ALBERT

Description: Management of immune thrombocytopenia (ITP) during pregnancy can be challenging since treatment choices are limited. Thrombopoietin receptor agonists (Tpo-RAs), which likely cross the placenta, are not recommended during pregnancy. To better assess safety and efficacy of off-label use of Tpo-RA during pregnancy, a multicenter observational and retrospective study was set up. Results from 15 pregnant women with ITP (17 pregnancies and 18 neonates) treated with either eltrombopag (N=8) or romiplostim (n=7) during pregnancy, including 2 patients with secondary ITP, were analyzed. Median time of Tpo-RA exposure during pregnancy was 4.4 weeks [range: 1-39 weeks]; the indication for starting Tpo-RA was preparation for delivery in 10/17 (58%) pregnancies whereas 4 had chronic refractory symptomatic ITP and 3 were on eltrombopag when the pregnancy started. Regarding safety, neither thromboembolic events among mothers nor Tpo-RA-related fetal or neonatal complications were observed except for one case of neonatal thrombocytosis. Response to Tpo-RA was achieved in 77% of cases, mostly in combination (70% of responders) with concomitant ITP therapy. Based on these preliminary findings, temporary off-label use of a Tpo-RA for severe and/or refractory ITP during pregnancy seems safe for both mother and neonate and likely to be helpful especially prior to delivery.

Description: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal disorder of hematopoietic stem cells with 2 major presentations: Classic PNH with hemolysis and aplastic anemia (AA) / PNH syndrome with marrow failure. PNH is associated with an increase incidence of thrombosis, which represent the most common cause of death. We address the thrombosis history of 460 PNH patients, diagnosed over a 55-year period (1950–2005), in France. Fifty eight hematological centers were contacted through the French Society of Hematology and/or the French Association of Young Hematologists. Patients who underwent transplantation were censored at that time. Sites and cumulative incidence of thrombotic events, as well as risk factors for thrombosis, were analyzed. The median (±SE) follow-up and survival times were 6.8 (±0.5) and 22 (±2.5) years, respectively. At time of diagnosis, 33 patients had thrombosis (7.2%) with 16 Budd Chiari (BC). During evolution, 145 episodes of deep-vein thrombosis occurred in 116 patients among the 454 assessable patients. Forty nine patients (43%) developed a BC syndrome, 35 patients (31%) presented a thrombosis of the central nervous system (CNS), 31 patients (27%) were diagnosed with limbs thrombosis and 29 patients presented thrombosis in other sites. The 10-years cumulative incidence was 31% (Interquartile range IQR: 25%–36%) in the global population, 38% in the 112 patients with Classic PNH and 28% in the 222 patients with (AA) / PNH syndrome. The median time from diagnosis to first thrombosis was 2.3 years (IQR 1.1 to 6.5). Through multivariate analysis, development of thrombosis was related to poor survival in the global population, as well as in each PNH subcategories (p

Description: PNH is a rare acquired disorder. We aimed to analyze a large cohort of patients on the long term to better determine prognostic factors. We already reported the analysis on 220 patients in 1996 (Socié et al, Lancet). Data were updated and we collected additional data on 247 patients (total of 467 patients, 252 female), diagnosed from 1950 to 2005 from 58 centers. The date of diagnosis was based on flow cytometry analysis if there was no prior positive Ham’s test. The age at diagnosis was 34 years (±17.3). The median follow-up time was 6.8 years (±0.5). Kaplan-Meier 10-year survival estimate was 76.3% (± 2.6). Sixty seven (14.6%) patients developed pancytopenia during follow-up [10-year cumulative incidence (CIn) rate of 18.3% (14% – 22%)]. Deep-vein thrombosis occurred in 108 patients (23.5%) [10-year CIn 28% (23% – 33.1%)]. Nineteen patients developed myelodysplastic syndrome (MDS) [10-year CIn 4.6% (2.4% to 6.8%)]. Eight patients developed acute leukemia [10-year CIn 2.3% (0.4% to 3.9%)]. The following factors were related to poor survival: Older age at diagnosis; age between 40 and 55 years [relative risk RR=2.4 (95% CI 1.4–4.1); p value

Description: Outcomes in the treatment of sclerodermatous chronic graft-versus-host disease (cGVHD) are generally disappointing. Imatinib mesylate enables selective, dual inhibition of the transforming growth factor beta (TGFβ) and platelet-derived growth factor (PDGF) pathways. Recently, the drug’s effects on fibroblasts have been reported in both in vitro and in vivo studies. Inhibiting fibroblast growth (and thus decreasing collagen production in dermal fibroblasts) is thus a logical therapeutic approach. Here, we report on our experience with 12 patients who received imatinib mesylate for refractory sclerodermatous cGVHD following allogeneic stem cell transplantation (allo-SCT). The patients’ characteristics were as follows: median age, 35 years (range: 15–59); 7 male recipients, 6 female donors; 4 cases of CML, 4 MDS, 2 ALL and 2 Hodgkin’s lymphoma. The patients had received either myelo-ablative conditioning with standard GVHD prophylaxis based on cyclosporine and short-course MTX (n=9) or nonmyelo-ablative conditioning with cyclosporine and MMF. Seven patients received a marrow graft and 5 received a peripheral blood graft. All displayed refractory, chronic, sclerodermatous GHVD with at least 3 lines (range 3–6) of prior immunosuppressive therapy. The modified Rodnan skin score was used to assess the extent of skin damage. Glivec was initiated at a dose of 400 mg/day between 16 and 119 months post-transplantation (median: 44). Despite an imatinib dose reduction and the administration of various symptomatic treatments, 4 patients (33%) had to discontinue their treatment soon after its initiation (range: 16–64 days) because of intolerance (especially muscle cramps) and were not evaluable in terms of the efficacy criterion. Other side effects reported were parenthesis, diarrhea and edema. In the remaining patients, the scleroderma symptoms improved within three months of treatment initiation. At the time of this report, all patients were alive and those who tolerated imatinib mesylate have experienced a complete or near-complete response (n=4) or partial response (n=4). All responders (except for one who discontinued the drug 157 days after initiation, due to cramps) were still on the treatment, after a median time period of 216 days (range: 80–2053). This retrospective report shows that when imatinib mesylate is well tolerated, it is effective in patients with refractory sclerodermatous cGVHD and is thus a promising candidate for the treatment of this complication. This study should provide useful background information for building prospective, multicenter studies.

Description: Background Everolimus is an orally bioavailable mTORC inhibitor that has cytostatic activity in lymphoma in vitroand has shown single agent activity in aggressive B-cell lymphomas and Hodgkin’s lymphomas. The combination of everolimus and rituximab has also been recently explored in aggressive CD20+ DLBCL lymphomas with an ORR of bout 40%. The current study investigates the combination of everolimus and rituximab as a treatment for relapsed or refractory indolent lymphoma or transformed indolent CD20+lymphomas. Methods Lymphoma patients were assigned to sequential cohorts of oral dose of RAD001 (5 mg per day, 5 mg every other day), and R, 375 mg/m2 every week (4W) followed by one infusion of R every 2 months. The primary objective was the determination of the maximum tolerated dose (MTD) and the recommended dose (RD) for RAD001/R. Secondary objectives included characterization of safety profile, pharmacokinetics (PK) and anti-tumor activity of RAD001/R. Results 21 patients were included and 20 patients treated (men: 11; women: 10 and median age of 72 (r: 51- 86). Histologies: FL: 8, MCL: 5, MZL: 4, transformed indolent lymphoma: 3, SLL: 1. The MTD was 5 mg/day of RAD001 and R 375mg/m2, as 2/6 patients experienced dose limiting toxicities (DLTs) [grade (G) 4 febrile neutropenia, one G 3 atrial fibrillation]. The RD was RAD001 5 mg every other day with R 375 mg/m2, with no patients experiencing DLTs. 6 pts were treated at the 5 mg every other day without DLT and 7 pts were treated at the same dose in an expansion cohort. Out of the 21 pts included, 2 pts planned at 5 mg every other day were not evaluable due to rapid progression before therapy in one case and at C1 day16 for one case. One pt is not evaluable (ongoing treatment before cycle 3 day1) and 2 pts had a DLT. 16 pts received 2 cycles and were evaluable for response. 6 achieved a response (5 PR and 1Cru), 6 had stable disease and 4 were progressive. As per 06-13, 5 patients are still ongoing in study with 2 pts showing a partial response and a CRu and 3 patients showing stable disease. 9 pts discontinued the treatment due to progression of disease, and 2 patients due to treatment-emergent adverse events: anorexia and pulmonary toxicity at C3 day 8 and C2day 28 respectively. One pt stopped therapy due to a pulmonary infection not related to treatment during cycle 6. Preliminary PK analysis showed a large variability of RAD001 exposure between pts. Preliminary PD analysis confirmed target engagement (S6K) in 5/7 evaluable pts and showed s6K inhibition of phosphorylation at 4 hours post dosing in peripheral blood mononuclear cells stimulated with GM-CSF. Conclusion Preliminary results indicate that the combination of RAD001/R may be effective for the treatment of relapsed or refractory indolent lymphomas or transformed indolent lymphomas and has an acceptable safety profile. Disclosures: Ribrag: Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Bayer: Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Johnson & Johnson: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Off Label Use: The abstract shows scientific information on SAR3419 which is an investigational product developed by Sanofi. This investigational product is not approved by any health authority for any indication. Karlin:Celgene: Expert board Other, Honoraria; Janssen: Honoraria. Morschhauser:novartis: Honoraria, Research Funding. Tilly:Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria; Janssen: Honoraria; Amgen: Research Funding. Coiffier:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Roche: Membership on an entity’s Board of Directors or advisory committees.

