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Biomarkers for immune checkpoint inhibitors (ICIs) response and resistance include PD‐L1 expression and other environmental factors, among which the gut microbiome (GM) is gaining increasing interest especially in lymphomas. To explore the potential role of GM in this clinical issue, feces of 30 relapsed/refractory lymphoma (Hodgkin and primary mediastinal B‐cell lymphoma) patients undergoing ICIs were collected from start to end of treatment (EoT). GM was profiled through Illumina, that is, 16S rRNA sequencing, and subsequently processed through a bioinformatics pipeline. The overall response rate to ICIs was 30.5%, with no association between patients clinical characteristics and response/survival outcomes. Regarding GM, responder patients showed a peculiar significant enrichment of Lachnospira, while non‐responder ones showed higher presence of Enterobacteriaceae (at baseline and maintained till EoT). Recognizing patient‐related factors that may influence response to ICIs is becoming critical to optimize the treatment pathway of heavily pretreated, young patients with a potentially long‐life expectancy. These preliminary results indicate potential early GM signatures of ICIs response in lymphoma, which could pave the way for future research to improve patients prognosis with new adjuvant strategies. [ABSTRACT FROM AUTHOR]

Introduction: Seizures may occur in up to 30% of non-Hodgkin lymphoma patients who received anti-CD19 CAR T-cell therapy, yet the optimal anti-seizure medication (ASM) prevention strategy has not been thoroughly investigated. Methods: Consecutive patients affected by refractory non-Hodgkin lymphoma who received anti-CD19 CAR T-cells were included. Patients were selected and assessed using similar internal protocols. ASM was started either as a primary prophylaxis (PP-group) before CAR T-cells infusion or as a pre-emptive therapy (PET-group) only upon the onset of neurotoxicity development. Results: One hundred fifty-six patients were included (PP-group = 88, PET-group = 66). Overall, neurotoxicity and severe neurotoxicity occurred in 45 (29%) and 20 (13%) patients, respectively, equally distributed between the two groups. Five patients experienced epileptic events (PET-group = 3 [4%]; PP-group = 2 [2%]). For all the PET-group patients, seizure/status epilepticus occurred in the absence of overt CAR-T-related neurotoxicity, whereas patients in the PP-group experienced brief seizures only in the context of critical neurotoxicity with progressive severe encephalopathy. ASMs were well-tolerated by all patients, even without titration. No patients developed epilepsy or required long-term ASMs. Conclusion: Our data suggest that both primary and pre-emptive anti-seizure prophylaxis are safe and effective in anti-CD19 CAR T-cell recipients. Clinical rationale suggests a possible more favourable profile of primary prophylaxis, yet no definitive conclusion of superiority between the two ASM strategies can be drawn from our study. [ABSTRACT FROM AUTHOR]

Poor literature report actual and detailed costs of chimeric antigen receptor (CAR) T-cell pathway in a real-life setting. We retrospectively collect data for all patients with relapsed/refractory aggressive large B-cell lymphoma who underwent leukapheresis between August 2019 and August 2022. All costs and medical resource consumption accountability were calculated on an intention-to-treat (ITT) basis, starting from leukapheresis to the time when the patient (infused or not) exited the CAR T-cell pathway for any reason. Eighty patients were addressed to leukapheresis and 59 were finally infused. After excluding CAR-T product cost, the main driver of higher costs were hospitalizations followed by the examinations/procedures and other drugs, respectively 43.9%, 26.3% and 25.4% of the total. Regarding costs of drugs and medications other than CAR T products, the most expensive items are those referred to AEs, both infective and extra-infective within 30 days from infusion, that account for 63% of the total. Density plot of cost analyses did not show any statistically significant difference with respect to the years of leukapheresis or infusion. To achieve finally 59/80 infused patients the per capita patients without CAR-T products results 74,000 euros. This analysis covers a growing concern on health systems, the burden of expenses related to CAR T-cell therapy, which appears to provide significant clinical benefit despite its high cost, thus making economic evaluations highly relevant. The relevance of this study should be also viewed in light of continuously evolving indications for this therapy. [ABSTRACT FROM AUTHOR]

Introduction Intensive treatment approaches are required for adult patients with Burkitt lymphoma (BL), although an univocal standard of care still does not exist. The use of frontline autologous stem cells transplantation (ASCT) is debated. Patients and Methods Between 2004 and 2020, 50 patients with BL were treated with the Berlin-Frankfurt-Münster (BFM). Treatment plan consisted of 3 blocks, A (ifosfamide, vincristine, methotrexate, etoposide, and cytarabine), B (vincristine, cyclophosphamide, methotrexate, and doxorubicin), and C (vindesine, methotrexate, etoposide, and cytarabine), each repeated twice, every 28 days. Rituximab was given at day 1 each block. Intrathecal prophylaxis was given once per each block. ASCT was scheduled at the end of the 6 blocks after conditioning. Results Median age at onset was 38 years (range 16-72); stages III-IV disease was observed in 82% of cases; bulky disease occurred in 44% of the patients, with B-symptoms in 38%. Stem cell harvest was performed in 72% of patients, who all received a subsequent ASCT. The full 6 blocks treatment was completed in 70% of the patients. The overall response rate was 74%, with a complete response rate of 60%. Ten-year overall survival and progression-free survival were 83.7% and 76.0%, respectively, without reaching the median. Ten-year disease-free survival was 80.3%. Grades 3-4 neutropenia, thrombocytopenia, anemia, and mucositis were seen in 96%, 60%, 32%, and 24% of patients. Infections occurred in 60% of patients. Conclusion Intensive treatment according to BFM protocol, with rituximab and ASCT, appears feasible, safe, and highly effective in adult patients with BL, as confirmed by long-term survival rates reflecting response maintenance. [ABSTRACT FROM AUTHOR]

