Treatment with Nilotinib 300 Mg Twice Daily in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia Albanian Patients

The introduction and the use of nilotinib in the first-line treatment of chronic myeloid leukemia have been based on company-sponsored trials. Independent confirmations are extremely important1. We are reporting a study study of nilotinib 300 mg twice daily in 41 chronic myeloid leukemia patients in chronic phase. A deep molecular response was achieved in 45 % (MR4.0) and 16 % (MR4.5) of patients at 18 months, 55 % of the enrolled patients achieved a MR4.0 at least once, with a sustained MR4.0 in 52 % of them. With a median observation of 50 months (range 4860 months), 95 % of patients were still on treatment with nilotinib. The reason for discontinuation was death in 2 patients. An evaluation of metabolic affects showed an increase of total cholesterol and an increase in fasting glucose2. This study in Albanian patients with newly diagnosed chronic myeloid leukemia confirms the efficacy of nilotinib 300 mg twice daily (BID) and provides information on the type and incidence of non-hematologic and metabolic adverse events3. Introduction Nilotinib is a second generation BCR-ABL1 tyrosine kinase inhibitor (TKI). It has been approved for the first-line treatment of newly diagnosed, chronic phase (CP) Philadelphia chromosome-positive (Ph+), BCR-ABL1-positive (BCR-ABL1+) chronic myeloid leukemia (CML), following phase 3 prospective randomized trial (ENESTnd) comparing nilotinib to imatinib 400 mg once daily (QD) 4. Several updates of the study, over 6 years, have confirmed the initial findings that nilotinib was superior to imatinib for any degree of molecular response, and for the rapidity of the response5. The progression-free survival (PFS) was reported to be marginally improved and no difference in overall survival (OS) was detectable. In the ENESTnd trial, two different nilotinib doses were tested, namely 300 mg twice daily (BID) and 400 mg BID 6. The 300 mg BID dose was selected for approval because it was reported to be as effective as, but less toxic than, the 400 mg BID dose4. This concern was by other independent studies, for the most part retrospective and mainly in second-line treatment, reporting a significant incidence of cardiovascular adverse events (CVAEs) during nilotinib treatment. With a minimum observation of 24 months, the molecular response rates in a second single-arm company-sponsored study of nilotinib 300 mg BID, the ENEST1st trial, were even higher compared to the ENESTnd results, with consistent safety data7 There are no independent, investigator-sponsored studies of the drug in first-line treatment, with the exception of the two small pilot studies that were performed prior to the approval of nilotinib in first-line treatment, at the dose registered for second-line treatment (400 mg bid). When the 300 mg BID dose became the standard in first-line therapy. Since all patients have now been followed for a minimum of 4 years, we report the results of the main analysis of response and adverse events (AEs) 8. Methods A single-arm study of nilotinib, 300 mg BID was applied in adult patients9. Pre-treatment with imatinib for up to 30 days was permitted. The primary endpoint was the rate of EMR at 3 months10. The cut-off date for this analysis was September 15.2017. The detection of a Ph chromosome and/or a BCR-ABL1 fusion gene associated with consistent morphologic features were required to confirm the CML diagnosis and the chronic (CP), accelerated (AP) or blast disease phase (BP) were defined according to current ELN criteria.10 Risk scores were calculated according to Sokal, 171819formulations. The molecular response (MR) was assessed by peripheral blood RT-PCR, according to the International Scale (IS). Definitions early molecular response (EMR), BCR-ABL1 transcript 10 % at 3 months, major molecular response (MMR or MR3.0), BCR-ABL1 transcript 0.1 %, MR4.0 and MR4.5, BCR-ABL1 transcript 0.01 %, and 0.0032 %, respectively, in samples with greater than 10, 000, and greater than 32, 000 ABL1 copies, respectively, sustained MR4.0 or MR4.5, stable response for greater than 1 year with greater than 3 evaluable tests. Molecular tests were performed every 6 months. The cytogenetic response was assessed by chromosome banding analysis at 3, 6 and 12 months, if there were less than 20 available metaphases, a fluorescence in situ hybridization (FISH) analysis on peripheral blood cells was accepted (complete cytogenetic response, CCyR, 1 % of BCR-ABL1 positive nuclei, greater than 200 nuclei analyzed). OS, PFS, and event-free survival were calculated from treatment start until death (OS), until death or progression to AP or BP (PFS), or until death, progression to AP or BP. Probabilities of OS, PFS and EFS were calculated using the Kaplan-Meier method.11 The time to response was calculated from treatment start until the first achievement of the response. The cumulative probability of response was calculated taking into consideration the presence of competing risks (failure, progression or death12). The AEs were graded according to the