A study to investigate dose escalation of doxorubicin in ABVD chemotherapy for Hodgkin lymphoma incorporating biomarkers of response and toxicity

作者：Gibb A; Greystoke A; Ranson M; Linton K; Neeson S; Hampson G; Illidge T; Smith E; Dive C; Pettitt A; Lister A; Johnson P; Radford J^*

来源：British Journal of Cancer, 2013, 109(10): 2560-2565.

DOI：10.1038/bjc.2013.605

• Hodgkin lymphoma
• ABVD chemotherapy
• cell death biomarkers
• phase I

Background: Myelotoxicity during initial cycles of chemotherapy for Hodgkin lymphoma is associated with better outcome, supporting the concept of individualised dosing based on pharmacodynamic end points to optimise results. This study was performed to identify the maximum tolerated dose (MTD) of doxorubicin within cycles 1-3 ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). Circulating biomarkers of response (nucleosomal DNA, nDNA) and epithelial toxicity (Cytokeratin 18, CK18) were also measured.
Methods: Dose escalation of doxorubicin in cycles 1-3 ABVD supported by pegfilgrastim was performed on a six-patient cohort basis (35, 45 and 55mgm(-2)) with doxorubicin reduced to 25mgm(-2) or omitted in cycles 4-6 to maintain cumulative exposure of 103-130% standard ABVD. BVD was given at standard doses throughout. Six additional subjects were recruited at the MTD.
Results: Twenty-four subjects were recruited. Dose-limiting toxicities (DLTs) of grade 3 neuropathy, pneumonitis, palmar-plantar erythema and neutropenic infection were observed at 55mgm(-2), so 45mgm(-2) was declared the MTD. In patients who subsequently experienced DLT at any time, large increases in CK18 were seen on day 3 of cycle 1 ABVD.
Conclusion: Escalated ABVD incorporating doxorubicin at 45mgm(-2) in cycles 1-3 can be delivered safely with pegfilgrastim support. Circulating cell death biomarkers may assist in the development of future individualised dosing strategies.

• 出版日期2013-11-12