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International audience; Prolonged Covid-19 is an emerging issue for patients with lymphoma or immune deficiency. We aimed to examine prolonged length of in-hospital stay (LOS) due to Covid-19 among patients with lymphoma and assess its determinants and outcomes. Adult patients with lymphoma admitted for Covid-19 to 16 French hospitals in March and April, 2020 were included. Length of in-hospital stay was analyzed as a competitor vs death. The study included 111 patients. The median age was 65 years (range, 19–92). Ninety-four patients (85%) had B-cell non-Hodgkin lymphoma. Within the 12 months prior to hospitalization for Covid-19, 79 patients (71%) were treated for their lymphoma. Among them, 63 (57%) received an anti-CD20 therapy. Fourteen patients (12%) had relapsed/refractory disease. The median LOS was 14 days (range, 1–235). After a median follow-up of 191 days (3–260), the 6-month overall survival was 69%. In multivariable analyses, recent administration of anti-CD20 therapy was associated with prolonged LOS (subdistribution hazard ratio 2.26, 95% confidence interval 1.42–3.6, p < 0.001) and higher risk of death (hazard ratio 2.17, 95% confidence interval 1.04–4.52, p = 0.039). An age ≥ 70 years and relapsed/refractory lymphoma were also associated with prolonged LOS and decreased overall survival. In conclusion, an age ≥ 70 years, a relapsed/refractory lymphoma and recent administration of anti-CD20 therapy are risk factors for prolonged LOS and death for lymphoma patients hospitalized for Covid-19. These findings may contribute to guide the management of lymphoma during the pandemic, support evaluating specific therapeutic approaches, and raise questions on the efficacy and timing of vaccination of this particular population.

We evaluated the outcome of 65 French patients with Extranodal NK/T-cell lymphoma, nasal type (ENKTL) undergoing haematopoietic stem cell transplantation (HSCT) (19 allogeneic and 46 autologous). Fifty-four patients (83%), most of which receiving L asparaginase (L-aspa) containing regimens (81%), achieved complete or partial response at time of HCST. After a median follow-up of 79.9 months, 4-years progression-free survival (PFS) and overall survival (OS) were similar in both autologous and allogeneic groups (PFS: 34% vs 26%, p=0.12 and OS: 52% vs 53%, p=0.74). Response status at HSCT was the major independent prognostic factor on survival (OS: HR: 4.013 [1.137; 14.16], p=0.031 and PFS: HR: 5.231 [1.625; 16.838], p=0.006). As compared to control patients receiving chemotherapy and/or radiotherapy containing regimens only, upfront HSCT did not improve the outcome of responder patients, including those treated by L-aspa. However, it tends to provide survival benefit for relapsed patients with initial high-risk clinical features who achieved second remission. Whereas the place of HSCT in upfront therapy has still to be clarified, these data confirm that HSCT should be considered for consolidation in selected patients with relapsed ENKTL. Based on a large non Asian ENKTL cohort since the L-aspa era, this study provides some insight into the survival patterns of ENKTL patients with HSCT in the Western hemisphere and may give future direction for the next clinical trial design. This article is protected by copyright. All rights reserved.

Blastic plasmacytoid dendritic cell neoplasm is an aggressive hematologic malignancy with a poor prognosis. No consensus regarding optimal treatment modalities is currently available. Targeting the nuclear factor-kappa B pathway is considered a promising approach since blastic plasmacytoid dendritic cell neoplasm has been reported to exhibit constitutive activation of this pathway. Moreover, nuclear factor-kappa B inhibition in blastic plasmacytoid dendritic cell neoplasm cell lines, achieved using either an experimental specific inhibitor JSH23 or the clinical drug bortezomib, interferes in vitro with leukemic cell proliferation and survival. Here we extended these data by showing that primary blastic plasmacytoid dendritic cell neoplasm cells from seven patients were sensitive to bortezomib-induced cell death. We confirmed that bortezomib efficiently inhibits the phosphorylation of the RelA nuclear factor-kappa B subunit in blastic plasmacytoid dendritic cell neoplasm cell lines and primary cells from patients in vitro and in vivo in a mouse model. We then demonstrated that bortezomib can be associated with other drugs used in different chemotherapy regimens to improve its impact on leukemic cell death. Indeed, when primary blastic plasmacytoid dendritic cell neoplasm cells from a patient were grafted into mice, bortezomib treatment significantly increased the animals’ survival, and was associated with a significant decrease of circulating leukemic cells and RelA nuclear factor-kappa B subunit expression. Overall, our results provide a rationale for the use of bortezomib in combination with other chemotherapy for the treatment of patients with blastic plasmacytoid dendritic cell neoplasm. Based on our data, a prospective clinical trial combining proteasome inhibitor with classical drugs could be envisaged.

