Kinase domain mutations and responses to dose escalation in chronic myeloid leukemia resistant to standard dose imatinib mesylate.

We studied kinase domain (KD) mutations, response to dose escalation, event free survival (EFS), and overall survival (OS) of 90 patients with chronic phase CML who were resistant to imatinib mesylate (IM) 400 mg. IM was escalated to 800 mg daily. There were 65 patients with hematologic failure and 25 with cytogenetic failure. Median duration on IM at resistance detection was 18 months (range, 3-48). Twenty nine (32.2%) patients had KD mutations. Of the 29, the most common were T315I in nine (31.2%) and G250E in eight (27.6%). No clinical or laboratory factor predicted for mutation detection. Of 90 patients, 50 (55.5%) achieved a complete hematologic response and 35 (39%) a major cytogenetic response. At a median of 18 months (range 3-40), 35 patients (39%) are event free and 84 (93%) are alive. The 2 year EFS and OS were 34% and 93%, respectively. The projected 2 year EFS was superior for patients with cytogenetic failure compared to those with hematologic failures (73 vs. 22%, p = 0.0001). Dose decreases were necessary in 16 (18%) and interruptions in 31 (34%). KD mutations were detected in a third of patients with T315I being the most common. IM dose escalation can induce sustained responses in patients with cytogenetic failures.