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In the validation using the MER cohort of 192 MZL patients, 5y PFS was 57% (95% CI 51-64). Applying the MZL-IPI to the MER, 41(21%), 113 (59%), and 38 (20%) patients were classified as LRG, IRG, and HRG, respectively. B Conclusions: b MZL-IPI is a new validated prognostic score for all patients with MZL who are considered for systemic treatment. [Extracted from the article]

Competing Interests: Anna Maria Frustaci received honoraria from Janssen, Beigene, Abbvie, AstraZeneca. Andrea Visentin participated scientific advisory boards organized by Johnson & Johnson, Abbvie, AstraZeneca, BeiGene, Takeda. Michele Merli participated scientific advisory boards organized by Eli Lilly. Alessandra Tedeschi received consulting fees and travel support for scientific events from Janssen, Beigene, Abbvie, Lilly, AstraZeneca. Andrea Visentin received advisory board participation fees from Janssen, Abbvie, Beigene, CSL Behring, Astrazeneca, Beigene, and Takeda. Isacco Ferrarini reports research fundings from Abbvie, BeiGene, and Eli‐Lilly. Simone Ferrero is a consultant for Janssen, EUSA Pharma, Recordati, Abbvie, and Sandoz; is on the advisory board of Janssen, EUSA Pharma, Recordati, Incyte, Roche, Astra Zeneca, and Italfarmaco; received speaker's honoraria from Janssen, EUSA Pharma, Recordati, Lilly, Beigene, Gilead, Novartis, Sandoz, and Gentili; and received research funding from Gilead, Incyte and Morphosys. Roberta Murru received scientific advisory board participation fees and travel support from Abbvie, AstraZeneca, Beigene, Johnson & Johnson. Marzia Varettoni participated scientific advisory boards and received speaker honoraria from Abbvie, AstraZeneca, Beigene and received advisory board participation fees from Johnson & Johnson. Francesco Piazza participated to advisory board and received speaker honoraria from Kite Gilead, Roche, and BeiGene and participated to advisory board from Abbvie and Johnson & Johnson.

Various aggressive lymphomas entities have been associated with immunodeficiency. To provide further evidence that also MYC-negative high-grade B-cell (formerly Burkitt-like) lymphoma with 11q aberrations comprises an immunodeficiency-related subtype, we here conducted a comprehensive pathological and genetic workup of a 25-year-old patient with this type of lymphoma and simultaneous papillary renal cell carcinoma. The patient developed both malignancies following extensive childhood immunosuppression and a kidney transplant. Germline and somatic genetic analyses included interphase cytogenetics, imbalance mapping, and exome sequencing. We identified potential germline-predisposition to inborn errors of immunity, kidney disease, and cancer, along with a germline region of homozygosity in 20q. Each tumor showed imbalances and single nucleotide variants typical for the respective diagnosis, with shared gains in the name-giving region in 11q, gain of the MYC gene in 8q24 and trisomy 12. While we can show that the imbalances in 8q and 11q arise from different mechanisms in both tumors, trisomy 12 involved gain of the same parental chromosome. Our findings corroborate the existence of a subtype of immunodeficiency-related high-grade B-cell lymphomas with 11q aberrations, provide further insights into its molecular pathogenesis, and reveal potential pitfalls in the molecular diagnosis of simultaneous tumors based on the technology applied., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Treatment strategies for early stage diffuse large B-cell lymphoma (ES-DLBCL) include R-CHOP, with a similar schedule to that used in advanced stage, or a reduced number of cycles followed by radiation therapy (RT). We retrospectively analyzed 179 ES-DLBCL patients, managed according to the clinical practice. Treatment regimens include chemoimmunotherapy 4-6 cycles +/- RT as consolidation. First-line therapy was R-CHOP/CHOP-like in 88.8% of cases. RT as consolidation was administered to 29.9% of cases. Complete response rate was 87.2%, median PFS and OS were not reached. IPI 2-3 and first-line regimen with 3-4 cycles of R-CHOP without RT were the 2 prognostic variables for OS in multivariate analysis. After a median follow-up of 48 months, 31 patients died (17.3%). We suggest that both R-CHOP 6 cycles and 3-4 cycles followed by RT as consolidation seem to be valid first-line regimens, while an abbreviated strategy without RT could be associated to inferior outcome.

