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X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression.

Chuvash polycythemia (MIM 263400) is an autosomal recessive disorder characterized by a high hemoglobin level, relatively high serum erythropoietin, and early death. It results from a Von Hippel-Lindau (VHL) gene mutation (C598T) that causes increased HIF-1α activity and erythrocyte production in the face of normoxia. This polycythemia is endemic in Chuvashia, whereas its worldwide frequency is very low. We investigated the incidence of the Chuvash-type VHL mutation in Campania (South Italy) and identified 14 affected subjects (5 families). Twelve live on the island of Ischia (Bay of Naples). From analysis of the mutated allele, we found that the disease was more frequent on Ischia (0.070) than in Chuvashia (0.057). The haplotype of all patients matched that identified in the Chuvash cluster, thereby supporting the single-founder hypothesis. We also found that nonaffected heterozygotes had increased HIF-1α activity, which might confer a biochemical advantage for mutation maintenance. In conclusion, we have identified the first large cluster of Chuvash erythrocytosis outside Chuvashia, which suggests that this familial polycythemia might be endemic in other regions of the world.

Indirect immunofluorescence staining with monoclonal antibody (MoAb) CL203.4 of malignant cells from 269 patients with hematologic malignancies showed a heterogeneous expression of CD54/intercellular adhesion molecule-1 (ICAM-1). This marker was expressed by malignant cells of 57 out of 118 patients with myeloid malignancies and 69 out of 135 with B-lymphoid malignancies. On the other hand, CD54 was not detected on malignant cells of 16 patients with T-lymphoid malignancies. In myeloid malignancies, CD54 is preferentially expressed by “stem cell-derived” malignancies, being detectable on blast cells from almost all patients affected by chronic myelogenous leukemia in blast phase or myelodysplastic syndromes and by only 34% of patients with de novo acute myeloid leukemia (AML). The expression of CD54 did not correlate with any specific myeloid FAB subtype, although three cases of highly undifferentiated AML (FAB MO) displayed maximal levels of the antigen. The expression of CD54 in AML was significantly associated with that of CD34 and HLA-DR antigens. In B-lymphoid malignancies, CD54 expression appears to correlate with the differentiation stage of malignant cells, since B-origin acute lymphoblastic leukemias and conventional B-chronic lymphocytic leukemias (B-CLL; ie, “dim Slg” CLL) expressed lower levels of CD54 than more mature lymphoproliferative disorders (“bright Slg” CLL, prolymphocytic leukemias, and lymphoplasma-cytic tumors). “High-grade” B-cell non-Hodgkin's lymphomas (B-NHL) express in general a higher level of CD54 than “low-grade” ones. This finding in conjunction with the expression of CD54 in all 17 patients with “bright Slg” CLL investigated (characterized by marked organomegaly and poor prognosis) suggest that the differential expression of CD54 in lymphoproliferative disorders may also relate to their degree of malignancy.

Survival rates of children with relapsed/refractory (r/r) BCP-ALL remain unsatisfactory and little progress has been made in the past 2 decades. Similarly, relapse of childhood B-NHL is usually associated with an aggressive disease and poor outcomes. Targeted immunotherapy with T-cells genetically modified to express a CD19-directed CAR showed an unprecedented antitumor efficacy, leading to the recent FDA and EMA approval of two CD19-CAR products for treatment of BCP-ALL and B-NHL. Relevant toxicities have, however, been reported, mainly related to the development of severe Cytokine Release Syndrome (CRS) and/or of neurotoxicity.

Merli: Novartis: Honoraria; Sobi: Consultancy; Amgen: Honoraria; Bellicum: Consultancy. Algeri:Miltenyi: Honoraria; Atara Biotherapeutics: Consultancy, Honoraria; Bluebird bio: Consultancy, Honoraria. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Zucca: Celltrion: Consultancy; AstraZeneca: Consultancy. Ghia:Sunesis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie, Inc: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding. Montillo:Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding. Tedeschi:Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy; AbbVie: Consultancy. Gaidano:AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Morphosys: Honoraria; Roche: Consultancy, Honoraria.

Background: Brain involvement in beta thalassemia is scarcely known so far, and available data show different degrees of abnormalities in terms of neuroradiologic findings and cognitive impairment, mainly showing asymptomatic white matter lesions in transfusion dependent thalassemia (TDT; Karimi et al, Ann Hematol 2016) or in non transfusion dependent thalassemia (NTDT; Karimi et al, Ann Hematol 2012; Pazgal et al, Thrombosis Research 2016), arterial stenosis in NTDT (Musallam et al, EJH 2011) and a general impairment in cognitive function in TDT (Elalfy et al, Hematology 2017). To our knowledge there are no studies investigating neuroimaging and cognitive function in both groups of patients, comparing results to healthy subjects.

Moseley: Bellicum Pharmaceuticals: Employment, Equity Ownership.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

HMG CoA reductase inhibitors (statins) are a class of cholesterol lowering drugs that affect many intracellular pathways and have implications for cancer chemo prevention. Statins have been shown to induce a phosphoprotein signature that shuts MYC activation and also have anti-inflammatory activity that may impact the risk of Non-Hodgkin’s lymphoma (NHL). Results from observational studies on the relationship between statin use and NHL are conflicting. We analyzed data from the Women’s Health Initiative (WHI) to assess the relationship between statins and the risk of NHL.The study population included 161,563 post-menopausal women ages 50-79 years. Women with incident NHL were identified over an average of 10.8 (SD +3.3) years of follow-up. Information on statin use was collected at study entry and at years 1, 3, 6 and 9. Statins were classified as lipophilic (simvastatin, lovastatin, fluvastatin) or hydrophilic (pravastatin, atorvastatin) by potency (low, medium, high) and by duration of use. Self and interviewer-administered questionnaires were used to collect information on other risk factors. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) to evaluate the relationship between statin use and NHL risk as a time-dependent exposure. Multivariable models were stratified by WHI trial, extension study and age group and were adjusted for education, ethnicity, smoking, alcohol, body mass index, waist circumference, % energy from fat, hormone therapy use, physical activity, current medical provider and history of lupus and rheumatoid arthritis. A separate analysis was performed for individual NHL subtypes: Diffuse Large B cell Lymphoma (DLBCL) (n=228), follicular lymphoma (n=169) and Small Lymphocytic Lymphoma/Chronic Lymphocytic Lymphoma (SLL/CLL) (n=74).All statistical tests were two-sided.Statins were used at baseline by 12,243 women (7.5%), 8266 of whom used lipophilic agents. The multivariable adjusted HR of overall statin use and risk of NHL was 0.66 (95% CI: 0.48-0.90). Hydrophilic statin use was associated with a significantly lower risk of developing NHL (HR 0.47, 95% C.I. 0.27-0.81); HR for pravastatin 0.46 (95% C.I. 0.20-1.02) and for atorvastatin 0.39 (95% C.I. 0.124-1.20). Lipophilic statins were not associated with NHL risk (HR 0.85, 95% C.I. 0.58-1.24). Among NHL subtypes, statin use was associated with a lower risk of DLBCL (HR 0.49, 95% C.I. 0.25-0.96) however there was no association with follicular lymphoma (HR 0.92, 95% C.I. 0.49-1.70) or CLL/SLL (HR 1.18, 95% C.I. 0.50-2.75).Prior use of statins was associated with a lower overall risk of NHL attributable to a lower risk of DLBCL in the WHI cohort. This effect was largely seen among users of hydrophilic statins.Safford: Amgen: Research Funding.