CD137 Is Expressed in Follicular Dendritic Cell Tumors and in Classical Hodgkin and T-Cell Lymphomas Diagnostic and Therapeutic Implications

CD137 (also known as 4-1BB and TNFRSF9) is a member of the tumor necrosis factor receptor superfamily. Originally identified as a costimulatory molecule expressed by activated T cells and NK cells, CD137 is also expressed by follicular dendritic cells, monocytes, mast cells, granulocytes, and endothelial cells. Anti-CD137 immunotherapy has recently shown promise as a treatment for solid tumors and lymphoid malignancies in preclinical models. We defined the expression of CD137 protein in both normal and neoplastic hematolymphoid tissue. CD137 protein is expressed by follicular dendritic cells in the germinal center and scattered paracortical T cells, but not by normal germinal-center B cells, bone marrow progenitor cells, or maturing thymocytes. CD137 protein is expressed by a select group of hematolymphoid tumors, including classical Hodgkin lymphoma, T-cell and NK/T-cell lymphomas, and follicular dendritic cells neoplasms. CD137 is a novel diagnostic marker of these tumors and suggests a possible target for tumor-directed antibody therapy

Urelumab alone or in combination with rituximab in patients with relapsed or refractory B-cell lymphoma

Altres ajuts: This study was supported by Bristol-Myers Squibb, Princeton, NJ.Urelumab, a fully human, non-ligand binding, CD137 agonist IgG4 monoclonal antibody, enhances T-cell and natural killer-cell antitumor activity in preclinical models, and may enhance cytotoxic activity of rituximab. Here we report results in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and other B-cell lymphomas, in phase 1 studies evaluating urelumab alone (NCT01471210) or combined with rituximab (NCT01775631). Sixty patients received urelumab (0.3 mg/kg IV Q3W, 8 mg IV Q3W, or 8 mg IV Q6W); 46 received urelumab (0.1 mg/kg, 0.3 mg/kg, or 8 mg IV Q3W) plus rituximab 375 mg/m 2 IV QW. The maximum tolerated dose (MTD) of urelumab was determined to be 0.1 mg/kg or 8 mg Q3W after a single event of potential drug-induced liver injury occurred with urelumab 0.3 mg/kg. Treatment-related AEs were reported in 52% (urelumab: grade 3/4, 15%) and 72% (urelumab + rituximab: grade 3/4, 28%); three led to discontinuation (grade 3 increased AST, grade 4 acute hepatitis [urelumab]; one death from sepsis syndrome [urelumab plus rituximab]). Objective response rates/disease control rates were 6%/19% (DLBCL, n = 31), 12%/35% (FL, n = 17), and 17%/42% (other B-cell lymphomas, n = 12) with urelumab and 10%/24% (DLBCL, n = 29) and 35%/71% (FL, n = 17) with urelumab plus rituximab. Durable remissions in heavily pretreated patients were achieved; however, many were observed at doses exceeding the MTD. These data show that urelumab alone or in combination with rituximab demonstrated manageable safety in B-cell lymphoma, but the combination did not enhance clinical activity relative to rituximab alone or other current standard of care

Brexucabtagene autoleucel in relapsed or refractory mantle cell lymphoma, intention-to-treat use in the DESCAR-T registry

Not available

Impact of prior therapies and subsequent transplantation on outcomes in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in ZUMA-3

Background Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the USA for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and in the European Union for patients ≥26 years with R/R B-ALL. After 2 years of follow-up in ZUMA-3, the overall complete remission (CR) rate (CR+CR with incomplete hematological recovery (CRi)) was 73%, and the median overall survival (OS) was 25.4 months in 78 Phase 1 and 2 patients with R/R B-ALL who received the pivotal dose of brexu-cel. Outcomes by prior therapies and subsequent allogeneic stem cell transplantation (alloSCT) are reported. Methods Eligible adults had R/R B-ALL and received one infusion of brexu-cel (1×106 CAR T cells/kg) following conditioning chemotherapy. The primary endpoint was the CR/CRi rate per central review. Post hoc subgroup analyses were exploratory with descriptive statistics provided. Results Phase 1 and 2 patients (N=78) were included with median follow-up of 29.7 months (range, 20.7-58.3). High CR/CRi rates were observed across all prior therapy subgroups examined: 1 prior line of therapy (87%, n=15) and ≥2 prior lines (70%, n=63); prior blinatumomab (63%, n=38) and no prior blinatumomab (83%, n=40); prior inotuzumab (59%, n=17) and no prior inotuzumab (77%, n=61); and prior alloSCT (76%, n=29) and no prior alloSCT (71%, n=49). The frequency of Grade ≥3 cytokine release syndrome, neurological events, and treatment-related Grade 5 adverse events were largely similar among prior therapy subgroups. Median duration of remission (DOR) in responders with (n=14) and without (n=43) subsequent alloSCT was 44.2 (95% CI, 8.1 to not estimable (NE)) and 18.6 months (95% CI, 9.4 to NE); median OS was 47.0 months (95% CI, 10.2 to NE) and not reached (95% CI, 23.2 to NE), respectively. Median DOR and OS were not reached in responders without prior or subsequent alloSCT (n=22). Conclusions In ZUMA-3, adults with R/R B-ALL benefited from brexu-cel, regardless of prior therapies and subsequent alloSCT status, though survival appeared better in patients without certain prior therapies and in earlier lines of therapy. Additional studies are needed to determine the impact prior therapies and subsequent alloSCT have on outcomes of patients who receive brexu-cel

Long-term analysis of the RiBVD phase II trial reveals the unfavorable impact of <i>TP53</i> mutations and hypoalbuminemia in older adults with mantle cell lymphoma; for the LYSA group

Between 2011 and 2012, a phase II trial evaluated the use of the RiBVD (rituximab, bendamustine, velcade and dexamethasone) combination as first-line treatment for mantle cell lymphoma (MCL) patients over the age of 65. We have now re-examined the classic prognostic factors, adding an assessment of TP53 mutation status. Patients (N=74; median age 73 years) were treated with the RiBVD combination. Median progression-free survival (mPFS) was 79 months and median overall survival (mOS) was 111 months. TP53 mutation status was available for 54/74 (73%) patients. TP53 mutations (TP53mt) were found in 12 patients (22.2%). In multivariate analysis, among the prognostic factors (PF) evaluated, only TP53mt and an albumin level (Alb) 3.6 g/dL were independently associated with a shorter mPFS. A hazard ratio (HR) of 3.16 (1.3-9.9, P=0.014) was obtained for TP53mt versus TP53 wild-type (wt), and 3.6 (1.39-9.5, P=0.009) for Alb <3.6 g/dL versus Alb ≥3.6 g/dL. In terms of mOS, multivariate analysis identified three PF: TP53mt (HR: 5.9 [1.77-19.5, P=0.004]), Alb <3.6 g/dL (HR: 5.2 [1.46- 18.5, P=0.011]), and ECOG=2 (HR: 3.7 [1.31-10.6, P=0.014]). Finally, a score combining TP53 status and Alb distinguished three populations based on the presence of 0, 1, or 2 PF. For these populations, mPFS was 7.8 years, 28 months, and 2.5 months, respectively. Our prolonged follow-up confirmed the efficacy of the RiBVD regimen, comparing it favorably to other regimens. TP53mt and hypoalbuminemia emerge as strong PF that can be easily integrated into prognostic scores for older adult patients with MCL

CAR T-cells: current limitations and future developments

National audienceChimeric antigen receptor (CAR) T-cells represent a great breakthrough in the treatment of hematologic malignancies. To date, two different CAR T-cells have been approved for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Despite a remarkable efficacy, their use is limited by the occurrence of resistances and/or severe toxicities. A better understanding of these mechanisms and the progress in molecular intervention are paving the way for the development of new generations of CAR T-cells, with enhanced efficacy and/or reduced toxicity. Here, we review the mechanisms of resistance and toxicity, and the strategies which are envisioned to optimize CAR T-cell therapy

Lymphomes survenant après l'âge de 90 ans (caractéristiques, prise en charge et devenir des patients)

Le lymphome est une pathologie fréquente du sujet âgé. Sa prise en charge est complexe et soulève des questions éthiques. Dans une étude rétrospective multicentrique, nous avons analysé les données de 234 patients âgés de 90 ans et plus au diagnostic entre 1990 et 2012. Parmi eux, 227 présentaient un lymphome non hodgkinien (LNH) et 7 un lymphome de Hodgkin (LH). Les types histologiques les plus représentés étaient les lymphomes diffus à grandes cellules (48%), les lymphomes de la zone marginale (9%) et les lymphomes folliculaires (8%). L'âge médian était de 92 ans (90-100). Parmi les LNH, 66% étaient des femmes, 68% vivaient au domicile. L'indice de Charlson était =2 (p3 médicaments par jour) (p=II (p=90 years at diagnosis between 1990 and 2012. We included 234 patients: 227 Non-Hodgkin (NHL) and 7 Hodgkin lymphoma. The most frequent histologies were diffuse large B cell lymphoma (48%), marginal zone lymphoma (9%) and follicular lymphoma (8%). Median age was 92 years (90-100). About LNH, most patients were female (66%) and still living at home (68%). Charlson index was low (i.e. =2 (p3 medicines by day (p=II (p<0.02), albumin level <=36g/L (p<10 ) and absence of treatment (p<0.0004). Causes of death were principally lymphoma in 58.8% of patients. Death due to treatment were involved in 8.8%. Lymphoma occurring over the age of 90 is more frequently aggressive than indolent. In this case, the prognostic is poor. Most of the patients die of lymphoma while toxicities of the treatment remain acceptable. Thus, it is possible that a subset of patients may benefit from adapted therapies. The management of these patients may be guided using prognostic factors such as the histological subtype, the PS, the Ann Arbor stage and the albumin level.RENNES1-BU Santé (352382103) / SudocSudocFranceF

Immunothérapie des lymphomes diffus à grandes cellules B chimioréfractaires ou en rechute postautogreffe

National audienceGiven the poor prognosis of patients with relapsed or refractory diffuse large B-cell lymphomas (R/R LDGCB), the development of novel alternative strategies is necessary. In these highly chemoresistant diseases, antitumoral responses may be obtained by enabling the immune system to kill malignant cells in an indirect manner. The last decade has witnessed the emergence of novel forms of immunotherapy, including immunoconjugates, immunomodulatory drugs (IMiDS), immune checkpoint blockers, bispecific antibodies and chimeric antigen receptor T cells (CAR-T cells). These treatments have shown phenomenal successes, sometimes curative, compared to the results obtained with conventional approaches. These immunotherapies will likely transform the treatment paradigms for R/R LDGCB and that their earlier use in the therapeutic strategy may be addressed in patients at high-risk of chemoresistance.Le pronostic défavorable des lymphomes diffus à grandes cellules B (LDGCB) chimioréfractaires ou en rechute postautogreffe appelle au développement de stratégies thérapeutiques alternatives. En effet, si ces hémopathies sont caractérisées par leur haute chimiorésistance, une réponse antitumorale pourrait être obtenue de façon indirecte en favorisant l’éradication des cellules malignes par le système immunitaire. Dans ce contexte, de multiples immunothérapies sont développées pour la prise en charge des LDGCB réfractaires ou en rechute, telles que les immunoconjugués, les immunomodulateurs, les inhibiteurs de points de contrôle immunitaires, les anticorps bispécifiques ou encore les lymphocytes T modifiés pour exprimer un récepteur antigénique chimérique. Ces traitements ont permis d’obtenir des résultats remarquables, possiblement curatifs, et plusieurs d’entre eux ont déjà été approuvés par les autorités de santé. Ces immunothérapies devraient donc continuer de transformer la prise en charge des LDGCB en échec de chimiothérapie

Hide or defend, the two strategies of lymphoma immune evasion potential implications for immunotherapy

International audienceEvading immune eradication is a prerequisite for neoplastic progression and one of the hallmarks of cancer. Here, we review the different immune escape strategies of lymphoma and classify them into two main mechanisms. First, lymphoma cells may "hide" to become invisible to the immune system. This can be achieved by losing or downregulating MHC and/or molecules involved in antigen presentation (including antigen processing machinery and adhesion molecules), thereby preventing their recognition by the immune system. Second, lymphoma cells may "defend" themselves to become resistant to immune eradication. This can be achieved in several ways by becoming resistant to apoptosis, by expressing inhibitory ligands that deactivate immune cells and/or by inducing an immunosuppressive (humoral and cellular) microenvironment. These immune escape mechanisms may have therapeutic implications. Their identification may be used to guide "personalized immunotherapy" for lymphoma