BTK inhibitors (BTKi) have reshaped the therapeutic algorithm of lymphoproliferative diseases, but class-specific adverse events (AEs) have emerged. Dose adjustment (DA) is often attempted to mitigate AEs, particularly with ibrutinib, the first BTKi approved for relapsed/refractory (R/R) mantle cell lymphoma (MCL) patients. We described ibrutinib DA in 226 consecutive R/R MCL who started ibrutinib between 2016 and 2023. We assessed DA rate and calculated single patient's relative ibrutinib dose as a percentage of the expected full dose during the entire treatment period, grouping patients into 4 dose levels (DL1a 95%-100%, DL1b 75%-94%, DL2a 50%-74%, DL2b < 50%). We evaluated changes in response, progression free survival (PFS), overall survival (OS) and time to next treatment (TTNT) between groups. Thirty-four percent of patients started ibrutinib at reduced dose, mainly due to age/comorbidities. Overall, 44% of patients reduced ibrutinib dose, mostly due to AEs. Thirty-five percent of patients interrupted treatment, predominantly for AEs, and 65% of patients discontinued ibrutinib, most often due to progressive disease (70%). No statistically significant differences in response rates/PFS/OS were observed across DLs. Interestingly, patients on the lowest dose tended to remain on treatment longer. This is the first real-life report evaluating ibrutinib DA in MCL. We showed that DA is common, particularly in older comorbid patients, and doesn't compromise efficacy, making it a feasible strategy for managing ibrutinib-related toxicities.

Most patients with large B-cell lymphoma (LBCL) progressing after CAR-T therapy experience poor survival and lack standardized treatment strategies. Prognostic tools are needed to guide decision-making at relapse. The Post-CAR Prognostic Index (PC-PI), recently proposed by Iacoboni et al., combines five routine clinical variables to stratify outcomes after CAR-T failure: ECOG (> 0), hemoglobin (< 10 g/dL), LDH (≥ 2xULN), number of extranodal sites (> 1) and time from CAR-T to progression (< 4 months). We evaluated the PC-PI in a retrospective multicenter study including 125 LBCL patients relapsing or refractory after axicabtagene-ciloleucel or tisagenlecleucel, treated between 2019 and 2023 across 16 Italian centers belonging to the Fondazione Italiana Linfomi network. Median overall survival (OS) was 4.9 months, with 6- and 12-month OS rates of 44.9% and 28.5%, respectively. The PC-PI discriminated prognosis effectively: high-risk patients had a median OS of 1.8 months, intermediate-high 2.2, intermediate-low 8.7, while in the low-risk group median OS was not reached (p<0.0001). Results remained consistent after excluding patients receiving only palliative care. Post-progression therapy markedly influenced survival: patients receiving active treatment achieved a median OS of 7.3 months versus 0.7 without further therapy (p<0.0001). Bispecific antibodies conferred the best outcomes (HR 0.44, p=0.02), with 6- and 12-month OS rates of 90% and 55%. Our findings confirm the prognostic value of the PC-PI and support its use in clinical practice as a tool for risk-adapted management of LBCL after CAR-T failure.

