IPSS Int-2 Research Articles

Randomized Open-Labeled Academic Trial Comparing Standard AZA Therapy with Combination of G-CSF with AZA in High Risk MDS Patients - Interim Analysis

Introduction: Myelodysplastic syndrome (MDS) is characterized by differentiation blockade, cytopenias with commontransfusion dependency and immune defects. Upon progression the myeloblasts accumulate and the patients become vulnerable to severe infection complications. Based on the Prague Charles University General Hospital registry (N=164, median age 73), the AZA therapy in higher-risk MDS patients results in median OS 13.8 Mo with ORR 48.5%. We also noted from our retrospective data that AZA-treated patients with higher G-CSF consumption had significantly reduced occurrence of Grade 4 neutropenias and longer OS (19 vs 16 Mo, p value 0.039). Rationale: To improve poor clinical outcomes we initiated a randomized open labeled academic trial that compares standard AZA therapy (A) with novel AZA-based therapy combination involving use of G-CSF added prior AZA (GA). Both AZA and also decitabine were preclinically shown to induce myeloid differentiation upon G-CSF preincubation. G-CSF binds its receptor in granulocytic precursors and neutrophils to stimulate their survival, proliferation, and differentiation via myeloid master regulator transcription factor and leukemia-suppressor PU.1. We also have previously shown that AZA increases PU.1. expression. Study design & Methods: GA/MDS-2013 (EudraCT No 2013-001639-38). Expected for enrollment are 134 patients, currently enrolled 53 patients (GA arm N=29, A arm N=24) with median age 74 years, M:F ratio 32:21 (GA 16:16, A 13:8),median IPSS-R 6, median follow up 11.2 Mo, median cycles of therapy 6. Diagnosis included:MDS (EB1, EB 2) with IPSS int-2/high (75%), MDS/AML<30% MB (22.5%), and CMML II (2.5%). Transplant candidates were excluded. Randomization is 2:1 for GA vs A arm. Primary endpoints: OS, PFS, time to AML transformation, ORR, infections & QoL. Secondary endpoints: biomarkers. Therapy schedule: 75mg/m2 of AZA 5-2-2, in GA: G-CSF s.c. injected 48 hrs before dose 1 and dose 6. G-CSF is measured in patient sera (prior therapy), myeloid surface markers are determined by flow cytometry (day -2, day 1, and day 9 of cycle 1). Genomic libraries from whole bone marrow are prepared by NEBNext Direct Kit involving 33 gene panel, sequencing runs are performed on Illumina platform. Statistics involved longitudinal multivariate data analysis including the joint models for the OS and response. Results: The presented data include 2.5 years since the beginning of the trial. Median survival for GA arm was 11 vs 6 Mo in the A arm. ORR (CR, CRm, PR, HI) was 56% in GA arm vs 33% in the A arm. Transformation to AML for both arms was comparable. The stratified longitudinal Cox proportional hazards model containing time-varying covariates together with the ordinal multilevel logistic mixed model were utilized. From this joint fitted model, a negative coefficient for the G-AZA treatment (significant p-value 0.0442) can be noticed in the case of the Cox Proportional Hazard part of the model. This means that G-AZA treatment improves patient survival. The estimated odds for the GA arm that responded to the therapy with remission rather than progression is 12.4x higher than for the A arm, controlling for the remaining patients' characteristics (p-value 0.0016).Both the GA and A arms are comparably tolerated. Data on serious infections and neutropenia gr4 were not yet available. The levels of G-CSF in sera prior the study in both arms (GA vs A) were comparable. Flow cytometry revealed G-CSF mediated upregulation of FCgRI (CD64) in the GA but not in the A arm. Multivariate analysis indicates the following: mutated genes: DNMT3A (p-value 0.0157), EZH2 (p-value 0.0091), TP53 (borderline p-value 0.0510), & CSF3R (p-value 0.0057) shorten the overall survival. The significant negative effects on response was noted for mutated EZH2 (p-value 0.0208) and CSF3R (p-value 0.0424) genes. Conclusions: The current results supported by different methods and statistics indicates a beneficial effect of G-CSF pre-treatment to standard AZA therapy in higher risk MDS patients. G-CSF pre-treatment to AZA increases OS and ORR. In addition, we identified biomarkers that are negatively associated with patient survival and response including EZH2, DNMT3A, TP53, & CSF3R. Grant Support: Ministry of Health, #16-27790A. Institutional resources: Progres Q49 & Q26, UNCE/MED/016, LQ1604, SVV 260374/2017, RVO-64165. Disclosures No relevant conflicts of interest to declare.

