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Though candidiasis is the most frequent invasive fungal infection, Candida spp. central nervous system (CNS) infections are rare but severe. To further describe clinico-patho-radiological presentations of this entity, we report a retrospective study from January 2005 to December 2018 including patients aged ≥ 28 days with proven or probable CNS candidiasis in France. Twenty-four patients were included. Seventeen patients (70%) had CNS localization secondary to disseminated candidiasis (10 with hematologic malignancies [HM]; the seven other patients had infective endocarditis [IE]). Among patients with HM, seven previously had lumbar puncture for intrathecal chemotherapy, the three others had IE. Among patients with disseminated infection, magnetic resonance imaging (MRI) evidenced meningitis (17%), micro-abscesses (58%), or vascular complications (67%). Seven patients (30%) had isolated CNS involvement related to neurosurgery (n = 2), CARD9 deficiency (n = 2), intravenous drug use, diabetes mellitus, or no identified predisposing condition (n = 1 each). All evaluated patients with isolated CNS involvement had meningitis on cerebrospinal fluid (CSF) and intracranial hypertension. For the latter patients, MRI evidenced meningitis (71%) or abscesses (57%). Among all patients, cerebrospinal fluid (CSF) culture grew Candida spp. in 31% of cases. CSF βDGlucan or mannan Ag were positive in respectively 86% and 80% of cases. Mortality attributed to CNS candidiasis was 42%: 53% in case of disseminated infection (70% for HM) and 14% in case of localized infection. CNS candidiasis are isolated or occur during disseminated infection in patients with HM and lumbar puncture for intrathecal chemotherapy or during IE. Clinical, radiological finding and outcome highly vary according to CNS localized versus disseminated candidiasis. Lay Summary Candida is a yeast and is the most common cause of fungal infections worldwide. Candida central nervous system (CNS) infections are rare, severe, and poorly described. We report a retrospective study from January 2005 to December 2018 including patients aged ≥ 28 days with proven or probable CNS candidiasis in France. Twenty-four patients were included (14 men, median age 51 years). Seventeen patients had CNS localization secondary to disseminated candidiasis from blood to CNS (10 with hematologic malignancies [HM], the seven other patients had infective endocarditis [IE]). Seven patients had isolated CNS involvement related to neurosurgery (n = 2), CARD9 deficiency (n = 2), intravenous drug use (n = 1), diabetes mellitus (n = 1), or no identified risk factor (n = 1). During Candida CNS infections, brain lesions were meningitis abscesses or vascular complications. Cerebrospinal fluid (CSF) culture grew Candida spp. in 31% of cases. Forty-two percent of patients died from infection: 53% in case of disseminated infection (70% for HM) and 14% in case of localized infection.

International audience; Scedosporiosis/lomentosporiosis is a devastating emerging fungal infection. Our objective was to describe the clinical pattern and to analyze whether taxonomic grouping of the species involved was supported by differences in terms of clinical presentations or outcomes. We retrospectively studied cases of invasive scedosporiosis in France from 2005 through 2017 based on isolates characterized by polyphasic approach. We recorded 90 cases, mainly related to Scedosporium apiospermum (n = 48), S. boydii/S. ellipsoideum (n = 20), and Lomentospora prolificans (n = 14). One-third of infections were disseminated, with unexpectedly high rates of cerebral (41%) and cardiovascular (31%) involvement. In light of recent Scedosporium taxonomic revisions, we aimed to study the clinical significance of Scedosporium species identification and report for the first time contrasting clinical presentations between infections caused S. apiospermum, which were associated with malignancies and cutaneous involvement in disseminated infections, and infections caused by S. boydii, which were associated with solid organ transplantation, cerebral infections, fungemia, and early death. The clinical presentation of L. prolificans also differed from that of other species, involving more neutropenic patients, breakthrough infections, fungemia, and disseminated infections. Neutropenia, dissemination, and lack of antifungal prescription were all associated with 3-month mortality. Our data support the distinction between S. apiospermum and S. boydii and between L. prolificans and Scedosporium sp. Our results also underline the importance of the workup to assess dissemination, including cardiovascular system and brain. Lay Summary Scedosporiosis/lomentosporiosis is a devastating emerging fungal infection. Our objective was to describe the clinical pattern and to analyze whether taxonomic grouping of the species involved was supported by differences in terms of clinical presentations or outcomes.

International audience; No abstract available

We describe the use and value of a lenalidomide/bortezomib/dexamethasone regimen for the treatment of three patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN, a disease that lacks a consensus treatment). After five cycles of chemotherapy, we observed two complete responses and one clinical remission. Together with the encouraging literature data on the effects of lenalidomide and bortezomib on BPDCN cells, our results might prompt further investigations of this regimen's value in BPDCN.

Context: Thrombocytopenia ( Methods: In this a phase I/II, open-label, single arm, multicenter study, key inclusion criteria were: WHO 2008 defined HMA-naive CMML, PLT < 50 x109/L, marrow blasts ≤ 5%, IPSS low/int-1 in MD-CMML, and in MP-CMML no or only 1 severity criteria (Hb < 10 g/dL, ANC > 16 x109/L, abnormal karyotype, extramedullary disease), spleen size < 16 cm. ELT was started at 100mg/d (amended to 50 mg/d) with escalating dose up to 300mg/d for at least 12 weeks. Primary endpoint was Platelet Response (HI-P) at 12 weeks, according to IWG 2006 criteria. Responders could continue ELT until protocol-defined progression, loss of response or toxicity. Results: Between August 2014 and September 2018, 30 pts (median age 77.5 years; M/F 22/8) including 21 MD-CMML and 9 MP-CMML were enrolled. 19 pts had CMML-0 and 11 pts CMML-1 with median PLT count of 32 x109/L (IQR 21-43 x109/L). 12 pts were PLT transfusion dependent (PLT-TD). In the 28 pts sequenced, TET2 mutation (mut) was found in 26 pts, RUNX1mut in 16 pts, SRSF2mut in 11 pts, ASXL1mut in 9 pts, signaling mut in 10 pts and PHF6mut in 5 pts. Median ELT dose at 12 weeks was 150 mg/d (IQR 100-262.5 mg/d). At 12 weeks, 14 pts (46.7%) achieved HI-P (95%CI 28 ; 66%) including 10 MD-CMML and 4 MP-CMML irrespective of PLT-TD status (p=0.46). Responders and non-responders mutational profile was comparable except that none of the 5 PHF6mut pts responded (p=0.06). Responders received ELT for a median of 33 weeks (IQR 17.3-49.5 weeks) with one responder still on therapy at 24 months. Median duration of response was 3.4 months (95%CI: 1.7-11.6 months). Loss of response were due to PLT decrease (11 pts) or transfusion (5 pts) and disease progression (3 pts). At 12 weeks, bleeding symptoms (all grades) were present in 3 (38%) non-responders and 4 (29%) responders. Clinical and biological grade≥ 3 adverse events (AE) were reported in 15 pts each. Before 12 weeks, 24 clinical and 16 biological AE occurred in 7 and 10 pts resp. Toxicity was cardiovascular, pulmonary or gastro intestinal in 2 pts each resp., hepatic and musculo-skeletal in 1 pt each and others in 3 pts. Biological toxicity was hepatic in 4 pts, electrolytic in 4 pts and others in 3 pts. Five pts discontinued ELT due to persistent drug related toxicity. No therapy-related deaths were reported. With a median follow-up of 17 months, 14 pts progressed (including 4 AML transformations) and 17 died. The12-month cumulative incidence of AML was 7% (95%CI: 1-21%). No factors were associated with risk of transformation in univariate analysis (neither WBC nor molecular mutational profile). Two-years OS and PFS were 47% (95%CI: 31-71%) and 28% (95%CI: 15-52%) respectively. Splice mutations were associated with better PFS in univariate analysis (HR=0.29, (95%CI: 0.11-0.76%); p=0.012). In the 21 CMML pts with PLT < 50 x109/L and ≤5% BM blasts from our previous CMML cohort (Itzykson JCO 2013) who were not exposed to ELT, the 12-month estimates cumulative incidence of AML was 10% (95%CI: 0-23%). Comparison with a larger historical cohort not exposed to ELT is ongoing. Conclusion: In CMML patients with severe thrombocytopenia and no marrow blast excess, treatment with ELT is safe and induces frequent but mostly transient responses without increasing the risk of CMML progression. ELT could thus help manage a situation at risk of bleeding such as a scheduled surgical procedure. Phase III studies may be useful to confirm the role of ELT in CMML patients with thrombocytopenia. Disclosures Rabian: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Braun:Daiichi Sankyo: Honoraria; Servier: Research Funding. Ades:jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; novartis: Research Funding; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Celgene/BMS: Research Funding. Solary:Janssen: Research Funding. Itzykson:Oncoethix (now Merck): Research Funding; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees; BMS (Celgene): Honoraria; Janssen: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Sanofi: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria; Abbvie: Honoraria; Stemline: Membership on an entity's Board of Directors or advisory committees.