Mantle cell lymphoma (MCL) presents a heterogeneous course with poor prognosis in relapsed/refractory (R/R) cases, particularly when therapy with covalent BTK-inhibitors (cBTK-i) fails. Pirtobrutinib, a reversible non-covalent BTK-i (ncBTK-i), has shown good tolerability and good efficacy in cBTK-i pre-treated patients with R/R MCL in a clinical trial, but real-world data are very limited. We retrospectively analyzed 40 patients with R/R MCL patients treated in 25 italian centers, within a compassionate use program between december 2022 and march 2024. Median time from MCL diagnosis to pirtobrutinib start was 4.7 years (1-23), and median number of prior lines was 3 (2-7). All patients had received prior cBTKi, with the majority of patients (87%) that had discontinued cBTKi because of progressive disease (PD). At the time of pirtobrutinib start median age of treated patients was 70 years (44-86), 88% were males, and 87% had high or intermediate Mantle Cell International Prognostic Index (MIPI). Twelve patients (30%) had blastoid or pleomorphic morphology, Ki67 was >30% in 74%, and 11 of 20 (55%) had TP53 mutation. After a median follow-up of 7 months (1-23), eight patients are still on active treatment. Overall response rate (ORR) to pirtobrutinib was 48%, with 25% of patients experiencing complete remission (CR), 23% that had partial response, 10% who had stable disease, and remaining 42% that had PD. Median progression-free survival (PFS) was 4.6 months, with seven patients that stopped the drug because of subsequent Car-T cell therapy and were censored at the time of infusion. For the 19 patients who achieved at least a PR, median duration of response (DOR) was not reached, with 65% of patients still in remission at one year (Figure 1). Duration of CR (DOCR) was even higher (78% at one year). Significant predictive factors for inferior DOR were elevated Ki67 (p=0.02), TP53 mutations (p=0.01), and POD24 since initial diagnosis to first relapse (p=0.03). Adverse events were rare and mild, with no patients that discontinued the drug due to toxicity. Conclusions: Our findings align with BRUIN trial results despite a population of very high risk R/R MCL patients, thus supporting the use of pirtobrutinib in this setting. Figure 1.

The present study comprehensively dissects the molecular landscape of elderly mantle cell lymphoma (MCL) patients enrolled in the phase II V-RBAC trial of the Fondazione Italiana Linfomi. Of the 140 patients enrolled in the trial, 132 had available gDNA extracted from lymph node biopsies or bone marrow aspirates and were included in the analysis. A CAPP-Seq assay targeting 146 genes relevant to MCL pathogenesis was employed to identify gene mutations and copy number variations. ATM was the most frequently mutated gene, detected in 55 patients (41.7%), followed by TP53 and KMT2D in 31 patients (23.5%). ATM deletion was observed in 32 patients (24%), while CDKN2A loss in 29 (22%). Beyond TP53 mutations, three other molecular lesions, including CDKN2A loss, CD36 mutations and single-hit ATM abnormalities (either mutation or deletion) were independently associated with progression-free survival after adjustment for high-risk trial-defining features, namely Ki-67 >30% and blastoid variant. Notably, patients harboring single-hit ATM alterations without any additional risk factors achieved durable long-term remission, while CD36 mutations were associated with adverse survival. Both findings represent previously unrecognized aberrations that in this cohort independently and inversely associated with survival. The four variables were integrated into a 4-factor molecular prognostic model internally validated using a bootstrapping approach, which identified four distinct patient subgroups with significantly different outcomes. These findings support the importance of i) molecular profiling in MCL, ii) risk-adapted trials like V-RBAC, and iii) the integration of other biological markers with TP53 mutations for a more precise risk assessment in MCL. (NCT03567876)