Description: BACKGROUND: Few therapeutic options are currently available for patients (pts) with severe aplastic anemia (SAA) refractory to antithymocyte globulin (ATG) plus ciclosporine (CsA) and not eligible for allogeneic stem cell transplantation. It has recently been reported that eltrombopag (ELT), a TPO receptor agonist, is efficient to improve tri-lineage blood counts in this setting. However, real-life use of this drug is still largely unknown. In pts with SAA refractory to ATG, physicians can accede to ELT in France through a compassionate use program. We took advantage of this program to assess the efficacy and safety of ELT in SAA pts. PATIENTS AND METHODS: The French National Reference Center for Aplastic Anemia conducted this study in pts who received ELT for the treatment of SAA. Latest guidelines were used to define disease severity, treatment indication, and response rates (Marsh et al, BJH 2014). The diagnosis of SAA was confirmed by marrow biopsy and Camita criteria for all pts. Pts were eligible if they received at least 2 months of ELT alone or in combination with other treatment in case of relapsed/refractory disease or front-line therapy for pts not eligible to the association of ATG and CsA. Pts were identified through a national e-mailing on behalf of the French reference center for SAA and the French Society of Hematology. All data presented here were collected at the reference date of June 26th, 2016. The study was conducted according to Helsinki's Declaration. RESULTS: Forty-six pts (male, 54%) who received ELT between July 2012 and February 2016 were identified in 17 French centers. Indications for ELT were relapsed/refractory SAA in 35 pts (76%) after 1 (49%), 2 (29%) or 3 (9%) courses of CsA+ATG. Eleven pts considered unfit for ATG also received the drug as first line therapy. The characteristics of the pts according to ELT indications are shown in Table 1. Median age at time of ELT initiation was 61 years [IQR 40 to 70]. 44 pts had idiopathic SAA including 17 (37%) with a detectable PNH clone (median size 7%). Two pts (4%) with dyskeratosis congenita also received ELT. ELT was introduced 17 months [8-50] after the initial diagnosis of SAA and with a median of 6 months [3-14] after the last course of immunosuppressive therapy. The maximal dose was 150 mg/day [100-150] for a median duration time of 6 months [4-12]. At last follow-up 22(48%) pts were still on treatment, 4(9%) pts stopped because of good hematological response, 1(2%) and 15(33%) after limited toxicity and failure to improve hematological status. Before treatment, median neutrophils count was 790/mm3 [500-1215] and pts received a median number of 4 red blood cells packs [2-4] and 3 platelets apheresis units [2-4] every month. Neutrophils counts were 765 [515-1475], 1100 [600-1800], 1200 [670-1915] and 1200/mm3 [757-2300] at 1, 3, 6 months and at last follow-up respectively. The rates of transfusion independence for both red cells and platelets were 7%, 33%, 46% and 46% at 1, 3, 6 months and at last follow-up. In pts achieving transfusion independence, hemoglobin and platelets level improved of 3 gr/dL [1.4, 4.5] and 42 G/L [11, 100], respectively. The rate of transfusion independence was not different among first line and refractory pts (p=0,5). We did not observe any response in the 2 patients with dyskeratosis congenita. No factor associated with hematological response to ELT was identified. Liver toxicity (cytolysis) occurred in 11 pts (1 grade 3 that required withdrawal of the treatment and 10 grade 1 who responded to dose reduction). 