Conference Coverage

Therapeutic dosing of busulfan helps reduce relapse in ASCT



– Compared with weight-based dosing, pharmacokinetic-directed therapeutic dose monitoring of busulfan used in combination with cyclophosphamide and etoposide reduced relapse risk in non-Hodgkin lymphoma (NHL) patients undergoing autologous stem cell transplantation (ASCT), according to a review of 336 cases.

Dr. Brian T. Hill, director of the lymphoid malignancies program and a staff physician at the Cleveland Clinic Taussig Cancer Institute, Ohio Sharon Worcester/MDedge News

Dr. Brian T. Hill

This was particularly true in patients with less than a complete response at the time of transplant, Brian T. Hill, MD, PhD, reported at the Transplantation & Cellular Therapy Meetings.

The relapse rate at 24 months after ASCT was 19% in 78 adult NHL patients who underwent ASCT with pharmacokinetic-guided therapeutic dose monitoring (PK-TDM), compared with 38% in 258 patients who received weight-based-dosing (WBD) of busulfan with cyclophosphamide and etoposide.

Progression-free survival (PFS) improved with PK-TDM vs. WBD (69% vs. 55%) but overall survival (OS) did not differ between the groups, most likely because of subsequent therapy given at the time of relapse, said Dr. Hill, director of the lymphoid malignancies program and a staff physician at the Cleveland Clinic Taussig Cancer Institute, Ohio.

The findings are from a retrospective comparison of outcomes in patients treated between 2014 and 2017 when PK-TDM was the standard practice, and patients treated between 2007 and 2013 when fixed weight-based dosing was standard, he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

“In 2013 we began a program of therapeutic dose monitoring at our site,” Dr. Hill said, explaining that with TDM the goal is to eliminate the low and high levels seen with weight-based dosing, and “to get the maximum number of patients into the therapeutic zone.”

TDM became the preferred approach for busulfan dosing because of the drug’s “unpredictable and widely variable pharmacokinetics,” and ASBMT guidelines now call for consideration of TDM with first-line busulfan to minimize the potential complications, he noted.

“But it’s noteworthy that ... there are really no data to show that TDM can reduce the rates of relapse,” he added.

For this study, WBD busulfan dosing was 2.8 mg/kg every 24 hours on day –9 to –6 of ASCT. For PK-TDM, plasma busulfan concentration was serially determined using a previously described and externally validated in-house liquid chromatography–tandem mass spectrometry assay, he said, explaining that busulfan area under the curve (AUC) after first dose was calculated for each patient and used to adjust subsequent doses to target a daily AUC of 4,500 micromol/min.

To account for baseline differences in the two groups, including a higher number of prior chemotherapy regimens in the WBD group and a higher proportion of aggressive B-cell and T-cell lymphoma in the TDM group, two propensity-matched cohorts of 47 patients each were derived via logistic regression analysis.

“In the propensity-matched cohorts we saw a similar pattern, with therapeutic dose monitoring patients having lower relapse and improved progression-free survival, but no change in the nonrelapse mortality or the overall survival,” Dr. Hill said.

Notably, PFS did not differ between the groups when the researchers looked only at those in complete remission at transplant, but a significant improvement in PFS was seen in the TDM vs. WBD cohorts when they looked only at patients with partial remission, stable disease, or progressive disease (collectively considered as those in less than CR at transplant), he said (P = .79 vs. .08, respectively).

On multivariate analysis, less than CR status was associated with an increased risk of relapse after ASCT (hazard ratio, 2.0), and TDM vs. WBD was associated with a decreased risk of relapse (HR, 0.5).

No differences were seen between the groups with respect to changes in pulmonary or liver function from baseline, or in treatment-related mortality rates, Dr. Hill noted.

The findings support the use of PK-TDM for NHL patients undergoing ASCT with busulfan, but further study is needed, he concluded.

Dr. Hill reported having no relevant financial disclosures.

SOURCE: Hill B et al. TCT 2019, Abstract 39.

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