S838 TRANSFUSION DEPENDENCY IS ASSOCIATED WITH PRESENCE OF TOXIC IRON SPECIES AND INFERIOR SURVIVAL IN PATIENTS WITH LOWER-RISK MYELODYSPLASTIC SYNDROMES

Background: There are limited treatment options for red blood cell (RBC) transfusion dependent (TD) LR (IPSS Low/Int-1) MDS patients who are relapsed/refractory to ESAs. Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomeres and active telomerase, characteristics observed in some MDS patients across all disease stages. Preliminary results show that imetelstat is effective treatment in LR-MDS patients inducing durable TI (Steensma et al ASH 2018 Abstr463). Aims: We report updated efficacy data with a median follow-up of 12.1 months in 38 LR non-del(5q) MDS patients, R/R to ESA and LEN/HMA naive from the open-label, single-arm Part 1 of IMerge, an ongoing phase 2/3 study (NCT02598661). Methods: Part 1 of the IMerge study included patients with LR MDS, who were heavily transfused (≥4U/8wks), were R/R to ESA or had sEPO >500 mU/mL. Imetelstat 7.5 mg/kg was administered IV every 4 weeks. The primary endpoint was 8-week TI rate; key secondary endpoints included 24-week TI rate, safety, duration of TI, and hematologic improvement (HI) rate. Among the initially enrolled patients, higher 8-week TI rate was observed in the non-del5q, LEN/HMA naive patients. Therefore, the study was amended to subsequently enroll only these patients. From a total of 57 patients enrolled in Part 1, 38 were non-del(5q), LEN/HMA naïve patients (13 in the initial and 25 in the expansion cohort). Here we report long-term efficacy, safety and biomarker data from these 38 patients. Results: Median baseline RBC transfusion burden was 8U/8weeks (range 4–14), 37% of the patients had IPSS Int-1; 71% had WHO 2001 RARS or RCMD-RS subtype and 32% with evaluable sEPO levels had baseline level >500 mU/mL. As of 23 January 2019, median follow-up was 12.1 months for the 38 patients, representing 30.4 and 11.6 months for the initial 13 and additional 25 patients, respectively. The 8-week TI rate was 45% (17/38) and median TI duration was 8.5 months (range 1.8–32.4). Of the 17 responding patients, 10 (59%) remained transfusion free for over 24 weeks. The 8-week TI rate did not differ based on the presence of ring sideroblasts or baseline sEPO levels. The 24-week TI rate was 26% (10/38). Erythroid HI, defined as transfusion reduction by at least 4 units /8 weeks (IWG2006), was achieved in 68% (26/38) of the patients. The most frequently reported adverse events were manageable and reversible grade ≥3 cytopenias. 6/38 patients had IPSS-R intermediate/poor cytogenetic risk. All 6 patents achieved 8-week TI; 2/6 patients achieved partial cytogenetic response. Post treatment decrease in telomerase hTERT RNA level was observed in 25/34 (73.5%) patients with available sample. Among 7 patients with pre- and post-treatment mutation analyses, six had SF3B1 mutations at baseline, and a decrease in the mutation VAF was observed in 2 patients that had longest TI duration on study. Summary/Conclusion: In high RBC transfusion burden patients with non-del(5q) LR-MDS R/R to ESA and naive to LEN/HMA, single-agent imetelstat yielded 8-week TI rate of 45%, with a median duration of 8.5 months (range 1.8–32.4). The 24-week TI rate was 26%. HI-E rate was 68%. All patients with IPSS-R intermediate and poor cytogenetic risk responded. Biomarker analyses of telomerase activity and mutation allele burden indicate an effect on the malignant mutant clone. These data support Part 2 of IMerge, Phase 3 placebo-controlled, randomized portion of the study, expected to open mid-2019.

Potential Barriers to Clinical Trials of New Therapeutics for Myelodysplastic Syndromes: Wide Variation in Risk Definitions and Trial Enrollment Criteria

