Cardioprotection and Safety of Dexrazoxane in Patients Treated for Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or Advanced-Stage Lymphoblastic Non-Hodgkin Lymphoma: A Report of the Children's Oncology Group Randomized Trial Pediatric Oncology Group 9404

Abstract

Purpose: To determine the oncologic efficacy, cardioprotective effectiveness, and safety of dexrazoxane added to chemotherapy that included a cumulative doxorubicin dose of 360 mg/m(2) to treat children and adolescents with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic non-Hodgkin lymphoma (L-NHL).

Patients and methods: Patients were treated on Pediatric Oncology Group Protocol POG 9404, which included random assignment to treatment with or without dexrazoxane given as a bolus infusion immediately before every dose of doxorubicin. Cardiac effects were assessed by echocardiographic measurements of left ventricular function and structure.

Results: Of 573 enrolled patients, 537 were eligible, evaluable, and randomly assigned to an arm with or without dexrazoxane. The 5-year event-free survival (with standard error) did not differ between groups: 77.2% (2.7%) for the dexrazoxane group versus 76.0% (2.7%) for the doxorubicin-only group (P = .9). The frequencies of severe grade 3 or 4 hematologic toxicity, infection, CNS events, and toxic deaths were similar in both groups (P ranged from .26 to .64). Of 11 second malignancies, eight occurred in patients who received dexrazoxane (P = .17). The mean left ventricular fractional shortening, wall thickness, and thickness-to-dimension ratio z scores measured 3 years after diagnosis were worse in the doxorubicin-alone group (n = 55 per group; P ≤ .01 for all comparisons). Mean fractional shortening z scores measured 3.5 to 6.4 years after diagnosis remained diminished and were lower in the 21 patients who received doxorubicin alone than in the 31 patients who received dexrazoxane (-2.03 v -0.24; P ≤ .001).

Conclusion: Dexrazoxane was cardioprotective and did not compromise antitumor efficacy, did not increase the frequencies of toxicities, and was not associated with a significant increase in second malignancies with this doxorubicin-containing chemotherapy regimen. We recommend dexrazoxane as a cardioprotectant for children and adolescents who have malignancies treated with anthracyclines.

Fig 1.

CONSORT diagram. Summary of patient enrollment for the POG 9404 randomized controlled trial. *In September 2000, based on interim analysis for efficacy, the Data Safety Monitoring Committee closed the methotrexate randomization. The 101 patients enrolled between September 2000 and September 2001, whether or not they received dexrazoxane, all received high-dose methotrexate and are included in this number.

Fig 2.

(A) Event-free survival and overall survival for all eligible, evaluable patients enrolled. (B) Event-free survival by treatment group. (C) Overall survival by treatment group. Dex, dexrazoxane.

Fig 3.

Estimated mean z scores by treatment group among 307 children with T-cell acute lymphoblastic leukemia or advanced-stage lymphoblastic non-Hodgkin lymphoma at baseline (n = 307), at end of therapy (n = 143), and at 3 years (n = 167). Comparison of change from baseline at each time point is noted at the bottom of the figure. (A) LV fractional shortening. (B) LV wall thickness. (C) LV thickness-to-dimension ratio. Bars represent 95% CIs; blue diamond, standard treatment only (doxorubicin [DOX]); gold triangle, dexrazoxane plus standard treatment (DRZ + DOX). †P values comparing the two groups at each time point (baseline, end of DOX treatment, and 3 years). ‡P values for differences in change in mean z scores since baseline in DOX- versus DOX- + DRZ-treated patients, for those patients with values at baseline and a second time point. n indicates number of patients with paired studies in each treatment group. Only patients with paired baseline and end-of-therapy or 3-year z scores were included in these analyses.

Fig 4.

Cumulative incidence of second malignant neoplasms by treatment group. Dex, dexrazoxane.