Benda‐EAM prior to ASCT and renal toxicity: Much ado about nothing
Authors: Alessandro Isidori, Federica Loscocco, Barbara Guiducci, Giuseppe Visani
Journal: American Journal of Hematology (2019)

We read with interest the paper by Chantepie et al. about Benda-EAM high-dose therapy (HDT) prior to ASCT,1 that put together real-life experience results by collecting retrospective data within LYSA sites. A high rate of grade I-IV toxicities, mainly related to gastro-intestinal or mucosal toxicities, and a 12.3% incidence of stage ≥2 acute renal failure (ARF) was reported. Moreover, the authors identified patients at higher risk of developing ARF, suggesting to reduce the dose of Bendamustine in certain patients, and increase hydration. The conclusions are strong: “drug shortage may have dangerous consequences”. It is necessary to deeply analyze the data reported, in order for clarity and critical interpretation of the overall results. Furthermore, it is important to report and discuss all data coming from phase II, prospective clinical trials, in order to correctly estimate the incidence of renal (and other) grade III-IV toxicities which could possibly be related to Benda-EAM HDT. First, the French experience is not a multicenter study, but rather retrospective data collection made from at least 22 French sites. This is relevant, because every transplant site has a different policy in terms of hydration, prophylaxis of infections, supportive care and management of post-transplant complications. Outside from a prospective, controlled clinical trial in which every site does the same thing, it is impossible to draw any conclusion, and possibly deemed incorrect to perform statistical analysis and generate an unvalidated score. Of noteworthy, the authors reported a median hydration volume of 3 L (range: 1-6), meaning that at least 200 patients received less than 3 L per day. It would be agreed among physicians involved with HDT/ASCT that less than 3 L per day is an underestimation of the hydration needed for any patient subjected to HDT, and not just necessarily with Bendamustine. Hydration was started at a median time of 18 hours prior to Bendamustine (range: 1-72); there is no mention made of details of the last day of hydration. This is another important indication of the high heterogeneity not only of the patient population, but also of the supportive care measures adopted. Second, at least two controlled phase II studies2, 3 and one retrospective experience4 on Benda-EAM prior to ASCT were recently published (Table 1). Only the retrospective, French study4 reported a high rate of grade ≥ III ARF. However, in this experience 7/29 (24%) patients were admitted in intensive care unit (ICU), 6/7 due to septic shock, and only patients experiencing septic shock also had a grade III to IV ARF.4 Noteworthy, also 11% of patients receiving standard BEAM at the same institution4 were admitted to ICU due to septic shock. Chantepie et al.1 reported a rate of ICU admissions of 10.8%, commenting that it is “acceptable”. We respectfully disagree, because ICU admission rate after HDT/ASCT in the modern era is 2% to 4%.5 Accordingly, ICU admission rates cannot be considered “an interesting endpoint and a reliable indicator in the context of a retrospective study”, as it seems abnormally high from the French reports. Third, cytarabine and etoposide were administered twice daily at the French sites, whereas in the Benda-EAM regimen which originated from our group, both drugs are given once daily at 400 mg/m2 and 200 mg/m2 dose, respectively. Even with this “minor” difference, it is another variable to consider before conclusions. Fourth, for cardiac toxicities, the French reported an incidence of bendamustine-related atrial fibrillation (AF) grades 1 to 4 between 4.8% and 10%.1, 4 However, dose limiting toxicity for bendamustine was defined to be 280 mg/m2/day5; at this dose, patients started to experience cardiac complications, mainly arrhythmia. When we fixed the MTD at 200 mg/m2,5 we carefully decided to keep the Bendamustine dose 25% lower than MTD. Furthermore, several anti-cancer drugs may induce AF.6 After high-dose melphalan alone, AF ranges between 8.3% and 22.5%.6 In patients with ARF and, probably, septic complications, the incidence of arrhythmia is expected to be higher than 4.8%. Finally, older age is one of the most important parameters of the CHA2DS2VASc score, a powerful predictor of AF development. As older age was related to higher ARF,1 it is easy to associate older age with ARF and AF, without necessarily identifying associating bendamustine as a contributing factor. Fifth, we previously stated that Benda-EAM is affected by a higher rate of infections.5 We strongly encouraged those opting to use Benda-EAM,5 to start with piperacilline-tazobactam and amikacine at the first episode of febrile neutropenia, avoiding any possible delay. In order to prevent opportunistic infections, we administer intravenous immunoglobulin 400 mg/kg (days +15, +30 after ASCT), intravenous acyclovir 250 mg/kg thrice daily (d + 1 to d + 10), and thereafter oral acyclovir 800 mg/day for 2 to 3 months, starting cotrimoxazole prophylaxis on day +35.5 Probably, the low incidence of grades III to IV infectious complications, comprising pneumonia (and not pneumonitis, which is typically an inflammation of the lung tissue arising from non-infectious causes) in our series are due to the early intervention we practiced in order to minimize serious consequences. In this light, it would be interesting to know how many patients in the French series died due to infectious complications, and how many to other causes. Finally, TRM was 3.3% in the Lysa group, lower than the acceptable TRM according to EBMT guidelines (5%). We reported a TRM of 1.5% with Benda-EAM,5 within the prospective, multi-institutional phase II study in R/R DLBCL which is now completing the enrolment. TRM under 5% in this hard-to-treat population is acceptable, and is in line with all the new conditioning regimens developed in recent years.5 In conclusion, Benda-EAM can be an effective chemotherapy combination with manageable toxicities, and this requires expertise which comes from experience with the regimen. Nonetheless, in a field in which the gold standard (BEAM) with inherent safety issues and lacks any evidence of superiority demonstrated in a phase III randomized trial, all physicians must carefully analyze what is reported and concluded from retrospective analysis. Benda-EAM has demonstrated efficacy with low renal toxicity in three phase II trials,2, 3, 5 and should be considered when deciding on conditioning regimens for hard-to treat lymphoma patients. The study was supported in part by AIL Pesaro Onlus. Nothing to report.