Search

Introduction COVID-19 is usually a mild disease in immunocompetent children, with ~1% requiring intensive care unit (ICU) admission and Methods Data on children following HCT who developed COVID-19 (diagnosed by positive SARS-CoV-2 PCR on respiratory tract samples) during 3.2020-4.2021 were prospectively collected by EBMT and GETH, including demography, HCT data, COVID-related manifestations, ICU admission and mortality. Factors associated with worse outcomes (ICU admission or mortality) were characterized. Results Sixty-two children (34 boys; median age 9; min-max; 0.7-17 years) were reported from 27 centers, 16 countries; 57 (92%) following allogeneic and 5 (8%) following autologous HCT. Underlying diseases were acute leukemia (23; 37%), inherited disorders (9; 15%), hemoglobinopathies (7; 11%), solid tumor (6; 10%), bone marrow failure (5; 8%), other malignant (8; 13%) and non-malignant (4; 6%) diseases. Five (8%) children had high blood pressure; 6 (10%) had underlying lung pathology. The median time from the most recent HCT to COVID was 5 months (min-max; 0-169). The stem cell source was bone marrow (33); peripheral (22) or cord blood (1). Among the patients with information available, 34 (62%) underwent in-vivo T cell depletion, 20 (33%) received corticosteroids, and 36 (60%) other immunosuppressant drugs(s) within two months prior to and after the COVID-19 episode. The presence of acute grade 2-4 or chronic graft versus host disease (GVHD) was reported in 12/54 (23%) and 8/51 (16%) children, respectively. Clinical presentation (n=57) included fever (28; 49%), cough (18; 32%), diarrhea (8; 14%), upper respiratory tract disease (as rhinorrhea, sinusitis, otitis, or pharyngitis; 12; 21%); six (10%) required oxygen to maintain oxygen saturation above 92%; 20 children (35%) were asymptomatic. The median time from symptoms onset to COVID diagnosis was 1 day (-43-40). Sixty-three percent of patients were hospitalized; 43% due to COVID. The proportion of children with neutropenia or lymphocytopenia ( Six (10%) children who developed COVID at a median 6.5 (min-max; 2- 16) months following allo-HCT (median age 6 years; 5 boys) required ICU care within a median 6 (min-max; -5-15) days after diagnosis. All of them were neutropenic, received steroids, and other immunosuppressive drugs at COVID diagnosis; 5 had undergone in-vivo T cell depletion; 5 were lymphocytopenic, 5 had GVHD (2 acute and 3 chronic); 3 received non-invasive and 2 invasive ventilation. Three children had viral or bacterial coinfections. Three children died. Six (10%) children (5 boys, median age 10.5 years; min-max; 4-13) who developed COVID at median 2 (min-max; 0-147) months following allo-HCT died within median 35 days (min-max; 5-54) after diagnosis. One had high blood pressure, and none suffered from underlying lung pathology. At the time of COVID, 3 were neutropenic, 2 lymphocytopenic; 4 had GVHD (2 acute, 2 chronic); 3 received steroids and 4 immunosuppressive drugs. Two had viral or bacterial coinfections. Five had positive SARS-CoV-2 PCR at the time of death. In 3, COVID was the primary cause of death. We compared nine children with the worse outcomes to 53 children with benign course. Among patients alive at 100-day post HCT, the probability of worse outcomes was higher in patients with vs. without chronic GVHD (Figure). No other significant differences were observed in demographic, underlying disease, and HCT-related characteristics. Compared to adults following HCT (Ljungman, Leukemia 2021), children had: - Shorter median time from HCT to COVID diagnosis, 5 vs 18 months; - Higher proportion of asymptomatic infections, 35% vs 9%; - Lower proportion of those who required oxygen, 10% vs 35%; - Lower all-cause mortality, 10% vs 29%. Conclusions Children following HCT with COVID-19 have a higher risk of ICU admission and mortality compared to immune competent children. The presence of chronic GVHD at COVID diagnosis was associated with worse outcomes. COVID course following HCT is milder in children compared to adults. Figure 1 Figure 1. Disclosures Averbuch: Takeda: Consultancy; Pfizer: Consultancy; GSK: Speakers Bureau. De La Camara: Roche: Consultancy; IQONE: Consultancy. Corbacioglu: Gentium/Jazz Pharmaceuticals: Consultancy, Honoraria. Mikulska: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau; MSD: Speakers Bureau; Janssen: Speakers Bureau; Biotest: Speakers Bureau. Kulagin: Roche: Speakers Bureau; Sanofi: Speakers Bureau; Generium: Speakers Bureau; Biocad: Research Funding; Apellis: Research Funding; Alexion: Research Funding; X4 Pharmaceuticals: Research Funding; Novartis: Speakers Bureau; Johnson & Johnson: Speakers Bureau; Pfizer: Speakers Bureau. Cesaro: Sobi: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau. Lawson: Alexion: Honoraria. Kroeger: Neovii: Honoraria, Research Funding; Sanofi: Honoraria; Jazz: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Gilead/Kite: Honoraria; AOP Pharma: Honoraria; Novartis: Honoraria. Styczynski: MSD, Pfizer, Giled, TEVA, Jazz, Novartis: Honoraria, Speakers Bureau. Ljungman: Takeda: Consultancy, Other: Endpoint committee, speaker; Enanta: Other: DSMB; Janssen: Other: Investigator; OctaPharma: Other: DSMB; Merck: Other: Investigator, speaker; AiCuris: Consultancy.

Adenosine deaminase 2 deficiency (DADA2) is a recently defined inborn error of immunity caused by loss-of-function mutations in the ADA2 gene. Patients suffer from severe manifestations, including early-onset lacunar strokes, intracranial hemorrhages, vasculitis/vasculopathy, systemic inflammation, immunodeficiency, and hematologic abnormalities. The therapeutic benefit of the current treatments is unsatisfactory. Anti-tumor necrosis factor therapy reduces strokes and systemic inflammation but does not correct cytopenia and bone marrow failure. Allogeneic hematopoietic stem/progenitor cell (HSPC) transplantation can ameliorate most disease manifestations, but patients are at risk for complications. Therefore, we proposed that autologous HSPC gene therapy may be an alternative curative option for patients who has no compatible donor or cannot receive intense chemotherapy. We performed an in-depth study, using multiparametric flow cytometry, of the bone marrow (BM) cell composition of three adult patients with the hematological phenotype of DADA2. Compared with healthy donors (HDs), patients' BM exhibited a reduced number of mature and immature populations belonging to different hematopoietic lineages. Patients exhibited a substantial reduction in circulating neutrophils and hematopoietic stem cells and progenitor pools in the BM. Severe neutropenia and HSPC defects are direct causes of DADA2. Indeed, ADA2 knock-down in zebrafish - as rodents do not harbor an ADA2 orthologue gene - caused a significant decrease in neutrophil and HSPC numbers, reminiscent of patients' phenotype. Administration of human recombinant ADA2 effectively corrected both neutropenia and defective hematopoiesis in the zebrafish embryo. We used a third-generation LV to restore constitutive ADA2 expression in HSPCs. Transduction of healthy donors' HSPCs allowed efficient delivery of the functional ADA2 enzyme with no toxicity. Supranormal ADA2 expression in healthy donors' and patients' HSPCs was well-tolerated and did not impact HSPC multilineage differentiation potential in vitro and in vivo. We also assessed whether LV-derived ADA2 could correct the hyperinflammatory M1 macrophage phenotype characteristic of DADA2. ADA2 reconstitution in patients' macrophages led to the normalization of IL-6 and TNF release. Similar results were obtained using M1 macrophages differentiated from ADA2-transduced HSPCs. Altogether, our findings indicate that HSPC gene therapy is a promising approach to re-establish stable ADA2 activity and correct the hematological and inflammatory manifestations in patients with DADA2. Disclosures Aiuti: Orchard Therapeutics: Other: PI of clinical trials sponsored by company.

Introduction: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, representing ~25% of cancer diagnoses in children. Approximately 20% of childhood leukemias are of myeloid origin with the majority being acute. Isatuximab (Isa) is a monoclonal antibody that binds to a specific epitope of CD38 and exerts anti-multiple myeloma (MM) effects through several modes of action. Isa is approved for use in MM in adults. CD38 expression is high in some acute leukemia subsets in pediatric patients, making CD38 a potential target for acute leukemia treatment in children. Methods: ISAKIDS (NCT03860844) is a Phase 2, single-arm, multicenter, open-label study evaluating the antitumor activity, safety, and pharmacokinetics (PK) of Isa in combination with standard salvage chemotherapies in children with relapsed or refractory (R/R) leukemia in first or second relapse; including both T-ALL and B-ALL and acute myeloid leukemia (AML), conducted in 3 separate cohorts. Children from 2 years (yrs) to Results: 24 pts were enrolled (10, B-ALL; 7, T-ALL; 7, AML) and treated. Baseline characteristics were comparable between cohorts; median age (range) B-ALL 6.5 (3-14) yrs; T-ALL 10.0 (7-16) yrs; AML 7.0 (2-17) yrs. Males (4/10 B-ALL; 6/7 T-ALL; 3/7 AML). Evaluable Lansky scores of 90 - 100 (9/10 B-ALL; 3/4 T-ALL; 4/6 AML). Mean (standard deviation) time from initial diagnosis to first dose of investigational medicinal product (IMP) was 2.6 (1.0) yrs, 1.2 (0.6) yrs, and 1.0 (0.3) yrs for the B-ALL, T-ALL, and AML groups, respectively. Number of prior regimens, median (range) was 6 (1-≥8), 3 (1-≥8), 4 (1-≥8) for the B-ALL, T-ALL, and AML groups, respectively, corresponding to inclusion of pts with very advanced disease. Three pts presented with hyperleukocytosis >20 x 10 9/L. Among 23 pts assessed for CD38 expression, all except 2 (1 B-ALL and 1 AML) were CD38 positive. There were 17 evaluable pts with valid response data collected up to the cutoff date (May 11, 2021). Of the evaluable participants, CR+CRi were observed for: 3/7 (42.9%) in the B-ALL cohort, 2/6 (33.3%) in the T-ALL cohort, and 2/4 (50.0%) in the AML cohort (Table). Safety data showed that Grade ≥3 TEAEs occurred in 17 pts (Table). Infusion reactions (majority Grade 1 or 2) occurred in 9/24 pts (2/10 B-ALL; 4/7 T-ALL; 3/7 AML). Three pts had Grade 5 TEAEs (deaths: 1 B-ALL and 2 AML). One subject in the AML cohort had cytokine-release syndrome (CRS) related to IMP with progressive disease as a confounding factor. The other 2 deaths were not treatment related. One subject in the AML cohort had cellulitis Grade 5 and 1 subject in the B-ALL cohort had septic shock Grade 5 as cause of death. Preliminary PK analysis on 18 pts (>2 yrs) showed that Isa PK parameters including exposure PK parameters in children with ALL or AML are consistent with those observed in adult ALL pts. PK modeling approaches predict a slightly lower exposure ( Conclusions: In a poor prognostic relapsed population, 7/17 (41.2%) pts achieved CR+CRi. Safety profile and exposure is consistent with the available data for adults. Enrollment will be opened for pts Figure 1 Figure 1. Disclosures Baruchel: Kite/Gilead: Other: Investigator; Novartis, Servier, Celgene, Jazz, Janssen, Sanofi, Amgen,Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: Satellite symposium; Shire Servier: Research Funding. Abrahamsson: wedish Children´s Cancer Foundation. Research grants and 50% senior research position for clinical research on pediatric leukemia: Research Funding. Nysom: Bayer, Y-mAbs, EUSA Pharma: Consultancy, Honoraria. Rizzari: Sobi: Other: personal fees; Jazz Pharmaceuticals: Other: Personal fees; Amgen: Other: Personal fees; Medac: Other: Grants and personal fees; Shire: Other: Grants and personal fees. Cesaro: Sobi: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau. Duarte: Amgen: Consultancy, Other: Advisory Board; Novartis: Consultancy; Jazz Pharma: Research Funding. Kang: Amgen Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cartexell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kattamis: Agios Pharmaceuticals: Consultancy; IONIS: Consultancy; VIFOR: Consultancy; CRISPR/Vertex: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; Chiesi: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy. Tøndel: Sanofi: Research Funding. Ivanina: Sanofi: Current Employment. Brillac: Sanofi: Current Employment. Wang: Sanofi: Current Employment. Oprea: Sanofi: Current Employment, Other: may have stock options . Abbadessa: Sanofi: Current Employment. Zwaan: Sanofi: Consultancy.

