The aim of this single-center, retrospective study was to investigate the impact of rituximab, reconsider the validity of International Prognostic Index (IPI), and evaluate the prognostic role of the cell of origin (CoO) in a relatively young cohort. Three hundred twelve diffuse large B cell lymphoma patients (median age: 52) were included. Rituximab significantly improved the 3- and 5-year progression free survival (PFS) (70% versus 65% and 41% versus 36%, resp.; ) but led only to a slight, insignificant increase in 3- and 5-year overall survival (OS) (71% versus 77.3% and %67 versus 74.5%, resp.; ). In the young, low risk patient subgroup (aaIPI = 0&1; ), rituximab improved 3- and 5-year PFS and OS rates ( and , resp.). The efficacy of rituximab in young high risk patients was comparable to the literature. CoO data were available in 190 patients. The OS at 3 years was 79% for GC and 64% for non-GC subgroups ( ). To the best of our knowledge, this is the first study which investigated the impact of R-CHOP in the context of CoO and IPI in a relatively young cohort. CoO was not an independent risk factor for prognosis in the multivariate analysis although patients with GC showed a significant survival advantage in the univariate analysis. CoO was also found to be a significant determinant of response in refractory/relapsed patients. Our results confirm the efficacy of rituximab in low and high risk, young patients outside of a randomized clinical trial setting. 1. Introduction Diffuse large B cell lymphoma (DLBCL), being the most common morphological type, constitutes about 40% of newly diagnosed non-Hodgkin’s lymphoma (NHL) cases. It is a heterogeneous disease with variable clinical course and prognostic outcome. Addition of the immunotherapeutic agent rituximab to chemotherapy improved the response rates in NHL [1]. However, despite major progress in the treatment, responses are not durable and the outcome is fatal in almost half of the patients with DLBCL. Therefore, great interest has been shown to develop prognostic scoring systems that would predict the outcome and identify patients with worst prognosis who would benefit from treatment strategies other than the standard regimens. Until recently, International Prognostic Index (IPI) [2] was almost the only widely used prognostic indicator in DLBCL. However, increasing evidence suggest that IPI fails to predict the prognosis in a considerable portion of patients with DLBCL. Consequently, there is a need for an improved and/or refined prognostic index which would predict the outcome more precisely. In
References
[1]
B. Coiffier, E. Lepage, J. Brière et al., “Chop chemotherapy plus rituximab compared with chop alone in elderly patients with diffuse large-B-cell lymphoma,” New England Journal of Medicine, vol. 346, no. 4, pp. 235–242, 2002.
[2]
M. A. Shipp, D. P. Harrington, J. R. Andersen et al., “A predictive model for aggressive non-Hodgkin's lymphoma,” New England Journal of Medicine, vol. 329, no. 14, pp. 987–994, 1993.
[3]
A. A. Alizadeh, M. B. Elsen, R. E. Davis et al., “Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling,” Nature, vol. 403, no. 6769, pp. 503–511, 2000.
[4]
A. Rosenwald, G. Wright, W. C. Chan et al., “The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma,” New England Journal of Medicine, vol. 346, no. 25, pp. 1937–1947, 2002.
[5]
C. P. Hans, D. D. Weisenburger, T. C. Greiner et al., “Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray,” Blood, vol. 103, no. 1, pp. 275–282, 2004.
[6]
M. Pfreundschuh, L. Trümper, A. ？sterborg et al., “CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group,” Lancet Oncology, vol. 7, no. 5, pp. 379–391, 2006.
[7]
S. H. Swerdlow, E. Campo, N. L. Harris, et al., Who Classification of Tumours of Haematopoietic and Lymphoid Tissues, IARC Press, Lyon, France, 2008.
[8]
T. A. Lister, D. Crowther, S. B. Sutcliffe et al., “Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: cotswolds meeting,” Journal of Clinical Oncology, vol. 7, no. 11, pp. 1630–1636, 1989.
[9]
M. M. Oken, R. H. Creech, and T. E. Davis, “Toxicology and response criteria of the Eastern Cooperative Oncology Group,” American Journal of Clinical Oncology, vol. 5, no. 6, pp. 649–655, 1982.
[10]
M. Pfreundschuh, A. D. Ho, E. Cavallin-Stahl et al., “Prognostic significance of maximum tumour (bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the MabThera International Trial Group (MInT) study,” The Lancet Oncology, vol. 9, no. 5, pp. 435–444, 2008.
[11]
N. Mounier, J. Briere, C. Gisselbrecht et al., “Rituximab plus CHOP (R-CHOP) overcomes bcl-2-associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL),” Blood, vol. 101, no. 11, pp. 4279–4284, 2003.
[12]
N. Mounier, J. Briere, C. Gisselbrecht, F. Reyes, P. Gaulard, and B. Coiffier, “Estimating the impact of rituximab on bcl-2-associated resistance to CHOP in elderly patients with diffuse large B-cell lymphoma,” Haematologica, vol. 91, no. 5, pp. 715–716, 2006.
[13]
C. Yoo, S. Kim, B. S. Sohn et al., “Modified number of extranodal involved sites as a prognosticator in R-CHOP-treated patients with disseminated diffuse large B-cell lymphoma,” Korean Journal of Internal Medicine, vol. 25, no. 3, pp. 301–308, 2010.
[14]
L. F. Porrata, K. Ristow, T. Habermann, D. J. Inwards, I. N. Micallef, and S. N. Markovic, “Predicting survival for diffuse large B-cell lymphoma patients using baseline neutrophil/lymphocyte ratio,” American Journal of Hematology, vol. 85, no. 11, pp. 896–899, 2010.
