The combined role of biomarkers and interim PET scan in prediction of treatment outcome in classical Hodgkin's lymphoma: a retrospective, European, multicentre cohort study.
BACKGROUND
Early-interim fluorodeoxyglucose (FDG)-PET scan after two ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy courses (PET-2) represents the most effective predictor of treatment outcome in classical Hodgkin's lymphoma. We aimed to assess the predictive value of PET-2 combined with tissue biomarkers in neoplastic and microenvironmental cells for this disease.


METHODS
We enrolled 208 patients with classical Hodgkin's lymphoma and treated with ABVD (training set), from Jan 1, 2002, to Dec 31, 2009, and validated the results in a fully matched independent cohort of 102 patients with classical Hodgkin's lymphoma (validation set), enrolled from Jan 1, 2008, to Dec 31, 2012. The inclusion criteria for both the training and validation sets were: the availability of a representative formalin-fixed, paraffin-embedded tissue sample collected at diagnosis; treatment with ABVD with or without radiotherapy; baseline staging and interim restaging after two ABVD courses with FDG-PET; no treatment change based solely on interim PET result; and HIV-negative status. We used Cox multivariate analysis classification and regression tree (CART) to compare the predictive values of these markers with that of PET-2 and to assess the biomarkers' ability to correctly classify patients whose outcome was incorrectly predicted by PET-2.


RESULTS
In multivariate analysis, PET-2 was the only factor able to predict both progression-free survival (hazard ratio [HR] 33·3 [95% CI 13·6-83·3]; p<0·0001) and overall survival (HR 31·3 [95% CI 3·7-58·9]; p=0·002). In the training set, no factor had a stronger adverse predictive value than a positive PET-2 scan and none was able to correctly reclassify PET-2 positive patients. In PET-2 negative patients, expression of CD68 (≥25%) and PD1 (diffuse or rosetting pattern) in microenvironmental cells, and STAT1 negativity in Hodgkin Reed Sternberg cells identified a subset of PET-2 negative patients with a 3 year progression-free survival significantly lower than that of the remaining PET-2 negative population (21 [64%] of 33 [95% CI 45·2-79·0] vs 130 [95%] of 137 [95% CI 89·4-97·7]; p<0·0001). These findings were reproduced in the validation set.


CONCLUSIONS
The CART algorithm correctly predicted the response to treatment in more than a half of patients who had a relapse or disease progression despite a negative PET-2 scan, thus increasing the negative predictive value of PET-2. In keeping with preliminary results from interim PET response adapted clinical trials of patients with advanced Hodgkin's lymphoma, there might be a non-negligible proportion of treatment failures in the interim PET negative group treated with standard ABVD.


