Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Abstract

Diffuse large B-cell lymphoma (DLBCL) constitutes 30%–58% of lymphoma series. The crude incidence in the European Union is 3–4/100 000/year. The incidence increases with age from 0.3/100 000/year (35–39 years) to 26.6/100 000/year (80–84 years) [1.Morgan G. Vornanen M. Puitinen J. et al.Changing trends in the incidence of non-Hodgkin's lymphoma in Europe. Biomed Study Group.Ann Oncol. 1997; 8: 49-54Abstract Full Text PDF PubMed Scopus (42) Google Scholar]. Diagnosis should be made on the basis of a surgical specimen/excisional lymph node or extranodal tissue biopsy providing enough material for formalin-fixed samples. Core biopsies may be appropriate as the only diagnostic test in the rare patients requiring emergency treatment. Minimal immunohistochemistry (CD45, CD20, and CD3) is mandatory. The collection of fresh frozen material for molecular characterization is recommended although gene expression profiling remains investigational. To ensure adequate quality, processing by an experienced pathology institute has to be guaranteed. The histological report should give the diagnosis according to the current World Health Organization classification [2.Swerdlow S.H. Campo E. Harris N.L. et al.World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC, Lyon2008Google Scholar]. The distinction between germinal center-like subtype and activated B-cell-like subtype, studied by gene expression profiling and suggested by immunohistochemistry, do not influence treatment choices at the moment [3.Held G. Pfreundschuh M. Hematology: germinal center or nongerminal center DLBCL?.Nat Rev Clin Oncol. 2009; 6: 188-190Crossref PubMed Scopus (6) Google Scholar]. A complete blood count, routine blood chemistry including lactate dehydrogenase (LDH) and uric acid as well as a screening test for human immunodeficiency virus and hepatitis B and C are required. Protein electrophoresis is recommended. Patients amenable to curative therapy should have at least a computed tomography (CT) scan of the chest and abdomen, as well as a bone marrow aspirate and biopsy. A diagnostic spinal tap should be considered in high-risk patients [V, D]. [18F]deoxyglucose positron emission tomography (PET) scanning is strongly recommended to better delineate the extent of the disease and in view to the evaluation of treatment response according to the revised criteria [4.Cheson B.D. Pfistner B. Juweid M.E. et al.Revised response criteria for malignant lymphoma.J Clin Oncol. 2007; 25: 579-586Crossref PubMed Scopus (3643) Google Scholar]. Performance status and cardiac function (left ventricular ejection fraction) should be assessed before treatment. The staging is established according to the Ann Arbor system [I, A] (Table 1). For prognostic purposes, International Prognostic Index (IPI) and age-adjusted IPI (aa-IPI) should be calculated [I, A] [5.The International Non-Hodgkin's Lymphoma Prognostic Factors ProjectA predictive model for aggressive non-Hodgkin's lymphoma.N Engl J Med. 1993; 329: 987-994Crossref PubMed Scopus (4906) Google Scholar].Table 1Ann Arbor staging classificationStageIInvolvement of a single lymphatic region (I) or localized involvement of single extralymphatic organ or site (IE)IIInvolvement of two or more lymphatic regions on the same side of the diaphragm (II) or localized involvement of a single extralymphatic organ or site and of one or more lymphatic regions on the same side of the diaphragm (IIE)IIIInvolvement of lymphatic regions on both side of the diaphragm.IVDiffuse or disseminated involvement of one or more extralymphatic organs with or without lymphatic involvement. Open table in a new tab Treatment strategies should be stratified according to age, age-adjusted IPI and feasibility of dose-intensified approaches (Table 2). Whenever available, the inclusion in a clinical trial should be considered.Table 2Recommended treatment strategies in diffuse large B-cell lymphomaYoung <61 yearsIPI low risk no bulkIPI low risk with bulk or IPI low-intermediate riskIPI intermediate-high risk or IPI high riskR-CHOP21 × 6R-ACVBP and sequential consolidation Or R-CHOP21 × 6 + IF-RT on bulkR-CHOP21 × 8 or R-CHOP14 × 6 with 8 R Consider more intensive regimens: R-CHOEP14 × 6 or R-ACVBP plus HDCT with ASCT or R-dose-dense (R-CHOP14 like) plus R-HDCT with ASCTConsider CNS prophylaxis in patients at risk for CNS progressionElderly >60 yearsHealthy>80 years without cardiac dysfunctionUNFIT or FRAIL or >60 years with cardiac dysfunctionR-CHOP21 × 8 (R-CHOP21 × 6 for IPI low risk) or R-CHOP14 × 6 with 8 Rattenuated regimens: R-miniCHOP21 × 6Doxorubicine substitution with etoposide or liposomal doxorubicine or others: R-C(X)OP21 × 6 or palliative careConsider CNS prophylaxis in patients at riskFirst relapse/progressEligible to transplantNot eligible to transplantPlatinum-based chemotherapy regimens (i.e. R-DHAP, R-ICE) as salvage treatment For chemosensitive patients: R-HDCT with ASCT as remission consolidation Consider allogeneic transplantation in patients relapsed after R-HDCT with ASCT or in patients with poor risk factors at relapsePlatinum and/or gemcitabine-based regimens Clinical trials with novel drugs>2 relapse/progressEligible to transplantNot eligible to transplantAllogeneic transplantation Clinical trials with novel drugsClinical trials with novel drugs Palliative care Open table in a new tab In cases with high tumor load, precautions, as example by administering prednisone 100 mg p.o. several days as ‘prephase’ treatment, are required to avoid tumor lysis syndrome. Dose reductions due to hematological toxicity should be avoided. Febrile neutropenia justifies prophylactic use of hematopoietic growth factors in patients treated with curative intent and in all elderly patients. Six cycles of combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) treatment combined with six doses of rituximab given every 21 days is the current standard [I, A] [6.Pfreundschuh M. Trumper L. Osterborg A. 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 Oncol. 2006; 7: 379-391Abstract Full Text Full Text PDF PubMed Scopus (1672) Google Scholar]. Consolidation by radiotherapy to initial sites has proven no clear benefit [I, A] [7.Reyes F. Lepage E. Ganem G. et al.ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma.N Engl J Med. 2005; 352: 1197-1205Crossref PubMed Scopus (282) Google Scholar]. R-CHOP 21 × 6 with radiotherapy to the sites of previous bulky disease was shown to be effective in this group of patients based on the results of the MINT study [6.Pfreundschuh M. Trumper L. Osterborg A. 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 Oncol. 2006; 7: 379-391Abstract Full Text Full Text PDF PubMed Scopus (1672) Google Scholar]. Alternatively, an intensification of chemotherapy with R-ACVBP (rituximab, doxorubicin, vindesine, cyclophosphamide, bleomycin, and prednisolone given every 2 weeks followed by sequential consolidation) has been shown to improve survival when compared with eight cycles of R-CHOP in this category, but in this trial, radiotherapy was omitted in both arms [I, A] [8.Recher C. Coiffier B. Haioun C. et al.Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03–2B): an open-label randomised phase 3 trial.Lancet. 2011; 378: 1858-1867Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar]. In this group of patients either R-CHOP21 × 6 with radiotherapy to the sites of previous bulky disease or the intensified regimen R-ACVBP are recommended [II, B] [8.Recher C. Coiffier B. Haioun C. et al.Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03–2B): an open-label randomised phase 3 trial.Lancet. 2011; 378: 1858-1867Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar, 9.Pfreundschuh M. Ho A.D. Cavallin-Stahl E. 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.Lancet Oncol. 2008; 9: 435-444Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar]. There is no current standard in this subgroup. Thus, especially this patient population should be treated preferably in clinical trials. Six to eight cycles of chemotherapy with CHOP combined with eight doses of rituximab given every 21 days are most frequently applied [III, B]. Dose-dense treatment with R-CHOP given every 14 days has not demonstrated survival advantage over standard R-CHOP given every 21 days [I, C] overall [10.Cunningham D, Smith P, Mouncey P. R-CHOP14 versus R-CHOP21: result of a randomized phase III trial for the treatment of patients with newly diagnosed diffuse large B-cell