Background/Objectives: Primary cutaneous lymphomas (PCL) are a heterogeneous group of non-Hodgkin lymphomas arising from malignant T (CTCL) or B (CBCL) cells, often mimicking other skin conditions. Recently, non-invasive diagnostic imaging modalities, including dermoscopy, Reflectance Confocal Microscopy (RCM), and Line-field Optical Coherence Tomography (LC-OCT), have become increasingly important, supporting clinicians in clinical practice. Hence, our study aimed to describe dermoscopic, RCM, and LC-OCT features of PCL and to explore their role in PCL management. Methods : Between December 2022 and January 2024, 40 lesions of 25 patients with PCL were retrospectively analyzed at the Dermatologic Unit of the University of Siena, Italy. Predefined dermoscopic, LC-OCT, and RCM criteria were assessed and their frequencies were calculated. Results: At dermoscopy, CTCL lesions were characterized by pinkish structureless areas (58,6%) and homogeneous distributed dotted vessels (35,7%), whereas 57.1% of CBCL presented with orange-yellow structureless areas. Considering CTCL, lymphocytes in the epidermis, dermal-epidermal junction, and dermis were detected by LC-OCT in 73.1%, 66.7%, and 51.9% and by RCM in 72.2%, 55.6%, and 61.1% of cases, respectively. The detection of lymphocytes was more precise using RCM than LC-OCT in CTCL ( p < 0.001). Dermal infiltration of medium-reflective cells was visible in 80% and 40% of CBCL cases by LC-OCT and RCM, respectively. Conclusions : Non-invasive imaging techniques may support clinicians in managing PCL; however, further studies are mandatory in this field.

The management of small lymphocytic lymphoma (SLL) as chronic lymphocytic leukemia (CLL) or an indolent non-Hodgkin lymphoma is highly debated. In this single-center, real-life study, 38 SLL patients managed between 2008 and 2022 were evaluated. Overall, 26/38 cases (68.4%) needed treatment and all but one received CLL concordant therapy, including BR (9/38 cases), fludarabine, cyclophosphamide, rituximab (5/38 cases), rituximab and chlorambucil (4/38 cases), BTK inhibitors (7/38 cases) and steroid (1 case with immune thrombocytopenia). Patients treated between 2008 and 2018 were more likely to receive chemoimmunotherapy compared to patients treated in 2019-2022, that were more likely to receive BTK inhibitors. The median PFS was 54 months and 3-y PFS was 58%, while the median OS was not reached, with a 3-y OS of 84%. We confirm a wide heterogeneity in SLL management and we suggest prospective studies are needed to improve the knowledge of its biology and harmonize its treatment.

Background: The mainstay of treatment for early-stage follicular lymphoma is local radiotherapy, with a possible role for anti-CD20 monoclonal antibody (mAb). We aimed to evaluate the effect of these treatments using a measurable residual disease (MRD)-driven approach., Methods: This prospective, multicentre, phase 2 trial was conducted at 27 centres of the Fondazione Italiana Linfomi (FIL) in Italy. Eligible participants were adults (≥18 years) with newly diagnosed, histologically confirmed follicular lymphoma (stage I or II; grade I-IIIa). Patients were initially treated with 24 Gy involved-field radiotherapy over 12 days; those who were MRD-positive after radiotherapy or during follow-up received eight intravenous doses (1000 mg per dose; one dose per week) of the anti-CD20 mAb ofatumumab. The primary endpoint was the proportion of patients who were MRD-positive after involved-field radiotherapy and became MRD-negative after ofatumumab treatment. Patients were included in the primary endpoint analysis population if they were positive for BCL2::IGH rearrangement at enrolment in peripheral blood or bone marrow samples. MRD positivity was defined as the persistence of BCL2::IGH rearrangement in peripheral blood or bone marrow, assessed centrally by laboratories of the FIL MRD Network. The trial was registered with EudraCT, 2012-001676-11., Findings: Between May 2, 2015, and June 1, 2018, we enrolled 110 participants, of whom 106 (96%) were eligible and received involved-field radiotherapy. Of these, 105 (99%) were White, one (1%) was Black, 50 (47%) were male, and 56 (53%) were female. Of 105 participants in whom BCL2::IGH status was evaluable, 32 (30%) had a detectable BCL2::IGH rearrangement at baseline. After radiotherapy, 12 (40%) of 