Novel prognostic scoring systems for severe CRS and ICANS after anti-CD19 CAR T cells in large B-cell lymphoma.

Autologous anti-CD19 chimeric antigen receptor (CAR) T cells are now used in routine practice for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Severe (grade ≥ 3) cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are still the most concerning acute toxicities leading to frequent intensive care unit (ICU) admission, prolonging hospitalization, and adding significant cost to treatment. We report on the incidence of CRS and ICANS and the outcomes in a large cohort of 925 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) in France based on patient data captured through the DESCAR-T registry. CRS of any grade occurred in 778 patients (84.1%), with 74 patients (8.0%) with grade 3 CRS or higher, while ICANS of any grade occurred in 375 patients (40.5%), with 112 patients (12.1%) with grade ≥ 3 ICANS. Based on the parameters selected by multivariable analyses, two independent prognostic scoring systems (PSS) were derived, one for grade ≥ 3 CRS and one for grade ≥ 3 ICANS. CRS-PSS included bulky disease, a platelet count < 150 G/L, a C-reactive protein (CRP) level > 30 mg/L and no bridging therapy or stable or progressive disease (SD/PD) after bridging. Patients with a CRS-PSS score > 2 had significantly higher risk to develop grade ≥ 3 CRS. ICANS-PSS included female sex, low level of platelets (< 150 G/L), use of axi-cel and no bridging therapy or SD/PD after bridging. Patients with a CRS-PSS score > 2 had significantly higher risk to develop grade ≥ 3 ICANS. Both scores were externally validated in international cohorts of patients treated with tisa-cel or axi-cel.

Epilepsy in Patients With Primary CNS Lymphoma: Prevalence, Risk Factors, and Prognostic Significance.

BACKGROUND AND OBJECTIVES: Epilepsy is a common comorbidity of brain tumors; however, little is known about the prevalence, onset time, semiology, and risk factors of seizures in primary CNS lymphoma (PCNSL). Our objectives were to determine the prevalence of epilepsy in PCNSL, to identify factors associated with epilepsy, and to investigate the prognostic significance of seizures in PCNSL. METHODS: We performed an observational, retrospective single-center study at a tertiary neuro-oncology center (2011-2023) including immunocompetent patients with PCNSL and no history of seizures. We collected clinical, imaging, and treatment data; seizure status over the course of PCNSL; and oncological and seizure outcome. The primary outcome was to determine the prevalence of epilepsy. Furthermore, we aimed to identify clinical, radiologic, and treatment-related factors associated with epilepsy. Univariate analyses were conducted using the χ2 test for categorical variables and unpaired t test for continuous variables. Predictors identified in the unadjusted analysis were included in backward stepwise logistic regression models. RESULTS: We included 330 patients, 157 (47.6%) were male, median age at diagnosis was 68 years, and the median Karnofsky Performance Status score was 60. Eighty-three (25.2%) patients had at least 1 seizure from initial diagnosis to the last follow-up, 40 (12.1%) as the onset symptom, 16 (4.8%) during first line of treatment, 27 (8.2%) at tumor progression and 6 (1.8%) while in remission. Focal aware seizures were the most frequent seizure type, occurring in 43 (51.8%) patients. Seizure freedom under antiseizure medication was observed in 97.6% patients. Cortical contact (odds ratio [OR] 8.6, 95% CI 4.2-15.5, p < 0.001) and a higher proliferation index (OR 5.7, 95% CI 1.3-26.2, p = 0.02) were identified as independent risk factors of epilepsy. Patients with PCNSL and epilepsy had a significantly shorter progression-free survival (median progression-free survival 9.6 vs 14.1 months, adjusted hazard ratio 1.4, 95% CI 1.0-1.9, p = 0.03), but not a significantly shorter overall survival (17 vs 44.1 months, log-rank test, p = 0.09). DISCUSSION: Epilepsy affects a quarter of patients with PCNSL, with half experiencing it at the time of initial presentation and potentially serving as a marker of disease progression. Further research is necessary to assess the broader applicability of these findings because they are subject to the constraints of a retrospective design and tertiary center setting.

A retrospective observational study of ibrutinib in chronic lymphocytic leukaemia in a real-life setting in France using the national claims database (OSIRIS).

BACKGROUND: Ibrutinib is a Bruton's tyrosine kinase inhibitor indicated for the first-line treatment and relapse of chronic lymphocytic leukaemia (CLL), Waldenström's macroglobulinemia (WM) and mantle cell lymphoma (MCL). This study aimed to describe the characteristics of CLL patients treated with ibrutinib and its effectiveness, safety, and treatment pattern in real life. METHODS: All patients covered by the general health scheme (approximately 80% of the French population) with a first ibrutinib dispensation from August 1, 2017 (date of reimbursement in France) to December 31, 2020, were identified in the French National Health Insurance database (SNDS). An algorithm was developed to identify the disease (CLL, MCL or WM) for which ibrutinib was prescribed. This article focused on CLL patients. The time to next treatment (TTNT) was plotted using Kaplan‒Meier curves. RESULTS: During this period, 6,083 patients initiated ibrutinib, among whom 2,771 (45.6%) patients had CLL (mean age of 74 years; 61% of men). At ibrutinib initiation, 46.6% of patients had a cardiovascular comorbidity. Most patients (91.7%) were not hospitalized during the exposure period for one of the cardiovascular or bleeding events studied. Hospitalizations were more frequent in patients with a cardiovascular comorbidity (5.9% versus 11.0%, p-value < 0.0001) and aged over 70 (5.9% versus 9.4%, p-value < 0.0001). The median TTNT was not reached. CONCLUSION: This is one of the largest cohorts of ibrutinib-treated patients in the world. The profile of CLL patients treated with ibrutinib was in accordance with the marketing authorization and reimbursement. This study confirmed effectiveness and safety data.

Prognostic Value of CSF IL-10 at Early Assessment of Induction Chemotherapy in Primary CNS Lymphomas: A LOC Network Study.

OBJECTIVES: Despite a high response rate at the first evaluation during induction chemotherapy, the risk of early relapse remains high and unpredictable in primary CNS lymphomas (PCSNLs). We aimed to assess the prognostic value of early IL-10 levels in CSF (e-IL-10) after 2 months of induction chemotherapy. METHODS: We retrospectively selected from the LOC (Lymphomes Oculo-Cérébraux) network database patients with PCSNLs who had complete or partial response at the 2-month evaluation of a high-dose methotrexate-based first-line chemotherapy for whom e-IL-10 was available. RESULTS: Thirty patients (median age: 62 years, brain involvement in 30/30, CSF involvement in 10/30, median baseline CSF IL-10: 27.5 pg/mL) met the selection criteria. e-IL-10 was undetectable in 22 patients and detectable in 8 patients. At the end of induction treatment, 7 of 8 and 4 of 22 of the patients with detectable and undetectable e-IL-10 had experienced progressive disease, respectively (p = 0.001, OR: 26.8, 95% CI 2-1,478). The median progression-free survival times were 5.8 months (95% CI 2.8-8.8) and 28.7 months (95% CI 13.4-43.9) in the groups with detectable and undetectable e-IL-10, respectively (p < 0.001). DISCUSSION: Our results suggest that despite an objective response, the persistence of detectable e-IL-10 is associated with a high risk of early relapse in PCNSL. A closer follow-up of such patients is warranted.

Epstein-Barr Virus and immune status imprint the immunogenomics of non-Hodgkin lymphomas occurring in immune-suppressed environments.

Non-Hodgkin lymphomas (NHL) commonly occur in immune-deficient (ID) patients, both HIV-infected and transplanted, and are often EBV-driven with cerebral localization, raising the question of tumor immunogenicity, a critical issue for treatment responses. We investigated the immunogenomics of 68 lymphoproliferative disorders from 51 ID (34 posttransplant, 17 HIV+) and 17 immunocompetent patients. Overall, 72% were Large B Cells Lymphoma (LBCL) and 25% were primary central-nervous-system lymphoma (PCNSL) while 40% were EBV-positive. Tumor whole-exome and RNA sequencing, along with a bioinformatics pipeline allowed analysis of tumor mutational burden (TMB), tumor landscape and microenvironment (TME) and prediction of tumor neoepitopes. Both TMB (2.2 vs 3.4/Mb, p=0.001) and neoepitopes numbers (40 vs 200, p=0.00019) were lower in EBVpositive than in EBV-negative NHL, regardless of the immune status. In contrast both EBV and the immune status influenced the tumor mutational profile, with HNRNPF and STAT3 mutations exclusively observed in EBV-positive and ID NHL, respectively. Peripheral blood T-cell responses against tumor neoepitopes were detected in all EBV-negative cases but in only half EBV-positive ones, including responses against IgH-derived MHC-class-II restricted neoepitopes. The TME analysis showed higher CD8 T cell infiltrates in EBVpositive vs EBV-negative NHL, together with a more tolerogenic profile composed of Tregs, type-M2 macrophages and an increased expression of negative immune-regulators. Our results highlight that the immunogenomics of NHL in patients with immunodeficiency primarily relies on the tumor EBV status, while T cell recognition of tumor- and IgH-specific neoepitopes is conserved in EBV-negative patients, offering potential opportunities for future T cell-based immune therapies.

Primary central nervous system lymphomas in immunocompromised patients require specific response criteria.

PURPOSE: Immunosuppression is a well-established risk factor for primary central nervous system lymphomas (PCNSLs), which present in this context distinct radiological characteristics. Our aim was to describe the radiological evolution of treated PCNSL in immunocompromised patients and suggest adapted MRI response criteria. METHODS: We conducted a multicenter retrospective study of patients from the French LOC, K-Virogref and CANCERVIH network databases and enrolled adult immunocompromised patients with newly diagnosed PCNSL. RESULTS: We evaluated the baseline, intermediate, end-of-treatment and follow-up MRI data of 31 patients (9 living with HIV, 16 with solid organ transplantation and 6 with an autoimmune disease under chronic immunosuppressive therapy). At baseline, 23/30 (77%) patients had necrotic lesions with ring enhancement and 28% of the lesions were hemorrhagic. At the end of the first-line treatment, 12/28 (43%) patients could not be classified according to the IPCG criteria. Thirteen of 28 (46%) patients still harbored contrast enhancement, and 11/28 (39%) patients had persistent large necrotic lesions with a median diameter of 15 mm. These aspects were not associated with a pejorative outcome and progressively diminished during follow-up. Six patients relapsed; however, we failed to identify any neuroimaging risk factors on the end-of-treatment MRI. CONCLUSION: In immunocompromised patients, PCNSLs often harbor alarming features on end-of-treatment MRI, with persistent contrast-enhanced lesions frequently observed. However, these aspects seemed to be related to the necrotic and hemorrhagic nature of the lesions and were not predictive of a pejorative outcome. Specific response criteria for this population are thereby proposed.

Cerebellum/liver index on baseline 18F-FDG PET/CT to improve prognostication in post-transplant lymphoproliferative disorders: a multicenter retrospective study.

BACKGROUND: Besides International Prognostic Index (IPI) score, baseline prognostic factors of post-transplant lymphoproliferative disorders (PTLD) are poorly identified due to the rarity of the disease. New indexes derived from healthy organ uptake in baseline 18F-FDG PET/CT have been studied in immunocompetent lymphoma patients. The aim of this study is to evaluate the performances of the cerebellum-to-liver uptake ratio (denoted as CLIP) as a prognostic factor for PFS and OS. This retrospective multicenter study is based on patients with PTLD included in the K-VIROGREF cohort. The previously published threshold of 3.24 was used for CLIP in these analyses. RESULTS: A total of 97 patients was included with a majority of monomorphic diffuse large B-cell lymphoma subtype (78.3%). Both IPI score (≥ 3) and CLIP (< 3.24) were significant risk factors of PFS with corresponding hazard ratios of 2.0 (1.0-4.0) and 2.4 (1.3-4.5) respectively. For OS, CLIP was not significant and resulted in a hazard ratio of 2.6 (p = 0.059). Neither IPI score or Total Metabolic Tumor Volume reached significance for OS. CONCLUSION: CLIP is a promising predictor of PFS and perhaps OS in PTLD. Further prospective studies are needed to confirm these results.

CAR T-cell therapy induces a high rate of prolonged remission in relapsed primary CNS lymphoma: Real-life results of the LOC network.

The prognosis of relapsed primary central nervous system lymphoma (PCNSL) remains dismal. CAR T-cells are a major contributor to systemic lymphomas, but their use in PCNSL is limited. From the LOC network database, we retrospectively selected PCNSL who had leukapheresis for CAR-T cells from the third line of treatment, and, as controls, PCNSL treated with any treatment, at least in the third line and considered not eligible for ASCT. Twenty-seven patients (median age: 68, median of three previous lines, including ASCT in 14/27) had leukapheresis, of whom 25 received CAR T-cells (tisa-cel: N = 16, axi-cel: N = 9) between 2020 and 2023. All but one received a bridging therapy. The median follow-up after leukapheresis was 20.8 months. The best response after CAR-T cells was complete response in 16 patients (64%). One-year progression-free survival from leukapheresis was 43% with a plateau afterward. One-year relapse-free survival was 79% for patients in complete or partial response at CAR T-cell infusion. The median overall survival was 21.2 months. Twenty-three patients experienced a cytokine release syndrome and 17/25 patients (68%) a neurotoxicity (five grade ≥3). The efficacy endpoints were significantly better in the CAR T-cell group than in the control group (N = 247) (median PFS: 3 months; median OS: 4.7 months; p < 0.001). This series represents the largest cohort of PCNSL treated with CAR T-cells reported worldwide. CAR T-cells are effective in relapsed PCNSL, with a high rate of long-term remission and a reassuring tolerance profile. The results seem clearly superior to those usually observed in this setting.

Tabelecleucel for allogeneic haematopoietic stem-cell or solid organ transplant recipients with Epstein-Barr virus-positive post-transplant lymphoproliferative disease after failure of rituximab or rituximab and chemotherapy (ALLELE): a phase 3, multicentre, open-label trial.

BACKGROUND: Survival in Epstein-Barr virus (EBV)-positive post-transplant lymphoproliferative disease following haematopoietic stem-cell transplant (HSCT) or solid organ transplant (SOT) is poor after failure of initial therapy, indicating an urgent need for therapies for this ultra-rare disease. With recent EU marketing authorisation, tabelecleucel is the first off-the-shelf, allogeneic, EBV-specific T-cell immunotherapy to receive approval for treatment of relapsed or refractory EBV-positive post-transplant lymphoproliferative disease. We aimed to determine the clinical benefit of tabelecleucel in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease following HSCT or SOT. METHODS: In this global, multicentre, open-label, phase 3 trial, eligible patients (of any age) had biopsy-proven EBV-positive post-transplant lymphoproliferative disease, disease that was relapsed or refractory to rituximab after HSCT and rituximab with or without chemotherapy after SOT, and partially HLA-matched and appropriately HLA-restricted tabelecleucel available. Patients received tabelecleucel administered intravenously at 2 × 106 cells per kg on days 1, 8, and 15 in 35-day cycles and are assessed for up to 5 years for survival post-treatment initiation. The primary endpoint was objective response rate. All patients who received at least one dose of tabelecleucel were included in safety and efficacy analyses. This trial is registered with ClinicalTrials.gov, NCT03394365, and is ongoing. FINDINGS: From June 27, 2018, to Nov 5, 2021, 63 patients were enrolled, of whom 43 (24 [56%] male and 19 [44%] female) were included, 14 had prior HSCT, 29 had SOT. Seven (50%, 95% CI 23-77) of 14 participants in the HSCT group and 15 (52%, 33-71) of 29 participants in the SOT group had an objective response, with a median follow-up of 14·1 months (IQR 5·7-23·9) and 6·0 months (1·8-18·4), respectively. The most common grade 3 or 4 treatment-emergent adverse events were disease progression (in four [29%] of 14 in HSCT and eight [28%] of 29 in SOT) and decreased neutrophil count (in four [29%] of 14 in HSCT and four [14%] of 29 in SOT). Treatment-emergent serious adverse events were reported in 23 (53%) of 43 patients and fatal treatment-emergent adverse events in five (12%); no fatal treatment-emergent adverse event was treatment-related. There were no reports of tumour flare reaction, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, transmission of infectious diseases, marrow rejection, or infusion reactions. No events of graft-versus-host disease or SOT rejection were reported as related to tabelecleucel. INTERPRETATION: Tabelecleucel provides clinical benefit in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease, for whom there are no other approved therapies, without evidence of safety concerns seen with other adoptive T-cell therapies. These data represent a potentially transformative and accessible treatment advance for patients with relapsed or refractory disease with few treatment options. FUNDING: Atara Biotherapeutics.

Interim FDG-PET improves treatment failure prediction in primary central nervous system lymphoma: An LOC network prospective multicentric study.

BACKGROUND: The purpose of our study was to assess the predictive and prognostic role of 2-18F-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)/MRI during high-dose methotrexate-based chemotherapy (HD-MBC) in de novo primary central nervous system lymphoma (PCNSL) patients aged 60 and above. METHODS: This prospective multicentric ancillary study included 65 immunocompetent patients who received induction HD-MBC as part of the BLOCAGE01 phase III trial. FDG-PET/MRI were acquired at baseline, post 2 cycles (PET/MRI2), and posttreatment (PET/MRI3). FDG-PET response was dichotomized with "positive" indicating persistent tumor uptake higher than the contralateral mirroring brain region. Performances of FDG-PET and International PCNSL Collaborative Group criteria in predicting induction response, progression-free survival (PFS), and overall survival (OS) were compared. RESULTS: Of the 48 PET2 scans performed, 9 were positive and aligned with a partial response (PR) on MRI2. Among these, 8 (89%) progressed by the end of the induction phase. In contrast, 35/39 (90%) of PET2-negative patients achieved complete response (CR). Among the 18 discordant responses at interim (PETCR/MRIPR), 83% ultimately achieved CR. Eighty-seven percent of the PET2-negative patients were disease free at 6 months versus 11% of the PET2-positive patients (P < .001). The MRI2 response did not significantly differentiate patients based on their PFS, regardless of whether they were in CR or PR. Both PET2 and MRI2 independently predicted OS in multivariate analysis, with PET2 showing a stronger association. CONCLUSIONS: Our study highlights the potential of interim FDG-PET for early management of PCNSL patients. Response-driven treatment based on PET2 may guide future clinical trials. TRIAL: LOCALYZE, NCT03582254, ancillary of phase III clinical trial BLOCAGE01, NCT02313389 (Registered July 10, 2018-retrospectively registered) https://clinicaltrials.gov/ct2/show/NCT03582254?term=LOCALYZE&draw=2&rank=1.

Transfusion needs after CAR T-cell therapy for large B-cell lymphoma: predictive factors and outcome (a DESCAR-T study).

ABSTRACT: Chimeric antigen receptor (CAR) T-cells targeting CD19 have been approved for the treatment of relapse/refractory large B-cell lymphoma. Hematotoxicity is the most frequent CAR T-cell-related adverse event. Transfusion support is a surrogate marker of severe cytopenias. Transfusion affects patients' quality of life, presents specific toxicities, and is known to affect immunity through the so-called transfusion-related immunomodulation that may affect CAR T-cell efficacy. We analyzed data from 671 patients from the French DESCAR-T registry for whom exhaustive transfusion data were available. Overall, 401 (59.8%) and 378 (56.3%) patients received transfusion in the 6-month period before and after CAR T-cell infusion, respectively. The number of patients receiving transfusion and the mean number of transfused products increased during the 6-month period before CAR T-cell infusion, peaked during the first month after infusion (early phase), and decreased over time. Predictive factors for transfusion at the early phase were age >60 years, ECOG PS ≥2, treatment with axicabtagene ciloleucel, pre-CAR T-cell transfusions, and CAR-HEMATOTOX score ≥2. Predictive factors for late transfusion (between 1 and 6 months after infusion) were pre-CAR T-cell transfusions, CAR-HEMATOTOX score ≥2, ICANS ≥3 (for red blood cells [RBC] transfusion), and tocilizumab use (for platelets transfusion). Early transfusions and late platelets (but not RBC) transfusions were associated with a shorter progression-free survival and overall survival. Lymphoma-related mortality and nonrelapse mortality were both increased in the transfused population. Our data shed light on the mechanisms of early and late cytopenia and on the potential impact of transfusions on CAR T-cell efficacy and toxicity.

Higher Levels of SARS-CoV-2 Genetic Variation in Immunocompromised Patients: A Retrospective Case-Control Study.

BACKGROUND: A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection lasts longer in immunocompromised hosts than in immunocompetent patients. Prolonged infection is associated with a higher probability of selection for novel SARS-CoV-2 mutations, particularly in the spike protein, a critical target for vaccines and therapeutics. METHODS: From December 2020 to September 2022, respiratory samples from 444 immunocompromised patients and 234 health care workers positive for SARS-CoV-2, diagnosed at 2 hospitals in Paris, France, were analyzed using whole-genome sequencing using Nanopore technology. Custom scripts were developed to assess the SARS-CoV-2 genetic diversity between the 2 groups and within the host. RESULTS: Most infections were SARS-CoV-2 Delta or Omicron lineages. Viral genetic diversity was significantly higher in infections of immunocompromised patients than those of controls. Minor mutations were identified in viruses sequenced from immunocompromised individuals, which became signature mutations for newer SARS-CoV-2 variants as the epidemic progressed. Two patients were coinfected with Delta and Omicron variants. The follow-up of immunocompromised patients revealed that the SARS-CoV-2 genome evolution differed in the upper and lower respiratory tracts. CONCLUSIONS: This study found that SARS-CoV-2 infection in immunocompromised patients is associated with higher genetic diversity, which could lead to the emergence of new SARS-CoV-2 variants with possible immune evasion or different virulence characteristics.

Fatigue visual analogue scale score correlates with quality of life in cancer patients receiving epoetin alfa (Sandoz) for chemotherapy-induced anaemia: The CIROCO study.

PURPOSE: Available tools to measure fatigue and health-related quality of life (HRQoL) in cancer patients are often difficult to use in clinical practice. The fatigue visual analogue scale (VAS) provides a simple method to assess fatigue. This study evaluated the correlation between HRQoL and fatigue perceived by cancer patients undergoing chemotherapy. METHODS: This was a non-interventional prospective study of adult cancer patients in France presenting with chemotherapy-induced anaemia (CIA) treated with epoetin alfa (Sandoz). Data were collected using an electronic case report form at study inclusion (T0), after 2-3 chemotherapy cycles (T1) and after 4-6 cycles (T2). RESULTS: The study included 982 patients from September 2015 to October 2017. Overall, there was a negative correlation between fatigue VAS and HRQoL. The overall haemoglobin (Hb) change between T0 and T2 was +17.8 % (± 18.1 %). Fatigue assessed by both patients and physicians showed a clinically significant improvement during the study. Global HRQoL also increased. CONCLUSION: Treatment of CIA with epoetin alfa (Sandoz) improved Hb levels, fatigue, and HRQoL, with a correlation observed between fatigue VAS score and HRQoL. Fatigue VAS could act as a simple alternative to more complex methods to measure HRQoL; however, further analyses are required to confirm this association.