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Background: When a hematological malignancy is diagnosed, the whole family carries the burden of the disease; parents often try to protect minor children from suffering by avoiding communication about their disease. Since 2009, patients with minors at the Adult Hematology Division at San Gerardo Hospital (Monza) can take part in the "Emanuela Project": children can visit parents and talk with psychologists and hematologists, who explain the disease through simple metaphors., Materials and Methods: The EMY STUDY aimed to evaluate the impact of illness-related communication on children's behavior, comparing Monza's experience with other Hematology Units, where the communication is delegated to parents or psychological support. Questionnaires exploring the children's main behaviors (school performance, appetite, sleeping patterns, attachment to family figures, and family dialogue) were administered to both sick (SP) and healthy (HP) parents. From 2017 to 2021, 32 patients were enrolled, 20 from Monza and 12 from other hospitals; 84 questionnaires were globally collected., Results: In Monza's group, no major changes in children's behavior were observed and an open dialogue about the disease was often possible. Disease communication is considered crucial and perceived as a responsibility of parents together with a professional figure, mainly the hematologist. Patients were satisfied with "Emanuela Project," reporting positive effects on doctor-patient relationship. Difficulties in separation were significantly higher at other hospitals (P = .019) than in Monza. While at other centers communication is considered parents' responsibility, Monza's patients emphasize the role of professional figures (P = .007). Differently from other hospitals, the role of the hematologist is crucial to Monza's patients (P = .001)., Conclusion: Disease communication to patients' offspring is a crucial moment in the process of care, and the hematologist can play a major role in this difficult task, with potential positive effects both on children's well-being and on doctor-patient relationship., (© The Author(s) 2024. Published by Oxford University Press.)

Mantle cell lymphoma (MCL) is a rare lymphoproliferative neoplasm considered incurable, with a median survival of 3-5 years. In recent years, Bruton's tyrosine kinase inhibitors (BTKi) have been introduced, demonstrating high therapeutic activity. However, the prognosis for MCL patients failing ibrutinib therapy is particularly poor, with a survival expectation of a few months. In this phase II trial, we assessed the efficacy and safety of the carfilzomib-lenalidomide-dexamethasone (KRD) combination in MCL patients who were relapsed/refractory (R/R) or intolerant to BTKi and in need of treatment. The primary objective of the study was to evaluate the antitumor efficacy of the KRD combination in terms of 12-month overall survival (12-month OS). From September 2019 to December 2020, 16 patients were enrolled from 11 Italian centers. After a median follow-up of 2.37 months (95% CI 0.92-6.47), the 12-month OS was 13%. The rate of grade 3-4 adverse events (AEs) was 35%, and the overall response rate (ORR) was 19%. These results led to the premature termination of enrollment, as defined in the protocol stopping rules. The efficacy of the KRD combination in advanced-stage MCL patients who are R/R to BTKi is unsatisfactory and too toxic., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

This real-world prospective observational study across 21 Italian centers (CART-SIE) compares axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) outcomes in 485 patients with relapsed/refractory large B-cell lymphoma with baseline characteristics matched by stabilized inverse propensity score weighting. Axi-cel versus tisa-cel had higher all-grade cytokine release syndrome (78.6% vs. 89.3%, P = 0.0017) and neurotoxicity (9.9% vs. 32.2%, P < 0.0001) but also superior progression-free survival (PFS) at 1 year (46.5% vs. 34.1%, P = 0.0009). Even among patients who failed bridging therapy, axi-cel PFS was superior to tisa-cel (37.5% vs. 22.7%, P = 0.0059). Differences in overall survival and high-grade immune toxicities were not significant. The CAR-HEMATOTOX score not only predicted hematologic toxicity but also 1-year survival outcomes (51.5% in CAR-HEMATOTOX high vs. 77.2% in CAR-HEMATOTOX low, P < 0.0001). Twenty patients developed second primary malignancies, including two cases of T-cell neoplasms. These findings enable more informed selection of anti-CD19 CAR T-cell therapy, balancing bridging, safety, and efficacy considerations for individual patients. Significance: The findings of this study on 485 patients with relapsed/refractory large B-cell lymphoma treated with commercial axi-cel and tisa-cel indicate axi-cel's superior PFS after propensity score weighting. The predictive utility of CAR-HEMATOTOX in assessing not only toxicity but also outcomes across both CAR T-cell products may guide future risk-stratified management strategies., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: The role of consolidation radiotherapy in patients with primary mediastinal B-cell lymphoma (PMBCL) is controversial., Methods: The IELSG37 trial, a randomized noninferiority study, aimed to assess whether irradiation can be omitted in patients with PMBCL with complete metabolic response (CMR) after induction immunochemotherapy. The primary end point was progression-free survival (PFS) at 30 months after random assignment. Patients with CMR were randomly assigned to observation or consolidation radiotherapy (30 Gy). With a noninferiority margin of 10% (assuming a 30-month PFS of 85% in both arms), a sample size of 540 patients was planned with 376 expected to be randomly assigned., Results: The observed events were considerably lower than expected; therefore, primary end point analysis was conducted when ≥95% of patients were followed for ≥30 months. Of the 545 patients enrolled, 268 were in CMR after induction and were randomly assigned to observation (n = 132) or radiotherapy (n = 136). The 30-month PFS was 96.2% in the observation arm and 98.5% in the radiotherapy arm, with a stratified hazard ratio of 1.47 (95% CI, 0.34 to 6.28) and absolute risk difference of 0.68% (95% CI, -0.97 to 7.46). The 5-year overall survival (OS) was 99% in both arms. Nonrandomized patients were managed according to local policies. Radiotherapy was the only treatment in 86% of those with Deauville score (DS) 4 and in 57% of those with DS 5. The 5-year PFS and OS of patients with DS 4 (95.8% and 97.5%, respectively) were not significantly different from those of randomly assigned patients. Patients with DS5 had significantly poorer 5-year PFS and OS (60.3% and 74.6%, respectively)., Conclusion: This study, the largest randomized trial of radiotherapy in PMBCL, demonstrated favorable outcomes in patients achieving CMR with no survival impairment for those omitting irradiation.

URBAN is a multicentric, ambispective study evaluating the effectiveness and safety of obinutuzumab-based immuno-chemotherapy and maintenance in patients with untreated advanced follicular lymphoma (FL). The study began before the COVID-19 emergency declaration in Italy. It is currently ongoing for follow-up, and the enrolment timeline encompassed different stages of the pandemic, various vaccination roll-out phases and prevalence of SARS-CoV-2 variants. Outcomes of interest of the present sub-analysis included SARS-CoV-2 infection rates and COVID-19-related hospitalizations/deaths. At data cut-off, 86 (28.8%) and 213 patients (71.2%) were treated before and during/after the COVID-19 outbreak respectively; 294 (98.3%) completed the induction, 31 (10.4%) completed maintenance and 170 (56.9%) were still on maintenance. Overall, 245 patients (81.9%) received at least one SARS-CoV-2 vaccine dose: 13.5%, 31.4% and 55.1% received one, two and three doses respectively. We observed a substantial decrease in COVID-19-related mortality rates in pre- versus post-vaccination phases, along with a reduction in COVID-19-related outcomes due to the shift from alpha/delta to omicron variant predominance. No differences emerged between patients given maintenance or not, although the schedule was modified in 65% of cases. To our knowledge, URBAN represents the largest dataset of COVID-19-related outcomes in FL patients extensively exposed to obinutuzumab. ClinicalTrials.gov identifier: NCT04034056., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

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.)