International audience; The prognostic value of cell of origin (COO) classification and BCL2 expression is not well established in diffuse large B-cell lymphoma (DLBCL) patients with human immunodeficiency virus (HIV) infection in the recent era. Phenotypic patterns were determined by immunohistochemistry (IHC) of pathological samples from patients with HIV-associated DLBCL prospectively enrolled in the French AIDS and Viral Hepatitis CO16 Lymphovir cohort between 2008 and 2015. Molecular subgroup classification into germinal centre B-cell (GCB) and non-GCB subtypes was determined using the Hans algorithm. Among 52 samples of systemic DLBCL subjected to centralized pathological analysis, 25 of the 42 tested for BCL2 expression were positive. Samples were further classified into GCB (n = 19) and non-GCB (n = 16) subtypes and 17 remained unclassified. In multivariable analysis, BCL2 expression was an independent pejorative prognostic biomarker [4-year progression-free survival (PFS): 52% for BCL2+ vs. 88% for BCL2- , P = 0·02] and tended to reduce 4-year overall survival (OS) (63% for BCL2+ vs. 88% for BCL2- , P = 0·06). The difference between CGB and non-GCB subtypes on PFS and OS did not reach significance (4-year PFS: 79% for GCB vs. 53% for non-GCB, P = 0·24 and 4-year OS: 78% for GCB vs. 69% for non-GCB, P = 0·34). BCL2 expression determined by IHC is an independent pejorative prognostic biomarker in HIV-associated DLBCL in the recent era. This supports the investigation of new therapeutic strategies in patients with BCL2 expression.

Introduction Treatment of B-lineage lymphoma with B-cell depleting immunotherapy causes B-cell aplasia and impairs immune response. Case studies have reported patients treated with anti-CD20 therapy who suffered from persistent Covid-19. We aimed to assess the incidence, risk factors and long-term outcomes of persistent Covid-19 in patients with lymphoma. Patients and methods This retrospective multicentric study was conducted in 16 French hospitals. All adult patients with lymphoma who were admitted for Covid-19 in March and April 2020 were included. Persistent Covid-19 was defined as persisting severe Covid-19 symptoms requiring in-hospital stay for >30 days. Patients who re-experienced severe Covid-19 symptoms after initial improvement, requiring repeated hospitalizations for a total in-hospital length of stay >30 days were added to the persistent Covid-19 cases. Results One hundred eleven patients were included. Thirty days after admission for Covid-19, 24 patients had died, 55 had been definitively discharged from hospital, 31 were still hospitalized and 1 was later rehospitalized for Covid-19 recurrence. The incidence of persistent Covid-19 was 32/111 (29%). Patients with persistent Covid-19 had a median age of 64 years (range, 43-87) and 63% were male. Twenty-two patients (69%) had at least one significant comorbidity. None of the patients with T-cell (n=8) lymphoma or classical Hodgkin’s disease (n=8) experienced persistent Covid-19. In the 32 patients with persistent Covid-19, the median time between first admission and final discharge was 58 days (range, 31-235) and the median duration of Covid-19 symptoms was 83 days (range, 32-237). Eight patients received corticosteroids and 9 convalescent plasma: all patients recovered from their symptoms, except one. Overall, 9 patients with persistent Covid-19 died (27%). After a median follow-up of 191 days (range, 3-260), the 6-month overall survival was 69% (95% CI 60-78%) for the whole cohort. In multivariate analysis, administration of anti-CD20 monoclonal antibody within 12 months before admission to hospital for Covid-19 was both associated with decreased overall survival (HR 2.13, 95% CI 1.03-4.44, p = 0.043) and prolonged in-hospital stay (HR 1.97, 95% CI 1.24-3.13, p = 0.004). The two other significant factors associated with decreased overall survival and prolonged in-hospital stay: age ≥ 70 years and refractory or relapsed lymphoma. Conclusion Patients with B-cell non-Hodgkin lymphoma hospitalized for Covid-19 have a high incidence of prolonged evolution of SARS-CoV-2 infection. Administration of anti-CD20 therapy within the last 12 months is one of the main risk factors for longer in-hospital stay and death of Covid-19. The risk of persistent Covid-19 was also higher in patients older than 70 years or with refractory or relapsed disease. These findings may contribute to guide the management of lymphoma patients during the Covid-19 pandemic. Citation Format: Sylvain Lamure, Remy Dulery, Marc Delord, Roberta Di Blasi, Adrien Chauchet, Thomas Hueso, Cédric Rossi, Bernard Drenou, Bénédicte Deau-Fischer, Carole Soussain, Pierre Feugier, Nicolas Noel, Sylvain Choquet, Serge Bologna, Bertrand Joly, Laure Philippe, Milena Kohn, Sandra Malak, Guillemette Fouquet, Etienne Daguindau, Sophie Bernard, Yassine Taoufik, Karine Lacombe, Guillaume Cartron, Catherine Thieblemont. High incidence of persistent COVID-19 among patients with lymphoma treated with B-cell depleting immunotherapy [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr S09-02.

Les lymphomes diffus a grandes cellules B (LDGCB) representent environ 40 % des lymphomes non hodgkiniens et sont ainsi les plus frequents des lymphomes agressifs. En 2012, l’incidence des LDGCB etait de 4 096 nouveaux cas par an en France. Il est bien reconnu aujourd’hui qu’il n’y a pas un seul et unique LDGCB, mais que les affections ainsi designees constituent un groupe heterogene de tumeurs. L’avenement des nouvelles techniques de biologie moleculaire a permis de mieux comprendre les origines genetiques des differents sous-types de LDGCB. Le choix du traitement depend de l’âge du patient et du score pronostique international prognostic index (IPI). Il repose sur l’association de rituximab et de cyclophosphamide-doxorubicine-vincristine-prednisone (CHOP). L’objectif du traitement est l’obtention d’une reponse complete metabolique, evaluee par TEP-FDG. Malgre les nombreuses avancees therapeutiques realisees ces dernieres annees, 30 a 50 % des patients rechutent apres une premiere ligne d’immunochimiotherapie. La strategie therapeutique a la premiere rechute est une immunochimiotherapie suivie d’une intensification therapeutique avec autogreffe de cellules souches hematopoietiques chez les patients eligibles en cas de reponse. Un tres grand nombre de nouvelles molecules ont vu le jour grâce a la meilleure comprehension de la physiopathologie des LDGCB et pourraient venir modifier les strategies therapeutiques dans les prochaines annees.

International audience; Blastic plasmacytoid dendritic cell (PDC) neoplasm (BPDCN) is an aggressive hematological malignancy with a poor prognosis that derives from PDCs. No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared with those of acute myeloid leukemia and T-acute lymphoblastic leukemia, as well as the transcriptomic signature of primary PDCs. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes. LXR agonist treatment of primary BPDCN cells and BPDCN cell lines restored LXR target gene expression and increased cholesterol efflux via the upregulation of adenosine triphosphate-binding cassette (ABC) transporters, ABCA1 and ABCG1. LXR agonist treatment was responsible for limiting BPDCN cell proliferation and inducing intrinsic apoptotic cell death. LXR activation in BPDCN cells was shown to interfere with 3 signaling pathways associated with leukemic cell survival, namely: NF-kB activation, as well as Akt and STAT5 phosphorylation in response to the BPDCN growth/survival factor interleukin-3. These effects were increased by the stimulation of cholesterol efflux through a lipid acceptor, the apolipoprotein A1. In vivo experiments using a mouse model of BPDCN cell xenograft revealed a decrease of leukemic cell infiltration and BPDCN-induced cytopenia associated with increased survival after LXR agonist treatment. This demonstrates that cholesterol homeostasis is modified in BPDCN and can be normalized by treatment with LXR agonists which can be proposed as a new therapeutic approach.