Introduction: Myelodysplastic syndromes (MDS) are neoplasms characterized by cytopenias, high risk of leukemic progression, and poor overall survival. Chemotherapy for MDS is not curative, and no new drugs have been approved for the treatment of MDS in over a decade. Clinical trials should be considered at any time during the management of patients with MDS, but enrollment criteria may be barriers that limit accrual. In this study, we extracted MDS clinical trial data from clinicaltrials.gov, and compared study indications and characteristics, including inclusion and exclusion criteria.Methods: We identified MDS clinical trials via clinicaltrials.gov (accessed: April 16, 2018). Studies were included if they allowed “MDS,” “Myelodysplastic syndromes,” “Preleukemia,” and/or “Myelodysplasia,” based on the pre-defined ‘related terms’ criteria in the database. We included interventional studies open in the United States that were listed as recruiting or not yet recruiting, for adults (age 18-64) and older adults (age 65+). We excluded studies that were observational in nature, involved a transplant-based intervention, or did not use a pharmacological intervention. We coded inclusion and exclusion criteria based on those provided by study authors in the database.Results: 83 interventional clinical trials enrolling patients with MDS were identified. Studies started enrollment between 4/1/2013 and 3/27/2018, and anticipated reaching the primary objective between 5/1/2017 and 6/1/2025. The median planned study duration was 38 mo (range 10-95). In total, studies sought to enroll 8866 patients over 273 study-years; the median study enrollment estimate was 1.7 patients/month, or across all trials 247 patients/month. Clinical trials could be exclusive to MDS patients (n=28), include MDS patients and other myeloid malignancies e.g. AML (n=44), or include MDS patients and other cancers including solid tumors (n=11). For clinical trials exclusive to MDS, the total enrollment goal was 1966 patients over 96 study-years, with a median rate of 1.4 patients/month (range 0.3-13.2) or total of 63 patients/month across all studies.33 trials were phase 1 studies, 17 were phase 1/2, 26 were phase II, 1 trial was phase 2/3, and 6 were phase III studies. The primary endpoint was typically MTD (n=50) or ORR (n=22), while 5 studies had an OS endpoint.Most trials specified “higher risk” MDS (n=44); 8 specified “lower risk” MDS and 31 allowed all MDS risk or did not specify risk (Figure 1). Lower risk MDS studies were all exclusive to MDS patients. Inclusion criteria related to MDS risk varied significantly according to whether a study was MDS-specific or not (p=0.021): 82% of MDS-specific trials had risk exclusions, compared to 72% of myeloid trials, and only 36% of trials open across cancers. Of 52 trials specifying MDS risk, 20 included IPSS criteria, 24 included IPSS-R criteria, and 27 had blast count criteria.Lower risk MDS criteria was variably defined as IPSS low or INT-1 disease (n=3), IPSS-R very low or low risk (n=1), IPSS-R VL, L, or intermediate risk (n=4), or blast counts < 5% (n=1), < 10% (n=2), or <20% (n=2). There were variations in the criteria for transfusion dependence, including 2 transfusion units in 8 weeks (n=3), 4 in 8 weeks (n=2), 2 in 4 weeks (n=2), 1 in 6 weeks (n=1), and 2 in 16 weeks (n=1).For higher risk MDS, criteria included IPSS INT-1, INT-2, or High risk (n=7), IPSS INT-2 or High risk (n=12), IPSS-R intermediate, high, or very high risk (n=12), or IPSS-R high or very high (n=9); blast counts were set at >5% (n=12) or >10% blasts (n=12). Most studies specified exclusion of CNS disease, even though CNS involvement is exceptionally rare in MDS.43 trials excluded concurrent cardiovascular disease; most often (n=18) requiring 6mo since a cardiovascular event. 46 trials had language excluding concurrent cancers, including 4 that did not allow any prior cancer, and 17 required ³24mo disease free. Exclusions for prior cancers did not vary according to primary outcome (MTD or PK, vs ORR/OS, p=0.16). 20 of 56 studies with MTD or early outcomes (e.g. PK) required cancer-free intervals of ³1y, while 7 allowed concurrent cancers if not on active therapy.Discussion: Currently enrolling MDS clinical trials show significant variation in their inclusion and exclusion criteria. Heterogeneous definitions of basic entry criteria, such as the definition of higher- and lower-risk MDS, may cause barriers to enrollment. [Display omitted] DisclosuresBrunner:Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Garcia:Celgene: Consultancy.

Impact of Donor Chimerism-Guided Immunomodulation after Allogeneic Stem Cell Transplant on the Outcome of Patients with AML and MDS

Impact of Donor Chimerism-Guided Immunomodulation after Allogeneic Stem Cell Transplant on the Outcome of Patients with AML and MDS

Addition of the SMO Inhibitor Sonidegib to Azacitidine in Patients with Higher Risk Myelodysplastic Syndrome (MDS) Who Failed to Respond or Lost Response to AZA Alone: Results of a Phase 1-2 Add-on Study By the GFM

