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International audience; Combining drugs could be an effective option for treating multirefractory ITP, that is, patients not responding to rituximab, thrombopoietin receptor agonists (TPO-RA) and splenectomy. We conducted a retrospective, multicenter, observational study including multirefractory ITP patients who received a combination of a TPO-RA and an immunosuppressive drug. We included 39 patients (67% women, median age 59 years [range 21-96]), with a median ITP duration of 57 months [3-393] and a median platelet count at initiation of 10 × 109 /L [1-35]. The combination regimen was given for a median duration of 12 months [1-103] and included eltrombopag (51%) or romiplostim (49%), associated with mycophenolate mofetil (54%), azathioprine (36%), cyclophosphamide (5%), cyclosporin (3%) or everolimus (3%). Overall, 30 patients (77%) achieved at least a response (platelet count ≥30 × 109 /L and at least doubling baseline during at least 3 months), including 24 complete responses (platelet count >100 × 109 /L during at least 3 months) with a median time to response of 30 days [7-270] and a median duration of response of 15 months [4-63]. Severe adverse event related to ITP treatment was observed in 31%. In conclusion, this study confirms that some patients with multirefractory ITP can achieve long lasting response with this combination.

Background Hydroxychloroquine (HCQ) levels can be measured in both serum and whole blood. No cut-off point for non-adherence has been established in serum nor have these methods ever been compared. The aims of this study were to compare these two approaches and determine if serum HCQ cut-off points can be established to identify non-adherent patients. Methods HCQ levels were measured in serum and whole blood from 573 patients with systemic lupus erythematosus (SLE). The risk factors for active SLE (SLEDAI score > 4) were identified by multiple logistic regression. Serum HCQ levels were measured in 68 additional patients known to be non-adherent, i.e. with whole-blood HCQ Results The mean (± SD) HCQ levels were 469 ± 223 ng/mL in serum and 916 ± 449 ng/mL in whole blood. The mean ratio of serum/whole-blood HCQ levels was 0.53 ± 0.15. In the multivariate analysis, low whole-blood HCQ levels (P = 0.023), but not serum HCQ levels, were independently associated with active SLE. From the mean serum/whole-blood level ratio, a serum HCQ level of 106 ng/mL was extrapolated as the corresponding cut-off to identify non-adherent patients with a sensitivity of 0.87 (95% CI 0.76–0.94) and specificity of 0.89 (95% CI 0.72–0.98). All serum HCQ levels of patients with whole-blood HCQ below the detectable level ( Conclusions These data suggest that whole blood is better than serum for assessing the pharmacokinetic/pharmacodynamic relation of HCQ. Our results support the use of serum HCQ levels to assess non-adherence when whole blood is unavailable.

Case series Patients: Male, 19-year-old • Female, 31-year-old Final Diagnosis: TAFRO syndrome Symptoms: Fever • splenomegaly • lymphadenopathies Medication: — Clinical Procedure: — Specialty: Hematology Objective: Unusual clinical course Background: Thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome is a variant of idiopathic multicentric Castleman disease. Adrenal hemorrhage has rarely been reported in TAFRO syndrome, and previous cases have mainly been Asian patients. This report is of two Caucasian patients with TAFRO syndrome presenting with acute adrenal insufficiency due to bilateral adrenal hemorrhage. Case Reports: Case 1 was a 19-year-old Caucasian man with no significant past medical history who was admitted with acute abdominal pain, vomiting, anorexia, and moderate weight loss. Case 2 was a 31-year-old Caucasian woman with no past medical history who was admitted to hospital with fever, dyspnea, thoracic and abdominal pain, polyarthralgia, and hypotension. Both patients had splenomegaly, mild lymphadenopathy, thrombocytopenia, acute kidney injury, and myelofibrosis. In both cases, lymph node biopsy histology showed mixed-type idiopathic multicentric Castleman disease. In both patients, a diagnosis of TAFRO was made, and they developed bilateral adrenal hemorrhage with adrenal insufficiency. Case 1 was treated with high-dose steroids, followed by tocilizumab infusion. Due to persistent thrombocytopenia, second-line treatment commenced with rituximab, but the patient relapsed two months later. Tocilizumab treatment was recommenced, which was followed by an immuno-allergic adverse event. He then had a good response to sirolimus. Case 2 died nine months after diagnosis due to acute respiratory distress. Conclusions: Two cases of TAFRO syndrome presented with acute adrenal insufficiency due to bilateral adrenal hemorrhage. The symptoms were only partially controlled with tocilizumab, rituximab, and tacrolimus. Adrenal hemorrhage may be a specific manifestation of TAFRO syndrome.

Erythroblastic synartesis is a rare cause of acquired dyserythropoiesis. Only 9 cases have been previously reported. We hereby report 3 cases of patients diagnosed with erythroblastic synartesis associated with monoclonal immunoglobulin and an overt malignant lymphoid disorder. A different B-cell clone may produce the monoclonal immunoglobulin, forming a biclonal disorder. In light of these data and literature review, treatment targeting the paraprotein seems to be efficient to control synartesis and correct anemia. In the case of monoclonal gammapathy associated with chronic lymphocytic leukemia, therapeutics should be adapted to control both chronic lymphocytic leukemia and monitored monoclonal immunoglobulin titer.

Heavy-chain deposition disease (HCDD) is characterized by tissue deposits of a truncated monoclonal immunoglobulin heavy-chain (HC) on basement membranes. Diagnosis is usually made on kidney biopsy, showing nodular glomerulosclerosis with HC deposits which can be missed, resulting in delay in diagnosis. We report four γ1-HCDD patients presenting with cutis laxa, hypocomplementemia and hypoalbuminemia. In two patients, unsuspected HCDD was revealed by cutis laxa and diagnosis was made on skin biopsy. In all patients, serum albumin and complement represented surrogate markers for disease monitoring. In γ-HCDD, extrarenal manifestations such as cutis laxa may precede renal injury and are precious tools for an early diagnosis, which is crucial to avoid progression of irreversible renal and elastic tissue damage.

Introduction Multirefractory adult ITP, defined as no response to splenectomy, rituximab, and thrombopoietin receptor agonists (TPO-Ra), is associated with high morbidity and mortality. In a previous study, we have shown that combining an immunosuppressant therapy with one TPO-Ra could be a promising therapeutic strategy for managing patients with multirefractory ITP. Objective The aim of this study was to assess the efficacy and safety of such combination in multirefractory ITP on a larger series of patients. Patients and methods We conducted a retrospective, multicenter, observational study in France. Adult patients treated by a combination of a TPO-Ra with an immunosuppressant therapy (i.e., mycophenolate mofetil, azathioprine, ciclosporin, everolimus, or cyclophosphamide) for chronic (> 12 months) or persistent (> 3 months) multirefractory ITP, were included through the national reference center for adult immune cytopenia (CERECAI) network. Multirefractory ITP was defined as disease not responding to rituximab, to splenectomy (or contraindication to splenectomy), and to the 2 TPO-Ras licensed in France (romiplostim and eltrombopag) administered at the maximal approved dose. Clinical and biological data were retrospectively collected using a standardized form. Complete response (CR) was defined by a platelet count >100 x109/L and response (R) by a platelet count between 30-100 x109/L with at least a 2-fold increase from baseline, according to the international recommendations. Results Thirty-one patients (65% female, median age 57 years [range 23 - 82]) were included. Five (16%) of them had secondary ITP (Evans syndrome (n=2), systemic lupus (n=1) with antiphospholipid syndrome (APS), primary APS (n=1), and Waldenstrom macroglobulinemia (n=1). Four patients had a monoclonal gammopathy of undetermined significance, and 11 (35%) had antinuclear antibodies (titer >1/160) without definite clinical autoimmune disease. All patients had previously received corticosteroids and 16/31 (52%) were corticosteroid-refractory. Previous treatments lines also included intravenous immunoglobulin (28/31, 90%) and at least one immunosuppressant therapy (16/31, 52%). Splenectomy was performed in 25 patients (81%), and not performed in the remaining 6 patients because of advanced age and comorbidities (n=3), underlying APS (n=2), or patient refusal (n=1). At the time of treatment combination initiation, median ITP duration was 57 months [3 - 393], with 28/31 (90%) chronic ITP and 3/31 (10%) persistent ITP. Bleeding symptoms were present in 23 patients (74%) and the median platelet count was 10 x109/L [range 1 - 35]. The combination regiment included eltrombopag (n=18) or romiplostim (n=13), associated with either mycophenolate mofetil (n=15), azathioprine (n=12), cyclophosphamide (n=2), ciclosporine (n=1), or everolimus (n=1). Median duration of combination therapy was 12 months [range 1 - 103]. Nineteen patients (61%) had no therapeutic intervention other than the combined treatment, while 10 patients were also given corticosteroids (either short course of high dose steroids [n=5], or on a long-term at low dose [n=5]), and/or hydroxychloroquine (n=5). Overall, 81% of patients (25/31) achieved at least a R, including 19/31 (61%) CR. Among responders, the median time to response was 30 days [range 7 - 270], and the median duration of the response was 12 months [4 - 55]. Response rates were similar in patients who did not receive concomitant corticosteroids (59% CR, 12% R), and in patients that were previously exposed to immunosuppressant therapy given alone (63% CR, 25% R). Regarding safety, 13/31 (42%) patients experienced at least one adverse event potentially related to treatment, including 7 severe adverse events. Three patients without APS but who were splenectomized had a thromboembolic event, including 3 deep vein thrombosis/pulmonary embolism, and 1 cerebral venous thrombosis; Three patients had an infection (one cholecystitis, one herpes zoster, and one dental abscess). After a median follow-up of 18 months [6-103], one patient died (from a previously diagnosed adenocarcinoma). Conclusion In summary, these data show that most of the patients managed for multirefractory ITP may benefit from the combination of TPOra with an immunosuppressant therapy by achieving a durable response. The safety profile of this combination in this population seems acceptable. Disclosures Moulis: Novartis SAS: Membership on an entity's Board of Directors or advisory committees, Other: meeting attendance grant, Research Funding; Amgen: Other: meeting attendance grant; Grifols: Research Funding. Michel:Bioverativ: Consultancy; Rigel: Consultancy; Alexion Pharmaceuticals: Consultancy. Godeau:LFB: Honoraria; Amgen: Research Funding; Amgen: Honoraria; Novartis: Honoraria. Mahevas:GSK: Research Funding. OffLabel Disclosure: Some immunosuppressant drugs were given off-label for adult ITP.

