Risk adapted high-dose and dose-dense therapies modulate the impact of biological classification in diffuse large B-cell lymphoma prognosis Diffuse large B-cell lymphoma (DLBCL) is a highly het- erogeneous disease entity. 1 Young patients with high-inter- mediate and high aa-IPI score seem to be good candidates to receive alternative treatments to standard RCHOP-21 including EPOCH-R, 2 R-ACVBP+HDT-ASCT 3 and upfront autologous stem cell transplantation. 4 Other risk factors can be used to identify patients for the use of more dose- intense regimens including bulky disease, interim PET pos- itivity and, importantly, molecular profiles. 5-7 The aim of our study was to evaluate whether high-dose regimens in patients enrolled in clinical trials might modify the prognostic impact of already recognized biological markers in DLBCL (Cell of Origin (COO) classification, MYC, BCL2 and BCL6 translocations, microRNA expres- sion, MYC and BCL2 protein overexpression). We analyzed a series of 156 patient samples. Patients were enrolled in four clinical trials from GELTAMO, PETHEMA and GOTEL and treated using first-line dose- dense or high-dose regimens (R-CHOP 14: 76 patient sam- ples from 209 (36%) patients; dose-adjusted EPOCH-R: 42 patient samples from 81 patients included (52%); and MegaCHOP-R plus stem cell transplantation based on interim PET results: 38 patient samples from 71 patients enrolled (53%)). 8 All samples received in the reference cen- ter were included in the study and biological marker analy- sis was only hampered by tissue limitations in specific cases. A summary of the major clinical characteristics of the patients included in this study is shown in Table 1. The study was approved by the Institutional Ethical Committee of all participating institutions and by the national regulatory agency according to Spanish law, and complied with the Declaration of Helsinki. A retrospective cohort of 240 cases of DLBCL treated with chemoim- munotherapy was used for comparison. 9 Centralized review of the histopathological diagnosis was performed by 2 hematopathologists (SMM, MAP) according to WHO classification. 1 All cases were classified according to the COO using the immunohistochemical algorithms by Hans, Choi and Visco-Young. 10-12 haematologica 2014; 99:e138 LETTERS TO THE EDITOR Table 1. Clinical features of the series. Number of patients 156 OS*, PFS** 76 OS*, PFS** 42 OS*, PFS** 38 OS, PFS Mega pooled set RCHOP-14 EPOCH-R CHOP-R and BMT (76 patients) (42 patients) (38 patients) IPI factors Age *0.02, **0.003 *0.01,**0.0007 *ns, **ns *ns, ns** ≤60 years 90 (57%) 45 18 27 >60 years 63 (40%) 28 24 10 Stage *ns,**ns *ns,**ns *ns, **ns *ns, ns** I-II 74 (47%) 31 42 1 III-IV 79 (50%) 42 0 36 LDH *ns,**ns *ns,**ns *ns,**ns *ns, ns** low 49 (31%) 35 4 9 high 100 (64%) 36 38 26 Performance status *ns, **0.04 *0.001,**0.01 *ns,**ns *ns, ns** Ambulatory (0-1) 107 (68%) 61 24 21 Not ambulatory (2-4) 43 (27%) 10 18 15 Extranodal site involvement *ns,**ns *ns,**ns *ns,**ns *ns, ns** ≤ 1 site 101 (64%) 54 30 17 > 1 site 49 (31%) 18 12 18 IPI score (number of IPI factors) *ns, **0.03 *ns,**ns *ns,**ns *ns, 0.03** Low risk (0,1) 34 (22%) 30 3 1 Low – intermediate risk (2) 38 (24%) 22 5 11 High – intermediate risk (3) 56 (36%) 15 22 18 High risk (4,5) 25 (16%) 6 12 7 COO-CLASSIFICATION GCB (according to Choi) 81/144 (56%) *ns,**ns 42 *ns,**ns 22 *ns,**ns 15 *ns,ns** ABC 63/144 (44%) 25 18 18 GCB (according to Hans) 63/146 (43%) *ns,**ns 35 *ns,**ns 16 *ns,**ns 8 *ns, ns** NON-GCB 83/146 (57%) 34 24 20 GCB (according to Visco-Young) 75/145 (52%) *ns,**ns 39 *ns,**ns 22 *ns,**ns 12 *ns, ns** ABC 70/145 (48%) 29 18 21 CONCURRENT MYC-BCL2 IHC EXPRESSION *ns,**ns *ns,**ns *ns,**ns *ns, ns** DP* 31/117 (26%) 35 29 19 NON DP 86/117 (73%) 17 4 9 LDH: lactic dehydrogenase levels, IPI: International Prognostic Index; COO: cell of origin classification. GCB: germinal center B-cell type; ABC: activated B-cell type; NON-GCB: non-germinal center B-cell type; DP: double-positive for MYC and BCL2 immunohistochemical expression. NON-DP: non-double positive.