Abstract: Background. Peripheral T cell Lymphoma (PTCL) represent a major therapeutic challenge. In the previous Verona experience (Todeschini G et al. Cancer2005;104:555–560), the novel intensive regimen HyperCHiDAM Verona897 (high-dose IV MTX 2 g/sqm 400 sqm bolus, 1600 sqm CI day 1 with IV leucovorin rescue; hyperfractionated IV CTX 300 mg/sqm Q12h, dd 2–4; high-dose IV AraC 2g/sqm Q12h, dd 2-4; plus G-CSF) achieved salutary results in refractory/relapsed aggressive lymphomas, in particular in PTCL. Supportive measures included hydratation 3000 ml/sqm/day, antimicrobial prophylaxis comprising oral ciprofloxacin, itraconazole, trimethoprim/sulfamethoxazole. CMV antigenemia (pp65) was monitored 2 times a week. Patients. Following these results, 7 centers belonging to the Italian co-operative group GITIL (Gruppo Italiano Terapie Innovative Linfomi) treated with 2 cycles of HyperCHiDAM Verona897, 33 patients affected by PTCL (17 upfront, 16 refractory/relapsed) followed in the majority of cases by stem cell transplant. Patients: M/F 21/12, median age 49 (19–63) years; histology: PTCL-NOS 15, ALCL ALK-negative 9, EALTC 4, AIL 3, T-NK nasal 1, Angiocentric 1; stage IV 19/33 (57.5%), bone-marrow positive 10/33 (30.3%), extranodal involvement 24/33 (72.7%), high LDH 18/33 (54.5%). Seven patients needing urgent treatment were treated before HyperCHiDAM with 1 cycle of Campath-CHOP (4 patients) or CHOP + L-ASE (3 patients). Results. Upfront patients: after 2 cycles of HyperCHiDAM, CR were 82.3% (14/17), early toxic deaths 0 (1 late toxic death occurred after SCT, due to CMV pneumonia), relapses 3/14. With a median follow-up of 21 months (3–90+), 11/17 (64.7%) patients are disease-free, 10 in first CR, 1 after rescue with stem cell transplant. Three of the CCR patients received HyperCHiDAM alone. Refractory/relapsed patients: CR were 5/16 (31.2%), CCR 4/16 (25%), with a median follow-up of 24 months (5–64+). The progression-free survival was significantly superior in upfront patients (p=0.036). Overall, toxic deaths were 3/33 (9%), 1/17 (5.8%) in upfront and 2/16 (12.5%) in refractory/relapsed patients. One patient had major cerebellar toxicity. Conclusions. The intensive regimen HyperCHiDAM Verona897 is effective in inducing CR in aggressive PTCL, in particular as upfront therapy. The intensiveness of this treatment requires a careful supportive therapy. Following these results, HyperCHiDAM has been included in a national trial for treatment of PTCL, after 2 cycles of Campath-CHOP and before stem cell transplant (allogeneic or autologous depending on the availability of an HLA-matched sibling). The co-operative study is recruiting.

Abstract: Abstract 746 Background The clinical benefit of high dose chemotherapy programs in patients with diffuse large B cell lymphomas (DLBCL) with unfavorable presentation (IPI 〉 2) is still matter of debate and several prospective randomized clinical trials have been conducted to address this point. Patients and study design In year 2005 the cooperative study group GITIL launched a multicenter phase III trial (R-HDS 0305, Clinical Trials.gov.number NCT00355199) in DLBCL patients without CNS involvement and the following inclusion criteria: age between 18–60 years, stage 〉 II B-bulk with ECOG-PS=0-3 and age adjusted IPI (aaIPI) 2–3 or age 61–65 years with ECOG-PS = 0–2 and IPI 〉 3. The control group received 8 courses of the conventional R-CHOP-14 chemotherapy program, followed by IFRT, in patients who achieved at least a partial response (PR) after 4 cycles. Cases refractory to R-CHOP-14 could be rescued by R-HDS. The experimental arm (R-HDS) included: 3 courses of doxorubicin-containing chemotherapy (APO), followed by high-dose cyclophosphamide (CTX) 7 g/sqm, Ara-C (2g/sqm every 12 hours for 6 days), etoposide 2 g/sqm plus cisplatin 100 mg/sqm. After R-HDS chemotherapy, a mitoxantrone-melphalan (60 and 180 mg/sqm, respectively) or BEAM conditioning regimen with autologous stem cell transplantation (ASCT) + IFRT, as above. Rituximab (375 mg/sqm) was given for a total of 6 doses, twice after CTX and Ara-C based cycles, as in vivo purging before CD 34+ cells harvest, and twice after ASCT (Tarella C. et al Leukemia 21:1802–1811, 2007). The primary end-point of the study was to test an increase of 2-year Event Free Survival (EFS) from 50% in the R-CHOP arm to 65% in the intensified