non Hodgkin lymphomaJ Clin Oncol2011 ASCO Annual Meeting Proceedings; 29(Suppl 15): (Abst 8000): 504sGoogle Scholar]. Moreover, in this trial, R-CHOP 14 failed to show a better outcome in each DLBCL subset, including young poor risk. The trial was however not powered enough to compare different clinical subgroups [10.Cunningham D, Smith P, Mouncey P. R-CHOP14 versus R-CHOP21: result of a randomized phase III trial for the treatment of patients with newly diagnosed diffuse large B-cell non Hodgkin lymphomaJ Clin Oncol2011 ASCO Annual Meeting Proceedings; 29(Suppl 15): (Abst 8000): 504sGoogle Scholar]. Intensive treatment with R-ACVBP or R-CHOEP is frequently used but these regimens have not been directly compared with R-CHOP in this category [II, B]. In the rituximab era, high-dose chemotherapy (HDC) with stem cell transplantation as consolidation treatment after immunochemotherapy has shown promising results in recent phase II trials [II, C] [11.Tarella C. Zanni M. Di Nicola M. et al.Prolonged survival in poor-risk diffuse large B-cell lymphoma following front-line treatment with rituximab-supplemented, early-intensified chemotherapy with multiple autologous hematopoietic stem cell support: a multicenter study by GITIL (Gruppo Italiano Terapie Innovative nei Linfomi).Leukemia. 2007; 21: 1802-1811Crossref PubMed Scopus (63) Google Scholar, 12.Vitolo U. Chiappella A. Angelucci E. 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. 2009; 94: 1250-1258Crossref PubMed Scopus (59) Google Scholar, 13.Fitoussi O. Belhadj K. Mounier N. et al.Survival impact of rituximab combined with ACVBP and upfront consolidation autotransplantation in high-risk diffuse large B-cell lymphoma for GELA.Haematologica. 2011; 96: 1136-1143Crossref PubMed Scopus (74) Google Scholar]. Recently, four randomized trials comparing R-HDC + ASCT versus R chemotherapy have been presented. Two trials show a PFS benefit for HDC with ASCT but no impact, at present, on survival [14.Stiff P.J. Unger J.M. Cook J. 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).J Clin Oncol. 2011; 29 (Abst (ASCO Meeting Abstracts) 504s): 8001)Google Scholar, 15.Vitolo U. Chiappella A. Brusamolino E. et al.A randomized multicentre phase III study for first line treatment of young patients with high risk (AAIPI 2–3) diffuse large B-cell lymphoma (DLBCL): rituximab (R) plus dose-dense chemotherapy CHOP14/MEGACHOP14 with or without intnesified high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). Results of DLCL04 trial of Italian Lymphoma Foundation (FIL).Ann Oncol. 2011; 22: 106Google Scholar], while two trials failed to demonstrate an improvement for the HDC arm [16.Schmitz N. Nickelsen M. Ziepert M. et al.Conventional chemoimmunotherapy (R-CHOEP-14) or high-dose therapy (R-MEGA-CHOEP) for young, high-risk patients with aggressive B-cell lymphoma: Final results of the randomized MEGA-CHOEP-Trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL).Ann Oncol. 2011; 22: 106-107Google Scholar, 17.Milpied N.-J. Legouill S. Lamy T. et al.No benefit of first-line rituximab (R)-high-dose therapy (R-HDT) over R-CHOP14 for young adults with diffuse large b-cell lymphoma. Preliminary results of the GOELAMS 075 Prospective Multicentre Randomized Trial.J Clin Oncol. 2010; 116 (ASH Annual Meeting Abstracts 2010): 685Google Scholar]. Therefore, HDC with ASCT in first line remains experimental in first-line therapy or may be suggested for selective high-risk patients [II, C]. Consolidation by radiotherapy to sites of bulky disease has proven no benefit [III, C]. The role of radiotherapy in partial remission remains to be established in patients treated with rituximab and evaluated with PET [18.Moser E.C. Kluin-Nelemans H.C. Carde P. et al.Impact of involved field radiotherapy in partial response after doxorubicin-based chemotherapy for advanced aggressive non-Hodgkin's lymphoma.Int J Radiat Oncol Biol Phys. 2006; 66: 1168-1177Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. Eight cycles of combination chemotherapy with CHOP treatment combined with eight doses of rituximab given every 21 days is the current standard [I, A] [19.Coiffier B. Lepage E. Briere J. et al.CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma.N Engl J Med. 2002; 346: 235-242Crossref PubMed Scopus (4384) Google Scholar]. R-CHOP given every 14 days did not demonstrate survival advantage over R-CHOP 21 [I, C] [10.Cunningham D, Smith P, Mouncey P. R-CHOP14 versus R-CHOP21: result of a randomized phase III trial for the treatment of patients with newly diagnosed diffuse large B-cell non Hodgkin lymphomaJ Clin Oncol2011 ASCO Annual Meeting Proceedings; 29(Suppl 15): (Abst 8000): 504sGoogle Scholar, 20.Delarue R. Tilly H. Salles A. et al.R-CHOP14 compared to R-CHOP21 in elderly patients with diffuse large B-cell lymphoma: results of the interim analysis of the LNH03–6B GELA study.Blood. 