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First-line therapy for patients with extranodal marginal zone lymphoma (EMZL) is not well established, except for eradication therapy for Helicobacter pylori in early gastric MZL. Various regimens, for example, locoregional treatment and systemic chemo-immunotherapy, can be used depending on the site and stage of disease. Single-agent rituximab is a useful approach in the setting of localized, low-intermediate risk EMZL. The aim our research was to analyze the effectiveness and safety of single-agent rituximab (375 mg/m2 once weekly for 4 weeks) in naïve EMZL in a real-life setting. The primary endpoint was the overall response rate (ORR), secondary endpoints were progression-free (PFS), overall (OS) and disease-free survivals (DFS), and drug tolerability. Fifty-nine patients were analyzed. Median time between diagnosis and rituximab was 3.6 months. The ORR was 89.9%, with 67.8% complete response (CR). Median DFS and PFS were reached at 6.3 and 5.3 years, respectively. After a median follow-up of 5 years, median OS was not reached. The most common adverse event was infusion reaction, reported in 28 cases, mainly during the first infusion and easily manageable. Single-agent rituximab may represent a valid therapeutic option in the first-line treatment of EMZL, at least for localized disease, with a favorable toxicity profile.
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BACKGROUND: The diffuse large B-cell lymphoma (DLBCL) variant of Richter transformation (DLBCL-RT) is typically chemoresistant with poor prognosis. Aiming to explore a chemotherapy-free treatment combination that triggers anti-tumour immune responses, we conducted a phase 2 study of atezolizumab (a PD-L1 inhibitor) in combination with venetoclax and obinutuzumab in patients with DLBCL-RT. METHODS: This was a prospective, open-label, multicentre, single-arm, investigator-initiated, phase 2 study in 15 hospitals in Italy and Switzerland. Eligible patients had a confirmed diagnosis of chronic lymphocytic leukaemia or small lymphocytic lymphoma as per the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria with biopsy-proven transformation to DLBCL; had not previously received treatment for DLBCL-RT, although they could have received chronic lymphocytic leukaemia therapies; were aged 18 years or older; and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. No previous treatment with any of the drugs in the triplet combination was allowed. Patients received 35 cycles of 21 days of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, 1000 mg on day 8 and day 15 of cycle 1; 1000 mg on day 1 of cycles 2-8) and intravenous atezolizumab (1200 mg on day 2 of cycle 1 and 1200 mg on day 1 of cycles 2-18), and continuous oral venetoclax (ramp-up from 20 mg/day on day 15 of cycle 1 according to chronic lymphocytic leukaemia schedule, then 400 mg/day from day 1 of cycle 3 to day 21 of cycle 35). The primary endpoint was overall response rate at day 21 of cycle 6 in the intention-to-treat population. We considered an overall response rate of 67% or more to be clinically active, rejecting the null hypothesis of a response of 40% or less. The study is registered with ClinicalTrials.gov, NCT04082897, and has been completed. FINDINGS: Between Oct 9, 2019, and Oct 19, 2022, 28 patients were enrolled (12 [43%] male patients and 16 [57%] female patients). Median follow-up was 16·8 months (IQR 7·8-32·0). At cycle 6, 19 of 28 patients showed a response, yielding an overall response rate of 67·9% (95% CI 47·6-84·1). Treatment-emergent adverse events that were grade 3 or worse were reported in 17 (61%; 95% CI 40·6-78·5) of 28 patients, with neutropenia being the most frequent (11 [39%; 21·5-59·4] of 28 patients). Serious treatment-emergent adverse events were reported in eight (29%; 14·2-48·7) patients, which were most commonly infections (five [18%; 6·1-36·9] of 28 patients). There were two (7%) deaths attributable to adverse events during the study: one from sepsis and one from fungal pneumonia, which were not considered as directly treatment-related by the investigators. Six (21·4%) patients had immune-related adverse events, none of which led to discontinuation. No tumour lysis syndrome was observed. INTERPRETATION: The atezolizumab, venetoclax, and obinutuzumab triplet combination was shown to be active and safe, suggesting that this chemotherapy-free regimen could become a new first-line treatment approach in patients with DLBCL-RT. FUNDING: Roche.
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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.
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Microbioma Gastrointestinal , Inhibidores de Puntos de Control Inmunológico , Humanos , Microbioma Gastrointestinal/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Linfoma/tratamiento farmacológico , Linfoma/microbiología , Adulto Joven , Pronóstico , Resultado del TratamientoRESUMEN
Follicular lymphoma (FL) is an indolent, germinal center B cell-derived lymphoid neoplasm, for which recent advances in treatment have substantially improved patient survival. However, FL remains an incurable and heterogeneous disease, with groups of patients experiencing early disease progression, histologic transformation, or a high risk of treatment-related toxicity. Additionally, FL is a continually relapsing disease, and response rates and disease-control intervals decrease with each subsequent line of therapy. In this review, we explore the current treatment landscape for relapsed or refractory FL and promising therapies in development, highlighting the efficacy and potential risks of each treatment. We provide a real-world perspective on the unmet needs of patients with FL. Novel therapeutic approaches in development offer a wide array of options for clinicians when treating relapsed or refractory FL. A nuanced approach is required to address the needs of individual patients, taking into consideration both the risks and benefits of each treatment option, as well as patient preferences.
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ABSTRACT: Copanlisib, a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the α and δ isoforms, previously demonstrated durable responses as monotherapy and improved progression-free survival (PFS) in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma (iNHL). CHRONOS-4 was a phase 3, randomized, double-blind, placebo-controlled study to investigate the efficacy and safety of copanlisib in combination with standard immunochemotherapy in patients with relapsed iNHL. Patients (n = 524) were randomized (1:1) to copanlisib (60 mg IV) plus immunochemotherapy (rituximab and bendamustine [R-B] or placebo plus R-B). Copanlisib/placebo were administered with R-B (days 1, 8, and 15 of each 28-day cycle) for ≤6 cycles and as monotherapy from cycle 7 up to 12 months. The primary study end point was PFS. Median exposure was 8.5 months (0.2-12.9) for copanlisib plus R-B and 11.4 months (0.1-12.6) for placebo plus R-B. Median PFS was 32.9 months (95% confidence interval [CI], 24.4-38.6) for copanlisib plus R-B and 33.3 months (95% CI, 27.8-42.8) for placebo plus R-B (hazard ratio, 1.13; 95% CI, 0.88-1.44; P = .83). No differences between treatment arms were observed in overall survival (data not yet mature), objective response rate, and duration of response for the overall population or individual histology types. Overall, copanlisib plus R-B was associated with higher rates of serious treatment-emergent adverse events (TEAEs), grade 4 and 5 TEAEs, and treatment discontinuation. A number of serious TEAEs were infections. Overall, copanlisib plus R-B did not provide clinical benefit vs placebo plus R-B and was associated with worse tolerability in patients with relapsed iNHL. This trial was registered at www.ClinicalTrials.gov as #NCT02626455.