Purpose: The emergence of chimeric antigen receptor (CAR) T-cell therapy fundamentally changed the management of individuals with relapsed and refractory large B-cell lymphoma (LBCL). However, real-world data have shown divergent outcomes for the approved products. The present study therefore set out to evaluate potential risk factors in a larger cohort. Methods: Our analysis set included 88 patients, treated in four German university hospitals and one Italian center, who had undergone 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (PET) before CAR T-cell therapy with tisagenlecleucel or axicabtagene ciloleucel. We first determined the predictive value of conventional risk factors, treatment lines, and response to bridging therapy for progression-free survival (PFS) through forward selection based on Cox regression. In a second step, the additive potential of two common PET parameters was assessed. Their optimal dichotomizing thresholds were calculated individually for each CAR T-cell product. Results: Extra-nodal involvement emerged as the most relevant of the conventional tumor and patient characteristics. Moreover, we found that inclusion of metabolic tumor volume (MTV) further improves outcome prediction. The hazard ratio for a PFS event was 1.68 per unit increase of our proposed risk score (95% confidence interval [1.20, 2.35], P = 0.003), which comprised both extra-nodal disease and lymphoma burden. While the most suitable MTV cut-off among patients receiving tisagenlecleucel was 11 mL, a markedly higher threshold of 259 mL showed optimal predictive performance in those undergoing axicabtagene ciloleucel treatment. Conclusion: Our analysis demonstrates that the presence of more than one extra-nodal lesion and higher MTV in LBCL are associated with inferior outcome after CAR T-cell treatment. Based on an assessment tool including these two factors, patients can be assigned to one of three risk groups. Importantly, as shown by our study, metabolic tumor burden might facilitate CAR T-cell product selection and reflect the individual need for bridging therapy. [ABSTRACT FROM AUTHOR]

This article discusses a case of fulminant cerebral edema (FCE) following CAR T-cell therapy, a treatment for certain types of cancer. FCE is a rare but severe complication that can lead to brain death within 24 hours. The patient in this case was successfully treated with prompt neurointensive support and immunosuppressive anti-cytokine therapy. The article emphasizes the importance of managing intracranial pressure (ICP) to prevent brain damage and highlights the need for aggressive neurointensive measures in addition to immunosuppressive therapy. The underlying pathophysiology of FCE is not fully understood, but the disruption of the blood-brain barrier and cytokine-mediated inflammation are believed to play a role. The article concludes that FCE is a potentially reversible complication and that early intervention is crucial for a positive outcome. [Extracted from the article]

Background: Chimeric antigen receptor T cells (CAR-T) represent an innovation but raise issues for healthcare payers because of the uncertainty on impact at market launch, high cost and important organisational impact. The literature has focused on their assessment, appraisal and market access solutions. No evidence on the costs sustained to implement CAR-T is available and a few studies reported the cost of the CAR-T clinical pathway, including the activities that are remunerated through inpatient or outpatient fee-for-service/episode. This paper aims at filling the information gap, assessing the cost of implementing CAR-T activity and the full cost of managing the CAR-T clinical pathway. Methods: Cost analysis relied on the Activity Based Costing approach, which was applied to two Italian healthcare organisations, both CAR-T Centres authorized by the regional governments with a minimum of 20 patients treated with the first two CAR-T therapies launched on the market. Results: The cost of implementing CAR-T was estimated at €1.31 million (calculated for one of the organizations with complete data). Most of these costs (77%) were generated by quality assurance activity. The mean cost per patient entering the CAR-T pathway (59 and 27) and surviving at follow-up (21 and 5) ranges from €48K to €57K and from €96K to €106K, respectively. Fees for hospitalization and infusion of gene therapy accounts for more than 70% of these costs. The actual hospitalisation cost varies greatly across patients and is in general lower than the fee-for-episode paid by the region to the hospital. Conclusions: Despite its limitations (exploratory nature; the time spent by staff on activities which are not remunerated through fees was estimated through interviews with the CAR-T coordinators; cost items are not fully comparable), this research highlighted the relevant organisational and economic impact of CAR-T and provided important insights for policy makers and healthcare managers: the necessity to invest resources in CAR-T implementation; the need for assessing activities which are not remunerated through fees for service / episode; the opportunity to shift from fee-for-episode / service to bundled payments for CAR-T clinical pathway. [ABSTRACT FROM AUTHOR]

Introduction: For primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT), there are no uniform recommendations for second-line treatment in case of relapse. Case Presentation: Here, we present the case of an elderly relapsed/refractory PCDLBCL-LT patient who obtained a prolonged clinical complete remission with lenalidomide. Conclusion: Lenalidomide as single agent led to an unexpected long complete response with manageable toxicity. [ABSTRACT FROM AUTHOR]

Despite global vaccination efforts, immunocompromized patients remain at high risk for COVID‐19‐associated morbidity. In particular, patients with impaired humoral immunity have shown a high risk of persistent infection. We report a case series of adult patients with B cell malignancies and/or undergoing B cell targeting therapies with persisting SARS‐CoV‐2 infection and treated with a combination antiviral therapy of remdesivir and nirmatrelvir/ritonavir, in three Italian tertiary academic hospitals. A total of 14 patients with impaired adaptive humoral immunity and prolonged SARS‐CoV‐2 infection were treated with the dual antiviral therapy. The median age was 60 (IQR 56–68) years, and 11 were male. Twelve patients had B cell lymphoma, one patient had chronic lymphocytic leukemia and one patient had multiple sclerosis. Thirteen out of 14 patients had received prior B cell‐targeting therapies, consisting of anti‐CD20 monoclonal antibodies in 11 patients, and chimeric antigen receptor T therapy in 2 patients. The median time between diagnosis and therapy start was 42.0 (IQR 35–46) days. Seven patients had mild, 6 moderate and one severe disease. Nine patients had signs of interstitial pneumonitis on chest computed tomography scans before treatment. The median duration of nirmatrelvir/ritonavir and remdesivir combination therapy was 10 days. All patients showed resolution of COVID‐19‐related symptoms after a median of 6 (IQR 4–11) days and viral clearance after 9 (IQR 5–11) days. Combination therapy with remdesivir and nirmatrelvir/ritonavir is a promising treatment option for persistent COVID‐19 in immunocompromized patients with humoral immunity impairment, worthy of prospective comparative trials. [ABSTRACT FROM AUTHOR]