Background Neutrophilic dermatoses refer to a group of cutaneous inflammatory disorders characterized by neutrophilic infiltration of the skin. Neutrophilic dermatoses have been reported in association with various conditions including autoimmune diseases, inflammatory bowel diseases, and neoplasia. In the later condition, myeloproliferative disorders and monoclonal gammopathy (monoclonal immunoglobulin [MIg]) are the most frequent. Only few data are available in case of neutrophilic dermatoses associated with MIg regarding the pathophysiology and the clinical outcome. Objective We sought to gain further insight into clinical and biological aspects of neutrophilic dermatoses associated with MIg. Methods We report a retrospective series of 26 patients with neutrophilic dermatoses associated with MIg focusing on clinical and biological aspects, with a study of a large panel of cytokines, chemokines, and adhesion molecules. Results This study reveals an association between MIg IgA isotype and neutrophilic dermatoses, and a specific inflammatory pattern including elevated interleukin 6, vascular endothelial growth factor, monocyte chemotactic protein-1, epidermal growth factor, and intercellular adhesion molecule-1. Limitations This is a retrospective study from a single institution with a limited number of participants. Conclusion Our data highlight a strong association between IgA isotype and neutrophilic dermatoses, and the existence of a specific inflammatory profile involving several molecules.

Blood concentrations of hydroxychloroquine (HCQ) vary widely among patients with systemic lupus erythematosus (SLE). A pharmacokinetic/pharmacodynamic relationship has been found in different situations, and a very low blood concentration of HCQ is a simple marker of nonadherence to treatment. Therefore, interest in blood HCQ concentration measurement has increased, but little is known about factors that influence blood HCQ concentration variability. This study was undertaken to analyze determinants of blood HCQ concentrations.

This retrospective analysis was conducted in 64 patients diagnosed with type I cryoglobulinaemia (CG) followed at two French centres. Median follow-up was 6·75 years. CG was IgG in 60% and IgM in 40% of all cases and was asymptomatic in 16 patients (25%). Cold-triggered ischaemic skin manifestations were observed in 33 patients (51%). Neurological manifestations were observed in 15 patients and renal manifestations in 13. Most of the patients with necrotic purpura (14/16, P = 0·009) and renal manifestations (11/13, P = 0·057) had IgG CG. IgG CG was associated with monoclonal gammopathy of undetermined significance (MGUS), myeloma, chronic lymphocytic leukaemia and lymphoplasmocytic lymphoma in 18, 13, 5 and 2 patients, respectively. IgM CG was associated with MGUS and Waldenström macroglobulinaemia in 8 and 18 cases, respectively. One third of patients did not receive any specific treatment. Various treatments, including rituximab, were administered to 25/31 patients with IgG CG and 6/25 patients with IgM CG due to CG-related symptoms. Rituximab was ineffective in all cases associated with a predominantly plasmacytic proliferation. To conclude, type I CG has specific clinico-biological characteristics compared to type II CG. Furthermore, there are differences in terms of related manifestations between type I IgG and type I IgM CG.

Introduction Le traitement de la thrombopenie immunologique (PTI) chronique de l’adulte repose sur la splenectomie, le rituximab et les agonistes du recepteur a la thrombopoietine (ARTPO). Les traitements immunosuppresseurs conventionnels sont reserves aux situations d’echec, avec des taux de reponse variables. Des donnees recentes suggerent qu’une combinaison d’un traitement immunosuppresseur avec un ARTPO pourrait permettre un taux de reponse important chez les patients multirefractaires (en echec du rituximab, des deux ARTPO et de la splenectomie ou ayant une contre-indication a celle-ci). L’objectif de ce travail etait d’evaluer l’efficacite et la tolerance de ce traitement combine chez les patients multirefractaires. Patients et methodes Nous avons realise une etude retrospective multicentrique observationnelle, incluant des patients adultes presentant un PTI multirefractaire et ayant recu un traitement combinant un ARTPO avec un traitement immunosuppresseur (mycophenolate mofetil, azathioprine, ciclosporine, everolimus, cyclophosphamide), via un appel a observations du centre de reference des cytopenies auto-immunes de l’adultes (CERECAI). Les donnees cliniques, biologiques, et evolutives des patients ont ete recueillies retrospectivement de facon standardisee. La reponse (R) et la reponse complete (RC) etaient definies selon les criteres internationaux selon le taux de plaquettes obtenu (R : > 30 G/L avec au moins un doublement du taux initial, et RC : > 100 G/L). Resultats Dix-huit patients provenant de 13 centres (58 % de femmes, âge median 56 ans [23–82] a l’introduction du traitement combine) ont ete inclus. Trois patients avaient un PTI secondaire (un lupus systemique avec syndrome de antiphospholipides (SAPL), un SAPL primaire, une maladie de Waldenstrom). On notait egalement 2 patients avec une cirrhose biliaire primitive, 3 patients avec une gammapathie monoclonale de signification indeterminee. Huit patients (44 %) avaient des anticorps antinucleaires de titre > 1/80. Avant le traitement combine, la mediane d’evolution du PTI etait de 57 mois [3–371]. Seize patients (89 %) avaient un PTI chronique, et 2 (11 %) un PTI persistant. Tous les patients avaient recu des corticoides, 15 patients (83 %) des immunoglobulines intraveineuses polyvalentes, 14 (78 %) etaient splenectomises. Neuf patients (50 %) avaient recu un traitement immunosuppresseur, different de celui utilise dans la combinaison pour 6 d’entre eux. Tous les patients avaient presente des manifestations hemorragiques au cours de l’evolution du PTI. A l’introduction de la combinaison, le chiffre de plaquettes median etait de 10 G/L [4–35], et 11 patients (61 %) presentaient un syndrome hemorragique. Le romiplostim (8 patients, dose mediane 10 μg/kg/semaine [5–10]) et/ou l’eltrombopag (10 patients, dose mediane 75 mg/jour [75–75]) etait combine a du mycophenolate mofetil (n = 9), de l’azathioprine (n = 8), ou de l’everolimus (n = 1), associe a une corticotherapie chez 44 % et/ou a de l’hydroxychloroquine chez 28 % des patients. Quatre patients (22 %) ont recu successivement plusieurs immunosuppresseurs pour echec et/ou intolerance. Apres un suivi median de 18 mois [2–103], 15 patients (83 %) obtenaient une reponse (11 RC [61 %] et 4 reponses [22 %]), qui survenait en mediane 30 jours (extremes 15–270) apres le debut du traitement, et d’une duree mediane de 9 mois [2–48]. Durant le suivi, on notait 2 infections (1 zona, 1 cholecystite), 3 patients (sans SAPL) ont presente des evenements thrombotiques (1 patiente avec thromboses veineuses profondes, embolies pulmonaires et thrombose carotidienne recidivante, 1 patiente avec thrombose veineuse profonde, et 1 patiente avec thrombose veineuse cerebrale), 2 cancers, 3 troubles digestifs sous mycophenolate mofetil (dont 2 imposaient un switch vers l’acide mycophenolique sans perte de l’efficacite), et 1 pancytopenie sous azathioprine imposant l’arret du traitement. Un patient decedait d’un adenocarcinome pancreatique. Conclusion En conclusion, ces donnees preliminaires retrospectives semblent confirmer que l’association d’un ARTPO avec un immunosuppresseur est une option therapeutique interessante chez des patients avec un PTI multirefractaire.

