[Evaluation of impact of baseline ABL kinase domain point mutations on response to nilotinib in imatinib-resistant or-intolerant patients with chronic myeloid leukemia].

Abstract

To evaluated the impact of baseline ABL kinase domain point mutations on responses to nilotinib in imatinib-resistant or-intolerant patients with chronic myeloid leukemia (CML).
34 CML patients after imatinib failure or intolerance received oral administration of 400 mg nilotinib twice daily. The median follow-up duration of nilotinib therapy was 14 (1.5-50) months. ABL kinase domain point mutations were detected from bone marrow of CML patients at baseline and once every 6 months before and after nilotinib therapy. Hematologic, cytogenetic, molecular response and progression were evaluated respectively at the same time.
Among 34 patients, 13 were in chronic phase (CP), 11 were in accelerated phase (AP), 10 were in blastic crisis (BC). Major cytogenetic response (MCyR) was achieved in 70% of patients with CP, 30% of patients with AP and BC (P = 0.027). Complete cytogenetic response (CCyR) was achieved in 70% of patients with CP and 20% of patients with AP and BP, respectively (P = 0.005). The 4-year progressive free survival of patients with CP and AP was (81.8 +/- 11.6)% and (20.5 +/- 12.9)%, respectively (P < 0.01). The cases of ABL kinase domain point mutations at baseline was 17 (50%). CHR was achieved in 56%, MCyR in 43%, CCyR in 37%, MMR in 31% of patients with baseline mutations versus 59% (P > 0.05), 53% (P > 0.05), 41% (P > 0.05), 18% (P > 0.05), respectively, of patients without baseline mutations. The CHR, MCyR, CCyR and MMR in patients who harbored mutations with high sensitivity to nilotinib in vitro (IC50 < or = 150 nmol/L) or mutations with unknown nilotinib sensitivity in vitro were equivalent to those responses in patients without mutations. Patients with mutations less sensitive to nilotinib in vitro (IC50 > 150 nmol/L, Y253H, F359V/C, T315I) achieved 17% of CHR and MCyR, none of them (6 cases) achieved CCyR, and 6 cases had disease progression within 24 mouth after treatment.
Nilotinib is a more effective option for imatinib-resistant or-intolerant CML patients. Response for patients with CP was better than patients with AP and BC. Mutational status at baseline may influence response. Less sensitive mutations may be associated with less favorable responses to nilotinb.