Abstract
BackgroundThe prognostic role of tumor-related parameters in diffuse large B cell lymphoma (DLBCL) is a matter of controversy.MethodsWe 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.ResultsOne 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.ConclusionPhenotypic 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0168-7) contains supplementary material, which is available to authorized users.
Highlights
The prognostic role of tumor-related parameters in diffuse large B cell lymphoma (DLBCL) is a matter of controversy
126 cases were further studied: DLBCL diagnosis could not be confirmed in three of these cases by conventional morphology and additional immunohistochemical evaluation
Factors predicting inferior PFS were failure to achieve response according to international criteria, failure to achieve complete combined metabolic and morphologic response (p < 0.005), higher International Prognostic Index (IPI) (p = 0.006), higher stage (p = 0.005), presence of either C-MYC or BCL2 gene rearrangements (p = 0.033; Fig. 2b), and expression of cyclin E in >12 % of tumor cells (p = 0.046; Fig. 2c)
Summary
The prognostic role of tumor-related parameters in diffuse large B cell lymphoma (DLBCL) is a matter of controversy. Diffuse large B cell lymphoma (DLBCL) is the most common nodal lymphoid malignancy, comprising approximately 30 % of all adult lymphomas, with a rapidly rising incidence [1, 2]. Prediction of survival and stratification of patients for risk-adjusted therapy is based on the International Prognostic Index (IPI) [4]. Recent data suggests that IPI and R-IPI no longer reliably identify DLBCL risk groups with a
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