Jun 11, 2020
This podcast describes a study addressing the use of dexrazoxane as a cardioprotectant in a cohort of more than 1,000 pediatric acute myeloid leukemia patients.
This JCO Podcast provides observations and commentary on the JCO article “Effect of Dexrazoxane on Left Ventricular Systolic Function and Treatment Outcomes in Patients with Acute Myeloid Leukemia: A Report From the Children’s Oncology Group” by Getz et al. My name is Elvira van Dalen, and I am an epidemiologist at the Princess Máxima Center for Pediatric Oncology in Utrecht, The Netherlands and a Coordinating Editor of Cochrane Childhood Cancer. My oncologic specialties are cardiotoxicity and systematic reviews and guidelines in the field of pediatric oncology. I have nothing to disclose.
Anthracyclines are widely used in pediatric oncology. Unfortunately, one of their most serious adverse effects is cardiotoxicity, which can occur during or shortly after treatment, but also decades later. In the Dutch LATER Childhood Cancer study, we found a 10.5% cumulative incidence of symptomatic heart failure 40 years after cancer diagnosis in survivors treated with cardiotoxic chemotherapy. The Childhood Cancer Survivor Study and St Jude LIFE show similar results. Siblings report significantly less congestive heart failure than survivors. These are high risks, especially in this young patient population. Cardiotoxicity impairs quality of life and can lead to premature death. Prevention is thus very important.
Extensive research has been devoted to the identification of possible cardioprotective interventions, like liposomal anthracyclines, increasing the anthracycline infusion duration and reducing the cumulative anthracycline dose. Concerning the cumulative anthracycline dose, it should be kept in mind that there is no safe dose. Another option is the use of cardioprotective agents like dexrazoxane.
As shown in our Cochrane systematic review published in 2011 which is currently being updated, it prevents cardiac damage. But unfortunately, the majority of the evidence comes from studies addressing adult patients with breast cancer and these data cannot be extrapolated to children. In children as of yet only a few randomized trials have been performed, none including acute myeloid leukemia patients. In these pediatric studies, for clinical heart failure there were no significant differences between dexrazoxane and control groups, while results for asymptomatic cardiotoxicity varied with the outcome definition used. All studies were relatively short-term, and we don’t know how longer follow-up will influence these results.
Thus far only a few small non-randomized studies including 50 children or less evaluated dexrazoxane in pediatric acute myeloid leukemia, all with limitations. The article by Getz and colleagues that accompanies this podcast adds important new information to the current knowledge of the use of dexrazoxane in pediatric acute myeloid leukemia patients and pediatric patients in general. It presents the results from the Children’s Oncology Group AAML1031 trial investigating the use of dexrazoxane during frontline treatment of pediatric acute myeloid leukemia. Between 2011 and 2016, patients younger than 30 years at diagnosis were enrolled. Almost 98% were younger than 21 years. The analyses included 1014 patients, of which 10% received dexrazoxane consistently at every anthracycline course and 90% were never exposed to dexrazoxane. Anthracycline treatment involved both daunorubicin and mitoxantrone. Low risk patients received a cumulative anthracycline dose of 444 mg/m2, while high risk patients received 294 mg/m2 assuming the daunorubicin equivalency conversion employed by the Children’s Oncology Group at the time of this protocol. Patients were followed for a median of 3.5 years, with an interquartile range of 2.5 to 4.7 years. Cardiac function was assessed using either echocardiography or multigated acquisition scans which were performed at regular intervals. Compliance with cardiac monitoring was more than 90% on-protocol, but less than 60% off-protocol. Left ventricular systolic dysfunction was primarily defined as a shortening fraction of less than 28% or an ejection fraction of less than 55%.
In the report by Getz and colleagues that accompanies this podcast, 26.5% of patients consistently treated with dexrazoxane and 42.2% of patients that never received any dexrazoxane developed left ventricular systolic dysfunction. The hazard ratio was 0.55 with a 95% confidence interval of 0.36 to 0.86. There was a trend towards a worse grade of left ventricular systolic dysfunction without dexrazoxane. Some evidence pointed to recovery of systolic function, but as this was based on mean values instead of number of patients below the cut-off value it is possible that patients with good and bad values balanced each other out resulting in an adequate mean value. This can give the impression that there is no problem, while for some patients this might not be true.
It is important to note that this was not a randomized trial, which would have provided the highest level of evidence to answer this type of question. Dexrazoxane was administered at the discretion of treating physicians. However, characteristics like sex, age, risk group, treatment arm, compliance with cardiac monitoring and follow-up were similar in both groups. Unfortunately, cumulative anthracycline dose was not reported for both groups, but it was stated that patients completed a median of 4 courses regardless of dexrazoxane exposure.
An important question regarding any cardioprotective intervention is whether it can reduce cardiotoxicity without negative effects on anti-tumor efficacy and non-cardiac toxicities. At the moment, despite its clear cardioprotective effects, at least in adults, dexrazoxane is not routinely used in clinical practice. This might be explained by the suspicion of interference with anti-tumor efficacy and the occurrence of secondary malignancies. However, as shown in our Cochrane systematic review no significant differences between treatment groups were identified, which is in line with more recently published randomized trials.
Studies often do not report data on anti-tumor efficacy and non-cardiac toxicities, but fortunately Getz and colleagues did. This is important as extrapolation of many of these data to other types of malignancies is difficult. Survival and relapse risk were comparable between groups. And even though this study did report on only a few non-cardiac toxicities, those that were reported were similar. Despite the relatively short follow-up period, four secondary malignancies occurred, three in the non-dexrazoxane group. This was not statistically significant different. None of the secondary malignancies was acute myeloid leukemia, but it might have been difficult to distinguish a secondary malignancy from a relapse.
In summary, although this is not a randomized trial, this large study provides new knowledge on the use of dexrazoxane in pediatric acute myeloid leukemia patients with regard to cardiac function, anti-tumor efficacy and non-cardiac toxicities. Overall, dexrazoxane seems to be cardioprotective, at least within the relatively short follow-up period of maximal 4 years, without negative effects on anti-tumor efficacy and non-cardiac toxicities including secondary malignancies. Hopefully the authors will continue to follow these patients for long-term results. Even though this study does have limitations, it definitely adds to the knowledge of the use of dexrazoxane in children. It can help to inform the development of a much-needed evidence-based clinical practice guideline that is currently being developed by the International Late Effects of Childhood Cancer Guideline Harmonization Group.
This concludes this JCO Podcast. Thank you for listening.