BACKGROUND:Bendamustine and rituximab combined with intermediate-dose cytarabine (RBAC) is one of the standard initial treatments for older, fit patients with mantle cell lymphoma. We aimed to investigate whether the addition of venetoclax to RBAC would improve progression-free survival in patients with high-risk mantle cell lymphoma. METHODS:FIL_V-RBAC was a multicentre, single-arm, phase 2 study done in 35 institutions of the Fondazione Italiana Linfomi in Italy. Treatment-naive patients with a histological diagnosis of mantle cell lymphoma, aged 65 years or older and fit according to the Fondazione Italiana Linfomi modified comprehensive geriatric assessment (or younger than 65 years and ineligible for high-dose chemotherapy with Eastern Cooperative Oncology Group performance status of 2 or less), were classified after enrolment as having low-risk or high-risk disease, based on the presence of blastoid morphology, Ki67 30% or higher, TP53, or 17p deletion. Patients with a low-risk profile received RBAC intravenously (rituximab 375 mg/m2 and day 1; bendamustine 70 mg/m2 on days 1 and 2; and cytarabine 500 mg/m2 on days 1, 2, and 3) every 4 weeks for 6 cycles. Patients with a high-risk profile received four cycles of RBAC followed by fixed-duration oral venetoclax consolidation (4 months, 800 mg/day) and maintenance (20 months, 400 mg/day). The primary endpoint was 2-year progression-free survival for patients with a high-risk profile who received at least one dose of RBAC. This trial was registered with ClinicalTrials.gov, NCT03567876, and this is the final report. FINDINGS:Between Sept 10, 2018, and July 26, 2021, 155 patients were screened for inclusion, 140 of whom were enrolled and analysed for study endpoints. Median age was 72 (IQR 69-76), 107 (76%) patients were male, 33 (24%) were female, and all were White. 54 (39%) patients had a high-risk profile (28 [20%] with TP53 mutations, 19 [14%] with 17p deletions, 34 [24%] with Ki67 ≥30%, and 13 [9%] with a blastoid morphology) and 86 (61%) had a low-risk profile. After a median follow-up of 45 months (IQR 40-55), the 2-year progression-free survival in the high-risk group was 60% (95% CI 48-74) and the median progression-free survival was 37 months (95% CI 19-not reached). The most frequent grade 3 or worse adverse events during venetoclax consolidation were neutropenia (12 [28%] of 43 patients), followed by thrombocytopenia (three [7%]) and skin reactions (three [7%]). During venetoclax maintenance, the most frequent grade 3 or worse adverse events were neutropenia (seven [19%] of 37 patients), followed by thrombocytopenia (two [5%]) and anaemia (two [5%]). One (1%) of 140 patients had a treatment-related death (tumour lysis syndrome during first induction with RBAC in a patient with a high-risk profile). INTERPRETATION:To our knowledge, this is the first prospective study to stratify patients with mantle cell lymphoma to different treatments according to their risk profile. Our results suggest that the addition of fixed-duration venetoclax improves the performance of RBAC in patients with a high-risk disease profile. Our findings point to the importance of identifying patients with high-risk disease at initial diagnosis. FUNDING:Fondazione Italiana Linfomi-Ente del Terzo Settore, Leukemia and Lymphoma Society, and Ministry of Health, Italy, and AbbVie. TRANSLATION:For the Italian translation of the abstract see Supplementary Materials section.

ABSTRACT Background Castleman disease (CD) encompasses a range of heterogeneous non‐clonal lymphoproliferative disorders, including unicentric (UCD), and multicentric (MCD) forms. The latter is subdivided into HHV‐8+ MCD, POEMS‐MCD, and idiopathic‐MCD, not otherwise specified (iMCD‐NOS). Methods Here we report the clinical characteristics and outcomes of 28 consecutive CD patients, diagnosed in two centers of northern Italy according to recently published diagnostic criteria. Results UCD was reported in 12 cases (43%) and MCD in 16 (57%). Among these, 6 (21%) were HHV‐8 positive (1 HIV‐positive and 5 HIV‐negative), and 10 (36%) had iMCD‐NOS. Treatment of UCD consisted of surgical excision in 10/12 cases, resulting in ongoing complete remission in all cases. Single nodal localization favorably affected overall survival (OS) and progression‐free survival (PFS) ( p < 0.05). Out of 16 MCD patients, 10 had iMCD‐NOS and 6 had HHV‐8+MCD. Anti‐IL‐6 monoclonal antibody was used as first‐line treatment in 5/10 iMCD‐NOS patients, 3 of whom relapsed, although none died. Two out of 6 patients with HHV‐8+ MCD were treated with single‐agent rituximab and one with rituximab plus chemotherapy. UCD patients had significantly better OS and PFS compared to iMCD and HHV‐8+MCD groups ( p < 0.001). Conclusions Our report confirms that UCD, iMCD‐NOS, and HHV‐8+MCD represent distinct clinical entities with different outcomes requiring specific treatment approaches. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission.