Daratumumab-based regimens are the new standard of care for newly diagnosed patients with AL amyloidosis based on the results of the ANDROMEDA study. However, real-world data on daratumumab efficacy in upfront therapy in unselected patients are scanty. In the framework of a prospective observational study, we investigated the efficacy and safety of daratumumab in 88 newly diagnosed patients, including subjects with IIIb cardiac stage (26%) or myeloma defining events (29%). Daratumumab was administered with bortezomib in 50 (56%) patients, lenalidomide in 31 (35%), and monotherapy in 7 (8%). The rate of serious adverse events was low (16%). The overall hematologic response rate was 75% with 52 (59%) patients attaining at least a very good partial response (VGPR) at six months. Amongst patients evaluable for organ response, the rate of cardiac and renal responses at 6 months was 31% and 21%, respectively. Comparing stage IIIb patients with the remaining ones, the rate of profound hematologic response was not significantly different (≥VGPR 57% vs. 59%, p 0.955) likewise the rate of cardiac (33% vs. 30%, p 0.340) and renal (40% vs. 16%, p 0.908) responses. Daratumumab-based regimens demonstrated to be safe and effective in treatment-naïve AL amyloidosis even in advanced stage disease., (© 2024 John Wiley & Sons Ltd.)

Hepatitis C virus (HCV)-associated diffuse large B-cell lymphoma (DLBCL) displays peculiar clinicopathological characteristics, but its molecular landscape is not fully elucidated. In this study, we investigated the clinicopathological and molecular features of 54 patients with HCV-associated DLBCL. The median age was 71 years. An underlying marginal zone lymphoma component was detected in 14.8% of cases. FISH analysis showed rearrangements involving BCL6 in 50.9% of cases, MYC in 11.3% and BCL2 in 3.7%. Lymph2Cx-based assay was successful in 38 cases, recognizing 16 cases (42.1%) as ABC and 16 cases as GCB subtypes, while six resulted unclassified. ABC cases exhibited a higher lymphoma-related mortality (LRM). Next-generation sequencing analysis showed mutations in 158/184 evaluated genes. The most frequently mutated genes were KMT2D (42.6%), SETD1B (33.3%), RERE (29.4%), FAS and PIM1 (27.8%) and TBL1XR1 (25.9%). A mutation in the NOTCH pathway was detected in 25.9% of cases and was associated with worst LRM. Cluster analysis by LymphGen classified 29/54 cases within definite groups, including BN2 in 14 (48.2%), ST2 in seven (24.2%) and MCD and EZB in four each (13.8%). Overall, these results indicate a preferential marginal zone origin for a consistent subgroup of HCV-associated DLBCL cases and suggest potential implications for molecularly targeted therapies., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT., Methods: The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II-IV mantle cell lymphoma, aged 18-65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m 2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m 2 on day 1, intravenous doxorubicin 50 mg/m 2 on day 1, intravenous vincristine 1·4 mg/m 2 on day 1, and oral prednisone 100 mg on days 1-5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m 2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, intravenous cytarabine 2 × 2 g/m 2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m 2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m 2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1-19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov, NCT02858258., Findings: Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84-92) versus 72% (67-79; hazard ratio 0·52 [one-sided 98·3% CI 0-0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67-79) versus 86% (82-91; hazard ratio 1·77 [one-sided 98·3% CI 0-3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3-5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3-5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238)., Interpretation: Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined., Funding: Janssen and Leukemia & Lymphoma Society., Competing Interests: Declaration of interests MD reports research grants for clinical studies from AbbVie, Bayer, Bristol-Myers Squibb/Celgene, Gilead/Kite, Janssen, and Roche; speakers' honoraria from AstraZeneca, BeiGene, Gilead/Kite, Janssen, Lilly, Novartis, and Roche; travel support from Janssen and Roche; and participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead/Kite, Janssen, Lilly/Loxo Oncology, Novartis, and Roche. JDo reports payment for expert testimony (once Advisory Board) from Lilly. EG reports grants from Janssen; honoraria (educational lecture) from Genmab, Gilead, Janssen, and Lilly; support for attending meetings or travel from Janssen and Roche; and participation on a Data Safety Monitoring Board or Advisory Board for Gilead/Kite and Miltenyi Biotec. MJ reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Gilead/Kite, and Roche; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Gilead/Kite, Janssen, and Pierre Fabre. JW reports grants to his institution from GlaxoSmithKline/Novartis and Roche; honoraria for lectures from AbbVie, Amgen, Gilead, Novartis, Roche, Servier, and Takeda; participation on an Advisory Board from AbbVie, Gilead, Novartis, Roche, and Takeda. MHu reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, Celgene, Genmab, Janssen, Merck, Roche, and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, AstraZeneca, Celgene, Genmab, Janssen, Merck, Roche, and Takeda. UM reports travel support from Amgen, Bristol-Myers Squibb/Celgene, Gilead, Janssen-Cilag, and Roche; Advisory Board role for Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen-Cilag, Novartis, Pfizer, Roche, Sanofi, and Takeda; participation in national Guideline committee for the German-Swiss-Austrian Guideline for Mantle Cell Lymphoma. JR reports participation on an Advisory Board for AstraZeneca. VV reports consulting fees from AbbVie, BeiGene, Gilead, Lilly, and Roche; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Janssen; payment for expert testimony from Gilead and Roche; support for attending meetings or travel from AbbVie and Gilead. MGdS reports a research grant from AstraZeneca; payment for Advisory Boards from AbbVie, Gilead, Janssen-Cilag, Roche, and Takeda; payment or honoraria for educational events from Gilead and Janssen-Cilag; support for attending meetings or travel from AbbVie, Janssen-Cilag, Roche, and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for Roche; leadership in a scientific society (Sociedade Portuguesa de Hematologia); administration board on a patient advocacy group (Associação Portuguesa Contra a Leucemia). SL reports grants or contracts to her institution from Bristol-Myers Squibb/Celgene, Genmab, HUTCHMED, Novartis, and Roche; consulting fees from AbbVie, Genmab, Gilead, Novartis, ORION Pharma, Roche, and Swedish Orphan Biovitrum (sobi); payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead, Incyte, and Novartis; participation on a Data Safety Monitoring Board or Advisory Board for Incyte. StS reports grants or contracts from any entity from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; consulting fees from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; support for attending meetings or travel from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; receipt of equipment, materials, drugs, medical writing, gifts, or other services from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem. AK reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Bristol-Myers Squibb/Celgene, Novartis, Roche, Swedish Orphan Biovitrum (sobi), and Takeda; support for attending meetings or travel from AbbVie, BeiGene, EUSA Pharma, Swedish Orphan Biovitrum (sobi), and Takeda. RJ reports travel support for meeting attendance from BeiGene; meeting fee from Janssen. GH reports grants or contracts for clinical research from AbbVie, Gilead/Kite, Incyte, Janssen, MorphoSys, Pfizer, and Roche; consulting fees from AbbVie, ADC Therapeutics, AstraZeneca, Bristol-Myers Squibb, Genmab, Gilead/Kite, Incyte, Janssen, Lilly, Miltenyi Biotec, Novartis, and Roche; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, BeiGene, Bristol-Myers Squibb, Genmab, Gilead, Incyte, Janssen, Lilly, and Roche; support for attending meetings or travel from Gilead/Kite and Janssen; participation on a Data Safety Monitoring Board or Advisory Board for Miltenyi Biotec. CV reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, BeiGene, Bristol-Myers Squibb, Gilead/Kite, Incyte, Istituto Gentili, Janssen, Lilly, Novartis, Pfizer, Roche, and Servier; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Bristol-Myers Squibb, Incyte, Janssen, Lilly, Pfizer, and Roche. TvM reports payment or honoraria for educational lectures from Bristol-Myers Squibb/Celgene, Gilead/Kite, Janssen, and Lilly; participation on a Data Safety Monitoring Board or Advisory Board for GE HealthCare and Gilead/Kite. SW reports payment to his institution from AbbVie, Stemline Therapeutics, and Takeda; payment for expert testimony from Stemline Therapeutics; support for attending meetings or travel from AbbVie and BeiGene; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Astra Zeneca, Roche, and Stemline Therapeutics. PLZ reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, BeiGene, Bristol-Myers Squibb, Gilead, Incyte, Janssen, Kyowa Kirin, Merck Sharp and Dohme, Novartis, Roche, Swedish Orphan Biovitrum (sobi), and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, BeiGene, Bristol-Myers Squibb, Gilead, Incyte, Janssen, Kyowa Kirin, Merck Sharp and Dohme, Novartis, Roche, Swedish Orphan Biovitrum (sobi), and Takeda. UN reports consulting fees to his institution from AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen-Cilag, Kyowa Kirin, Novartis, Pierre Fabre, Roche, and Takeda; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events to his institution from Bristol-Myers Squibb/Celgene, Gilead, Novartis, and Takeda; support for attending meetings or travel from Janssen, Gilead, Roche, and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen-Cilag, Kyowa Kirin, Novartis, Pierre Fabre, Roche, and Takeda. CH reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bristol-Myers Squibb, Janssen, and Pfizer; support for attending meetings or travel from AbbVie and Janssen. MHa reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Falk Foundation, Gilead, Novartis, and Swedish Orphan Biovitrum (sobi); payment for expert testimony from Amgen, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen, Novartis, Pizer, Roche, Sanofi-Aventis, and Swedish Orphan Biovitrum (sobi). WK reports research grants provided to his institution from Amgen, Janssen, Roche, and Takeda. DG reports support for attending meetings and travel from Janssen. CS reports consulting fees from Bristol-Myers Squibb and Janssen; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca and Bristol-Myers Squibb; support for attending meetings or travel from Gilead/Kite. MU reports institutional funding of the TRIANGLE trial from Janssen. ML reports consulting fees from AstraZeneca, BeiGene, Janssen, and Lilly; honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, BeiGene, Janssen, and Lilly; participation on a Data Safety Monitoring Board with Acerta. All other authors (MT, OS, LJ, MC, LA, PH, FB, KS, JDi, CP, and EH) declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Classical Hodgkin lymphoma is a lymphoproliferative disease with a good prognosis mainly seen in young people. Nevertheless secondary malignancy, cardiac disease and infertility may affect the long survivors with significant impact on quality of life, morbidity and overall survival. In the last decades several treatment strategies were evaluated to reduce the toxicity of first line treatment such as avoiding radiotherapy or its reduction in terms of dosage and extension. Many trials including interim Positron Emission Tomography evaluation fail to compare efficacy between combined modality treatment versus chemotherapy alone in particular in early stage disease. In this review we analyze which subset of patients could take advantage from proton therapy in terms of toxicity and cost effectiveness., (© 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).)