Background: Primary HLH is a rare, life-threatening immune disorder characterized by a hyperinflammatory state. In patients with primary HLH, interferon gamma (IFNy) is often markedly elevated and is considered one of the key cytokine driving the hyperinflammatory state. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation to bring patients to allogeneic hematopoietic stem cell transplantation, the only curative therapy. Conventional HLH therapy comprises immunotherapies (namely, dexamethasone and etoposide), which, unfortunately, predispose patients to infections and toxicity. Emapalumab is a fully human, anti-IFNy monoclonal antibody that neutralizes IFNy. Currently, there is no regulatory precedent or validated response criteria for efficacy assessment to guide clinical trials in primary HLH. In the pivotal study of emapalumab in primary HLH, objective response criteria were used to define the primary endpoint of overall response (Locatelli et al NEJM 2020). These response criteria were defined based on the Histiocyte Society HLH diagnostic criteria (Henter et al Pediatr Blood Cancer 2007), clinical considerations from the study's Scientific Steering Committee, and available experience reported with conventional HLH treatments. We now report on findings of a sensitivity analysis of overall response rate (ORR) to emapalumab using various assessment criteria. Methods: The open-label pivotal study included patients aged ≤18 years with a diagnosis of primary HLH and active disease (NCT01818492; Locatelli et al NEJM 2020). The initial dose of emapalumab was 1 mg/kg given intravenously every 3 days. Subsequent doses could be increased to 10 mg/kg if required, based on predefined laboratory and clinical response parameters, for a treatment duration of 8 weeks. In addition to emapalumab, all patients received dexamethasone, and a protocol amendment allowed for concomitant use of other HLH treatments if deemed appropriate by the investigator. ORR at end of treatment was analyzed as per the protocol definition in the 27 patients previously treated with conventional therapies. In addition, several pre-specified and post hoc sensitivity analyses were performed to pressure test the data; including: (i) a pre-specified analysis using a more conservative approach where any patient who received concomitant HLH therapies during the study was imputed as non-responder; (ii) a pre-specified analysis with physician-reported response rates recorded by the study investigators, based on their clinical judgement and previous experience in treating patients with primary HLH; and (iii) a post hoc sensitivity analysis using a previously published definition of overall response (Henter et al Pediatr Blood Cancer 2007). Results: 63% (95% confidence interval [CI], 0.42, 0.81) of 27 treatment-experienced patients had a response according to the pivotal study protocol definition of ORR (Fig. 1). A pre-specified sensitivity analysis on the primary endpoint where any patient who received concomitant HLH therapy and imputed as non-responders showed a magnitude of response similar to that observed in the protocol-defined primary analysis (59.3%; 95% CI 0.39, 0.78; n=22). Use of the response criteria defined by Marsh et al (Pediatr Blood Cancer 2013) in a retrospective analysis of 27 patients with primary HLH also resulted in a similar ORR to the protocol-defined primary endpoint in treatment-experienced patients (70.4%; 95% CI 0.50, 0.86). When platelet count was added to this analysis, the percentage of responders to emapalumab increased to 74.1% (95% CI 0.54, 0.89). The pre-specified analysis of physician-reported response rates was also in line with the primary analysis, with 70.4% (95% CI 0.50, 0.86) of 27 treatment-experienced patients deemed to have a response to emapalumab. Conclusion: The current analyses using different definitions of treatment response support the primary analysis results by having a numerically comparable point estimate to the primary endpoint, therefore confirming the positive benefit of emapalumab in patient's refractory or intolerant to conventional HLH therapies. Taken together, these findings also suggest that the clinically objective ORR, utilized in the pivotal emapalumab trial, may be used as a primary endpoint in primary HLH. Disclosures Locatelli: Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jordan:Sobi: Consultancy. Allen:Sobi: Other: Scientific Steering Committee, Data And Safety Monitoring. Rizzari:Sobi: Consultancy, Other: Advisory Board. Rao:Sobi: Consultancy, Other: Advisory Board. Sevilla:Amgen: Other: Advisory Board; Rocket Pharma: Consultancy; Sobi: Other: Advisory Board; Novartis: Other: Advisory Board. Henry:Sobi: Consultancy. De Benedetti:Abbvie: Research Funding; F Hoffmann-La Roche AG: Research Funding; Novartis Pharma: Research Funding; Pfizer: Research Funding; Sanofi-Aventis: Research Funding; Sobi: Consultancy, Research Funding. Grom:Sobi: Consultancy; Novartis Pharma: Consultancy; AB2Bio: Consultancy. Stoltenberg:Sobi: Current Employment. Vågerö:Sobi: Consultancy. de Min:Sobi: Consultancy.