This article discusses the use of pixantrone as a bridging therapy (BT) for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are undergoing chimeric antigen receptor (CAR) T-cell therapy or allogeneic stem cell transplantation (allo-SCT). Pixantrone is a drug with low cardiotoxic potential and few side effects. The study, conducted in Italy, collected data from 13 patients who received pixantrone as BT. The results showed that pixantrone effectively controlled lymphoma-related symptoms and allowed patients to proceed with subsequent planned therapy. The overall response rate (ORR) was 23% after pixantrone, and the ORR after CAR T-cell therapy or allo-SCT was 76.9%. Adverse events were limited, and no cardiotoxicities were reported. The median overall survival was 10.5 months, and the median progression-free survival was 5.2 months. The authors recommend considering pixantrone as a valid and widely available option for bridging therapy in DLBCL patients. [Extracted from the article]

The majority of patients with Follicular Lymphoma (FL) experience subsequent phases of remission and relapse, making the disease "virtually" incurable. To predict the outcome of FL patients at diagnosis, various clinical-based prognostic scores have been proposed; nonetheless, they continue to fail for a subset of patients. Gene expression profiling has highlighted the pivotal role of the tumor microenvironment (TME) in the FL prognosis; nevertheless, there is still a need to standardize the assessment of immune-infiltrating cells for the prognostic classification of patients with early or late progressing disease. We studied a retrospective cohort of 49 FL lymph node biopsies at the time of the initial diagnosis using pathologist-guided analysis on whole slide images, and we characterized the immune repertoire for both quantity and distribution (intrafollicular, IF and extrafollicular, EF) of cell subsets in relation to clinical outcome. We looked for the natural killer (CD56), T lymphocyte (CD8, CD4, PD1) and macrophage (CD68, CD163, MA4A4A)-associated markers. High CD163/CD8 EF ratios and high CD56/MS4A4A EF ratios, according to Kaplan–Meier estimates were linked with shorter EFS (event-free survival), with the former being the only one associated with POD24. In contrast to IF CD68+ cells, which represent a more homogeneous population, higher in non-progressing patients, EF CD68+ macrophages did not stratify according to survival. We also identify distinctive MS4A4A+CD163-macrophage populations with different prognostic weights. Enlarging the macrophage characterization and combining it with a lymphoid marker in the rituximab era, in our opinion, may enable prognostic stratification for low-/high-grade FL patients beyond POD24. These findings warrant validation across larger FL cohorts. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy is a promising approach for some relapse/refractory hematological B-cell malignancies; however, in most patients, cytokine release syndrome (CRS) may occur. CRS is associated with acute kidney injury (AKI) that may affect the pharmacokinetics of some beta-lactams. The aim of this study was to assess whether the pharmacokinetics of meropenem and piperacillin may be affected by CAR T-cell treatment. The study included CAR T-cell treated patients (cases) and oncohematological patients (controls), who were administered 24-h continuous infusion (CI) meropenem or piperacillin/tazobactam, optimized by therapeutic drug monitoring, over a 2-year period. Patient data were retrospectively retrieved and matched on a 1:2 ratio. Beta-lactam clearance (CL) was calculated as CL = daily dose/infusion rate. A total of 38 cases (of whom 14 and 24 were treated with meropenem and piperacillin/tazobactam, respectively) was matched with 76 controls. CRS occurred in 85.7% (12/14) and 95.8% (23/24) of patients treated with meropenem and piperacillin/tazobactam, respectively. CRS-induced AKI was observed in only 1 patient. CL did not differ between cases and controls for both meropenem (11.1 vs. 11.7 L/h, p = 0.835) and piperacillin (14.0 vs. 10.4 L/h, p = 0.074). Our findings suggest that 24-h CI meropenem and piperacillin dosages should not be reduced a priori in CAR T-cell patients experiencing CRS. [ABSTRACT FROM AUTHOR]

Purpose: One of the most critical issues in the management of Hodgkin lymphoma (HL) patients who resulted as primary relapsed or refractory is to obtain a minimal disease status before autologous stem cell transplantation (ASCT). Finding a salvage regimen able to induce this status without severe toxicity would represent a major achievement in this setting. Methods: A single‐center retrospective study was conducted to assess effectiveness and safety of BEGEV (bendamustine, gemcitabine, and vinorelbine) regimen as first salvage setting prior to ASCT in HL patients. Results: Forty-three patients were treated in our institution between October 2017 and November 2020. Median age at BEGEV therapy was 35.0 years (range 17.2– 70.0), and the median time from frontline therapy to the first cycle of BEGEV was 79.5 days (range 4–2267). At the end of treatment, 31 patients achieved a complete response (CR), with an overall response rate of 76.7%. Forty-one patients harvested CD34+ cells and 35/43 (81.4%) patients underwent ASCT. With a median follow‐up of 22 months, 4 CR patients had disease relapse, yielding an estimated disease-free survival of 73.9% at 34 months. The estimated 2‐year progression-free survival was 66.7%. Response to first-line chemotherapy did not significantly influence prognosis. Conclusions: BEGEV regimen was well tolerated, and reversible haematological toxic effects were the most common adverse events. Real-life data on BEGEV regimen as first salvage setting showed a relevant rate of objective responses and a limited myelotoxicity with no impairment of a subsequent mobilization of peripheral blood stem cells. [ABSTRACT FROM AUTHOR]