30 patients reached MRD-negative status, which was long-lasting (at least 36 or 42 months) in three (25%). In those who were MRD-positive after radiotherapy, ofatumumab induced MRD-negativity in 23 (92%; 95% CI 74-99) of 25 evaluable patients. After a median follow-up of 46·1 months (IQR 42·8-50·8), 14 (61%) of these 23 patients remain in complete response and are MRD-negative. The most common grade 3-4 adverse events were infusion-related reactions, observed in four patients., Interpretation: Local radiotherapy is frequently not associated with the eradication of follicular lymphoma. An MRD-driven, anti-CD20 monoclonal antibody consolidation enables molecular remission to be reached in almost all patients and is associated with a reduced incidence of relapse over time. A clinical advantage of an MRD-driven consolidation is therefore suggested., Funding: AIRC Foundation for Cancer Research in Italy, Novartis International, and GlaxoSmithKline., Competing Interests: Declaration of interests AP reports support for the study from Novartis and AIRC 5 × 1000; payment or honoraria for lectures or presentations from Takeda Pharmaceuticals, Roche, Janssen Pharmaceuticals, and BeiGene; payment for expert testimony from Takeda Pharmaceuticals and Roche; support for attending meetings and/or travel from Takeda Pharmaceuticals, Roche, Janssen Pharmaceuticals, BeiGene, Pfizer, and AbbVie; and participation on a data safety monitoring board or advisory board for Takeda Pharmaceuticals, Roche, and Janssen Pharmaceuticals. SL reports payment or honoraria for lectures or presentations from Roche, BeiGene, Regeneron Pharmaceuticals, and Kite Pharma; support for attending meetings and/or travel from Roche and BeiGene; and participation on a data safety monitoring board or advisory board from Roche, Regeneron Pharmaceuticals, Miltenyi Biomedicine, Takeda Pharmaceuticals, Sobi, and Incyte. GG reports consulting fees from AbbVie, AstraZeneca, BeiGene, Incyte, Lilly, and Johnson & Johnson and payment or honoraria for lectures or presentations from AbbVie, AstraZeneca, BeiGene, Incyte, Lilly, Johnson & Johnson, and Hikma Pharmaceuticals. PC received consulting fees from AbbVie, ADC Therapeutics, Amgen, BeiGene, Celgene, Daiichi Sankyo, Eli Lilly, Gilead/Kite, GSK, Incyte, Janssen Pharmaceuticals, Jazz Pharma, Novartis, Pfizer, Roche, Sanofi, Sobi, and Takeda Pharmaceuticals and payment for lectures from AbbVie, Amgen, Celgene, Gilead/Kite, Incyte, Janssen Pharmaceuticals, Jazz Pharma, Novartis, Roche, Sanofi, Sobi, and Takeda Pharmaceuticals. LA received consulting fees from Roche, Janssen-Cilag, Verastem Oncology, Incyte, EUSA Pharma, Celgene/Bristol Myers Squibb, Kite/Gilead, ADC Therapeutics, and Novartis and payment or honoraria for lectures or presentations from EUSA Pharma and Novartis. ML received grants or contracts from Roche, BeiGene, ADC Therapeutics, and Janssen Pharmaceuticals and consulting fees and/or payment or honoraria from AbbVie, Amgen, ADC Therapeutics, Sobi, BeiGene, Bristol Myers Squibb, EUSA Pharma, Gilead/Kite, Novartis, Incyte, Janssen Pharmaceuticals, Jazz Pharma, Lilly, Regeneron Pharmaceuticals, Roche, Ellipses Pharma, GSK, and Istituto Gentili. IDG received payment or honoraria for lectures or presentations from Takeda Pharmaceuticals, Janssen Pharmaceuticals, Roche, and AstraZeneca; support for attending meetings and/or travel from Takeda Pharmaceuticals, Janssen Pharmaceuticals, Roche, and AstraZeneca; and support for participation on a data safety monitoring board or advisory board from Takeda Pharmaceuticals and Roche. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Aim: Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma (NHL). Despite the availability of clinical and molecular algorithms applied for the prediction of prognosis, in up to 30%-40% of patients, intrinsic or acquired drug resistance occurs. Constitutional genetics may help to predict R-CHOP resistance. This study aimed to validate previously identified single nucleotide polymorphisms (SNPs) in the literature as potential predictors of R-CHOP resistance in DLBCL patients, SNPs. Methods: Twenty SNPs, involved in R-CHOP pharmacokinetics/pharmacodynamics or other pathobiological processes, were investigated in 185 stage I-IV DLBCL patients included in a multi-institution pharmacogenetic study to validate their previously