Introduction Extranodal NK/T-cell lymphoma (ENKTL) is a rare disease; in Western countries it represents less than 1% of all Non-Hodgkin lymphoma. When localized, ENKTL is associated with a good prognosis. In contrast, patients (pts) with a disseminated disease still have a dismal outcome despite the use of asparaginase (ASPA) containing regimens that have significantly improved the prognosis of this lymphoma. Production of neutralizing anti-ASPA antibodies leading to inactivation of the enzyme can reduce its activity. Inactivation of ASPA activity is correlated with a worse prognosis in acute lymphoblastic leukemia (ALL). Monitoring of ASPA activity is therefore recommended in ALL pts with 100 IU/L as threshold value of serum enzymatic activity considered to be sufficient for complete depletion of l-asparagine in serum. However, ASPA monitoring is not routinely performed in pts with ENKTL, despite the frequent use of ASPA-containing regimens. The main objective of this study was to determine the proportion of pts with an insufficient ASPA activity corresponding to production of neutralizing anti-ASPA antibodies, risk of allergic reaction and inefficacy of the drug. Methods Adult pts with histologically confirmed ENKTL who received an ASPA-containing regimen between 2014 and 2018 and had a monitoring of ASPA activity were included. ASPA activity measurement was usually performed with a quantitive enzyme assay 48 hours after the last ASPA injection of each cycle for native forms of ASPA and 14 days after injection of the pegylated form. Activity below 100 UI/L was considered as insufficient. ASPA activity was correlated with pts outcome. The choice of initial form of ASPA and reasons to switch between two forms of ASPA were also analyzed. Results From 2014 to 2018, a total of 21 pts received an ASPA-containing regimen and were monitored for ASPA activity. Median age was 53 years with 14 men and 7 women. More than half of these pts had a stage IV disease (n=11/21), 6 were in stage I and 4 in stage II. Fifteen pts were in first line and 6 pts were in relapse. Pts have received either native e-coli L-asparaginase (Kidrolase®: KID) (n= 13 in the treatment-naïve group, n=2 in the relapsing group) or a pegylated form of e-coli- L-asparaginase (Oncaspar®: ONC) (n=2 in the treatment-naïve group, n=4 in the relapsing group). Most of the pts received ASPA (8 injections at each cycle for native forms and 1 injection for the pegylated form) associated with gemcitabine, methotrexate and dexamethasone, plus oxaliplatine for disseminated diseases. Six pts had optimal ASPA activity, 3/6 had localized disease: 2 had persistent RC and 1 relapsed, 3/6 had a disseminated disease: 2 progressed during treatment and 1 relapsed. Fifteen pts displayed low ASPA activity, 12/15 pts with a KID containing regimen after 1 cycle (n=10) or 3 cycles (n=2) and 3/6 pts with an ONC containing regimen after the first cycle (n=2) or the second (n=1). Among these 3 pts, 2 have been previously treated with KID that could induce an immunization against ONC. Ten pts received a second form of asparaginase: Erwinia asparaginase (Erwiniase®: ERW) in 9 pts and ONC in 1 pt. In 9/10 cases, this switch was justified by detection of low ASPA activity. Measurement of enzymatic activity in these 9 pts showed satisfactory levels in 2/5 pts treated with ERW and monitored for ASPA activity and in the pt receiving ONC, 4/6 pts with a localized form and 1/3 with a disseminated form are in persistent RC. Six pts with low ASPA activity including one case with a localized form and 5 cases with a disseminated disease, did not receive another form of ASPA, they all progressed or relapsed. Conclusion More than 2/3 of pts had sub-optimal ASPA activity after 1 to 3 cycles of ASPA containing regimens. This finding is probably due to the development of anti-ASPA inhibitory antibodies and may explain the poor outcome of pts with a disseminated disease despite the remarkable efficacy of ASPA in this disease. Although the series reported here is small and heterogeneous, our results still suggest a better outcome in pts with good ASPA activity or in case of switch between ASPA molecules in the context of low activity. ASPA activity monitoring should be recommended in pts with ENKTL, to avoid allergic reaction and ineffective treatment by switching ASPA molecules. Pegylated forms of ASPA, or encapsulated in red cells may, be less immunogenic, should be used in the first line setting instead of native forms. Table. Table. Disclosures Bachy: Celgene: Consultancy; Janssen: Honoraria; Gilead Sciences: Honoraria; Takeda: Research Funding; Sandoz: Consultancy; Amgen: Honoraria; Roche: Research Funding.