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Protocolos de Quimioterapia Combinada Antineoplásica , Pirimidinas , Rituximab , Humanos , Rituximab/uso terapéutico , Rituximab/administración & dosificación , Femenino , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano , Pirimidinas/uso terapéutico , Pirimidinas/administración & dosificación , Adulto , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/mortalidad , Quinazolinas/uso terapéutico , Quinazolinas/administración & dosificación , Anciano de 80 o más Años , Resultado del Tratamiento , Método Doble Ciego , RecurrenciaRESUMEN
BACKGROUNDPredicting immune effector cell-associated neurotoxicity syndrome (ICANS) in patients infused with CAR T cells is still a conundrum. This complication, thought to be consequent to CAR T cell activation, arises a few days after infusion, when circulating CAR T cells are scarce and specific CAR T cell-derived biomarkers are lacking.METHODSCAR+ extracellular vesicle (CAR+EV) release was assessed in human CD19.CAR T cells cocultured with CD19+ target cells. A prospective cohort of 100 patients with B cell lymphoma infused with approved CD19.CAR T cell products was assessed for plasma CAR+EVs as biomarkers of in vivo CD19.CAR T cell activation. Human induced pluripotent stem cell-derived (iPSC-derived) neural cells were used as a model for CAR+EV-induced neurotoxicity.RESULTSIn vitro release of CAR+EVs occurs within 1 hour after target engagement. Plasma CAR+EVs are detectable 1 hour after infusion. A concentration greater than 132.8 CAR+EVs/µL at hour +1 or greater than 224.5 CAR+EVs/µL at day +1 predicted ICANS in advance of 4 days, with a sensitivity and a specificity outperforming other ICANS predictors. ENO2+ nanoparticles were released by iPSC-derived neural cells upon CAR+EV exposure and were increased in plasma of patients with ICANS.CONCLUSIONPlasma CAR+EVs are an immediate signal of CD19.CAR T cell activation, are suitable predictors of neurotoxicity, and may be involved in ICANS pathogenesis.TRIAL REGISTRATIONNCT04892433, NCT05807789.FUNDINGLife Science Hub-Advanced Therapies (financed by Health Ministry as part of the National Plan for Complementary Investments to the National Recovery and Resilience Plan [NRRP]: E.3 Innovative health ecosystem for APC fees and immunomonitoring).
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Antígenos CD19 , Vesículas Extracelulares , Inmunoterapia Adoptiva , Linfoma de Células B , Humanos , Vesículas Extracelulares/inmunología , Vesículas Extracelulares/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Antígenos CD19/inmunología , Linfoma de Células B/inmunología , Linfoma de Células B/terapia , Linfoma de Células B/sangre , Adulto , Anciano , Receptores Quiméricos de Antígenos/inmunología , Estudios ProspectivosRESUMEN
INTRODUCTION: Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment. METHODS: Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs). RESULTS: Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy. CONCLUSIONS: Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.
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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/m2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m2 on day 1, intravenous doxorubicin 50 mg/m2 on day 1, intravenous vincristine 1·4 mg/m2 on day 1, and oral prednisone 100 mg on days 1-5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m2 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.
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Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Linfoma de Células del Manto , Piperidinas , Rituximab , Trasplante Autólogo , Vincristina , Humanos , Linfoma de Células del Manto/terapia , Linfoma de Células del Manto/tratamiento farmacológico , Adenina/análogos & derivados , Adenina/administración & dosificación , Adenina/uso terapéutico , Piperidinas/administración & dosificación , Piperidinas/uso terapéutico , Persona de Mediana Edad , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Vincristina/administración & dosificación , Vincristina/uso terapéutico , Rituximab/administración & dosificación , Rituximab/uso terapéutico , Adulto , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Anciano , Europa (Continente) , Trasplante de Células Madre Hematopoyéticas/métodos , Prednisona/administración & dosificación , Prednisona/uso terapéutico , Doxorrubicina/administración & dosificación , Adulto Joven , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Adolescente , Israel , Resultado del TratamientoRESUMEN
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.
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Antígenos CD19 , Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso , Humanos , Masculino , Femenino , Inmunoterapia Adoptiva/economía , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Italia , Linfoma de Células B Grandes Difuso/economía , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/inmunología , Adulto , Receptores Quiméricos de Antígenos/uso terapéutico , Leucaféresis/economíaRESUMEN
Concern has emerged about the prevalence of second cancers among patients with hairy cell leukemia (HCL) treated with purine analogs. We investigated 513 patients with HCL treated with cladribine over the last 30 years at 18 Italian centers and calculated their standardized incidence ratios (SIRs). We identified 24 patients with a second cancer diagnosed at a median time from treatment with cladribine of 59.9 months (range: 9.2-169.7 months). All patients with solid neoplasms presented with a limited-stage disease, except four cases of locally advanced cancer; multiple myeloma patients had a smoldering disease, while lymphoma patients had stage Ie and stage IV diseases. Response to therapy was complete in 19 cases; 1 patient is still receiving treatment for a relapsing bladder disease, while 2 patients progressed during treatment and died. These two patients died from unrelated causes: one from infection and one due to surgery complications. The median OS from HCL was 98.5 months (range: 38.4-409.2 months), while the median OS from second cancer was 27.6 months (range: 1-117.8 months). The SIR was 0.86 (95% CI: 0.54-1.30) for males and 1.13 (95% CI: 0.36-2.73) for females: no statistically significant differences were highlighted. We were not able to demonstrate an excess of second cancer or a significant association with the specific studied neoplasm.