identified correlations with resistance to R-CHOP. Results: Correlations between rs2010963 ( VEGFA gene) and sex ( P = 0.046), and rs1625895 ( TP53 gene) and stage ( P = 0.003) were shown. After multivariate analyses, a concordant effect (i.e., increased risk of disease progression and death) was observed for rs1883112 ( NCF4 gene) and rs1800871 ( IL10 gene). When patients were grouped according to the revised International Prognostic Index (R-IPI), both these SNPs further discriminated progression-free survival (PFS) and overall survival (OS) of the R-IPI-1-2 subgroup. Overall, patients harboring the rare allele showed shorter PFS and OS compared with wild-type patients. Conclusions: Two out of the 20 study SNPs were validated. Thus, these results support the role of previously identified rs1883112 and rs1800871 in predicting DLBCL resistance to R-CHOP and highlight their ability to further discriminate the prognosis of R-IPI-1-2 patients. These data point to the need to also focus on host genetics for a more comprehensive assessment of DLBCL patient outcomes in future prospective trials., Competing Interests: Mini E is an Editorial Board Member of the journal Cancer Drug Resistance, while the other authors have declared that they have no conflicts of interest., (© The Author(s) 2024.)

Few data are known regarding the use of interim positron emission tomography (iPET) after the first two cycles (iPET2) of chemotherapy in treatment-naïve classical Hodgkin lymphoma (cHL) in routine clinical practice, and about the real-life adoption of intensification strategies for iPET positive patients. We conducted a multicenter retrospective study on cHL to investigate the use of iPET in the real-life setting, its prognostic role and outcomes of patients early shifted to intensification. Six hundreds and forty-one patients were enrolled (62% had advanced stage). iPET2 was positive in 89 patients (14%) including 8.7% and 17% early and advanced stage patients, respectively (p = 0.003). Among iPET 2 positive cases treatment was immediately modified in 19 cases; in 14 cases treatment was modified after an additional positive iPET4. Overall 56 iPET2 positive patients never received intensified therapies. Most frequently used intensified therapy was autologous stem cell transplantation followed by BEACOPP. After a median follow-up of 72 months, the 5-year progression-free survival (PFS) was 82% with iPET2 positive patients showing a worse PFS compared with iPET2 negative cases: 31% versus 85%. Focusing on advanced stage patients with a positive iPET2, the 5-year PFS was 59% for patients shifted to intensified therapy at any time point versus 61% for patients who never received intensified therapy. Our study confirmed the higher curability of naïve cHL patients in a real-world setting, and the prognostic role of iPET2 in this setting. A poor adherence to response-adapted strategy which however did not translate into a difference in patient outcomes., (© 2024 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

Background: Marginal zone lymphomas (MZL), comprised of three unique but related subtypes, lack a unifying prognostic score applicable to all the patients in need for systemic chemotherapy and/or immunotherapy., Methods: Patients from the prospective NF10 study (NCT02904577) with newly diagnosed MZL and receiving frontline systemic therapy at diagnosis or after observation were used to train a prognostic model. The primary endpoint was progression-free survival (PFS) from start of treatment. The model was externally validated in a pooled analysis of two independent cohorts from the University of Iowa and Mayo Clinic Molecular Epidemiology Resource and the University of Miami., Findings: We identified 501 eligible patients. After multivariable modeling, lactate dehydrogenase (LDH) above upper normal limit, hemoglobin <12 g/dL, absolute lymphocyte count <1 × 10 9 /L, platelets <100 × 10 9 /L, and MZL subtype (nodal or disseminated) were independently associated with inferior PFS. The proposed MZL International Prognostic index (MZL-IPI) combined these 5 factors, and we defined low (LRG, 0 factors, 27%), intermediate (IRG, 1-2 factors, 57%) and high (HRG, 3+ factors, 16%) risk groups with 5-y PFS of 85%, 66%, and 37%, respectively (c-Harrell = 0.64). Compared to the LRG, the IRG (Hazard Ratio [HR] = 2.30, 95% CI 