IgM-secreting monoclonal B-cell proliferations can cause, in addition to symptoms directly related to the clonal cells, such as bone marrow infiltration, lymphadenopathy and splenomegaly, symptoms due to the monoclonal IgM, either by deposition of all or part of its molecule or because of a symptomatic auto-antibody activity. Some of these IgM-related manifestations, such as hyperviscosity, occur in presence of high tumour mass proliferation. Others caused by either the antibody activity of the monoclonal IgM or to its tissue deposition, most often occur in the context of an indolent proliferation or even of a MGUS; the so-called “dangerous” small B-cell clone and monoclonal gammopathy of renal significance. This chapter describes IgM-related AL amyloidosis and the skin and kidney manifestations of IgM gammopathies, which are not uncommon and could in some cases involve other mechanisms than deposition or autoantibody activity.

Background Schnitzler syndrome is characterized by an urticarial rash, a monoclonal gammopathy, and clinical, histological, and biological signs of neutrophil-mediated inflammation. The aim of this study was to assess the applicability and validity of the existing diagnostic criteria in real-life patients. Methods This multicentric study was conducted between 2009 and 2014 in 14 hospitals in which patients with Schnitzler syndrome or controls with related disorders were followed up. We compared the sensitivities and specificities and calculated the positive and negative predictive values of the Lipsker and of the Strasbourg criteria for the patients with Schnitzler syndrome and for the controls. We included 42 patients with Schnitzler syndrome, 12 with adult-onset Still's disease, 7 with cryopyrin-associated periodic disease, 9 with Waldenstrom disease, and 10 with chronic spontaneous urticaria. Results All patients with Schnitzler syndrome met the Lipsker criteria. According to the Strasbourg criteria, 34 patients had definite Schnitzler syndrome, five had probable Schnitzler syndrome, and three did not meet the criteria. One control met the Lipsker criteria and had probable Schnitzler syndrome according to the Strasbourg criteria. Sensitivity and specificity of the Lipsker criteria were 100% and 97%, respectively. For the Strasbourg criteria, sensitivity for definite and probable diagnosis was 81% and 93%, respectively, with a corresponding specificity of 100% and 97%. Conclusion Diagnostic criteria currently in use to diagnose Schnitzler syndrome are reliable. More investigations must be done to attest their efficiency in patients with recent-onset manifestations.

The vasculitis of Behcet disease (BD) is distinctive because of involvement of both arteries and veins of all sizes. The concept of vasculo-Behcet disease has been adopted for cases in which vascular manifestations are present and often dominate the clinical features. While venous manifestations are frequent and have been reported in many publications, data regarding arterial lesions in patients with BD are rare and often isolated. In this study, we report the main characteristics, treatment, and long-term outcome of 101 patients with arterial lesions among a cohort of 820 (12.3%) BD patients. Factors that affect prognosis were assessed by multivariate analysis. There were 93 (91.2%) male patients; the median (Q1-Q3) age at diagnosis of BD was 33 (27-41) years. Arterial lesions included aneurysms (47.3%), occlusions (36.5%), stenosis (13.5%), and aortitis (2.7%). Lesions mainly involved the aorta (n = 25) and femoral (n = 23) and pulmonary (n = 21) arteries. Patients with arterial lesions were more frequently male (91.2% vs. 62.4%, respectively; p = 0.017) and had higher rates of venous involvement (80.4% vs. 29.8%, respectively; p < 0.001) compared to patients without arterial manifestations. Thirty-nine (38.6%) patients achieved complete remission. In multivariate analysis, the presence of venous involvement (odds ratio [OR], 0.29; 95% confidence interval [CI], 0.08-1.11) and arterial occlusive lesions (OR, 0.13; 95% CI, 0.01-1.25) were negatively associated with complete remission. The use of immunosuppressants (OR, 3.38; 95% CI, 0.87-13.23) was associated with the occurrence of complete remission. The 20-year survival rate was significantly lower in BD patients with arterial involvement than in those without arterial lesions (73% vs. 89%, respectively; p < 0.0001). In conclusion, the long-term outcome of arterial lesions in BD is poor, especially in the case of occlusive lesions and associated venous involvement. The use of immunosuppressants improved the prognosis.

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.

The t(4;14) translocation, found in 15% of multiple myeloma (MM), indicates a poor prognosis. Clinico-biological features associated with this severe outcome and the impact of novel agents are unknown. We report a series of 102 consecutive patients with t(4;14) MM. The median age was 56 years. The isotype was IgA in 42%, and the median serum β(2)-microglobulin was 2.3 mg/L. FGFR3 expression was lacking in 20 (19%) cases. Monoclonal gammopathy of undetermined significance (MGUS) or smoldering MM (sMM) was found in 26 patients (25%). Seven (27%) became symptomatic in a median time of 9 months. Fifty-six of 76 patients with symptomatic MM received high-dose therapy (HDT). The overall response rate (ORR) was 93% (22% CR, 44% VGPR), and the median progression-free survival (PFS) was 12 months. Twenty-four (37%) patients experienced aggressive relapse. Post-second-line ORR was 51% and the median PFS was 7 months, with a trend for longer PFS in patients treated with a bortezomib-based regimen. Median overall survival after HDT was 31 months. t(4;14) is detected in patients with MGUS/sMM and this does not require immediate chemotherapy. Patients with t(4;14) MM have a high ORR after HDT, contrasting with a short PFS and aggressive relapses, and, despite novel agents, still have a poor prognosis.

We retrospectively studied a series of 23 patients (median age 50 years, range 29-59 years) with multiple myeloma (MM), treated in first relapse by a sequential autologous-allogeneic tandem approach. Tandem transplantation (TT) consisted in high dose melphalan (HDT) and auto-SCT followed by an (allo-SCT) preceded by two gray TBI non-myeloablative conditioning. All patients received a first HDT as frontline treatment. At day 100 post allo-SCT, complete donor chimerism was detected in 22 patients (95%). Acute GVHD was observed in 19 patients (15 grade I-II (65%) and 4 grade III-IV (17%)). Ten patients (43%) developed an extensive chronic GVHD. The non-relapse mortality at 1 year was 17%. After TT, the overall response rate was 91% (17% partial response, 35% very good partial remission and 39% complete remission). At 2 years, OS was 61%. Median event-free survival and OS were 36.8 and 60 months, respectively. Based on the propensity score matching method, a significant survival advantage could be seen in patients treated with TT as compared with non-allografted patients. Thus, allo-SCT, in TT approach, provides a high response rate with low toxicity and may improve survival of patients with relapsing MM.

The impact of reducing immunoglobulin dosage while switching from intravenous to subcutaneous replacement therapy was evaluated. Sixty-five patients with primary hypogammaglobulinemia on stable intravenous replacement therapy were included in a monocentric longitudinal trial. IgG trough levels were measured at baseline and during 1 year following the switch to the subcutaneous route. Mean IgG trough level after 12 months of subcutaneous therapy was increased by 5.4% (8.37–8.82 g/l, p = 0.3), while immunoglobulin dosage had been reduced by 28.3% (151–108 mg/kg/week, p

The t(4;14)(p16;q32) translocation, found in 15% of multiple myeloma (MM) cases, indicates a poor prognosis. Plasma cells (PC) with t(4;14) ectopically express the fibroblast growth factor receptor 3 (FGFR3) tyrosine kinase receptor, which has potential transforming activity and may represent a therapeutic target. To detect FGFR3 protein expression, bone marrow (BM) aspirate from 200 consecutive newly diagnosed (n = 116) or relapsing (n = 74) MM patients was studied by flow cytometry (FC) using anti-CD138 and anti-FGFR3 antibodies. FC data was compared to real time quantitative-polymerase chain reaction (RQ-PCR) of the IGH-MMSET and FGFR3 transcripts. An IGH-MMSET transcript was found in 24/200 patients (12%). In 20 of these, FC detected CD138(+)/FGFR3(+) cells. No expression of FGFR3 was detected in the 4 FGFR3(-) cases by RQ-PCR. FGFR3 was never expressed on PC without t(4;14). Circulating PC (CPC) were detected in patients with (11/11) and patients without (13/41) t(4;14). In 2/8 t(4;14) cases studied longitudinally, coexisting FGFR3(+) and FGFR3(-) CPC were observed. Fluorescent in situ hybridisation (FISH) analysis of the FGFR3(-) subclones showed deletion of the der(14) in one patient. In conclusion, as a supplemental method to RQ-PCR or FISH, FC analysis of FGFR3 expression is a reliable and routinely available method for the detection and management of new therapeutic approaches of t(4;14) MM.

