ALBERT

Description: Xanthomas are a common manifestation of lipid metabolism disorders. They include hyperlipemic xanthoma, normolipemic xanthoma, and a related condition, necrobiotic xanthogranuloma (NXG). All 3 forms can be associated with monoclonal immunoglobulin (MIg). In an attempt to improve diagnosis, understanding, and treatment of this association, we retrospectively analyzed a personal series of 24 patients (2 hyperlipemic xanthoma, 11 normolipemic xanthoma, and 11 NXG) and 230 well-documented reports from the literature. With the exception of the nodules and plaques featured in NXG, the clinical presentation of xanthomatous lesions usually resembled that seen in common hyperlipidemic forms and could not be used to suspect MIg-associated xanthomas. Extracutaneous sites were not rare. The MIg was an IgG in 80% of cases. Myeloma was diagnosed in 35%. Hypocomplementemia with low C4 fraction was present in 80% of studied patients. Low C1 inhibitor serum levels were found in 53%. Cryoglobulinemia was detected in 27%. These abnormalities suggest immune complex formation because of interactions between the MIg and lipoproteins and argue in favor of a causal link between MIg and xanthomas. Monoclonal gammopathy therapy could thus be an option. Indeed, among the patients who received chemotherapy, hematologic remission was accompanied by improvement in xanthoma lesions in several cases.

Description: Background: B-PTLD is a rare but severe complication observed after organ transplantation. There is no consensus on treatment modalities in this setting but Rituximab monotherapy has been presented as an effective and well tolerated treatment. Long term efficacy is unknown. Aim: We recently published results of the first prospective study on PTLD treatment, using four weekly injection of Rituximab in progressive or non responding tumours after immunosuppression diminution (Blood2006; 107; 3053–7). We present here update results up to 6 years after inclusion. Methods: From may 2000 to December 2001, 43 PTLD after solid organ transplantation have been enrolled in M39037, a franco-belgian multicentric prospective trial. The primary end point was day 80 response rate and one year results were also presented. Participating centres were contacted in order to obtain update data on surviving patients at one year, especially for their tumour status (complete response (CR), partial response (PR) or progressive disease (PD)), date of last information, eventual death and cause of death. Results: At one year, on 43 included patients, 26 were still alive, 12 in CR or Cru, one in PR, 10 in PD and two with insufficient information. At this time, update data are available on eight patients, six were in CR or Cru at one year and two in PD. Five patients died by organ failure (n=1), graft rejection (n=1), sudden death (n=2) or heart biopsy complication (n=1); all but one were in CR at this time. Three patients are still alive and in CR. No relapse has been diagnosed and median survival is 1188 days (with a median follow up of 1689 days for surviving patients). Final analysis on all patients will be presented at the ASH meeting. Conclusion: Rituximab in monotherapy seems to have a durable efficacy on PTLD after solid organ transplantation with a follow up of more than 4,5 years. Complete results will be presented at the ASH Meeting.

Description: Successful immunologic control of HIV infection is achieved only in rare individuals. Dendritic cells (DCs) are required for specific antigen presentation to naive T lymphocytes and for antiviral, type I interferon secretion. Two major blood DC populations are found: CD11c+ (myeloid) DCs, which secrete IL-12, and CD123+ (IL-3–receptor+) DCs (lymphoid), which secrete type I interferons in response to viral stimuli. The authors have previously found a decreased proportion of blood CD11c+ DCs in chronic HIV+ patients. In this study, 26 to 57 days after infection and before treatment, CD123+ and CD11c+ DC numbers were dramatically reduced in 13 HIV+ patients compared with 13 controls (P = .0002 and P = .001, respectively). After 6 to 12 months of highly active antiretroviral therapy, DC subpopulation average numbers remained low, but CD123+ DC numbers increased again in 5 of 13 patients. A strong correlation was found between this increase and CD4 T-cell count increase (P = .0009) and plasma viral load decrease (P = .009). Reduced DC numbers may participate in the functional impairment of HIV-specific CD4+ T cells and be responsible for the low type I interferon responsiveness already known in HIV infection. The restoration of DC numbers may be predictive of immune restoration and may be a goal for immunotherapy to enhance viral control in a larger proportion of patients.

