Ethical and Clinical Aspects of Intensive Care Unit Admission in Patients with Hematological Malignancies: Guidelines of the Ethics Commission of the French Society of Hematology

Admission of patients with hematological malignancies to intensive care unit (ICU) raises recurrent ethical issues for both hematological and intensivist teams. The decision of transfer to ICU has major consequences for end of life care for patients and their relatives. It also impacts organizational human and economic aspects for the ICU and global health policy. In light of the recent advances in hematology and critical care medicine, a wide multidisciplinary debate has been conducted resulting in guidelines approved by consensus by both disciplines. The main aspects developed were (i) clarification of the clinical situations that could lead to a transfer to ICU taking into account the severity criteria of both hematological malignancy and clinical distress, (ii) understanding the process of decision-making in a context of regular interdisciplinary concertation involving the patient and his relatives, (iii) organization of a collegial concertation at the time of the initial decision of transfer to ICU and throughout and beyond the stay in ICU. The aim of this work is to propose suggestions to strengthen the collaboration between the different teams involved, to facilitate the daily decision-making process, and to allow improvement of clinical practice

Role of NK Receptors in Peripheral T-cell Lymphoma. Example of Adult T-cell Leukemia/Lymphoma and Primary Gastro-intestinal T-cell Lymphoproliferative Disease.

Les lymphomes T périphériques (PTCLs) sont des entités hétérogènes dont la classification a récemment été révisée. Plus de 25 entités de lymphomes T ou NK matures sont ainsi classées selon leur présentation clinico-biologique et leur origine cellulaire présumée, justifiant l’étude approfondie de leur phénotype. Des récepteurs NK (NKRs) ont été mis en évidence dans certains lymphomes cutanés. En outre, un lymphome intra-épithélial intestinal, appelé maladie coeliaque réfractaire de type II (MCRII), dérive d’un lymphocyte caractérisé par des marqueurs T et NK. Ces constatations nous ont amenés à évaluer l’expression de NKRs sur un panel représentatif de PTCLs, constitué en particulier de PTCLs primitifs intestinaux et de leucémies/lymphomes T de l’adulte associés à l’HTLV-1 (ATL). Dans l’ATL, nous montrons que KIR3DL2 est exprimé par les cellules tumorales des formes aigües. Le virus HTLV-1 et la méthylation de son promoteur jouent un rôle dans l’expression de KIR3DL2. Enfin, un anticorps monoclonal dirigé contre KIR3DL2, IPH4102, est capable de tuer spécifiquement les cellules primaires d’ATL KIR3DL2 ex vivo par un mécanisme dépendant d’effecteurs NK autologues. Dans les lymphoproliférations T intestinales primitives, nous montrons que NKp46 est un nouveau biomarqueur pour leur diagnostic et leur stratification thérapeutique. En effet, NKp46 est exprimé sur les cellules anormales de la MCRII, et sur les lymphomes T primitifs intestinaux agressifs, mais pas sur les indolents et les MC non compliquées. Enfin, les cellules primaires exprimant NKp46 sont sensibles ex vivo à la cytotoxicité induite par un anticorps monoclonal dirigé contre NKp46 et couplé à une toxine.Ces résultats nous ont permis de discuter l’origine cellulaire de ces lymphomes et le rôle de ces NKRs dans la lymphomagénèse. Dans une optique translationnelle, l’expression des NKRs peut aider au diagnostic de ces entités parfois difficiles à individualiser, et enfin constituer une cible thérapeutique intéressante.Peripheral T-cell lymphoma (PTCLs) are heterogeneous entities whose classification has recently been revised. More than 25 entities are thus classified according to their clinico-biological presentation and their presumed cellular origin, justifying the in-depth study of their phenotype. NK receptors (NKRs) have been demonstrated in some cutaneous lymphomas. In addition, a less known intestinal lymphoma, called type II refractory celiac disease (RCDII), arises from an intraepithelial lymphocyte characterized by T and NK markers. These findings led us to evaluate the expression of NKRs on a representative panel of PTCLs, focusing on primary gastrointestinal (GI) T-cell lymphoproliferative diseases (T-LPD) and HTLV-1 associated adult T leukemia/lymphoma (ATL).In ATL, we show that KIR3DL2 expression is mainly associated with acute-type ATL. HTLV-1 has a preferential tropism for KIR3DL2+ lymphocytes and may play a role in KIR3DL2 expression induction, combined with the hypomethylation status of KIR3DL2 promoter. The benefit of targeting KIR3DL2 by IPH4102 should be further investigating in acute ATL patients.In GI T-LPD, we show that NKp46 is a novel biomarker useful for diagnosis and therapeutic stratification, as NKp46 is a hallmark of RCDII tumor cells, shared by EATL. Strong preclinical rationale identifies anti-NKp46-PBD as a promising therapy for RCDII, EATL and MEITL.These results allowed us to discuss the cellular origin of these lymphomas and the role of NKRs in lymphomagenesis. From a translational point of view, NKRs could represent useful biomarkers in these entities that are sometimes difficult to individualize, and finally constitute an interesting therapeutic target

Rôle des récepteurs NK dans les lymphoproliférations T matures. Exemple des leucémies/lymphomes T de l'adulte associés à l'HTLV-1 et des lymphoproliférations T intestinales primitives

Peripheral T-cell lymphoma (PTCLs) are heterogeneous entities whose classification has recently been revised. More than 25 entities are thus classified according to their clinico-biological presentation and their presumed cellular origin, justifying the in-depth study of their phenotype. NK receptors (NKRs) have been demonstrated in some cutaneous lymphomas. In addition, a less known intestinal lymphoma, called type II refractory celiac disease (RCDII), arises from an intraepithelial lymphocyte characterized by T and NK markers. These findings led us to evaluate the expression of NKRs on a representative panel of PTCLs, focusing on primary gastrointestinal (GI) T-cell lymphoproliferative diseases (T-LPD) and HTLV-1 associated adult T leukemia/lymphoma (ATL).In ATL, we show that KIR3DL2 expression is mainly associated with acute-type ATL. HTLV-1 has a preferential tropism for KIR3DL2+ lymphocytes and may play a role in KIR3DL2 expression induction, combined with the hypomethylation status of KIR3DL2 promoter. The benefit of targeting KIR3DL2 by IPH4102 should be further investigating in acute ATL patients.In GI T-LPD, we show that NKp46 is a novel biomarker useful for diagnosis and therapeutic stratification, as NKp46 is a hallmark of RCDII tumor cells, shared by EATL. Strong preclinical rationale identifies anti-NKp46-PBD as a promising therapy for RCDII, EATL and MEITL.These results allowed us to discuss the cellular origin of these lymphomas and the role of NKRs in lymphomagenesis. From a translational point of view, NKRs could represent useful biomarkers in these entities that are sometimes difficult to individualize, and finally constitute an interesting therapeutic target.Les lymphomes T périphériques (PTCLs) sont des entités hétérogènes dont la classification a récemment été révisée. Plus de 25 entités de lymphomes T ou NK matures sont ainsi classées selon leur présentation clinico-biologique et leur origine cellulaire présumée, justifiant l’étude approfondie de leur phénotype. Des récepteurs NK (NKRs) ont été mis en évidence dans certains lymphomes cutanés. En outre, un lymphome intra-épithélial intestinal, appelé maladie coeliaque réfractaire de type II (MCRII), dérive d’un lymphocyte caractérisé par des marqueurs T et NK. Ces constatations nous ont amenés à évaluer l’expression de NKRs sur un panel représentatif de PTCLs, constitué en particulier de PTCLs primitifs intestinaux et de leucémies/lymphomes T de l’adulte associés à l’HTLV-1 (ATL). Dans l’ATL, nous montrons que KIR3DL2 est exprimé par les cellules tumorales des formes aigües. Le virus HTLV-1 et la méthylation de son promoteur jouent un rôle dans l’expression de KIR3DL2. Enfin, un anticorps monoclonal dirigé contre KIR3DL2, IPH4102, est capable de tuer spécifiquement les cellules primaires d’ATL KIR3DL2 ex vivo par un mécanisme dépendant d’effecteurs NK autologues. Dans les lymphoproliférations T intestinales primitives, nous montrons que NKp46 est un nouveau biomarqueur pour leur diagnostic et leur stratification thérapeutique. En effet, NKp46 est exprimé sur les cellules anormales de la MCRII, et sur les lymphomes T primitifs intestinaux agressifs, mais pas sur les indolents et les MC non compliquées. Enfin, les cellules primaires exprimant NKp46 sont sensibles ex vivo à la cytotoxicité induite par un anticorps monoclonal dirigé contre NKp46 et couplé à une toxine.Ces résultats nous ont permis de discuter l’origine cellulaire de ces lymphomes et le rôle de ces NKRs dans la lymphomagénèse. Dans une optique translationnelle, l’expression des NKRs peut aider au diagnostic de ces entités parfois difficiles à individualiser, et enfin constituer une cible thérapeutique intéressante

Les leucémies aigues lymphoblastiques (LAL) de la lignée B avec translocation (1;19) (Analyse génomique comparative de 20 enfants et 14 adultes)

Les LAL de la lignée B de l adulte et de l enfant diffèrent en termes d incidence, de pronostic et de caractéristiques cytogénétiques. La translocation chromosomique récurrente t(1;19)/TCF3-PBX1 est réputée être associée à un mauvais pronostic chez l adulte alors qu elle n a pas d impact défavorable chez l enfant. Une analyse des anomalies en nombre de copies des gènes par CGH-array a été réalisée chez 14 adultes et 20 enfants porteurs d une LAL avec t(1;19), et a confirmé leur hétérogénéité génétique. En effet, tous les adultes étudiés avaient des anomalies associées à la t(1;19), principalement des délétions, souvent clonales. Parmi les enfants, les anomalies génomiques étaient moins nombreuses, souvent sous-clonales et 7/20 (35%) n avaient que la t(1;19) identifiée. Au niveau du chromosome 9 ont été fréquemment observées des délétions de CDKN2A, un gène suppresseur de tumeur, avec 8 adultes et 2 enfants (57% vs. 10%, P=0,006) et de PAX5, un gène impliqué dans la différenciation lymphoïde B, avec 6 adultes et 4 enfants (43% vs. 20%, NS). Des délétions 9p complètes étaient souvent associées mais des pertes focales de CDKN2A n ont été identifiées que chez les adultes. A l inverse, les pertes focales de PAX5 sans del(9p) n ont été vues que chez l enfant, à l exception d un adulte. Ces anomalies étaient associées à des délétions 6q et des isochromosomes 9. Elles n avaient pas d impact sur la survenue de rechutes. Au total, les LAL de la lignée B avec t(1;19) de l adulte et de l enfant ont des caractéristiques biologiques différentes, notamment au niveau des gains et des pertes géniques associés qui pourraient contribuer à expliquer leurs différences en terme de pronostic.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Tumor Microenvironment and Immunotherapy-Based Approaches in Mantle Cell Lymphoma

International audienceMantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation t(11;14) (q13;q32) and a poor response to rituximab–anthracycline-based chemotherapy. High-dose cytarabine-based regimens offer a durable response, but an important number of MCL patients are not eligible for intensive treatment and are ideal candidates for novel targeted therapies (such as BTK, proteasome or BCL2 inhibitors, Immunomodulatory Drugs (IMiDs), bispecific antibodies, or CAR-T cell therapy). On the bench side, several studies aiming to integrate the tumor within its ecosystem highlighted a critical role of the tumor microenvironment (TME) in the expansion and resistance of MCL. This led to important insights into the role of the TME in the management of MCL, including potential targets and biomarkers. Indeed, targeted agents often have a combined mechanism of action on the tumor B cell but also on the tumor microenvironment. The aim of this review is to briefly describe the current knowledge on the biology of the TME in MCL and expose the results of the different therapeutic strategies integrating the TME in this disease

A Transmissible Rash of Palms and Soles in a 58-Year-Old Man

International audienceDiagnosis: Atypical hand, foot, and mouth disease caused by coxsackievirus A6 (CVA6)

Curative allogeneic hematopoietic stem cell transplantation following reduced toxicity conditioning in adults with primary immunodeficiency

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Targeted deep sequencing reveals clonal and subclonal mutational signatures in Adult T-cell leukemia/lymphoma and defines an unfavorable indolent subtype

International audienceAdult T-cell leukemia/lymphoma (ATL) carries a poor prognosis even in indolent subtypes. We performed targeted deep sequencing combined with mapping of HTLV-1 proviral integration sites of 61 ATL patients of African and Caribbean origin. This revealed mutations mainly affecting TCR/NF-kB (74%), T-cell trafficking (46%), immune escape (29%), and cell cycle (26%) related pathways, consistent with the genomic landscape previously reported in a large Japanese cohort. To examine the evolution of mutational signatures upon disease progression while tracking the viral integration architecture of the malignant clone, we carried out a longitudinal study of patients who either relapsed or progressed from an indolent to an aggressive subtype. Serial analysis of relapsing patients identified several patterns of clonal evolution. In progressing patients, the longitudinal study revealed NF-kB/NFAT mutations at progression that were present at a subclonal level at diagnosis (allelic frequency < 5%). Moreover, the presence in indolent subtypes of mutations affecting the TCR/NF-kB pathway, whether clonal or subclonal, was associated with significantly shorter time to progression and overall survival. Our observations reveal the clonal dynamics of ATL mutational signatures at relapse and during progression. Our study defines a new subgroup of indolent ATLs characterized by a mutational signature at high risk of transformation

Obinutuzumab Versus Rituximab in Transplant Eligible Untreated MCL Patients, a Matching Comparison between the Lyma and Lyma-101 Trials

International audienceAim: Obinutuzumab (O) and Rituximab (R) have never been compared in a prospective randomized trial in mantle cell lymphoma (MCL). The LYMA-101 trial (NCT02896582) investigated the Obinutuzumab-DHAP (O-DHAP) regimen followed by autologous stem cell transplant (O-BEAM, ASCT) plus O maintenance (OM) in transplant eligible patients &amp;amp;amp;lt;66y with untreated MCL (Le Gouill et al, Lancet Hem 2020). The LYMA trial (NCT00921414) used the same regimen with Rituximab instead of Obinutuzumab (Le Gouill et al, NEJM 2017). Herein, we report the long-term outcome of patients enrolled in the LYMA-101 trial and used a propensity score matching (PSM) approach to allow a comparison with patients treated in the LYMA trial (i.e. O versus R group matched comparison). Method: LYMA (n=299 pts, of whom 120 received R Maintenance, RM) is a phase III prospective trial with a median follow-up of 7.5 years (7.4-7.7) from inclusion (Sarkozy et al, ASCO 2023) that randomized, after ASCT, 240 pts between observation and RM. LYMA-101 (n=86) is a prospective single arm phase 2 trial with a median FU of 5.1y (5-5.25) at the time of the present analysis. We first compared minimal residual disease (MRD) at end of induction (EOI), assessed in both trial with quantitative PCR of clonal immunoglobulin gene and used PSM based on clinical characteristics at inclusion (Sex, Ann Arbor stage, MIPI score, B symptoms, blastoid variant, bulky disease) to balance patients&amp;#039; discrepancies between LYMA-101 and LYMA. To compare PFS and OS from inclusion of patients treated with R versus O based regimen, half of the non-randomized LYMA patients (29 out of 58) were randomly reattributed to the RM arm to create an intention to treat RM (RM-ITT) arm including 149 pts (29 non-randomized and 120 randomized) subsequently matched with the 86 LYMA-101 pts. Balance between populations was checked using standardized mean differences (SMD). Results: Eighty-five LYMA-101 pts received the first course of O-DHAP (1 withdrew consent before treatment), 81 (95.3%) completed the 4 cycles and 73 (85.9%) underwent ASCT followed by OM in 69 (81.2%). The estimated 5y PFS and OS since inclusion were 83.4% (95%CI: 73.5-89.8%) and 86.9% (95%CI: 77.6-92.5%) respectively. At EOI, ORR were similar in both studies (89.6% versus 91.8% in LYMA versus LYMA-101 respectively), but within responders, pts treated in LYMA-101 (O-DHAP) had a more frequent MRD negativity than pts treated in LYMA (R-DHAP) both in bone marrow (BM, 82.1% versus 65.3% MRD negativity in O vs R group, Chi2 p=0.011) and blood (95.5% versus 79.2% of MRD negativity in O vs R group, Chi2 p=0.002). These results were confirmed using the propensity score matched populations, with a more frequent MRD negativity in the O versus R group in BM (82.1% vs 63.4%, Chi-2, p=0.01) and blood (95.5% vs 72.9%, Chi-2, p&amp;amp;amp;lt;0.001). To compare PFS and OS since induction, a PSM was performed using the 149 patients treated in the R-group with an RM-ITT and the 85 patients in the O group, resulting in 2 sets of 82 patients with comparable characteristics at inclusion. From treatment initiation, patients treated with O presented a prolonged PFS (p=0.029, figure 1A) and OS (p=0.039, figure 1B) compared to those treated with R, with an estimated 5-year PFS of 82.8% versus 66.6% (HR 1.99, IC95 1.05-3.76) and OS of 86.4% versus 71.4% (HR 2.08, IC95 1.01-4.16) with O and R based regimen respectively. Finally, 37/120 (30.8%) patients in LYMA and 23/69 (33.3%) in LYMA-101 prematurely stopped R and OM respectively (with a similar mean maintenance duration of 29 and 29.4m with R and OM respectively). Reason for maintenance discontinuation were adverse events in 15 cases in R group (12.5% of the population) versus 14 cases in O group (20% of the population), progression or death in 10 (8.3%) versus 3 (4.3%) cases in the R versus O group respectively. Causes of death were comparable in O and R groups, the most common being lymphoma (42% in O and 53% in R group). Infectious deaths in the O group (N=3) were all COVID related (3/12 deaths, 25%), whereas in the R group (LYMA being conducted before the pandemic), 8 deaths were related to infection (8/97 deaths, 8%, including 1 infectious death out of 22 deaths during RM, 5%). Conclusion: O-DHAP followed by OM post ASCT provide prolonged PFS and OS in young patients with MCL. O-based therapy in MCL induce deeper response with increased MRD negativity and seems to outperform R-based therapy in term of PFS and OS, without any significant excess of toxicity