Background: Infusion of second generation autologous CD19-targeted chimeric antigen receptor (CAR) T cells in patients with R/R relapsed/ refractory B-cell lymphoma (BCL) is affected by inflammatory complications, such as Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). Current literature suggests that the immune profile prior to CAR-T infusion modifies the chance to develop ICANS. Methods: This is a monocenter prospective study on 53 patients receiving approved CAR T-cell products (29 axi-cel, 24 tisa-cel) for R/R-BCL. Clinical, biochemical, and hematological variables were analyzed at the time of prelymphodepletion (pre-LD). In a subset of 21 patients whose fresh peripheral blood sample was available, we performed cytofluorimetric analysis of leukocytes and extracellular vesicles (EVs). Moreover, we assessed a panel of soluble plasma biomarkers (IL-6/IL-10/GDF-15/IL-15/CXCL9/NfL) and microRNAs (miR-146a-5p, miR-21-5p, miR-126-3p, miR-150-5p) which are associated with senescence and inflammation. Results: Multivariate analysis at the pre-LD time-point in the entire cohort (n=53) showed that a lower percentage of CD3+CD8+ lymphocytes (38.6% vs 46.8%, OR=0.937 [95% CI: 0.882-0.996], p=0.035) and higher levels of serum C-reactive protein (CRP, 4.52 mg/dl vs 1.00 mg/dl, OR=7.133 [95% CI: 1.796- 28], p=0.005) are associated with ICANS. In the pre-LD samples of 21 patients, a significant increase in the percentage of CD8+CD45RA+CD57+ senescent cells (median % value: 16.50% vs 9.10%, p=0.009) and monocytic-myeloid derived suppressor cells (M-MDSC, median % value: 4.4 vs 1.8, p=0.020) was found in ICANS patients. These latter also showed increased levels of EVs carrying CD14+ and CD45+ myeloid markers, of the myeloid chemokine CXCL-9, as well of the MDSC-secreted cytokine IL-10. Notably, the serum levels of circulating neurofilament light chain, a marker of neuroaxonal injury, were positively correlated with the levels of senescent CD8+ T cells, M-MDSC, IL-10 and CXCL-9. No variation in the levels of the selected miRNAs was observed between ICANS and no-ICANS patients. Discussion: Our data support the notion that pre-CAR-T systemic inflammation is associated with ICANS. Higher proportion of senescence CD8+ T cells and M-MDSC correlate with early signs of neuroaxonal injury at pre-LD time-point, suggesting that ICANS may be the final event of a process that begins before CAR-T infusion, consequence to patient clinical history. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Primary vs. pre-emptive anti-seizure medication prophylaxis in anti-CD19 CAR T-cell therapy" published in the journal Neurological Sciences. The correction addresses errors in the author affiliations. Alessandra Crespi and Alessandro Buizza should have double affiliations, while Stefania Bramanti should have a single affiliation. The affiliations have been updated in the article. The publisher, Springer Nature, remains neutral regarding jurisdictional claims and institutional affiliations. The correction notice is authored by Umberto Pensato, Federica Pondrelli, Chiara de Philippis, Gian Maria Asioli, Alessandra Crespi, Alessandro Buizza, Daniele Mannina, Beatrice Casadei, Enrico Maffini, Laura Straffi, Simona Marcheselli, Pier Luigi Zinzani, Francesca Bonifazi, Maria Guarino, and Stefania Bramanti. [Extracted from the article]

An endobronchial localization of Hodgkin lymphoma is rare, and few experiences since the 1900s have been reported in the literature. Here we report the first case of a relapsed/refractory Hodgkin lymphoma with a critical vegetative mass at the level of the trachea successfully treated with pembrolizumab. [ABSTRACT FROM AUTHOR]

We retrieved a total of 25 patients from our database who had been affected by either MF or SS. No patients were excluded. Mycosis fungoides (MF) and Sezary syndrome (SS) are the most common cutaneous T-cell lymphomas (CTCL).[1] While the early-stage can be treated with skin-directed therapies, advanced phases require systemic treatments. All patients with a diagnosis either of MF or of SS from January 2015 to January 2022 were retrieved through our cutaneous lymphoma database. [Extracted from the article]

Background: T cells engineered to target CD19 antigen on neoplastic B cells represent the most striking example of CAR-T cell therapy. The success rate of this therapy is affected by several limitations: target antigen loss, and/or acquisition of a senescent/exhausted phenotype by CAR and non-CAR T cells. Case presentation: We report on a patient affected by refractory Diffuse Large B-cell Lymphoma who was resistant to CAR T-cell therapy and to two cycles post CAR-T of pembrolizumab (PBZ) due to the evolution into a B-cell Hodgkin-like lymphoma. Owing to the CD30 expression and the Hodgkinlike phenotype, the patient was ultimately treated with Brentuximab-Vedotin and finally underwent remission. Upon PBZ treatment, 100% of circulating CAR-T+ cells showed a persistent CD8+ senescent/exhausted phenotype, while an increase in the percentage of senescent cells was found in the non-CAR CD8+ T cells compartment. Conclusions: PBZ is not able to reinvigorate exhausted CAR+ T cells and to confer durable clinical response. We hypothesize that the phenomenon is due to the senescent phenotype of CAR+ T cells, which did not allow PBZ-induced reactivation and proliferative rescue. The phenomenon, together with the loss of CAR-T target CD19 and the shift of non-CAR CD8+ T cells towards a senescent phenotype likely contributed to set up an immune landscape with poor antitumor capacity. [ABSTRACT FROM AUTHOR]

Underpinning pathophysiology of fulminant cerebral edema following CAR T-cell therapy remains not fully elucidated, yet histological and neuroimaging evidence supports cerebral vasogenic edema triggered by cytokine-mediated blood-brain barrier (BBB) dysfunction as the underlying mechanism [[1]-[4]]. The brainstem appears hypo-attenuated compared to other infra-tentorial brain structures Our case illustrates the potentially fatal evolution of neurotoxicity related to CAR T-cells therapy resulting from fulminant cerebral edema. In the RocKet trial, a study evaluating anti-CD19 CAR T-cells in adult patients with B cell acute lymphoblastic leukemia, five patients developed fatal cerebral edema, leading to early termination of the study [[8]]. [Extracted from the article]