R-HDS arm. Secondary end-points were Disease Free Survival (DFS), Overall Survival (OS) and toxicity. Results From June 2005 to June 2011, 248 patients were enrolled in the study (R-CHOP-14=127; R-HDS=121) and 241 were evaluable as to completeness of information. The median age was 51 years (range, 18–65), 32 subjects (13.3%) had 〉 60 years and the M/F ratio was 1.39. Clinical features were as follows: advanced Ann Arbor clinical stage (93%), BM infiltration (22%), bulky disease (69%), elevated LDH (87%), elevated beta 2-microglobulin (60%), poor ECOG-PS (61%), B-symptoms (57%), ≥2 extranodal sites (71%), IPI 2 (51%) and IPI 〉 3 (49%). The two arms were well balanced for all these features. No significant difference could be detected in the response rates of patients treated with R-CHOP and R-HDS that in detail, were the following: complete response (CR, 76% vs. 76%), partial response (PR, 4.7% vs. 7.9%), progressive disease (PD, 15% vs. 8.8%), stable disease (SD, 1.6% vs. 0.9%), treatment discontinuation for any reason (0 vs. 1.8%), early death (ED, 2.4% vs. 4.4%). On the contrary, the relapse rate was higher in the R-CHOP vs. the R-HDS arm (14% vs. 4.6%, p= 0.025). After a median follow-up of 27.7 months (range 0.3 – 52.5) the 2-year DFS of patients treated with R-CHOP or R-HDS is 83% vs. 93% (p=0.07) while the EFS is 68% vs. 73% (p= 0.345) (Figure 1 and 2). Similarly, with the current follow up, no significant difference could be detected in OS (77% vs. 80%, p= 0.398). The OS was better for patients with IPI 2 in comparison to those with IPI 〉 3 (84% vs. 73%; p= 0.04), but without any significant difference according to treatment arm. Although the rate of death in remission (2% in both arms) was similar, the overall toxicity of the R-HDS arm was higher in terms of hematologic toxicity (CTC G 〉 2) (p 〈 0.001) and infectious complications (p 〈 0.001). So far, no secondary malignancies have been observed. Conclusion In DLBCL patients with unfavorable presentation a conventional R-CHOP and a more intensive R-HDS chemotherapy achieved the same excellent rate of response. Despite a trend for a better DFS observed in patients treated with R-HDS, the EFS (primary endpoint of the study) and the OS are not different. A longer follow-up is needed in order to definitively rule out the role of intensified R-HDS program as first line treatment for poor-prognosis DLBCL patients. Disclosures: Tarella: Hoffmann-La Roche: Consultancy, Honoraria. Gianni:Hoffmann-La Roche: Consultancy, Honoraria. Pizzolo:Hoffmann-La Roche: Consultancy, Honoraria. Rambaldi:Hoffmann-La Roche: Consultancy, Honoraria.

Abstract: High-dose chemotherapy with peripheral blood progenitor cell (PBPC) autograft is effective in high-risk lymphoma, particularly with the addition of rituximab; however, it is associated with risk of secondary malignancy. These issues have been addressed in a series of 1,347 patients with lymphoma treated with a high-dose sequential (HDS) program. Patients and Methods A total of 1,024 patients with B-cell lymphoma, 234 patients with Hodgkin's lymphoma, and 89 patients with T-cell lymphoma were treated with HDS between 1985 and 2005 at 11 Gruppo Italiano Terapie Innovative Linfomi centers. HDS was given as salvage treatment to 707 patients (52%); 655 patients (49%) received a modified HDS, with high-dose cytarabine and two consecutive PBPC harvests. Rituximab-supplemented HDS was given to 523 patients (39%). Results At a median follow-up of 7 years, the median overall survival (OS) was 16.2 years; in B-cell lymphoma the OS was significantly superior with rituximab HDS compared to HDS alone. The cumulative incidence at 5 and 10 years of secondary myelodysplasia/acute leukemia (sMDS/AL) were 3.09% and 4.52%, respectively, that of solid tumors were 2.54% and 6.79%, respectively. Factors associated with sMDS/AL were male sex and use of the second harvest PBPC for the graft; factors found to be associated with solid tumor were advanced age, post-HDS radiotherapy, and rituximab addition to HDS. Despite the increased risk of solid tumors, rituximab addition to HDS was still associated with survival advantages. Conclusion This analysis has relevant implications for the design and use of intensive chemoimmunotherapy with autograft. In addition, it offers useful insights toward the understanding and prevention of tumor development.