Introduction: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy derived from plasmacytoid dendritic cells (pDC). Today, no therapeutic consensus exists and only allogeneic hematopoietic cell transplantation provides a durable remission. BPDCN cells express high levels of the IL-3 receptor alpha chain (CD123) and exhibit an increased survival and growth in response to IL-3 (Chaperot et al. 2001). Recently, aberrant NF-κB activation has been reported in BPDCN (Sapienza et al. 2014), and we identified that liver X receptor (LXR) stimulation inhibits NF-κB activation in non-leukemic pDC. LXR represent nuclear receptors promoting cholesterol efflux via the ATP binding cassette A1 and G1 (ABCA1 and ABCG1, respectively) transporters and lipid acceptors, such as apolipoprotein A1 (ApoA1). This process has been shown to repress IL-3-induced proliferation of murine hematopoietic stem cells (Yvan-Charvet et al. 2010). The aim of this study was to investigate LXR activation in BPDCN, and determine whether LXR agonists possess therapeutic effects. Material and Methods: Cells from 13 BPDCN, 22 undifferentiated AML, 23 ALL patients and 4 normal pDC were evaluated for expression of LXR or cholesterol exchange related genes (lxra, lxrb, abca1, abcg1, apoe, srebp1c, ldlr, vldlr), plus nfkb1 gene by Affymetrix mRNA microarray. BPDCN cells (2 established cell lines [GEN2.2, CAL-1], a primary cell line [BES1] and 5 fresh BPDCN samples) were treated with two LXR agonists (T0901317 [T09] or GW3965 [GW] at 1 µM, 10 µM or 50 µM), NF-κB inhibitors (JSH 23, or Bortezomib [Bort]) and the cholesterol acceptor ApoA1 (10 µg/mL). Gene expression (abca1, abcg1, nfkb1, bcl2, bax and bak1) was assessed by qRT-PCR. Cell death was assessed by Annexin V/7AAD staining (flow cytometry) and caspase activation (Western blot). CAL-1 cell proliferation was assessed by dye dilution (cytometry). Cholesterol efflux was measured directly by H3 cholesterol efflux from cells and indirectly by membrane ABCA1 expression (confocal microscopy). NF-κB and IL-3 signaling pathway activation was explored by protein phosphorylation (phospho-RelA and phospho-STAT5, respectively; [confocal microscopy and Western blot]). A BPDCN xenograft model was used to evaluate LXR agonist effect in-vivo with blast cell infiltration attested by human CD45/CD123/BDCA4 staining (cytometry). Results: BPDCN cells showed a unique transcriptomic signature with LXR-related gene downregulation. LXR agonist treatment for 24h restored LXR target gene expression, including abca1 and abcg1, and induced a significant concentration-dependent killing (Fig. 1). Moreover, caspase 8 and 9 cleavage associated with bcl2 downregulation and bax and bak1 upregulation (0.78, 8 and 12.2 fold mRNA levels, respectively, for GW 50 µM, 6h, n=3) were observed. At a lower non cytotoxic concentration (10 µM), GW treatment inhibited cell proliferation (-25%, p Conclusion: BPDCN exhibit a specific transcriptomic signature with LXR-related gene downregulation. LXR stimulation of BPDCN restores LXR-related gene expression and inhibits survival and proliferation. This may occur via several mechanisms: inhibition of IL-3 and NF-κB signaling, and/or increased cholesterol efflux. A cytotoxic or cytostatic effect was confirmed in-vivo by reduced BPDCN infiltration. Disclosures No relevant conflicts of interest to declare.