BTK inhibitors (BTKi) have reshaped the therapeutic algorithm of lymphoproliferative diseases, but class-specific adverse events (AEs) such as bleeding, atrial fibrillation and cytopenia emerged. Dose modification (DM) is often attempted to mitigate AEs, particularly with ibrutinib, the first BTKi approved for relapsed/refractory (R/R) mantle cell lymphoma (MCL). The REDOT study described ibrutinib DM in R/R MCL from 14 Italian centers, evaluating DM impact on outcomes. We assessed DM rate in a real-life series of MCL patients who started ibrutinib between 2016 and 2023. We calculated single patient’s relative cumulative ibrutinib dose as a percentage of expected full dose during the entire treatment period. Patients were grouped into 4 dose levels (DL1a 95-100%, DL1b 75-94%, DL2a 50-74%, DL2b <50%). We evaluated ibrutinib-related AEs, changes in response and PFS/OS/TTNT between groups. We included 226 consecutive patients with median age 73 years at ibrutinib start. Overall, 34% of patients started ibrutinib at reduced dose, in most cases (67%) due to age or comorbidities, concomitant therapies (16%), cytopenia (9%) or unknown reason (9%). Forty-four percent of patients reduced ibrutinib either at start or during treatment. Median time to first reduction was 5 months. In 73% of cases reductions were caused by AEs. Thirty-five percent of patients interrupted ibrutinib, due to AEs (65% of interruptions), surgical procedures or patient choice (35%). Sixty-five percent of patients permanently discontinued ibrutinib due to progressive disease (70%), AEs or other reasons (15% each) including allo-SCT. Overall, 54% and 15% of patients were grouped into DL1a and 1b, 22% and 9% into DL2a and 2b, respectively. No statistically significant difference in response rates emerged between the 4 DLs (p=0.516; Fig1A). We showed similar 3y-PFS (DL1a 25%, 1b 40%, 2a 30%, 2b 36%, p=0.426; Fig1B). Accordingly, there was no statistically significant difference in 3y-OS (DL1a 42%, 1b 45%, 2a 37%, 2b 51%, p=0.657). Contrarily regarding TTNT, DL2b patients tended to stay in treatment longer than those who took higher doses (p=0.058). This is the first report evaluating ibrutinib DM in a real-life MCL setting. We showed higher DM rates than in clinical trials, probably due to advanced age and comorbidities. Since ibrutinib dose did not significantly impact responses and outcomes, DM is a viable strategy especially for elderly MCL patients with comorbidities or drug-related AEs.

Patients with mantle cell lymphoma (MCL) who experience first relapse/refractoriness can be categorized into early or late progression-of-disease (POD) groups, with a threshold of 24 months from the initial MCL diagnosis. Bruton tyrosine kinase inhibitors (BTKi) are established standard treatment at first relapse, but their effectiveness as compared to chemoimmunotherapy (CIT) in late-POD patients remains unknown. In this international, observational cohort study, we evaluated outcomes amongst patients at first, late-POD beyond 24 months. Patients treated upfront with BTKi were excluded. The primary objective was progression-free survival from time of second-line therapy (PFS-2) of BTKi versus CIT. After accrual, all patients were prospectively followed-up. Overall, 385 late-POD patients were included from 10 countries. Their median age was 59 (range:19-70) years and 77% were males. Median follow-up from time of first relapse was 53 months (range:12-144). Overall, 114 patients had second-line BTKi, while 271 had CIT, consisting of rituximab-bendamustine (R-B, n=101), R-B and cytarabine (R-BAC, n=70), or other regimens (mostly cyclophosphamide-hydroxydaunorubicin-vincristine-prednisone-CHOP- or platinum-based, n=100). The two groups were balanced for clinicopathological features, and median time to first relapse (48 months for both). Overall, BTKi was associated with significantly prolonged median PFS-2 than CIT [not reached-NR vs 26 months, respectively, P=.0003], and overall survival [NR and 56 months, respectively, P=.03]. Multivariate analyses showed that BTKi was associated with lower risk of death than R-B and other regimens (hazard ratio-HR, 0.41 for R-B, 0.46 for others), but similar to R-BAC. These results may establish BTKi as the preferable second-line approach in BTKi-naïve MCL patients.

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.