Abstract: We updated a cohort study with the aim of evaluating if an up-front Rituximab supplemented high-dose sequential chemotherapy (R-HDS), supported by autologous bone marrow transplantation (ASCT) can induce log-term remissions in Mantle Cell Lymphoma (MCL), with an acceptable toxic profile. From 1997 to 2005, 77 consecutive MCL patients, 〈 61 year old, considered suitable for ASCT in 11 Italian cancer centres were enrolled in this study (Group 1). Their clinical outcome was compared with that of 79 age-matched historic controls treated between 1978 and 1999 with standard-dose anthracyclin or fludarabine containing regimens (group 2). The majority of both groups had an advanced stage, bone marrow infiltration and 〉 1 IPI risk factors, while 〉 1 extranodal sites prevailed in Group 1 and a poor ECOG-PS in Group 2. After 2–3 cycles of either doxorubicin- or cisplatin-containing chemotherapy, Group 1 received R-HDS including: HD-cyclophosphamide (CTX) 7 gr/sqm and HD-Ara-C (2 g/sqm every 12 hours for 6 days), followed by HDS HD-melphalan (180 mg/sqm) and/or HD-mitoxantrone plus melphalan (60 and 180 mg/sqm) and ASCT. Rituximab (375 mg /sqm) was given for a total of 6 doses, twice after HD-CTX and HD-Ara-C, as in vivo purging before CD34+ cells harvest and twice after ASCT. Sixty-nine patients (90%) in Group 1 completed the planned program and a median number of 6.3 x 10^6 cells CD34+/kg were transplanted. In Group 2, 85% of patients received the planned chemotherapy. The CR rate was 86% in Group 1 and 35% in Group 2 and the treatment-related mortality was 1.3% and 0.8%, respectively. Moreover, in Group 1, 4 patient developed sMDS, and 4 died of solid tumors (n=3), or septic shock (n=1). After a median follow-up of 50 months (range 3–111) in Group 1 and 37 months (range 1–141) in Group 2, the rate of 1st CCR was 65% and 14%, respectively. The 5-year projected OS, EFS and DFS were 74%, 61% and 70%, in Group 1 and 31%, 14% and 25%, in Group 2, respectively. Cox multivariate analysis failed to identify within potential prognostic markers factors predictive for OS and EFS. In conclusion, R-HDS induces long-term remissions with a manageable toxicity in patients with newly diagnosed MCL. Studies comparing this program with other intensive regimens are needed for ascertaining the role of R-HDS in the treatment of this otherwise incurable disease.

Abstract: Abstract 519 Introduction High-dose (hd) therapy with stem cell autograft is an effective treatment for both non-Hodgkin's (NHL) and Hodgkin's Lymphoma (HL). However, the occurrence of secondary malignancies, particularly myelodysplastic syndromes/acute leukemias (sMDS/AL), is a critical issue, representing a major cause of failure in patients potentially cured after hd-chemotherapy. Aim of the study To evaluate: frequency-cumulative incidence-risk factors, of both sMDS/AL and solid tumors in a large series of lymphoma patients, treated with the hd-sequential (HDS) chemotherapy approach, followed by peripheral blood progenitor cell (PBPC) autograft. Patients and Methods Data have been collected on 1,347 lymphoma patients treated in the last two decades at 11 Centers, associated to GITIL. Patients received either the original or modified HDS regimens; PBPC were collected after hd-cyclophosphamide, and, in a subgroup, after a 2nd round of mobilization with hd-Ara-C. The series included 1,024 B-cell NHL, 234 HL and 89 T-cell NHL; there were 695 high-grade, 278 low-grade and 140 mantle-cell lymphoma; median age was 46 yrs; 57% were male. Overall, 640 (47%) patients received HDS front-line. Autograft was usually performed with PBPC (median CD34+ cells: 7×106/kg); most patients (n=774) received PBPC collected at the 1st mobilization course, whereas some others (n=298) were autografted with PBPC collected following a 2nd high-dose course. The Mitoxantrone/L-PAM combination was the most frequently employed conditioning for autograft (n=643), followed by BEAM (n=301); TBI-conditioning regimen was employed only in 79 patients. Results At a median follow-up of 7 yrs, the 5 and 10 yr Overall Survival (OS) projections are 64% and 56%, respectively. Among B-cell NHL, 70.5% of patients treated with Rituximab-supplemented HDS are presently alive vs. 55.6 of those treated with Rituximab-free HDS (p=0.001). Overall, 54 (4.0%) patients developed s-MDS/AL, with a cumulative incidence of sMDS/AL of 3.1% at 5 yrs and 4.6% at 10 yrs. (Figure 1A). Median time of s-MDS/AL occurrence was 3.2 yrs (range: 1.3-13.7) since autograft. In addition, 64 patients had a diagnosis of solid tumor, at a median time of 5.5 yrs (range: 0.5-14.6) since autograft. The cumulative incidence of 2ry-solid tumor is 2.5 % at 5 yrs and 6.6 % at 10 yrs. (Figure 1B). In univariate analysis, age 〉 45 yrs., male sex and autograft with PBPC collected at the 2nd mobilization round had a significantly higher risk of sMDS/AL; a trend for a higher incidence was observed in patients receiving HDS with Rituximab (p=0.066) and in those presenting with BM involvement (p=0.097); on multivariate analysis, male gender and autograft with PBPC of the 2nd mobilization round were the only parameters associated with sMDS/AL occurrence (SDHR: 2.74, p=0.004 and 2.44, p=0.002, respectively). Concerning solid tumors, in univariate analysis, age 〉 45 yrs, Rituximab addition to HDS, HDS with hd-Ara-C, and autograft with PBPC collected at the 2nd mobilization round had a significantly higher risk of solid tumor; on multivariate analysis, age 〉 45 yrs., Rituximab addition and consolidation Radiotherapy following HDS were the only parameters associated with solid tumor occurrence (SDHR: 2.10, p=0.002, 1.99, p=0.011 and 2.13, p=0.024, respectively). Conclusions The incidence of sMDS/AL observed following HDS is among the lowest reported so far in lymphoma patients treated with hd-therapy and autograft. However, the risk of solid tumor occurrence can not be ignored. Among risk factors, male gender and the quality, rather than the quantity, of grafted PBPC are the strongest factors associated with sMDS/AL. Other factors, namely older age, Rituximab addition and consolidation Radiotherapy, are mainly associated with the development of solid tumors. Despite the increased risk of secondary solid tumor, addition of Rituximab resulted in significant improvements in the overall survival of patients undergoing HDS. Further analysis are required to understand the biological meaning of the variable association between risk factor and secondary malignancy development. Disclosures: Tarella: Roche: Honoraria, research financial support. Rambaldi:Roche: Consultancy, Honoraria.

Abstract: Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.

Abstract: Introduction. The majority of SMZLs display an indolent course, however the disease is still incurable and a significant proportion of patients (~25-30%) experience poor outcomes surviving 〈 5 years. Molecular alterations of SMZL are promising biomarkers, which might improve risk stratification of patients. The main objective of the study is to test the impact of molecular aspects on disease-specific survival prognostication in newly diagnosed SMZL. Methods. IELSG46 is a multicenter, international, retrospective, observational study in which already existing and coded health-related personal and biological material is used. The study included adults, who received a diagnosis of SMZL on spleen histology with a follow up 〉 5 years, and for whom tumor material collected before initiation of medical therapy was available. Mutation analysis was performed by CAPP-seq targeted deep next generation sequencing of tumor genomic DNA. A stringent bioinformatic pipeline was applied to suppress the background noise allowing to call variants with a sensitivity of 5x10-2 in FFPE derived DNA. Copy number variations (CNVs) were identified by using the sequencing reads-based GATK4-CNV algorithm. IGHV rearrangements were obtained by using LymphoTrack® IGH FR1 Assay Panel kit. Molecular clusters were identified by an iterative algorithm that maximizes genetic distinctiveness of subgroups by reassigning patients between clusters that are created a priori based on the co-occurrence of genetic lesions. Relative survival, defined as the ratio between actuarial survival observed in the SMZL cohort and expected survival of the general population matched to patients by geographical origin, sex, age and calendar year of diagnosis, was calculated using the Ederer II method. Results. The analysis included 303 patients with a SMZL diagnosis confirmed on spleen histology. The sample size allowed to identify 30% differences in survival for molecular subgroups comprising at least 5% of cases with a statistical power between 80-100%. Median follow-up was 9.2 years. At 10 years, 85% of patients were alive, consistent with the known indolent behavior of this lymphoma. Genes recurrently affected by non-synonymous somatic mutations in 〉 10% of SMZL included KLF2 (24%), NOTCH2 (19%), KMT2D (15%), TNFAIP3 (13%), EP300 and TP53 (10%). Deletion 7q was documented in 25% of cases and IGHV1-2*04 usage in 32%. By cluster analysis, three major molecular subgroups were identified, each of them characterized by a NOTCH pathway mutated gene (Fig. 1A). The first cluster was defined by NOTCH2 and/or KLF2 mutations and was enriched in TNFAIP3 mutations and IGHV1-2*04 gene usage (Fig. 1A). The second cluster was defined by SPEN mutations, and was enriched in KMT2D and other epigenetic gene mutations (Fig. 1A). The third cluster was enriched in NOTCH1 mutations (Fig. 1A). By relative survival analysis, the NOTCH2/KLF2 cluster showed a lower survival compared to the matched general population, indicating a significant impact of the disease on patients' expected survival (Fig. 1B). Conclusions. The large sample size and inclusion of SMZL confirmed by spleen histopathology review allowed for precise estimation of the prevalence of KLF2 and NOTCH2 mutations in this lymphoma. Three molecular clusters were identified in SMZL, each of them containing a NOTCH pathway gene, supporting the relevance of NOTCH signaling in the pathogenesis of SMZL. Patients belonging to the NOTCH2/KLF2 cluster had a lower relative survival compared to the matched general population. Disclosures Traverse-Glehen: Astra Zeneca: Other: Travel; Takeda: Research Funding. Gomes da Silva:Roche: Other: Institution's payment for consultancy, Travelling support; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Celgene: Other: Travelling support; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Institution's payment for consultancy, Travelling support; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Research Funding. Ladetto:Celgene: Honoraria; Jannsen: Honoraria; Acerta: Honoraria; Abbvie: Honoraria; Sandoz: Honoraria; Roche: Honoraria. Rambaldi:Pfizer: Consultancy; Novartis: Consultancy; Omeros: Consultancy; Italfarmaco: Consultancy; Amgen Inc.: Consultancy; Roche: Consultancy; Celgene: Consultancy. Vitolo:Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Zinzani:MSD: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau. Gaidano:Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Morphosys: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Salles:Servier: Honoraria; Abbvie: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Honoraria; BMS: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Acerta: Honoraria; Janssen: Honoraria, Other: Advisory Board; Merck: Honoraria; Pfizer: Honoraria; Morphosys: Honoraria; Gilead: Honoraria, Other: Advisory Board; Epizyme: Honoraria; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria. Zucca:Celltrion: Consultancy; AstraZeneca: Consultancy.

Abstract: The benefit of high-dose chemotherapy with autologous stem-cell transplantation (ASCT) as first-line treatment in patients with diffuse large B-cell lymphomas is still a matter of debate. To address this point, we designed a randomized phase III trial to compare rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-14 (eight cycles) with rituximab plus high-dose sequential chemotherapy (R-HDS) with ASCT. Patients and Methods From June 2005 to June 2011, 246 high-risk patients with a high-intermediate (56%) or high (44%) International Prognostic Index score were randomly assigned to the R-CHOP or R-HDS arm, and 235 were analyzed by intent to treat. The primary efficacy end point of the study was 3-year event-free survival, and results were analyzed on an intent-to-treat basis. Results Clinical response (complete response, 78% v 76%; partial response, 5% v 9%) and failures (no response, 15% v 11%; and early treatment-related mortality, 2% v 3%) were similar after R-CHOP versus R-HDS, respectively. After a median follow-up of 5 years, the 3-year event-free survival was 62% versus 65% ( P = .83). At 3 years, compared with the R-CHOP arm, the R-HDS arm had better disease-free survival (79% v 91%, respectively; P = .034), but this subsequently vanished because of late-occurring treatment-related deaths. No difference was detected in terms of progression-free survival (65% v 75%, respectively; P = .12), or overall survival (74% v 77%, respectively; P = .64). Significantly higher hematologic toxicity ( P 〈 .001) and more infectious complications ( P 〈 .001) were observed in the R-HDS arm. Conclusion In this study, front-line intensive R-HDS chemotherapy with ASCT did not improve the outcome of high-risk patients with diffuse large B-cell lymphomas.