Abstract: Large B-cell lymphoma (LBCL) carrying MYC rearrangement, alone or together with BCL2 and/or BCL6 translocations, have shown a poor prognosis when treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the HIV population. Scanty data are available on the prevalence and prognostic impact of MYC rearrangements in HIV-associated LBCL. We conducted a retrospective study to evaluate the clinical effect of MYC rearrangement in HIV-associated LBCL. We evaluated clinical characteristics, treatment received, and outcome of LBCL in patients with HIV with MYC rearrangement (MYC+) and without MYC rearrangement (MYC-). A total of 155 patients with HIV who had received fluorescence in situ hybridization analysis for MYC were enrolled in 11 European centers: 43 with MYC+ and 112 MYC-. Among patients with MYC, 10 had double-/triple-hit lymphomas, and 33 had isolated MYC rearrangement (single-hit lymphoma). Patients with MYC+ had more frequently advanced stage, >2 extranodal site at presentation, and higher proliferative index. There were no significant differences in overall survival and progression-free survival (PFS) between the 2 groups. However, patients with MYC+ received more frequently intensive chemotherapy (iCT) (44%) than (R)CHOP alone (35%) or infusional treatment (DA-EPOCH-R and R-CDE) (19%). Among patients with MYC+, those who received iCT achieved a better outcome than patients who received nonintensive treatment (complete remission, 84% vs 52%; P = .028; 5-year PFS, 66% vs 36%; P = .021). Our retrospective results suggest that HIV-associated LBCL with MYC+ could be considered for an intensive therapeutic approach whenever possible, whereas (R)CHOP seems to give inferior results in this subset of patients in terms of complete remission and PFS., (© 2024 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.)

Objective: Human papillomavirus (HPV) persistence is considered the main risk factor for neoplastic progression, and evidence suggests that regulatory T cells play an important role in the failure of viral elimination. Regulatory T cells may be involved in maintaining a microenvironment favourable for viral persistence and neoplasticity, through a deregulation of the local immune response. The association between altered immune function and the development of chronic infections, cancer (solid and haematological), and autoimmune diseases is documented in the literature. The purpose of this retrospective analysis was to evaluate the possible correlation between HPV cervical infection and lymphoma incidence in women attending colposcopy due to an abnormal Pap smear during a period of 15 years., Design: This is a cross-sectional study., Participants: We investigated retrospectively the incidence of haematological diseases in women aged 21-84 with an abnormal Pap smear who referred to our centre between 2004 and 2019., Setting: This study was conducted at the university hospital., Methods: In our analysis, we included women with diagnoses of HL and NHL after the detection of abnormal Pap smears and HPV infections. We excluded patients with a diagnosis of lymphoma preceding the date of the abnormal Pap smear and HPV test., Results: We divided the patients into two groups in order to analyse the standard incidence ratio (SIR): HL patients (19/7,064, 0.26%) and NHL patients (22/7,064, 0.31%). In our sample, we reported a significant risk of developing lymphoma compared to the general population, both for HL and NHL disease, at age &lt;45 years. Regarding HL, the SIR of disease in women &lt;45 years was 4.886 (95% CI 2.775-9.6029) and in women between 45 and 59 years was 2.612 (95% CI 0.96-7.108804). On the other hand, for NHL in women &lt;45 years, we reported an SIR of about 3.007 (95%, CI 1.273-7.101575), in women aged 45-59 years, the SIR was 4.291 (95% CI 2.444-7.534399), and in women aged 60-74 years, the SIR was 3.283 (95% CI 1.054-10.22303)., Limitations: This retrospective analysis was conducted in a single centre in Northern Italy and did not consider all interregional differences existing in the country in terms of HPV genotypes, ethnicity, and population characteristics. Regarding the analysis of SIR for HL and NHL, we did not divide the disease into subtypes because of the small sample of cases. Finally, we considered in our analysis only women with an abnormal Pap smear and not the general population., Conclusions: Women with chronic and persistent HPV infections may have a higher relative risk of developing lymphoma. This possible association may be caused by the deregulation of the immune system response against HPV and the failure of viral clearance, especially in younger women., (© 2024 S. Karger AG, Basel.)

