In this issue of Leukemia and Lymphoma, Dell'Olio and colleagues demonstrate encouraging tolerability as well as early efficacy when substituting non-pegylated liposomal doxorubicin into the otherwise standard R-CHOP 21 regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, every 3 weeks) [Citation1]. These results highlight one approach to address the concern of cardiotoxicity in the growing number of elderly patients with lymphoma at risk for this severe complication. Commonly used first-line treatment regimens for diffuse large B-cell lymphoma universally contain doxorubicin. Anthracycline associated myocyte death is thought to be secondary to oxidative stress from free radical induction, and the effect is dose related and largely irreversible. Numerous reports have documented the subclinical and clinical cardiotoxicity associated with anthracycline use. Approaches to limit this potentially severe side effect are equally as numerous. One of the first attempts at mitigating the cardiac effects included administering doxorubicin as a prolonged infusion. This led to a decrease in peak plasma levels and appeared to induce less cardiomyopathic changes in a small study [Citation2]. Based on results from subsequent larger experiences, an ongoing trial is testing whether infusional doxorubicin, as part of the dose adjusted R-EPOCH regimen (rituximab, etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone), compares favorably with R-CHOP. Another strategy, the use of structural analogs of doxorubicin, demonstrated a similar incidence of cardiac events. When randomized against CHOP, inferior outcomes were noted in aggressive lymphomas, emphasizing the importance of doxorubicin in treating diffuse large B-cell lymphoma [Citation3]. Acting as a free radical scavenger, dexrazoxane has demonstrated limited success in preventing cardiotoxicity when coadministered with anthracyclines [Citation4]. However, concerns remain whether a diminution of efficacy occurs as well.
More recently, encouraging results were demonstrated using a strategy similar to that studied by Dell'Olio. Two separate formulations of non-pegylated liposomal doxorubicin were substituted into the CHOP 21 and R-CHOP 21 regimens, respectively [Citation5,Citation6]. Cardiac events were few and efficacy data were similar to historic controls in these small trials. In the current trial, the investigators concomitantly monitored the left ventricular ejection fraction at five time points throughout the study. In a population with significant cardiac risks, none of the patients developed early cardiac dysfunction. Rather, the investigators observed a trend toward an increase in the average left ventricular ejection fraction. Additionally, 77.5% of patients remained in remission at a median follow-up of 31 months. As encouraging as these results are, the list of attempts to improve or replace standard doxorucibin is a reminder of the tolerability and efficacy of R-CHOP 21. For the majority of patients receiving the included 300–400 mg/m2 of doxorubicin, clinically significant cardiac events will not occur. Further, large randomized controlled trials requiring group cooperation are necessary to accurately compare outcomes of alternative regimens. The timeline from the observation that infusional administration of doxorubicin may lessen cardiotoxicity to the ongoing randomized trial is a testament to this. Nonetheless, alternatives are needed for those in whom standard anthracyclines are contraindicated. While a consensus defining this population does not exist, we currently include those with a left ventricular ejection fraction <40%. Further, in our practice, the treatment plan typically includes a doxorucibin alternative such as etoposide in these patients, despite the lack of randomized comparisons [Citation7,Citation8]. The data presented here by Dell'Olio may lend themselves to such a trial in order to further address this unmet need.
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