Human Immunoglobulin M Memory B Cells Controlling Streptococcus pneumoniae Infections Are Generated in the Spleen

Splenectomized and asplenic patients have a high incidence of infections by encapsulated bacteria and do not respond to polysaccharide vaccines. To understand whether the absence of the spleen is associated with a defined B cell defect, we analyzed B cell subsets in the peripheral blood. We found that a population of B cells known as immunoglobulin (Ig)M memory is lacking in patients without spleen. The absence of IgM memory B cells correlates with an impaired immune response to encapsulated bacteria not only in splenectomized patients, but also in individuals with an intact spleen. We show that the physiological and transient predisposition to pneumococcal infections of young children (0–2 yr) is associated with the lack of circulating IgM memory B cells and of serum antipolysaccharide IgM. We also demonstrate that IgM memory B cells are undetectable in a fraction of patients with common variable immunodeficiency, who have recurrent and invasive infections by encapsulated bacteria. IgM memory B cells, therefore, require the spleen for their generation and/or survival and are responsible for the protection against encapsulated bacteria

Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas.

Angioimmunoblastic T-cell lymphoma (AITL) and other lymphomas derived from follicular T-helper cells (TFH) represent a large proportion of peripheral T-cell lymphomas (PTCLs) with poorly understood pathogenesis and unfavorable treatment results. We investigated a series of 85 patients with AITL (n = 72) or other TFH-derived PTCL (n = 13) by targeted deep sequencing of a gene panel enriched in T-cell receptor (TCR) signaling elements. RHOA mutations were identified in 51 of 85 cases (60%) consisting of the highly recurrent dominant negative G17V variant in most cases and a novel K18N in 3 cases, the latter showing activating properties in in vitro assays. Moreover, half of the patients carried virtually mutually exclusive mutations in other TCR-related genes, most frequently in PLCG1 (14.1%), CD28 (9.4%, exclusively in AITL), PI3K elements (7%), CTNNB1 (6%), and GTF2I (6%). Using in vitro assays in transfected cells, we demonstrated that 9 of 10 PLCG1 and 3 of 3 CARD11 variants induced MALT1 protease activity and increased transcription from NFAT or NF-κB response element reporters, respectively. Collectively, the vast majority of variants in TCR-related genes could be classified as gain-of-function. Accordingly, the samples with mutations in TCR-related genes other than RHOA had transcriptomic profiles enriched in signatures reflecting higher T-cell activation. Although no correlation with presenting clinical features nor significant impact on survival was observed, the presence of TCR-related mutations correlated with early disease progression. Thus, targeting of TCR-related events may hold promise for the treatment of TFH-derived lymphomas

Long-term outcomes from the Phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma

Tafasitamab (MOR208), an Fc-modified, humanized, anti-CD19 monoclonal antibody, combined with the immunomodulatory drug lenalidomide was clinically active with a good tolerability profile in the open-label, single-arm, phase II L-MIND study of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem-cell transplantation. To assess long-term outcomes, we report an updated analysis with ≥35 months' follow-up. Patients were aged >18 years, had received one to three prior systemic therapies (including ≥1 CD20-targeting regimen) and Eastern Cooperative Oncology Group performance status 0-2. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during cycles 1-3, then every 2 weeks during cycles 4-12. Lenalidomide (25 mg orally) was administered on days 1-21 of cycles 1-12. After cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. The primary endpoint was best objective response rate. After ≥35 months' follow-up (data cut-off: October 30, 2020), the objective response rate was 57.5% (n=46/80), including a complete response in 40.0% of patients (n=32/80) and a partial response in 17.5% of patients (n=14/80). The median duration of response was 43.9 months (95% confidence interval [95% CI]: 26.1-not reached), the median overall survival was 33.5 months (95% CI: 18.3-not reached) and the median progression-free survival was 11.6 months (95% CI: 6.3-45.7). There were no unexpected toxicities. Subgroup analyses revealed consistent long-term efficacy results across most subgroups of patients. This extended follow-up of L-MIND confirms the long duration of response, meaningful overall survival, and well-defined safety profile of tafasitamab plus lenalidomide followed by tafasitamab monotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplantation. ClinicalTrials.gov identifier: NCT02399085

Allogeneic hematopoietic cell transplantation for patients with TP53 mutant or deleted chronic lymphocytic leukemia : Results of a prospective observational study

Non peer reviewe

DYNAMO: A Phase II Study of Duvelisib (IPI-145) in Patients With Refractory Indolent Non-Hodgkin Lymphoma

PURPOSE Indolent non-Hodgkin lymphoma (iNHL) remains largely incurable and often requires multiple lines of treatment after becoming refractory to standard therapies. Duvelisib was approved by the Food and Drug Administration for relapsed or refractory (RR) chronic lymphocytic leukemia or small lymphocytic lymphoma (SLL) and RR follicular lymphoma (FL) after two or more prior systemic therapies. On the basis of the activity of duvelisib, a first-in-class oral dual inhibitor of phosphoinositide 3-kinase-δ,-γ, in RR iNHL in a phase I study, the safety and efficacy of duvelisib monotherapy was evaluated in iNHL refractory to rituximab and either chemotherapy or radioimmunotherapy. PATIENTS AND METHODS Eligible patients had measurable iNHL (FL, SLL, or marginal zone B-cell lymphoma) double refractory to rituximab (monotherapy or in combination) and to either chemotherapy or radioimmunotherapy. All were treated with duvelisib 25 mg orally twice daily in 28-day cycles until progression, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) using the revised International Working Group criteria for malignant lymphoma. RESULTS This open-label, global phase II trial enrolled 129 patients (median age, 65 years; median of three prior lines of therapy) with an ORR of 47.3% (SLL, 67.9%; FL, 42.2%; MZL, 38.9%). The estimated median duration of response was 10 months, and the estimated median progression-free survival was 9.5 months. The most frequent any-grade treatment-emergent adverse events (TEAEs) were diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and cough (27.1%). Among the 88.4% of patients with at least one grade 3 or greater TEAE, the most common TEAEs were neutropenia (24.8%), diarrhea (14.7%), anemia (14.7%), and thrombocytopenia (11.6%). CONCLUSION In the DYNAMO study, oral duvelisib monotherapy demonstrated clinically meaningful activity and a manageable safety profile in heavily pretreated, double-refractory iNHL, consistent with previous observations. Duvelisib may provide a new oral treatment option for this patient population of which many are elderly and in need of additional therapies

Evolution des stratégies thérapeutiques de première ligne

International audienc

Allogeneic hematopoietic cell transplantation for patients with TP53 mutant or deleted chronic lymphocytic leukemia: Results of a prospective observational study

International audienc

Azacytidine and Venetoclax in Relapsed and Refractory Patients With Angioimmunoblastic T-cell Lymphoma

International audienc

Autogreffe et hémopathies lymphoïdes chroniques

L'intensification thérapeutique suivie d'autogreffe de cellules souches hématopoïétiques (CSH) est utilisée depuis une quinzaine d'année dans les hémopathies lymphoïdes chroniques (HLC). Dans le but de simplifier la procédure d'autogreffe et de diminuer son coût, nous avons dans un 1er temps étudié 109 autogreffes (dont 51 lymphopathies) réalisées après congélation et stockage des CSH à -80C pendant une médiane de 7 (1-98) semaines. Avec cette technique plus simple que la cryoconservation habituelle à -196C dans l'azote, nous avons montré que la reconstitution hématologique était satisfaisante. Une évaluation de l'effet d'un stockage à -80C à plus long terme est en cours. Dans un 2ème temps, en raison du nombre très faible de publications concernant l'autogreffe dans la macroglobulinémie de Waldenström, nous avons réalisé une étude rétrospective dans l'ensemble des centres de greffes français. Nous avons ainsi rapporté que l'autogreffe (n=18) était faisable jusqu'à 70 ans et permettait d'obtenir 95% de réponses globales, avec une médiane de survie sans rechute de 16 mois, qui en comparaison avec la littérature parait influencée par le nombre de lignes thérapeutiques préalables. Nous nous proposons de poursuivre cette étude et d'initier un protocole prospectif. Enfin, la Fludarabine (FDR) ayant été suspectée d'altérer la mobilisation des CSH dans la Leucémie Lymphoïde Chronique (LLC), nous avons évalué prospectivement les collections de CSH dans la LLC, après traitement de 1ère ligne par FDR (n=75), et constaté que la mobilisation par facteurs de croissance hématopoïétiques (FCH) seuls échoue dans 70 à 85% des cas, spécialement en cas de thrombopénie inférieure à 150G/L avant mobilisation. L'utilisation d'une mobilisation mixte par chimiothérapie et FCH (n=47) permet de réduire ces échecs à 20%. Le mécanisme par lequel la FDR altère la mobilisation des CSH reste à préciser. Une étude évaluant l'impact de la FDR sur les CSH et les cellules souches mésenchymateuses du microenvironnement médullaire est en cours.High dose therapy (HDT) followed by autologous transplantation of hematopoietic stem cells (HSC) has been used for 15 years in chronic lymphoid malignancies. In order to simplify the HDT process and to lower its costs, we first, studied 109 autologous transplantations in various cancers including 51 cases of lymphoid malignancies, following HSC freezing and storage at 80C for a median of 7 (1-98) weeks. Using this cryoconservation approach easier to use than the standart liquid nitrogen storage at -196C, we demonstrate a satisfying hematological reconstitution. We also evaluate the effect of storage at -80C for an extended time. Only few cases of autologous transplantation have been published in Waldenström Macroglobulinemia. We therefore conducted a retrospective study among the French institutions. Hence, we report that autologous transplantation (n=18) is safe up to 70 years-old and induces the high response rate of 95%, with a median relapse free survival of 16 months, whose survival, in comparison with published data appears to be influenced by the mumber of previous cytotoxic lines. We propose to make a follow up this study and to initiate a prospective trial. Finally, fludarabine (FDR) being suspected to jeopardize CSH mobilization in Chronic Lymphocytic Leukemia (CLL), we prospectively evaluate the HSC collection in CLL patients treated by FDR containing first line regimens FDR. We have shown that steady state mobilization using hematopoietic growth factor (HGF) alone (n=75) is sanctioned by 70 to 85% failure, especially in patients who are thrombocytopenic below 150G/L before mobilization. In addition, a mobilization combining chemotherapy plus HGF (n=47) can reduce the failure rate to 20%. The mechanism inducing mobilization impairment remains unclear. A study evaluating the impact FDR on the bone marrow microenvironmental mesenchymal cell has been initiated.CLERMONT FD-BCIU-Santé (631132104) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF