Philadelphia-Positive Leukemia Patients With The Y253H Or F359V Mutations Have a High Risk Of Developing New Mutations In The Setting Of Dasatinib Resistance

The clinical significance of individual mutations in Philadelphia-positive (Ph+) leukemia patients is not well-characterized on dasatinib therapy. The treatment outcomes and development of new mutations in imatinib- and/or nilotinib-failure Ph+ leukemia patients with highly nilotinib-resistant mutations (Y253H, E255K/V and F359V/C) were assessed during dasatinib therapy.

One hundred and eight Ph+ leukemia patients, including 36 with chronic myeloid leukemia in the chronic phase, 18 in the accelerated phase, 40 in the blastic phase and 14 with Ph+ acute lymphoblastic leukemia, who failed imatinib (n=79) or imatinib and nilotinib (n=29) were treated with dasatinib. Those harbored highly dasatinib-resistant mutations (T315I/A, V299L and F317L/V/I/C) were excluded. The patients were grouped into 3 cohorts by baseline BCR-ABL kinase domain (KD) mutation status: no mutation (n=42), non-nilotinib-resistant mutation (any mutation except highly nilotinib-resistant mutations; n=25), or nilotinib-resistant mutation (Y253H, E255K/V or F359V/C; n=41). BCR-ABL KD mutation analysis was detected by direct sequencing at the time of dasatinib resistance.

With a median follow-up of 6 months (range 2-60 months), the frequencies of hematological and cytogenetic responses and clinical resistance to dasatinib, failure-free survival, progression-free survival and alternative treatment-free survival were comparable by baseline BCR-ABL KD mutation status. Sixty of sixty-four patients (93.8%) underwent BCR-ABL KD mutation analysis at the time of developing clinical resistance to dasatinib. Among the 60 evaluated patients, 33 new mutations were first identified in 29 (48.3%) patients at a median of 3 months (range, 2-26 months) of dasatinib therapy, including 8 of 28 (28.6%) with no mutation, 4 of 9 (44.4%) with non-nilotinib-resistant mutations and 17 of 23 (73.9%) with nilotinib-resistant mutations at baseline. New mutations were most frequently observed in the cohort with nilotinib-resistant mutations (P=0.031). Specially, the subset with the Y253H (12/13, 92.3%) or F359V (5/5, 100%) in the cohort with nilotinib-resistant mutations was more likely to acquire new mutations. Multivariate analyses revealed that harboring the Y253H (HR=9.0, 95%CI: 2.7-30.5; P<0.001) or F359V (HR=7.6, 95%CI: 1.5-39.4; P=0.016) mutation at baseline and a lack of any hematologic response to dasatinib (HR=2.1, 95%CI: 1.4-3.1; P<0.001) were identified as independent predictors of developing new mutations during dasatinib therapy.

Our study suggested that Ph+ leukemia patients with the Y253H or F359V mutation had a high likelihood of developing new mutations in the setting of dasatinib resistance. Our data highlight the importance of closer monitoring and mutation follow up for therapeutic choices, especially alternative therapies, which should be considered for patients with the Y253H or F359V mutation during dasatinib therapy. Larger studies are needed to assess the significance of various BCR-ABL KD mutations prior to and during sequential TKI therapy for Ph+ leukemia patients.

No relevant conflicts of interest to declare.