High incidence of reversible renal toxicity of dose-intensified bendamustine-based high-dose chemotherapy in lymphoma and myeloma patients

INTRODUCTION High-dose chemotherapy (HDCT)/autologous stem cell transplantation (ASCT) is the standard for patients with relapsed/refractory lymphomas and multiple myeloma (MM), thereby improving DFS and OS. Relapse after HDCT/ASCT remains the major cause of death in patients with lymphomas or MM after melphalan-based HDCT. Dose-intensified bendamustine by replacing carmustine in the BEAM regimen (BeEAM) or by combining it with melphalan (BenMel) is a promising strategy to lower the relapse rates.Renal toxicity after BeEAM emerges as a major concern. METHODS We investigated renal toxicity in consecutive lymphoma patients treated with BeEAM and in consecutive MM patients treated with the same dose of 400 mg/m2 bendamustine (split into 200 mg/m2 on two consecutive days) together with full-dosed (200 mg/m2) melphalan. Patients with a history of renal impairment before HDCT were included. We assessed renal damage summarized as acute kidney injury (AKI) by measuring renal parameters on a daily basis starting from the first day of HDCT until the last day of hospitalization for HDCT/ASCT. AKI: rise of s-creatinine ≥26.5 μmol/L in 48 hours or increase to more than or equal to twofold compared to baseline s-creatinine within 7 days (Kidney Disease International Global Organization, KDIGO, criteria). Grading of AKI: KDIGO. Treatment-related AKI (rAKI): occurred within 10 days from the last administration of bendamustine; no relation to sepsis. Consequently, we defined as treatment-unrelated AKI (uAKI) all renal damage occurring because of sepsis or later than 10 days since the last administration of bendamustine. Statistical Analysis Subgroup differences: Chi-squared test, Fisher Exact test. IBM SPSS software version 21. RESULTS Patient characteristics and therapy regimen: 122 consecutive patients with lymphomas or MM who underwent high- dose bendamustine regimen before ASCT in 01/2013-06/2016. Factors related to rAKIOccurrence of rAKI: correlated (p<0.05) with age >60 years, previous AKI, cardiovascular comorbidities and concomitant nephrotoxic drugs. In addition, rAKI correlated (p=0.004) with cardiovascular complications during hospitalization; details of subgroups analysis: Table 2.No differences in the incidence of rAKI MM (n=7/15; 46.7%) and lymphoma patients (n=44/107; 41.1%), p=0.683. Acute kidney Injury related to High Dose Bendamustine is reversible and manageable • Acute kidney injury related to bendamustine (rAKI): in 51 patients (41.8%); completely reversible in n=50/51 (98.0%). • rAKI: mild to moderate in 90% of affected patients; did not increase TRM after ASCT. • 3/51 patients (5.9%) with rAKI required transient renal dialysis to enable recovery from renal damage, whereas approaches such as additional hydration were sufficient in the vast majority (n=48 with rAKI; 94.1% of this subgroup). • The median duration of rAKI was 7 days (range, 1-22). ­ According to Cox ZL et al., Adverse Drug Events during AKI and its recovery, Clin J Am Soc Nephrol 2013; 8:1070-1078. CONCLUSION • Our data suggest that treatment-related acute renal toxicity is common in lymphoma and MM patients receiving dose-intensified bendamustine HDCT before ASCT. • However, renal impairment is reversible and manageable. • Our data identify a subgroup of patients at increased risk for the development of renal damage following bendamustine-based HDCT. • Such patients should be strictly monitored during hospitalization, and a generous hydration strategy before, during and after administration of bendamustine is recommended. • Assessing the pre-transplant renal risk profile may help to identify those patients, which may not be candidates for bendamustine-based HDCT thereby avoiding prolonged hospitalization due to rAKI and eventual transient dialysis treatment. • Our results may contribute to design appropriate selection criteria for dose-intensified bendamustine as part of the conditioning regimens preceding HDCT/ASCT in lymphoma and MM patients.