Assessment of circulating biomarkers for potential pharmacodynamic utility in patients with lymphoma.
OBJECTIVE
Treatment efficacy and toxicity are difficult to predict in lymphoma patients. In this study, the utility of circulating biomarkers in predicting and/or monitoring treatment efficacy/toxicity were investigated.


METHODS
Circulating biomarkers of cell death (nucleosomal DNA (nDNA) and cytokeratin 18 (CK18)), and circulating FLT3 ligand, a potential biomarker of myelosuppression, were assessed before and serially after standard chemotherapy in 49 patients with Hodgkin and non-Hodgkin lymphoma. Cytokeratin 18 is not expressed in lymphoma cells so is a potential biomarker of epithelial toxicity in this setting. Tumour response was assessed before and after completion of chemotherapy by 2D and 3D computed tomography radiological response.


RESULTS
Baseline nDNA level was significantly higher in all lymphoma subtypes compared with 61 healthy controls and was prognostic for progression-free survival in diffuse large B-cell lymphoma (DLBCL). Decreases in nDNA levels were observed in the first week after chemotherapy; in FL, early falls in nDNA predicted for long remission following therapy. In DLBCL, elevations in nDNA occurred in cases with progressive disease. Circulating CK18 increased within 48 h of chemotherapy and was significantly higher in patients experiencing epithelial toxicity graded >3 by Common Terminology for Classification of Adverse Events criteria. FLT3 ligand was elevated within 3-8 days of chemotherapy initiation and predicted those patients who subsequently developed neutropenic sepsis.


CONCLUSIONS
These data suggest circulating biomarkers contribute useful information regarding tumour response and toxicity in patients receiving standard chemotherapy and have potential utility in the development of individualised treatment approaches in lymphoma. These biomarkers are now being tested within multicentre phase III trials to progress their qualification.
Clinical and Experimental Pharmacology Group, The Paterson Institute for Cancer Research, The University of Manchester, Wilmslow Road, Withington, Manchester M20 4BX, UK.
A
A
Greystoke
J P B
JP
O'Connor
K
K
Linton
M B
MB
Taylor
J
J
Cummings
T
T
Ward
F
F
Maders
A
A
Hughes
M
M
Ranson
T M
TM
Illidge
J
J
Radford
C
C
Dive
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000097:blood; D014408:Biomarkers, Tumor / Q000032:analysis / Q000097:blood*; D001761:Bleomycin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D004247:DNA / Q000032:analysis / Q000097:blood; D003606:Dacarbazine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D004317:Doxorubicin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D053538:Keratin-18 / Q000032:analysis / Q000097:blood; D008223:Lymphoma / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009707:Nucleosomes / Q000235:genetics; D011237:Predictive Value of Tests; D011241:Prednisone / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011379:Prognosis; D000069283:Rituximab; D014747:Vinblastine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D014750:Vincristine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000032:analysis / Q000097:blood
D058846:Antibodies, Monoclonal, Murine-Derived; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D053538:Keratin-18; D009707:Nucleosomes; D001761:Bleomycin; D000069283:Rituximab; D014750:Vincristine; D014747:Vinblastine; D003606:Dacarbazine; D004317:Doxorubicin; D003520:Cyclophosphamide; D004247:DNA; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D011241:Prednisone
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