Low-Dose Nilotinib and Imatinib Combination In CML Patients, With Failure, Suboptimal Response Or Treatment Intolerance To First Line Imatinib Treatment. A Pilot Study

Introduction of tyrosine kinase inhibitors (TKI) as first-line therapy has reduced mortality related to CML in the last 10 years. According to IRIS study probability of maintaining CCyR to 5 years with imatinib is 63%. Therefore 30-35% of patients will require alternative treatment for primary, secondary resistance or intolerance to treatment. Nilotinib has shown to be 20 times more potent than imatinib in cells expressing unmutated BCR / ABL and is effective against up to 30 different mutations present in the imatinib resistant patient. It now has a role as first line CML therapy or second line in the case of imatinib failure. Drug combinations are common in the treatment of other neoplasms, preclinical studies showed that nilotinib has a synergistic effect when used in conjunction with imatinib, for inducing apoptosis and decreases cell proliferation without relevant toxicity. Combination of these two drugs has been used in the treatment of gastrointestinal stromal tumor (GIST) and in at least 2 reported cases of CML, with good results and without increased toxicity.

Low-dose nilotinib in combination with low-dose imatinib appears to be another option for patients with failure, suboptimal response or intolerance to imatinib therapy. In this pilot and prospective study, we analyzed the effectiveness and tolerability of this combination.

To evaluate cytogenetic and molecular response to low-dose imatinib and nilotinib combined treatment in CML patients with failure, suboptimal response or intolerance to imatinib therapy and the potential toxicity of the combination.

CML patients with failure, suboptimal response or intolerance to imatinib therapy were evaluated. Cytogenetic analysis, quantitative PCR for BCR/ABL and evaluation for mutations were performed at baseline. All patients received treatment as follows: imatinib 200 mg daily and nilotinib 300 mg daily for 6 months. Quantitative PCR for BCR/ABL was performed at 3 months, and cytogenetic analysis and quantitative PCR for BCR/ABL at 6 months. If hematologic progression occurred, stepwise dose escalation of imatinib 200 mg and nilotinib 150-300 mg monthly was permitted until a maximum dose of 800 or 750 mg each. Kolmogorov-Smirnov was use to test for normality, T-test, Friedman test and Q Cochran were used for parametric and non parametric variables respectively.

Ten patients were included, 6 men and 4 women, median age of 38 years (27-68). Median time from diagnosis was 65.8 (13.7-149.3) months, and time of previous imatinib treatment was 60.8 (30.0-113.3) months; with a median imatinib dose of 400 mg (400-800), 80% had treatment failure and 20% suboptimal response according to European Leukemia Net criteria. No patients with treatment intolerance were included. Mutations were detected in 40% of patients. At baseline only 2 patients had complete cytogenetic response, at 6 months 6 patients had complete cytogenetic response (p=0.046), at 6 months 40% of patients had achieved major molecular response (p=0.039). Mean percentage of BCR/ABL transcripts detected by quantitative PCR before treatment and at 3 and 6 months was 15.62% IS (SD±18.39), 7.25% IS (SD± 8.48) and 1.05% IS (SD± 1.32) respectively, with a significant difference, p= 0.045. The most frequent side effect was rash in 4 patients; with mild severity and complete response to antihistaminic treatment in all cases. One patient had to be withdrawn from the study after 3 months of treatment because of grade 4 thrombocytopenia. None of the patients presented disease progression.

Our results support the information that preclinical studies showed, that nilotinib has a synergistic effect when used in conjunction with imatinib. Low-dose imatinib and nilotinib combination is an effective and safe treatment alternative for some patients with failure, suboptimal response or intolerance to imatinib monotherapy at standard dose.

Off Label Use: Nilotinib and imatinib at low dose.