Background : Patients with acute myeloid leukemia in relapse or refractory to induction therapy have dismal prognosis. Response rates to common salvage regimens are low and allogenic hematopoietic stem cell transplantation is the only curative option. Several studies have demonstrated that salvage chemotherapy with sequential conditioning could reduce leukemia relapse risk with an acceptable toxicity profile for unfavorable acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). [1] Therefore, we decided to assess this procedure in our center at Amiens University Hospital. Methods We conducted a monocentric retrospective study, including 53 patients aged over 18 years undergoing a hematopoietic stem cell transplant (HSCT) with sequential conditioning between January 2012 and December 2018, for relapse/refractory AML or high risk MDS. 44 (83%) patients received sequential conditioning containing clofarabine (SET-RIC) or Amsacrine (FLAMSA) and 9 (17%) thiotepa based (TEC-RIC) with post-transplant cyclophosphamide for mismatched donors. Patients who were GVHD free after immunosuppressors withdrawal received immunomodulation as relapse prevention with azacytidine 37.5mg/m²/day 5 days every 4 weeks for 12 cycles with 3 donor lymphocyte infusions (DLI) alterned between azacytidine cycles. Results The median age was 52 years (range 18-70). Before conditioning, 48 patients had unfavorable AML with ELN intermediate score refractory to at least one course of induction therapy or in relapse, or unfavorable ELN score; 5 patients had high risk MDS with complex karyotype. 32 patients (60,5%) had active disease and 21 (39,5%) were in complete remission (CR) including 12 with positive MRD. 13 (24,5%) patients had HLA-identical sibling donors, 27 (51%) match unrelated donors (MUD), 4 (7,5%) mismatch unrelated donors (MMD) and 9 (17%) haploidentical donors. Majority of patients (90,5%) received peripheral blood stem cell (PBSC) PBSC with median CD34+ count of 7,94.106/kg (1,84-8,44). Acute GvHD prophylaxis with Ciclosporin A, in combination with Mycophenolate mofetil for MUD/MMR/Haplo, was withdrawal with a median time of 90 days. With a median follow-up of 40 months, overall survival (OS) at 1 and 2 years was 68% and 52%. Median OS was 18,7 months (0-72,4 months) and median disease free survival (DFS) was 14,9 months (0-72,4 months). 17 patients (32%) experienced relapse after HSCT with a median time from HSCT to relapse of 6 months (1-35 months). 22 (41,5%) of patients presented with grade I-II acute graft versus host disease (GVHD) and 6 (11,3%) with grade III IV aGVHD . GVHD free relapse free survival (GRFS) at 1 and 2 years was 53% and 34,2%. One-year cumulative incidence of disease related death and non-relapse mortality was 12,6% and 17% respectively. 19 patients received immunomodulation with 5 Azacitidine and DLI if no GVHD occurred within day 120. OS was 79 % in the 19 patients receiving DLI. In univariate analysis immunomodulation post HSCT (Figure 1) was significantly associated with overall survival and leukemia free survival (p=0,0164 and p=0,0359 respectively) but not the disease status before HSCT (p=0,7). Immunomodulation administration with azacytidine and DLI was not significantly associated with cGVHD occurrence (p=0.31). Benefit of immunomodulation OS persisted in multivariate analysis (p=0.0284). Conclusion: Sequential conditioning regimen on refractory AML with secondary immunomodulation with azacytidine and DLI shows very good results with an acceptable toxicity profile in unfavorable AML. We achieve very good OS and DFS whatever disease status before HSCT. GRFS is also encouraging comparing to previously report datas [1]. Reference: [1] Similar outcome of allogeneic stem cell transplantation after myeloablative and sequential conditioning regimen in patients with refractory or relapsed acute myeloid leukemia: A study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire. Decroocq et al. Am J Hematol 2018 ;93 :416-423. Figure 1 Disclosures No relevant conflicts of interest to declare.

Introduction: Corticosteroid-refractory graft-versus-host disease (GVHD) remains a serious complication of hematopoietic stem cell transplantation (HSCT) with high morbidity and mortality rates. Unfortunately, no standard therapy exists for this setting. Ruxolitinib (ruxo), an oral selective Janus-associated kinase (JAK) inhibitor, achieved good results for corticoresistant acute and chronic GVHD in preclinical and clinical studies, with 80% overall response rates. Recent studies showed an increased risk of infections in patients treated with ruxo, especially Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivations. Patients and methods: In order to assess the efficacy and the safety of ruxo, we reviewed here the outcome of 57 patients who received ruxo for corticosteroid-refractory GVHD (in case of digestive tract involvement or in the absence of available ongoing clinical trials) or as a steroids-sparing medication. EBV and CMV reactivation risks were also assessed in the 137 consecutive patients received HSCT between January 1, 2012 and December 31, 2017 and who presented acute or chonic GVHD (57 of whom received ruxo). For this purpose, each reactivation were analyzed separately as a competing risk with death in a cause specific Cox model of survival after the first GVHD occurrence and the onset of ruxo therapy was coded as time dependent covariate. Results: The median age of 57 patients with ruxo was 55 years (range, 49 to 61). Indication for HSCT was acute myeloid leukemia for 25% patients, lymphoma for 30%, acute lymphoblastic leukemia for 11%, myeloproliferative neoplasm for 14% and myelodysplastic syndrome for 7%. Only 9% of this patients received ruxo before HSCT. Unrelated donor was used for 60% patients and main source of hematopoietic stem cells was peripheral stem cells (93%). T cell depletion with polyclonal anti-thymocyte globulin was performed for 89% of patients. Conditioning with high doses cyclophosphamide was used for 21% patients. A lymphopenia 4 log or increasing viral charge of 0.5 log) occurred in 19 patients after ruxo with a 6-weeks cumulative incidence (6WCuI) of 22% (95CI [95% confidence interval]: 15-34). It was the first reactivation in 13 patients. CMV reactivation (> 3 log) occurred in 8 patients after ruxo with a 6WCuI of 4% (95CI: 7-25). It was the first reactivation in 3 patients (Figure 1). The distribution of first reactivation before ruxo and in the remaining 80 patients is shown in Table 1. Thus, 6WCuI of first EBV and CMV reactivation after the first episode of GVHD was 24% (95CI: 19-31) and 20% (95CI: 15-25) respectively. Finally, onset of ruxo coded as time dependent covariates retained a significant adverse prognostic value for the competing risks of death and first episode of EBV reactivation (HR [Hazard Ratio]: 2,657, p Discussion /Conclusion: Ruxo initiation coded as a time-dependent covariate was significantly associated with the overall risk of viral reactivation after the first episode of GVHD and the viral reactivations incidences after ruxo were similar with the incidence of reactivation at the onset of GVHD. Thus, it might be linked to the immuno-compromised state induced by both HSCT and GVHD. Furthermore, as we used ruxo for serious gastro intestinal GVHD, we could have selected patients with a more severe GVHD, requiring multiple immunosuppressive therapy, worsening immune reconstitution. To our knowledge it is the first study to assess the competing risk of CMV and EBV reactivation during ruxo treatment for GVHD. Given its effectiveness in corticoresistant GVHD, ruxo use must not be limited by the fear of viral reactivation at the light of our data, conditioned upon a close monitoring of viral loads in the first weeks. Disclosures No relevant conflicts of interest to declare.

