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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]

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.)

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).)

Several studies have strengthened the link between the gut microbiota (GM) and the response to immunotherapy in patients with tumors, highlighting the potential role of GM as a biomarker of response. Targeted therapies including B-cell receptor (BCR) inhibitors (BCRi) represent the newest approach to the treatment of chronic lymphocytic leukemia (CLL); however, not all patients achieve a satisfactory response, and immune-related adverse events (irAEs) can also impact the efficacy. The aim of the study was to compare GM biodiversity in patients with CLL, treated with BCRi for at least 12 months. Twelve patients were enrolled: 10 patients in the responder group (R) and 2 patients in the non-responder group (NR). We identified seven patients (58.3%) who experienced adverse reactions (AE). Although we did not observe a significant difference across the study population in terms of relative abundance and alpha and beta diversity, we found a differing distribution of bacterial taxa between the analyzed groups. We noted a higher level of the class Bacteroidia and the order Bacteroidales in the R group, and an inversion in the Firmicutes and Bacteroidetes ratio in the AE group. No prior studies have focused on linking GM and response to BCRi in these patients. Although the analyses are preliminary, they provide suggestions to guide future research.

Early therapies to prevent severe COVID-19 have an unclear impact on patients with hematological malignancies. The aim of this study was to assess their efficacy in this group of high-risk patients with COVID-19 in preventing hospitalizations and reducing the SARS-CoV-2 shedding. This was a single-center, retrospective, observational study conducted in the Fondazione IRCSS Policlinico San Matteo of Pavia, Northern Italy. We extracted the data of patients with hematologic malignancies and COVID-19 who received and did not receive early COVID-19 treatment between 23 December 2021, and May 2022. We used a Cox proportional hazard model to assess whether receiving any early treatment was associated with lower rates of hospitalization and reduced viral shedding. Data from 88 patients with hematologic malignancies were extracted. Among the patients, 55 (62%) received any early treatment, whereas 33 (38%) did not. Receiving any early therapy did not significantly reduce the hospitalization rate in patients with hematologic malignancies (HR 0.51; SE 0.63; p -value = 0.28), except in the vaccinated non-responders subgroup of patients with negative anti SARS-CoV-2 antibodies at the time of infection, who benefited from early therapies against SARS-CoV-2 (HR 0.07; SE 1.04; p -value = 0.001). Moreover, no difference on viral load decay was observed. In our cohort of patients with hematologic malignancies infected with SARS-CoV-2, early treatment were not effective in reducing the hospitalization rate due to COVID-19, neither in reducing its viral shedding.

Purpose: We prospectively treated patients with hepatitis C virus (HCV)-associated indolent lymphomas with genotype-appropriate direct-acting antivirals (DAAs) with the aim to evaluate virologic and hematologic outcomes. No prospective studies in this setting have been published so far., Methods: FIL&#95;BArT is a prospective, multicenter, phase II trial that evaluated genotype-appropriate DAAs in untreated HCV-positive patients with indolent lymphomas without criteria for immediate conventional antilymphoma treatment. The primary objective was sustained virologic response, whereas the main secondary objectives were overall response rate of lymphoma and progression-free survival., Results: Forty patients were enrolled, including 27 with marginal zone lymphoma. Median age was 68 years. Extranodal sites were involved in 14 cases (35%). Main genotypes were 1 in 16 patients and 2 in 21 patients. All patients received genotype-guided DAAs: 17 ledipasvir/sofosbuvir, eight sofosbuvir plus ribavirin, and 15 sofosbuvir/velpatasvir. All patients achieved sustained virologic response (100%). DAAs were well tolerated, with only two grade 3-4 adverse events. Overall response rate of lymphoma was 45%, including eight patients (20%) achieving complete response and 10 (25%) partial response, whereas 16 exhibited stable disease and six progressed. With a median follow-up of 37 months, two patients died (3-year overall survival 93%; 95% CI, 74 to 98) and three additional patients progressed, with a 3-year progression-free survival of 76% (95% CI, 57 to 87)., Conclusion: HCV eradication by DAAs was achieved in 100% of HCV-positive patients with indolent lymphomas not requiring immediate conventional treatment and resulted in non-negligible rate of lymphoma responses. Treatment with DAAs should be considered as the first-line therapy in this setting.

Cryoglobulinemic Vasculitis (CV) is an autoimmune/lymphoproliferative disorder associated with HCV infection that in 5%-10% of cases evolves into a B cell Non-Hodgkin's Lymphoma (NHL). B-cell activating factor (BAFF) is a key regulator in B-cell development and survival. Particular genetic variants are responsible for BAFF signaling impairment in autoimmune and neoplastic diseases. We evaluated BAFF and BAFF-receptor (BAFF-R) polymorphisms in order to determine if they predispose to HCV-related CV and NHL. The analysis was performed on 416 HCV-chronically infected patients: 136 HCV without signs/symptoms of lymphoproliferations/autoimmunity (HCV), 166 HCV with CV (HCV-CV) and 114 HCV with NHL (HCV-NHL). Rs9514828 SNP on BAFF promoter, rs61756766 on BAFF-R and rs12428930 on the BAFF gene were evaluated by Real-Time PCR. Concerning rs9514828, the frequency of C/T genotype was significantly higher in HCV-CV than in HCV. The difference in the distribution of the T/T mutant genotype in HCV-CV compared to HCV was significant as well as the distribution of C/T and T/T genotype in HCV-NHL versus HCV. T minor allele was more frequent in HCV-NHL and HCV-CV than in HCV. The distribution of C/T + T/T (for the dominant model of penetrance C/T + T/T vs. C/C) was significantly higher in HCV-CV and HCV-NHL than in HCV. Genotyping of rs61756766 on BAFF-R coding gene, revealed C/T heterozygosis at a frequency of 11% in HCV-NHL versus 3% in HCV. The T minor allele frequency was higher in HCV-NHL than in HCV. No differences emerged by genotyping rs12428930 SNP on BAFF coding gene. Our results reinforce the hypothesis that BAFF/BAFF-R genetic pattern has a role in the pathogenesis of HCV-related lymphoproliferations. BAFF/BAFF-R variants could identify a risk haplotype for HCV related CV and NHL and a BAFF/BAFF-R genetic profile assessment could potentially contribute to tailoring anti-BAFF therapy by identifying patients with BAFF alterations in which the treatment could be more beneficial., (© 2022 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

Introduction : Marginal zone lymphoma (MZL) is a heterogeneous disease with a wide range of possible frontline therapies depending on the subtype; there are no shared guidelines for the treatment of relapsed/refractory MZLs. The growing evidence of the importance of the BCR pathway in the pathogenesis of B lymphoproliferative forms has led researchers to consider BTK as a potential therapeutic target in MZL. Area covered : The authors provide the reader with an evaluation of ibrutinib as a treatment option for refractory marginal zone lymphoma. The review includes an overview of the drug's pharmacokinetics and pharmacodynamics, efficacy, and safety. The authors also provide the reader with their expert perspectives on the drug and its place in the treatment of MZL. Expert opinion : The availability of new non-chemotherapeutic agents represents an important opportunity to spare excessive exposure to cytotoxic compounds. Immunomodulators and targeted agents, alone or often in combination with immunotherapy, have been shown to be effective and safe therapies in patients with relapsed/refractory (R/R) MZL. In addition, numerous studies involving new generation targeted agents, alone or in combination, are currently active in both R/R and untreated patient populations, some with encouraging preliminary results.