Introduction: WIdiopathic aplastic anemia is a rare and life threatening disorder characterized by immune mediated hematopoietic stem cells dysfunction. The standard treatment strategy of severe aplastic anemia (SAA) has been hematopoietic stem cell transplant (HSCT) for children and adults younger than the age of 40 if an HLA matched sibling donor (MSD) is available. Immunosuppressive therapy (IST) is the mainstay of treatment for older patients or when MSD is not available. The response rate to IST with the use of horse anti-thymocyte globulin (ATG) is around 70%. Despite that, many patients suffer from relapse or clonal evolution. The use of alternative donor transplant (ADT) from matched unrelated donor (MUD) or HLA haploidentical donor (HID) is not commonly used in frontline setting. We herein, conducted a systematic review and meta-analysis of retrospective studies to compare the outcome of IST versus ADT as upfront therapy for SAA. Methods: WWe conducted a comprehensive search in PUBMED/MEDLINE and EMBASE (1998-2019) for retrospective studies that compared the outcome of ADT with IST as upfront therapy in patients with SAA. The study was conducting in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We included the studies with 10 patients or more in each arm. Studies that included patients with inherited aplastic anemia or PNH are excluded. The primary outcome is the 5-year overall survival. Two authors independently screened the studies, extracted the data, and evaluated the quality of included studies and discrepancies were resolved by a third author. Study quality was evaluated by description of study characteristics, patients' characteristics, treatment details, and outcome. The odd ratio (OR) for 5-year survival was measured by Mantel-Haenszel test using random effect model. We also conducted another search and meta-analysis to compare upfront with salvage ADT. The meta-analyses were performed using Review Manager software version 5.3. Result: WWe screened a total of 697 articles (506 EMBASE, 191 PUBMED/MEDLINE). Five studies met our inclusion criteria included a total of 343 patients (176 in ADT group and 167 in IST group) for upfront ADT versus IST comparison and 6 studies with a total of 298 patients (198 in upfront ADT group and 100 in salvage ADT group) for upfront versus salvage ADT comparison. Included patients were of pediatric age group in 4 out of 5 studies. Xu ZL et al, included adult patients with median age 28 (18-49) years in upfront ADT arm and 32 (18-62) years in IST arm. Of those, only 10 patients in ADT group and 12 patients in IST group were above age of 40. In ADT versus IST comparison, the type of transplant was HID in three studies (total of 124 patients) and MUD/MMUD in two studies (total of 52 patients). The rabbit ATG was used in three studies, horse ATG in one study, and both types were used in one study (total of 68 patients received horse ATG and 99 patients received rabbit ATG). In term of disease severity, all included patients were SAA and very SAA (VSAA). Five studies were included in meta-analysis for 5-year overall survival. The pooled OR is statistically significant at 0.44 [95% CI 0.23-0.85] in favor of upfront ADT (Fig 1-A). The survival outcome was compared between upfront versus salvage ADT in 6 studies. The pooled OR is statistically significant at 0.31 [95% CI 0.15-0.64] in favor of upfront ADT (Fig 1-B). Conclusion: WThe pooled analysis of this study showed a potential survival advantage of upfront ADT over IST in patients with SAA who lack an HLA identical sibling donor. The use of ADT earlier in the disease course rather than as a salvage in young patients with severe disease, may improve survival. Data in older patients are limited, and at present, we cannot recommend ADT upfront in older patients. Given the limitations of our study including various types of IST, heterogeneity of patient population, health care systems, and retrospective nature of included studies; further studies are needed to confirm our findings. Disclosures Peffault De Latour: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Hoechsmann:Apellis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Introduction Asplenic patients are at high risk of potentially fatal invasive infections, such as sepsis, meningitis, and pneumonia. It has been shown that infection from influenza viruses can precede or increase the risk of bacterial infection and of serious complications of the underlying disease. International and national guidelines recommend annual influenza vaccination in asplenic subjects. Following the Covid-19 pandemic, the major government and medical-scientific institutions in the US and in Europe have been planning how to contain infection during the 2020-2021 influenza season. Extending influenza vaccination is the safest and most effective way to reduce the circulation of influenza virus and to promote the correct diagnosis and management of suspected cases of SARS-CoV-2. Influenza vaccination also reduces complications associated with the underlying disease and visits to Emergency Units. Our study aims to evaluate influenza vaccination in a large population of asplenic patients and explore the main causes for non-vaccination to identify critical areas for improvement in the vaccination programme in these at-risk patients for the 2020-2021 influenza season. Methods The Italian Network of Asplenia (INA) is made up of 88 doctors working in 50 clinical centers in 27 cities and 16 of the 20 regions of Italy. It aims to build a large, prospective cohort of asplenic patients throughout Italy through which to study the interaction between asplenia and its associated underlying conditions, collecting precise, accurate data also in cases of rarer diseases. The study also aims to improve the quality of healthcare for this at-risk population. The number of patients enrolled in the Network who had had at least one dose of influenza vaccine at the time of diagnosis of asplenia was retrieved from the INA database. All participating centers were asked to answer a questionnaire to report the main obstacles for influenza vaccination. Results At 1st August 2020, 1,670 patients had been enrolled in the INA (783 females; 887 males). All underlying causes of asplenia are shown in Table 1. Only 466 (28%) patients had had at least one influenza vaccination, while 1,204 (72%) had never been vaccinated since diagnosis of asplenia. Thirty-five (70%) of the 50 centers answered the questionnaire. Main causes of non-vaccination were physicians' ambivalence concerning vaccination and patients' inadequate awareness or logistical problems. Conclusions These data show very low seasonal influenza vaccination cover even though asplenic patients are considered at-risk of complications associated with infection from influenza viruses. Since the 2020-2021 influenza season could see influenza viruses in circulation with SARS-CoV-2, influenza vaccination must be expanded as widely as possible, in particular to subjects of all ages at high risk. These results reveal important areas of concern in the management of asplenic patients and the need to improve the quality of information to physicians and patients alike. The INA co-ordinating center will launch a campaign to provide information and organize ad hoc meetings to widen influenza vaccination coverage in asplenic patients and reduce the pressure on the national health service during the next influenza season. Disclosures Forni: Novartis: Membership on an entity's Board of Directors or advisory committees. Colombatti:Addmedica: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Giona:Sanofi Genzyme: Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Novartis: Research Funding. Ferrero:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Servier: Speakers Bureau. Perrotta:Novartis: Consultancy, Research Funding, Speakers Bureau. Casale:Novartis: Membership on an entity's Board of Directors or advisory committees.