Blastic plasmacytoid dendritic cell neoplasm is a rare and aggressive neoplasm for which there is still no current consensus on the best therapeutic approach. Most patients respond to intensive chemotherapy, but relapses are almost inevitable with median overall survival (OS) in the largest patient series ranging from 8 to 12 months except for patients who could benefit from allogenic hematopoietic stem cell transplantation (allo-HSCT). We present results of the first line treatments used in France between 2000 and 2013 for 86 patients recruited in the French network of BPDCN (abstract ASH 2015 N°78460). Seventeen patients were treated with acute lymphoid leukemia (ALL)-like therapy (median age : 63 yo) , 19 with acute myeloid leukemia (AML)-like therapy (median age : 40 yo), 16 patients with CHOP-like therapy (median age : 72 yo), 16 patients with NK/T-like therapy (based on high-dose methotrexate and L-asparaginase, ± dexamethasone, median age: 59 yo), and 12 patients received "other treatments" (OT, means variable drugs, median age : 82 yo). Thirty four patients obtained a complete remission (CR) and received HSCT (autologous n=4, or allogeneic n=30). The response rates for CHOP-like and OT groups were 31.3% and 25.0% respectively. For ALL-like, AML-like, and NK/T-like groups, response rates reached 70.6%, 78.9%, and 62.5% respectively (no statistic difference). Relapse rates among responders for CHOP-like and OT groups were 60% and 33.3% whereas there were only 25%, 26.7%, and 20% in ALL-like, AML-like, and NK/T-like groups respectively. For patients who obtained remission, the median of remission duration was 8.0 and 14.0 months for patients who received CHOP-like treatments (n=5) and OT (n=3) respectively and 10.0, 10.0, and 9.0 months for ALL-like (n=11), AML-like (n=14), and NK/T-like groups (n=9) respectively (p = 0.6339). In preclinical studies, we have shown that BPDCN cells are sensitive in vitro to idarubicine (Angelot Delettre F et al, 2015) so we studied patients receiving idarubicine in first line therapy in our series (n=9). From these 9 patients, 7 obtained CR and only one relapsed after 10 months. The 6 patients in continuous CR without any relapse have received HSCT (allo, n=5 or auto, n=1). Two out of those 6 patients are alive at the time of data collection with a follow-up of 40 and 87 months; the other 4 patients died after the graft, one relapsed after auto-HSCT, and 3 died of infectious complications after allo-HSCT. The median OS for patients who received HSCT, auto or allo (n=34) and other patients (n = 52) is respectively 49 and 8 months (p < 0.0001, Figure 1). The beneficial effect of HSCT persists independently of age in multivariate analysis. These results suggest that NK/T-like, AML-like, and ALL-like groups give better results than CHOP-like and OT groups. However, there is no significant statistical difference between AML-like, ALL-like, and NK/T-like groups. Thus it seems to be wise to combine "lymphoid" drugs like methotrexate, L-asparaginase and dexamethasone with "myeloid" drug such as idarubicine. The importance of allogenic stem cell transplantation to sustain remission is clear in this study and other one (Roos-Weil et al, 2013). We also observed a prolonged CR in one patient after auto-HSCT. Based on our results, we will propose the first prospective, multicentric, phase II trial in BPDCN, testing a combination of 3 cycles of methotrexate, L-asparaginase, idarubicine and dexamethasone followed by an allo-HSCT in first clinical remission for all eligible patients or repeated cycle of these drugs for unfit patients with auto-HSCT if possible. Kaplan-Meier overall survival curves compared by the Log-Rank test in the cohort of 34 HSCT patients (auto and allo, blue line) and 52 non HSCT patients (red line) (p Figure 1. Overall survival of HSCT patients and non HSCT patients. Figure 1. Overall survival of HSCT patients and non HSCT patients. Disclosures Recher: Celgene; Amgen; Chugai: Research Funding; Janssen; Novartis; Amgen: Other: Travel, accommodations, expenses; Sunesis; Celgene: Consultancy. Deconinck:CHUGAI: Other: Travel for international congress; NOVARTIS: Other: Travel for international congress; ALEXION: Other: Travel for international congress; LFB loboratory: Consultancy; JANSSEN: Other: Travel for international congress; PFIZER: Research Funding; ROCHE: Research Funding.