Introduction: The Warburg effect (WE) is an uncommon cause of type B lactic acidosis (LA) due to a deregulation of carbohydrate metabolism in neoplastic cells where lactic fermentation predominates over oxidative phosphorylation regardless of the oxygen level. Case presentation: We report the case of a 57-year-old man presenting with concomitant acute myeloid leukemia and type B LA with asymptomatic hypoglycemia. We did not find arguments for a septic state, liver dysfunction, or acute mesenteric ischemia. The Warburg effect was suspected, and chemotherapy was immediately undertaken. We observed a rapid and sustained decrease in lactate level and normalization of blood glucose. Unfortunately, we noted a relapse of acute leukemia associated with WE soon after treatment initiation and the patient died in the Intensive Care unit. Discussion: Some patients may present complications directly related to an underlying hematological malignancy. The Warburg effect is one of these complications and should be suspected in patients with both hypoglycemia and LA. We propose a checklist in order to help clinicians manage this life-threatening complication. Before considering WE, clinicians should eliminate diagnoses such as septic shock or mesenteric ischemia, which require urgent and specific management. Conclusion: The diagnosis of WE can be challenging for clinicians in the Hematology department and the Intensive Care unit. Prompt diagnosis and rapid, adapted chemotherapy initiation may benefit patient survival.

// Jean-Emmanuel Bibault 1,3,* , Martin Figeac 2,3,* , Nathalie Helevaut 1 , Celine Rodriguez 1 , Sabine Quief 2,4 , Sheherazade Sebda 2,4 , Aline Renneville 1,3,5 , Olivier Nibourel 1,3,5 , Philippe Rousselot 6 , Berengere Gruson 7 , Herve Dombret 8 , Sylvie Castaigne 6 and Claude Preudhomme 1,3 1 Laboratory of Hematology, CHRU de Lille, France 2 Functional and Structural Genomic Platform, Lille, France 3 University of Lille Nord de France, Lille, France 4 Institut Pour la Recherche sur le Cancer de Lille, Lille, France 5 Inserm, UMR-S1172, Lille, France 6 Department of Hematology, Hopital de Versailles, Le Chesnay, Universite de Versailles-Saint Quentin, Versailles, France 7 Department of Hematology, CHU d’Amiens, Amiens, France 8 Department of Hematology, Hopital Saint Louis, AP-HP, Paris, France * These authors have contributed equally to this work Correspondence to: Claude Preudhomme, email: // Keywords : acute myeloid leukemia, FLT3 internal tandem duplication, minimal residual disease, next-generation sequencing Received : November 08, 2014 Accepted : May 25, 2015 Published : June 02, 2015 Abstract Minimal Residual Disease (MRD) detection can be used for early intervention in relapse, risk stratification, and treatment guidance. FLT3 ITD is the most common mutation found in AML patients with normal karyotype. We evaluated the feasibility of NGS with high coverage (up to 2.4.10 6 PE fragments) for MRD monitoring on FLT3 ITD. We sequenced 37 adult patients at diagnosis and various times of their disease (64 samples) and compared the results with FLT3 ITD ratios measured by fragment analysis. We found that NGS could detect variable insertion sites and lengths in a single test for several patients. We also showed mutational shifts between diagnosis and relapse, with the outgrowth of a clone at relapse different from that dominant at diagnosis. Since NGS is scalable, we were able to adapt sensitivity by increasing the number of reads obtained for follow-up samples, compared to diagnosis samples. This technique could be applied to detect biological relapse before its clinical consequences and to better tailor treatments through the use of FLT3 inhibitors. Larger cohorts should be assessed in order to validate this approach.

Introduction Although the median age at diagnosis of acute myeloid leukemia (AML) is 67 years, with approximately one third of patients aged 75 years or older, limited treatment options are available for the elderly. There is no standard of care for older patients with AML unfit for intensive chemotherapy. In this case, despite specific treatment such as low-dose cytarabine (LDA) and 5 azacytidine (5AZA), outcome remains extremely poor, without cure (Thomas X, Current Treat Options Oncol 2017, 18(1):2). The goal of our study is to establish a prognostic model of survival in order to identify whether the absence of specific treatment may not be harmful in a subset of patients. Patients and Methods The French Hauts-de-France AML observatory is a population-based database reporting AML cases diagnosed and supported in 9 Hospital Centers from the French region Haut-de-France. From January 2008 to December 2016, 572 patients older than 75 years were included in the observatory. Among them 324 patients received best supportive care (BSC) alone, 142 hypomethylating agents, 82 low doses aracytine, and 24 other treatments. As a general consensus accepted in all participating centers, BSC was proposed in unfit patients, after performance status and comprehensive geriatric assessment according to results of a preliminary fast geriatric assessment oncodage G8 (Bellera CA, Ann Oncol 2012, 23(8):2166-72). Clinical data were collected in each center. The study was conducted according to the Declaration of Helsinki and was approved by the Human Research Committee of Lille and the internal review board of the Lille University Hospital Tumor Bank (certification NF 96900-2014/65453-1). Results In the BSC group, median age at diagnosis was 82 years (interquartile range [IQR] 78-86). Median WBC count was 7.3 x10^3/mL (IQR 2.18-42.5) with a median peripheral blood blasts percentage of 21% (IQR 6-59.5). Median bone marrow blasts was 51% (IQR 30-75). Karyotype was available for 181 patients. Two patients were in the favorable, 111 patients (61%) were in the intermediate, 68 patients (38%) were in the unfavorable cytogenetics group and 58 patients (32%) had a complex karyotype. For the BSC group, median survival was 3.2 months (IC 2.3- 4) with a 18% 12-months survival estimate. In univariate Cox models, WBC count (p Multivariate analysis selected two independent covariates namely circulating blasts percentage without identifiable cutoff (p=0.0002), and complex karyotype (p=0.05). Prediction of risk according to this proportional hazard model showed that patients at lowest risk could be defined by the absence of both complex karyotype and circulating blasts. The survival of this subgroup of unfit patients who received BSC (7% of patients, median 16 months) was not significantly different from the survival of fit patients with the same characteristics (absence of both complex karyotype and circulating blast) who received 5AZA or LDA (median survival of 26.6 months, p=0.07) (Figure 1.). Remaining patients (with complex karyotype or circulating blast), of the BSC cohort had a shorter survival than patients treated with 5AZA or LDA (3.7 months vs 13 months, p Conclusion In a population of elderly AML patients (> 75 years), 18% are alive at 12 months without any chemotherapy. Our results indicate that the absence of chemotherapy may not be detrimental in a small subset of unfit patients identified by the absence of both complex karyotype and circulating blasts. However further studies are mandatory for characterizing most of patients alive at 12 months with BSC. Figure 1. Survival of patients with both complex karyotype and circulating blasts Disclosures No relevant conflicts of interest to declare.

International audience; After failure of erythropoiesis-stimulating agents (ESAs), lenalidomide (LEN) yields red blood cell (RBC) transfusion independence (TI) in 20-30% of lower-risk non-del5q myelodysplastic syndrome (MDS). Several observations suggest an additive effect of ESA and LEN in this situation. We performed a randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement six RBC units per 8 weeks) lower-risk ESA-refractory non-del5q MDS. Patients received LEN alone, 10 mg per day, 21 days per 4 weeks (L arm) or LEN (same schedule) + erythropoietin (EPO) beta, 60,000 U per week (LE arm). In an intent-to-treat (ITT) analysis, erythroid response (HI-E, IWG 2006 criteria) after four treatment cycles (primary end point) was 23.1% (95% CI 13.5-35.2) in the L arm and 39.4% (95% CI 27.6-52.2) in the LE arm (P=0.044), while RBC-TI was reached in 13.8 and 24.2% of the patients in the L and LE arms, respectively (P=0.13). Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47). Side effects were moderate and similar in the two arms. Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E. Combining LEN and EPO significantly improves erythroid response over LEN alone in lower-risk non-del5q MDS patients with anemia resistant to ESA

FLT3 internal tandem duplication (FLT3-ITD) is usually considered as a bad marker for minimal residual disease (MRD) follow-up in acute myeloid leukemia (AML). Our objective was to evaluate the suitability of FLT3-ITD as a target for MRD detection by real-time quantitative PCR, in comparison with two other molecular MRD markers, NPM1 mutation and WT1 overexpression, in 20 adult AML patients treated in Acute Leukemia French Association (ALFA) trials. Overall, these 3 MRD markers showed comparable kinetics in 17/20 (85%) cases. Furthermore, we found that FLT3-ITD MRD levels after induction chemotherapy are predictive of complete remission duration.