INTRODUCTION: The FIL V-RBAC trial (EudraCT: 2017-004628-31) is a phase 2 study which enrolled patients with previously untreated mantle cell lymphoma (MCL), stratifying them at initial diagnosis depending on risk factors. High-risk patients, defined as either Ki67≥30% and/or blastoid variant and/or TP53 mutations and/or 17p deletion, received an abbreviated course of R-BAC followed by consolidation and maintenance with venetoclax. Conversely, standard-risk patients with no risk factors received standard R-BAC. The aim of the project was to evaluate the prognostic role of gene mutations and copy-number analysis (CNV) in patients enrolled in the FIL V-RBAC trial. METHODS: Patients enrolled in the trial with availablegDNA extracted from lymph node biopsy were included in this mutational analysis.A CAPP-Seq assay including 146 genes relevant for MCL pathogenesis was used coupled with a robust and previously validated bioinformatic pipeline. Based on CAPP-Seq data, CNV analysis was performed using CNVkit (version 0.9.10) and GISTIC2.0 was used to identify statistically significant CNVs. The primary endpoint was progression-free survival (PFS) according to molecular lesions. RESULTS: Among the 140 patients enrolled in the V-RBAC trial, 132 were analyzed (53 high-risk and 79 standard-risk). The median age of analyzed patients was 72 years and the median follow-up was 32.0 months. The CAPP-Seq analysis recapitulated the mutational landscape of MCL and identified ATM as the most frequently mutated gene (41.7%, N=55), followed by KMT2D (23.5%, N=31), TP53 (23.5%, N=31), WHSC1 (14.4%, N=19), and BIRC3 (9.8%, N=13). As expected, TP53 mutated patients displayed a significantly inferior PFS compared to TP53 unmutated patients (3-year PFS 30.8% versus 79.9%, p<0.001). Among other genes analyzed, only NOTCH1/2 mutations (10.2%, N=14) and CD36mutations (7.3%, N=7) were associated with significantly inferior PFS. In multivariate analysis adjusted for blastoid variant and Ki67>30%, only CD36 (HR 4.73, 95% CI 1.82-12.28, p=0.001) and TP53 (HR 4.75, 95% CI 2.35-9.60, p<0.001) mutations were independently associated with inferior PFS. Interestingly, CD36 mutations significantly stratified the outcome of standard risk patients (p<0.001), but not of high-risk patients (p=0.348), suggesting that CD36may capture additional high-risk patients that are not currently identified by standard prognostic markers. Regarding CNVs, the most frequently detected were amp3q (36.4%, N=51), del13q (35.0%, N=49), CDKN2A loss (30%, N=42) and del11q (27.9%, N=39). After Bonferroni correction, only CDKN2A loss retained prognostic value (HR 2.47, 95% CI 1.20-5.09, p=0.014), when adjusted for TP53 and CD36 mutations. Finally, non-negative matrix factorization based on gene mutations and CNVs identified 3 different clusters characterized by different molecular composition and with clinical relevance for both PFS (p<0.001) and OS (p=0.0037). Cluster 1 (N=41, 29.3%) was enriched in TP53 and CDKN2A loss and was associated with the worst prognosis (3-year PFS of 39.7% and OS of 50.0%); cluster 2 (N=50, 35.7%) was enriched in ATM mutations and associated with the best prognosis (3-year PFS of 87.5% and OS of 82.0%); cluster 3 (N=35, 25.0%) was enriched in KMT2D mutations and presented an intermediate prognosis (3-year PFS of 77.4% and OS of 76.1%). CONCLUSIONS: Molecular analysis of the FIL V-RBAC trial indicates that, together with TP53 mutations, CD36mutations and CDKN2A loss are associated with adverse outcome in MCL patients treated with chemo-immunotherapy and the BCL2-inhibitor venetoclax.

Introduction: The R-BAC regimen is considered among standard first-line treatments for elderly fit patients with mantle cell lymphoma (MCL). We previously reported (RBAC500 trial) a significantly inferior progression-free survival (PFS) for patients with high risk (HR) features, namely blastoid morphology and/or elevated Ki67 proliferative index, as compared to other patients, that were defined as low risk (LR). Indeed, when treated with R-BAC, LR patients had excellent outcome, albeit no maintenance therapy was delivered. Methods: We designed a phase 2 prospective multicenter study, which enrolled patients aged ≥65 years and fit according to the geriatric CGA assessment, or age ≤64 years if not eligible to high-dose chemotherapy plus transplantation. Asymptomatic patients with non-nodal disease were excluded. At presentation patients were allocated by central review as LR or HR, depending on tumor morphology (blastoid versus others), Ki67 expression (≥30% versus others), or presence of TP53 mutation and/or deletion. Patients with any of the three risk factors were classified as HR. Patients with LR disease were treated with 6 cycles of R-BAC (rituximab 375 mg/m2 d 1; bendamustine 70 mg/m2 d 1,2; cytarabine 500 mg/m2 d 1,2,3), while HR patients received abbreviated induction with 4 R-BAC followed by consolidation (4 months, 800 mg/d), and maintenance (20 months, 400 mg/d) with venetoclax. The primary endpoint was 2-years PFS for the HR patients. The sample size was calculated with the one arm non parametric survival analysis (alpha-error 0.05, power 90%), assuming that the addition of venetoclax would improve 2-years PFS from 40% (null hypothesis) to 60%. Tumor response was assessed with Lugano criteria. All patients were analyzed by real-time quantitative PCR at baseline on peripheral blood and bone marrow samples for minimal residual disease (MRD) evaluation, and HR patients were followed up at different time points. Results of this specific analysis will be subject of future reports. This trial was registered at ClinicalTrials.gov Identifier: NCT03567876. Results: Overall, 140 patients from 35 centers of the Fondazione Italiana Linfomi (FIL) were prospectively enrolled between 2018 and 2021. Of them, 54 were HR (39%). Median age was 72 (range 57-79), and 44% had elevated MIPI. LR and HR patients had similar clinical characteristics, but differed for LDH, and MIPI, both being significantly higher in the HR group. Overall, 28 (20%) patients had TP53 mutations, 19 (14%) had TP53 deletions, Ki67 was ≥30% in 34 (24%), and blastoid variant was diagnosed in 13 patients (9%, Figure 1A). Toxicity during R-BAC was in line with previous reports, while most frequent grade >=3 adverse events during venetoclax treatment consisted of neutropenia (21%), followed by skin reactions (10%). Of note, there were 5 deaths due to COVID-19 infection in patients in CR (4 LR, 1 HR). Overall response at the end of R-BAC differed between HR and LR patients (85% vs 99%, p=0.001), as was for complete response (61% vs 91%, p=0.0001). Of the 54 HR patients, 43 (80%) started venetoclax consolidation, 37 (69%) started the maintenance phase, with 26 patients (48%) completing the whole treatment per protocol. Of 10 patients that started Venetoclax in partial remission (PR) or stable disease after R-BAC, 3 converted to CR, 1 maintained PR, while 6 patients progressed during maintenance. After a median follow-up of 34 months, the 2-years PFS for the whole population was 74.9% (95% CI 66-82), and OS was 80% (95% CI 72-85). Patients with HR MCL had 2-years PFS and OS of 58% (95% CI 43-70) and 66% (95% CI 50-77), respectively, which were significantly lower than LR patients (85% and 88%, respectively, p=0.0001 for both, see Figure 1B). Predictors of PFS using Cox regression models adjusted for MIPI were blastoid morphology (Hazard Ratio 3.51), and TP53 mutation (Hazard Ratio 4.17), with Ki67, and TP53 deletions that lost their power in multivariate analysis. Conclusions: The VR-BAC trial represents the first prospective study that stratified upfront patients with MCL to different treatments according to the risk profile. In this trial the null hypothesis (2-years PFS 40%) was rejected in HR patients, suggesting that the addition of venetoclax to R-BAC improves the performance of the induction strategy. These results point to the importance of identifying HR patients since initial diagnosis.