Background: although azacitidine (AZA) is an established frontline therapy for HR-MDS, approximately 40% of the patients fail to respond and virtually all of the responders will ultimately relapse. We previously reported the poor outcome of patients who failed AZA treatment for whom a median survival of 6 months is expected (Prebet, J Clin Oncol. 2011;29(24):3322). Overexpression of SMO a member of the hedgehog pathways has been observed in HR-MDS. Preclinical data have shown the activity of hedgehog pathway inhibitors and suggested synergism with Hypomethylating agents (HMA) (Zou, PLoSONE 2015; 10(8):e0136843). To harness potential synergism, we designed an add-on trial in which sonidegib (LDE-225), an oral inhibitor, was added to AZA in patients who failed AZA monotherapy.Patients and methods:Eligible patients should have IPSS Int-2 or HR-MDS or AML, (to have 10% to 30% marrow blasts), have received a minimum of 6 cycles of AZA monotherapy and to have failed to achieve a response to AZA (defined as CR, CRi, PR or HI as per IWG criteria) in the absence of marrow progression or have relapsed after achieving a response. Patients were scheduled to receive sonidegib daily from day 1 to 28 of 28-day cycles while continuing on AZA at the maximum previously tolerated dose (ie 50 to 75 mg/m²/d for 5-7 days). Two sonidegib dose levels were evaluated in the phase 1 part of the trial (400 and 800 mg/d) according to a classical 3+3 scheme.Results:23 patients, median age 76, were included in the study. One withdrew consent before starting the study treatment and is not included in the analysis. Characteristics of the remaining 22 patients are summarized in the Table. At the 800 mg/d dose level, 3 pts experienced DLT (grade 4 ASAT elevation (1 pt); grade 4 CPK elevation (2 pts)). The recommended dose for the expansion phase was 400 mg/d and no DLT was observed. 19 patients received 400 mg/d. Pts received a median of 3.5 cycles [IQR 2 ; 5], and 5 pts (23 %) received ≥ 6 cycles. All of them were withdrawn from study: 5 (26%) for disease progression (including 1 pt who progressed before starting cycle 1 and did not received treatment), 5 (26%) for death (all due to infection in the context of active disease) and 9 for miscellaneous reasons. 25 SAEs were reported including 23 infections, 1 intra cranial hemorrhage and 1 urinary retention. The most frequent non-hematologic toxicity was infection that occurred in 16/22 (73%) pts. In addition, 243 non hematologic toxicities of any grade were recorded in 20 pts for a total of 83 cycles, all but 3 of grade 1-2, including GI, cutaneous and musculo-skeletal toxicities and fatigue. Hospitalization was required in 45% of the pts. Only 3 responses were observed (1 CR, 1 marrow CR and 1 PR). Response durations were 1, 9 and 15 months .With a median follow-up of 23 months, 13 pts have died and the median overall survival is 6.8 months.ConclusionSonidegib at the dose of 400 mg/d can be given in combination with azacitidine with an acceptable toxicity. With a response rate of only 13%, our results indicate that the addition of sonidegib failed to reverse resistance to azacitidine in pts with higher risk MDS. This contrasts with the positive effect of the combination of glasdegib, another hedgehog pathway inhibitor with cytarabine in pts with AML and MDS (Cortes, Blood 2016 128:99). Besides potential differences in drug potency, our results may highlight the difficulty to identify active agents in the difficult-to-treat patient population selected after HMA therapy failure. The recommended dose-schedule of AZA-sonidegib established here could be used for further investigation in previously untreated patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Higher Monocyte Chemoattractant Protein-1 Levels in Myelofibrosis Are Sustained By the rs1024611 Single Nucleotide Polymorphism and Correlate with Disease Subtype and Severity

