Abstract
The use of adjusted body weight for dosing of conditioning chemotherapy is recommended in obese stem cell transplant (SCT) patients. Busulfan (Bu), specifically, has several acceptable dosing regimens per evidence based guidelines. We evaluated whether a 25% correction in dosing weight may underestimate the targeted area under the curve (AUC) for this narrow therapeutic agent.
The primary objective was the number of patients requiring a clinically relevant PK-guided dose adjustment (change in dose of 10% or more). Secondary objectives include any increase or decrease in dosing, as well as the magnitude of dose adjustments.
Single center retrospective chart review of adult obese SCT patients receiving Bu as a part of their conditioning regimen. Bu was administered intravenously once daily at a dose of 130 mg/m2 for 4 planned doses in the allogeneic (allo) and 3 planned in the autologous (auto) population with an AUC goal of 5000 µmol*min/dose. The dose was calculated using the 25% adjusted body weight equation (AdjBW25) and pharmacokinetic (PK) samples were sent from the first day of Bu.
Fifty-five obese SCT patients (51 allo and 4 auto) were identified between 2017 to 2019 who underwent PK levels with Bu. Majority of allo patients were transplanted for acute myeloid leukemia (61%); received matched unrelated (43%) or matched related donor transplants (33%), and received fludarabine/Bu (95%) based conditioning. All the auto patients received thiotepa, Bu, and cyclophosphamide (TBC) regimen. Forty-four (80%) patients required a clinically relevant dose adjustment. In the allo SCT group, 45/51 (88%) patients required a dose change with 36 (71%) requiring a median increase in dose by 37% (range 3 -126%) and 9 (18%) requiring a median decrease in dose by 12% (range 7-29%). Following the first dose, the median AUC was 4318 µmol*min (range 2994 - 5854 µmol*min) and after PK-guided adjustment the median AUC of all doses was 4934 µmol*min (range 4215 - 5061 µmol*min). In the auto SCT group, 4/4 (100%) patients required a dose change with 1 (25%) requiring an increase in dose by 28%, and 3 (75%) requiring a median decrease in dose by 100% (range 13 – 100%). Following the first dose, the median AUC was 6285 µmol*min (range 4213 - 8995 µmol*min) and after PK-guided adjustment the median AUC of all doses was 4948 µmol*min (range 4609 - 5997 µmol*min).
Overall, the majority of our allo SCT patients required a clinically significant increase in Bu dose. However, in our auto SCT patients, the majority required a significant decrease in dose that translated into omitting the last dose in two patients. Using PK-guided dose adjustments were critical in achieving our desired AUC goal and, based on our findings, using AdjBW25 may not be adequate. Further studies are warranted to identify the most appropriate dosing weight for obese patients, as well as allo versus auto recipients.