Chimeric antigen receptor (CAR) T-cell therapy is an emerging highly effective treatment for refractory haematological malignancies. Unfortunately, its therapeutic benefit may be hampered by treatment-related toxicities, including neurotoxicity. Early aggressive treatment is paramount to prevent neurological sequelae, yet it potentially interferes with the anti-cancer action of CAR T-cells. We describe four CAR T-cells infused patients who presented with reiterative writing behaviours, namely paligraphia, as an early manifestation of neurotoxicity, and eventually developed frontal predominant encephalopathy (one mild, three severe). Paligraphia may represent an early, specific, and easily detectable clinical finding of CAR T-cell therapy-related neurotoxicity, potentially informing its management. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) show efficacy in the treatment of non-Hodgkin lymphomas (NHL). However, these agents are associated with a unique group of side effects called immune-related adverse events (irAEs). We conducted an observational retrospective/prospective study on patients with relapsed/refractory NHL treated with ICI to determine the incidence of irAEs assessing the type, severity, and timing of onset, outcome and relationship with study drugs of these events. Thirty-two patients underwent ICI as single agent (N = 20) or in combination (N = 12). Ten patients (31.3%) developed at least one irAE for a total of 17 irAEs. Median time to presentation of irAEs was 69 days (range 0–407) with a median resolution time of 16 days (range 0–98). Progression free survival at 24 months for patients who developed an irAE was 40% and 31.8% for who did not. Overall survival for the two groups did not differ (at 24 months 40.0% and 62.5% for patients without and with irAE, respectively), but the median for who developed an irAE was not reached. The incidence of irAEs was associated with better long-term survival in NHL treated with ICIs but patients' disease conditions need to be carefully evaluated to decide the optimal management. [ABSTRACT FROM AUTHOR]

BRAFV600E mutation is the pathogenic driver of hairy cell leukemia (HCL) found in the vast majority of cases both at onset and during recurrences. The identification of the mutated allele in blood and marrow correlates with the presence of neoplastic cells and can be considered a marker of active disease. Likewise, the absence of the mutation after treatment may indicate a state of deep response. The BRAFV600E burden was measured by droplet digital polymerase chain reaction (ddPCR) and expressed as fractional abundance in 35 HCL patients at different stages of disease (onset, relapse, complete response [CR] after treatment, long‐term remission) in peripheral blood and/or bone marrow (when available). Mean values of fractional abundance for patients at diagnosis, relapse and response, respectively, were 12.26%, 16.52% and 0.02% in peripheral blood and 23.51%, 13.96% and 0.26% in bone marrow. Four patients out of 6 evaluated at response were molecularly negative for BRAFV600E in peripheral blood. Mean fractional abundance in peripheral blood tested in 14 patients with long lasting CR was 0.05%, and 10 patients were BRAFV600E negative. These preliminary results suggest that ddPCR permits to assess the active tumor burden in HCL at different disease phases and support the hypothesis that some patients in CR qualify for a molecular CR. [ABSTRACT FROM AUTHOR]

Considering the good patient performance status (PS), the young age and the several blood transfusions, patient was addressed to allo-SCT, performed four months after CAR-T cells therapy. Chimeric antigen receptor T-cell therapy in paediatric B-cell precursor acute lymphoblastic leukaemia: curative treatment option or bridge to transplant? To the Editor, Chimeric antigen receptor (CAR)-T cells therapy, consisting in gene-modified autologous T-lymphocytes with an anti-CD19 receptor, has completely changed the outcome of relapse/refractory diffuse large B-cell lymphoma (rrDLBCL) patients. [Extracted from the article]

It is administered continuously until disease progression or intolerable toxicity [[6]]: patients discontinuing treatment due to either causes display significantly different survival rates, as those who stop the drug due to intolerance behave much better than those who discontinue because of disease progression or histologic transformation [[7]]. Ibrutinib is a first-generation oral BTK inhibitor approved for the treatment of patients with I de novo i or relapsed or refractory CLL [[4]]. Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder caused by the clonal proliferation and accumulation of small, mature-appearing CD5 SP + sp B-lymphocytes in the blood, bone marrow and lymphoid tissues [[1]]. Disease flare during temporary interruption of ibrutinib therapy in patients with chronic lymphocytic leukemia. [Extracted from the article]

Patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL) have a poor prognosis, with an expected survival of less than 1 year using standard salvage therapies. Recent advances in our understanding of the biology of PTCL have led to identifying B-Cell Lymphoma 2 (BCL2) protein as a potential therapeutic target. BLC2 inhibitor venetoclax was investigated in a prospective phase II trial in patients with BCL2-positive R/R PTCL after at least one previous standard line of treatment (NCT03552692). Venetoclax given alone at a dosage of 800 mg/day resulted in one complete response (CR) and two stable diseases (SDs) among 17 enrolled patients. The majority of patients (88.2%) interrupted the treatment due to disease progression. No relationship with BCL2 expression was documented. At a median follow-up of 8 months, two patients are currently still on treatment (one CR and one SD). No case of tumor lysis syndrome was registered. Therefore, venetoclax monotherapy shows activity in a minority of patients whose biological characteristics have not yet been identified. Clinical Trial Registration: www.clinicaltrials.gov (NCT03552692, EudraCT number 2017-004630-29). [ABSTRACT FROM AUTHOR]

Primary mediastinal B cell lymphoma is a rare entity and often should be promptly treated as a hematological emergency: The initial treatment decision is crucial for the management of this disease. An observational retrospective study was conducted with the aim to improve information on treatment and outcomes of primary mediastinal B cell lymphoma in real practice. After 12 cycles of MACOP-B regimen (methotrexate, doxorubicin, cyclophosphamide, vincristine, bleomycin, and prednisone) with or without rituximab, 120 patients out of 151 (79.5%) achieved a complete response and 12 (7.9%) a partial response leading to a global response of 87.4%. The 21-year overall survival is 82.6%; progression-free and disease-free survivals are 69.3% and 86.4%, respectively. Regarding the role of radiotherapy (RT), patients with a negative PET scan after MACOP-B did not undergo RT: One out of these 48 (2.1%) showed a relapse at 11 months. All relapsed/refractory patients who achieved a response with checkpoint inhibitors are still in continuous complete response with a median follow-up of 14 months. Data that we have gathered over a 30-year experience in the treatment of primary mediastinal B cell lymphoma patients clearly indicate that a third-generation chemotherapy regimen such as MACOP-B is feasible and easily deliverable on an outpatient basis. Regarding the unmet medical need of relapsed/refractory patients, new encouraging results occurred with the advent of the checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Hepatosplenic T-cell lymphoma is a very difficult lymphoma to deal with, almost impossible to cure. "Tandem" consolidation therapy with auto-stem cell transplant and allo-stem cell transplant can induce a long-lasting response and potentially cure this disease. [ABSTRACT FROM AUTHOR]

Mycosis fungoides (MF) is a disease almost impossible to cure. In the context of heavily pretreated patients, the anti-programmed cell death protein 1 (anti-PD-1) pembrolizumab is a valid therapeutic option. The alteration of the PD-1-PD ligand 1 (PD-L1) axis is often present in MF, and this aspect explains the feasibility of this therapy. We report the case of a 60-year-old woman diagnosed with MF in 2003, Olsen stage IA (T1M0NXBO). Since the moment of the diagnosis, she received 10 lines of therapy, with a short duration of response after each one of them. In April 2020, our patient started pembrolizumab 2 mg/kg every 3 weeks, and she achieved a partial response after the 4th cycle, consistent with the modified severity assessment tool (mSWAT) 1, which she is still maintaining after 10 cycles. No grade ≥3 adverse events were recorded. We conclude that pembrolizumab can induce extremely rapid responses in MF, with very low toxicity. [ABSTRACT FROM AUTHOR]

In recent years, novel drugs are available for the patients with relapsed/refractory Hodgkin lymphoma (HL), like immune checkpoint inhibitors (CPi). These drugs have been able to rescue a cohort of patients who subsequently could receive an allogeneic stem‐cell transplant (SCT). No data were reported for subsequent autologous SCT (ASCT) after CPi. Here, we report our real‐life experience in heavily pretreated HL patients undergoing ASCT as consolidation approach after CPi treatment. A retrospective observational study was conducted. Patients had CPi therapy in the context of clinical trials (n = 6) or in the named patient program (n = 7) between July 2014 and November 2019: 9 out of 13 received pembrolizumab and the remaining four underwent nivolumab. A median of 12 cycles (range, 3–16) of CPi therapy were infused. Thirteen patients underwent ASCT after CPi: 11 (84.6%) patients obtained a complete response (CR) and 2 had progression of disease, with an overall response rate of 84.6%. With a median follow‐up of 3.3 years (range, 1.1–5.5), only one CR patient had disease relapse after 3.9 months from ASCT, leading to an estimated disease‐free survival of 87.5% at 56.9 months. The estimated 5‐year progression‐free survival was 73.4% and overall survival was 92.3% at 4.8 years, respectively. No unexpected or cumulative toxicity was observed. Our results indicated that ASCT may represent a further effective therapeutic option as consolidation in HL after CPi treatment that today represents the last conventionally recognized therapeutic line. [ABSTRACT FROM AUTHOR]

There is an unmet clinical need for elderly or unfit diffuse large B-cell lymphoma (DLBCL) patients ineligible for autologous stem cell transplantation. Lenalidomide is an immunomodulatory agent with antitumor activity in non-Hodgkin lymphoma, with an acceptable toxicity profile and manageable side effects. A 79-year-old Caucasian male with non-germinal center B-cell-like DLBCL achieved complete remission (CR) after first-line treatment with seven out of eight scheduled cycles of a polychemotherapy containing anthracycline, which had to be discontinued early due to the onset of atrial fibrillation. After 5 months, the patient had an early epicardial relapse. He underwent lenalidomide considering age, cardiological comorbidities, and chronic renal failure. After the third cycle, he achieved CR, confirmed at restaging after the sixth cycle of treatment. Lenalidomide was safe and well tolerated in a patient with atrial fibrillation developed after an anthracycline-based regimen and a relapse of the DLBCL. Moreover, this regimen was effective in a case with a rare extranodal involvement of the epicardium. [ABSTRACT FROM AUTHOR]

Programmed death‐1 (PD1) blockade is an efficient and safe therapeutic option in patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL). However, a substantial proportion of patients' progresses or loses the response to anti‐PD1 treatment. We retrospectively investigated the effectiveness of salvage chemotherapies (CHT) for unsatisfactory response to anti‐PD1, in 25 R/R cHL patients. Twenty‐three patients (92%) were refractory to the last treatment before anti‐PD1. After a median of 14 cycles (range 3‐52), 68% (17/25) of patients had unsatisfactory responses to anti‐PD1 therapy, whereas 6 had a partial response (PR) and 2 patients achieved complete response (CR), with an overall response rate (ORR) of 32%. After a median time of 1.5 months, 15 patients received a single agent treatment and 10 had a multi‐agents regimen, due to the failure of PD1 blockade. The ORR was 60% (8 CR and 7 PR). Seven patients (3 in PR and 4 in CR) underwent a consolidation strategy with stem cell transplantation. Median progression‐free survival (PFS) with salvage treatment was reached at 19.1 months, while median PFS after anti‐PD1 has been reached at 8.2 months. After a median follow‐up of 32.4 months, 6 patients died while 13 are still in CR. The median overall estimated from the start of CHT was not reached. The efficacy of treatment following anti‐PD1 is not yet established, especially in lymphoma patients. To note, in our series, a subset of heavily pre‐treated and chemo‐refractory patients increased response rates to and survival with CHT given after exposure to immune‐checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