Introduction: Host genetic variations have an essential role in the mutational landscape of Philadelphia-negative myeloproliferative neoplasm (MPNs), with JAK2 46/1 and TERT rs2736100 polymorphisms predisposing to disease onset (Tapper W et al, Nat Commun. 2015). However, the contribution of inherited factors in disease phenotype and evolution is poorly characterized. We recently demonstrated that the -2518 A/G SNP of the Monocyte Chemoattractant Protein-1 (MCP-1, rs1024611) is an inherited host genetic factor associated with secondary myelofibrosis (sMF) and a biomarker of disease severity in MF, correlating with adverse hematologic characteristics at the time of diagnosis, such as higher IPSS risk category (Masselli E et al, Leukemia 2018). Here we aimed to: i) provide a correlation between MF patients' genetic readout, chemokine expression/production and hematopoietic progenitor differentiation, ii) correlate MCP-1 levels with disease subtype and severity.Methods: 16 MF patients were genotyped for MCP-1 SNP by TaqMan Predesigned SNP Genotyping Assays and added to our previously reported dataset (Masselli E et al, Leukemia 2018), reaching 81 MF (20 prePMF, 36 overtPMF and 25 sMF). Samples from 15 therapy-naïve MF were dedicated to in vitro-experiments. Eleven healthy subjects and 4 apheresis bags were utilized as controls (CTRL). MF were stratified according to their rs1024611 genotype in A/A (wild types), A/G and G/G (polymorphics). Peripheral blood mononuclear cells (MNCs) were isolated by Ficoll-Hypaque gradient, in part pelleted (resting, T0) and in part seeded in RPMI-1640 medium and activated with 1.1 ng/ml of IL-1β for 20h (T1). CD34+-cells were purified from MF peripheral blood and from apheresis by immunomagnetic selection and differentiated toward the MK lineage as described in Masselli E et al, Leukemia 2015, up to 14 days. MK differentiation was assessed by CD41-flow cytometric expression. MCP-1 levels were evaluated by real-time PCR and western blot.Results: We confirmed, in a cohort of 81 MF patients, that polymorphic subjects were significantly more frequent in sMF vs. PMF (17/25, 68% vs. 21/56, 37.5%, respectively, P=.011, Fig.1A). Of note, sMF was significantly more frequent in A/G and G/G individuals than either prePMF (6/20, 30%, P=.011) or overtPMF (15/36, 41.7%, P=.034, Fig.1B). In overall MF patients, a higher frequency of allele-G carriers was also confirmed in IPSS int-2/high vs. low/int-1 risk group (17/25, 68% vs. 19/51, 37.3%, respectively, P=.011, Fig.1C - all comparisons made by Χ2 test).We proved that MF MNCs significantly over-expressed MCP-1 mRNA and protein as compared to CTRL MNCs at basal state (P=.04 and P=.006 by t-test, respectively, Fig.1D-E), consistently with reports from Tefferi et al. on serum ELISA (Tefferi A et al, JCO 2011). Of note, basal MCP-1 mRNA levels in MF correlated with genotypes, with polymorphic patients displaying significantly higher transcript levels vs. wild types (~20-times higher 2-ΔΔCT, P=.018 by t-test). When MF MNCs were stimulated ex-vivo with IL-1β, a dose-dependent effect of the SNP on MCP-1 expression was observed, with A/G patients displaying >20-times higher and G/G patients showing >60-times-higher fold-increase in MCP-1 expression as compared to wild types (P<.05 G/G vs. A/A by ANOVA and Dunnett test, Fig.1F). sMF patients, that we proved to be enriched in polymorphic genotypes as compared to overall PMF, prePMF and overtPMF patients, significantly over-expressed MCP-1 as compared to PMF (P<.0001 by t-test, Fig. 1G) and prePMF (P<.05 by Anova and Dunnett test, Fig. 1H). Similarly, IPSS intermediate-2/high risk MF patients, also enriched in the G allele, showed significantly higher MCP-1 mRNA levels vs. both IPSS low and intermediate-1 (P<.05 by ANOVA and Dunnett test, Fig. 1I). Finally, we demonstrated that polymorphic CD34+-cells displayed impaired megakaryocytic differentiation, indicated by a significantly lower number of CD41+-cells obtained in culture as compared to A/A (P=.04 by t-test, Fig.1L).Conclusions: Our data proved a dose-dependent effect of the rs1024611 SNP on MCP-1 production in MF and establish a correlation between patients' genetic readout and chemokine levels. These results suggest that MF patients harboring the G allele - and thus producing more MCP-1 - are genetically prone to a higher inflammatory burden, to display a more severe disease and abnormal MK differentiation. [Display omitted] DisclosuresAversa:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Astellas: Honoraria; Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Imetelstat Treatment Leads to Durable Transfusion Independence (TI) in RBC Transfusion-Dependent (TD), Non-Del(5q) Lower Risk MDS Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Who Are Lenalidomide (LEN) and HMA Naive