Langerhans dendritic cells are antigen presenting cells (APC) that reside within the epidermis and are capable of stimulating naive T cells. Reciprocally, lymphocytes may play a role in Langerhans cells (LC) differentiation. Our results show that the differentiation of skin LC is unaffected in the absence of lymphocytes and/or signaling through the common cytokine receptor γ chain ( γ c ) required for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 signaling. Migration of LC and other dendritic cells (DC) from the skin to the draining lymph nodes (LNs) after FITC skin sensitization, is unaffected in the absence of lymphocytes or CD40. FITC + LC/DC sorted from the LNs of lymphoid deficient or control mice stimulated naive T cells with similar efficiency. However, while the absence of lymphocytes did not appear to affect the phenotype or number of emigrating LN DC/LC, their persistence in the LN appears to depend on αβ T cells. Thus, DC are strikingly reduced in numbers in the peripheral LNs of T-cell deficient mice. Finally, CD8 α expression on skin emigrants was low and dependent on the presence of CD8 + lymphocytes, while spleen CD8 + DC were present in the absence of lymphocytes. We conclude that the presence of T cells is not required for the differentiation and migration of resident skin DC but is critical for the maintenance of DC and LC migrating into the LNs.

BACKGROUND Good syndrome (GS) is a rare condition in which thymoma is associated with hypogammaglobulinemia. It is characterized by increased susceptibility to bacterial, viral, and fungal infections, as well as autoimmunity. Most patients have no circulating B cells. METHODS The French DEFicit Immunitaire de l'adulte cohort provides detailed clinical and immunological descriptions of 690 adults with primary hypogammaglobulinemia. Comparisons between patients with GS, those with common variable immunodeficiency (CVID), and those with B(-) CVID (circulating B cells

Objectives Growing evidence suggests that vitamin D plays a key role in the pathogenesis and progression of autoimmune diseases, including systemic lupus erythematosus (SLE). Recent studies have found an association between lower serum 25-hydroxyvitamin D (25(OH)D) levels and higher SLE activity. We studied the relationship between 25(OH)D levels and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, and we assessed for the first time the role of vitamin D in predicting SLE flare-ups. Methods Serum 25(OH)D levels were measured in 170 patients with SLE who were prospectively followed up for 6 months (Plaquenil LUpus Systemic study, ClinicalTrials.gov number NCT00413361). Results The mean SLEDAI score was 2.03±2.43 and 12.3% patients had active disease (SLEDAI ≥6). The mean 25(OH)D level was 20.6±9.8 ng/mL. Deficiency (25(OH)D

International audience; INTRODUCTION: Hydroxychloroquine (HCQ) is an important medication for treating systemic lupus erythematosus (SLE). Its blood concentration ([HCQ]) varies widely between patients and is a marker and predictor of SLE flares. This prospective randomised, double-blind, placebo-controlled, multicentre study sought to compare standard and adjusted HCQ dosing schedules that target [HCQ] ≥1000 ng/ml to reduce SLE flares. PATIENTS AND METHODS: [HCQ] was measured in 573 patients with SLE (stable disease and SELENA-SLEDAI≤12) treated with HCQ for at least 6 months. Patients with [HCQ] from 100 to 750 ng/ml were randomised to one of two treatment groups: no daily dose change (group 1) or increased HCQ dose to achieve the target [HCQ] (group 2). The primary end point was the number of patients with flares during 7 months of follow-up. RESULTS: Overall, mean [HCQ] was 918±451 ng/ml. Active SLE was less prevalent in patients with higher [HCQ]. A total of 171 patients were randomised and followed for 7 months. SLE flare rates were similar in the two groups (25% in group 1 vs 27.6% in group 2; p=0.7), but a significant spontaneous increase in [HCQ] in both groups between inclusion and randomisation strongly suggested improved treatment adherence. Patients at the therapeutic target throughout follow-up tended to have fewer flares than those with low [HCQ] (20.5% vs 35.1%, p=0.12). CONCLUSIONS: Although low [HCQ] is associated with higher SLE activity, adapting the HCQ dose did not reduce SLE flares over a 7-month follow-up.

Item does not contain fulltext Schnitzler's syndrome is characterized by recurrent urticarial rash and monoclonal gammopathy, associated with clinical and biological signs of inflammation and a long-term risk of AA amyloidosis and overt lymphoproliferation. An extensive literature review was performed, and the following questions were addressed during an expert meeting: In whom should Schnitzler's syndrome be suspected? How should the diagnosis of Schnitzler's syndrome be established? How should a patient with Schnitzler's syndrome be treated? How should a patient with Schnitzler's syndrome be followed up?. A diagnosis of Schnitzler's syndrome is considered definite in any patient with two obligate criteria: a recurrent urticarial rash and a monoclonal IgM gammopathy, and two of the following minor criteria: recurrent fever, objective signs of abnormal bone remodeling, elevated CRP level or leukocytosis, and a neutrophilic infiltrate on skin biopsy. It is considered probable, if only 1 minor criterion is present. In patients with monoclonal IgG gammopathies, diagnosis is definite if three minor criteria are present and possible if two are present. First-line treatment in patients with significant alteration of quality of life or persistent elevation of markers of inflammation should be anakinra. Follow-up should include clinical evaluation, CBC and CRP every 3 months and MGUS as usually recommended.

International audience; POEMS syndrome is a rare disorder characterized by polyneuropathy, monoclonal gammopathy, multiorgan involvement, and elevated vascular endothelial growth factor levels. Localized bone lesions require irradiation, whereas young patients with disseminated disease receive intensive treatment with stem cell support. Treatment of older and non responding patients is not yet standardized. We report the use of a combination of lenalidomide and dexamethasone in 20 patients with POEMS syndrome. Four patients were newly diagnosed, and 16 had relapsed or progressed after treatment. All but one of the patients responded: clinical improvements were noted in neuropathies (16/20) organomegaly (13/13), peripheral edema (14/15), and pulmonary hypertension (5/5). At least a very good partial response was noted in 68% of patients, with partial responses in 26%. Serum VEGF levels fell markedly in all 17 patients with available values. Twelve patients had 18-FDG-PET/CT at diagnosis (11 with positive findings), and nine patients during follow-up. The number of lesions fell markedly in five cases and remained stable in two cases, while two patients became negative. During a median follow-up of 22 months, four patients relapsed. Toxicity, predominantly hematological, was mild and manageable. Lenalidomide thus appears to be effective in POEMS syndrome, inducing high rate of clinical and biological responses.

http://content.nejm.org/cgi/content/abstract/357/11/1083; International audience; High-dose chemotherapy followed by autologous hematopoietic stem-cell transplantation has been reported to provide higher response rates and better overall survival than standard chemotherapy in immunoglobulin-light-chain (AL) amyloidosis, but these two strategies have not been compared in a randomized study. METHODS: We conducted a randomized trial comparing high-dose intravenous melphalan followed by autologous hematopoietic stem-cell rescue with standard-dose melphalan plus high-dose dexamethasone in patients with AL amyloidosis. Patients (age range, 18 to 70 years) with newly diagnosed AL amyloidosis were randomly assigned to receive intravenous high-dose melphalan plus autologous stem cells or oral melphalan plus oral high-dose dexamethasone. RESULTS: Fifty patients were enrolled in each group. The results were analyzed on an intention-to-treat basis, with overall survival as the primary end point. After a median follow-up of 3 years, the estimated median overall survival was 22.2 months in the group assigned to receive high-dose melphalan and 56.9 months in the group assigned to receive melphalan plus high-dose dexamethasone (P=0.04). Among patients with high-risk disease, overall survival was similar in the two groups. Among patients with low-risk disease, there was a nonsignificant difference between the two groups in overall survival at 3 years (58% in the group assigned to receive high-dose melphalan vs. 80% in the group assigned to receive melphalan plus high-dose dexamethasone; P=0.13). CONCLUSIONS: The outcome of treatment of AL amyloidosis with high-dose melphalan plus autologous stem-cell rescue was not superior to the outcome with standard-dose melphalan plus dexamethasone. (ClinicalTrials.gov number, NCT00344526 [ClinicalTrials.gov].). Copyright 2007 Massachusetts Medical Society.

Background Schnitzler syndrome is characterized by chronic urticarial rash and monoclonal IgM gammopathy and is sometimes associated with periodic fever, arthralgias, and bone pain. Current treatment is unsatisfactory. Observations Eleven patients with Schnitzler syndrome were treated with oral pefloxacin mesylate (800 mg/d). In 10 patients, we observed a dramatic and sustained improvement of urticarial and systemic manifestations. Corticosteroid therapy could be stopped or reduced in 6 patients. In 9 patients, pefloxacin was administered for more than 6 months (≤ 10 years), with a good safety profile. Conclusions Pefloxacin therapy can be considered for patients with Schnitzler syndrome because it usually improves chronic urticaria and the systemic symptoms of the disease.