Background :AZA improves overall survival (OS) in higher risk MDS, but only 50-60% of the patients respond, and median OS with AZA is only 20-24 months. As OS improvement is obtained at modest response rates, OS rather than response should probably remain the primary endpoint for all combinations with AZA, requiring large phase III trials with significant follow up. On the other hand, combinations that do not increase response will likely not improve OS. We therefore tested, based on a "pick the winner" approach, AZA combinations with the HDAC inhibitor VPA, LEN or IDA to identify, based on response, the most promising combination with AZA in higher risk MDS, that could be subsequently compared with AZA alone in a larger phase III study. Methods : AZA-PLUS (#NCT01342692)was an adaptive two-stage phase II trial based on Jung design (Stat Med.2008;27:568) that randomly assigned higher-risk MDS, low blast count AML (20-30%) and CMML to: AZA (75 mg/m2/d d1-7 of 28-day cycles); AZA plus LEN (10 mg/d on d1-14); AZA plus VPA( 50 mg/kg/d on d1-7; 35 mg/kg/d in patients> 60y) or AZA plus IDA (10 mg/m2on d1 for the first 9 cycles). The primary end point was response rate (RR, including CR, PR, marrow CR, based on IWG 2006) of the combination arms vs AZA alone. Given a 30% RR with AZA alone, we considered that a ≥45% RR would make combination(s) promising. Controlling for type I and type II errors at 0.15 and 0.20, 40 patients per arm were to be enrolled at each stage. Any experimental arms with RR lower than those observed in the AZA arm at the first stage should be stopped. At the second stage, any arm with > 6 more responses than AZA alone should be selected for further testing. Secondary endpoint were ORR (RR+ stable disease with HI (HI) and OS. Results : After inclusion of 40 pts/arm (first stage) all experimental arms had at least the same number of responses as the control arm and were continued in second stage. Overall, 322 pts were enrolled from 06/2011 to 07/2017: 81, 80, 80, 81 in the AZA, AZA+VPA, AZA+LEN and AZA+IDA arms, respectively. Baseline characteristics were well-balanced across arms. Median age was 74.6 y, 213 pts were male, IPSS was INT-2 in 54% and High in 46%. IPSS Karyotype was fav, int and poor in 40%, 26% and 34%, respectively. Pts received a median of 7 cycles and median follow-up was 15.1 months. Prevalence of trial discontinuation due to adverse events was 32%, 29%, 28% and 31% in the AZA , AZA+VPA , AZA+LEN and AZA+IDA arms, respectively (p=0.95). Rates of hospitalization during the first 6 cycles were 38%, 44.7% , 55.1%, 59.7% in the AZA, AZA +VPA, AZA+LEN and AZA+IDA arms, respectively (p=0.028), suggesting increased myelosuppression in the experimental arms, especially in the LEN and IDA arm. In the control arm, 29 responses (CR+PR+mCR) after 6 cycles were observed, with 29, 25 and 29 responses observed in AZA+VPA , AZA+LEN and AZA+IDA arms, respectively. Thus, no combination demonstrated benefit over AZA. The RR was estimated at 34.8% (18.6% CR, 3.1% PR, and 13.0% mCR) and the ORR after 6 cycles was 40.4%. The RR after 6 cycles (35.8% for AZA, 36.2% for AZA+VPA, 31.2% for AZA+LEN, and 35.8% for AZA+IDA) and the ORR after 6 cycles (41.9% for AZA; 41.2% for AZA+VPA, 40.0% for AZA+LEN and 38.3% for AZA+IDA) were close across study arms. By multivariate analysis, factors associated with better ORR were higher Hb level (p=0.05), low fibrinogen (p=0.008) and low LDH (p=0.01). 17 (5%) pts were bridged to allogeneic SCT: 6 on AZA, 5 on AZA+VPA, none in the AZA+LEN arm and 6 on AZA+IDA arm (p=0.03). At the reference date of July 2018, median EFS was 16.6 months for in AZA, 14.5 months for in AZA+VPA, 15.1 months for in AZA+LEN and 13.2 months for in AZA+IDA (p=0.74) (Fig A). Multivariable Cox model selected Hb level (p=0.02), presence of circulating blasts (p Conclusion : Although OS differences may occur with longer follow up, the combination of VPA, LEN or IDA to AZA did not improve response or OS over AZA alone and worsened myelosuppression. With newer, potentially more potent drugs that can be combined with AZA, the "pick the winner " approach may still be useful to select promising combinations based on response in phase II trials. Molecular data of the pt cohort will be presented at the meeting. Figure. Figure. Disclosures Ades: silent pharma: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; JAZZ: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Laribi:Novartis: Other: Grant and personal fees; Sandoz: Other: Grant; Teva: Other: Grant; Hospira: Other: Grant; Takeda: Other: Grant and personal fees; Roche: Other: Grant; Amgen: Other: Personal fees; Gilead: Other: Personal fees. Stamatoullas:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA: Consultancy. Beyne-Rauzy:Novartis: Research Funding. Cluzeau:MENARINI: Consultancy; CELGENE: Consultancy; JAZZ PHARMA: Consultancy. Quesnel:Sunesis: Honoraria; Astellas: Honoraria; Novartis: Honoraria; Celyad: Honoraria. Fenaux:Jazz: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Immune thrombocytopenia (ITP) is an autoimmune, acquired disease of adults and children characterized by transient or persistent thrombocytopenia. Variability in natural history and response to therapy suggests that primary ITP is heterogeneous from a clinical and pathophysiological point of view. Most cases are considered idiopathic or primary, whereas some are secondary to coexisting conditions. Certain of the cases which are secondary to autoimmune diseases or infections may be unapparent. Alternatively, underlying immune deficiencies may emerge. In addition, genetic factors may impact platelet turnover, propensity to bleed, and response to ITP-directed therapy. Here, we review the clinical and epidemiological features of children and adults with ITP. We then present an overview of the link between ITP and other autoimmune diseases or primary immunodeficiencies. Finally, we try to do an update on pathologic effector mechanisms of this complex autoimmune disease.

Introduction : Cancer-related malnutrition occurred in 30 to 80 % of patients (pts) with cancer (Br J Cancer. 2010;102:966). Malnutrition affects well-being and it is associated with an impaired survival in pts with solid cancer (Eur J Cancer 2008;44:1238). By contrast, few studies focused on the nutritional status of adult patients with acute myeloid leukemia (AML) eligible to intensive therapy and its prognostic consequences. Materials and methods: Therefore, we systematically assessed nutritional status with the body mass index (BMI) before starting induction therapy and again 3 weeks later in AML patients who received intensive induction regimen from January 2008 to December 2011 at Amiens University Hospital. Weight loss, albumin and Glasgow prognostic score (GPS, Brit J Cancer, 2003; 89: 1028) were also monitored during hospitalization and enteral or parenteral nutrition was initiated in case of denutrition. The prognostic value associated with nutrition parameters was evaluated with the model of Fine and Gray (JASA, 94: 496 1999) in order to take the 2 competing risks of relapse/initial failure (R/F) or death without R/F into account. Results: A total of 106 AML pts (mean age 49.8 years [18-75 years], M/F=0.88) entered the study. Eleven pts presented with acute promyelocytic leukemia. Mean serum albumin concentration was 35.6 g/L (15.7-40.8). At treatment initiation, underweight, normal weight, overweight and obesity was identified by BMI in 4%, 41%, 22% and 33% of pts respectively and 3 weeks later in 4%, 49%, 26% and 21% of pts respectively. Severe infections (Common Terminology Criteria for Adverse Events grade 3 to 5) occurred during the hospitalization in 68 pts. Fifteen pts died during hospitalization. Twelve pts failed to respond to induction chemotherapy regimen, all but one received a salvage regimen. Allogeneic bone marrow transplantation was performed in 15 pts. R/F occurred in 33 pts and 17 have died in remission after initial hospitalization. Finally, 62 pts have died at the stopping date. With a median follow-up of 64.6 months in alive pts, median overall survival was 29.3 months, and it was only negatively influenced by advanced age (p=0.003) and adverse molecular characteristics (p=0.01). BMI, GPS and albumin evaluated at treatment initiation and 3 weeks later did not influence the duration of hospitalization (p>0.16) nor the risk of severe infection during the initial hospitalization (p>0.14 in a logistic regression model). Among parameters listed above, only high BMI at 3 weeks after initiation of the induction regimen was significantly associated with an increased risk of R/F (p=0.04, hazard ratio 1.45, [1.01-2.12]), whereas none of these parameters retained a significant prognostic value for the risk of death without R/F. Conclusion: We confirmed the high incidence of overweight in adult pts with AML treated with intensive induction regimen and the absence of prognostic value of initial BMI (Am J Hematol 2016; 91: 199). However, high BMI at 3 weeks after treatment initiation was associated with an increased risk of subsequent R/F. Further studies are ongoing to assess the role of delay or dose reduction in treatment delivery and the potential statistical interactions between nutritional status and molecular characteristics of AML. Thus, our findings highlight the importance of taking any nutritional status into account during the management of AML pts with intensive induction chemotherapy. Disclosures No relevant conflicts of interest to declare.