2009; 114 (Abstracts 406) 52Google Scholar]. If rituximab-CHOP is given every 14 days, six cycles of CHOP with eight cycles of rituximab are sufficient [21.Pfreundschuh M. Schubert J. Ziepert M. et al.Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60).Lancet Oncol. 2008; 9: 105-116Abstract Full Text Full Text PDF PubMed Scopus (858) Google Scholar]. In patients with localized disease, consolidation by radiotherapy has proven no benefit [I, A] [22.Bonnet C. Fillet G. Mounier N. et al.CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: a study by the Groupe d'Etude des Lymphomes de l'Adulte.J Clin Oncol. 2007; 25: 787-792Crossref PubMed Scopus (208) Google Scholar] in patients treated prior the introduction of rituximab. A comprehensive geriatric assessment is recommended to help determine choice of treatment in these patients. R-CHOP treatment could usually be used until 80 years of age in healthy patients. The combination of rituximab with attenuated chemotherapy, as R-miniCHOP, could induce complete remission and long survival in healthy patients older than 80 years [III, B] [23.Peyrade F. Jardin F. Thieblemont C. et al.Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial.Lancet Oncol. 2011; 12: 460-468Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar]. The doxorubicin substitution with etoposide or liposomal doxorubicin or even its omission can be considered from the beginning or after a few cycles in patients with cardiac dysfunction or otherwise unfit [IV, C]. Patients with high-intermediate and high-risk IPI, especially those with more than one extranodal site or elevated LDH are at higher risk of central nervous system (CNS) relapse [24.Kridel R. Dietrich P.Y. Prevention of CNS relapse in diffuse large B-cell lymphoma.Lancet Oncol. 2011; 12: 1258-1266Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. CNS prophylaxis should be recommended in this population but intrathecal injections of methotrexate are probably not an optimal method. Intravenous high-dose methotrexate associated with efficient disease control could be an interesting alternative [IV, C] [25.Tilly H. Lepage E. Coiffier B. et al.Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma.Blood. 2003; 102: 4284-4289Crossref PubMed Scopus (282) Google Scholar, 26.Abramson J.S. Hellmann M. Barnes J.A. et al.Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma.Cancer. 2010; 116: 4283-4290Crossref PubMed Scopus (162) Google Scholar]. Whether some specific involvement sites as paranasal sinus, upper neck or bone marrow should receive prophylaxis remains to be established [27.Barosi G. Carella A. Lazzarino M. et al.Management of nodal diffuse large B-cell lymphomas: practice guidelines from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation.Haematologica. 2006; 91: 96-103PubMed Google Scholar]. Testicular lymphoma must receive CNS prophylaxis. Treatment of primary DLBCL of the central nervous system must contain high-dose methotrexate. Addition of high-dose cytarabine seems to improve complete remission rate and outcome [28.Ferreri A.J. Reni M. Foppoli M. et al.High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial.Lancet. 2009; 374: 1512-1520Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar]. CNS irradiation is usually administered as consolidation. Primary DLBCL of the testis (PTL) is characterized by an increased risk of extranodal, CNS, and contralateral testis recurrence with poor outcome [29.Zucca E. Conconi A. Mughal T.I. et al.Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the International Extranodal Lymphoma Study Group.J Clin Oncol. 2003; 21: 20-27Crossref PubMed Scopus (347) Google Scholar]. The standard treatment of localized (stage I to II) PTL is R-CHOP21 with CNS prophylaxis and contralateral testis irradiation [III, A] [30.Vitolo U. Chiappella A. Ferreri A.J. et al.First-line treatment for primary testicular diffuse large B-Cell lymphoma with rituximab-CHOP, CNS Prophylaxis, and contralateral testis irradiation: final results of an international phase II trial.J Clin Oncol. 2011; 29: 2766-2772Crossref PubMed Scopus (148) Google Scholar]. An open issue remains the type of CNS prophylaxis either with intrathecal chemotherapy or with the addition of intravenous high-dose methotrexate or both. Primary mediastinal large B-cell lymphoma is probably a distinct entity. R-CHOP 21 is not established as the definitive treatment option and radiotherapy remains controversial [31.Martelli M. Ferreri A.J. Johnson P. Primary mediastinal large B-cell lymphoma.Crit Rev Oncol Hematol. 2008; 68: 256-263Crossref PubMed Scopus (50) Google Scholar]. Abnormal radiological tests at baseline should be repeated after three to four cycles and after the last cycle of treatment. Bone marrow aspirate and biopsy should be only repeated at the end of treatment if initially involved [4.Cheson B.D. Pfistner B. Juweid M.E. et al.Revised response criteria for malignant lymphoma.J Clin Oncol. 2007; 25: 579-586Crossref PubMed Scopus (3643) Google Scholar]. PET is highly recommended for the post-treatment assessment to define complete remission according to the revised criteria of response [4.Cheson B.D. Pfistner B. Juweid M.E. et al.Revised response criteria for malignant lymphoma.J Clin Oncol. 2007; 25: 579-586Crossref PubMed Scopus (3643) Google Scholar]. In case of therapeutic consequences, a histological confirmation of PET positivity at this time is strongly recommended. Early PET, performed after one to four cycles of treatment, have been shown to be predictive of clinical outcome in some studies, but others did not find any correlations and its results should not lead to treatment change outside of a clinical trial. History and physical examination every 3 months for 1 year, every 6 months for 2 more years, and then once a year with attention to development of secondary tumors or other long-term side-effects of chemotherapy [V, D]. Blood count and LDH at 3, 6, 12, and 24 months, then only as needed for evaluation of suspicious symptoms or clinical findings in those patients suitable for further therapy [V, C]. Minimal adequate radiological examinations at 6, 12, and 24 months after end of treatment by CT scan are usual practice, but there is no definitive evidence that routine imaging in patients in complete remission provides any outcome advantage [27.Barosi G. Carella A. Lazzarino M. et al.Management of nodal diffuse large B-cell lymphomas: practice guidelines from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation.Haematologica. 2006; 91: 96-103PubMed Google Scholar, 32.Armitage J.O. Loberiza F.R. Is there a place for routine imaging for patients in complete remission from aggressive lymphoma?.Ann Oncol. 2006; 17: 883-884Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar]. Routine surveillance with PET scan is not recommended. High-risk patients with curative options may potentially mandate more frequent controls. Overall, >30% of DLBCL will ultimately relapse. The incidence in the European Union is therefore estimated to be around 1/100 000/year. Histological verification should be obtained whenever possible, and is mandatory in relapses >12 months after the initial diagnosis, especially in order to ensure CD20 positivity. Image-guided core biopsy may be appropriate in this context. Patients still amenable to curative therapy should have the same examinations as at first diagnosis. The following recommendations apply to patients with adequate, rituximab-associated anthracycline-containing first-line therapy. In suitable patients with adequate performance status (no major organ dysfunction, age <65–70 years), salvage regimen with association of rituximab and chemotherapy followed in responsive patients by high-dose treatment with stem-cell support is recommended [II, A] [33.Horwitz S.M. Negrin R.S. Blume K.G. et al.Rituximab as adjuvant to high-dose therapy and autologous hematopoietic cell transplantation for aggressive non-Hodgkin lymphoma.Blood. 