High-dose carboplatin and regimen-related toxicity following autologous bone marrow transplant

Abstract

Summary:Pharmacokinetic analysis of carboplatin dosing suggests a more accurate prediction of toxicity when the dose is based on the area under the plasma concentration vs time curve (AUC) instead of body surface area (BSA). We retrospectively calculated the carboplatin AUC of 117 patients who received an autologous stem cell transplant following a conditioning regimen consisting of carboplatin 1800 mg/m 2 and cyclophosphamide 6000 mg/m 2 to identify whether higher carboplatin exposure resulted in an increase in regimen-related non-hematologic toxicities. The most common non-hematologic toxicities were gastrointestinal and hepatic. Twenty (17%) patients experienced additional уgrade 2 toxicity, specifically, renal toxicity significantly associated with a higher median AUC of 10.2 mg/ml ؊1 min (P = 0.001). Prior platinum therapy was also significantly associated with toxicity (P = 0.052). While carboplatin dose based on BSA varied minimally (median 990 (range 450-1340) mg, the calculated AUC showed a near four-fold range of exposure (median 7.8 (range 3.6 to 13.8) mg/ml ؊1 min). These data suggest a relationship between nonhematologic adverse events and the estimated AUC. Prospective trials will be necessary to identify the target carboplatin AUC which optimizes outcome and minimizes toxicity in the autologous transplant setting.

The Xpc gene markedly affects cell survival in mouse bone marrow

“…The data indicate that the Xpc gene can contribute substantially (10-fold) to cell survival in bone marrow. The cell survival end point was biologically relevant as bone marrow myelosuppression was dose limiting for carboplatin, consistent with other studies (13) and the majority of Xpc−/− mice died during the course of the experiments (Figures 4 and 5). No deaths were observed in wild-type mice irrespective of the carboplatin regimen and/or duration (Figure 4 and results not shown).…”

Hematopoietic stem cell transplantation and acute kidney injury in children: A comprehensive review

“…Furthermore, AUC of 8 mg/mL/min or more was associated with higher incidence of nephrotoxicity and commonly encountered adverse effects were hepatic and gastrointestinal. This study recommends AUC between 7 and 8 that has low adverse effect profile for conditioning regimen with carboplatin, but further research is warranted to establish concrete evidence to this relationship . Another study by Foreman et al.…”

End-stage renal disease after high-dose carboplatinum in preparation of autologous stem cell transplantation

“…To avoid hematologic toxicity, an AUC of 5–7 mg/mL/min has been recommended for conventional dosing schemes (23), but no well‐defined target AUCs exist for preventing organ toxicity when carboplatinum is used in pretransplant conditioning regimens. A single report demonstrated a higher risk of renal toxicity in patients undergoing autologous SCT whose target AUCs were ≥ 8 mg/mL/min (24) using the Calvert equation [AUC = dose in mg/(GFR + 25)] (25). Although our patient's surface area based cumulative dose for carboplatinum was within the non‐toxic range (2 g/m 2 ), the mean calculated AUCs for the three doses, based on her estimated GFR, was determined to be 9 mg/mL/min, which would put her in the high‐risk group for renal toxicity.…”