BACKGROUND:Patients with TD lower-risk (LR)-MDS relapsed or refractory to ESA have limited treatment options. Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomere lengths and active telomerase, characteristics observed in some MDS patients. IMerge is an ongoing global study of imetelstat in RBC TD patients with LR-MDS (IPSS Low or Int-1). In the first 32 patients enrolled, 8-week TI rate was 34%, with 24-week TI of 16%, and HI-E of 59%. The most frequently reported adverse events were reversible grade ≥3 cytopenias (Fenaux et al EHA 2018 Abstr S1157). Higher response rates were observed in patients (n=13) who were LEN and HMA naïve without del(5q). We report here results in an additional 25 LEN and HMA naïve patients without del(5q), with longer term follow-up of the 13 initial patients meeting the same criteria.METHODS:IMerge is a phase 2/3 trial (NCT02598661) that includes LR-MDS patients with a high transfusion burden (≥4 units / 8 weeks) who are relapsed/refractory to ESA or have sEPO >500 mU/mL. The additional 25 were required to be LEN and HMA naïve and lack del(5q). Imetelstat 7.5 mg/kg was administered IV every 4 weeks. In addition to the key endpoints noted above, secondary endpoints include safety, time to and duration of TI. Biomarkers are also being explored, including telomerase activity, hTERT, telomere length, and genetic mutations.RESULTS:Overall, for the 38 LEN/HMA naïve and non-del(5q) patients, median age was 71.5 years and 66% were men. 63% of patients were IPSS Low and 37% Int-1. Median prior RBC transfusion burden was 8.0 (range 4-14) U, and 71% had WHO 2008 RARS or RCMD-RS. 9/37 (24%) patients with evaluable sEPO levels had baseline level >500 mU/mL.As of July 2018, with a median follow-up of 25.8 months for the initial 13 patients, and 5.2 months for the 25 recently included patients, the 8-week RBC-TI rate was 37% (14/38). Durability of 24-week TI responses was demonstrated, with a median duration of 10 months and the longest ongoing response now >2 years. Among the patients achieving durable TI, all showed a Hb rise of ≥3.0 g/dL compared to baseline during the transfusion-free interval. Response rates were similar in RARS/RCMD-RS (33% [9/27]) and other patients (27% [3/11]), and those with baseline EPO levels >500 mU/mL (33% [3/9]) and ≤500 mU/mL (32% [9/28]).Reversible grade ≥3 neutropenia and thrombocytopenia were each reported in 58% of the patients. Liver function test (LFT) elevations were mostly grade 1/2. Reversible grade 3 LFTelevations were observed in 3 (8%) patients on study. An independent Hepatic Review Committee deemed the observed LFT elevations were not imetelstat-related hepatic toxicities.SUMMARY / CONCLUSIONS:In this cohort of 38 non-del(5q) LR-MDS patients with a high RBC transfusion burden who were ESA relapsed/refractory and naïve to LEN/HMA, single-agent imetelstat yielded a TI rate of 37%, with a median duration of 10 months and limited side effects. Durable responses were characterized by transfusion independence >24 weeks and accompanied by Hb rise. Updated data will be presented. DisclosuresSteensma:Takeda: Consultancy; Syros: Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Janssen: Consultancy, Research Funding; H3 Biosciences: Research Funding; Celgene: Research Funding; Amphivena: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy. Platzbecker:Celgene: Research Funding. Van Eygen:Janssen: Consultancy, Research Funding; Roche: Research Funding; Amgen: Research Funding. Raza:Kura Oncology: Research Funding; Onconova: Research Funding, Speakers Bureau; Celgene: Research Funding; Novartis: Speakers Bureau; Geoptix: Speakers Bureau; Janssen: Research Funding; Syros: Research Funding. Santini:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding. Germing:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding. Font:Celgene: Membership on an entity's Board of Directors or advisory committees. Samarina:Janssen: Research Funding. Díez-Campelo:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Bussolari:Janssen: Employment, Equity Ownership. Sherman:Janssen: Employment, Equity Ownership. Sun:Janssen: Employment, Equity Ownership. Varsos:Janssen: Employment, Equity Ownership. Rose:Janssen: Employment, Equity Ownership. Fenaux:Roche: Honoraria; Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Phase 3 trial of momelotinib (MMB) vs ruxolitinib (RUX) in JAK inhibitor (JAKi) naive patients with myelofibrosis (MF).

7000 Background: MMB, an oral JAKi, has been shown in early trials to reduce spleen volume, improve disease associated symptoms (Sx) and improve RBC transfusion (Tx) requirements in patients (pts) with MF. This study was designed to test non-inferiority of MMB vs RUX in splenic volume reduction and Sx amelioration, and superiority in Tx requirement, in JAKi naïve MF pts. Methods: Eligibility: MF, IPSS high risk, Int-2, or symptomatic Int-1; palpable spleen ≥5cm; platelets ≥ 50 K/μl, and no Gr ≥2 peripheral neuropathy (PN). Stratification by Tx dependency and platelets (&lt;100, 100-200 and &gt;200 K/μl). Pts were randomized 1:1 to 24 wks of MMB 200 mg qd + RUX placebo or RUX 20 mg bid (or modified per label) + MMB placebo, after which all pts could receive open label MMB. Assessments: spleen volume by MRI, and pt reported Sx using a daily eDiary of modified MPN-SAF Total Sx Score (TSS). Primary endpoint was splenic response rate (SRR; ≥35% reduction in volume from baseline) at 24 wks. Secondary endpoints, evaluated sequentially at 24 wks, were rates of TSS response (≥50% reduction from baseline), RBC Tx independence (TI), RBC Tx dependence (TD) and of RBC Tx . Results: 175 of 215 (81%) and 201 of 217 (93%) pts randomized to MMB and RUX, respectively, completed the 24 wk DB phase. Efficacy results are shown in Table. Most common Gr ≥3 AEs in the DB phase with MMB were thrombocytopenia (7%) and anemia (6%), and with RUX were anemia (23%), thrombocytopenia (5%) and neutropenia (5%). Gr ≥3 infections occurred in 7% of MMB and 3% of RUX pts. Treatment emergent PN occurred in 22 (10%) of MMB (all Gr ≤2) and 10 (5%) of RUX (9 Gr ≤2, 1 Gr 3) pts in DB phase, none discontinuing study drug for PN. Overall, AEs led to study drug D/C in 13% of MMB and 6% of RUX pts in DB phase. Conclusions: In pts with JAKi naive MF, 24 weeks of MMB is non-inferior to RUX for spleen response but not for symptom response. MMB treatment is associated with a reduced transfusion requirement. NCT01969838. [Table: see text]