First line therapy of patients with marginal zone lymphomas (MZL) is not well established and various regimens with chemo‐immunotherapy can be used. Rituximab plus bendamustine (BR) is an effective and manageable treatment option for patients affected by indolent non‐Hodgkin lymphoma. The aim of this monocentric retrospective study was to analyze the effectiveness and safety of the use of BR regimen in MZL patients in first line in daily clinical practice. The treatment schedule was rituximab at the dose of 375 mg/m2 on day 1 of each cycle and bendamustine at the dose of 90 mg/m2 on day 2 and 3, every 28 days for a maximum of 6 cycles. We analyzed 65 MZL patients (28 extranodal [EMZL], 23 splenic [SMZL], and 14 nodal [NMZL]) who underwent BR regimen as first line treatment. The median time from diagnosis to therapy was 2.5 months. Final responses were: 38 complete response (CR, 58.5%), 20 partial response and 7 progressive disease, leading to an overall response rate (ORR) of 89.2%. With respect to the histology, the ORR was 89.3% for EMZL, 82.6% for SMZL and 100% for NMZL, respectively (difference not statistically significant). With a median follow‐up time of 44.6 months (range, 3.3‐175.0 months), 2 (one EMZL after 42 months and one SMZL after 10 months) of 38 (5.2%) CR patients had disease relapse, yielding an estimated disease free survival of 89.2% at 61.1 months. The estimated 6‐year progression free survival was 71.8% with 15 relapsed/progressed patients showing lymphoma recurrence within 48 months from end of treatment. The most frequently reported adverse events (any grade) were neutropenia (N = 35, 53.8%), fatigue (N = 15, 23.0%), and nausea (N = 12, 18.4%). All toxicities quickly resolved and no treatment‐related death occurred. The BR regimen is effective and feasible in MZL patients inducing prolonged disease control with manageable toxicities. [ABSTRACT FROM AUTHOR]

In primary mediastinal large B‐cell lymphoma, central nervous system (CNS) relapse is an uncommon event with a dismal prognosis. We report about the successful management of CNS relapse with chemoimmunotherapy according to MATRix (methotrexate, cytarabine, thiotepa, and rituximab) protocol followed by autologous stem cell transplant. [ABSTRACT FROM AUTHOR]

90Y-ibritumomab tiuxetan in patients with extra-nodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) - The Zeno Study Keywords: 90Y-ibritumomab tiuxetan; extra-nodal marginal zone B-cell lymphoma; MALT lymphoma; relapsed; treatment-naïve EN 90Y-ibritumomab tiuxetan extra-nodal marginal zone B-cell lymphoma MALT lymphoma relapsed treatment-naïve e6 e9 4 03/31/20 20200401 NES 200401 Marginal zone lymphomas (MZL) represent about 17% of all non-Hodgkin lymphomas (NHL) (Zinzani & Broccoli, [8]) and are composed of three different entities: splenic MZL, nodal MZL and marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). In conclusion, YIT represents a highly effective and tolerable treatment option for MALT lymphoma, in a setting where currently there are no standard treatments and the therapy options are limited, especially in R/R patients. [Extracted from the article]

Background: Diffuse large B‐cell lymphoma (DLBCL) is the most common non‐Hodgkin lymphoma subtype, and approximately 50% of the patients are >60 years of age. Patients with relapsed/refractory (rr) disease have a poor prognosis with currently available treatments. Lenalidomide is available in Italy for patients with rrDLBCL based on a local disposition of the Italian Drug Agency. Subjects, Materials, and Methods: An observational retrospective study was conducted in 24 Italian hematology centers with the aim to improve information on effectiveness and safety of lenalidomide use for rrDLBCL in real practice. Results: One hundred fifty‐three patients received lenalidomide for 21/28 days with a median of four cycles. At the end of therapy, there were 36 complete responses (23.5%) and 9 partial responses with an overall response rate (ORR) of 29.4%. In the elderly (>65 years) subset, the ORR was 33.6%. With a median follow‐up of 36 months, median overall survival was reached at 12 months and median disease‐free survival was not reached at 62 months. At the latest available follow‐up, 29 patients are still in response out of therapy. Median progression‐free survivals differ significantly according to age (2.5 months vs. 9.5 in the younger vs. elderly group, respectively) and to disease status at the latest previous therapy (15 months for relapsed patients vs. 3.5 for refractory subjects). Toxicities were manageable, even if 30 of them led to an early drug discontinuation. Conclusion: Lenalidomide therapy for patients with rrDLBCL is effective and tolerable even in a real‐life context, especially for elderly patients. Implications for Practice: Diffuse large B‐cell lymphoma (DLBCL) is the most common subtype of non‐Hodgkin lymphoma, and approximately 50% of the patients are >60 years of age. Patients with relapsed/refractory (rr) disease have a poor prognosis, reflected by the remarkably short life expectancy of 12 months with currently available treatments. The rrDLBCL therapeutic algorithm is not so well established because data in the everyday clinical practice are still poor. Lenalidomide for patients with rrDLBCL is effective and tolerable even in a real‐life context, especially for elderly patients. This article reports an Italian observational retrospective study conducted on the use of lenalidomide in everyday clinical practice to determine if clinical trial results are confirmed in real‐life situations. [ABSTRACT FROM AUTHOR]

Residual masses in patients with mediastinal lymphoma may be positron emission tomography (PET) positive during follow-up also in cases of complete response. The aim of this retrospective study is to verify the reliability of mediastinal PET-positive findings in suggesting disease relapse or progression during follow-up by histological verification. From January 2002 to March 2016, 96 patients with mediastinal lymphoma underwent PET follow-up after front-line treatment. A surgical biopsy was performed to confirm the suspected relapse (for a total of 113 procedures). A lymphoma relapse was diagnosed in 66/102 successful procedures (64.7%). Diagnosis at relapse was concordant with the initial diagnosis in all but 3 cases. Standardized uptake value was significantly higher among patients with relapse than among those who remained in remission (10 versus 5, p <.05). PET scan helps individuate patients with a high suspect of lymphoma relapse and may guide the surgeon to the most suitable target. [ABSTRACT FROM AUTHOR]

Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients. Cold agglutinin mediated autoimmune hemolytic anemia is rare condition, constituting approximately the 15% of all autoimmune hemolytic anemia [[4]]. Autologous peripheral blood stem cell harvest and transplant in a patient with cold agglutinin disease secondary to lymphoma. Cold agglutinin mediated autoimmune hemolytic anemia is an uncommon disorder characterized by the presence of cold agglutinins and it is associated with clinical symptoms caused by anemia and agglutination of red blood cells (RBC) in the coolest and peripheral parts of the body causing circulatory disorders such as acrocyanosis, Raynaud-like symptoms and livedo reticularis [[1]]. [Extracted from the article]

Diffuse large B-cell lymphoma is the most frequent histology at diagnosis among non-Hodgkin B lymphomas and can be cured in 50-70% of cases after the first-line chemotherapy regimen. Patients who do not respond to first-line treatment can undergo numerous subsequent steps, culminating in allogeneic stem cell transplant (alloSCT). A relapse after alloSCT, however, carries an awful prognosis, seeing the demise of the patient usually in the following months. Here we present the case of a multiple relapsed patient who successfully underwent therapy with pixantrone after alloSCT, obtaining a complete remission without any considerable side effects. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study is to investigate the most suitable first-line approach and the best combination treatment for primary mediastinal large B-cell lymphoma (PMLBCL) as they have been matter of debate for at least two decades.Methods: Our single centre experience in the treatment of 98 de novo PMLBCL patients over the last 20 years is reviewed. All patients received MACOP-B chemotherapy. Thirty-seven received both rituximab and mediastinal radiotherapy; 30 were irradiated after chemotherapy, although not receiving rituximab and 20 received rituximab without radiotherapy consolidation. Eleven patients received chemotherapy only.Results: Sixty-one (62.2%) patients achieved a complete response after MACOP-B (with or without rituximab); among the 27 (27.6%) partial responders, 21 obtained a complete response after radiotherapy. At the end of their scheduled treatment, 82 patients (83.7%) had a complete and 6 a partial response (6.1%). Eleven patients relapsed within the first 2 years of follow-up. The 17-year overall survival is 72.0% (15 patients died); progression-free and disease-free survival are 67.6% and 88.4%, respectively. A statistically significant difference in overall and progression-free survival was noted among treatment groups, although no disease-free survival difference was documented.Conclusions: Our data indicate that a third-generation regimen like MACOP-B could be considered a suitable first-line treatment. Mediastinal consolidation radiotherapy impacts on survival and complete response rates and remains a good strategy to convert partial into complete responses. Data suggest that radiotherapy may be avoided in patients obtaining a complete response after (immuno)chemotherapy, but this requires confirmation with further ad hoc studies. [ABSTRACT FROM AUTHOR]

Background. Brentuximab vedotin (BV) has shown high overall response rate in refractory/relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL) with reported long-term response duration in clinical trials, but few data are available regarding its role in long-term outcomes in real life. Patients and Methods. A single-center observational study was conducted on patients treated with BV in daily clinical practice to evaluate the long-term effectiveness of BV in HL and sALCL patients and to check whether clinical trial results are confirmed in a real-life context. Results. The best response rate in the treated 53 patients (43 HL and 10 sALCL) was 69.8% (with 46.5% complete response [CR]) in HL and 100% (80% CR) for sALCL, respectively. With a median patient follow-up of 36.8 months, the estimated median duration of response was 31.5 months for HL and 17.8 for sALCL, respectively. At the latest available follow-up, 75% of patients were still in response, with 43% without any consolidation. Toxicity was primarily neurological and it was rarely so serious to require dose reduction or interruption. In addition, it always reversed completely after the end of treatment. Conclusion. Our data showed that 51% of patients treated with BV can be regarded as "long-term responders." Among these cases, for all patients who underwent stem cell transplantation immediately after BV, the procedure was consolidative. For patients who have remained in continuous CR without any consolidation after therapy, BV can induce prolonged disease control. [ABSTRACT FROM AUTHOR]

Existing therapies for Sézary syndrome (SS) are limited in efficacy and in disease control, and patients have very poor prognosis. Here, we report a case report of a patient who has a 16-year history of SS and related treatments (both standard and experimental). In particular, two drugs, one conventional (gemcitabine) and one experimental (mogamulizumab), were able to induce long lasting response. Patient refused to undergo allogeneic stem cell transplantation. After eleven lines of therapeutic approaches, the patient is in very good partial response and free of therapy at the latest available follow-up. [ABSTRACT FROM AUTHOR]

30385043 6 Ruff A, Hatcher JB, Austin RP, Esin CN, Mitchell EH, Sunita DN. 18F-Fluorodeoxyglucose positron emission tomography/computed tomography following chimeric antigen receptor T-cell therapy in large b-cell lymphoma. After 8 months, patient relapsed and was candidate for chimeric antigen receptor (CAR) T-cell therapy. [Extracted from the article]

Radioimmunotherapy ( RIT) after an induction phase with conventional chemoimmunotherapy became an attractive strategy of consolidation for patients with advanced follicular lymphoma: in particular, in many studies RIT was represented by yttrium-90-ibritumomab tiuxetan (90Y- IT). Independently by the different front-line treatment, updates on the long-term follow-up of these studies are needed because the disease course of follicular lymphoma is characterised by multiple relapses and progressively shorter durations of response. We report updated long-term efficacy and toxicity results of a multicenter phase II study on sequential treatment with four cycles of fludarabine, mitoxantrone, and rituximab followed by 90Y- IT as front-line therapy for untreated patients with intermediate/high-risk follicular lymphoma. With a median follow-up of 84 months, only 19/49 (38.8%) complete response patients relapsed, yielding an estimated long-term disease-free survival of 62.6%. The 7-year overall survival was 72.7%. Four (7.3%) second acute myeloid leukemia occurred, with a median time following RIT of 42 months. A relevant patients' responsiveness to subsequent therapies occurred: approximately 65% of relapsed patients obtained a good clinical response after the second-line treatment. These data represented the first evidence of a real role even in the long period of 90Y- IT after a fludarabine-containing regimen plus rituximab in the treatment of high-risk follicular lymphoma. [ABSTRACT FROM AUTHOR]