1.39-3.80) and HRG (HR = 5.41, 95% CI 3.12-9.38) had inferior PFS. Applying the MZL-IPI to the pooled US cohort (N = 353), 94 (27%), 192 (54%), and 67 (19%) patients were classified as LRG, IRG, and HRG, respectively, and the model was validated for PFS (log-rank test p = 0.0018; c-Harrell = 0.578, 95% CI 0.54-0.62). The MZL-IPI was also prognostic for OS in both the training and the external validation sets., Interpretation: MZL-IPI is a new prognostic score for use in all patients with MZL considered for systemic treatment., Funding: The MER was supported by P50 CA97274 and U01 CA195568., Competing Interests: LA: Grants or contracts from any entity: My First AIRC grant n. 11,415 2012–2014; Investigator Grant AIRC (2018–2022); Honoraria: EUSA Pharma, Novartis. Participation on a Data Safety Monitoring Board or Advisory Board Roche, Janssen-Cilag, Verastem, Incyte, EUSA Pharma, Celgene/Bristol Myers Squibb, Kite/Gilead, ADC Therapeutics, Novartis; Support for attending meetings and/or travel: Roche. CB: Grants or contracts from any entity: INSERM, AvieSan ITMO Cancer, LYSA/ELI: Bertrand Coiffier Prize Institut Servier; Consulting fees: Currety; Support for attending meetings and/or travel: Mayo Clinic. JPA: Grants or contracts from any entity: Lymphoma Research Foundation, US Department of Defense; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: ADC Therapeutics, Regeneron, Genentech. MM: Support for attending meetings and/or travel: Janssen. MJM: Grants or contracts from any entity: BMS, Roche, GenMab; Consulting fees: BMS; Participation on a Data Safety Monitoring Board or Advisory Board: AstraZeneca. CV: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Janssen, Lilly, Novartis, Gilead, Takeda, Kyowa-Kirin, Roche, Astra Zeneca, Beigene, Gentili. BKL: Grants or contracts from any entity: Roche/Genentech, Seattle Genetics, Genmab, AstraZeneca. OA: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Roche, Janssen, Beigene, Ely Lilli, Amgen, Sanofi. AP: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Roche, Msd, Pfizer, Sandoz, Takeda, Gilead, Bms, Janssen, Beigene; Participation on a Data Safety Monitoring Board or Advisory Board: Takeda, Roche. TMH: All support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.): Lymphoma SPORE NCI CA 97274; Participation on a Data Safety Monitoring Board or Advisory Board: Seagen, Eli Lilly & Co. LM: Other financial or non-financial interests: Scientific consultant for Sandoz spa, 2022–2023, free of fee. JRC: All support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.): National Cancer Institute, Grants P50 CA97274 and U01 CA195568 (to Mayo); Grants or contracts from any entity: BMS, Genentech, and Genmab; Participation on a Data Safety Monitoring Board or Advisory Board and SMC member: Protagonist Therapeutics. SL: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Roche, Novartis, Incyte, BMS, Kite, Regeneron, Abbvie, Genmab, Sobi, Beigene; Support for attending meetings and/or travel: Roche, Beigene, Regeneron. NF, MEN, VT, SF, SR, AT, RM, AK, RM, MD, EC, FR, ALF, MDT, MS, AJMF, CS, EP, SH, IMR, ISL: no COI., (© 2024 The Author(s).)

Mantle cell lymphoma (MCL) prognosis has significantly improved in recent years; however, the possible survival benefit of new treatment options should be evaluated outside of clinical trials. We investigated 73 consecutive MCL patients managed from 2006 to 2020. For younger patients <65 years old, the median PFS was 72 months and we reported a 2-year, 5-year, and 10-year PFS of 73%, 62%, and 41%; median OS was not reached and we reported a 2-year, 5-year, and 10-year OS of 88%, 82%, and 66%. For patients aged 75 years or older, the median PFS was 36 months and we reported a 2-year, 5-year, and 10-year PFS of 52%, 37%, and 37%; median OS was not reached and we reported a 2-year, 5-year, and 10-year OS of 72%, 55%, and 55%. The median PFS was significantly reduced for patients treated between 2006 and 2010 compared to patients treated between 2011 and 2015 ( p = 0.04). Interestingly, there was a trend towards improved OS for patients treated between 2016 and 2020 compared to between 2006 and 2010 and between 2011 and 2015 (5-year OS was 91%, 44%, and 33%). These findings could be due to the introduction of BR as a first-line regimen for elderly patients and to the introduction of ibrutinib as a second-line regimen.

