ALBERT

Beschreibung: 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.

Beschreibung: Introduction : Hematological complications (HC) as Aplastic anemia (AA) and myelodysplasia and acute leukemia (MDS/AL) are frequent and life threatening in patients with Shwachman Diamond Syndrome (SDS) with SBDS mutations. The therapy of such events is based on Hematopoetic stem cell transplantation (HSCT), which results remain quite poor, especially in case of malignancy. So far, it is difficult to anticipate to such HC and a lot is expected from the study of clonal evolution prior HC. Methods: A Targeted panel of 43 genes involved in MDS/AL (sensibility 1%) has been evaluated in 80 patients with SBDS mutation, representative of a nation based cohort of 154 patients. This cross sectional study has been completed by a prospective study for 40 patients evaluated at several time points. Results: The evaluation was performed in various situations: steady state i.e. no haematological complication, in MDS/AL and AA and lastly after HSCT. At the first evaluation, somatic mutation was found in 21 patients (30%) among the 70 in steady state and in 7 of the 8 cases with HC (6/6 cases with MDS/AL, in 1 among the 2 cases with AA) while the 1 of the 2 patients long term survivors after HSCT have no mutation and the other one kept a TP53 clone with a normal blood count and a low (1.5%) variant allele frequency (VAF). Among the 40 patients with several time points, 17 have a mutation at the first time points, but 10 others had additional mutation later. Globally, the most frequent gene involved was TP53 (82%) while mutations in other genes have been observed rarely. VAF in patients with vs without HC is lower (median VAF 0% vs 22.8% respectively p 〈 0.001) . Complex caryotype, monosomy 7, Iso7q were associated with P53 clone while in Del20q, 8 patients out 14 have a P53 mutations. The comparison between blood and bone marrow results allow the possibility to monitor such mutations in blood. Clonal evolution in one patient who presents a MDS in the course of the follow up had shown a competition between clones. Conclusion: Acquired TP53 is extremely frequent in patients with SBDS mutations, even in the absence of HC, but the prevalence as well as the VAF increased in case of HC. When sequential evaluation could be performed, competition between clones is frequent and a clinical decision remains therefore difficult, just on the evaluation of a time point. Acknowledgments: The French SCN registry is supported by grants from Amgen, Chugai, Prolong Pharma, X4 Pharma, Inserm, the Association 111 les Arts, the Association RMHE, the Association Sportive de Saint Quentin Fallavier. The authors thank the association IRIS and Mrs Grosjean and Mr Gonnot(ASSQF), the association Barth France for their support. Disclosures Sicre de Fontbrune: Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Renard:Jazz Pharmaceuticals: Research Funding. Tournilhac:ABBVIE: Consultancy, Honoraria, Other: Travle grant; INNATE Pharma: Consultancy, Honoraria; GILEAD: Consultancy, Honoraria, Other: Travel Grant; Takeda: Consultancy, Honoraria, Other: Travel grant; Janssen: Consultancy, Honoraria, Other: Travel grant.

Beschreibung: Introduction: GCSF is a key drug in the medical management of chronic neutropenia (ChrN). Two major marketed forms of G-CSF are used. Filgrastim (F), marketed initially with the brand name Neupogen®;, now available with generic presentation, is a non-glycosylated GCSF. A pegylated (PegF) formulation of F exists too. Lenograstim (L) is the second form of bio-engineering GCSF and is glycosylated and marketed with the brand name Granocyte®. L is distributed in 263 µg and 105 µg vials while F is distributed in 300 and 480 µg vials. L and F have a similar PK profile (1/2 time ~3.7 h), contrary to PegF (1/2 time 42H). Here we compare the efficacy and safety of F and L in ChrN. METHODS The French Severe Chronic Neutropenia Registry (FSCNR) since 1993 prospectively monitors patients with ChrN and collects routinely information about G-CSF therapy (type of product including the Brand names, dose per injection, number of injections, duration of the period of daily treatment, infections, blood counts, side effects..)(1). On 1 October 2019, the FSCNR had enrolled 1068 patients with ChrN (idiopathic neutropenia(2) n=231 and Congenital neutropenia(3) n=837 patients). To take into account individual changes in G-CSF regimens, for a given patient, treatment was divided into elementary periods during which the characteristics of G-CSF treatment remained constant. Several parameters were calculated by summing up the elementary periods: duration of follow-up after G-CSF start, Cumulative duration, Cumulative dose, Time averaged dose (TAD). Three treatment groups were defined according to the type of G-CSF received: "group F" for patients who received only F, "group L" for patients who received only L , "group FL" for patients who received both F and L in succession. As there are no guidelines for GCSF prescription (F or L), even if L is here prescribed off-labelled, treating physician made is own choice. Because PegF have a very specific PK profile, we excluded the Peg F periods from this analysis (only 29 patients have received PegF as part of their therapy). The analysis presented here is limited only to the "L group', the "F group' and the "FL group'. 434 of the 1068 patients with ChrN have received a GCSF therapy: 172 received Lenograstim alone (group L), 148 Filgrastim alone (group F) and 112 received both cytokines consecutively (group FL). RESULTS : The key parameters defining the disease, the severity of the clinical and hematological presentation, the median neutrophil count, the proportion of patients with bone marrow blockage and the number of severe and oral infections was similar between the 3 patient groups (table 1). For group FL and more over the L group the median age at the start of G-CSF was younger (p

Beschreibung: Introduction: Congenital neutropenia (CN) is characterized by chronic neutropenia caused by a constitutional genetic defect and can be considered an orphan disease. Nationwide estimations of its incidence and prevalence are poorly documented but would provide key information to better follow-up of CN patients. Notably, orphan-drug status also is accorded based on such epidemiological parameters. Methods: The French Severe Chronic Neutropenia Registry (FSCNR) has prospectively enrolled CN patients since 1993, with multiple source verifications in France of that information: pediatric and adult hemato-immunology units, diagnostic labs... We also actively collect all cases followed in France, regardless of the healthcare facility monitoring the patient. To calculate incidence at birth, we considered subjects born between 1/1/1995 and 12/31/2017, because information completeness has been validated for this 22-year period. Number of births per year was provided by the French National Institute of Statistics and Economic Studies (INSEE). We used American College of Medical Genetics class 4 and 5 variants for genetic classification and the overall CN classification developed elsewhere.1 To estimate expected prevalence, we assumed 50-year life expectancy for these patients and compared ongoing enrolment to the prevalence estimation and calculated FNSCR coverage. A Poisson distribution was assumed. Results: On 15 July 2020, the FSCNR had identified 3205 patients. Reasons for non-enrolment of 2096 were, mainly: autoimmune neutropenia (n=501), foreign residency (n=214), other diagnosis (n=882) and diagnostic work-up not completed (n=249). Among the 1109 patients who fulfilled Chronic Neutropenia criteria, 242 had idiopathic neutropenia2 and 867 patients were considered to have CN1. Global results are presented in Table 1. In France, the CN incidence at birth (all subtypes combined) was 2.6×10-5 (95% CI: 2.04-2.8×10-5), which represents a mean of 23 new cases/year in a country with ~870,000 births/year. For all CN combined, the expected prevalence, assuming 50-year life expectancy, would be 1131 cases in a country of 65×106 inhabitants while the FCSNR currently has 867 cases enrolled or an estimated 77% nationwide coverage. Based on our results and our assumptions for life expectancy, estimated prevalence of CN for 10 millions inhabitants is therefore 174 CN. Genetic subtype representation is as follows: 20% SBDS, 17% ELANE (8% cyclic, 9% permanent), 9% GATA2, 7% SLC37A4, ~4-5% each of TAZ and CXCR4 and VPS13B, while the other subtypes are even rarer. At present, no cause has been identified for 25% of the cases. Conclusion: The results of this analysis provide an estimation of the major CN-descriptive epidemiological parameters and the relative frequencies of several subtypes. Despite the FSCNR's quite large registry, we estimate that about a quarter of the prevalent cases in France were missed, mainly those followed as adults. References 1 Donadieu J, Beaupain B, Fenneteau O, Bellanne-Chantelot C. Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history. Br.J.Haematol. 2017; 179(4): 557-574. 2 Sicre De Fontbrune F, Moignet A, Beaupain B et al. Severe chronic primary neutropenia in adults: report on a series of 108 patients. Blood 2015; 126(14): 1643-1650. Acknowledgments: The French SCN registry is supported by grants from Amgen, Chugai, Prolong Pharma, X4 Pharma, Inserm, the Association 111 les Arts, the Association RMHE, the Association Sportive de Saint Quentin Fallavier. The authors thank the association IRIS and Mrs Grosjean and Mr Gonnot(ASSQF), the association Barth France for their support. Disclosures Sicre de Fontbrune: Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. cohen Beaussant:X4 Pharmaceuticals, Inc.: Current Employment.