The combination of rituximab, bendamustine, and low-dose cytarabine (R-BAC) has been studied in a phase 2 prospective multicenter study from Fondazione Italiana Linfomi (RBAC500). In 57 previously untreated elderly patients with mantle cell lymphoma (MCL), R-BAC was associated with a complete remission rate of 91% and 2-year progression-free survival (PFS) of 81% (95% confidence interval [CI], 68-89). Here, we report the long-term survival outcomes, late toxicities, and results of minimal residual disease (MRD) evaluation. After a median follow-up of 86 months (range, 57-107 months), the median overall survival (OS) and PFS were not reached. The 7-year PFS and OS rates were 55% (95% CI, 41-67), and 63% (95% CI, 49-74), respectively. Patients who responded (n = 53) had a 7-year PFS of 59% (95% CI, 44-71), with no relapse or progression registered after the sixth year. In the multivariate analysis, blastoid/pleomorphic morphology was the strongest adverse predictive factor for PFS (P = .04). Patients with an end of treatment negative MRD had better, but not significant, outcomes for both PFS and OS than patients with MRD-positive (P = 0.148 and P = 0.162, respectively). There was no signal of late toxicity or an increase in secondary malignancies during the prolonged follow-up. In conclusion, R-BAC, which was not followed by maintenance therapy, showed sustained efficacy over time in older patients with MCL. Survival outcomes compare favorably with those of other immunochemotherapy regimens (with or without maintenance), including combinations of BTK inhibitors upfront. This study was registered with EudraCT as 2011-005739-23 and at www.clinicaltrials.gov as #NCT01662050.

The gastrointestinal (GI) tract is the most common extranodal site of occurrence of nonHodgkin 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.

Background: Salvage chemotherapy (CHT) followed by autologous stem cell transplant (ASCT) is considered the standard of care for classical Hodgkin lymphoma (cHL) patients who are primary refractory (PrRef) to first line treatment. However, among the few studies based solely on PrRef cHL cases, it has been reported that this strategy leads to a sustained complete response (CR) in almost a half of PrRef patients (pts). Furthermore, Horning et al. reported an overall survival (OS) of 50% at a median follow up of 42 months in a cohort of 29 PrRef pts. Although it is conventionally believed that chemorefractory pts are poor ASCT candidates, recent studies reported promising results in terms of response rate and survival among PrRef cases receiving anti-PD-1 salvage treatment and subsequent ASCT. Methods: We retrospectively collected 9 consecutive PrRef cHL pts who did not respond to salvage CHT and brentuximab-vedotin (BV) and were treated with pembrolizumab monotherapy as fourth-line. Pts defined as PrRef were those who did not achieve a durable (>90 days) CR at the end of first line therapy or those with a Deauville score of 5 (DS 5) at interim PET (PET-2). Results: The majority of pts were male (67%). Systemic symptoms were reported in 56% of cases. Stage at the onset was 2 in 5 cases and 3 and 4 in 2 pts each. An unfavourable prognostic score was seen in 75% of pts. Nodular sclerosis was the predominant histological variant (67%); LMP-1 was positive in 2 out of 7 evaluable cases. The median number of cycles of pembrolizumab administered was 6 (range, 2 to 9). After anti-PD-1 therapy, 75% pts obtained a CR and 25% a partial response (PR). Seven pts underwent ASCT subsequently to pembrolizumab: among these, 87% pts achieved a metabolic CR and 14% a PR at the pre-ASCT PET scan. Disease evaluation after ASCT showed a CR in 100% of cases. After a median follow-up time of 40.3 months (interquartile range: 20.4–54.7 months) from first-line treatment failure, all pts still maintain a CR. Conclusion: If compared to similar series of PrRef cases reported in literature, our experience using pembrolizumab before ASCT resulted in successful outcomes in terms of quality and duration of response in this difficult-to-treat subset of cHL pts.

