Clinical Safety and Efficacy Of Nilotinib Or Dasatinib In Patients (Pts) With Newly Diagnosed Chronic-Phase Chronic Myelogenous Leukemia (CML-CP) With Pre-Existing Liver and/Or Renal Dysfunction

Dasatinib and nilotinib have become standard frontline therapy for pts with CML-CP. Their clinical safety and efficacy in the setting of pre-existing liver and/or renal dysfunction has not been described.

215 CP-CML pts treated with nilotinib or dasatinib as a frontline therapy in clinical trials at our institution between 5/05 and 10/12 were analyzed. Renal and liver functions were classified according to the National Cancer Institute Organ Dysfunction Working Group. Normal renal function was defined as creatinine clearance (CrCl) ≥ 60 ml/min; mild as CrCl 40-59 ml/min; moderate as CrCl 20-39 ml/min; and severe as CrCl ≤ 20 ml/min. Normal liver function was defined as total bilirubin (TB) levels ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) ≤ ULN; mild as TB ≤ 1.5 x ULN and AST > ULN; moderate as TB 1.5 to 3.0 x ULN and AST of any value; and severe as TB > 3.0 x ULN and AST of any value. Starting doses were nilotinib 400 mg twice daily and dasatinib 100 mg daily. Survival was dated from the start of nilotinib or dasatinib until death from any cause. Event free survival (EFS) was calculated from the start of nilotinib or dasatinib to loss of complete hematologic response, loss of major cytogenetic response, transformation to accelerated or blast phase, or death from any cause.

The results of patient characteristics, EFS and OS are summarized in Table 1 and Figure 1. The median age for all pts was 48.8 yrs (range, 16.2 to 86.4) and the median follow-up was 48 months (2 to 93). Of the 107 pts treated with dasatinib, 6 pts (6%) had mild renal dysfunction and 13 pts (12%) mild liver dysfunction. Of 108 pts treated with nilotinib, 8 pts had mild renal dysfunction, 1 pt moderate renal dysfunction and 9 pts mild liver dysfunction. Of 89 pts with normal organ function treated with dasatinib, the Sokal risk score was low in 73% for those with normal organ function, intermediate in 22%, and high in 4%. For the 18 pts with liver or renal dysfunction treated with dasatinib, low in 77%, intermediate in 17% and high in 6%. Of 91 pts with normal organ function treated with nilotinib, low in 71%, intermediate in 20%, and high in 9%. Of 17 pts with liver or renal dysfunction, low in 76%, intermediate in 24% and high in 0%. A complete cytogenetic response (CCyR) was achieved in 167 pts (93%) with normal organ function compared to 32 pts (91%) in pts with renal or liver organ dysfunction. Corresponding rates for major molecular response (MMR) were 160 pts (89%) and 31 pts (89%), respectively, and for complete molecular response (CMR) 89 pts (49%) and 12 pts (34%), respectively. The rate of CCyR at 12 months was 143 pts (79%) for those with normal organ function and 28 pts (80%) for those with organ dysfunction. There were no significant differences by treatment arm or between renal and liver dysfunction. Treatment was overall well tolerated in all patients with no significant difference in adverse events, except for a trend for more grade 3/4 pleural effusion in pts with renal dysfunction treated with dasatinib (2/6), and grade 3/4 bleeding in pts with renal dysfunction treated with nilotinib (2/9). Overall, 38 pts (21%) in the normal organ function group and 10 pts(29%) in the organ dysfunction group have discontinued therapy, including 16 pts (9%) and 5 pts (14%) respectively for intolerance. Overall survival in renal dysfunction was significantly worse compared to normal organ function (p= 0.034).

Figure 1

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Event-free survival and overall survival in patients with pre-existing liver dysfunction, renal dysfunction and normal organ function treated with front-line dasatinib or nilotinib.

Figure 1

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Event-free survival and overall survival in patients with pre-existing liver dysfunction, renal dysfunction and normal organ function treated with front-line dasatinib or nilotinib.

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Figure 2

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Figure 2

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Pts with mild to moderate renal or liver dysfunction can be safely treated with dasatinib or nilotinib as initial therapy for CML-CP and can achieve similar rates of response as their counterparts with normal organ function at the start of therapy.

Jabbour:BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Ariad: Consultancy.