Results of Randomized Study on Dexrazoxane Administration in Children with De Novo Acute Leukaemia.

Anthracyclins and anthracenediones represent major drugs for both myeloid and lymphoblastic acute leukemia. Among their efficient mechanisms, these drugs induce free radical production responsible of cardiac toxicity. Even though toxicity is mainly dose related, there is an inter-individual sensitivity, and then it appeared very important to develop drugs able to protect cardiomyocytes. Dexrazoxane was developed in this goal in adult patients where its efficiency was demonstrated both to protect heart and to respect anticancer therapy results. We conducted a prospective single bind randomized study using dexrazoxane associated with first-line therapy in pediatric acute leukemia.

Patients and Methods: From Dec’00 to Sept’03, 16 patients (pts) were enrolled and randomized for receiving or not dexrazoxane (1000mg for 50mg of anthracyclines or anthracenedione doxorubicin dose equivalent) with chemotherapy. Cardiac function was evaluated by echocardiogram before induction and after each chemotherapy course of either CLG-EORTC 58951 trial arm VHR or French acute myeloid leukemia trial LAME01 and each year after treatment completion. The cardiologist operator did not know if child received dexrazoxane or not. The cumulative equivalent doxorubicin dose was 310mg/m² for EORTC 58951 VHR group and 460mg/m² for LAME01. The primary end-point was cardiac function evolution. The secondary end points were OS, EFS and the respect of initial therapy schedule.

Results: 16 pts (9M/7F), median age 8.5y (range: 2.4 – 16.1) were enrolled. Initial diagnoses were AML: 11 and ALL: 5. Five AML pts and 3 ALL pts received dexrazoxane. Median follow-up was 28.5 months (10–47). 12 pts were alive, 6 in each arm of study. One pt relapsed in arm with dexrazoxane and 3 in the other arm. Two pts died of disease and 2 from infection equally dispatched in the 2 study arms. Mean left ventricular shortening fraction was 39.4+/−1.9% and 35.6+/−1.2% in pts without dexrazoxane and 40.2+/− 2.2% and 38.7+/− 2% in pts with dexrazoxane before chemotherapy and 1 year after diagnosis. All these values were comparable. Mean duration between day1 of each chemotherapy course was the same in different arms of study.

Discussion and conclusion: Dexrazoxane may be used safely in children receiving anthracycline. No difference in OS and DFS appear in our study. Median follow-up was probably too short for distinguishing any cardiac alteration and patient number was low. In addition, shortening fraction may be not the better cardiac indicator and wall stress could be more efficient. Further investigations are on-going.