Diffuse large B-cell lymphoma (DLBCL), 2 versus 3: end of a debate?
Authors: C. Sarkozy, B. Coiffier
Journal: Annals of Oncology (2017)

In the subgroup analysis from the phase III UK-NCRI trial, Kuhnl et al. bring two important messages: eight cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) every 3 weeks (R-CHOP21) or six every 2 weeks (R-CHOP14) do as well in elderly patients; and MYC rearrangement or double hit lymphoma (DHL) are independent poor prognostic factors [1.Kühnl A. Cunningham D. Counsell N. et al.Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial.Ann Oncol. 2017; 28: 1540-1546Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar]. DLBCL is the most common non-Hodgkin lymphoma with an incidence that increases with age [2.Morton L.M. Wang S.S. Devesa S.S. et al.Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001.Blood. 2006; 107: 265-276Crossref PubMed Scopus (1214) Google Scholar]. When treated with curative intent, elderly patients without comorbidities can achieve a long outcome, and it is now established that age itself should not be considered as a reason to decrease anthracycline dose [3.Sarkozy C. Coiffier B. Diffuse large B-cell lymphoma in the elderly: a review of potential difficulties.Clin Cancer Res. 2013; 19: 1660-1669Crossref PubMed Scopus (48) Google Scholar]. If the R-CHOP regimen is recognized as the standard of care for patients with DLBCL older than 60 years, the schedule of administration is debated with intensification from cycles every 3–2 weeks to improve the response rate (Table 1). The main limit will be the tolerability profile. Before the rituximab era, the German group showed that toxicity of six cycles of CHOP14 and CHOP21 was similar with a better PFS and OS for CHOP14 [4.Pfreundschuh M. Trumper L. Kloess M. et al.Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL.Blood. 2004; 104: 634-641Crossref PubMed Scopus (633) Google Scholar]. The RICOVER trial subsequently showed that six cycles of R-CHOP14 was feasible and led to an impressive 3 years EFS (event-free survival) of 66.5% [5.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 (876) Google Scholar] but that eight cycles of R-CHOP14 increased toxicity without improvement in OS. The randomized phase III trial from the LYSA LNH03-6B demonstrated that eight cycles of R-CHOP21 could provide comparable results with comparable hematological toxicities but fewer requirements in red blood cell transfusion than eight cycles of R-CHOP14. In patients aged 19–88 years, the UK-NCRI R-CHOP14v21 [6.Cunningham D. Hawkes E. Jack A. et al.Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles.Lancet. 2013; 381: 1817-1826Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar] trial did not demonstrate any difference in outcome between six cycles of R-CHOP14 and eight cycles of R-CHOP21. Given the biological and clinical particularities of DLBCL in elderly patients, a subgroup analysis in the ≥60 years patients was required.Table 1R-CHOP prospective clinical trial in elderly patients with a DLBCL. The German group showed that 6 cycles CHOP14 offered a better PFS than 8 of CHOP21. RICOVER showed that 8 cycles of R-CHOP14 was more toxic than 6 without any benefice in outcome. The GELA LNH03-6B showed that 8 cycles of R-CHOP14 and 21 offered similar results with more toxicities with 8 cycles of R-CHOP14. Finally, the UK-NCRI trial showed that 6 cycles of R-CHOP14 and 8 cycles of R-CHOP21 had comparable toxicity and efficacy profileNGrade 3–4 neutropenia and infectious toxicitiesCREFSOSNHL-B2 [4.Pfreundschuh M. Trumper L. Kloess M. et al.Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL.Blood. 2004; 104: 634-641Crossref PubMed Scopus (633) Google Scholar]Antibiotics6 CHOP1417248%76%5 years 43.8%5 years 53.3%6 CHOP2117837%60%5 years 32.5%5 years 40.6%Coiffier et al. [23.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 (4472) Google Scholar, 24.Coiffier B. Thieblemont C. Van Den Neste E. et al.Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte.Blood. 2010; 116: 2040-2045Crossref PubMed Scopus (997) Google Scholar]8 R-CHOP21202Infection: 65%76%2 years 57%2 years 70%10 years10 years 43.7%Habermann et al. [25.Habermann T.M. Weller E.A. Morrison V.A. et al.Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma.J Clin Oncol. 2006; 24: 3121-3127Crossref PubMed Scopus (1140) Google Scholar]6-8 R-CHOP21aMaintenance therapy was randomized after response and had no effect on FFS.26778%77% CR/PR3-year FFS 53%3 years 67%LNH03-6B [8.Delarue R. Tilly H. Mounier N. et al.Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial.Lancet Oncol. 2013; 14: 525-533Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar]8 R-CHOP2129864%74%3 years: 60%72%8 R-CHOP1430474%71%3 years: 50%69%RICOVER [5.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 (876) Google Scholar]Antibiotic use6 R-CHOP1430653%78%3 years: 66.5%3 years 78.1%8 R-CHOP1430462%76%3 years: 63.1%3 years 72.5%UK-NCRI trial (≥60 years)5-year PFS 64%5-year OS 69%6 R-CHOP1430336% (GCSF)61%NSNS8 R-CHOP2130161% (no GCSF)67%a Maintenance therapy was randomized after response and had no effect on FFS. Open table in a new tab This subgroup analysis from the UK-NCRI R-CHOP14vs21 trial in patients over 60 years provides several answers for this specific population [1.Kühnl A. Cunningham D. Counsell N. et al.Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial.Ann Oncol. 2017; 28: 1540-1546Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar]. First, six cycles of R-CHOP 14 regimen did not improve the response rate, with 61% of CR/CRu compared to 67% with eight cycles of R-CHOP21. The toxicity profile was marked by a higher rate of neutropenia in the R-CHOP21 arm, due to less use of G-CSF prophylaxis. This did not translate into higher febrile neutropenia. However, the main reason for treatment discontinuation remained toxicity and G-CSF prophylaxis should be considered for all the elderly patients, given this higher sensitivity to haematological toxicities [7.Smith T.J. Bohlke K. Lyman G.H. et al.Recommendations for the use of WBC growth factors: American Society of Clinical Oncology Clinical Practice Guideline Update.J Clin Oncol. 2015; 33: 3199-3212Crossref PubMed Scopus (552) Google Scholar]. After a long median follow-up period of 77.7 months, the global 5-year PFS was 64% and OS 69% and there was no difference between the two arms. Remarkably, the difference in PFS with the younger population was not important (8%) underlying the necessity to treat elderly patients as younger to reach comparable results. Given the long follow-up and the recent EFS24 data [1.Kühnl A. Cunningham D. Counsell N. et al.Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial.Ann Oncol. 2017; 28: 1540-1546Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar], these non-relapsing patients can be considered as cured. Therefore, Kuhn et al. showed here that ∼65% of elderly patients with DLBCL can be cured with R-CHOP21, with only 1% treatment related mortality (TRM). This low TRM contrasts with 9% reported in the LNH03-6B trial [8.Delarue R. Tilly H. Mounier N. et al.Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial.Lancet Oncol. 2013; 14: 525-533Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar] and this might be related to a difference in initial clinical characteristics (patients in the LNH03-6B being older and with higher IPI). Of note, radiation did not improve the outcome of PR or stable disease patients. The physician will have to choose between 6 R-CHOP14 and 8 R-CHOP21: given that patients treated in the routine setting often present with a poorer PS and more comorbidities than patients treated in clinical trials, the toxicity profile of the LNH03-6B trial would indicate that we should choose R-CHOP 21. Age over 60 years is part of the international prognostic score (IPI) [9.Fisher R.I. Gaynor E.R. Dahlberg S. et al.Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma.N Engl J Med. 1993; 328: 1002-1006Crossref PubMed Scopus (2007) Google Scholar], along with LDH, Ann Arbor, ECOG-PS and the number of nodal sites. Aiming to better discriminate high risk patients, different prognostic scores, derived from the IPI [10.Advani R.H. Chen H. Habermann T.M. et al.Comparison of conventional prognostic indices in patients older than 60 years with diffuse large B-cell lymphoma treated with R-CHOP in the US Intergroup Study (ECOG 4494, CALGB 9793): consideration of age greater than 70 years in an elderly prognostic index (E-IPI).Br J Haematol. 2010; 151: 143-151Crossref PubMed Scopus (80) Google Scholar], have been developed: from the age adjusted IPI (excluding age and number of extra nodal site), the revised IPI (redistributing the five elements from the IPI) [11.Sehn L.H. Berry B. Chhanabhai M. 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. 2007; 109: 1857-1861Crossref PubMed Scopus (1028) Google Scholar], the elderly IPI (cut off of 70 years) or the ABE4 score based on age over 70 years, WHO PS ≥1, bulky disease [11.Sehn L.H. Berry B. Chhanabhai M. 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. 2007; 109: 1857-1861Crossref PubMed Scopus (1028) Google Scholar]. In this analysis, age and beta2microglobuline level were independently associated with OS and the ABE4 was the best score to discriminate patient’s outcome compared to IPI, R-IPI or E-IPI. As mentioned by the authors, the utility of the ABE4 score [12.Prochazka V. Pytlik R. Janikova A. et al.A new prognostic score for elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: the prognostic role of blood monocyte and lymphocyte counts is absent.PLoS One. 2014; 9: e102594Crossref PubMed Scopus (23) Google Scholar] to stratify patients and guide strategy at diagnosis is limited by the low number of high risk patients identified (only 9% with the ABE4 score), below the proportion of primary refractory patients in this study (∼20%). The cell of origin assessment by gene expression profiling recently refined the biology and prognostication of DLBCL by discriminating DLBCL with a germinal centre (GC) cell of origin (COO) from those with an activated B cell (ABC) profile that present a poorer outcome with R-CHOP but higher response to specific targeted therapy [13.Rosenwald A. Wright G. Chan W.C. et al.The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma.N Engl J Med. 2002; 346: 1937-1947Crossref PubMed Scopus (3178) Google Scholar]. An average increase of 13.7% in ABC DLBCL has been observed for every 10 years above the age of 50 years, showing that the poor prognosis of elderly patients with DLBCL could be related to the specific intrinsic biology of the tumor [14.Mareschal S. Lanic H. Ruminy P. et al.The proportion of activated B-cell like subtype among de novo diffuse large B-cell lymphoma increases with age.Haematologica. 