Hereditary thrombocytosis (HT) is a rare inherited disorder with clinical features resembling those of sporadic essential thrombocythemia. This study included 933 patients with persistent isolated thrombocytosis for whom secondary reactive causes were excluded. Of 933 patients screened, 567 were JAK2-mutated, 255 CALR-mutated, 41 MPL-mutated, 2 double-mutated, and 68 were triple-negative. Two patients carried germline non-canonical mutations in exon 10: MPL W515* and MPL V501A. One triple-negative patient carried another germline non-canonical MPL mutation outside exon 10: MPL R102P. As germline MPL mutations may be underlying causes of HT, we recommend screening patients with triple-negative isolated thrombocytosis for non-canonical MPL mutations. Although clear evidence concerning HT treatment is still lacking, individuals with HT should probably be excluded from cytoreductive treatment. Thus, an accurate diagnosis is pivotal in avoiding unnecessary treatments., Competing Interests: Conflict of Interest Disclosure The authors declare no competing financial interest., (Copyright © 2023 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Recent clinical studies demonstrated the achievement of lymphoma responses in patients with Hepatitis C virus-associated indolent lymphoproliferative disorders (LPD) receiving direct-acting antivirals (DAAs) as their sole treatment. However, the molecular mechanisms underlying LPD responses to DAAs are still poorly understood. In their paper the authors provide new molecular insights on this issue, reporting intraclonal diversification and persistence of B-cell clones in most cases, despite viral eradication and beneficial clinical outcome. These provocative data suggest that the achievement of molecular response is probably not required for a 'functional cure' of these patients. Further comprehensive immunogenetic and mutational studies would be fundamental to dissect this biological puzzle and, ultimately, to refine improved treatment strategies in this setting. Commentary on: Mazzaro et al. Persistence of monoclonal B-cell expansion and intraclonal diversification despite virus eradication in patients affected by hepatitis C virus-associated lymphoproliferative disorders. Br J Haematol 2023;203:237-243., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Background: The pathogenesis of eosinophilic dermatosis of hematologic malignancy (EDHM) is poorly understood. Previously thought to be a hypersensitivity reaction to insect bites, immune dysregulation and cytokine imbalance are now thought to be responsible. Its prognostic significance is unclear., Objective: To describe the clinical, pathological and immunological findings in a series of oncohematological patients with EDHM., Methods: An observational prospective cohort study of oncohematological patients receiving a diagnosis of EDHM between April 2017 and December 2018., Results: A total of 15 patients with EDHM (10 females and 5 males) were identified among 422 oncohematological patients. Disease presentation varied from firm erythematous papules to more polymorphic presentations. The lesions were most prevalent on the exposed sites, 8/15 patients recalled an insect bite. Lesion seasonality was reported in 13/15 patients. IgE levels were elevated in six patients, circulating IL-4 and IL-5 were within a normal range. Twelve out of 15 patients developed skin manifestations after chemotherapy. The infiltrate could be eosinophil-rich or lymphocytic-rich. Interestingly, the histopathologic findings were in accordance with arthropod bites., Conclusion: A role for insect bites in EDHM is supported by our findings. EDHM may be related to aggressive hematologic disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Michelerio, Tomasini, Fiandrino, De Amici, Varettoni, Defrancesco, Cavalloni, Brazzelli, Derlino, Paulli, Arcaini and Vassallo.)

In the Fondazione Italiana Linfomi MCL0208 phase 3 trial, lenalidomide maintenance (LEN) after autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL) improved progression-free survival (PFS) vs observation (OBS). The host pharmacogenetic background was analyzed to decipher whether single-nucleotide polymorphisms (SNPs) of genes encoding transmembrane transporters, metabolic enzymes, or cell-surface receptors might predict drug efficacy. Genotypes were obtained via real-time polymerase chain reaction of the peripheral blood germ line DNA. Polymorphisms of ABCB1 and VEGF were found in 69% and 79% of 278 patients, respectively, and predicted favorable PFS vs homozygous wild-type (WT) in the LEN arm was 3-year PFS of 85% vs 70% (P < .05) and 85% vs 60% (P < .01), respectively. Patients carrying both ABCB1 and VEGF WT had the poorest 3-year PFS (46%) and overall survival (76%); in fact, in these patients, LEN did not improve PFS vs OBS (3-year PFS, 44% vs 60%; P = .62). Moreover, the CRBN polymorphism (n = 28) was associated with lenalidomide dose reduction or discontinuation. Finally, ABCB1, NCF4, and GSTP1 polymorphisms predicted lower hematological toxicity during induction, whereas ABCB1 and CRBN polymorphisms predicted lower risk of grade ≥3 infections. This study demonstrates that specific SNPs represent candidate predictive biomarkers of immunochemotherapy toxicity and LEN efficacy after ASCT in MCL., (© 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.)

The Food and Drug Administration currently approves the combination of hypomethylating agents (HMA), azacytidine or decitabine with venetoclax (VEN) for acute myeloid leukemia (AML) patients aged more than 75 years and for patients unsuitable for intensive chemotherapy. The risk of fungal infection in the early phase of treatment is not negligible; therefore, posaconazole (PCZ) is commonly administered as primary prophylaxis. A drug-drug interaction between VEN and PCZ is well known, but the trend of serum levels of venetoclax when both drugs are overlapped is not clear. In total, 165 plasma samples from 11 elderly AML patients receiving combined treatment with HMA, VEN and PCZ were analyzed by a validated analytical method (high-pressure liquid chromatography-tandem mass spectrometry). Venetoclax trough plasma concentrations were detected during the 3 days of ramp-up as well as on day 7 and day 12 of treatment when the exposure as the area under the plasma concentration-time curve and the accumulation ratio were also calculated. The results were compared with the expected data for 400 mg/dose VEN administered alone-the confirmed high inter-individual variability in pharmacokinetics suggests the need for therapeutic drug monitoring.

Competing Interests: The authors have no conflicts of interest to disclose.