Central nervous system (CNS) relapse of mantle cell lymphoma (MCL) is a rare phenomenon with dismal prognosis, where no standard therapy exists. Since the covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in relapsed/refractory MCL and penetrates the blood-brain barrier (BBB), on behalf of Fondazione Italiana Linfomi and European Mantle Cell Lymphoma Network we performed a multicenter retrospective international study to investigate the outcomes of patients treated with ibrutinib or chemoimmunotherapy. In this observational study, we recruited patients with MCL with CNS involvement at relapse who received CNS-directed therapy between 2000 and 2019. The primary objective was to compare the overall survival (OS) of patients treated with ibrutinib or BBB crossing chemotherapy. A propensity score based on a multivariable binary regression model was applied to balance treatment cohorts. Eighty-eight patients were included. The median age at study entry was 65 years (range, 39-87), 76% were males, and the median time from lymphoma diagnosis to CNS relapse was 16 months (range, 1-122). Patients were treated with ibrutinib (n = 29, ibrutinib cohort), BBB crossing chemotherapy (ie, high-dose methotrexate +/- cytarabine; n = 29, BBB cohort), or miscellaneous treatments (n = 30, other therapy cohort). Both median OS (16.8 vs 4.4 months; P =.007) and median progression-free survival (PFS) (13.1 vs 3.0 months; P =.009) were superior in the ibrutinib cohort compared with the BBB cohort. Multivariable Cox regression model revealed that ibrutinib therapeutic choice was the strongest independent favorable predictive factor for both OS (hazard ratio [HR], 6.8; 95% confidence interval [CI], 2.2-21.3; P <.001) and PFS (HR, 4.6; 95% CI, 1.7-12.5; P =.002), followed by CNS progression of disease (POD) >24 months from first MCL diagnosis (HR for death, 2.4; 95% CI, 1.1-5.3; P =.026; HR for death or progression, 2.3; 95% CI, 1.1-4.6; P =.023). The addition of intrathecal (IT) chemotherapy to systemic CNS-directed therapy was not associated with superior OS (P =.502) as the morphological variant (classical vs others, P =.118). Ibrutinib was associated with superior survival compared with BBB-penetrating chemotherapy in patients with CNS relapse of MCL and should be considered as a therapeutic option.

Letermovir (LTV), recently approved for the prophylaxis of human cytomegalovirus (HCMV) reactivation after hematopoietic stem cell transplantation (HSCT), has been shown to decrease the rate of infection in the first months post-transplantation. The aim of this study was to evaluate the impact of LTV prophylaxis on immune reconstitution and late-onset infection. We studied HCMV infection and HCMV-specific T cell reconstitution in 2 matched groups of HSCT recipients, those treated with LTV prophylaxis (n = 30; LTV group) and those receiving preemptive therapy (n = 31; PET group). We analyzed the rates of graft-versus-host disease (GVHD), neutropenia, baseline disease recurrence, and overall survival in the 2 groups. Clinically significant infections necessitating preemptive therapy showed a similar rate in the 2 groups (PET: 21 of 31 [68%]; LTV: 17 of 30 [57%]; P = .434) but occurred significantly later (after prophylaxis discontinuation) in the LTV group. There was no between-group difference in peak HCMV DNAemia level (P = .232). HCMV-specific T cell recovery was delayed by approximately 100 days in the LTV group. HCMV-specific CD4 and CD8 T cell counts were significantly lower in the LTV group at days 120 to 360 and days 90 to 120, respectively. A lower rate of chronic GVHD (P = .024) was seen in the LTV group. Time to engraftment, rate of disease relapse, and 1-year survival were not different between the 2 groups, whereas trends toward a lower rate of neutropenia (P = .124) and a higher rate of acute GVHD grade III-IV (P = .103) were observed in the LTV group. Because LTV prophylaxis delays HCMV infection and HCMV-specific immune reconstitution, immunologic and virologic monitoring should be implemented after discontinuation of prophylaxis. The potential effect of LTV prophylaxis in reducing chronic GVHD should be evaluated in prospective studies.

Background: Hepatitis C virus (HCV) chronic infection has been associated with increased risk of non-Hodgkin lymphoma (NHL) in people living with human immunodeficiency virus (HIV) as well as with a trend of inferior overall survival (OS) in HIV-associated NHL in the modern antiretroviral therapy (ART) era (Besson 2020). The recent introduction of interferon (IFN)-free direct-acting antivirals (DAAs) led to the achievement of sustained virologic response (SVR) in nearly all treated patients (pts) with negligible toxicity in all settings, including HIV/HCV coinfected pts, in which, however, careful attention to interactions with ART is required. We recently showed that DAAs' administration after immuno-chemotherapy (I-CT) may improve long-term outcome in HIV-negative HCV-associated diffuse large B-cell lymphomas (DLBCL) pts (Merli 2019), however, only scant data have been reported so far about the use of DAAs in HIV/HCV coinfected NHL pts.