Pharmacokinetic-Guided Therapeutic Dose Monitoring (TDM) of Busulfan Reduces Relapse of Non-Hodgkin Lymphoma (NHL) Patients Undergoing Autologous Stem Cell Transplantation (ASCT)

Autor: Lisa Rybicki, Navneet S. Majhail, Theresa A. Urban, Brad Pohlman, Aaron T. Gerds, Edward A. Copelan, Brian T. Hill, Ronald Sobecks, Brian J. Bolwell, Mariana Lucerna, Betty K. Hamilton, Deepa Jagadeesh, Matt Kalaycio, Robert M. Dean
Rok vydání: 2019
Předmět:
Zdroj: Biology of Blood and Marrow Transplantation. 25:S31-S32
ISSN: 1083-8791
DOI: 10.1016/j.bbmt.2018.12.103
Popis: Introduction Busulfan (Bu) is integral to many preparative regimens for hematopoietic stem cell transplantation but its metabolism is variable and unpredictable. At our institution, Bu was administered with fixed weight-based dosing (WBD) for NHL patients (pts) undergoing ASCT until 2014 when we initiated a prospective clinical trial (NCT01959477) with pharmacokinetic (PK)-guided therapeutic dose monitoring (TDM) of Bu with cyclophosphamide (Cy) and etoposide (VP16). We subsequently adopted this practice as a standard for all NHL pts. Here, we compare outcomes of NHL pts who received ASCT with WBD vs. PK-directed TDM. Methods We collected clinical features and outcomes of 336 adult NHL pts who underwent ASCT with Bu/Cy/VP16 using WBD (n=258) from 1/2007-12/2013 or TDM from 5/2014-12/2017 (n=78) excluding mantle cell lymphoma. For WBD, Bu was given at 2.8 mg/kg q24 hours on day -9 to -6. For TDM, plasma Bu concentration was serially determined via an in-house liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay as previously described and externally validated. Bu area under the curve (AUC) after first dose was calculated for each pt and used to adjust subsequent doses to target a daily AUC of 4500 μM-minute. Results Baseline features of WBD and TDM pts were similar, although more TDM pts received plerixafor for stem cell mobilization and TDM pts were more often categorized as having a complete remission (CR) prior to ASCT (Table), likely due to more use of PET scan. To adjust for differences, propensity-matched cohorts of WBD and TDM pts were also studied (Table). 36% of TDM pts had increases and 41% had decreases in Bu dose. As shown in the Figure, 24 months after ASCT, relapse was significantly lower with TDM vs. WBD (19% vs. 38%, P = 0.004) and relapse-free survival (RFS) was also improved (69% vs. 55%, P = 0.038). Overall survival (OS) did not differ between WBD and TDM cohorts, likely due to subsequent therapy at the time of relapse. Propensity matched cohorts displayed similar patterns of outcomes. For pts in CR at time of ASCT, RFS did not differ between WBD and TDM (P = 0.79) whereas RFS was improved for pts in Conclusion Compared to WBD, PK-directed TDM of Bu safely reduces relapse when used in combination with Cy + VP16 for NHL pts undergoing ASCT, particularly for pts in
Databáze: OpenAIRE
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