Description: Erythroblastic synartesis is a rare form of acquired dyserythropoiesis, first described by Breton-Gorius et al in 1973. This syndrome is characterized by the presence of septate-like membrane junctions and “glove finger” invaginations between erythroblasts, which are very tightly linked together. This phenomenon, responsible for ineffective erythropoiesis, leads to an isolated severe anemia with reticulocytopenia. In the following report, we describe 3 new cases of erythroblastic synartesis associated with dysimmunity and monoclonal gammapathy. In all cases, the diagnosis was suggested by characteristic morphological appearance of bone marrow smears, and further confirmed by electron microscopy. Ultrastructural examination of abnormal erythroblast clusters showed that these cells were closely approximated with characteristic intercellular membrane junctions. The pathogenesis of the dyserythropoiesis was modeled in vitro using crossed erythroblast cultures and immunoelectron microscopy: when cultured in the presence of autologous serum, the erythroblasts from the patients displayed synartesis, whereas these disappeared when cultured in normal serum. Moreover, synartesis of normal erythroblasts were induced by the patient IgG fraction. Immunogold labeling showed that the monoclonal IgG were detected in, and restricted to, the synartesis. A discrete monoclonal plasmacytosis was also found in the patient bone marrow. The adhesion receptor CD36 appeared to be concentrated in the junctions, suggesting that it might be involved in the synartesis. These experiments indicated that a monoclonal serum immunoglobulin (IgG in the present cases) directed at erythroblast membrane antigen was responsible for the erythroblast abnormalities. Specific therapy of the underlying lymphoproliferation was followed by complete remission of the anemia in these cases.

Description: We characterized the localization, phenotype, and some functions of plasmacytoid dendritic cells (pDCs) in the human spleen. pDCs were localized in the marginal zone and the periarteriolar region. Some were also found in the red pulp. pDCs were immature by phenotypic labeling, consistently with their capacity to internalize Dextran in a functional assay. In spleens from HIV-infected patients with thrombocytopenic purpura, these characteristics were unaffected. However, an accumulation of pDCs, but not myeloid dendritic cells (mDCs), was observed in some HIV+ patients, correlating with high proviral loads. Moreover, although undetectable in most HIV− patients, interferon-α (IFN-α) production was evidenced in situ and by flow cytometry in most HIV+ patients. IFN-α was located in the marginal zone. Surprisingly, IFN-α colocalized only with few pDCs, but rather with other cells, including T and B lymphocytes, mDCs, and macrophages. Therefore, pDCs accumulated in spleens from HIV+ patients with high proviral loads, but they did not seem to be the main IFN-α producers.