Castleman disease describes a group of heterogeneous clinicopathological disorders now included in the tumor-like lesions with B-cell predominance of the World Health Organization classification. Managing idiopathic multicentric Castleman disease (iMCD) is challenging, because few systematic studies or comparative randomized clinical trials have been conducted. International, consensus evidence-based guidelines for iMCD were published in 2018, but gaps in the therapeutic options for difficult-to-treat patients, who do not respond to siltuximab and other conventional therapies, still exist. This article presents the results of group discussion among an ad hoc constituted Panel of Italian experts to identify and address unmet clinical needs (UCNs) in managing iMCD. Recommendations on the appropriateness of clinical decisions and proposals for new research concerning the identified UCNs were issued through formalized multiple-step procedures after a comprehensive analysis of the scientific literature. The following key UCNs were addressed: strengthening the diagnostic certainty in iMCD patients before planning first-line therapy; management of siltuximab therapy; choice and management of immune-modulating, or chemotherapy agents in patients resistant/intolerant to siltuximab therapy. While most of the conclusions reached by the Panel are consistent with the existing guidelines, some alternative therapeutic options were stressed, and the discussion contributed to bringing forth the issues that need further investigation. Hopefully, this comprehensive overview will improve the practice of iMCD and inform the design and implementation of new studies in the field., Competing Interests: PLZ received a grant as speaker bureau from Celltrion, Gilead, Janssen-Cilag, BMS, Servier; MSD, AstraZeneca, Takeda, Roche, EUSA Pharma, Kyowa Kirin, Novartis, Incyte, Beigene; a consultant fee from MSD, EUSA Pharma, Novartis; and a grant for advisory board participation from Secura Bio, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Sandoz, MSD, AstraZeneca, Takeda, Roche, EUSA Pharma, Kyowa Kirin, Novartis, ADC Therap, Incyte, Beigene. LA received consulting or advisory role fees from Roche, Janssen-Cilag, Verastem, Incyte, EUSA Pharma, Celgene/Bristol Myers Squibb, Kite/Gilead, ADC Therapeutics. Speakers’ Bureau: EUSA Pharma, Novartis. Research funding: Gilead Sciences. EDT received a consulting and advisory board fee from EUSA Pharma. SF received speaker honoraria from Servier, Gentili, EUSA Pharma, and Janssen; grants for a consultancy from Janssen, EUSA Pharma; fee for advisory board participation from Janssen, EUSA Pharma, Incyte, and Clinigen; and research funding from Janssen, Gilead, and Morphosys. AF received a consulting fee from EUSA Pharma and an advisory board grant from Abbvie and SOBI. FF received fees for speaker bureau and advisory board participation from Celgene, Janssen-Cilag, BMS, GSK, Abbvie, EUSA Pharma, and Novartis. MM received a consultancy fee from Roche, Janssen, Novartis, Gilead, EUSA pharma, Takeda Incyte, BMS; and a grant for membership on an entity’s board or advisory committees from Roche, Celgene, Janssen, Sandoz, Novartis, Gilead, Servier, EUSA pharma, Takeda Incyte. ES, in the last 2 years, received grants for educational events and advisory board from EUSA Pharma and Novartis. RS received a consulting and advisory board fee from EUSA Pharma. All the other authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

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.

The gastrointestinal (GI) tract is the most common extranodal site of occurrence of non-Hodgkin lymphomas. Most GI lymphomas are of B-cell lineage, while T-cell lymphomas are less frequent. The aim of our retrospective study was to depict the clinical-pathological profile of a series of patients affected by intestinal T-cell lymphomas (ITCL) and possibly define hallmarks of these neoplasms. A total of 28 patients were included: 17 enteropathy-associated T-cell lymphomas (EATL), 5 monomorphic epitheliotropic T-cell lymphomas (MEITL), 3 indolent T-cell lymphoproliferative disorders of the gastrointestinal tract (ITCLDGT), and 3 intestinal T-cell lymphomas not otherwise specified (ITCL-NOS). Celiac disease (CD) was diagnosed in around 70% of cases. Diagnosis of EATL showed a significant correlation with CD30 expression, whereas MEITL with angiotropism and CD56 positivity. ITCLDGT cases showed plasma cells infiltration. Peripheral lymphocytosis, the absence of a previous diagnosis of CD, an advanced Lugano clinical stage, and the histological subtype ITCL-NOS were significantly associated with worse survival at multivariate analysis. Our findings about the epidemiological, clinical, and histopathological features of ITCL were in line with the current knowledge. Reliable prognostic tools for these neoplasms are still lacking but according to our results lymphocytosis, diagnosis of CD, Lugano clinical stage, and histological subtype should be considered for patient stratification.

Up to 10%-15% of diffuse large B-cell lymphoma (DLBCL) are related to hepatitis C virus (HCV) infection, in particular in elderly patients. The Fondazione Italiana Linfomi has recently published a multicentre prospective observational study, the 'Elderly Project', on the outcome of DLBCL in patients aged ≥65 years, evaluated using a simplified comprehensive geriatric assessment. The aim of this study was to compare biological and clinical features of HCV positive (HCV+) with HCV negative (HCV-) cases. A total of 89 HCV+ patients were identified out of 1095 evaluated for HCV serology (8.1%). The HCV+ patients were older, less fit, and had frequent extranodal involvement. The cell-of-origin determination by Nanostring showed that HCV+ cases less frequently had an activated B-cell profile compared to HCV- patients (18% vs. 43%). In all, 86% of HCV+ patients received rituximab-cyclophosphamide, doxorubicin, vincristine (Oncovin) and prednisone (R-CHOP)-like immunochemotherapy. Grade 3-4 liver toxicity occurred in 3% of cases. Among centrally reviewed cases confirmed as DLBCL, the 3-year overall survival of HCV+ patients was very similar to HCV- (63% vs. 61%, p = 0.926). In all, 20 HCV+ patients were treated with direct-acting antiviral agents (DAAs), with good tolerance and sustained virological response in all cases. The 3-year progression-free survival for this subgroup was excellent (77%), suggesting DAAs' possible role in reducing the risk of relapse by eliminating the viral trigger., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Castleman disease (CD) is a rare lymphoproliferative disorder that includes various clinico-pathological subtypes. According to clinical course, CD is divided into unicentric CD (UCD) and multicentric CD (MCD). MCD is further distinguished based on the etiological driver in herpes virus-8-related MCD (that can occur in the setting of HIV); in MCD associated with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes); and idiopathic MCD (iMCD). The latter can also be divided in iMCD-TAFRO (thrombocytopenia, anasarca, fever, myelofibrosis, organomegaly) and iMCD not otherwise specified. To date, CD pathogenesis is still uncertain, but CD may represent the histological and clinical result of heterogeneous pathomechanisms. Transcriptome investigations in CD lymph nodes have documented the expression and up-regulation of different cytokines; furthermore, few recent studies have shown alterations of different T-cell subsets in CD patients, suggesting a possible role of the nodal microenvironment in CD development. On this basis, our study aimed to investigate the distribution of T-cell subsets in the clinico-pathological spectrum of CD. We evaluated the CD4/CD8 ratio and the number of T-regulatory (T-reg) FOXP3+ cells in 28 CD cases. In total, 32% of cases showed a decreased CD4/CD8 ratio due to increased CD8+ T-cells, including both UCD, iMCD, and HHV8+ MCD cases. The T-reg subset analysis revealed a statistically significant ( p < 0.0001) lower mean number of FOXP3+ T-reg cells in CD cases when compared with non-specific reactive lymph nodes. We did not find statistically significant differences in T-reg numbers between the different CD subtypes. These findings may suggest that alterations in T-cell subpopulations that can lead to disruption of immune system control may contribute to the numerous changes in different cellular compartments that characterize CD.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare entity whose neoplastic cells retain a B-cell phenotype with expression of CD20. Radiotherapy is recommended for favorable stage IA disease while for other stages guidelines suggest therapeutic strategies similar to those used for classic HL. The role of rituximab, although quite widespread, is not completely elucidated. We retrospectively analyzed baseline characteristics of 308 consecutive patients with NLPHL diagnosed in 19 Italian centers from 2000 to 2018. With a median follow-up of 8.4 years (interquartile range: 4.5-12.4) for treated patients, median overall survival (OS) was not reached and estimated 5-year OS was 97.8% and 5-year progression-free survival (PFS) was 84.5%. Five-year cumulative incidence of histological transformation was 1.4%, 95% confidence interval (CI), 0.5%-3.8%. After adjusting for lymphocyte count, splenic involvement, bulky disease and B symptoms (fever, drenching night sweats, unintentional loss >10% of body weight within the preceding 6 months), patients with stage II or more showed superior PFS with immunochemotherapy in comparison to chemotherapy alone (hazard ratio = 0.4, 95% CI, 0.2-0.8; P = 0.015). Our data suggest an advantage of the use of rituximab combined with chemotherapy ± radiotherapy in the treatment of stage II-III-IV NLPHL., Competing Interests: LA received advisory honoraria from Roche, Celgene, Janssen-Cilag, Verastem, Eusa Pharma, and Incyte, research support from Gilead, and travel expenses from Roche, Celgene, Janssen-Cilag, and Eusa Pharma, speakers bureau from Novartis. AP declares honoraria from Roche. All the other authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Lenalidomide and dexamethasone (Rd)-based triplets, in particular carfilzomib-Rd (KRd) and daratumumab-Rd (DaraRd), represent a standard of care in lenalidomide-sensitive multiple myeloma (MM) patients in first relapse. Meta-analysis of randomized clinical trials (RCT), suggested better outcome with DaraRd. Trying to address this issue in clinical practice, we collected data of 430 consecutive MM patients addressed to Rd-based triplets in first relapse between January 2017 and March 2021. Overall, the most common used regimen was DaraRd, chosen in almost half of the cases (54.4%), followed by KRd (34.6%). Different triplets were used much less commonly. In an attempt to limit the imbalance of a retrospective analysis, we conducted a propensity score matching (PSM) comparison between DaraRd and KRd. After PSM, efficacy of DaraRd versus KRd was similar in terms of overall-response rate (ORR) (OR: 0.9, P=0.685) as well as of very good partial response (VGPR) or better (OR: 0.9, P=0.582). The median progression-free survival (PFS) was significantly longer for DaraRd (29.8 vs. 22.5 months; P=0.028). DaraRd was tolerated better, registering a lower rate of grade 3-4 non-hematological toxicity (OR: 0.4, P<0.001). With the limitations of any retrospective analysis, our real-life PSM comparison between DaraRd and KRd, in first-relapse MM patients, showed better tolerability and prolonged PFS of DaraRd, although with some gaps of performance, in particular of DaraRd, with respect to RCT. Carfilzomib-containing regimens, like KRd, still remain a valid second-line option in the emerging scenario of first-line daratumumab-based therapy.

Mutant calreticulin (CALR) proteins resulting from a -1/+2 frameshifting mutation of the CALR exon 9 carry a novel C-terminal amino acid sequence and drive the development of myeloproliferative neoplasms (MPNs). Mutant CALRs were shown to interact with and activate the thrombopoietin receptor (TpoR/MPL) in the same cell. We report that mutant CALR proteins are secreted and can be found in patient plasma at levels up to 160 ng/mL, with a mean of 25.64 ng/mL. Plasma mutant CALR is found in complex with soluble transferrin receptor 1 (sTFR1) that acts as a carrier protein and increases mutant CALR half-life. Recombinant mutant CALR proteins bound and activated the TpoR in cell lines and primary megakaryocytic progenitors from patients with mutated CALR in which they drive thrombopoietin-independent colony formation. Importantly, the CALR-sTFR1 complex remains functional for TpoR activation. By bioluminescence resonance energy transfer assay, we show that mutant CALR proteins produced in 1 cell can specifically interact in trans with the TpoR on a target cell. In comparison with cells that only carry TpoR, cells that carry both TpoR and mutant CALR are hypersensitive to exogenous mutant CALR proteins and respond to levels of mutant CALR proteins similar to those in patient plasma. This is consistent with CALR-mutated cells that expose TpoR carrying immature N-linked sugars at the cell surface. Thus, secreted mutant CALR proteins will act more specifically on the MPN clone. In conclusion, a chaperone, CALR, can turn into a rogue cytokine through somatic mutation of its encoding gene., (© 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.)

COVID-19, the disease caused by SARS-CoV-2, is still afflicting thousands of people across the globe. Few studies on COVID-19 in chronic lymphocytic leukemia (CLL) are available. Here, we analyzed data from the CLL cohort of the Italian Hematology Alliance on COVID-19 (NCT04352556), which included 256 CLL patients enrolled between 25 February 2020 and 1 February 2021. Median age was 70 years (range 38-94) with male preponderance (60.1%). Approximately half of patients (n = 127) had received at least one line of therapy for CLL, including 108 (83.7%) who were on active treatment at the time of COVID-19 or received their last therapy within 12 months. Most patients (230/256, 89.9%) were symptomatic at COVID-19 diagnosis and the majority required hospitalization (n = 176). Overall, after a median follow-up of 42 days (IQR 24-96), case fatality rate was 30.1%, and it was 37.5% and 24.4% in the first (25 February 2020-22 June 2020) and second wave (23 June 2020-1 February 2021), respectively (p = 0.03). At multivariate analysis, male sex (HR 1.82, 95% CI 1.03-3.24, p = 0.04), age over than 70 years (HR 2.23, 95% CI 1.23-4.05, p = 0.01), any treatment for CLL given in the last 12 months (HR 1.72, 95% CI 1.04-2.84, p = 0.04) and COVID-19 severity (severe: HR 5.66, 95% CI 2.62-12.33, p < 0.0001; critical: HR 15.99, 95% CI 6.93-36.90, p < 0.0001) were independently associated with poor survival. In summary, we report a dismal COVID-related outcome in a significant fraction of CLL patients, that can be nicely predicted by clinical parameters., (© 2022 John Wiley & Sons Ltd.)

