title: Multiparameter analysis of homogeneously R-CHOP-treated diffuse large B cell lymphomas identifies CD5 and FOXP1 as relevant prognostic biomarkers: report of the prospective SAKK 38/07 study.
abstract: BACKGROUND
  The prognostic role of tumor-related parameters in diffuse large B cell lymphoma (DLBCL) is a matter of controversy.
  
  
  METHODS
  We investigated the prognostic value of phenotypic and genotypic profiles in DLBCL in clinical trial (NCT00544219) patients homogenously treated with six cycles of rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone (R-CHOP), followed by two cycles of R (R-CHOP-14). The primary endpoint was event-free survival at 2 years (EFS). Secondary endpoints were progression-free (PFS) and overall survival (OS). Immunohistochemical (bcl2, bcl6, CD5, CD10, CD20, CD95, CD168, cyclin E, FOXP1, GCET, Ki-67, LMO2, MUM1p, pSTAT3) and in situ hybridization analyses (BCL2 break apart probe, C-MYC break apart probe and C-MYC/IGH double-fusion probe, and Epstein-Barr virus probe) were performed and correlated with the endpoints.
  
  
  RESULTS
  One hundred twenty-three patients (median age 58 years) were evaluable. Immunohistochemical assessment succeeded in all cases. Fluorescence in situ hybridization was successful in 82 instances. According to the Tally algorithm, 81 cases (66%) were classified as non-germinal center (GC) DLBCL, while 42 cases (34%) were GC DLBCL. BCL2 gene breaks were observed in 7/82 cases (9%) and C-MYC breaks in 6/82 cases (8%). "Double-hit" cases with BCL2 and C-MYC rearrangements were not observed. Within the median follow-up of 53 months, there were 51 events, including 16 lethal events and 12 relapses. Factors able to predict worse EFS in univariable models were failure to achieve response according to international criteria, failure to achieve positron emission tomography response (p < 0.005), expression of CD5 (p = 0.02), and higher stage (p = 0.021). Factors predicting inferior PFS were failure to achieve response according to international criteria (p < 0.005), higher stage (p = 0.005), higher International Prognostic Index (IPI; p = 0.006), and presence of either C-MYC or BCL2 gene rearrangements (p = 0.033). Factors predicting inferior OS were failure to achieve response according to international criteria and expression of FOXP1 (p < 0.005), cyclin E, CD5, bcl2, CD95, and pSTAT3 (p = 0.005, 0.007, 0.016, and 0.025, respectively). Multivariable analyses revealed that expression of CD5 (p = 0.044) and FOXP1 (p = 0.004) are independent prognostic factors for EFS and OS, respectively.
  
  
  CONCLUSIONS
  Phenotypic studies with carefully selected biomarkers like CD5 and FOXP1 are able to prognosticate DLBCL course at diagnosis, independent of stage and IPI and independent of response to R-CHOP.
authors.affiliation: Institute of Pathology, University Hospital Basel, Schoenbeinstrasse 40, CH-4031, Basel, Switzerland. alexandar.tzankov@usb.ch.
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: Institute of Pathology, University Hospital Basel, Schoenbeinstrasse 40, CH-4031, Basel, Switzerland. nora.leu@ukbb.ch.
authors.forename: Nora
authors.initials: N
authors.lastname: Leu
authors.affiliation: Institute of Pathology, University Hospital Basel, Schoenbeinstrasse 40, CH-4031, Basel, Switzerland. simone.muents@usb.ch.
authors.forename: Simone
authors.initials: S
authors.lastname: Muenst
authors.affiliation: Institute of Pathology, University Hospital Basel, Schoenbeinstrasse 40, CH-4031, Basel, Switzerland. darius.juskevicius@usb.ch.
authors.forename: Darius
authors.initials: D
authors.lastname: Juskevicius
authors.affiliation: Swiss Group for Clinical Cancer Research (SAKK), Effingerstrasse 40, CD-3008, Bern, Switzerland. dirk.klingbiel@sakk.ch.
authors.forename: Dirk
authors.initials: D
authors.lastname: Klingbiel
authors.affiliation: Division of Hematology and Oncology, Cantonal Hospital Aarau, Tellstrasse house Nr. 40, CH-5001, Aarau, Switzerland. christoph.mamot@ksa.ch.
authors.forename: Christoph
authors.initials: C
authors.lastname: Mamot
authors.affiliation: Institute of Pathology, University Hospital Basel, Schoenbeinstrasse 40, CH-4031, Basel, Switzerland. stephan.dirnhofer@usb.ch.
authors.forename: Stephan
authors.initials: S
authors.lastname: Dirnhofer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D018956:CD5 Antigens / Q000378:metabolism*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011241:Prednisone / Q000008:administration & dosage / Q000627:therapeutic use; D011379:Prognosis; D011446:Prospective Studies; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D014408:Biomarkers, Tumor; D018956:CD5 Antigens; D051858:Forkhead Transcription Factors; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone