Primary testicular lymphoma (PTL) and diffuse large B-cell lymphoma with secondary testicular involvement (DLBCL-T) are rare subtypes of lymphomas associated with poor prognosis and a high risk of central nervous system (CNS) relapse. The optimal CNS prophylaxis strategy for these subtypes remains uncertain. High-dose methotrexate (HD-MTX) is debated for CNS prophylaxis, but its efficacy in this setting is unknown. This study aimed to retrospectively analyze the use of HD-MTX in combination with chemotherapy (R HD-MTX CHOP) as frontline treatment for PTL and DLBCL-T and to compare the biological characteristics of these two forms of testicular involvement. Data from patients who received R HD-MTX CHOP as first-line treatment for DLBCL-T or PTL between 2010 and 2020 were collected retrospectively. The study included 15 patients, 5 with PTL and 10 with DLBCL-T. The overall response rate was 86%, with 73% of patients achieving complete remission. Treatment-related adverse events were generally manageable, with febrile neutropenia being the most common. Two patients experienced CNS relapse, both from the DLBCL-T subgroup, with a median time of 10.7 months from diagnosis to CNS relapse. None of the PTL patients receiving HD-MTX experienced relapse during the median follow-up of 6.08 years (Figure 1A), compared to 8/10 DLBCL-T (p=0.007). All five PTL cases had a non-germinal center phenotype, while 7 out of 10 DLBCL-T cases were non-germinal center. One DLBCL-T case exhibited high-grade lymphoma. Myc expression was positive in 3 out of 10 patients assessed, of whom all were double expressors. Bcl-2 expression was positive in all 13 assessable patients, while Bcl-6 expression was positive in 6 patients. Myc, Bcl-2, and Bcl-6 rearrangements were assessed in 10 patients and were present in 1 patient who was found to have triple-hit lymphoma. No other patient had double-hit lymphoma or any significant rearrangement. Polysomy of Myc, Bcl-2, and/or Bcl-6 was found in 2 patients. PDL1 expression was observed in one out of six patients analyzed, while no PD1 expression was detected. In 8 out of 15 patients with available tissue material, next-generation sequencing using a panel targeting 43 lymphoid genes was performed. Among these 8 patients, 87% exhibited gain-of-function mutations in MYD88 (MYD88 L265P), and 62% had missense mutations in CD79B at position Y196. Multiple mutations in the PIM1 gene, a known target of aberrant somatic hypermutation, were also observed in 7 patients. Non-recurrent mutations were detected in various genes, including PRDM1, CD58, B2M, CREBBP, CIITA, CARD11, CDKN2A, EP300, CCDND3, FOXO1, IRF4, NFKBIE, and TCF3 (Figure 1B). Ig rearrangement was analyzed in 4/9 patients with available DNA. All 4 were clonal, with distinct but mutated VH segments (sequence identity between 81 and 89%). This study suggests that HD-MTX in combination with RCHOP chemotherapy is highly effective in preventing CNS relapse in PTL but less so in DLBCL-T. DLBCL-T had a higher risk of CNS relapse and poorer outcomes compared to PTL. Further studies are needed to determine the optimal timing and sequence of HD-MTX in DLBCL-T, as well as alternative treatment approaches. PTL and DLBCL-T have distinct clinical presentations and responses to frontline chemotherapy with HD-MTX prophylaxis. PTL may benefit from HD-MTX in preventing relapse, while alternative treatments should be explored for DLBCL-T. Future studies should consider PTL and DLBCL-T as separate entities to better understand their characteristics and optimize treatment strategies.

Introduction: Cancer cells rely on metabolic reprogramming to meet the increased bioenergetic and biosynthetic demand required for tumor initiation and progression. L-asparaginase (ASNase), an enzymatic drug depleting plasmatic asparagine (ASN), is the only clinically approved targeted therapy of a specific amino acid addiction that clearly demonstrated efficacy in hematological malignancies such as acute lymphoblastic leukemia (ALL) and extranodal NK/T cell lymphoma (ENKTL). Despite the benefits of ASNase, refractory forms are observed in 40% of the patients, either by immunization against the enzyme or by metabolic adaptation to ASN deprivation. APR-246 was originally known to reactivate transcriptional activity by refolding p53 mutants. Additional p53-independent effects have been reported, including oxidative stress increase, particularly by decreasing glutathione (GSH) levels through direct covalent binding to cysteine residues. Due to its effect on antioxidant defense systems, APR-246 might represent an efficient anti-cancer therapeutic strategy in ASNase-resistant (ASNase -R) cells by targeting metabolic cell vulnerabilities. This study evaluated APR-246 as a new candidate to overcome ASNase resistance in lymphoid malignancies treated with ASNase-containing regimens as frontline therapy. Methods: We used the two following ASNase-R cell lines: NALM6, a human acute lymphoblastic leukemia cell line, and KHYG1, a human natural killer (NK) leukemia/ lymphoma cell line. Cells were treated in vitro with either APR-246, Asparaginase, or both and incubated for 24 to 48 hours. Cell viability was determined by flow cytometry using Annexin V / Propidium Iodide (PI). Metabolites were analyzed by mass spectrometry (UPLC-MS/MS) in the supernatant and dried pellets. To validate the metabolic findings further, we evaluated intracellular GSH and lipid peroxidation levels by flow cytometry after cell-labeling with MBCI and C11- BODIPY, respectively. To assess the drug combination's effect in vivo, we established a xenograft murine model by injecting luciferase-expressing NALM6 cells into immunocompromised mice. Mice tumor burden was evaluated using an in vivo imaging system (IVIS) based on bioluminescence quantification. Results: Using an untargeted metabolomic approach, we showed that ASNase treatment in both ASNase-R models decreased GSH levels and reduced the GSH to oxidized GSSG ratio. Specific quantification confirmed decreased GSH levels and increased mitochondrial reactive oxygen species (ROS) in ASNase-R cells. This suggests that resistance to ASNase induces metabolic vulnerability related to cellular redox imbalance. APR-246, an antioxidant-inhibitor, was then considered to target the ASNase-induced redox imbalance. Our results showed a synergistic efficacy of APR-246 and ASNase combination in vitro, especially with Erwinase. Next, we showed that tumor growth was significantly reduced in vivo in mice treated with the combination of APR-246 and Erwinase, compared to placebo, APR-246, or Erwinase as single agents. Mechanistically, APR-246 combined with Erwinase dramatically decreased GSH levels and increased lipid peroxidation levels compared to each drug alone. Given that accumulation of lipid peroxides leads to ferroptosis, an iron-dependent mechanism of cell death, we investigated whether APR-246/Erwinase-induced cytotoxicity was mediated by ferroptosis. KHYG-1 cells were treated with Erwinase associated with a ferroptosis inducer (RSL3) and/or a ferroptosis inhibitor (ferrostatin-1). Combining Erwinase with RSL3 resulted in a similar GSH decrease, lipid peroxidation accumulation, and decreased cell viability as observed with APR-246/Erwinase combination, and cell death was partially rescued by ferrostatin-1. Conclusion: APR-246, a p53 activator, should be also considered as the first ferroptosis-inducing agent that can be used therapeutically in humans, and our results suggest its efficacy in overcoming ASNase-R in lymphoid malignancies both in vitro and in vivo. In our work, APR-246/Erwinase combination effectively disrupts the balance between ROS generation and antioxidation dependent on glutamine/GSH metabolism in ASNase-R cells and leads to cell death by ferroptosis. Prospective phase I/II studies are now required to confirm the clinical efficacy of APR-246/Erwinase combination in ASNase-R ENKTL and ALL patients.

Abstract Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein–Barr virus (EBV)–related neoplasm with male dominance and a poor prognosis. A better understanding of the genetic alterations and their functional roles in ENKTCL could help improve patient stratification and treatments. In this study, we performed a comprehensive genetic analysis of 178 ENKTCL cases to delineate the landscape of mutations, copy number alterations (CNA), and structural variations, identifying 34 driver genes including six previously unappreciated ones, namely, HLA-B, HLA-C, ROBO1, CD58, POT1, and MAP2K1. Among them, CD274 (24%) was the most frequently altered, followed by TP53 (20%), CDKN2A (19%), ARID1A (15%), HLA-A (15%), BCOR (14%), and MSN (14%). Chromosome X losses were the most common arm-level CNAs in females (∼40%), and alterations of four X-linked driver genes (MSN, BCOR, DDX3X, and KDM6A) were more frequent in males and females harboring chromosome X losses. Among X-linked drivers, MSN was the most recurrently altered, and its expression was lost in approximately one-third of cases using immunohistochemical analysis. Functional studies of human cell lines showed that MSN disruption promoted cell proliferation and NF-κB activation. Moreover, MSN inactivation increased sensitivity to NF-κB inhibition in vitro and in vivo. In addition, recurrent deletions were observed at the origin of replication in the EBV genome (6%). Finally, by integrating the 34 drivers and 19 significant arm-level CNAs, nonnegative matrix factorization and consensus clustering identified two molecular groups with different genetic features and prognoses irrespective of clinical prognostic factors. Together, these findings could help improve diagnostic and therapeutic strategies in ENKTCL. Significance: Integrative genetic analyses and functional studies in extranodal NK/T-cell lymphoma identify frequent disruptions of X-linked drivers, reveal prognostic molecular subgroups, and uncover recurrent MSN alterations that confer sensitivity to NF-κB inhibition.

HIV infection is associated with an increased risk of diffuse large B-cell lymphoma (DLBCL). In this prospective study, we analyzed the evolution of B-cell activating cytokines (interleukin-6 [IL-6], IL-10, and B-cell activating factor [BAFF]) and main functional subsets of circulating B and T cells in 51 patients with HIV-associated DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, Oncovin [vincristine], and prednisone). R-CHOP therapy was associated with a decrease of IL-10, whereas IL-6 levels fluctuated, and BAFF levels increased during the first 3 months and decreased thereafter. We observed a rapid rise in CD19+ B cells composed mostly of na & iuml;ve B cells whereas marginal zone-like B cells and memory B cells recovered gradually. With a median follow-up of 41 months, progression-free survival and overall survival at 5 years were 61.8% (95% confidence interval [CI], 47.6-80.4) and 67.4% (95% CI, 53.4-85.0), respectively. Progression (17.5%) and sepsis (12.5%) were the main causes of death. Baseline risk factors for death and progression were poor revised International Prognostic Index (P = .049), natural killer cell lymphopenia (P = .001), lower proportion of na & iuml;ve B cells (P = .017), and higher IL-6 serum levels (P = .001). Our data suggest that patients treated with R-CHOP for HIV-associated DLBCL have a disturbed peripheral Bcell compartment and that the low pool size of circulating na & iuml;ve B cells negatively affects their clinical outcome. In an era of development of B-cell-depleting therapies including B-cell- targeting chimeric antigen receptor T cells, assessment of perturbations within nontumoral Bcell counterparts are warranted for risk profiling in HIV-associated DLBCL. This trial was registered at www.ClinicalTrials.gov as #NCT01164436.

Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related neoplasm preferentially involving the upper aerodigestive tract. Here we show that NK-cell-specific Trp53 disruption in mice leads to the development of NK-cell lymphomas after long latency, which involve not only the hematopoietic system but also the salivary glands. Before tumor onset, Trp53 knockout causes extensive gene expression changes, resulting in immature NK-cell expansion, exclusively in the salivary glands. Both human and murine NK-cell lymphomas express tissue-resident markers, suggesting tissue-resident NK cells as their cell-of-origin. Murine NK-cell lymphomas show recurrent Myc amplifications and upregulation of MYC target gene signatures. EBV-encoded latent membrane protein 1 expression accelerates NK-cell lymphomagenesis and causes diverse microenvironmental changes, particularly myeloid propagation, through interferon-gamma signaling. In turn, myeloid cells support tumor cells via CXCL16-CXCR6 signaling and its inhibition is effective against NK-cell tumors in vivo. Remarkably, KLRG1-expressing cells expand in the tumor and are capable of repopulating tumors in secondary recipients. Furthermore, targeting KLRG1 alone or combined with MYC inhibition using an eIF4 inhibitor is effective against NK-cell tumors. Therefore, our observations provide insights into the pathogenesis and highlight potential therapeutic targets, including CXCL16, KLRG1, and MYC, in ENKTCL, which can help improve its diagnostic and therapeutic strategies. Extranodal NK/T-cell lymphoma (ENKTCL) is an aggressive Epstein-Barr virus (EBV)-related neoplasm. Here the authors report a genetically engineered mouse model harboring NK-cellspecific Trp53 deletion to model ENKTCL in mice

Les mastocytoses sont des néoplasies rares et hétérogènes liées à une accumulation clonale de mastocytes dans divers organes. Des mutations somatiques activatrices dans le gène KIT (notamment D816V) sont identifiées chez la majorité des patients. Ces mutations n’expliquent pas à elles seules l’hétérogénéité des présentations cliniques observées. L’objectif de notre étude était d’identifier dans des formes rares de mastocytoses des évènements génétiques primitifs agissant en synergie avec la mutation de KIT. Caractérisation moléculaire d’un cas de mastocytose systémique agressive congénitale. Analyses fonctionnelles (Crispr-Cas9) et transcriptomiques sur des mastocytes tumoraux. Nous avons identifié chez un patient présentant une mastocytose systémique congénitale agressive et une dysplasie épiphysaire multiple une mutation homozygote perte de fonction dans le gène SLC26A2 codant pour un transporteur de sulfate transmembranaire. À partir de ce patient, nous avons étudié le rôle de la sulfatation dans la physiopathologie de la mastocytose, notamment des formes sporadiques agressives. Ainsi, nous avons étudié l’expression de l’ensemble des gènes impliqués dans le métabolisme du sulfate par transcriptomique sur des mastocytes primaires tumoraux d’une cohorte de 30 patients atteints de mastocytoses systémiques et sur des mastocytes contrôles. Nous avons identifié une diminution significative de l’expression de PAPSS2, qui code pour l’enzyme qui synthétise le PAPS, la forme biologiquement active du sulfate. Nous avons ensuite montré qu’une inhibition de PAPSS2, soit chimique soit par Crispr-Cas9, dans les lignées mastocytaires tumorales HMC-1.2 entraînait systématiquement via un défaut de sulfatation : (i) un excès de prolifération ; (ii) une augmentation globale de la phosphorylation des résidus tyrosines, suggérant pour la première fois, l’existence d’une régulation entre phosphorylation et sulfatation ; (iii) une hyperactivation de la voie oncogénique Hedgehog en lien avec une désulfatation du réseau de protéoglycane extramembranaire. Enfin, nous avons montré que l’expression de PAPSS2 était au moins régulée par la signalisation de KIT et notamment par la voie des MAPK. De plus, une diminution significative de PAPSS2 était observée dans les leucémies aiguës myéloïdes (LAM) FLT3 mutées, avec une activation constitutive de la voie des MAP kinases, comparées aux LAM FLT3 non mutées (données publiques de transcriptomique). À partir d’une forme exceptionnelle de mastocytose dans un contexte syndromique particulier, nous avons mis en lumière pour la première fois le rôle du métabolisme du sulfate, largement méconnu, dans la prolifération des mastocytes. Nous avons identifié un nouveau mécanisme de régulation des modifications post-traductionnelles sur les tyrosines, avec une balance entre phosphorylation et sulfatation. PAPSS2 agit comme un nouveau gène suppresseur de tumeur dans la mastocytose mais probablement dans de nombreux autres cancers.

Background. Higher white blood cell (WBC) count at diagnosis is associated with specific gene lesions and higher early death rates in AML patients (pts) treated intensively. Whether higher WBC count at diagnosis affects outcome beyond remission independently of genetics is unknown. Methods. 1,371 AML pts treated intensively in 3 ALFA trials (0702 18-60y, 0701 50-70y, 1200 60y+) with centralized genetics were studied. Genetic alterations found in >5% of pts (n=22) were analyzed. Hyperleukocytosis (HL) was defined as WBC > 50 x10 9/L. NPM1 MRD was stratified as published (Balsat, J Clin Oncol 2017). All prognostic analyses were stratified on trial. Time-dependent effects were introduced in multivariable Cox models when the proportional hazard (PH) assumption was violated. Results. The median WBC count at diagnosis was 7.1 x10 9/L (range 0.3-546.6), and 235 pts (17.1%) had HL. HL pts had poorer performance status (p<0.001), lower platelet counts (p=0.003), higher frequency of de novo AML (p=0.006) and more favorable genetic risk (ELN 2022 criteria, p<0.001). In a multivariable model, HL was independently associated with more frequent NPM1, FLT3-ITD and -TKD mutations, and less frequent STAG2 and -17/17p- alterations (all p<0.05, Figure 1A). Complete remission (CR [including CR with incomplete platelet recovery, CRp]) and early death (ED) rates were 77.4 vs 80.0% (p=0.38) and 8.9 vs 5.0% (p=0.03) in pts with and without HL, respectively (resp). In a multivariable model accounting for ELN22 risk and age, HL was independently associated with more frequent ED (OR =2.20, 95%CI 1.26-3.75, p=0.004), and a trend to more frequent primary induction failure (OR=1.40, 95%CI 0.95-2.05, p=0.08). In the 1,091 pts achieving CR/CRp (182 and 909 with and without HL resp), 1-y and 2-y cumulative incidence of relapse were 39.0% vs 26.1% and 44.0% vs 40.2% resp, suggestive of a time-dependent effect of HL on post-remission outcome ( Figure 1B). Considering relapse and death as competing events, a multivariable model revealed a significant impact of HL on relapse (subdistribution hazard ratio, sHR=1.59, p=0.0003), independent of ELN22 risk and age, but not on non-relapse mortality (sHR=0.69, p=0.23). HL violated the PH assumption in a univariable Cox model for DFS (p=0.0003). We thus performed multivariable Cox models for DFS separating early (< 1 year from CR) and late (≥1 year) effects for HL. In a multivariable time-dependent model, HL significantly impaired early (HR=1.89, p<10 -4), but not late (HR=0.79, p=0.29) DFS, independently of ELN risk and age. These results were confirmed considering WBC count as a (log-transformed) continuous variable, accounting for all differentially represented genetic lesions instead of ELN22 risk or censoring at allogeneic HCT. In a validation cohort of 1,089 pts <60y reaching CR after intensive chemotherapy in the BIG-1 trial (NCT02416388) where median WBC was 7.7 x10 9/L and 16.1% of pts were HL, the adverse risk of HL on CIR (sHR=1.39, p=0.007) but not NRM (sHR=1.02, p=0.95) and on early (HR=1.42, p=0.01), but not late (HR=1.24, p=0.23) DFS independent of ELN22 risk and age was validated. Finally, to explore the mechanism underlying the higher early relapse rate of HL pts, we analyzed NPM1 MRD (n=152) and LSC17 (n=504) data from the 0702 trial. A higher WBC count was predictive of suboptimal MRD (OR=1.97, p=0.05) independently of FLT3-ITD status. A higher WBC count was significantly correlated to lower LSC17 score (Spearman rho=0.23, p<10-5). Conclusion. A high WBC count at diagnosis predicts higher rates of early, but not late relapse, independent of genetic risk. Our results strengthen the hypothesis that distinct biological mechanisms underpin early vs late chemoresistance in AML.

Extranodal NK/T cell lymphoma (ENKTCL) is a rare subset of peripheral T lymphoma of which Asparaginase containing regimens are the standard of care. Despite recent improvements in the therapeutic strategy, patient’s prognosis remains poor, especially for those who experienced relapsed or refractory (R/R) disease. Recent studies highlighted that immune escape mechanisms are involved in ENKTCL pathogenesis. Particularly, the frequent PD-L1 upregulation led to assess the efficacy of anti-PD1 (aPD1) therapy in small cohorts of R/R ENKTCL patients, with encouraging results. Our study aims to evaluate the efficacy of aPD1 therapy alone or in combination in 37 patients with R/R ENKTCL. We also performed a comparative analysis with a historic cohort of 38 patients treated for R/R ENKTCL before immunotherapy era. 37 patients from 24 French centers, with R/R ENKTCL treated with at least one cycle of aPD1 as salvage therapy between 2017 and 2022 were analyzed in this study. Among them, 12 were included in the prospective ACSE Unicancer study and received aPD1 as monotherapy. The historic cohort used for the comparative analysis was established from the ENKTCL national observatory and composed of 38 R/R ENKTCL patients who received at least one cycle of first salvage therapy without aPD1 between 2006 and 2019. All patients were treated with Asparaginase-containing regimen as frontline therapy. Patient characteristics were as follows: median age of 52 years (19–79), sex ratio M/F of 2/1, disseminated stage and high PINK score respectively in 57% and 41% of the cases. The overall response rate at the last follow-up was 40.5% in the aPD1 group. With a median follow-up time of 6.5 months for the whole cohort and 23.4 months for survivors, progression free survival and overall survival (OS) at 2 years were 22.4% and 50.2%. Among the 22 patients who experienced progression or relapse after aPD1 initiation, 14 patients (64%) received salvage therapy, mostly containing gemcitabine in association with immunotherapy continuation. This cohort was then compared to the historic cohort after matching on a propensity score. 23 patients in each group were included in this analysis. OS was significantly improved in patients treated with aPD1 as salvage therapy alone or in combination (48.4% versus 23.1%, p = 0011). We report here the largest cohort of R/R ENKTCL treated with aPD1. Our study confirms the efficacy of aPD1 therapy in R/R ENKTCL and highlights its superiority as compared to other types of salvage therapy used in this setting before immunotherapy era. Our results will prompt us to now prospectively evaluate the benefit of aPD1 therapy as first line therapy in patients with high risk disseminated stage of ENKTCL, in combination with chemotherapy agents able to enhance anti-tumor immunity. Encore Abstract - previously submitted to regional or national meetings (up to <1’000 attendees), EHA 2023 Keywords: Extranodal non-Hodgkin lymphoma, Immunotherapy No conflicts of interests pertinent to the abstract.

Patients with previous CD19 directed chimeric antigen receptor T cell therapy (CAR T)-cell therapy have a prolonged vulnerability to viral infections. Coronavirus diseases 2019 (COVID-19) has a great impact and has previously been shown to cause high mortality in this population. Until now, real world data of the impact of vaccination and treatment on patients with COVID-19 after CD19 directed CAR T-cell therapy are lacking. Therefore, this multicenter retrospective study was conducted with data from the EPICOVIDEHA survey. Sixty-four patients were identified. The overall mortality caused by COVID-19 was 31%. Patients infected with the Omicron variant had a significantly lower risk of death due to COVID-19 compared to patients infected with previous variants (7% versus 58% (P=0.012)). Twenty-six patients were vaccinated at time of COVID-19 diagnosis. Two vaccinations showed marked but unsignificant reduction risk of COVID-19 caused mortality (33.3% versus 14.2% (P=0.379)).Also the course of disease appears milder with less frequent ICU admissions (39% versus 14% (P=0.054)) and shorter duration of hospitalization (7 versus 27.5 days (P=0.022)). Of the available treatment options, only monoclonal antibodies seemed to be effectively reducing mortality from 32% to zero (P=0.036). We conclude that survival rates of CAR T-cell recipients with COVID-19 improved over time and that the combination of prior vaccination and monoclonal antibody treatment significantly reduces their risk of death.

Classical Hodgkin Lymphoma incidence increases in HIV-1-infected patients (HIV-cHL). HIV infection is associated with higher B-cell activation. Here, in 38 HIV-cHL patients from the French cohort ANRS-CO16 Lymphovir, we examined longitudinally over 24 months the serum levels of the B-cell activating cytokines IL10, IL6, and BAFF, and blood distribution of B-cell subsets. Fourteen HIV-cHL patients were also compared to matched HIV-infected controls without cHL. IL10, IL6, and BAFF levels were higher in HIV-cHL patients than in controls (p < 0.0001, p = 0.002, and p < 0.0001, respectively). Cytokine levels increased in patients with advanced-stage lymphoma compared to those with limited-stage (p = 0.002, p = 0.03, and p = 0.01, respectively). Cytokine levels significantly decreased following HIV-cHL diagnosis and treatment. Blood counts of whole B-cells were similar in HIV-cHL patients and controls, but the distribution of B-cell subsets was different with higher ratios of naive B-cells over memory B-cells in HIV-cHL patients. Blood accumulation of naive B-cells was more marked in patients with advanced cHL stages (p = 0.06). During the follow-up, total B-cell counts increased (p < 0.0001), and the proportion of naive B-cells increased further (p = 0.04). Together the results suggest that in HIV-infected patients, cHL is associated with a particular B-cell-related environment that includes increased production of B-cell-activating cytokines and altered peripheral distribution of B-cell subsets. This B-cell-related environment may fuel the process of tumorigenesis.

Limited data are available on breakthrough COVID-19 in patients with hematologic malignancy (HM) after anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Adult patients with HM, ≥1 dose of anti-SARS-CoV-2 vaccine, and breakthrough COVID-19 between January 2021 and March 2022 were analyzed. A total of 1548 cases were included, mainly lymphoid malignancies (1181 cases, 76%). After viral sequencing in 753 cases (49%), the Omicron variant was prevalent (517, 68.7%). Most of the patients received ≤2 vaccine doses before COVID-19 (1419, 91%), mostly mRNA-based (1377, 89%). Overall, 906 patients (59%) received COVID-19-specific treatment. After 30-day follow-up from COVID-19 diagnosis, 143 patients (9%) died. The mortality rate in patients with the Omicron variant was 7.9%, comparable to other variants, with a significantly lower 30-day mortality rate than in the prevaccine era (31%). In the univariable analysis, older age (P < .001), active HM (P < .001), and severe and critical COVID-19 (P = .007 and P < .001, respectively) were associated with mortality. Conversely, patients receiving monoclonal antibodies, even for severe or critical COVID-19, had a lower mortality rate (P < .001). In the multivariable model, older age, active disease, critical COVID-19, and 2-3 comorbidities were correlated with a higher mortality, whereas monoclonal antibody administration, alone (P < .001) or combined with antivirals (P = .009), was protective. Although mortality is significantly lower than in the prevaccination era, breakthrough COVID-19 in HM is still associated with considerable mortality. Death rate was lower in patients who received monoclonal antibodies, alone or in combination with antivirals.

Chimeric Antigen Receptor T cells (CAR-T) are an outbreaking treatment option for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the most common specific toxicities, while severe neutropenia and infections are often observed as well. From March 2020, early G-CSF prophylaxis at day (D) two post-infusion was systematically proposed. We then compared patients treated before that date who did not receive G-CSF or who received late (after D5) G-CSF as control group. Patients administered with early G-CSF had similar duration of grade 4 neutropenia but significantly decreased incidence of febrile neutropenia (58% versus 81%, p = 0.018). Similar rate of toxicities was observed, including overall and grade 3-4 CRS ( p = 0.93 and p = 0.28, respectively), and overall and grade 3-4 ICANS ( p = 0.62 and p = 0.88, respectively). We observed no difference in the quality of CAR T-cells expansion ( p = 0.79, %Cmax), nor in response rate (best ORR, 57.6% vs 61.8%, p = 0.93), nor survival even in a group of patients adjusted by a propensity score. In conclusion, early G-CSF administration was safe and effective in reducing febrile neutropenia without impact on toxicities nor on anti-lymphoma activity of CAR-T.

To the Editor: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has caused high mortality in patients with hematological malignancies (HM). 1 The newly emerged omicron variants of SARS-CoV-2 harbor multiple novel spike protein mutations that raise concerns about vaccine efficiency and antiviral efficacy of the available thera-peutic monoclonal antibodies. 2 The first published clinical data in immunocompetent patients have found that infection with omicron variants is associated with reduced vaccine efficiency compared to the delta variants, but decreased hospital admission and mortality. 3,4 Preliminary, prepublished, data from a large case – control study have shown that the vaccine effect against omicron in immunocompro-mised patients, including HM patients, is even more reduced, but data regarding clinical outcomes are lacking. 5 The aim of this study was to describe risk factors, antiviral treatment and outcomes of SARS-CoV-2 omicron variant infection in 593 HM patients included in the EPICOVIDEHA registry. EPICOVIDEHA is an international open web-based registry for patients with HM infected with SARS-CoV-2. 1,6 Both hospitalized and nonhospitalized patients are eligible for inclusion. The questionnaire includes data on the HM, SARS-CoV-2 vaccination status, risk factors for severe COVID-19 infection, SARS-CoV-2 virus variant, antiviral treatment, and outcomes including mortality (eFigure 1 and eTable 4). Classification of attributable, contributable, or nonattributable death is made by the reporting physician. All included cases are validated by experts with previous experience in research studies of hematological malignancies and infectious