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Background: Activated phosphoinositide 3-kinase-δ syndrome 2 (APDS2) is characterized by lymphoproliferation and increased risk of malignancy. FDG-PET/CT may represent a helpful diagnostic tool for differentiating these clinical features and correctly diagnosing inborn errors of immunity (IEI). Case report: We present the case of a female patient diagnosed with Hodgkin's lymphoma at 19 years of age, although atypical imaging aspects emerged: baseline FDG-PET/CT revealed several hot lymph nodes with a symmetrical distribution, and increased tracer uptake in spleen, axial, and appendicular bone marrow. Imaging repeated after chemotherapy and autologous stem cell transplantation showed persistent increased FDG uptake at multiple supradiaphragmatic nodes and in bone marrow. After the diagnosis of APDS2 and rapamycin treatment, FDG-PET/CT confirmed complete metabolic normalization of all sites. Conclusions: In the IEI scenario, FDG-PET/CT plays an effective role in differentiating malignant proliferation and immune dysregulation phenotypes. Atypical patterns at FDG-PET/CT should be interpreted as a red flag for the need of an early immunological evaluation.
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ABSTRACT: Several single-arm studies have explored the inclusion of brentuximab vedotin (BV) in salvage chemotherapy followed by autologous stem cell transplantation (ASCT) for relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL). However, no head-to-head comparisons with standard salvage chemotherapy have been performed. This study presents a propensity score-matched analysis encompassing individual patient data from 10 clinical trials to evaluate the impact of BV in transplant-eligible patients with R/R cHL. We included 768 patients, of whom 386 were treated with BV with or without chemotherapy (BV cohort), whereas 382 received chemotherapy alone (chemotherapy cohort). Propensity score matching resulted in balanced cohorts of 240 patients each. No significant differences were observed in pre-ASCT complete metabolic response (CMR) rates (P = .69) or progression free survival (PFS; P = .14) between the BV and chemotherapy cohorts. However, in the BV vs chemotherapy cohort, patients with relapsed disease had a significantly better 3-year PFS of 80% vs 70%, respectively (P = .02), whereas there was no difference for patients with primary refractory disease (56% vs 62%, respectively; P = .67). Patients with stage IV disease achieved a significantly better 3-year PFS in the BV cohort (P = .015). Post-ASCT PFS was comparable for patients achieving a CMR after BV monotherapy and those receiving BV followed by sequential chemotherapy (P = .24). Although 3-year overall survival was higher in the BV cohort (92% vs 80%, respectively; P < .001), this is likely attributed to the use of other novel therapies in later lines for patients experiencing progression, given that studies in the BV cohort were conducted more recently. In conclusion, BV with or without salvage chemotherapy appears to enhance PFS in patients with relapsed disease but not in those with primary refractory cHL.
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Brentuximab Vedotina , Enfermedad de Hodgkin , Puntaje de Propensión , Humanos , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/terapia , Brentuximab Vedotina/uso terapéutico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Terapia Recuperativa , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia , Adulto Joven , Adolescente , Resultado del Tratamiento , Anciano , Recurrencia Local de Neoplasia/tratamiento farmacológico , Resistencia a AntineoplásicosAsunto(s)
Brentuximab Vedotina , Linfoma Cutáneo de Células T , Linfoma de Células T Periférico , Nivolumab , Humanos , Brentuximab Vedotina/uso terapéutico , Linfoma de Células T Periférico/tratamiento farmacológico , Nivolumab/uso terapéutico , Nivolumab/administración & dosificación , Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma Cutáneo de Células T/patología , Masculino , Persona de Mediana Edad , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patologíaRESUMEN
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.