Data on primary cutaneous lymphomas (PCLs) patients in the Italian population are limited, and, despite the existence of several treatment options, the management of those patients remains challenging. Our study aimed to investigate the clinical and therapeutic features of PCL patients in a referral center in Italy. We conducted a retrospective study on 100 consecutive PCL patients between January 2017 and December 2022. The mean (SD) age of our cohort was 70.33 (14.14) years. Cutaneous T-cell lymphomas (CTCLs) represented 65% of all cases; the majority were mycosis fungoides (42%), followed by cases of Sezary syndrome (10%) and primary cutaneous anaplastic large cell lymphoma (4%). Cutaneous B-cell lymphomas (CBCLs) accounted for 35 % of PCLs, with 15 cases of primary cutaneous follicle center lymphoma, 10 cases of primary cutaneous diffuse large B-cell lymphoma leg type, and 9 cases of marginal zone B-cell lymphoma. A higher frequency of pruritus ( p = 0.008) and higher peripheral blood levels of beta-2 microglobulin ( p ≤ 0.001) and lactate dehydrogenase ( p = 0.025) were found in CTCLs compared to those of CBCLs. Considering all therapeutic lines performed, treatments were extremely heterogeneous and skin-directed therapies represented the most frequently used approach. Our study confirms the distribution of PCL subtypes formerly reported in the literature and highlights the utility of real-life data in treatments to improve the current management of PCL patients.

The variability in disease outcome for indolent non-Hodgkin lymphomas (iNHL) and mantle-cell lymphoma (MCL) could be related to single nucleotide polymorphisms (SNPs) in genes that affect immune and inflammatory response. We investigated SNPs that could have a prognostic role for patients receiving bendamustine and rituximab (BR). All samples were genotyped for the IL-2 (rs2069762), IL-10 (rs1800890, rs10494879), VEGFA (rs3025039), IL-8 (rs4073), CFH (rs1065489) and MTHFR (rs1801131) SNPs by allelic discrimination assays using TaqMan SNP Genotyping Assays. We report a long-term follow-up analysis of 79 iNHL and MCL patients that received BR. Overall response rate was 97.5% (CR rate 70.9%). After a median follow-up of 63 months, median PFS and OS were not reached. We report a significant association between SNP in IL-2 (rs2069762) and reduced PFS and OS ( p <.0001). We suggest a role for cytokine SNPs in disease outcome, while SNPs seem not related to long-term toxicity or secondary malignancies.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the most commonly used regimen for the upfront treatment of diffuse large B-cell lymphoma (DLBCL). However, it is associated with cardiotoxicity, especially in older patients. Substituting doxorubicin with non-PEGylated liposomal doxorubicin (R-COMP) may reduce the risk of cardiac events, but its efficacy has never been demonstrated in prospective trials. We describe the characteristics and outcome of patients with DLBCL aged ≥65 years prospectively enrolled in the Elderly Project by the Fondazione Italiana Linfomi and treated with full doses of R-CHOP or R-COMP per local practice. Starting from 1163 patients, 383 (55%) were treated with R-CHOP and 308 (45%) with R-COMP. Patients treated with R-COMP were older (median age, 76 vs 71 years), less frequently fit at simplified geriatric assessment (61% vs 88%; P < .001), and had a more frequent baseline cardiac disorders (grade >1, 32% vs 8%; P < .001). Three-year progression-free survival (PFS) was similar between R-CHOP and R-COMP (70% and 64%); 3-year overall survival was 77%, and 71% respectively. R-CHOP was associated with better PFS vs R-COMP only in the Elderly Prognostic Index (EPI) low-risk group. The two groups had similar rates of treatment interruptions due to toxicities or of cardiac events (P = 1.00). We suggest R-COMP is a potentially curative treatment for older patients with intermediate- or high-risk EPI, even in the presence of a baseline cardiopathy. R-CHOP is confirmed as the standard therapy for low risk patients., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)