Background: Primary hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, immune disorder characterized by a hyperinflammatory state in which patients typically develop fever, splenomegaly, cytopenias and coagulopathy. In patients with primary HLH, interferon gamma (IFNy) is considered to be the key player driving the hyperinflammatory state. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation in order to bring patients to allogeneic hematopoietic stem cell transplantation (HSCT), the only potentially curative therapy. Current conventional therapy for HLH is based on the combined use of dexamethasone and etoposide, and, although effective in many patients, these drugs may promote the development of opportunistic infections and tissue toxicity, and are associated with high morbidity and mortality. Emapalumab is a fully human, anti-IFNy monoclonal antibody that neutralizes IFNy. It is approved by the FDA for the treatment of adult and pediatric patients with primary HLH with refractory, recurrent or progressive disease, or intolerance with conventional HLH therapy. Herein, we report on the safety of emapalumab in primary HLH seen in the pivotal phase 2/3 study (Locatelli et al. NEJM 2020) and investigate the relationship of adverse events (AE) to dose and duration of treatment. Methods: Due to the rare and life-threatening nature of the disease, the efficacy and safety of emapalumab was assessed in an open-label pivotal study (NCT01818492) which included patients aged ≤18 years with a diagnosis of primary HLH and active disease (Locatelli et al NEJM 2020). The initial dose of emapalumab was 1 mg/kg given intravenously every 3 days. Subsequent doses could be increased to 3, 6 and 10 mg/kg if required, based on predefined laboratory and clinical response parameters. Treatment duration was 8 weeks, with possible shortening to a minimum of 4 weeks, or extension up to the time of HSCT if needed. Analysis was performed on 34 patients at a database cut-off date of July 2017 (Locatelli et al NEJM 2020). The relationship of AE to emapalumab treatment was reported by the study investigator. The impact of treatment duration on AE or infection occurrence was measured by the number of events with onset in a predefined time interval from emapalumab initiation. The impact of the dosing scheme on AE and infection occurrence was assessed by the number of AEs or infections in a predefined dose range. Results: Overall, 29% of patients had at least one AE deemed related to emapalumab use. Most (90%) of these events were infusion-related reactions, all of which were mild to moderate and resolved. No severe or serious hypersensitivity reactions were reported. Infections caused by pathogens potentially favored by IFNy neutralization occurred in 1 patient during emapalumab treatment (disseminated histoplasmosis) and resolved with appropriate treatment. There was no increase in AE frequency or the number of viral, bacterial, or fungal infections with increased dose or duration of emapalumab treatment. Conclusion: Neutralization of IFNy with emapalumab in this very fragile population of patients with active primary HLH was associated with a favorable and manageable safety profile across all doses and treatment durations assessed, allowing for flexible and tailored use based on patient clinical response. In addition, 102 patients have been treated in the US following FDA approval, and post-marketing surveillance has not revealed any additional safety concerns with the use of emapalumab in primary HLH (cutoff date 19 May 2020). Taken together, these safety results suggest that emapalumab may offer an additional advantage over conventional HLH therapies. Disclosures Locatelli: Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jordan:Sobi: Consultancy. Allen:Sobi: Other: Scientific Steering Committee, Data And Safety Monitoring. Rizzari:Sobi: Consultancy, Other: Advisory Board. Rao:Sobi: Consultancy, Other: Advisory Board. Sevilla:Novartis: Other: Advisory Board; Amgen: Other: Advisory Board; Rocket Pharma: Consultancy; Sobi: Other: Advisory Board. Henry:Sobi: Consultancy. De Benedetti:Pfizer: Research Funding; Novartis Pharma: Research Funding; Sanofi-Aventis: Research Funding; Sobi: Consultancy, Research Funding; Abbvie: Research Funding; F Hoffmann-La Roche AG: Research Funding. Grom:Novartis Pharma: Consultancy; Sobi: Consultancy; AB2Bio: Consultancy. de Min:Sobi: Consultancy.