The standard treatment for young patients with untreated PTCLs is based on anthracycline containing-regimens followed by high-dose-chemotherapy and stem-cell-transplantation (HDT + SCT), but only 40% of them can be cured. Romidepsin, a histone-deacetylase inhibitor, showed promising activity in relapsed PTCLs; in first line, Romidepsin was added with CHOP. We designed a study combining romidepsin and CHOEP as induction before HDT + auto-SCT in untreated PTCLs (PTCL-NOS, AITL/THF, ALK-ALCL), aged 18-65 years. A phase Ib/II trial was conducted to define the maximum tolerated dose (MTD) of Ro-CHOEP, and to assess efficacy and safety of 6 Ro-CHOEP as induction before HDT. The study hypothesis was to achieve a 18-month PFS of 70%. Twenty-one patients were enrolled into phase Ib; 7 dose-limiting toxicities were observed, that led to define the MTD at 14 mg/ms. Eighty-six patients were included in the phase II. At a median follow-up of 28 months, the 18-month PFS was 46.2% (95%CI:35.0-56.7), and the 18-month overall survival was 73.1% (95%CI:61.6-81.7). The overall response after induction was 71%, with 62% CRs. No unexpected toxicities were reported. The primary endpoint was not met; therefore, the enrollment was stopped at a planned interim analysis. The addition of romidepsin to CHOEP did not improve the PFS of untreated PTCL patients., (© 2023. The Author(s).)

Background: Studies suggest that immune checkpoint inhibitors may represent a promising strategy for boosting immune responses and improving the antitumor activity of standard therapies in patients with relapsed/refractory hematologic malignancies., Aims: Phase 1/2 FUSION NHL 001 was designed to determine the safety and efficacy of durvalumab, an anti-programmed death ligand 1 (PD-L1) antibody, combined with standard-of-care therapies for lymphoma or chronic lymphocytic leukemia (CLL)., Methods and Results: The primary endpoints were to determine the recommended phase 2 dose of the drugs used in combination with durvalumab (durvalumab was administered at the previously recommended dose of 1500 mg every 4 weeks) and to assess safety and tolerability. Patients were enrolled into one of four arms: durvalumab monotherapy (Arm D) or durvalumab in combination with lenalidomide ± rituximab (Arm A), ibrutinib (Arm B), or rituximab ± bendamustine (Arm C). A total of 106 patients with relapsed/refractory lymphoma were enrolled. All but two patients experienced at least one treatment-emergent adverse event (TEAE); those not experiencing a TEAE were in Arm C (diffuse large B-cell lymphoma [DLBCL]) and Arm D (DLBCL during the durvalumab monotherapy treatment period). No new safety signals were identified, and TEAEs were consistent with the respective safety profiles for each study treatment. Across the study, patients with follicular lymphoma (FL; n = 23) had an overall response rate (ORR) of 59%; ORR among DLBCL patients (n = 37) was 18%. Exploratory biomarker analysis showed that response to durvalumab monotherapy or combination therapy was associated with higher interferon-γ signature scores in patients with FL (p = .02)., Conclusion: Durvalumab as monotherapy or in combination is tolerable but requires close monitoring. The high rate of TEAEs during this study may reflect on the difficulty in combining durvalumab with full doses of other agents. Durvalumab alone or in combination appeared to add limited benefit to therapy., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

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.

Marginal zone lymphomas (MZLs) represent about 7% of B-cell non-Hodgkin lymphomas and include 3 different subtypes-namely, extranodal (EMZL), nodal, and splenic (SMZL). The initial assessment requires specific diagnostic and staging procedures depending on organ-related peculiarities. In particular, although positron emission tomography/computed tomography was not initially recommended, recent data have reassessed its role in the routine staging of MZL, especially when only localized treatment is planned or there is a suspicion of histologic transformation. Recent findings have improved the risk stratification of MZL patients, highlighting the association of early progression after frontline therapy with worse overall survival. A significant fraction of MZL cases may be related to specific bacterial (ie, Helicobacter pylori in gastric EMZL) or viral infections (hepatis C virus), and in the earlier phases of disease, a variable percentage of patients may respond to anti-infective therapy. Involved-site radiotherapy has a central role in the management of localized EMZL not amenable to or not responding to anti-infective therapy. Although rituximab-based treatments (bendamustine- rituximab in advanced EMZL or rituximab monotherapy in SMZL) have demonstrated favorable results, the current therapeutic scenario is predicted to rapidly change as emerging novel agents, especially Bruton's tyrosine kinase inhibitors, have demonstrated promising efficacy and safety profiles, leading to their approval in the relapsed setting. Moreover, a large variety of novel agents (phosphatidylinositol 3-kinase inhibitors, chimeric antigen receptor T-cells, bispecific antibodies) are being tested in MZL patients with encouraging preliminary results., (Copyright © 2022 by The American Society of Hematology.)

The impact of secondary infections (SI) on COVID-19 outcome in patients with hematological malignancies (HM) is scarcely documented. To evaluate incidence, clinical characteristics, and outcome of SI, we analyzed the microbiologically documented SI in a large multicenter cohort of adult HM patients with COVID-19. Among 1741 HM patients with COVID-19, 134 (7.7%) had 185 SI, with a 1-month cumulative incidence of 5%. Median time between COVID-19 diagnosis and SI was 16 days (IQR: 5-36). Acute myeloid leukemia (AML) and lymphoma/plasma cell neoplasms (PCN) were more frequent diagnoses in SI patients compared to patients without SI (AML: 14.9% vs. 7.1%; lymphoma/PCN 71.7% vs. 65.3%). Patients with SI were older (median age 70 vs. 66 years, p = 0.002), with more comorbidities (median Charlson Comorbidity Index 5 vs. 4, p < 0.001), higher frequency of critical COVID-19 (19.5% vs. 11.5%, p = 0.046), and more frequently not in complete remission (75% vs. 64.7% p = 0.024). Blood and bronchoalveolar lavage were the main sites of isolation for SI. Etiology of infections was bacterial in 80% (n = 148) of cases, mycotic in 9.7% (n = 18) and viral in 10.3% (n = 19); polymicrobial infections were observed in 24 patients (18%). Escherichia coli represented most of Gram-negative isolates (18.9%), while coagulase-negative Staphylococci were the most frequent among Gram-positive (14.2%). The 30-day mortality of patients with SI was higher when compared to patients without SI (69% vs. 15%, p < 0.001). The occurrence of SI worsened COVID-19 outcome in HM patients. Timely diagnosis and adequate management should be considered to improve their prognosis., (© 2022 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

A multicenter retrospective study was designed to assess clinical outcome of COVID-19 in patients with hematological malignancies (HM) following treatment with anti-SARS-CoV-2 convalescent plasma (CP) or standard of care therapy. To this aim, a propensity score matching was used to assess the role of non-randomized administration of CP in this high-risk cohort of patients from the Italian Hematology Alliance on COVID-19 (ITA-HEMA-COV) project, now including 2049 untreated control patients. We investigated 30- and 90-day mortality, rate of admission to intensive care unit, proportion of patients requiring mechanical ventilatory support, hospitalization time, and SARS-CoV-2 clearance in 79 CP recipients and compared results with 158 propensity score-matched controls. Results indicated a lack of efficacy of CP in the study group compared with the untreated group, thus confirming the negative results obtained from randomized studies in immunocompetent individuals with COVID-19. In conclusion, this retrospective analysis did not meet the primary and secondary end points in any category of immunocompromized patients affected by HM., (© 2022 John Wiley & Sons Ltd.)