We report the clinical response and biological effects of treatment with rituximab and fludarabine (RF) in five patients with IgM anti-myelin-associated glycoprotein (MAG) demyelinating neuropathy. Between November 2006 and October 2009, four men and one woman aged 52-85 years received intravenous rituximab at 375 mg/m(2) on day 1 and oral fludarabine at 40 mg/m(2) /day from days 1 to 5, in a treatment cycle that was repeated every month for up to 6 months. Two patients had IgM monoclonal gammopathy of undetermined significance and three low tumor mass Waldenstrom's macroglobulinemia. Four patients showed a major hematological response with a decrease in anti-MAG titer in three and clearing in one. One patient did not respond. For the responding patients, symptoms and electrophysiological parameters improved significantly. No patient relapsed at post-RF treatment follow-up (12-45 months), and no toxicity was reported. The combination of RF induced significant responses in IgM anti-MAG demyelinating neuropathies, without toxicity. Clinical improvements were correlated to hematological and immunological results.

Respiratory failure in patients with hematological malignancies can be optimally treated only if the cause is identified. Risk factors for cardiogenic dyspnea include the use of cardiotoxic chemotherapeutic agents, hyperhydration during chemotherapy, specific clinical situations (e.g., acute tumor lysis syndrome or bone marrow transplantation), and comorbidities. Identifying cardiac dysfunction as the cause of respiratory failure has major therapeutic consequences. Here, we discuss the cardiac causes of respiratory failure in patients with hematological malignancies and the diagnostic tools available for identifying them.

Blastic plasmacytoid dendritic cell neoplasm is a rare and aggressive neoplasm for which there is still no current consensus on the best therapeutic approach. Most patients respond to intensive chemotherapy, but relapses are almost inevitable with median overall survival (OS) in the largest patient series ranging from 8 to 12 months except for patients who could benefit from allogenic hematopoietic stem cell transplantation (allo-HSCT). We present results of the first line treatments used in France between 2000 and 2013 for 86 patients recruited in the French network of BPDCN (abstract ASH 2015 N°78460). Seventeen patients were treated with acute lymphoid leukemia (ALL)-like therapy (median age : 63 yo) , 19 with acute myeloid leukemia (AML)-like therapy (median age : 40 yo), 16 patients with CHOP-like therapy (median age : 72 yo), 16 patients with NK/T-like therapy (based on high-dose methotrexate and L-asparaginase, ± dexamethasone, median age: 59 yo), and 12 patients received "other treatments" (OT, means variable drugs, median age : 82 yo). Thirty four patients obtained a complete remission (CR) and received HSCT (autologous n=4, or allogeneic n=30). The response rates for CHOP-like and OT groups were 31.3% and 25.0% respectively. For ALL-like, AML-like, and NK/T-like groups, response rates reached 70.6%, 78.9%, and 62.5% respectively (no statistic difference). Relapse rates among responders for CHOP-like and OT groups were 60% and 33.3% whereas there were only 25%, 26.7%, and 20% in ALL-like, AML-like, and NK/T-like groups respectively. For patients who obtained remission, the median of remission duration was 8.0 and 14.0 months for patients who received CHOP-like treatments (n=5) and OT (n=3) respectively and 10.0, 10.0, and 9.0 months for ALL-like (n=11), AML-like (n=14), and NK/T-like groups (n=9) respectively (p = 0.6339). In preclinical studies, we have shown that BPDCN cells are sensitive in vitro to idarubicine (Angelot Delettre F et al, 2015) so we studied patients receiving idarubicine in first line therapy in our series (n=9). From these 9 patients, 7 obtained CR and only one relapsed after 10 months. The 6 patients in continuous CR without any relapse have received HSCT (allo, n=5 or auto, n=1). Two out of those 6 patients are alive at the time of data collection with a follow-up of 40 and 87 months; the other 4 patients died after the graft, one relapsed after auto-HSCT, and 3 died of infectious complications after allo-HSCT. The median OS for patients who received HSCT, auto or allo (n=34) and other patients (n = 52) is respectively 49 and 8 months (p < 0.0001, Figure 1). The beneficial effect of HSCT persists independently of age in multivariate analysis. These results suggest that NK/T-like, AML-like, and ALL-like groups give better results than CHOP-like and OT groups. However, there is no significant statistical difference between AML-like, ALL-like, and NK/T-like groups. Thus it seems to be wise to combine "lymphoid" drugs like methotrexate, L-asparaginase and dexamethasone with "myeloid" drug such as idarubicine. The importance of allogenic stem cell transplantation to sustain remission is clear in this study and other one (Roos-Weil et al, 2013). We also observed a prolonged CR in one patient after auto-HSCT. Based on our results, we will propose the first prospective, multicentric, phase II trial in BPDCN, testing a combination of 3 cycles of methotrexate, L-asparaginase, idarubicine and dexamethasone followed by an allo-HSCT in first clinical remission for all eligible patients or repeated cycle of these drugs for unfit patients with auto-HSCT if possible. Kaplan-Meier overall survival curves compared by the Log-Rank test in the cohort of 34 HSCT patients (auto and allo, blue line) and 52 non HSCT patients (red line) (p Figure 1. Overall survival of HSCT patients and non HSCT patients. Figure 1. Overall survival of HSCT patients and non HSCT patients. Disclosures Recher: Celgene; Amgen; Chugai: Research Funding; Janssen; Novartis; Amgen: Other: Travel, accommodations, expenses; Sunesis; Celgene: Consultancy. Deconinck:CHUGAI: Other: Travel for international congress; NOVARTIS: Other: Travel for international congress; ALEXION: Other: Travel for international congress; LFB loboratory: Consultancy; JANSSEN: Other: Travel for international congress; PFIZER: Research Funding; ROCHE: Research Funding.

To the editor: Drug-induced immune thrombocytopenia (DITP) may occur after exposure to many medications and is sometimes indistinguishable from idiopathic thrombocytopenic purpura (ITP).[1][1]–[3][2] When suspected, the causative drug must be stopped and the platelet count returns to normal in

Introduction As clinical trials for relapsed Acute Myeloid Leukaemia (AML) patients do not accurately reflect the daily clinical reality, data regarding the outcome of these patients is scarce. We thus conducted a retrospective analysis to quantify the prospects of salvage treatment of primary refractory or first-relapse AML patients and to assess the contribution of allograft and intensive treatment regimens with respect to major risk groups in a real-life setting. Methods We performed a retrospective analysis of 163 patients diagnosed from 2005-2012, in 5 haematological centres in the north of France (Lille, Amiens, Roubaix, Valenciennes and Lens). We considered every patient in that time frame who was treated following an intensive pathway. Statistical analysis as performed using Kaplan-Meier survival analysis and logrank test in the SPSS software Results The mean age at diagnosis was 45 (range 16-70 years) and the median age at relapse was 48 (ranging 17-70 years). The median time from diagnosis to relapse was 8 months. 20.6% of patients were considered primary refractory (relapse within 60 days from diagnosis). The median overall survival was 28 months (95% CI was 17-38 months). There was no statistically significant survival difference between primary refractory patients and first relapsed patients. Unsurprisingly, survival was significantly (p Discussion This data suggests that for patients with favourable disease delaying transplant to first relapse and treating them with intensive salvage regimen is a valuable option. High risk patients still perform poorly. The relative low representation of these patients (23.6%) is probably due to the fact that these patients are transplanted upfront and often not treated using intensive regimens at relapse. Discussion remains for the intermediate patients. In our study, although numbers are small, they do not seem to behave similarly. The outcome of intermediate I patients resembles more unfavourable patients: this should be considered when discussing both upfront transplantation and management at first relapse. Conclusion This data suggests that delaying transplant for low risk patients is feasible and associated with a good outcome. Salvage intensive chemotherapy and transplant is an effective approach for these patients. Intermediate I patients behave like unfavourable patients and should thus be considered for upfront transplantation and experimental treatments. Disclosures: Preudhomme: CELGENE: Research Funding. Quesnel:CELGENE: Research Funding. Berthon:CELGENE: Research Funding.

