YNK01, an Oral Cytosine Arabinoside Derivative in Acute Myeloid Leukemia and Chronic Myeloid Leukemia

Twenty-eight patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) were treated in a phase I/II multicenter trial and pilot single-center trial with YNK01 an oral cytosine arabinoside (ara-C) derivative. In contrast to ara-C, YNK01 is resistant to cytidine deaminases. Therefore YNK01 is converted to ara-C in the liver and released slowly into blood. It has been shown in ongoing pharmacokinetic studies that a mean of 16% of YNK01 is secreted as ara-U into the urine. Twenty-two patients with AML (12 patients with relapse, five with secondary AML, five with primary, not qualifying for intensive chemotherapy) were included, median age 67 (range 22–79 years, 13 pretreated /11 with ara-C). In the AML trial the doses of YNK01 were escalated interindividually from a daily 100 mg/kg body weight up to 1200 mg/kg body weight for 14 days. Cycles were repeated every 21–28 days. Major toxicities at the 900- and 1200-mg dose levels were nausea grade 3 (WHO) in one patient; diarrhea grade 3 in five patients, grade 4 in one patient; exanthema grade 3 in one patient; and stomatitis grade 3 in one patient, grade 4 in one patient. At the lower dose levels no grade 3 or 4 organ toxicities were observed. Six patients (median age 53 years, range 26–64 years) were included in the CML pilot trial. Treatment was started with interferon (IFN)-α-2b5 x 106 units s.c. daily. After 1 week YNK01 600 mg daily continuously was added. IFN and YNK01 were modified according to toxicity and effectivity. Maximum toxicities were diarrhea grade 3 in one patient bone pain grade 3 in one patient.