2 pts had a grade 2 intestinal toxicity which improved after dose reduction. Other side effects where related to SAA (28% infections, 13% hemorrhages). Bone marrow karyotype analysis after ELT was done in twelve pts (26%) (median time 14 months [5-22] after ELT start). In 10 pts the karyotype was normal, in one, trisomy 8 was identified (already seen at SAA diagnosis), and karyotype was a failure in 1 pt. CONCLUSION: We report here the first real-life multicenter study about the use of ELT in SAA. In a particular severe pts population with no other treatment possibility, we confirm a 40% rate of hematological improvement with transfusion independence. Some of the pts who were not eligible to ATG plus CsA (comorbidities) also received ELT first line with similar response rates. Elderly pts unfit for ATG may thus benefit from this treatment which at the best should be given through prospective clinical trials. Table 1 Table 1. Disclosures Ades: Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Terriou:Novartis: Consultancy; amgen: Consultancy. Peffault de Latour:Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

Description: Abstract 2726 Background. There is a need for improving conditioning regimens in poor risk Non Hodgkin Lymphoma (NHL) patients (pts) eligible for autologous stem cell transplantation (ASCT). Incorporating radioimmunotherapy in the conditioning is an option. Bexxar-BEAM does not appear to be superior to BEAM in relapsed Diffuse Large B –cell lymphoma (DLBCL). The benefic risk ratio of 90-yttrium ibritumomab tiuxetan (Zevalin) BEAM remains to be established. Aims and methods. We analyzed retrospectively the efficacy and the toxicity of Zevalin combined with BEAM chemotherapy (Z-BEAM) compared with BEAM alone followed by ASCT. From January 2000 to November 2004 (BEAM group) and from June 2005 to December 2011 (Z-BEAM group), 55 and 68 pts respectively were treated in 6 French centers (male n=78, female n=45). Zevalin was administered on day-14 prior to ASCT with standard dose of 0.4 mci/kg (n=32) or 0.3 mci/kg (n=36) chosen according to bone marrow reserve. The efficacy and toxicity were compared between the two groups. Results. The study included 123 pts (median age: 53 years old; range 21–69) with different histological subtypes (58 DLBCL, 19 Mantle cell lymphomas, 37 follicular lymphoma, 3 marginal zone lymphoma, 4 MALT lymphoma and 2 B-lymphocytic lymphoma). Fifty-four pts were treated in first line (20 in the Z-BEAM group and 34 in the BEAM group) and 69 pts in second line (Z-BEAM, n=48; BEAM, n=21). The median time to platelets engraftment (〉20000/mm3) was 9 days and 10 days in the Z-BEAM and BEAM group respectively (p=0.334), and the median time to neutrophil engraftment (〉500/mm3) was 11 days and 12 days respectively (P=0.117). Grade 3/4 infectious events were more frequent in the Z-BEAM group (80.9%) than in the BEAM group (56.4%), p=0.0001. Grade 3/4 mucositis were observed in 42.6% in the Z-BEAM group Vs 12.7% in the BEAM group (p60 y.o), histological subtype, first line treatment Vs second line, or IPI (0–1 Vs 2–3). In a subset analysis of the Z-BEAM group, female gender was associated with worse outcome; 3 years-OS was 69% (95%CI, 48–85%) in female and 93% (95%CI, 79–98%) in male (p=0.042); 3 years-PFS was 54% (95%CI, 34–73%) in female and 81% (95%CI, 65–91%) in male (p=0.032). Those results may be linked to a higher TRM, 23.1% Vs 0% (P=0.002), more respiratory complications 23.1% Vs 4.8 % ( P=0.047) and more admissions to intensive care unit 46,1% Vs 2 % (P〈 0.0001) in female than in male group respectively. Conclusions. Z-BEAM is possibly as effective as BEAM alone as a conditioning regimen for ASCT with an increased toxicity. Surprisingly, our series report for the first time an increased toxicity and TRM in female. A longer follow up is needed to asses this results. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Autologous Hematopoietic Stem Cell transplantation (AHSCT) is used since 1994 worldwide to treat severe autoimmune disease (AD) refractory to standard therapy. Despite early release and regular update of the European Society for Blood and Marrow Transplantation (EBMT) practice guidelines (Snowden JA et al BMT 2012, Alexander T et al BMT 2014) along with 3 randomised Clinical trials (CTs) for Systemic Sclerosis (SSc) ASTIS, Crohn's Disease (CD) ASTIC and Multiple sclerosis (MS) ASTIMS, the uptake of this approach varies according to each ADs and between countries. We therefore design this retrospective study to evaluate patients (pts) outcomes as reported to the French Bone Marrow Transplantation Society registry (SFGMT-TC) in light of the other States activity published or reported to the EBMTregistry. Materials and methods All AHSCT for adult AD pts (〉 18 years (yrs)) reported in France from 1997 to 2013 with at least one yr follow-up after AHSCT were included in the study. Primary data were derived from the EBMT registry (MED-A/B forms) with additional data obtained through a specific questionnaire (MED-C) for the study. Primary end point is overall survival (OS), defined as time since the day of transplant to death, irrespective of the cause. Secondary end points are Progression Free Survival (PFS), 100 day treatment related mortality (100-day TRM) and non-relapse related mortality (NRM). The probabilities were estimated using the Kaplan-Meier estimator for OS and PFS, cumulative incidence for NRM, relapse/progression being the competing event. All tests were two-sided. Statistical analyses were performed with IBM SPSS Statistics 22.0 and R version 3.1.2 (R Development Core Team, Vienna, Austria) software packages. Results 96 adult pts (55% Female), median age 45 yrs [20-71], underwent a first AHSCT for ADs in 19 HSCT Units. Most of the ADs were rheumatological(72%) with 55 SSc, 7 polymyositis-dermatomyositis, 3 polychondritis, 2 Lupus Erythematosus, 1 Rheumatoid Arthritis (RA), 1 Ankylosing Spondylitis, or neurological (15%) with 14 MS, whereas the others were 5 CDs, 5 immune thrombocytopenic purpura, 1 hemolytic autoimmune anemia, 1 IgM neuropathy and 1 POEMS syndrome. Two pts had 2 simultaneous ADs (1 SSc and RA, 1 CD and RA). Median duration between AD diagnosis and AHSCT was 3.5 yrs [1-33]. With a median follow-up of 7 yrs [

Description: Background. Bortezomib has improved overall survival (OS) in light chain (AL) amyloidosis; however, data on its activity in severe cardiac AL are sparse. Furthermore, the impact of the safety profile of Bortezomib on overall survival in severe cardiac AL amyloidosis remains unknown given the fragile population. We sought to outline the activity and safety profile of Bortezomib in severe cardiac AL amyloidosis. Methods. Twenty-seven patients diagnosed with AL amyloidosis and treated with Bortezomib were included, mean age was 63 years (36-85), with a sex ratio of 18/9. Eighteen patients had cardiac involvement, among which all had Mayo-Clinic stage III staging but 3, and 9 had kidney involvement only. Seventy percent of patients received Bortezomib as a 1st-line therapy, once (19%) or twice weekly (81%), given IV at the starting dose of 1.3g/m2 in combination to Dexamethasone. Thirteen (48%) patients also received an alkylating agent. Results. Overall hematological response rate was 75% in patients who received at least 1 cycle of Bortezomib, and 83% and 62.5% in patients with and without cardiac involvement, respectively. Complete response was obtained in 45%, and 42% and 50% in the 2 groups, respectively. 44% patients with cardiac involvement had an organ response. An hematological toxicity occurred in 26% of patients, similarly in the 2 groups, consisting mainly of thrombocytopenia with no need for treatment modification. Non-hematological toxicity (grade ≥2) rate was 62% in patients with cardiac involvement and 38% in patients with kidney involvement (p=ns), consisting mostly of fatigue, peripheral neuropathy, infection and gastro-intestinal adverse effects, and leading to 25% of dose reduction, and 33% of Bortezomib interruption before cycle 4, similarly in both groups. The median follow-up was 41 months from start of Bortezomib. Seven patients died during the first cycle of treatment, all of them but one had severe stage III cardiac involvement with LVEF