ALBERT

Description: Abstract 991 Smoldering Multiple Myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells (PCs) defined by a serum monoclonal component (MC) of 30 g/L or higher and/or 10% or more plasma cells in the bone marrow (BM). There are several risk factors predicting high-risk of progression to symptomatic disease: 〉10% of PCs in BM, serum MC 〉30g/L, 〉95% aberrant PCs by immunophenotyping, or abnormal free-light chains. Standard of care of SMM is no treatment until progression disease. In this phase III trial, SMM patients at high-risk of progression were randomized to receive Len-dex as induction followed by Len alone as maintenance vs no treatment in order to evaluate whether the early treatment prolongs the time to progression (TTP) to symptomatic disease. The high-risk population was defined by the presence of both 〉PC 10% and MC 〉30g/L or if only one criterion was present, patients must have a proportion of aberrant PCs within the total PCsBM compartment by immunophenotyping of 95% plus immunoparesis. Len-dex arm received an induction treatment consisting on nine four-weeks cycles of lenalidomide at dose of 25 mg daily on days 1–21 plus dexamethasone at dose of 20 mg daily on days 1–4 and 12–15 (total dose: 160mg), followed by maintenance until progression disease with Lenalidomide at dose of 10 mg on days 1–21 every two months (amended in May 2010 into monthly). The 124 planned patients were already recruited, and 118 were evaluable (six patients didn't meet inclusion criteria). According to baseline characteristics, both groups were well balanced. On an ITT analysis (n=57), based on IMWG criteria, the overall response rate during induction therapy was 81%, including 56% PR, 11% VGPR, 7% CR and 7% sCR. 51 patients have completed the nine induction cycles, and the ORR was 87%, including 12% VGPR, 8% CR and 8% sCR. After a median of 7 cycles of maintenance therapy (1-21), the sCR increased to 12%. After a median follow-up of 22 months (range: 5–42), six patients progressed to symptomatic disease in the Len-dex arm: four of them during maintenance therapy and the other two progressed 3 and 8 months after early discontinuation of the trial due to personal reasons. In addition, twelve patients have developed biological progression during maintenance, and dex was added according to the protocol. In nine of them, the addition of dex was able to control again the disease without CRAB symptoms (median of 11 months). In the therapeutic abstention arm, 28 out of 61 patients (46%) progressed to active MM. The estimated hazard ratio was 6·2 (95%CI= 2·6-15), corresponding to a median TTP from inclusion of 25 months for the not treatment arm vs median not reached in the treatment arm (p

Description: Abstract 4547 Background Fungal infections remain a vital threat to the immunocompromised patient. Due to the high mortality rate of invasive mycoses, antifungal prophylaxis and prevention appear appropriate in some settings. Patients (pts) with prolonged and severe neutropenia or recipients of allogeneic hematopoietic stem cell transplantation (HSCT) appear to be at high risk for filamentous fungal infections, which are associated with low survival rates. However, there is no consensus on the optimal prophylaxis, eligible patients or its effectiveness and clinical impact. Objective To analyze the need for antifungal prophylaxis in Acute Leukemia patients receiving chemotherapy and the effectiveness of fluconazol, followed by posaconazol if GVHD developed, in recipients of allo-HSCT as antifungal prophylaxis. Methods and patients Period: from june’07 through june’09. Acute leukemia adult patients receiving chemotherapy as induction or re-induction therapy did not received primary antifungal prophylaxis. Recipientes of Allo-HSCT received 400 mg/d of fluconazole until discharge followed by 200 mg/8h of posaconazole if graft-versus-host disease (GVHD) developed, until its resolution. Patients received secondary antifungal prophylaxis according to their IFI. There were 77 pts who presented 218 episodes of post-chemotherapy neutropenia (80 in ALL and 138 in AML), 207 received no antifungal prophylaxis. On the other hand, we analyzed 40 consecutive Allo-HSCT adult recipients with an average age of 39 years (15-65) followed as in-patient and out-patient basis during a mean period of 18 months (3-24). Standard myeloablative or reduced intensity conditioning schemes were used and donors were HLA-identical sibling (27), unrelated donor (8) and umbilical cord blood (5). Diagnoses: AML (21), ALL (10), NHL (3), MDS (2), CML (2), HL (1) and AAS (1). The GVHD prophylaxis was according to standard protocols with MTX and CsP/MMF or standard umbilical cord blood protocols. Non-normal distribution data were expressed as median values (range). Chi-square test or Fisher exact test were used to compare differences between groups of categorical data. Differences were considered statistically significant for p-values 〈 0.05. All statistical analyses were performed using SPSS 16.0 software (Chicago, IL). Results Acute leukemia patients: There were 8 proved or probable fungal infections (EORTC/MSG consensus), with an incidence of 3.6%. The incidence of IFI in the whole induction AML group was 2.4%, (6.9% in the consolidation AML group, 25% in the re-induction AML group) and 5.2% in induction LLA and no case (0%) in the re-induction ALL group. As etiology, Aspergillus Fumigatus (1), Aspergillus spp (4), Candida tropicalis (1) and Candida spp (2). There were 3 deaths caused by IFI (37.5% of IFI); two of them in the re-induction AML group. Allogenic hematopoietic stem cell transplantation recipients: 33 patients received fluconazole (82.5%) and 4 pts (10%) fluconazole followed by posaconazole. Other 3 received posaconazole (2) or voriconazole 200 mg/12 hours (1) as secondary prophylaxis since the conditioning. There were 7 cases of IFI (incidence of 17.5%), 3 proved IFIs and 4 probable IFIs. As etiology, Aspergillus Fumigatus (2), Aspergillus spp (4) and Candida albicans (1). Six patients had received fluconazole and one (candidiasis), fluconazole and posaconazole. The mortality attributable to IFI were 4 cases (57% of IFI). There was no IFI in the group of 9 pts without GVHD and all IFIs occurred in patients treated for GVHD. Conclusions 1) Patients in re-induction of AML may require an effective prophylaxis against fungal infections, but not AML during induction or ALL in any situation. 2) The prophylaxis regimen studied in allogenic HSCT recipients was effective in preventing IFIs in patients without GVHD but not in patients with GVHD, particularly in the case of filamentous fungi. 3) The overall incidence of IFI in allo-HSCT was similar to that reported in other series of high risk and mortality from IFI similar to that described in recent years. 4) Patients with GVHD require more effective antifungal prophylaxis regimens and are candidates for clinical trials. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1935 Smoldering Multiple Myeloma (SMM) is an asymptomatic proliferative disorder of plasma cells (PCs) defined by a serum monoclonal component (MC) of 30 g/L or higher and/or 10% or more plasma cells in the bone marrow (BM), but no evidence of end-organ damage. There are several risk factors predicting high-risk of progression to symptomatic disease (〉50% at 2 years): 〉10% of PCs in BM, serum MC 〉30g/L, 〉95% aberrant PCs by immunophenotyping, or abnormal free-light chains. Standard of care of SMM is close follow-up without treatment until progression disease. Several trials have evaluated the role of early treatment with convencional agents (melphalan), bisphosphonates and novel agents (thalidomide, anti-IL1a), with no clear benefit, but they didn't focus on high-risk patients. In this phase III trial, SMM patients at high-risk of progression were randomized to receive Len-dex as induction followed by Len alone as maintenance vs no treatment in order to evaluate whether the early treatment prolongs the time to progresión (TTP) to symptomatic disease. The high risk population was defined by the presence of both 〉PC 10% and MC 〉30g/L or if only one criterion was present, patients must have a proportion of aberrants PCs within the total PCsBM compartment by immunophenotyping of 95% plus immunoparesis. Len-dex arm received an induction treatment consisting on nine four-weeks cycles of lenalidomide at dose of 25 mg daily on days 1–21 plus dexamethasone at dose of 20 mg daily on days 1–4 and 12–15 (total dose: 160mg), followed by maintenance until progression disease with Lenalidomide at dose of 10 mg on days 1–21 every two months (ammended in May 2010 into monthly). The 124 planned patients were recruited between October 2006 and June 2010, and 118 were evaluables (three in Len-dex and three in therapeutic abstention arm didn't meet inclusion criteria). This second interim analysis was planned when all patients were recruited. According to baseline characteristics, both groups were well balanced. On an ITT analysis (n=57), based on IMWG criteria, the overall response rate during induction therapy was 75%, including 51% PR, 12% VGPR, 5% CR and 7% sCR. If we select the group of 33 patients who completed the nine induction cycles, the ORR was 91%, including 15% VGPR, 9% CR and 9% sCR. After a median of 8 cycles of maintenance therapy (1-15), the sCR increased to 16%. After a median follow-up of 16 months (range:1-33), four patients progressed to symptomatic disease in the Len-dex arm: two of them during maintenance therapy after 24 and 28 months from inclusion and the other two progressed 3 and 8 months after early discontinuation of the trial due to personal reasons. In addition, nine patients have developed biological progression during maintenance, but in all but one of these, Len has been able to control the disease without CRAB symptoms (median of 9·5 months (1-18)). In the therapeutic abstention arm, 21 out of 61 patients progressed to active MM. The estimated hazard ratio was 6·7 (95%CI= 2·3-19·9), corresponding to a median TTP from inclusion of 25 months for the not treatment arm vs median not reached in the treatment arm (p

Description: Abstract 1457 Background Factors such as hypoxia, angiogenesis and increased cell proliferation have been described to the pathogenesis of myeloid neoplasms. In the current study we have analyzed the expression of different genes involved in such pathways and its correlation with clinical and biological parameters in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Methods and patients: A total of 83 bone marrow (BM) samples were analysed including: Lower-risk MDS (LR-MDS; defined as IPSS low/Int-1; n=37), higher-risk MDS (HR-MDS; IPSS Int-2/high risk; n=13) and AML (blasts 〉20%; n=33). All samples were collected at the time of diagnosis. Bone marrow samples from healthy controls were used as control group (n=11). Baseline characteristics are shown in table 1. Total RNA from BM was treated with DNase, and cDNA was synthesized using a cDNA Sinthesis kit. Gene expression was quantified by qRT-PCR in triplicate using §-actin gene as control. Relative gene expression was determined by 2 (ΔΔCt) method. Cells populations of blasts (CD45+,CD34+,CD117+) were sorted with MoFlo Cell Sorting and separated by positive selection. No differences in gene expression were noticed by sorting as compared to total RNA from whole BM samples. Genes analysed were: vascular endothelial growth factor (VEGF) for angiogenesis, cMYC, macrophage migration inhibitory factor (MIF) and glycogen synthase (GYS) for metabolism and cell-proliferation. Clinical and biological parameters evaluated were: peripheral counts, BM blast percentage, karyotype (good, int and poor by IPSS in MDS and favourable, Int-I, Int-II and adverse by the European Leukemia Net Prognostic System in AML), transfusion dependency, response to intensive chemotherapy (IC) and survival. Statistical significance was determined by t-test, Wilcoxon test and Kaplan Meier with SPSS software (v.16). P values

Description: Abstract 2914 Background: Based on clinical and biological data, a multistep model of disease progression starting in monoclonal gammopathy of undetermined significance (MGUS) continuing through MM, sometimes with an intermediate entity called smoldering MM (SMM), and ending in extramedullary disease, has been proposed. Material and Methods: To gain further insights into the role of the transcriptome deregulation in the transition from normal plasma cells (NPC) to clonal PC and from indolent clonal PC to malignant PC, we performed gene expression profiling (GEP) by Human Gene 1.0 ST Array (Affymetrix) in purified PC from 41 patients with MM, 33 with high-risk SMM and 20 with MGUS. In addition, 5 healthy donors were also included in order to relate the deregulation of GEP of clonal populations to normal condition. Results: Initially, we investigated whether the selected PC population from monoclonal gammopathy patients displayed specific GEP that were clearly distinguishable from NPC. 126 common genes were differentially expressed in MGUS, SMM and MM as compared to NPC (q-value 〈 10−5). The two most significant molecular and cellular functional categories were cell cycle and cell death (P 〈 0.01). The top 3 canonical pathways were EIF2 signaling, regulation of EIF4 and p70S6K signaling, and mTOR signaling (P 〈 0.001). Interestingly, 17 and 9 out of the 126 significant deregulated genes were small nucleolar RNA molecules and zinc finger proteins. GADD45A was the most significant up-regulated gene in clonal PC vs NPC. Subsequently, we looked for genes deregulated in MGUS vs MM, SMM vs MM and MGUS vs SMM, in order to identify gene categories and molecular pathways involved in MM development. A total of 1,184 genes were differentially expressed between MGUS and MM (q-value 〈 10−5) with an imbalance in favor of antiapoptotic state in MM. Thus, BAG3, GADD45B, AKT1 and AKT2 were overexpressed in MM while APAF1 and BCL2L1 were underexpressed in MM. The