Severe hepatic VOD/SOS is a potentially life-threatening complication of HCT conditioning that may also develop after high-dose chemotherapy. The most severe form of VOD/SOS is often accompanied by multi-organ failure (MOF) and is associated with a mortality rate of >80% when managed with supportive care alone. As part of the marketing authorization in Europe, there was an obligation to set up a disease registry of patients with severe VOD/SOS post-HCT who were treated with defibrotide. The goal of this registry was to collect safety and outcome data and assess patterns of defibrotide utilization in the post-approval setting. This multicenter, multinational, prospective observational study (NCT03032016) was performed by the European Society for Blood and Marrow Transplantation (EBMT). The study included patients with severe VOD/SOS post-HCT who were treated with defibrotide and enrolled from April 2015 to July 2018. Participating centers were members of the EBMT. Physicians registered patients diagnosed with severe VOD/SOS, as assessed by the investigator using classical/standard criteria (including but not limited to hyperbilirubinemia, hepatomegaly, ascites, and weight gain >5%), who consented to participate in the study. In addition, patients who were prescribed defibrotide for purposes other than the approved indication (eg, VOD/SOS prophylaxis, treatment of non-severe VOD/SOS or thrombotic microangiopathy) and consented to participate were registered and information collected. There were no specific exclusion criteria; however, treating physicians were alerted to contraindications, special warnings, and precautions detailed in the defibrotide summary of product characteristics. After inclusion, patient information was collected from participating centers at 100 days, 6 months, and 12 months post-HCT. The primary objective was to assess the incidence of specific serious adverse events (SAEs) of interest, which were hemorrhage and site of bleeding, hypotension, coagulopathy, allergic or hypersensitivity reactions, injection-site reaction, infection and septicemia, and thromboembolic events. Secondary endpoints included Day 100 survival, and overall rate of VOD/SOS (and MOF, if present) resolution (based on standard criteria). Summary statistics were calculated for baseline data and safety variables; outcome analyses are descriptive. Here we report an analysis of data with a cutoff of June 18, 2019. Database lock is planned for October 2019, and the presentation will be updated to include the final data. A total of 61 patients with severe VOD/SOS were included; MOF was diagnosed at registration in 34 (56%) patients. The median age of patients with severe VOD/SOS was 14.4 (range: 0-68) years, 34 (56%) aged An SAE of interest occurred in 19 (31%; 95% confidence interval [CI]: 20%-43%) patients with severe VOD/SOS. The most common SAEs of interest by category were infection (n = 13 [21%; 95% CI: 11%-32%]) and bleeding events (n = 8 [13%; 95% CI: 5%-22%]). The most common individual SAEs of interest (≥5% of patients) were pneumonia (8%), gastrointestinal bleeding (8%), and sepsis (5%). Death occurred in 30 (49%) patients within 1 year, with VOD/SOS indicated as a cause of death in 13/30 (43%) patients. The Kaplan-Meier-estimated survival rate at Day 100 for patients diagnosed with severe VOD/SOS post-HCT who were treated with defibrotide was 74% (95% CI: 61%-83%). At latest follow-up, the survival rate was 51%, with median Kaplan-Meier-estimated survival post-HCT not yet reached. VOD/SOS resolved in 46 (75%) patients; the cumulative rate of VOD/SOS resolution at Day 100 was 87% (95% CI: 72%-94%). Resolution of MOF was achieved in 19/34 (56%) patients who had MOF at VOD/SOS diagnosis. In conclusion, among patients with severe VOD/SOS post-HCT (with/without MOF), the incidence of SAEs of interest was consistent with that observed in previous defibrotide clinical trials. Treatment with defibrotide resulted in high rates of Day 100 survival and VOD/SOS resolution. Disclosures Mohty: Jazz Pharmaceuticals: Honoraria, Research Funding. Blaise:Sanofi: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Pierre Fabre medicaments: Honoraria. Labopin:Jazz Pharmaceuticals: Honoraria. Hanvesakul:Jazz Pharmaceuticals: Employment, Equity Ownership. Ryan:Jazz Pharmaceuticals: Employment, Equity Ownership. Lawson:Jazz Pharmaceuticals: Consultancy, Honoraria.

Introduction: Primary hemophagocytic lymphohistiocytosis (pHLH) is a rare, genetic life-threatening syndrome characterized by hyper-inflammation that is mainly driven by high production of interferon (IFN)-𝛾, leading to the development of fever, splenomegaly, cytopenias and coagulopathy. There are currently no approved treatments for HLH, and recent attempts to improve the dexamethasone/etoposide-based regimen (HLH-94) did not show a significant improvement in overall probability of survival. Emapalumab (NI-0501) is a fully human, anti-IFN-𝛾 monoclonal antibody that binds to and neutralizes IFN-𝛾 and is in development for treatment of HLH. Methods: This open-label pivotal study (NCT01818492) includes patients ≤18 years with a diagnosis of pHLH based on genetic confirmation, family history, or the presence of ≥5 of the 8 HLH-2004 diagnostic criteria. Patients were either treatment-naïve or had failed previous conventional HLH therapy prior to study entry. The emapalumab initial dose was 1 mg/kg given intravenously every 3-4 days. Subsequent doses could be increased up to 10 mg/kg based on the evolution of clinical and laboratory response parameters. Emapalumab was administered concomitantly with 5 to10 mg/m2/day of dexamethasone which could be tapered during the study. Treatment duration was 8 weeks (with possible shortening to a minimum of 4 weeks). Treatment could be extended up to allogeneic hematopoietic stem cell transplantation (HSCT) whenever needed. The primary efficacy endpoint of the study was overall response at end of treatment assessed by pre-defined objective parameters. Overall Response Rate (ORR) was assessed as normalization or at least 50% improvement from baseline of fever, splenomegaly, cytopenias, hyperferritinemia, fibrogen and/or D-Dimer levels, central nervous system (CNS) abnormalities, with no sustained worsening of sCD25 serum levels. The primary analysis used an exact binomial test to evaluate the null hypothesis that ORR be at most 40% at a one-sided 0.025 significance level. Data presented are from 34 patients of whom 27 entered the study after failing conventional HLH therapy. Following completion of the main study patients entered into an extension phase (NCT02069899). The data cut-off applied is July 20 2017. Results: Patient characteristics are summarized in Table 1. Disease presentation at study entry was consistent with the broad spectrum of pHLH abnormalities, both in terms of HLH-2004 diagnostic criteria and other known HLH features; over 30% of patients had signs and/or symptoms of CNS disease. Efficacy results are summarized in Table 2. ORR was significantly higher than the pre-specified null hypothesis of 40%; thus the primary endpoint was met. The response rate based on investigator's clinical judgement was 70.6% and 70.4% in the two groups. Emapalumab infusions were in general well tolerated, with mild to moderate infusion-related reactions reported in 27% of patients. The observed safety events pre-HSCT conditioning mostly included HLH manifestations, infections or toxicities due to other administered drugs. Infections caused by pathogens potentially favored by IFN-𝛾 neutralization occurred in 1 patient during emapalumab treatment (Disseminated histoplasmosis), and resolved with appropriate treatment. No off-target effects were observed. Conclusions: This is the first prospective HLH study that reports response rates based on pre-defined objective criteria. Our results indicate that emapalumab should be considered as a new therapeutic option in pHLH thanks to its targeted mode of action. Treatment with emapalumab was able to control HLH activity with a favorable safety and tolerability profile in a very fragile population. The majority of patients proceeded to HSCT with favorable outcome. Disclosures Jordan: Novimmune: Consultancy, Membership on an entity's Board of Directors or advisory committees. Allen:Novimmune: Membership on an entity's Board of Directors or advisory committees. Sevilla:Rocket Pharmaceuticals Inc: Honoraria, Patents & Royalties; Novimmune: Other: currently participating in and have participated in Novimmune-sponsored clinical trials within the past two years . Grom:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AB2Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; NovImmune: Consultancy, Membership on an entity's Board of Directors or advisory committees. De Benedetti:Novartis: Consultancy, Research Funding; SOBI: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; UCB: Consultancy; Eli-Lylli: Consultancy; Abbvie: Research Funding; Novimmune: Research Funding; Pfizer: Research Funding. Ferlin:Novimmune: Employment, Equity Ownership, Patents & Royalties. Ballabio:Novimmune: Employment, Equity Ownership. De Min:Novimmune: Employment, Equity Ownership.

Background: Immune Thrombocytopenia (ITP) is one of the most common conditions encoutered by the pediatric hematologist. Current first-line therapy includes: observation without drug therapy, corticosteroids and intravenous immune globulin. A minority of patients are refractory to first-line approaches. Second-line treatment options are: immunosuppressive agents and thrombopoietin receptor agonists (TPO-RA). Eltrombopag and Romiplostin are TPO-RA licensed for clinical use. Eltrombopag is, actually, the only TPO-RA approved in Italy (since two years ago) for children, over one year old, with a chronic and/or refractory ITP. Real life data of Eltrombopag are limited. Methods: We performed an Italian multicenter retrospective survey to study the clinical on-label use of TPO-RA, focus on Eltrombopag, in pediatric ITP. Our aims were, primarily, to bring out the prevalence of the use in clinical practice and secondarily to collect data on efficacy and toxicity. Results: We enrolled 69 pediatric ITP subjects from 15 Italian treatment centers (TC). 4 patients received Romiplostin as TPO-RA and were excluded by the analysis. 36/65 patients weer female (55%). Median age at ITP diagnosis: 6 years + 6 months (min 1 y + 2 m; max 16 y + 7 m). Median age at first Eltrombopag assumption: 11 years + 5 months (min 2 y + 0 m; max 17 y + 8 m). Accounting in 344 the total number of chronic ITP subjects treated by TC in the same observation period (July 2016-June 2018), we observed an Eltrombopag clinical use prevalence of 0.19 (95% CI 0.15 to 0.26). We underlined a "no response" to Eltrombopag (platelet count persistently less than 30000 per microliter) in 16/65 (25%); a "partial response" (platelet count between 30000 and 100000 per microliter) in 14/65 (21%) and a "complete response" (platelet count persistently up than 100000 per microliter) in 35/65 (54%). The overall response (partial or complete) was described in 49/65 (75%) children. During the follow up was seen in 16/49 (33%) subjects with initial response a platelet rise that waned to no response. There was no evidence of significant adverse events (clinicians are obliged, to monthly surveillance, by Italian drug agency for hypertransaminasemia and peripheral smear cell abnormalities). Conclusions: Our results demonstrate that Eltrombopag is a therapeutic option quite considered by Italian clinicians. Moreover, according with the percentages of clinical trials, Eltrombopag is safe and effective to rise platelet count. Further studies need to emphasize how factors favor a complete response and to know the incidence of long-term adverse effects. A prospective study designed and driven by Italian Association of Pediatric Hematology Oncology (AIEOP) Coagulation Disorders Working Group is, already, in progress. Disclosures No relevant conflicts of interest to declare.

A retrospective study was performed to collect information regarding efficacy and toxicity of cidofovir (CDV) in allogeneic stem cell transplant patients. Data were available on 82 patients. The indications for therapy were cytomegalovirus (CMV) disease in 20 patients, primary preemptive therapy in 24 patients, and secondary preemptive therapy in 38 patients. Of the patients, 47 had received previous antiviral therapy with ganciclovir, foscarnet, or both drugs. The dosage of CDV was 1 to 5 mg/kg per week followed by maintenance every other week in some patients. The duration of therapy ranged from 1 to 134 days (median, 22 days). All patients received probenecid and prehydration. Ten of 20 (50%) patients who were treated for CMV disease (9 of 16 with pneumonia) responded to CDV therapy, as did 25 of 38 (66%) patients who had failed or relapsed after previous preemptive therapy and 15 of 24 (62%) patients in whom CDV was used as the primary preemptive therapy. Of the patients, 21 (25.6%) developed renal toxicity that remained after cessation of therapy in 12 patients. Fifteen patients developed other toxicities that were potentially due to CDV or the concomitantly given probenecid. No toxicity was seen in 45 (61.6%) patients. Cidofovir can be considered as second-line therapy in patients with CMV disease failing previous antiviral therapy. However, additional studies are needed before CDV can be recommended for preemptive therapy.

