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.

Background: 2^ndgeneration 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(

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 2^nd generation TKI. 24 pts had such mutations at the start of 2^nd 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 3^rd 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 4^th line TKI [1 N (1 CP), 2 INNO-406 (1 AP, 1 CP)]. 7/9 pts responded to D as 3^rd 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 3^rd line: 2 (both F317L) had a transient CHR (6 and 9 mo). INNO-406 was used as 3^rd line in 1 in CP (Y253H) and 4^th line in 2 [CP (F317L), AP (V299L)] with no response.

Conclusion: Clinical efficacy of 2^nd 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.