2011; 96: 1888-1890Crossref PubMed Scopus (80) Google Scholar, 15.Klapper W. Kreuz M. Kohler C. et al.Patient age at diagnosis is associated with the molecular characteristics of diffuse large B-cell lymphoma.Blood. 2012; 119: 1882-1887Crossref PubMed Scopus (137) Google Scholar]. This COO stratification will impact treatment decisions but the translation of this gene expression profiling (GEP) score in routine practice is challenging. Several immunohistochemistry (IHC) scores have been developed [16.Batlle-Lopez A. Gonzalez de Villambrosia S. Francisco M. et al.Stratifying diffuse large B-cell lymphoma patients treated with chemoimmunotherapy: GCB/non-GCB by immunohistochemistry is still a robust and feasible marker.Oncotarget. 2016; 7: 18036-18049Crossref PubMed Scopus (25) Google Scholar], but reproducibility is clearly an issue [17.Coutinho R. Clear A.J. Owen A. et al.Poor concordance among nine immunohistochemistry classifiers of cell-of-origin for diffuse large B-cell lymphoma: implications for therapeutic strategies.Clin Cancer Res. 2013; 19: 6686-6695Crossref PubMed Scopus (99) Google Scholar]. MYC [18.Copie-Bergman C. Cuilliere-Dartigues P. Baia M. et al.MYC-IG rearrangements are negative predictors of survival in DLBCL patients treated with immunochemotherapy: a GELA/LYSA study.Blood. 2015; 126: 2466-2474Crossref PubMed Scopus (171) Google Scholar], BLC2 and/or BLC6 gene rearrangements (double hit lymphoma (DHL)), have also been associated with outcome [19.Johnson N.A. Savage K.J. Ludkovski O. et al.Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival.Blood. 2009; 114: 2273-2279Crossref PubMed Scopus (468) Google Scholar]. In this report, the combined analysis of FISH data from the RICOVER trail and UK-NCRI study allowed confirmation of the prognostic value of MYC-R and DHL, independently from IPI score, in patients prospectively treated with R-CHOP. In this analysis, MYC-R represents 10% of the cases and DHL 6% with 3 years OS of 73.7% and 60.9% compared to 78.3% and 85.3% for negative cases and BLC2-R only cases. COO determined by IHC (Hans) had no impact on PFS or OS. These data contrast with the prognostic value of COO with the Hans evaluation recently reported by Petrella et al. [20.Petrella T. Copie-Bergman C. Briere J. et al.BCL2 expression but not MYC and BCL2 coexpression predicts survival in elderly patients with diffuse large B-cell lymphoma independently of cell of origin in the phase 3 LNH03-6B trial.Ann Oncol. 2017; 28(5): 1042-1049Abstract Full Text Full Text PDF Scopus (17) Google Scholar] in the LNH03-6B study. The differences reported here might be related to the difference in clinical characteristics of patients in the different clinical trials. Nevertheless, this underlies the need to establish a robust consensus review on the different methodologies to evaluate the COO status in DLBCL. Indeed, other techniques, such as nanostring [21.Scott D.W. Wright G.W. Williams P.M. et al.Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin embedded tissue.Blood. 2014; 123: 1214-1217Crossref PubMed Scopus (423) Google Scholar] and RT-MLPA [22.Mareschal S. Ruminy P. Bagacean C. et al.Accurate classification of germinal center B-cell-like/activated B-cell-like diffuse large B-cell lymphoma using a simple and rapid Reverse Transcriptase-Multiplex Ligation-Dependent Probe Amplification Assay: a CALYM study.J Mol Diagn. 2017; 17: 273-283Abstract Full Text Full Text PDF Scopus (44) Google Scholar], also applicable in routine clinical practice have been evaluated but need to be further validated in prospective trials. This will be done in the RT3 (Real Time Molecular Characterization of Diffuse Large B-Cell Lymphoma (DLBCL), NCT03104478) study from the LYSA (Lymphoma study association). In summary, eight cycles of R-CHOP21 (or even 6 cycles of RCHOP21) should remain the standard of care and be used as a backbone to develop associations with new drugs aiming at improving the outcome of elderly patients. Several trials have already evaluated the tolerability and efficacy of R-CHOP in association with targeted therapies (such as bortezomib, lenalidomide, enzastorin and ibrutinib). Among the 35% of relapsing patients reported in these analyses (which is consistent with others), around two-thirds can be considered as primary R-CHOP failure (refractory or relapsing within a year). For these chemo-refractory patients, an alternative strategy should be discussed at diagnosis incorporating targeted therapies association. The main pitfall consists in identifying them at diagnosis. The DHL status identifies <10% of high risk patients, as well as the ABE4 score. The different and sometimes discordant results on prognostication of outcome with biological markers underlie the fact that the replacement of IPI score by a composite score including more biological markers, if desired, will need confirmation in a prospective fashion and should be viewed with caution. None declared.