To optimise management of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection identifying high-risk patients and maintaining treatment dose intensity is an important issue in patients with aggressive lymphomas. In the present study, we report on the presentation, management, and outcome of an international series of 91 patients with primary central nervous system lymphoma and SARS-CoV-2 infection. SARS-CoV-2 was diagnosed before/during first-line treatment in 64 patients, during follow-up in 21, and during salvage therapy in six. Among the 64 patients infected before/during first-line chemotherapy, 38 (59%) developed pneumonia and 26 (41%) did not clear the virus. Prolonged exposure to steroids before viral infection and/or treatment with high-dose cytarabine favoured pneumonia development and virus persistence and were associated with poorer survival; 81% of patients who did not clear virus died early from coronavirus disease 2019 (COVID-19). Vaccination was associated with lower pneumonia incidence and in-hospital mortality. Chemotherapy was initiated/resumed in 43 (67%) patients, more commonly among patients who did not develop pneumonia, cleared the virus, or did not receive steroids during infection. Chemotherapy resumption in patients with viral persistence should be indicated cautiously as it was associated with a poorer survival (6-month, 70% and 87%, p = 0.07). None of the 21 patients infected during follow-up died from COVID-19, requiring similar measures as infected subjects in the general population., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Salvage immunochemotherapy and transplant consolidation is the standard treatment for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We tested a combination of Obinutuzumab and DHAP for treating R/R DLBCL. The primary end point was the rate of complete metabolic response (CMR). Secondary end points were stem cell mobilization, stem cell engraftment, overall survival, and feasibility. In this prospective, phase-2, single-arm trial (EudraCT 2014-004014-17) patients received the standard three doses of Obinutuzumab for the first cycle, and then one dose. Patients with CMR were consolidated with an autologous stem cell transplantation (ASCT). An interim analysis was provided after the first 29 patients to confirm the initial null hypothesis that at least 10/29 patients would achieve CMR. Among the 29 patients evaluated for the first stage only six patients (6/29, 21%) achieved CMR, thus, study enrollment was stopped. Nine patients exhibited extra-hematologic toxicities ≥ grade 3. Among the 19 patients that started stem cell mobilization, one failed (5%) and 18 achieved mobilization (95%). Of these 18 patients, nine were reinfused. Mobilization was observed in 16 patients (89%) after one or two apheresis rounds. The mean number of CD34 + cells mobilized was 5.8 × 10 6 /Kg (median: 5.5, IQR: 5-6.75). The mean number of reinfused CD34 + cells in the nine patients was 4.1 × 10 6 /Kg (median: 4.1, IQR: 3.5-5). Obinutuzumab combined with DHAP did not compromise stem cell mobilization or engraftment after ASCT in patients with DLBCL. However, Obinutuzumab + DHAP provided a lower CMR rate than expected., (© 2022 John Wiley & Sons Ltd.)

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.)

Patients with Philadelphia-negative myeloproliferative neoplasms are at high risk of thrombotic events (TEs). Predisposing factors have been identified in essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (primary MF, PMF), while yet not recognized in post PV/ET-MF (known as secondary MF, SMF). Within the 1258 SMF of the MYSEC (MYelofibrosis SECondary to PV and ET) dataset, 135 (10.7%) developed a TE at a median follow-up of 3.5 years (range, 1-21.4), with an incidence of 2.3% patients per year. Venous events accounted for two-thirds of the total. Cox multivariable analysis, supported by Fine-Gray models with death as competitive risk, showed that being on cytoreductive therapy at time of SMF evolution is associated with an absolute risk reduction of thrombosis equal to 3.3% within 3 years. Considering individually cytoreductive therapies, univariate regression model found that both conventional cytoreduction, mainly hydroxyurea, (HR 0.41, 95% CI: 0.26-0.65, p = 0.0001) and JAK inhibitors, mostly ruxolitinib, (HR 0.50, 95% CI: 0.24-1.02, p = 0.05) were associated with fewer thrombosis. Our study informs treating physicians of a non-low incidence of TEs in post PV/ET-MF and of the potential protective role of cytoreductive therapy in terms of thrombotic events., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Immunoglobulin light chain (AL) amyloidosis is caused by a small, minimally proliferating B-cell/plasma-cell clone secreting a patient-unique, aggregation-prone, toxic light chain (LC). The pathogenicity of LCs is encrypted in their sequence, yet molecular determinants of amyloidogenesis are poorly understood. Higher rates of N-glycosylation among clonal κ LCs from patients with AL amyloidosis compared to other monoclonal gammopathies indicate that this post-translational modification is associated with a higher risk of developing AL amyloidosis. Here, we exploited LC sequence information from previously published amyloidogenic and control clonal LCs and from a series of 220 patients with AL amyloidosis or multiple myeloma followed at our Institutions to define sequence and spatial features of N-glycosylation, combining bioinformatics, biochemical, proteomics, structural and genetic analyses. We found peculiar sequence and spatial pattern of N-glycosylation in amyloidogenic κ LCs, with most of the N-glycosylation sites laying in the framework region 3, particularly within the E strand, and consisting mainly of the NFT sequon, setting them apart with respect to non-amyloidogenic clonal LCs. Our data further support a potential role of N-glycosylation in determining the pathogenic behavior of a subset of amyloidogenic LCs and may help refine current N-glycosylation-based prognostic assessments for patients with monoclonal gammopathies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Extranodal marginal zone lymphoma (EMZL) is a heterogeneous non-Hodgkin lymphoma. No consensus exists regarding the standard-of-care in patients with advanced-stage disease. Current recommendations are largely adapted from follicular lymphoma, for which bendamustine with rituximab (BR) is an established approach. We analyzed the safety and efficacy of frontline BR in EMZL using a large international consortium. We included 237 patients with a median age of 63 years (range, 21-85). Most patients presented with Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (n = 228; 96.2%), stage III/IV (n = 179; 75.5%), and intermediate (49.8%) or high (33.3%) Mucosa Associated Lymphoid Tissue International Prognosis Index (MALT-IPI). Patients received a median of 6 (range, 1-8) cycles of BR, and 20.3% (n = 48) received rituximab maintenance. Thirteen percent experienced infectious complications during BR therapy; herpes zoster (4%) was the most common. Overall response rate was 93.2% with 81% complete responses. Estimated 5-year progression-free survival (PFS) and overall survival (OS) were 80.5% (95% CI, 73.1% to 86%) and 89.6% (95% CI, 83.1% to 93.6%), respectively. MALT-IPI failed to predict outcomes. In the multivariable model, the presence of B symptoms was associated with shorter PFS. Rituximab maintenance was associated with longer PFS (hazard ratio = 0.16; 95% CI, 0.04-0.71; P = .016) but did not impact OS. BR is a highly effective upfront regimen in EMZL, providing durable remissions and overcoming known adverse prognosis factors. This regimen is associated with occurrence of herpes zoster; thus, prophylactic treatment may be considered., (© 2022 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.)