A randomized trial of continuous infusion versus bolus mitoxantrone in combination with cytarabine in newly diagnosed patients with acute myeloblastic leukemia

Abstract

SUMMARYMitoxantrone (MTZ) has been shown to be effective in the treatment of newly diagnosed acute myeloblastic leukemia (AML). The objective of this randomized study was to evaluate the impact of mode of administration of MTZ on the response and recurrence rates in newly diagnosed patients with AML and to compare the toxicity patterns associated with bolus and continuous infusion (CI) of MTZ. From March 1987 to March 1994, 40 newly diagnosed patients with AML were randomized to receive either bolus or CI-MTZ, administered for 3 days at 10 mg/m 2 /day in combination with CI-cytarabine for 7 days at 100 mg/m 2 /day. Patients achieving complete remission (CR) received two consolidation cycles followed by monthly maintenance cycles, aiming a total of 12 cycles of chemotherapy. Fifteen patients (75%) in the bolus arm and 16 patients (80%) in the CI arm achieved CR. There were no significant differences in rates of early death and time to myeloid recovery between the two groups. After 11 years from the initiation of the study, median disease-free survival (DFS) in bolus and CI groups were 19 and 29 months after a median follow-up of 10 and 14 months, respectively. DFS rates at 10 years were 16.7% in the bolus group and 28.6% in the CI group ( p ¼ 0.36). Overall survival (OS) rates during the same period were 10.7 and 21.3% in the bolus and CI groups, respectively ( p ¼ 0.26). No relapse was observed in either group after 4 years. In patients younger than 40 years of age, DFS and OS were found to be significantly longer in the CI arm ( p ¼ 0.02 and p ¼ 0.03, respectively). Mild asymptomatic cardiotoxicity associated with a decrease of 10 to 20% in the ejection fraction occurred in a patient in CI-MTZ arm and in two patients in the bolus arm. None of these patients showed any evidence of cardiac failure during their subsequent follow-up. Grade III-IV alopecia ( p ¼ 0.05) and grade I-II hepatotoxicity ( p ¼ 0.01) were more frequent in the CI arm. A tendency for higher frequency of grade III-IV nausea was observed in the bolus arm (9 vs. 3%, p ¼ 0.10). As a conclusion, bolus and CI administration of MTZ were equally effective and tolerated well. Development of new anti-leukemia agents with novel treatment approaches is still needed to improve the high relapse rates in patients with AML who do not have an HLA-matched donor.

Mitoxantrone‐Induced Cardiotoxicity in Acute Myeloid Leukemia—A Velocity Vector Imaging Analysis

“…One of the reasons for the higher incidence of cardiotoxicity could be a higher induction bolus dose of mitoxantrone (80 mg/m 2 ) in the current study as compared to the 50 mg/m that has been typically utilized in the modified AIDA protocol and for induction regimens . The higher incidence of cardiotoxicity could also be due to the older population in the current study (66 ± 14 years) as compared to a median age of 30 years in a study by Koc et al, which showed that the risk of symptomatic cardiotoxicity was 5–10% in patients with AML who were treated with mitoxantrone. Also, the current study included patients with previous comorbidities including coronary artery disease, hypertension, diabetes, and atrial fibrillation that could possibly explain an increased baseline risk to develop cardiotoxicity.…”

“…Most of the current evidence on chemotherapy‐related cardiotoxicity is based on studies from breast cancer and pediatric cancer survivors who received anthracyclines and (or) trastuzumab as chemotherapeutic agents. Mitoxantrone hydrochloride is an anthracenedione that is believed to be associated with less cardiotoxicity . Most of the evidence on mitoxantrone‐related cardiotoxicity stems from studies evaluating long‐term cardiotoxic effects of low‐dose maintenance mitoxantrone therapy in patients with multiple sclerosis and from pediatric leukemia survivors .…”

“…Mitoxantrone hydrochloride is an anthracenedione that is believed to be associated with less cardiotoxicity. 1,2 Most of the evidence on mitoxantrone-related cardiotoxicity stems from studies evaluating long-term cardiotoxic effects of low-dose maintenance mitoxantrone therapy in patients with multiple sclerosis and from pediatric leukemia survivors. 1,3 There are few studies that have evaluated mitoxantroneinduced cardiotoxicity in adults with AML, although none of them have studied myocardial deformation parameters as predictors of cardiotoxicity.…”

“…1,3 There are few studies that have evaluated mitoxantroneinduced cardiotoxicity in adults with AML, although none of them have studied myocardial deformation parameters as predictors of cardiotoxicity. 2,18 Previous studies have reported the incidence of anthracycline-induced cardiotoxicity to range from 3% to 26%. 19,20 A 2004 meta-analysis of mitoxantrone-induced cardiotoxicity in pediatric leukemia survivors included 17 studies and concluded that the cumulative incidence of symptomatic and asymptomatic mitoxantroneinduced cardiotoxicity varied between 0% and 6.7% and 0-80%.…”

“…Mitoxantrone hydrochloride is an anthracenedione that has a spectrum of activity against multiple sclerosis, breast cancer, and acute myeloid leukemia and is similar to other anthracyclines, but traditionally believed to be associated with less cardiotoxicity. 1,2 Most of the current evidence on mitoxantrone-induced cardiotoxicity stems from studies evaluating long-term cardiotoxic effects of low-dose maintenance mitoxantrone therapy in patients with multiple sclerosis. 3 However, there is a paucity of literature on the effects of high-dose mitoxantrone induction chemotherapy on cardiac function.…”