Allogeneic Hematopoietic Stem Cell Transplantation Is Underutilized in Patients with Myelodysplastic Syndromes

▪Introduction: Allogeneic hematopoietic stem cell transplantation (Allo-HCT) is the only curative treatment for myelodysplastic syndrome (MDS). The portion of patients referred for transplant and the proportion who are subsequently transplanted is unknown.Aim: Tostudy the frequency of allo-HCT in pts with MDS and identify factors associated with transplant referral and barriers to transplant.Methods: Pts were included if they were under the age of 75 and seen at our center by a leukemia physician between 2008-2015 and within 6 months of MDS diagnosis. Pts were eligible for allo-HCT if they did not have major organ dysfunction, i.e. left ventricular ejection fraction <40%, Creatinine >2mg/dL, FEV1 <1L, DLCO <50%, metastatic solid organ malignancy within 5 years of MDS diagnosis and had KPS <60. Allo-HCT was indicated in pts with therapy related MDS (tMDS), MDS with excess blasts (RAEB-1 or 2), IPSS int-2 or High risk and in cases of life threatening cytopenia (ANC <0.5x109/L, Plt<30x109/L, Hb <7gm/dL). Pts not meeting any of these criteria at diagnosis but who developed >5% marrow blasts during follow-up were eligible for allo-HCT from date of disease progression.Results: This was a single center study.362 pts were identified with a median follow-up of 14 months. 294 (81.2%) were eligible for allo-HCT and in this group transplant was indicatedin 244 (83%). Of these 158 (65%) were referred for transplant evaluation and 109 (69%) of those underwent allo-HCT (figure 1).Reasons for transplant ineligibility at diagnosis and reasons for eligible patients not undergoing transplant are listed in table 1. Metastatic solid organ malignancy within 5 years of MDS diagnosis accounted for most cases of transplant ineligibility (54%), and death due to MDS and progression of disease at last follow-up (60%) were the major reasons for eligible patients not undergoing transplant. Lack of a suitable donor was rarely the primary reason for not proceeding with transplant (3%).Factors associated with a lower likelihood of referral for transplant evaluation were primarily patient related including age over 65 (p=0.001), presence of 3 or more co-morbidities (p=0.003) and RAEB-1 or 2 (p=0.009) at diagnosis. Earlier referral was associated with high-risk disease including tMDS (p=0.006); excess blasts (p=0.001); high-risk IPSS (p=0.001) or IPSS-R (p=0.001) while patient factors including age (p=0.421), gender (p=0.258), KPS (p=0.143) and number of comorbidities (p=0.247) were not associated with time to referral. Pts diagnosis between 2014 and 2015 were referred earlier then in prior years (p<0.001).Among eligible pts in whom transplant was indicated, patient factorswere associated with a higher likelihood of undergoing transplant (table 2) including younger age, female gender, KPS over 90 and having fewer co-morbidities. Specific comorbidities associated with a reduced likelihood of undergoing transplant included coronary or cerebrovascular disease or diabetes. MDS disease features including IPSS (p=0.390), blast percentage at diagnosis (p=0.061), progression to RAEB (p=0.992) or AML (p=0.776) and earlier referral for transplant evaluation (p=0.068) were not associated with a greater likelihood of undergoing transplant. 11 pts were transplanted despite not meeting our transplant indications. These pts had a longer median time to transplant from the time of BMT assessment and underwent allo-HCT most likely due to progressive cytopenia (Figure 1)Conclusion: Allo-HCT is underutilized in MDS patients with only 64% of eligible patients referred for evaluation and 69% of those referred undergoing transplant. Death due to MDS and disease progression were the major barriers to transplantation. The decision to refer a patient for transplant evaluation was influenced by the physician's assessment of the patient's functional eligibility (age, KPS, number of comorbidities) while the urgency of referral was influenced by disease risk. Development of reduced toxicity conditioning protocols, improved GVHD prophylaxis, extended donor options and optimization of supportive care mean older pts with higher co-morbidity scores should be referred for transplant assessment and those with low risk disease should be referred early so that donor options can be identified and a plan for transplant can be prepared prior to disease progression. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Impact of Bone Marrow Fibrosis in MDS Patients Treated with Azacitidine

