 (50) 2/4 (50) Table 2. Nilotinib followed by Dasatinib Dasatinib followed by Nilotinib Best response (%) Best response (%) Cytogenetic Cytogenetic Mutation CHR Any CCyR CHR Any CCyR NA=Not applicable Intermediate sensitivity to N Y253F/H 1/3 (33) 1/3 (33) 0 NA NA NA E255G/K/V 0 2/3 (66) 1/3 (33) NA NA NA F359C/V 2/3 (66) 1/3 (33) 1/3 (33) NA NA NA Intermediate sensitivity to D F317L NA NA NA 0 0 1/2 (50)