Sera of 658 patients who had completed treatment for pediatric malignancy were analyzed by a second-generation enzyme-linked immunosorbent assay and recombinant immunoblot assay test to assess the prevalence of hepatitis C virus (HCV)-seropositivity. All HCV-seropositive patients underwent detailed clinical, laboratory, virologic, and histologic study to analyze the course of HCV infection. One hundred seventeen of the 658 patients (17.8%) were positive for HCV infection markers. Among the 117 anti-HCV+ patients, 41 (35%) were also positive for markers of hepatitis B virus infection with or without delta virus infection markers, 91 (77.8%) had previously received blood product transfusions, and 25 (21.4%) showed a normal alanine aminotransferase (ALT) level during the last 5-year follow-up (11 of them never had abnormal ALT levels). The remaining 92 patients showed ALT levels higher than the upper limit of normal range. Eighty-one of 117 (70%) anti-HCV+ patients were HCV-RNA+, with genotype 1b being present in most patients (54%). In univariate analysis, no risk factor for chronic liver disease was statistically significant. In this study, the prevalence of HCV infection was high in patients who were treated for a childhood malignancy. In about 20% of anti-HCV+ patients, routes other than blood transfusions are to be considered in the epidemiology of HCV infection. After a 14-year median follow-up, chronic liver disease of anti-HCV+ positive patients did not show progression to liver failure.

Introduction. Multiresistant (MR) bacteria colonization is considered predictive of related bloodstream infections (BSI), which are worrisome among hematological patients (pts). Few data are available about the actual incidence of MR colonization and the probability of developing a BSI in this population. A multicentric prospective observational study has been carried out within the SEIFEM group, with the aim of detecting the incidence of MR bacterial colonization and the probability of developing MR BSI in hematological pts. Patients and Methods. Between March 1st and August 31st 2015, all pts with a hematological neoplasm admitted to 18 Italian Centres participating to SEIFEM were screened for MR colonization with a rectal swab; cultures of other sites were performed if clinically indicated. Patients showing MR bacterial colonization were recorded in a database where the occurrence of any BSI was correlated with age, gender, type and phase of disease, stem cell transplantation (SCT), presence of invasive devices, type of colonizing bacteria. Results. During a 6-month period, 189 pts with MR colonization were observed. Incidence was 8.9% among all admissions (189/2122). Median age was 59y (range 0-89) and M/F ratio 116/73. Eighty-two pts were affected by acute leukemia, 75 by lymphoma, 24 by myeloma, 6 by chronic myeloproliferative/myelodysplastic syndromes and 2 by aplastic anemia. Forty-four pts underwent SCT (28 autologous and 16 allogeneic). Vancomycin resistant enterococci (VRE) were responsible for colonization in 15 (7.9%) pts, extended spectrum beta-lactamases producing (ESBL-P) enterobacteria in 80 (42.3%) and carbapenemase producing (CP) Gram-Negative Rods (GNR) in 108 (57.1%). Thirteen of 14 pts with multiple colonizations had both ESBL and carbapenemase producing enterobacteria. Multivariate analysis of risk factors for type of MDR colonization showed that a complete hematologic remission was associated to ESBL-P enterobacteria colonization, but protective for CP strains (OR 2, 1.1-3.7, p=0.02 and 0.43, 0.23-0.79, p=0.006, respectively). Overall, 62 pts (32.8%) colonized with MR bacteria developed at least one BSI during the period of observation; 36 of them (58.1%; 19% of the whole series) developed BSI by the same pathogen (MRrel-BSI) (2 VRE, 14 ESBL-P E. coli, 2 ESBL-P K.pneumoniae, 1 ESBL-P E. aerogenes, 12 CP K. pneumoniae, 3 CP P. aeruginosa and 2 CP Acinetobacter spp). The rate of MRrel-BSI according to antibiotic resistance was 13.3% for VRE colonization, 19.5% for ESBL-P enterobacteria and 17.6% for CP GNR. CP K. pneumoniae, but not other CP enterobacteria, was predictive of MRrel-BSI (26.7%). In 82% of cases, MRrel-BSI occurred during neutropenia. At multivariate analysis of predictors of BSI, a relapsed/refractory hematological disease was associated to MRrel-BSI (OR 3.1, 1.4-6.7, p=0.005). Unrelated BSI were also observed in 32 pts (51.6%; 16.9% of the whole series), including 6 MR BSI (2 CP P. aeruginosa, 3 CP K. pneumoniae and 1 VRE). After a median follow-up of 80 days (range 0-270), 25 pts died (13.2%). Three-month overall survival (OS) of the entire cohort was 86%±2.9SE, being significantly lower for pts colonized with VRE (71%) and CP (82%) in comparison with those colonized with ESBL-P bacteria (97%, p=0.0018 and 0.0043 respectively) (Fig.1). Death was attributable to CP GNR related BSI in 5 pts and to VRE related BSI in 1. Multivariate analysis showed that CP GNR related BSI (OR 8.3, 2.2-30.5, p=0.001) and VRE related BSI (OR 87.9, 1.1-675.9, p=0.04), together with intensive care unit admission (OR 50.6, 4.5-570.9, p=0.001) were independent predictors of mortality at 30-days from known colonization, whereas having disease in complete remission was protective (OR 0.02, 0.001-0.43, p=0.01). Conclusions. Incidence of MR colonizing bacteria, particularly ESBL-P and CP GNR, affects nearly 10% of italian hematological cancer pts and results in a MRrel BSI in about one fifth of cases, mainly during neutropenia. MRrel-BSI are responsible for more than 50% of BSI observed in MR colonized pts and are significantly more frequent in relapsed/refractory hematologic disease. VRE and CP GNR colonizations but not ESBL-P are associated to lower OS and predict for a higher fatality of related BSI. Among CP enterobacteria, only K. pneumoniae is associated with MRrel-BSI. Empiric antibiotic treatment should be better tailored taking into account these results. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.