BACKGROUND
Italian Association for Cancer Research, Bologna Association against leukaemia, lymphoma and myeloma, and Bologna University.
Haemopathology Section, Bologna University School of Medicine, Bologna, Italy. Electronic address: claudio.agostinelli@unibo.it.
Claudio
C
Agostinelli
Research, Innovation and Statistics Department, Centre Antoine Lacassagne, Nice, France.
Andrea
A
Gallamini
Statistics Department, University of Bologna, Bologna, Italy.
Luisa
L
Stracqualursi
Statistics Department, University of Bologna, Bologna, Italy.
Patrizia
P
Agati
Tumour Immunology Unit, Human Pathology Section, University of Palermo, Palermo, Italy.
Claudio
C
Tripodo
Haemopathology Section, Bologna University School of Medicine, Bologna, Italy.
Fabio
F
Fuligni
Haemopathology Section, Bologna University School of Medicine, Bologna, Italy.
Maria Teresa
MT
Sista
Department of Experimental, Diagnostic and Specialty Medicine and Nuclear Medicine Unit, Bologna University School of Medicine, Bologna, Italy.
Stefano
S
Fanti
Nuclear Medicine Department, S Croce e Carle Hospital, Cuneo, Italy.
Alberto
A
Biggi
Department of Haematology, Città della Salute e della Scienza Hospital, Torino, Italy.
Umberto
U
Vitolo
Oncology Department, University of Florence, Florence, Italy.
Luigi
L
Rigacci
Haematology Department, Arcispedale S Maria Nuova, Reggio Emilia, Italy.
Francesco
F
Merli
Haematology Department, Azienda Ospedaliera Cervello, Palermo, Italy.
Caterina
C
Patti
Haematology Department, Catania University School of Medicine, Catania, Italy.
Alessandra
A
Romano
Haematology Department, Azienda Ospedaliera S Antonio e Biagio, Alessandria, Italy.
Alessandro
A
Levis
Experimental Medicine Department, Padua University School of Medicine, Padua, Italy.
Livio
L
Trentin
Haematology Department, Azienda Ospedaliera Melacrino, Reggio Calabria, Italy.
Caterina
C
Stelitano
Haematology Department, S Croce e Carle Hospital, Cuneo, Italy.
Anna
A
Borra
Haemopathology Section, Bologna University School of Medicine, Bologna, Italy.
Pier Paolo
PP
Piccaluga
Departments of Haematology and Pathology, Aarhus University Hospital, Aarhus, Denmark.
Stephen
S
Hamilton-Dutoit
Departments of Haematology and Pathology, Aarhus University Hospital, Aarhus, Denmark.
Peter
P
Kamper
Department of Clinical Oncology, Gdynia Oncology Centre and Department of Propaedeutic Oncology-Medical University of Gdańsk, Gdynia, Poland.
Jan Maciej
JM
Zaucha
Department of Nuclear Medicine, Oncology Centre, Bydgoszcz, Poland.
Bogdan
B
Małkowski
Department of Haematology, Regional Oncology Centre, Olsztyn, Poland.
Waldemar
W
Kulikowski
Department of Lymphoproliferative Diseases, Maria Sklodowska-Curie Memorial Institute, Warsaw, Poland.
Joanna
J
Tajer
Department of Haematology and Internal Medicine, Military Institute of Medicine, Warsaw, Poland.
Edyta
E
Subocz
Department of Haematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.
Justyna
J
Rybka
Department of Pathology and Laboratory Medicine, Centre for Lymphoid Cancer, Vancouver, BC, Canada; Department of Lymphoid Cancer Research-BCCRC, British Columbia Cancer Agency, Vancouver, BC, Canada.
Christian
C
Steidl
Haematology Section, Bologna University School of Medicine, Bologna, Italy.
Alessandro
A
Broccoli
Haematology Section, Bologna University School of Medicine, Bologna, Italy.
Lisa
L
Argnani
Department of Pathology and Laboratory Medicine, Centre for Lymphoid Cancer, Vancouver, BC, Canada; Department of Lymphoid Cancer Research-BCCRC, British Columbia Cancer Agency, Vancouver, BC, Canada.
Randy D
RD
Gascoyne
Departments of Haematology and Pathology, Aarhus University Hospital, Aarhus, Denmark.
Francesco
F
d'Amore
Haematology Section, Bologna University School of Medicine, Bologna, Italy.
Pier Luigi
PL
Zinzani
Haemopathology Section, Bologna University School of Medicine, Bologna, Italy; European Institute of Oncology, IEO, Milan, Spain.
Stefano A
SA
Pileri
D000328:Adult; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D001761:Bleomycin / Q000627:therapeutic use; D015331:Cohort Studies; D003606:Dacarbazine / Q000627:therapeutic use; D003718:Denmark; D018450:Disease Progression; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D006689:Hodgkin Disease / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007558:Italy; D008297:Male; D015999:Multivariate Analysis; D011044:Poland; D049268:Positron-Emission Tomography / Q000379:methods*; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis; D012008:Recurrence; D016539:Reed-Sternberg Cells / Q000737:chemistry / Q000473:pathology; D012189:Retrospective Studies; D050794:STAT1 Transcription Factor / Q000032:analysis; D017211:Treatment Failure; D059016:Tumor Microenvironment; D014747:Vinblastine / Q000627:therapeutic use; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D001761:Bleomycin; D003606:Dacarbazine; D004317:Doxorubicin; D061026:Programmed Cell Death 1 Receptor; D050794:STAT1 Transcription Factor; D014747:Vinblastine; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C105992:PDCD1 protein, human; C494079:STAT1 protein, human