Description: Abstract 1578 Background: Castleman Disease (CD) is a rare atypical lymphoproliferative disorder of unknown aetiology that covers an extremely wide clinical spectrum. It ranges from a localized disease with benign outcome after surgical removal to a life threatening multicentric disease (MCD). In the context of HIV infection, CD is almost always multicentric and linked to HHV-8. Clinical, pathological and laboratory features of HIV+ MCD are well described. In contrast, there is no published series of HHV-8 related CD in HIV negative patients. Methods: From January 1995 through June 2012, we identified in a single centre 55 HIV seronegative patients with pathologically proven CD (25 localized and 30 multicentric). Among them 18 were related to HHV-8. We report on their clinical, pathological and laboratory features. Results: All cases were multicentric. Patients were aged 42–83 years old (median 65,9) and were referred with a relapsing remitting syndrome of fever (94%), general status alteration (100%), peripheral lymphadenopathy (100%), splenomegaly (72%), hepatomegaly (50%) and oedema (28%). Kaposi Sarcoma was observed in 9 cases. Anaemia was a constant finding. White blood cells abnormalities were noted on blood smear during the flares in 13/16 patients. Serum markers of inflammation were present in all cases: a high level of C reactive protein (median 111mg/L; range 36–423), hypergammaglobulinemia (median 31g/L; range 7,3–55), hypoalbuminemia (median 32g/L; range 16–52). PCR for HHV-8 DNA was positive on blood samples in all cases (median 5,5 Log10 copies of KSHV DNA/106PBMCs; range 2,3–6,6), whereas only 12/16 patients tested had a positive HHV-8 serology at diagnosis. All cases showed the classic histological features of the mixed cell type or of the plasma cell type, and LANA-1 immunostaining identified HHV-8 infected plasmablasts in 16/16 tested cases. Reactive hemophagocytic syndrome (44%), Autoimmune Haemolytic Anaemia (33%) and lymphoma (22%) (2 Primary Effusion Lymphoma, 1 lymphoplasmacytic lymphoma and 1 unproved) were the commonest associated complications. Ten patients (55%) have received corticosteroids (CS). CS had little or no effect on lymphoid organs enlargement, inflammatory markers or hemophagocytic syndrome. Occurrence or worsening of KS appeared in one patient each soon after corticosteroids introduction. Remission was obtained with low dose and usually single agent chemotherapy with etoposide in 13/16 cases. Nevertheless, etoposide had only suspensive effect in most cases. Thirteen patients were treated with rituximab, all of them achieved prolonged remission off therapy. After a median follow up of 18 months (range 1–99) after rituximab treatment, only 2 patients experienced relapses. These relapses were successfully retreated with the association of rituximab and etoposide. Fatal outcome occurred in 3 patients not treated with rituximab. Altogether, these features were similar to those described in HIV+ HHV-8 related MCD. On the contrary, comparison between these 18 cases and 12 HIV- HHV-8 unrelated MCD cases showed marked discrepancies. Arthritis, cutaneous manifestations, renal disease, lupus symptoms or POEMS symptoms were more frequently observed in patients with HHV-8 negative MCD. Conclusion: HHV-8 associated MCD should be considered as a single clinicopathological entity whatever the HIV status is. This is a step forward towards a better delineation of CD clinical spectrum, and subsequently of HHV-8 related lymphoproliferative disorders. It also offers the opportunity to improve clinical management of such patients, as it appears that the treatments used in HIV+ HHV-8 related MCD are efficient in HIV- HHV-8 related MCD. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1391 Poster Board I-413 Background: Primary immunodeficiency diseases (PID) encompass more than 200 different rare diseases that share at least two characteristics, inheritance and increased susceptibility to infections. The mechanisms imply different components such as B-cells, T-cells, phagocytes or complement, and more than 150 genes are known to be involved in PID. While several studies have analyzed specific PID, very little is known about the exact repartition of the different groups of deficiencies. To assess epidemiological characteristics of these heterogeneous diseases, the French National Reference Centre for PID (CEREDIH) was established in November 2005 and created a dedicated registry to determine the distribution of PID patients in France who are under care in expert University hospitals. Methods: The CEREDIH set up a national network of 18 regional centres including 58 University hospitals medical departments with experience in the care of both children and adults patients with PID. Data collected relied on the European Society for Immunodeficiencies core dataset. Overall, regional and detailed prevalence for major PID groups, and improvement of diagnosis over time were assessed. Data provided by our registry were compared to the ones previously reported by other National registries. Results: At April 2009, The CEREDIH registry encompasses a total of 3,083 patients. The overall prevalence is 4.4 cases for 100,000 inhabitants based on 2,682 alive patients. A majority of cases are children. Median age (Q1-Q3) at diagnosis was 3.3 years (0.7-10.3). Predominantly B-cell immunodeficiencies are the most common diseases observed (43%), the proportion of Common Variable Immunodeficiency (CVID) being 14%. Predominantly T cell disorders and phagocytic disorders were observed in 38% and 19.2% of patients, respectively. The 2 main phagocytic disorders were severe congenital neutropenias (65%) and chronic granulomatous diseases (27.6%). Immunoglobulin replacement therapy was given in 42% of all registered patients, by intravenous or subcutaneous route in 74% and 26% of cases, respectively. A significantly heterogeneous distribution of PID was observed in distinct geographical areas with variation in prevalence by a factor of 3. For B-cell deficiencies, there is a steady increase of identified cases between 1984 up to 2000. Noticeably, incidences for predominantly T cell and for innate immune deficiencies are likely to reach prevalence. Overall prevalence in France is quite similar to the one observed in other countries that have built a PID national registry, although the methodologies used were somehow different. The proportion of CVID is lower than in other national registries previously reported. Conclusion: These results suggest that, while detection and referral to expert centres is fairly adequate for children, it is not yet the case in France for adult patients. There are still a number of unrecognised patients with PID (or patients not referred to university medical centres) as depicted by the heterogeneous distribution of PID observed, also pinpointing to regional differences in patients' care. This analysis provides the basis for further studies in assessing causes for observed differences and for taking action to increase awareness of PID, notably in adults, at national and regional levels. The CEREDIH registry could be a useful tool for measuring improvements in access to care for French PID patients and referral to centres with expertise. Disclosures: No relevant conflicts of interest to declare.

Description: Primary effusion lymphoma (PEL) is a rare high-grade B-cell non-Hodgkin lymphoma associated with Kaposi sarcoma-associated Herpesvirus/Human Herpesvirus 8 (KSHV/HHV-8) infection, and mostly observed in the course of HIV infection. The prognosis is poor with reported median survival time shorter than 6 months. To date, no prognostic factor has been identified in this subset of lymphoma. We described here the largest series of HIV-infected patients with PEL, including 30 cases diagnosed in six French centers over a 15-year time period. Prognosis analysis was performed using a Cox proportional hazard regression model. Statistically significant covariates were further analyzed in a forward, stepwise multivariate model. After a median follow-up of 3.2 years (range, 10 months-8.2 years), 9 patients (30%) were still alive, and 8 of them remained progression free. The overall median survival was 5.5 months and the 1-year overall survival rate was 36.7%. Fourteen patients (47%) achieved complete remission, with a 1-year disease-free survival rate at 78.6%. In multivariate analysis, only a performance status 〉 2 [hazard ratio 6.27, 95% confidence intervals (CI),1.91–20.58] and the absence of highly active antiretroviral therapy (HAART) before PEL diagnosis [hazard ratio 0.28, 95% CI, 0.10–0.77] were found to be independent predictors for shorter survival. Based on a retrospective series of 30 patients, two prognostic factors were identified as being independently associated with impaired clinical outcome in HIV-related PEL, (i) a poor performance status and (ii) the absence of HAART prior to PEL diagnosis.

Description: Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8–negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti–interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.