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Anticonvulsivantes , Antígenos CD19 , Inmunoterapia Adoptiva , Linfoma no Hodgkin , Convulsiones , Humanos , Masculino , Femenino , Persona de Mediana Edad , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Convulsiones/prevención & control , Antígenos CD19/inmunología , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/uso terapéutico , Linfoma no Hodgkin/terapia , Linfoma no Hodgkin/inmunología , Adulto , Anciano , Síndromes de Neurotoxicidad/prevención & control , Síndromes de Neurotoxicidad/etiologíaRESUMEN
Axicabtagene ciloleucel showed efficacy for relapsed/refractory large B-cell lymphomas (LBCL), including primary mediastinal B-cell lymphomas (PMBCL); however, only few PMBCLs were reported. Aim was to evaluate efficacy and safety of axicabtagene ciloleucel in patients with PMBCL compared to those with other LBCL, enrolled in the Italian prospective observational CART-SIE study. PMBCLs (n = 70) were younger, with higher percentage of bulky and refractory disease, compared to other LBCLs (n = 190). Median follow-up time for infused patients was 12.17 months (IQR 5.53,22.73). The overall (complete + partial) response rate (ORR,CR + PR) after bridging was 41% for PMBCL and 28% for other LBCL, p = 0.0102. Thirty days ORR was 78% (53/68) with 50% (34) CR in PMBCL, and 75% (141/187) with 53% (100) CR in other LBCL, p = 0.5457. Ninety days ORR was 69% (45/65) with 65% (42) CR in PMBCL, and 54% (87/162) with 47% (76) CR in other LBCL; progressive disease was 21% in PMBCL and 45% in other LBCL, p = 0.0336. Twelve months progression-free survival was 62% (95% CI: 51-75) in PMBCL versus 48% (95% CI: 41-57) in other LBCL, p = 0.0386. Twelve months overall survival was 86% (95% CI: 78-95) in PMBCL versus 71% (95% CI: 64-79) in other LBCL, p = 0.0034. All grade cytokine release syndrome was 88% (228/260); all grade neurotoxicity was 34% (88/260), with 6% of fatal events in PMBCL. Non-relapse mortality was 3%. In conclusion, PMBCLs achieved significantly better response and survival rates than other LBCLs.
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Productos Biológicos , Linfoma de Células B Grandes Difuso , Neoplasias del Mediastino , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/mortalidad , Femenino , Masculino , Persona de Mediana Edad , Productos Biológicos/uso terapéutico , Neoplasias del Mediastino/patología , Neoplasias del Mediastino/tratamiento farmacológico , Neoplasias del Mediastino/mortalidad , Adulto , Estudios Prospectivos , Italia/epidemiología , Anciano , Inmunoterapia Adoptiva/métodos , Estudios de Seguimiento , Tasa de Supervivencia , Antígenos CD19 , Resultado del TratamientoRESUMEN
Zanubrutinib has been approved for treating patients with different lymphoproliferative disorders and now represents a significant breakthrough in treating relapsed/refractory and previously untreated patients with chronic lymphocytic leukemia (CLL). Because few systematic studies or comparative randomized clinical trials have been conducted, optimal use of zanubrutinib in approved indications may be challenging. This article presents the results of a group discussion among an ad hoc constituted panel of experts to identify and address unmet clinical needs (UCNs) in using zanubrutinib in patients with CLL. Key UCNs were selected according to the criterion of clinical relevance using the Delphi process. Panel members reviewed the results of first-line and upstream controlled trials in which the efficacy and toxicity profile of zanubrutinib and other BTK inhibitors were investigated in patients with CLL. Based on a critical discussion of data, the panel produced recommendations for using zanubrutinib and proposals for new studies to increase the evidence for the optimal treatment of patients with CLL. The recommendations given by the panel are intended for use not only by expert centers but, above all, by less experienced hematologists as well as general practitioners.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Piperidinas , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Consenso , Pirazoles/efectos adversos , Pirimidinas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
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.