We report a case of hepatitis C virus infection in association with primary hepatic large B-cell non-Hodgkin's lymphoma. Primary hepatic non-Hodgkin's lymphoma is a rare disease. Association of hepatitis C virus infection with primary hepatic B-cell non-hodgkin's lymphoma is probably not fortuitous. Indeed, in case of primary hepatic non-hodgkin's lymphoma' patients are often hepatitis C virus positive. Moreover, several studies have reported a high prevalence of chronic hepatitis C virus infection among patients with B-cell non-Hodgkin's lymphoma whatever the localization of the lymphoma. A recent study found a high rate of remission of a splenic form of lymphoma after treatment of hepatitis C virus infection. Our case report confirms the hypothesis of a key role of hepatitis C virus in the pathogenesis of various forms of B-cell lymphoproliferative disorders and in particular in primary hepatic lymphoma.

Background Benefits of use of HCQ on physician reported outcomes (PRO) have been well documented in SLE and Rheumatoid arthritis (RA). HCQ can be measured in blood ([HCQ]) and a target threshold of 1000ng/ml has been proposed. No studies have assessed the predictive role of [HCQ] on PRO in SLE. Objectives Assess the predictive value of [HCQ] with health related quality of life (HRQOL) among patients with SLE. Methods Data from the PLUS study (a prospective randomized, double-blind, placebo-controlled, multicentre study comparing standard and adjusted HCQ dosing schedules and [HCQ]) were utilized. Blood HCQ levels were quantified by HPLC, along with HRQOL PRO assessments (Medical Outcomes Study-Short Form 36 or SF-36) at baseline (J0) and month 7 visits (M7). Paired t test were used to compare HCQ concentrations at the two visits. Spearman correlation coefficients between HCQ concentrations (continuous variable) and HRQOL at J0 and M7 were obtained. Nonparametric t test to compare HRQOL (J0) stratified by HCQ concentrations categories (0-499, 500-1000, >1000 ng/ml) was performed. Linear regression analysis with physical or mental component summary scores as dependent variables, and HCQ (J0) concentration as the predictor variable was performed. P value of ≤0.05 on two tailed tests was considered significant. Results 166 SLE patients9 data were analyzed. Mean (SD) age and disease duration were 44.4 (10.7) and 9.3 (6.8) years. Eighty seven percent were women. Mean (SD, median, IQR) HCQ concentrations in the blood at J0 were 660 (314, 615, 424) ng/ml and increased to 1020 (632, 906, 781) ng/ml at M7 (mean difference 366 units, 95% CI -472 to -260, p Conclusions No association of HCQ concentrations with current or future HRQOL (when measured by SF36) were found. This could be a real finding, or reflect inadequacy of sample size or the tool used to capture relevant HRQOL in SLE. Latter is hypothesized as no changes in HRQOL over time were noted irrespective of HCQ concentrations, despite physician-assessed changes in disease activity. Further studies are suggested. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2311

Background Monoclonal gammopathies (MoG) and HIV infection are two common diseases. A higher incidence of MoG of undetermined significance (MGUS) has been suggested in HIV patients (pts). The clinical outcome of MGUS and the characteristics of MM in such patients are largely unknown. In the last decade, therapeutics advances have improved the prognosis of both diseases. We report the laboratory findings and clinical course of 18 HIV infected patients with a detectable serum monoclonal protein( MGUS, MM, plasma cell leukemia) treated in our center. Patients, disease and methods Patients’ demographic characteristics, stage of HIV infection and clinical course were studied. Laboratory studies included determination of CD 4 T-lymphocyte cell counts, HIV loads, serum protein electrophoresis, Ig isotype, hemoglobin, serum β2-microglobulin, calcium and creatinine levels, bone marrow aspiration with cytogenetic analysis at diagnosis. Results 18 pts (9 MGUS/stage I asymptomatic myeloma, 6 stage III myeloma, 1 leukemia plasma cell and 2 multiple plasmocytomas) were studied. The median age at diagnosis was 54.5 years (38,75). The median age at diagnosis of HIV infection was 42 years (29,68). the time Median between seropositivity and monoclonal gammopathy was 10.5 years. 1 patient's HIV status was discovered during the treatment of myeloma. 14 patients received protease inhibitors, including 9 before developing gammopathy. The monoclonal gammapathy was IgG Kappa for 9 patients,IgG Lambda for 6. At the diagnosis of gammopathyt the median CD 4 T lymphocyte count was 442 cells/µL(range 190-915). Half of the patients had negative HIV viral load (the median of the others was 9904 copies/ml). A polyclonal hypergammaglobulinemia (median 15.4 g / l (3.6, 26.9)) was found in addition to the Ig monoclonal in 17 patients and one patient had a symptomatic immunoparesis with repeated infections. Two patients with asymptomatic MM progressed with a period of time of 6and 11 years. All patients with symptomatic myeloma had bone lesions, 3 had an hypercalcemia ( including a case of primary hyperparathyroidism), 2 patients had kidney injury ( 1 end stage renal disease requiring hemodialysis). Extramedullary lesions were found in 5 patients (lymph node). 11 patients have been treated with chemotherapy, 4 received autologous stem cell transplantation and 7 relapsed. The median event free survival was 4 years. 4 patients died of disease. The overal survivalwas 4.25 years. Conclusion The presence of a monoclonal gammapathy or asymptomatic myeloma with infection by the human immunodeficiency virus does not seem to change the clinical presentation at diagnosis. The prognosis myeloma does not seem different from the HIV non infected patients population infected and justifies a similar therapeutic approach, including therapeutic intensification and novel agents. Disclosures: No relevant conflicts of interest to declare.

Abstract 2035 Background: We previously reported 23 MM patients, treated in first relapse by a sequential autologous-allogeneic tandem transplantation (aATT) approach. Data from this series compared favorably with a non allografted control population (Karlin, 2011). However, most of the patients were treated before the availability of novel anti-myeloma agents. We now report a larger series of 50 patients and conducted an overall survival (OS) comparison with a matched cohort. Patients and methods: From 2002 to 2011, fifty patients with MM were treated by a sequential autologous-allogeneic tandem approach in our institution. All were included in the study. A series of 64 non-allografted MM patients treated during the same period was used as a control group. An individual matching procedure was completed using the following factors: response to first line therapy, delay from first treatment to relapse, patient's age, year of relapse, ISS, serum Beta 2 microglobulin and albumin. OS comparisons were performed by using proportional hazards models stratified on each individual matched pair, or adjusted on strata to allow interaction test between cohort and stratum. Results: Median age of the allografted patients was 50.8 years (range 28.5 to 59.5 years). Forty-three (86%) were in first relapse, 7 (14%) in second relapse. First line treatment included a first high dose therapy with an autologous blood stem cell transplantation (aSCT) for all patients; 31 (62%) pts relapsed less than 2 years after this aSCT. At relapse, all patients received novel agents (IMID's and/or bortezomib). Overall response rate before aATT was 96%, including 8% complete response (CR), 42% of very good partial response (VGPR), and 46% of partial response (PR). First transplant of aATT was performed after high dose melphalan alone (n=28, 56%) or combined with bortezomib (n=22, 44%). For allotransplant, all patients received a reduced intensity conditioning regimen based on 2 Gy TBI with (n=14) or without (n=22) fludarabine). Acute GvHD prophylaxis used cyclosporine plus MMF. Donors were HLA-identical siblings in 29 patients (58%) while 21 (42%) had an unrelated-donor including 2 with one mismatch. The source of stem cells was peripheral blood in all patients. After allotransplant, complete donor chimerism was detected in all cases at day 100. The cumulative incidence function (CIf) of acute graft-versus-host disease (GvHD) grade II to IV was 27% at day 100 (95%CI 14 – 40) and 27 patients developed a chronic GvHD. After a median follow-up of 24.3 months (IQR: 11.3–44.2), 23 patients died, including 12 free of relapse (Infections, n=7; GvHD, n=5) leading to a 1 year-CIf of TRM of 16.4% (5.8–27.0). Twenty four patients relapsed. Sixteen patients received a revlimid-based salvage therapy. Donor lymphocyte infusions were performed for 3 patients. The disease free survival (DFS) at 2-year was 61.2% (95%CI 47.0–75.4). The OS at 2 and 5 years was 72.3% and 46.1% respectively (Figure 1A). No factor allowed to predict neither TRM, relapse, DFS nor OS. In the non-allograft group, within a median post relapse follow up of 1.8 years, post relapse 2 year OS was 47.8%. We identified 19 pairs of allograft and non-allograft pts eligible for a matched-pair comparison. All experienced their first relapse less than 2 year after initial high dose therapy with aSCT performed frontline. There was no significant difference between survival of allografted pts as compared to the control group (p = 0.35, HR = 0.68 [95% IC 0.3 – 1.55]) (Figure 1B). Conclusion: In this single center study of 50 young MM patients treated in relapse by tandem autologous-allogeneic transplantation, we observed a relatively low TRM of 16.8%. In contrast to our first series, a matched-pair analysis suggested similar OS between allografted and non-allografted patients. These results questioned the role of non myeloablative allogeneic hematopoietic stem cell transplantation in the management of multiple myeloma in the era of novel anti-myeloma agents, but they should be confirmed. Incidence of relapse post aATT may justify a systematic post allo maintenance therapy. Disclosures: No relevant conflicts of interest to declare.

Abstract 3971 Background: The presence of a t(4;14) translocation in myeloma cells dysregulates two potential oncogenes FGFR3 and MMSET. It usually indicates a poor prognosis but some patients have a very good survival including pts with indolent multiple myeloma (MM) and even MGUS. Biologically, t(4;14) are featured by a high frequency of IgA isotype reaching 40 to 50 % of cases. FGFR3 protein is ectopically expressed in 75% of cases but is lacking in 25%, mostly due to the loss of der(14) chromosome. Three major breakpoints on chromosome 4 result in the over-expression of a full length (MB4-1) or 2 distinct amino-truncated (MB4-2 and MB4-3) MMSET proteins. The different subcellular localization, the DNA repair and histone methyltransferase activities of the MB4-2 and MB4-3 products are poorly known. It has been reported that IgA isotype and FGFR3 expression have no prognostic value whereas the impact of the different breakpoints has not been evaluated in a large series of patients. Method: Between 2003 and 2011, we studied all patients with monoclonal gammapathy and a t(4;14) in bone marrow plasma cells, as detected using quantitative RT-PCR searching for IgH/MMSET fusion transcripts. MB4-1, MB4-2 and MB4-3 breakpoints and FGFR3 expression were systematically studied by PCR and correlated with clinical outcome. Results: Among the 173 pts identified, there were 38 MGUS/Stage I MM (median age 61 yrs, M/F ratio: 1/1.7) and 135 symptomatic MM (median age 58 yrs, M/F ratio: 1.5/1). IgA isotype was found in 42% and FGFR3 expression was not detected in 25% of cases. MB4-1, MB4-2 and MB4-3 breakpoints were detected in 114 (66%), 25 (14%) and 34 (20%) pts, respectively. IgA isotype was found twice more frequently in pts with MB4-2 breakpoint (64%) as compared to pts with MB4-2 and MB4-3 (38% in both groups). In pts with MGUS/Stage I MM, MB4-1 was detected in 75% of cases whereas MB4-2 and MB4-3 were found in 4% and 21%, respectively. Median time of MGUS/Stage I MM to symptomatic MM was significantly longer in patients harboring an MB4-1 breakpoint (90 months versus 40 months in MB4-2 and 3 breakpoints, p Conclusion: Among patients with a t(4;14) MM, those harboring an MB4-2 breakpoint in the MMSET gene are featured by 1) a very high expression (64%) of IgA isotype 2) a poorer prognosis. Further studies are needed to understand the role and the biological significance of this particular truncated form of MMSET. Disclosures: No relevant conflicts of interest to declare.

Abstract 4501 Despite recent improvement of overall survival of MM due to the use of novel agents, the high risk sub group of patients, especially with 17p deletion and/or t(4;14) still have a poor prognosis. New therapeutic strategies are needed to improve this outcome. We report preliminary results of a study using TBI or intravenous Bu to reinforce the high dose Melphalan after a Bz containing regimen as induction therapy in patients with 17p- and/or t(4;14) MM. Between 01/2009 and 08/2010, twenty three patients (7F and 16M, median age 55 years) were treated. At diagnosis, anemia and hypercalcemia and renal failure were noted in 14, 8 and 4 patients, respectively. The median percentage of bone marrow plasma cell was 30% and 10 (43%) had an IgA isotype. One patient had a light chain MM (65g/dl), a plasma cell leukemia was diagnosed in one patient and one patient presented with specific fever and biological inflammatory features. A 17p deletion and t(4;14) translocation were detected, using RQ-PCR and FISH analysis, in 7 and 17 patients, respectively with one patient harboring the two abnormalities. Patients were treated with a median of 3 cycles of the VTD (Bz/Thalidomide/dexamethasone) combination, 12 received a PAD regimen (Bz/doxorubicine/dexamethasone) and 1 had 4 cycles of VD (Bz/ dexamethasone). High dose therapy consisted in Melphalan 140 mg/m2 associated with Bu in 16 patients and TBI in 7 patients. Thirteen patients (4 with 17p- and 9 with t(4;14) had a consolidation with 4 cycles of VTD (n=11) or TD (n=2). Grade >2 mucositis and gastrointestinal toxicity was noted in all patients treated with TBI but Bu was well tolerated. No patient died early from toxicity. One patient had a reactivation of a virus B hepatitis and one patient had a peripheral thrombocytopenia 3 months after HDT. No venous occlusion disease was observed. Overall response rate after high dose therapy (HDT) was 91% (21/23) including 9 VGPR, 6 CR+nCR and 6 PR. Consolidation treatment led to an improvement of response in 4 patients. Nine patients relapsed, including 6 within 6 months after HDT and 3 at 8,9, and 10 months, respectively. At analysis, five patients had died, all because of progressive disease, and 14 patients (10 CR and 4 VGPR) patients were still in first remission. Although a larger number of patients and additional follow up are needed, these data suggest that intensifying high dose therapy regimen is feasible and correctly tolerated in pts with high risk MM, especially using intravenous Busulfan, and may be an interesting approach to improve the current poor prognosis of patients with 17p deletion and/or t(4;14). Disclosures: No relevant conflicts of interest to declare.

Abstract 1802 Schnitzler syndrome is a rare plasma cell disorder which is characterized by the presence of a monoclonal IgM component in association with a chronic urticarial skin rash and at least 2 of the following criteria: fever, joint and/or bone pain, organomegaly (enlarged lymph nodes, spleen and/or liver), increased neutrophil counts and increased ESR. Abnormal bone findings with imaging evidence of osteosclerosis are also frequent. The pathogenesis of this syndrome is unclear and there is no information on bone remodeling and angiogenesis in these patients. To address this issue we studied 13 patients (12M/1F, median age 55 years, range: 39–79 years) with a well characterized Schnitzler syndrome. Patients were diagnosed between 1989 and 2009 and were treated and followed in Hôpital Saint-Louis, Paris (France) and in the University of Athens (Greece). We evaluated the following serum indices of bone remodeling and angiogenesis at diagnosis and after treatment: i) osteoclast regulators [soluble receptor activator of nuclear factor kappa-B ligand (sRANKL) and osteoprotegerin (OPG)]; ii) osteoblast inhibitor dickkopf-1 (Dkk-1); iii) bone resorption marker C-telopeptide of collagen type-1 (CTX); iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin (OC)]; and v) angiogenic cytokines [vascular endothelial growth factor (VEGF), angiogenin (ang), angiopoietin (angp)-1 and -2]. The above molecules were also measured in 24 gender- and age-matched controls. All patients presented with urticaria and monoclonal IgM(kappa) component (median M-peak 0.79 g/dl; range 0.1–2.36 g/dl), while 10 (76%) patients had fever, 9 (69%) had joint and/or bone pain, 5 (38%) had lymphadenopathy and 2 (15%) had splenomegaly. Four patients had documented sclerotic bone lesions in plain X-rays. A technetium bone scintigraphy was performed in 11 patients; all of them had high uptake in at least one site. At diagnosis, 11/13 patients received various symptomatic therapies, including low dose corticosteroids that were ineffective. Two patients at diagnosis and 6 after initial symptomatic therapy were treated with the quinolone antibiotic pefloxacin, while 7 patients were treated with the interleukin-1 inhibitor anakinra (including 3 previously treated by pefloxacine) usually with a complete and sustained efficacy on clinical manifestations of the disease. In a median follow up time of 10 years (range 1–20 years), 3 patients developed overt Waldenström macroglobulinemia (WM) at 5, 7 and 20 years post diagnosis. At diagnosis patients had increased serum levels of bALP (mean±SD: 36.5±15.0 IU/L vs. 26.8±7.1 IU/L; p=0.049), osteocalcin (20.5±18.6 ng/ml vs. 7.4±3.5 ng/ml; p At diagnosis, patients had also elevated VEGF (809±598 pg/ml vs. 263±257 pg/ml; p=0.001) and ang (221±96 ng/ml vs. 169±33; p=0.013) and decreased angp-1 (18.7±9.1 ng/ml vs. 25.4±10.9 ng/ml; p=0.048) and angp-1/angp-2 ratio (13.9±8.7 vs. 63.4±102.1; p=0.005). Patients presenting with fever had reduced angp-1 levels (14.8±5.2 ng/ml) compared to others (32.7±10.3 ng/ml; p=0.03). Interestingly, patients who progressed to WM had also decreased levels of angp-1 (10.2±7.5 ng/ml) compared to others (21.2±8.2 ng/ml; p=0.04) and angp-1/angp-2 ratio (5.3±4.6 vs. 16.5±8.0; p=0.04), suggesting that low angp-1/angp-2 ratio at diagnosis, which reflects increased angiogenesis, may indicate a predisposition for evolution of the gammopathy towards an overt WM. After successful treatment, VEGF levels decreased (387±207 pg/ml) compared to baseline (770±456 pg/ml; p=0.04). In conclusion our analysis shows increased serum levels of angiogenic cytokines in Schnitzler syndrome and documents enhanced bone formation which appears not to be balanced by a comparable increase in bone resorption; this result may explain the presence of sclerotic bone lesions in this entity. Successful therapy with either anakinra or pefloxacin is associated with reduction of the major angiogenic cytokine VEGF. Disclosures: No relevant conflicts of interest to declare.

Abstract 3872 Poster Board III-808 Introduction POEMS syndrome is a rare disease characterized by peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cells, skin changes, papilledema, volume overload, sclerotic bone lesions, thrombocytosis, and high serum VEGF level. Efficient treatments consist in irradiation for patients with localized solitary plasmocytoma and high-dose chemotherapy with autologous stem cell transplantation for appropriate candidates without a focal lesion. Conventional myeloma chemotherapy can only control the disease in a limited number of patients. Results of monoclonal anti-VEGF antibodies, which seem to be attractive due to the role of VEGF in this disease, are controversy with efficacy in 3 patients but treatment related deaths in 2 other patients. Thalidomide effectiveness has been reported in Japanese patients but enthusiasm for its use is tempered by the high incidence of thalidomide-induced peripheral neuropathy. Lenalidomide, which efficacy has been described in one observation (Dispenzieri, Blood 2007 110: 1075-1076), has the advantage of being anti-angiogenic, cytotoxic to malignant plasma cells and with a much lower risk of peripheral neuropathy. We reported here a multicentric French experience with this drug in POEMS syndrome. Patients and Methods There were 3 women and 6 men treated with Lenalidomide in 7 French centres. Median age was 60 (41-76). All patients had sensitive polyneuropathy with motor deficiency in 5 patients. A monoclonal component was present in all cases (IgA lambda in 7 patients, IgG lambda and lambda light chain only in 1 patient each). Other manifestations of POEMS syndrome included sclerotic bone lesions in 6 patients, endocrinopathies in 7 patients, skin changes in 8 patients, oedema in 7 patients, organomegaly in 5 patients, papilledema in 5 patients, thrombocytosis in 3 patients. VEGF serum level was elevated in 4 among 5 patients with a dosage. Previous treatments were high-dose chemotherapy with autologous stem cell transplantation in 3 patients, Melphalan-Prednisone in 3 patients because of advanced age, and prolonged steroid treatment in 2 patients. One patient received Lenalidomide as primary treatment before high-dose therapy. Lenalidomide was given during 21 days each month and sequentially associated with dexamethasone, 5 patients received 25 mg/day and 4 patients received 10 or 15 mg, for a median of 5 cycles (1 to 11). Results Serious side effects were noted in 3 patients with 2 hematologic toxicities (grade III and IV) and a cutaneous allergy. Six patients could be evaluated for hematologic response and all responded, complete response in 3 patients and partial in 3 (>25%). Clinical responses occurred early, before 3 months of treatment, in 6 cases among 8 (1 patient is not yet evaluable), with a marked improvement in performance and in neurological syndrome. Other manifestations of POEMS syndrome improved, especially oedema in 5 cases among 6. VEGF level (normal value < 500 pg/ml) could be serially measured in 4 patients with a normalization in 1 patient and a significant decrease in 3 patients, median 7100 pg/ml (2100-10100) before treatment to 887 pg/ml (304-3270). In 1 of these 3 patients VEGF level increased to initial value while he was still taking Lenalidomide. A second patient experimented a relapse 5 months after ending Lenalidomide, he is still in good response after Lenalidomide reintroduction. With a median follow-up of 12 months (1-26) all patients are alive. Conclusion Lenalidomide seems to be a very promising therapy in POEMS syndrome. It should be tested in larger studies in patients with a systemic disease, who are not able to receive high dose therapy, in relapsing patients and before high dose treatment to avoid transplant related morbidity, particularly engraftment syndrome. Disclosures: Jaccard: Celgene: Membership on an entity's Board of Directors or advisory committees. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees and Speakers Bureau. Moreau:Celgene: Membership on an entity's Board of Directors or advisory committees. Fermand:Celgene: Speakers Bureau.

Abstract 3883 Poster Board III-819 Treatment of peripheral neuropathies (PN) related to IgM monoclonal (MIgM) gammopathy with anti Myelin-Associated-Glycoprotein (MAG) antibodies remains unsatisfactory. Reducing the serum level of the MIgM is likely to be a reasonable goal because of its auto-antibody activity against antigens expressed on peripheral nerve and because of various data, including studies of MIgM and complement deposition along nerve fibers and transfer experiments in animals, which argue in favour of a causal link between the MIgM and the nerve lesions. Rituximab (R) in combination with Fludarabine (F) and/or alkylating agents is considered as a highly effective regimen for achieving excellent remission in Waldenström's macroglobulinemia. It has been poorly evaluated in MIgM anti-MAG antibody-related PN. We retrospectively studied a cohort of 15 patients (pts) who were treated with such association or with R alone. Median age at diagnosis was 64 years (range, 47-84). 13/15 pts had MIgM with kappa-light-chain. All pts had sensory symptoms including 9 with ataxia, and 3 presented with disabling motor involvement. Median INCAT (Inflammatory Neuropathy Course and Treatment) disability score was 4 (range, 2-12). Median MIgM level was 5.9 g/l (range: 1.8-28). In 2 pts, it was not detectable by serum electrophoresis (SEP) but only by serum immunofixation (SIF). No pt had evidence for an associated overt lymphoid proliferation. Anti-MAG antibodies were assessed by immuno-blot and ELISA techniques. Electrophysiologic evaluation showed a demyelinating, axonal or mixed neuropathy in 8, 2 and 5 pts, respectively. Nine pts had been previously treated (7 with alkylating agents alone and 2 with intravenous immunoglobulin infusions) and none had experienced any clinical or biological improvement. Median interval time between PN diagnosis and treatment with R +/- chemotherapy was 25.6 months (range, 1-159). Twelve pts received a combination of R + chemotherapy (7 R + F + Cyclophosphamide (C), 4 R + C or chlorambucil, 1 R + F) and 3 received R alone. Significant and durable clinical improvement (including INCAT disability score) occurred in 7 pts, all treated with R + chemotherapy. Among these responders, 5 had a major reduction (>90%) of the serum MIgM level (including 3 with disappearance of monoclonal component on SEP but not on SIF). On the opposite, neither clinical response nor INCAT disability score improvement was observed in any pt treated with R alone. Electromyography significantly improved in 3 of the 9 evaluable pts, all of whom with concomitant major reduction on the MIgM serum level while on R + chemotherapy. Seven pts experienced drug-induced cytopenias including 4 grade III-IV neutropenia and 1 grade III thrombopenia. Treatment-related infections occurred in 3 pts (2 herpes zoster, 1 cytomegalovirus retinitis). One pt developed parotid adenocarcinoma one year after completion of R+F+C therapy. One pt died from cardiac arrest during a surgical procedure for lithiasic cholecystitis. In conclusion, combination of R, F and alkylating agents in MIgM anti-MAG antibodies-related PN provides high rates of durable clinical improvement, even in first-line refractory pts. Response is most often correlated with significant reduction of the MIgM serum level but does not need its disappearance. R + chemotherapy toxicity is acceptable but adding F implies immunosuppressive consequences that should be carefully evaluated. Although this remains to be formally demonstrated, R + chemotherapy seems to be more effective than R alone. Disclosures: No relevant conflicts of interest to declare.

Abstract 3408 Poster Board III-296 The t(4;14)(p16.3;q32), leading to the ectopic expression of two potential oncogenes, the Multiple Myeloma Set Gene (MMSET) and the Fibroblast Growth Factor 3 (FGFR3), is found in 15% of patients with multiple myeloma (MM) and is associated with a very poor prognosis. We previously shown in patients under 65 years of age that High Dose Therapy followed by Peripheral Blood Stem Cell Transplantation (HDT-PBSCT) provides a high response rate (RR) but a very short median relapse-free survival of only 11 months. In addition, relapses are often aggressive and chemoresistant. Thus, more effective regimen is urgently needed. We prospectively studied 23 t(4;14) MM patients treated with 3 or 4 cycles of a combination of Bortezomib and Dexamethasone (VD) (n=4) or of Bortezomib, Adriamycine and Dexamethasone (PAD) (n=19) as induction treatment before HDT-PBSCT (Melphalan 200 mg/m2). T(4;14) was detected using real time quantitative PCR searching for IGH/MMSET and FGFR3 transcripts. RR, event-free survival (EFS) and overall survival (OS) were evaluated. Median age at diagnosis was 51 years (range, 33-64). Isotype was IgA in 12 (52%) patients. All patients had stage II or III MM. An elevated serum β2m level (>3.5 mg/L) was found in 14 (61%) patients, and a low haemoglobin (Hb) level ( Disclosures: No relevant conflicts of interest to declare.

Despite recent advances in the treatment including Autologous Stem Cell Transplantation (A-PBSCT) and new drugs, Multiple Myeloma (MM) is still an incurable disease and the outcome of relapsing patients is still extremely grim. The use of conventional allogeneic hematopoietic SCT is limited by a high transplantation-related mortality (TRM). Allografting with nonmyeloablative conditioning (NMA-C) has therefore been considered to improve survival. We retrospectively studied a series of 23 consecutive patients with relapsing MM who underwent allogeneic transplantation after NMA-C and compared their outcome with those of patients who relapsed but were not allografted. Owing to these non-randomized available data, there was a need to correct for potential recruitment bias. The propensity score (PS) methodology allows coping with the presence of such a bias (Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika1983;70:41–55). The idea was to model, for each patient with MM alive at 6 months after relapse, the probability of receiving NMA-C transplantation, according to a set of baseline characteristics (namely, baseline age, serum beta2 microglobulin level (b2M), and time to progression (TTP) after the first A-PBSCT). This PS was estimated using logistic regression. It was then used to match 1:1 patients with similar propensity to receive allograft, based on nearest neighbor matching using calipers of width 0.2. Data of patients treated in the MAG-95 and MAG-2002 trials were used. Standardized differences in covariates between subjects in the matched sample were computed, with imbalances tested by paired t tests. A random effects model was finally fitted in order to account for the matched nature of the data. 23 patients with MM in first (n=21) or second (n=2) relapse were treated with high dose therapy (melphalan 200 mg/m2 followed by A-PBSCT) preceding allogeneic PBSCT with a 2 Gy TBI NMA-C. Donors were HLA-identical siblings in 13 (56 %) patients. Six patients (26%) had a high b2M (>3 mg/L). Median age at allograft was 50 years (29–59 years). Median follow-up after allograft was 27.4 months (1.8–61.8 months). Post-allograft response was CR in 9 patients, VGPR in 8, PR in 4 and progressive disease (PD) in 2. TRM at one year was 13 % (1 severe GvHD, 2 infections). Two patients died from PD at 2 and 9 months after allograft respectively. Acute GvHD occurred in 19 patients (15 grade I/II, 4 grade III/ IV) and 11 developed chronic GvHD. Among the 10 patients (41.6%) who relapsed with a median of 10,7 months, 6 are alive with a median survival of 38.3 months. So far, 8 patients (34,7%) including 5 in CR and 3 in VGPR are still alive without relapse with a median follow-up of 36.8 months. From the 23 allografted patients, 21 matched pairs were successfully constituted. Expectedly, the distribution of age (mean difference: −0.97, p= 0.54), b2M (p=1.00), and TTP (mean difference: 3.2 months, p= 0.37) were not different between treated by allograft and untreated subjects. Based on these matched pairs, the estimated hazard ratio of death was 0.35 (95% confidence interval: 0.14–0.88, p=0.027) for allografted patients compared with non allografted. In conclusion, the PS is a useful tool for the analysis of observational data. Applied to MM data, it suggests that NMA-C allograft in MM patients in first relapse provides a high and durable response rate with a low TRM. These promising results must be further evaluated in clinical trials.

The t(4;14)(p16.3;q32) leads to the ectopic expression of two oncogenes, the Multiple Myeloma Set Gene (MMSET) and the Fibroblast Growth Factor 3 (FGFR3). It is found in 15% of patients with multiple myeloma (MM) and indicates a poor prognosis. To identify the clinico-biological features associated with this adverse prognosis, we prospectively studied a series of 79 patients with t(4;14) MM.Between March 2002 and July 2007, a t(4;14) was detected by real time quantitative PCR of the IGH/MMSET and FGFR3 transcripts in 79 patients. The clinico-biological data were analysed at diagnosis and at relapse. Response rate and time to progression (TTP) after successive lines of chemotherapy, and overall survival (OS), according to beta2m and haemoglobin level, and expression of FGFR3, were evaluated. Among the 79 patients (median age:55 years), 18 (22.8%) had a MGUS or smouldering myeloma and 61 (77.2%) had a symptomatic MM. At diagnosis, no clinical or radiological feature was significantly associated. As expected, 15 patients (18%) had a t(4;14) without expression of FGFR3. IgA isotype was found in 41% and del(13) in 90% of patients. Contrasting with previous studies, only 52% of symptomatic MM had elevated beta2m (>3mg/L). Fourty-two patients (53.1%) received autologous stem cell transplantation (ASCT). In those, the overall response (OR) was 90%. Among those responders, 16% had a complete response (CR) and 53% had a very good partial response (VGPR). Median TTP after ASCT was only 12 months. At relapse, aggressive features (plasmocytoma, cytopenias, acute renal failure, circulating plasma cells) were observed in 23% of cases. After 2nd line chemotherapy, response rate was only 49% and TTP was 6.4 months. Noteworthy, there was a trend toward a better TTP in patients treated with bortezomib as compared to thalidomide in 2nd line therapy (p=0.06). Median OS after ASCT was 31 months, independently of FGFR3 expression and isotype. OS was not significantly different in patients with and without high beta2m (>3mg/L) or low hemoglobin (

Adult-acquired Fanconi syndrome (FS) is a rare complication of monoclonal gammopathy. It is characterized by urinary leak of phosphorus, uric acid and glucose. We retrospectively reviewed 21 patients diagnosed with adult-acquired FS between 1988 and 2012 in seven French centers.At diagnosis most patients had smoldering multiple myeloma (47%) or monoclonal gammopathy of undetermined significance (28%). They were usually referred for osteomalacia (30%) or chronic renal failure (55%). Every patient had tubular dysfunction and median creatinine level was 141 μmol/L (range 94-298). 19/21 patients had a renal biopsy performed, 40% showing characteristic crystal inclusions.18 patients received chemotherapy. The main indication for treatment was renal preservation. High dose melphalan followed by autologous stem cell transplantation was administrated in nine cases, without major complications. Six patients received bortezomib based therapy, with frequent grade III neuropathy. Imids were usually second line treatment, with acceptable safety and efficiency. Hematological response to treatment was satisfying. Six patients (33%) had an improvement of tubular disorder; every patient had a stabilization of creatinine level until free light chain (FLC) elevation.In conclusion, chemotherapy treatment may be proposed to patients with Fanconi syndrome if they are fit with a prolonged life expectancy. Benefice on renal function is probably better in case of early treatment.; Le syndrome de Fanconi est une complication rare des gammapathies monoclonales, caractérisée par une dysfonction tubulaire proximale généralisée. Nous avons revu 21 patients suivis entre 1988 et 2012 dans 7 centres français. Au diagnostic la plupart des patients présente un myélome multiple de faible masse tumorale (47%) ou une gammapathie monoclonale de signification indéterminée (28%). Ils consultent pour ostéomalacie (30%) ou insuffisance rénale chronique (55%). Tous les patients ont une dysfonction tubulaire avec une hypophosphorémie associée à une hypouricémie, la créatinémie médiane est de 141 µmol/L (de 94 à 298 µmol/L). 19/21 patients ont eu une biopsie rénale, avec des inclusions cristallines dans le cytoplasme des cellules tubulaires dans 40% des cas. Des cristaux intra-histiocytaires évoquant le diagnostic d’histiocytoses cristallines ont été vus chez cinq patients.18 patients ont eu une chimiothérapie, majoritairement afin de préserver la fonction rénale. 9 patients ont reçu du melphalan à haute dose sans complications majeures. Six patients ont reçu un traitement à base de bortezomib, avec de fréquentes neuropathies de grade III conduisant à l’arrêt du traitement. Les IMIDs sont généralement des traitements de seconde ligne, avec une tolérance acceptable et une bonne efficacité.La réponse hématologique globale est satisfaisante. Les paramètres tubulaires s’améliorent chez 6 patients (33%) et dans tous les cas la créatinémie se stabilise jusqu’à ce que le taux de chaînes légères libre remonte.En conclusion, la chimiothérapie peut être proposée en ciblant l’hémopathie sous jacente. La récupération rénale est meilleure dans le cas d'un traitement précoce.