Phase I/II Clinical Study of Idarubicin Dose Intensification for Remission Induction Therapy in Acute Myeloid Leukemia Patients Age of 65 Years or Less
Up to nowadays, a standard induction therapy for acute myeloid leukemia(AML) has consisted
of cytarabine 100-200 mg per square meter of body surface area(BSA) per day continuous
infusion for 7 days with idarubicin 12 mg per square meter or daunorubicin 45 mg per square
meter of BSA per day for 3 days. This standard therapy induces a complete remission(CR) in
50-75% of young adults and 40-50% of older adults. Recently two cooperative groups
prospectively compared 45 mg per square meter of daunorubicin to 90 mg per square meter of
BSA. They reported high-dose daunorubicin, as compared with a standard dose one, resulted in
a significantly higher CR rate and improved overall survival(OS) up to age 65 without
additional toxic effects.
Daunorubicin has been more commonly used anthracycline; however, idarubicin has a longer
intracellular retention time and has shown more rapid clearance of marrow blasts. In the
early 1990, three prospectively randomized studies showed that a combined regimen of
idarubicin and cytarabine was superior to one of daunorubicin and cytarabine for the
induction therapy of AML in adults. When they compared daunorubicin 45-50 mg per square
meter with idarubicin 12-13 mg per square meter for induction therapy, there were no
significant differences in hematologic and non-hematologic toxicities, including cardiac
Phase I studies of idarubicin in patients with acute leukemia and chronic myelogenous
leukemia in blast crisis reported the dose-limiting toxicities(DLT) were stomatitis and
anorexia at the maximum tolerated dose(MTD) of 15 mg per square meter of BSA per day for 3
days. Based on the results of these studies, the investigators have generally administered
idarubicin 12 mg per square meter per day for 3 days for the remission induction therapy of
AML. Meanwhile Sanz et al. had administered idarubicin 12 mg per square meter per day for 4
days in patients with acute promyelocytic leukemia, and Tedeschi et al. had done a single
high-dose idarubicin 40 mg per square meter combined with high-dose cytarabine 3 g per
square meter per day for 5 days in patients with acute lymphoblastic leukemia, with no
significant increase of severe toxicity. The MTD of idarubicin should be reevaluated in the
treatment of acute leukemia, especially in the era of granulocyte colony-stimulating factor
and better supportive care available.
In this phase I study, idarubicin 12 mg per square meter of BSA per day for 3 days will be
given to three patients at the first stage and then the idarubicin dose will be increased by
3 mg per square meter of BSA each stage. The phase I study consists of 3 stages and the
idarubicin dose will be increased up to 18 mg per square meter of BSA per day for 3 days
unless DLTs do not develop in more than 33% of enrolled patients at each stage. In the
subsequent phase II study, the MTD being determined from the phase I study or 18 mg per
square meter of idarubicin will be given to the enrolled patients. There were three large
studies which enrolled a total of 942 previously untreated adult patients with AML and in
which idarubicin 12-13 mg per square meter of BSA per day for 3 days and cytarabine 100 mg
per square meter daily for 7 days were administered intravenously. Therefore, the
investigators can adopt them as historical control groups in terms of statistical
In conclusion, the investigators desire to determine the safety and effectiveness of the
intensified dose of idarubicin in the treatment of acute myeloid leukemia through this phase
I and II study.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose of idarubicin in the phase I study.
Within 2 months after induction therapy in the phase I study.
Mark H Lee, M.D., Ph.D.
Konkuk University Medical Center
South Korea: Korea Food and Drug Administration (KFDA)