Abstract 4854 The incidence of B cell Non Hodgkin Lymphoma (NHL) is steadily increasing with age and about 40% of cases occur in patients aged over 70 years. Some series have reported that low grade NHL lymphomas represent about 35% of all B NHL in elderly patients. However few data are available on the outcome of patients aged over 75 years. Methods We report in a retrospective study the outcome and management of 62 patients aged over 75 years and followed between Jan, 2006, and Jan, 2012 from 2 french centers (Amiens, Abbeville). The primary endpoint was overall survival (OS); secondary endpoints were response rates, progression free survival (PFS), and toxicity. Results 62 patients were registered with median age of 80,4 years (75–92): 31 patients with follicular lymphomas (FL) and 31 other low grade LNH: 15 Marginal Zone Lymphomas (MZL) of witch 11/31 splenic MZL, 1 gastric MALT, 5 lymphoplasmocytic and 10 lymphocytic lymphomas. At diagnostic, evaluation included: computed tomography scan for 46/62 patients (76%), bone marrow biopsy: 17/62 (27%), abdominal echography for 13/62 (24%) patients, echocardiography 24/62 (39%) and positron emission tomography for 11/62 (17%) patients. Charlson score (0–27) was evaluable for all of them with a median score of 2(0–4). At analysis, the median follow up was 23 months (range 0–79). Median FLIPI was 3 (0–5) for FL and median IPI 3(0–5) for other NHL. 21/31 (68%) FL patients and 27/31 (87%) other NHL had stage III or IV in the Ann Arbor classification. 47/62 (76%) patients received chemotherapy: 27/31 (89%) FL patients and 20/31 (65%) with other NHL. 12/62 (19%) patients were undergoing watchfull waiting (11 patients with other NHL, 1 FL); 1 patient refused chemotherapy; 1 FL patient died before any treatment. 29/47 (61%) treated patients received Rituximab (R). In the FL group, 12/31 (39%) received RCVP (C=Cyclophosphamide, V=Etoposide, P=Prednisone), 12/31 (39%) RCHOP-like regimen, 2/31 (6%) chlorambucil, 1/31 (3%) corticotherapy alone, 1/31 (3%) radiotherapy alone and 2/31 (6%) chemotherapy plus radiotherapy. For other low grade NHL, 2/31 (6%) received RCVP, 3/31 (9%) RCHOP-like regimen, 10/31 (32%) Chlorambucil, 1/31(1%) Fludarabine, 4/31(13%) orally cyclophosphamide and corticosteroid. 17 on 47 treated patients (36%) were in complete remission: 10/27 (37%) FL and 7/20 (35%) other NHL. The 2-years OS was 67%: 61% in the FL group and 74% other NHL (difference not significative); the 2-years PFS was 68%: 60% for FL and 77% for other low grade NHL. In univariate analysis, OS was affected by IPI (p=0,02) and FLIPI (p=0,008) (figure), but not by serum albumin concentration ≤ 35g/L, lymphopenia ≤1G/L, or Charlson score. 25 deaths were reported (14 FL and 11 other NHL): 9 lymphoma progressions, 6 sepsis, 3 attributed to cardiac failure and 1 to pulmonary embolism. The most frequent side-effects were hematological: febrile neutropenia (15 patients) and cardiac: acute failure (4 patients). Conclusion Our results in older patients with low grade lymphoma compare favorably with results in younger population. IPI and FLIPI only affect OS whereas geriatric evaluation with Charlson score is not relevant, possibly due to the small number of patients and short follow-up. These results prompt us to realize prospective studies in this population, reducing toxicity and improving efficacy with novel approach. Disclosures: No relevant conflicts of interest to declare.

Abstract 4332 Background: Azacitidine (Aza), inhibitor of DNA methyltransferases, plays an important role in epigenetic regulation of gene expression and tumorogenesis, and is active in myeloid neoplasia such as myelodysplasia (MDS) and de novo acute myeloid leukemia (AML). Efficacy of Aza for relapsed and refractory AML has not been so far reported. Methods: We report in 2 french centers (Amiens, Rouen) retrospective study, the results of Aza for relapsed or refractory patients. All patients received Aza (75 mg/m2 per day over 7 days for 4 weeks cycles), until progression, and at least one cycle. Leukocyte blood count was < 10109/l. The primary endpoint was overall response rate (ORR), according to IWG 2006: complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD), hematological improvement (HI). Secondary endpoints were duration of response and overall survival (OS). Results: 41 patients (26 males and 15 females) with a median age of 59 years (range 28–78) were studied from August, 2007 and November, 2011 (Table): 15 had refractory and 26 relapsed AML. At relapse 11/26 had MDS, defined by blast count Patients received in average 6 cycles (1–30): 4 (1–7) for refractory; 7 (1–30) for relapsed (11 (3–30) for MDS post AML; 3 (3–5) for relapsed AML). Overall, the ORR was 34% (7 CR, 5 RP, and 9 HI). For patients with MDS post AML OR was 82% (7 CR, 2 RP, 7 HI), 13% (1 RP, 1 HI) for relapsed AML, and 13% (2 PR and 1HI) for refractory AML. The average duration of response was 4 months (0–39) for the 41 patients: 14 months (0–39) for MDS post AML, 0.3 for relapsed AML, and 0.5 for refractory. Overall survival from diagnosis was 29 months (6.9–87): 38.2 (12–57) for MDS post AML, 30.1 (6.9–87) for relapsed AML and 13.3 (6.9–35.5) for refractory (no significant differences). Overall survival from initiation of Aza was 9.4 months (1.1–39.2): 22.6 (4.8–39.2) for MDS post relapsed and 3.9 (0.3–11.3) for relapsed AML and 6.2 (1.1–13.3) for refractory patients. The differences are not statically significant probably due to small effective of our study. Contrarily to the others 2 groups, 6 patients (55%) with MDS post AML are alive in CR at the latest report; moreover three of them underwent an allogeneic transplantation. Conclusion: Aza seems to efficient for relapsed AML patient, especially for MDS post AML, but inappropriate for refractory patients. Disclosures: No relevant conflicts of interest to declare.

