Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia

Abstract

4′-Demethoxydaunorubicin (idarubicin [IDR]) is a new anthracycline that differs from its parent compound by the deletion of a methoxy group at position 4 of the chromophore ring. This minor structural modification results in a more lipophilic compound with a unique metabolite that has a prolonged plasma half-life as well as in vitro and in vivo antileukemia activity. To determine its activity in acute myelogenous leukemia (AML), 130 consecutive adult patients between the ages of 16 and 60 with newly diagnosed disease were randomized in a single institution study to receive either IDR in combination with cytosine arabinoside (Ara-C) or standard therapy with daunorubicin (DNR) and Ara- C. The trial was analyzed using the O′Brien-Fleming multiple testing design that allowed for periodic inspection of the data at specific patient accession points. After accrual of 60 patients per arm, analysis showed that patients who received IDR/Ara-C had a superior response compared with those who received standard therapy: 48 of 60 patients (80%) achieved complete remission on the former arm compared with 35 of 60 patients on the latter (58%, P = .005). Logistic regression analysis of factors associated with complete response indicated that treatment with IDR/Ara-C offered a significant advantage to patients who presented with a high initial white blood cell count compared with treatment with DNR/Ara-C. The degree of marrow aplasia was approximately the same on each arm as was nonhematologic toxicity. Overall survival for patients on the IDR/Ara-C arm was 19.5 months compared with 13.5 months on the DNR/Ara-C arm (P = .025) at a median follow-up of 2.5 years. We conclude that IDR/Ara-C can effectively replace standard therapy with DNR/Ara-C in adult patients less than age 60 with newly diagnosed AML.

Second‐line mitoxantrone, etoposide, and cytarabine for acute myeloid leukemia: A single‐center experience

“…All patients received first‐line therapy with standard induction regimens including idarubicin and cytarabine, idarubicin and high‐dose cytarabine or daunorubicin and cytarabine. Dosing and schedules were as previously described; idarubicin 12 mg/m 2 /day, days 1–3; cytarabine 100 mg/m 2 /day, days 1–7 [11–13]; idarubicin 12 mg/m 2 /days, days 1–3; and cytarabine 3000 mg/m 2 every 12 hr, days 1–4; [14] daunorubicin 45 mg/m 2 /day, days 1–3 and cytarabine 100 mg/m 2 /day, days 1–7 [15]. Among patients who obtained a CR to induction, postremission therapy consisted of two cycles of idarubicin or daunorubicin and cytarabine or four cycles of high‐dose cytarabine.…”

On Assessing Surrogacy in a Single Trial Setting Using a Semicompeting Risks Paradigm

“…The motivating data example comes from a phase III clinical trial (Berman et al, 1991) comparing two treatments for acute myelogenous leukemia. The first treatment is the standard, daunorubicin (DNR), and cytosine arabinoside (Ara‐C), whereas the experimental therapy was idarubicin (IDR) and Ara‐C, all three of which are chemotherapeutic agents.…”

“…Although IDR and DNR are have similar functions, there are slight differences in the molecular structure of the two compounds that lead clinicians to believe that the IDR might be less toxic than DNR. The goal of the study is to determine and compare the efficacy of the DNR/Ara‐C combination versus that of IDR/Ara‐C with respect to several study endpoints, among them complete remission and survival, as discussed by Berman et al (1991). Complete remission refers to leukemia cells being killed by the therapy.…”

Therapeutic options for acute myelogenous leukemia

“…Numerous randomized trials have attempted to identify which anthracycline (e.g. idarubicin, daunorubicin, mitoxantrone, aclarubicin) should be combined with ara‐C 13–15. The general consensus16 favors idarubicin, which is generally administered at a dose of 12 mg/m 2 3 times daily.…”