[15]
M. C. Cox, I. Nofroni, L. Ruco et al., “Low absolute lymphocyte count is a poor prognostic factor in diffuse-large-B-cell-lymphoma,” Leukemia and Lymphoma, vol. 49, no. 9, pp. 1745–1751, 2008.
[16]
A. Bari, L. Marcheselli, S. Sacchi et al., “Prognostic models for diffuse large B-cell lymphoma in the rituximab era: a never-ending story,” Annals of Oncology, vol. 21, no. 7, pp. 1486–1491, 2009.
[17]
L. Chen, S. Lin, and M. Yu, “Prognostic value of platelet count in diffuse large B-cell lymphoma,” Clinical Lymphoma, Myeloma and Leukemia, vol. 12, no. 1, pp. 32–37, 2012.
[18]
C. Tarella, M. Zanni, M. Magni et al., “Rituximab improves the efficacy of high-dose chemotherapy with autograft for high-risk follicular and diffuse large B-cell lymphoma: a multicenter Gruppo Italiano Terapie Innnovative nei Linfomi survey,” Journal of Clinical Oncology, vol. 26, no. 19, pp. 3166–3175, 2008.
[19]
U. Vitolo, A. Chiappella, E. Angelucci et al., “Dose-dense and high-dose chemotherapy plus rituximab with autologous stem cell transplantation for primary treatment of diffuse large B-cell lymphoma with a poor prognosis: a phase II multicenter study,” Haematologica, vol. 94, no. 9, pp. 1250–1258, 2009.
[20]
B. Glass, M. Ziepert, M. Reiser et al., “High-dose therapy followed by autologous stem-cell transplantation with and without rituximab for primary treatment of high-risk diffuse large B-cell lymphoma,” Annals of Oncology, vol. 21, no. 11, pp. 2255–2261, 2010.
[21]
A. Okamoto, M. Yanada, Y. Inaguma et al., “Differences in outcome for consecutive patients with diffuse large b-cell lymphoma before and after the advent of rituximab: a single-center experience,” Hematology, vol. 18, pp. 74–80, 2013.
[22]
L. H. Sehn, J. Donaldson, M. Chhanabhai et al., “Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia,” Journal of Clinical Oncology, vol. 23, no. 22, pp. 5027–5033, 2005.
[23]
C. Chang, S. McClintock, R. P. Cleveland et al., “Immunohistochemical expression patterns of germinal center and activation B-cell markers correlate with prognosis in diffuse large B-cell lymphoma,” American Journal of Surgical Pathology, vol. 28, no. 4, pp. 464–470, 2004.
[24]
R. Seki, K. Ohshima, T. Fujisaki et al., “Prognostic impact of immunohistochemical biomarkers in diffuse large B-cell lymphoma in the rituximab era,” Cancer Science, vol. 100, no. 10, pp. 1842–1847, 2009.
[25]
Y. Liu, F. Xu, H. Zhuang et al., “Clinicopathologic significance of immunophenotypic profiles related to germinal center and activation B-cell differentiation in diffuse large B-cell lymphoma from Chinese patients,” Human Pathology, vol. 39, no. 6, pp. 875–884, 2008.
[26]
I. Alacacioglu, M. A. Ozcan, S. Ozkal et al., “Prognostic significance of immunohistochemical classification of diffuse large B-cell lymphoma,” Hematology, vol. 14, no. 2, pp. 84–89, 2009.
[27]
C. Thieblemont, J. Briere, N. Mounier et al., “The germinal center/activated B-cell subclassification has a prognostic impact for response to salvage therapy in relapsed/refractory diffuse large B-cell lymphoma: a bio-CORAL study,” Journal of Clinical Oncology, vol. 29, no. 31, pp. 4079–4087, 2011.
[28]
H. Veelken, S. Vik Dannheim, J. Schulte Moenting, U. M. Martens, J. Finke, and A. Schmitt-Graeff, “Immunophenotype as prognostic factor for diffuse large B-cell lymphoma in patients undergoing clinical risk-adapted therapy,” Annals of Oncology, vol. 18, no. 5, pp. 931–939, 2007.
[29]
N. Rayman, K. H. Lam, B. Van Der Holt et al., “Prognostic relevance of immunohistochemical subclassification of diffuse large B-cell lymphoma in two prospective phase III clinical trials,” Clinical Lymphoma, Myeloma and Leukemia, vol. 11, no. 1, pp. 23–32, 2011.
[30]
L. Ngo, S. W. Hee, L. C. Lim et al., “Prognostic factors in patients with diffuse large B cell lymphoma: before and after the introduction of rituximab,” Leukemia and Lymphoma, vol. 49, no. 3, pp. 462–469, 2008.
[31]
L. H. Sehn, B. Berry, M. Chhanabhai et al., “The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP,” Blood, vol. 109, no. 5, pp. 1857–1861, 2007.
[32]
U. Vitolo, A. Chiappella, E. Brusamolino, et al., ICML Annual Meeting, Annals of Oncology, Lugano, Switzerland, 2011.
[33]
P. Stiff, J. Unger, J. Cook et al., “Randomized phase iii u.S./canadian intergroup trial (swog s9704) comparing chop ± r for eight cycles to chop ± r for six cycles followed by autotransplant for patients with high-intermediate (h-int) or high ipi grade diffuse aggressive non-hodgkin lymphoma (nhl),” in Proceedings of the ASCO Annual Meeting, p. 29, Journal of Clinical Oncology, Chicago, Ill, USA, 2011.