2004; 103: 777-783Crossref PubMed Scopus (201) Google Scholar, 34.Kewalramani T. Zelenetz A.D. Nimer S.D. et al.Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma.Blood. 2004; 103: 3684-3688Crossref PubMed Scopus (341) Google Scholar]. Salvage regimens such as R-DHAP (rituximab, cisplatin, cytosine arabinoside, and dexamethasone) or R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) did not exhibit different outcome [35.Gisselbrecht C. Glass B. Mounier N. et al.Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era.J Clin Oncol. 2010; 28: 4184-4190Crossref PubMed Scopus (1049) Google Scholar]. The possible advantage of R-DHAP in the germinal center B-cell-like subtype must be confirmed [36.Thieblemont C. Briere J. Mounier N. 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.J Clin Oncol. 2011; 29: 4079-4087Crossref PubMed Scopus (212) Google Scholar]. BEAM (carmustine, etoposide, cytosine-arabinoside, and melphalan) is the more frequently used high-dose regimen. Additional involved-field radiation or iceberg radiation may be used especially in the few cases with limited stage disease, but it has been never evaluated in controlled trials. Maintenance with rituximab in responding patients is not recommended [I, D] [37.Gisselbrecht C. Glass B. Laurent G. et al.Maintenance with rituximab after autologous stem cell transplantation in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL): CORAL final analysis.J Clin Oncol. 2011; 29 (abstr 8004) 505sCrossref Google Scholar]. Allogeneic transplantation following chemotherapy should probably be considered in patients with refractory disease, early relapse or relapse after ASCT [III, B] [38.Glass B. Hasenkamp J. Wulf G. et al.High-dose chemotherapy followed by allogeneic stem cell transplantation in high-risk relapsed and refractory aggressive non-Hodgkin lymphoma: results of a prospective study of the German high-grade non-Hodgkin lymphoma study group.J Clin Oncol. 2012; 30 (abstr 8004)Crossref Google Scholar]. Patients not suitable for high-dose therapy may be treated with the same or other salvage regimens as R-GEMOX (rituximab, gemcitabine, and oxaliplatin), which may be combined with involved-field radiotherapy [39.El Gnaoui T. Dupuis J. Belhadj K. et al.Rituximab, gemcitabine and oxaliplatin: an effective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy.Ann Oncol. 2007; 18: 1363-1368Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar] or preferentially be enrolled in clinical trials testing the activity of novel drugs. Response criteria are identical to those of first-line treatment evaluation [4.Cheson B.D. Pfistner B. Juweid M.E. et al.Revised response criteria for malignant lymphoma.J Clin Oncol. 2007; 25: 579-586Crossref PubMed Scopus (3643) Google Scholar]. An evaluation should be performed after three to four cycles of salvage regimen (before high-dose treatment) and after the end of all therapy. The results of PET before high-dose treatment are correlated to clinical outcome. Follow-up of patients in second response could be the same as first response. Levels of evidence [I–V] and grades of recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty. Dr. André has reported research funding from Roche, Celgene, Mundipharma and GlaxoSmithKline. Prof. Tilly has reported: advisory board for Celgene, Roche, Seattle Genetics; research grants from Amgen, Celgene; lectures for Celgene, Amgen, Janssen-Cilag. Dr. Vitolo has reported: advisory board for Roche; lectures for Celgene, Mundipharma. Prof. Walewski has reported: advisory board for Mundipharma, Celgene, GlaxoSmithKline, Janssen Cilag; research grants from Roche, GlaxoSmithKline, Mundipharma, Cephalon; lectures for Roche, Mundipharma; travel grants for Roche, Celgene, Genzyme. Dr. Gomes da Silva has reported: consultancy and travel grants from Celgene, Roche. Prof. Shpilberg has reported: research grants from Roche, Janssen. Prof. Pfreundschuh has reported: advisory boards for Roche, Celgene, Pfizer, Onyx; research grants from Roche, Amgen. Prof. Dreyling has reported consultancy/honoraria: Celgene, Janssen, Mundipharma, Pfizer, Roche; research funding to the institution: Celgene, Janssen, Pfizer, Mundipharma, Roche.