Abstract 2623 Introduction. Relapsed or refractory acute myeloid leukemia (AML) patients (pts) have a dismal outcome and conventional chemotherapy offers almost no chance of cure. Consequently, allogeneic transplantation (alloSCT) has been widely used for these patients, but outcome is limited by a high relapse rate. There is no generally established standard for reinduction of remission. Clofarabine is a second-generation purine nucleoside analogue mainly evaluated in older adults with untreated AML, but there are limited data in relapsed/refractory AML. The aim of the present study was to establish the role of clofarabine in a large series of adults with relapsed/refractory AML. Methods. Eighteen French centers participated in this retrospective study. Eligibility criteria were as follows: confirmed diagnosis of AML, pts >18 years (yrs) old at clofarabine treatment, and clofarabine used outside of a clinical trial. Relapses after alloSCT were included, but use of clofarabine as part of the conditioning regimen of alloSCT was not included. Data were collected regarding patient demographics, leukemia characteristics, previous treatments and the use of clofarabine including the regimen used and the outcome following treatment. Results. Between January 2007 and June 2011, 100 pts were treated with clofarabine for relapsed/refractory AML. At first diagnosis of AML, median age was 58 yrs, male:female ratio was 60:40, 86% of pts had performance status 0–1, 57% had white blood cells < 10000/mm3, 37% had secondary AML (prior myelodysplastic syndrome 54%), 39% had unfavorable cytogenetics, 58% had intermediate cytogenetics and 3% had favorable cytogenetics, 14/55 had NPM1 mutation, 19/69 had FLT3 internal tandem duplication. At clofarabine treatment, median age was 59 yrs (range 18–77), 42 pts were in first relapse, 35 in relapse >1, and 23 had primary refractory AML. Anthracycline was previously used in 92 pts. Twenty three relapses occurred after alloSCT. Clofarabine was used as single agent (n=22) or in combination with low-dose cytarabine (LDAC, 20–40 mg/m2/d for 4–14 days, n=18) or intermediate-dose cytarabine (IDAC, 1000–2000 mg/m2/d for 3–5 days, n=56) or other drugs (n=4). The dose of clofarabine at cycle 1 was 20 mg/m2/d (n=26), 30 mg/m2/d (n=32), 40 mg/m2/d (n=40) or other (n=2) for a median number of 5 days (mean 4.9, range 3–5). Among all pts, 30 achieved complete remission (CR), and 9 achieved CR with incomplete recovery (CRi), for an overall response rate of 39%. Six pts died during cycle 1, all of infection. Responding pts received a median number of 2 cycles (mean 2.1, range 1–6). Thirteen pts underwent subsequent alloSCT and four pts proceeded to donor lymphocyte infusion. No predictive factor of response was found in univariate analysis among age (cut-off at 60 yrs), sex, de novo vs secondary AML, cytogenetics (unfavorable vs intermediate), molecular genetics, line of treatment (first relapse vs relapse>1 vs refractory AML), relapse after alloSCT vs other relapse (for patients < 65 yrs with equally distributed cytogenetics), regimen (monotherapy vs LDAC vs IDAC) or dose of clofarabine (20 vs 30 vs 40 mg/m2/d). The median disease-free survival (DFS) was 17 months (mo). No factor significantly influenced DFS in univariate analysis, even though DFS tended to be better in relapse after alloSCT than in other relapse (for patients < 65 yrs with equally distributed cytogenetics) with 1-yr DFS being 100% vs 60% (p=0.1). Median overall survival (OS) was 19 mo for responding pts (CR+CRi) vs 3 mo in treatment failure (p Conclusion. This study suggests that clofarabine-based salvage regimen is safe and can be effective in the treatment of relapsed/refractory AML. Durable remissions were achieved, especially in AML relapsed after alloSCT, allowing pts the option of (second) transplantation with the potential of long term cure. Disclosures: Off Label Use: clofarabine is approved for relapsed ALL in children.

Abstract 1754 Background: Mastocytosis is characterized by the abnormal accumulation of mast cells in various tissues responsible for organ failure and/or systemic symptoms that can be disabling and alter the quality of life (QOL). Beside symptomatic treatments, cytoreductive drugs such as a-interferon, purine analogs and to a less extent imatinib mesylate (in case of c-kit mutation other than D816V) and masatinib were shown to be effective but rare complete or long-term remissions were obtained. Thalidomide is an anti-angiogenic immuno-modulatory and anti-inflammatory drug that has preliminary been shown to have an activity in aggressive systemic mastocytosis (ASM) (Damaj et al, BJH 2008). We report the result of a multicentric, open-label, phase II study using thalidomide as a single agent in advanced SM (NCT00769587). Patients and Methods: Twenty patients (pts) were enrolled (1 missing data): smoldering systemic (SSM, n=9), ASM (n=6) and with an associated clonal hematologic non mast cell lineage disease (SM-AHNMD, n=4). Infiltrated organs were bone marrow (n=16), skin (n=14), splenomegaly (n=10), hepatomegaly (n=6), intestinal tract (n=6), lymph nodes (n=1). Median serum tryptase level at inclusion was 83.4 ng/L (range 5.3–775) and all patients except one carried the c-kit D816V mutation. Patients presented with anemia (n=6), thrombocytopenia (n=6) and neutropenia (n=1). Four patients were excluded, 1 for missing data and 3 were not evaluable. Thalidomide was administered orally at a starting dose of 50 mg/day and was progressively increased up to 200 mg/day or appearance of side effects. The duration of treatment was 6 months (1 cycle= 1 month). Responder patients may continue on thalidomide for a maximum of 12 months or progression. Primary objective was to determine the effective response rate by assessing the tumor burden. Secondary objectives were to assess the tolerance of thalidomide and to evaluate the QOL, depression (Hamilton score), pruritis, and handicap (Afirmm V2 score) related to mast cell disease. Results: Sixteen pts [7 males, 9 females; median age 65 years (range 43–76)] who received at least one cycle of thalidomide were analyzed. The median number of thalidomide cycles was 6 (range 1–20) and the median dose received was 100mg/d. Partial response was obtained in 9 pts (56%), 4 pts remained stable (25%) and 3 pts progressed (19%). Pruritis score decreased significantly from 6.5 (95% CI 4.74–12.26) to 4 (95% CI 0–5.25) (p=0.03); the Afirmm score tended to improve from 116.5 (95% CI 55.0–168.3) to 92.5 (95% CI 37.4–131.2) (p=0.38) with no improvement of QoL and Hamilton scores, median tryptase level or cytopenia. Skin infiltration disappeared only in 2 of 14 patients concerned. Treatment discontinuation was due to failure in 4 pts, side effect in 2 pts and patient's decision in 2. Thalidomide was continued in five pts as a maintenance therapy for a median duration of 6 mo (4–14). The most relevant toxicities (grade 3–4) consisted in peripheral neuropathy (12.5%) and myelosuppression (18.7%). Conclusions: Thalidomide is an acceptable and effective treatment in advanced SM. Disclosures: No relevant conflicts of interest to declare.

Abstract 2194 Blastic plasmacytoid dendritic cell neoplasm (BPDCN), previously named CD4 CD56 haematodermic neoplasia is a rare malignancy, associated with poor prognosis; it affects older patients and has a typical clinical pattern, with initially skin involvement and evolution toward leukaemia. To date, best responses for patients younger than 60 yrs are obtained after induction chemotherapy acute lymphoblastic leukaemia-like and allogeneic bone marrow transplantation (Dalle, BJD 2010); for older patients there is no standardized treatment in first line; the CHOP or CHOP-like regimens don't improve the outcome of these patients. We report our experience in 6 patients with BPDCN treated with Methotrexate-Asparaginase (MTX ASP) steroid regimen, active in lymphoid malignancies. From august 2006 to December 2009, 6 patients (pts) were newly diagnosed BPDCN according to main immunophenotyping features of this entity: CD4+, CD56+, HLA-DR+, CD123+, absence of B-, T- and myeloid associated markers (Tsagarakis, Leukemia Research, 2010); the mean age was 62 yrs (range, 55–74); 83% were males; 100% of patients presented at diagnosis with cutaneous disease and bone marrow involvement; all patients received the MTX-ASP steroid regimen; 4 pts were treated in 1st line and 2 pts in relapse, after CHOP-like regimen. The treatment schema was: Methotrexate 3g/m2 day 1, L-asparaginase 6000UI/m2, on day 2, 4, 6, 8 and Dexamethasone 40 mg day 1 to 4; the treatment was administered monthly till progression. Results: Overall complete remission (CR) rate was 83, 3% after 3 cycles: 5 pts were in CR and one patient had a progressive disease (PD). The 5 responders followed the same regimen until progression (total number of cycles for 6 to 11). The mean CR duration was 7, 8 months. One patient underwent allo HSCT after 7 courses and is still alive. The MTX-ASP regimen was well tolerated without severe haematological and non-haematological toxicity; there was no episode of infection and despite high doses of L-Asparaginase, no deep venous thrombosis was seen. Conclusions: The BPCDN treatment is not standardised, mainly due to the rarity of this entity; for younger patients best responses are obtained after allogeneic bone marrow transplantation and induction chemotherapy LAL-like; for older patients the CHOP or CHOP-like regimens don't improve the outcome of these patients. In our experience, methotrexate-asparaginase steroid regimen induces a high rate of CR and seems an interesting treatment option especially for older patients. The treatment toxicity is acceptable. We need to standardize our therapeutic approach in this rare malignancy. Disclosures: No relevant conflicts of interest to declare.

Abstract 4148 Background 5-azacytidine (AZA) is an hypomethylating drug. The international multicenter AZA-001 trial established that AZA significantly improves overall survival (OS) in patients with high risk myelodysplastic syndromes (MDS) compared with conventional care regimens (Fenaux, Lancet Oncol 2009). Some recent reports have raised the question of a possible efficacy of AZA in selected patients with acute myeloid leukaemia (AML). In this study we retrospectively analysed the safety and efficacy of a 7 days-schedule of AZA alone or in combination with an HDAC inhibitor, Valproic acid (VA) and with All-trans retinoic acid (ATRA) in patients with newly-diagnosed and refractory/relapsed AML not eligible for intensive chemotherapy. Patients and Methods A monocentric retrospective study from October, 2006 until March, 2009 analysed 29 patients with AML. Among these patients. There were 11 males and 18 females, median age 70,8 years (range 51,2-84,1), AML de novo in 15 patients (3 relapse) and secondary in 14 patients (2 post MPD and 12 post MDS). Median WBC count was 2,5 (range 0,7-140).109/L, 4 patients had WBC more than 10.109/L. The median rate of bone marrow blasts is 30%. 12/27 (44%) patients and 15/26 (56%) have respectively an intermediate and poor risk caryotype. Fifteen (54%) were newly-diagnosed patients, 14 (46%) were refractory/relapsed patients. Median co morbidity index (Sorror, J Clin Oncol 2007) of patients is 2 (0-7). Patients received daily AZA 75mg/m2 J1-J7, ± VA 35 to 50 mg/kg J1-J7 and ATRA 45mg/m2 J8-J28 every 4 weeks. Results 5 azacytidine was used alone for 6/29 (21%) patients and in combination with VA and ATRA for 23/29 (79%) patients. Compliance to the planned therapy was good. Average number of AZA administration was 6 days. To date a total 150 treatment-cycles with a median of 5 cycles/patient were applied (1-14). Treatment was well tolerated. Neutropenia grade3III and thrombopenia grade3III occurred respectively in 26/150 cycles (17%) and in 31/150 (20%). Infections grade3III were observed in 14/150 cycles (9,3 %). Overall response was 62% (17/29): 9 complete response (CR=31%), 3 partial response (PR=10%), 5 haematological improvement (HI=21%), There were 2 stable diseases (SD=7%). 28% of responses were obtained after 1 cycle, 56% after 3 and 89% after 4. Median overall survival (OS) was 13,2 months (0.3-26). We did not observe any significant difference on OS regarding: age, cytogenetics, de novo vs secondary AML, newly diagnosed vs refractory/relapsed patients. OS for patients with SD was similar to patients with CR, PR or HI. WBC >10.109/L before treatment was not correlated with a shorter survival (7.73 months vs 13.2 months p=0,6). Correlation was found between OS and clearance of the creatinine (p=0.005). In conclusion, AZA based regimens seems well tolerated and an effective treatment in AML, with an overall response of 62% and an OS of 13,2 months. A minimum of 4 cycles of treatment is necessary to evaluate the efficacy. OS of patients achieving CR, PR or HI is not significantly different of those with SD. Treatment should be continued until progression of the disease. Disclosures: No relevant conflicts of interest to declare.

Abstract 4960 High-dose melphalan (HDM) with autologous stem cell transplantation (ASCT) is the standard of care for myeloma (MM) patients aged < 70 years. Achievement of complete/very good partial response (CR/VGPR) is prognostic for improvement overall survival (OS) and use of more effective induction regimens prior to HDT-ASCT may result in improvement post-transplant responses. We performed a retrospective analysis of newly MM pts treated with bortezomib-doxorubicin-dexamethasone (PAD) prior HDM-ASCT. From October 2005 and July 2008, 20 previously untreated MM pts were enrolled: median age was 56 years (range 44-68), 50% male. Of them, 3 had primary plasma cell leukemia (pPCL), 5 were on dialysis for MM-related renal impairment. Cytogenetic was available for 9: 2 (1 pPCL and 1 MM) had t(4;14). PAD included Bortezomib (1.3 mg/m2 on D1, 4, 8, 11), doxorubicin (9mg/m2 D1-D4), dexametasone (40mg D1-D4): 4 cycles (13 pts), 3 (6 pts), and 2 (1). Response rates after PAD were CR 10%, VGPR 50%, PR 20%, SD 10%. 1 pt died of pulmonary hypertension related to MM after 2 cycles of PAD. Neurologic toxicity ' grade 2 was observed in 3 pts and DVT in 1. Following induction, 17 pts underwent PBSC harvesting: cyclopsphamide + G-CSF (8), G-CSF only (10). Median yields were 7.9 106 CD34/kg (6-10.5). 17 pts underwent HDM: 200 mg/m2 (12 pts) and 140 mg/m2 (5 pts with renal insufficiency, including 3 on dialysis), followed with ASCT. 1 pt benefited a double HDM/ASCT and 1 (pPCL) a mini-allotransplant 3 monts after. There was no treatment related mortality. Response rates 3 months post ASCT (17 pts) were: CR 18%, VGPR 70%, PR 6%, SD 6%. 1 SD post PAD obtained VGPR after Thal-Dex had double HDM/ASCT with CR. With a median follow-up of 23 months (7-34), median OS has not been reached and 1-year survival was 95%. At the reference date of July 2009 85% are alive, 5 pts relapsed: median 12 months (6-14), EFS was 31 months and 2 pts with t(4;14) are alive in CR/VGPR at 23 and 31 months Concerning the 3 pPCL pts: 1 remained alive in CR 12 months post allo-transplant (follow-up 23 months), 1 was in CR post PAD and relapsed 11 months post HDM/ASCT (survival = 20 months) and 1 is alive at 12 months from diagnosis with a refractory disease. Dialysis could be interrupted for 3 pts in CR/VGPR: 1 after PAD, 2 after ASCT.. In conclusion, according to previously published results (Popat R, British Journal of Haematology 2008), PAD regimen in preparation of HDM/ASCT is safe and highly active in MM patients. Moreover, prolonged remissions and survivals could be obtained in pPCL patients and reversal of severe renal insufficiency observed. Disclosures No relevant conflicts of interest to declare.

Except in MD Anderson Center, seric β2-m is not recognized as a strong prognostic factor in CLL and seric LDH too, despite this factor is more and more important among lymphoma with a continuous prognostic value. So we studied 248 CLL aged less than 75 yrs, without elevated creatininemia or evident hemolysis. There were 201 pts with stage A, 29 B and 18 C and sex-ratio M/F was 1.48. Median survival time is 10 yrs and median “corrected” (i.e., without not CLL-related deaths including those due to a solid tumor because this complication is independent of initial prognostic factors of CLL) survival time is 10.9 yrs. LDH values range from 0.55 to 3.54 N, and mean and median values are 1.05±0.40 and 0.96 N. LDH level is only correlated with blood lymphocytosis and hemoglobin levels studied as continuous values (p=0.015 and 0.002). When looking at “corrected” survival, all cut-off values from 0.75 N, N, 1.25 N… to 2.5 N are statistically significant but the best one is 1.25 N (p=6 10−6). β2-m values range from 0.81 to 16.5 mg per l, and mean and median values are 2.67±1.75 and 2.15 mg. When studied as continuous values, β2-m is linked to age, number of lymphoid areas according to Binet’s system, and hemoglobin and platelets levels (p=0.0009, 1.25 N and β2-m > 3 mg. Global median survival times of the 3 defined groups were respectively > 10.8 yrs (160 pts), 6.5 yrs (68 pts) and 4.2 yrs (20 pts) with a p value < 10−6. This system is also efficient among stage A pts (p=10−5). When we compare this prognostic system with Binet’s and Rai’s prognostic systems, Cox model rules out Binet’s one and keeps Rai’s system and ours (p=0.01 and 0.0005). Among patients with stage A, Cox model keeps only this LDH and β2-m system. We conclude on the strong prognostic values of seric LDH and β2-m initial levels in CLL and we claim that these 2 simple biological parameters have to been compared with “modern” biological prognostic factors of CLL.