Prior Response to Imatinib Predicts Response to Second Line Treatment with Nilotinib in CML Patients Resistant or Intolerant to Imatinib.

Abstract 3297

Poster Board III-185

Nilotinib is active in imatinib resistant or intolerant CML patients and was recently FDA and EMEA approved for these indications in chronic and accelerated phases. We report the efficacy and safety of 400mg BID nilotinib treatment in 88 CML patients (CP=58, AP=11, BP=19) treated within 2 phase II expanded access clinical trials (CAMN107AIL01 and ENACT).

Median age of included patients was 60 years (range 23-85) and the median disease duration 44 months (range 2-200). Imatinib resistance was the reason for inclusion in 66 (75%) and intolerance in 22 (25%). Thirty-five percent were previously treated with α interferon, 18% with another 2^nd generation TKI and 7.5% have undergone SCT. Twenty-six percent harbored ABL KD mutations at study entry.

Overall 90% of patients responded to nilotinib therapy with best responses of CHR in 23 (27%), PCyR in 10 (12%), CCyR in 12 (14%), MMolR in 16 (19%), stable disease in 15 (18%) and return to CP in 1 patient (1%). In CP, CHR was newly achieved in 25/35 (71%), PCyR in 14/32 (44%), CCyR in 14/37 (38%) and MMolR in 8/41 (20%) of patients not having those responses at study entry, while the respective responses in advanced phase (AP+BP) were 58% (CHR), 30% (PCyR), 33% (CCyR) and 7.7% (MMolR). In imatinib resistant and imatinib intolerant patients, response rates were, respectively, 61% and 75% for CHR, 36% and 50% for PCyR, 29% and 47% for CCyR and 16% and 33% for MMolR with group comparisons NS in all cases.

The best response achieved on imatinib therapy was predictive of the best response to nilotinib while imatinib resistance as defined in the study inclusion criteria was predictive of progression or lack of response to nilotinib therapy. Sixty-one percent of patients whom best response to imatinib was a CHR achieved a CHR as their best response to nilotinib while 83% of patients with at least a MCyR to imatinib have achieved at least a MCyR to nilotinb therapy (p=0.0025). Moreover, at the time of analysis, 32% of imatinib resistant patients have discontinued therapy due to lack of efficacy or disease progression compared to none of the imatinib intolerant patients (p=0.0012).

Responses were not statistically different in patients with ABL KD mutations compared to those without mutations, patients with and without additional cytogentic abnormalities at study entry and patients with prior treatment with another 2^nd generation tyrosine kinase inhibitor compared to those without prior treatment.

Adverse hematological events during nilotinib treatment included thrombocytopenia in 27% and leucopenia in 18%, being grade 3-4 in 13% and 10%, respectively. Common biochemical abnormalities included hyperbilirubinemia (17%, [grade 3-4 2%]), elevated liver enzymes (14%, [1%]) hyperglycemia (7%) and elevated amylase or lipase (6%). The majority of the non-hematological events were mild, the common being rash (14%, [1%]), infection (9%, [1%]), bone pain (6% [1%]), headache (5%) and nausea and vomiting (4%).

In summary, nilotinib treatment is an efficient and safe therapy for imatinib resistant or intolerant patients. Prior response to imatinib therapy is a predictor for response to nilotinib.