molecular and cellular function most significantly affected in this comparison was cell death with 106 genes involved (P 〈 0.01). One of the top 10 genes upregulated in MM vs MGUS was TERC. In the SMM vs MM comparison, 1,163 genes were deregulated (q-value 〈 10−5). DNA replication, recombination and repair (ATM, RAD17, RAD50) was the most significant deregulated molecular and cellular function. Telomere extension by telomerase and Myc mediated apoptosis were included within the most significant canonical pathways. The analysis showed that a set of 627 differentially expressed genes was able to differentiate MGUS from SMM (q-value 〈 10−5). Cell death was identified as the most significant molecular function affected (P 〈 0.01). The RAC signaling pathway deregulation (P 〈 0.01) was included within the five most significant canonical pathways. In addition, NFKB signaling was also in the top canonical pathways (P 〈 0.01). Finally, we also looked for those genes significantly deregulated among the three entities, which in turn were progressively up or downregulated from MGUS to SMM and to MM. We reasoned that these genes could be the most significant for promoting multistep transformation. Surprisingly, only eight out of the 2,974 significant genes exhibited a progressive deregulation (P 〈 0.0001) in the evolving stages of monoclonal gammopathies (Figure 1). All the genes with a progressive increase from MGUS to SMM and to MM were snoRNA. APAF1, VCAN and MEGF9 showed a progressive downregulation in the transition from MGUS to SMM and to MM. Conclusion: Our data show that although MGUS, SMM and MM are not clearly distinguishable groups according to their GEP, several signaling pathways and genes were significant deregulated in the different steps of transformation process. Disclosures: Lahuerta: Janssen: Honoraria; Celgene: Honoraria. Oriol:Janssen: Honoraria; Celgene: Honoraria.

Description: Abstract 1730 Background: Prognosis of patients (pts) with myelodysplastic syndrome (MDS) is very heterogeneous. Currently, several classifications for MDS as well as different scoring systems are available, that allow to stratify pts in terms of overall survival and risk of transformation to acute myeloid leukemia (AML). However, the subgroup of pts categorized as lower-risk MDS (International Prognostic Scoring System; IPSS, low or intermediate-1 or less than 10% bone marrow blasts) are not properly stratified by IPSS. Factors as age, severity of cytopenias and transfusion dependency (TD) are not considered in classical scoring systems except for TD in World Health Organization (WHO)-Based Prognosis Scoring System (WPSS). Recently, García-Manero et al reported a prognostic score for lower-risk MDS, identifying age (〉60y), degree of cytopenias, bone marrow blasts 〉4% and karyotype as variables which significantly influenced on survival. Three groups of pts were identified with significant differences in estimated survival. Methods: We analyzed baseline characteristics of 335 lower-risk MDS pts from a single institution and their impact on survival and risk for AML progression in a two decade time period (1990–2010). Median age was 72 years (range: 18–93). Most frequent MDS subtypes were refractory anemia (RA) and RA with ringed sideroblasts. Treatment approach included best supportive care and/or observation in 85% pts. Patients on lenalidomide, 5 azacitidine or allogeneic stem cell recipients were excluded from analysis. Baseline characteristics are shown in table 1Results: After a mean follow-up of 39 months, severity of cytopenias: anemia

Description: Abstract 4955 Introduction Infectious complications are among the most recurrent causes of mortality in patients (pts) with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) undergoing intensive chemotherapy (IC). These pts routinely receive anti-infective prophylaxis (AIP) with flourquinolones and antifungals. 5-azacytidine has recently been incorporated to treatment options for AML and MDS. However, the evidence of the effectiveness of AIP in patients treated with 5 azacytidine (AZA) is limited [1–3]. Objectives To analyze the incidence of episodes of infectious fever (IF), type of microbiological isolation and clinical relevance of infectious complications in AML and MDS pts treated with AZA who did not received prophylaxis. Identification a subgroup of pts who may benefit from AIP in this setting. Material/methods We retrospectively analyzed 48 pts with AML and MDS who received AZA from 2008, with a total of 365 cycles administered. Median age was 68 years (29–83y). Distribution: LMA (n=17) and MDS (n=31). One third of these pts had an absolute neutrophil count (ANC)