▪Background: Myelofibrosis (MF) in primary myelodysplastic syndromes (MDS) is a distinct clinicopathological entity from primary myelofibrosis. In the absence of therapy, it has been shown to be an independent predictor of worse overall survival (OS) and leukemia-free survival (LFS) in both low and high risk MDS (Della Porta, J. Clin. Oncol, 2009). However, there are conflicting reports as to whether this applies to higher-risk patients treated with azacitidine, the recommended first line therapy in this group (Fu, Mod. Pathol, 2014).Methods: 93 consecutive patients from our centre treated with azacitidine for MDS or CMML between 2008 and present were identified from a national prospective MDS registry. The pre-treatment marrows of 53 patients were available for independent and retrospective MF scoring by a hematopathologist (MJ) using both the European Consensus and Bauermeister criteriafor myelofibrosis grading. Qualitative fibrosis status of either none/mild or increased/marked were extracted from original reports in 8 additonal patients for which marrows were not available for hematopathologic review. The remaining patients were excluded due to: >20% blasts pre-treatment (1), lack of pre-treatment bone marrows (20), lack of fibrosis status indicated in original report and marrow not available for review (10), and lack of response data (1). Those with European Consensus MF <2 or qualitatively mild/none were compared to those with MF >or= 2 or qualitatively increased/marked. Patients were also compared as Bauermeister grades 1-2 or mild/none vs. Bauermeister grades 3-4 or increased/marked.Results: Median age of the 61 patients was 72 years and 74% were male. According to WHO classification, 2 had del(5q) syndrome, 5 RARS, 8 RCMD, 16 RAEB-1, 23 RAEB-2, 2 CMML1, 4 CMML2 and 1 MDS/MPN. Median hemoglobin level, neutrophil count, platelet count, LDH, ferritin, and marrow blast count were 91 g/L (range 64-136), 1 x109/L (0-46), 51 x109/L (2-459), 263 U/L (110-1442), 746 mcg/L (56-7983) and 7% (2-18), respectively. 58% were transfusion dependent at start of treatment. IPSS was High, Int-2, Int-1, and Low in 9%, 46%, 33%, and 4% of patients. 32 patients (53%) had European Consensus MF grades >or=2 or increased/marked fibrosis, and this was significantly (p=0.011) associated with higher pre-treatment ferritin levels (1110 vs. 532mcg/L). The increased MF group also showed trends towards younger age (68 vs 72 years), longer time from diagnosis until treatment (18.3 vs. 7.1 mos), greater transfusion dependence (69 vs. 45%), and pre-treatment LDH >250 U/L (61 vs. 42%), which did not meet statistical significance given limited sample size. Otherwise there were no significant relationships between MF score and WHO classification, IPSS/IPSSR, karyotype/cytogenetics, or other covariates. The results were similar when comparing groups by the alternative Bauermeister criteria, with increased fibrosis associated with a ferritin of >1000 mcg/L (p=0.038). After a median of 9 cycles (1-62) of azacitidine,complete remission (CR), marrow CR, and hematologic improvement (HI) was achieved in 9 (15%), 5 (8%), and 27 (44%) patients, respectively. Stable disease was seen in 29 (48%) patients. After a median follow-up of 3 years, median OS by Kaplan-Meier survival curve was 3.6 years in all treated patients and 2.7 years in IPSS Int-2/High patients. Regardless of which fibrosis grading system was used to compare patients, there were no significant differences in time to achieve best response, response rates, OS, or LFS based on pre-treatment MF grades (Figure 1).Conclusion: In this prospective registry series of azacitidine treated MDS with retrospective, pathology reviewed semi-quantitative MF grading, the degree of myelofibrosis did not significantly impact response to azacitidine, progression to leukemia, or overall survival. However, increased fibrosis was significantly associated with higher pre-treatment ferritin values and resulted in a non-significant trend towards younger age, longer time to treatment, transfusion dependence, and higher pre-treatment LDH levels. [Display omitted] DisclosuresWells:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Buckstein:Novartis: Honoraria; Celgene: Honoraria, Research Funding.

Evaluation of Salvage Induction Chemotherapy Regimens in Higher Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia after Hypomethylating Agent Treatment Failure

▪Background. Hypomethylating agents (HMA) are standard therapy for patients with higher-risk MDS and AML patients (pts) declining induction chemotherapy. However, >60% do not respond and all responding patients ultimately relapse. Prognosis after HMA failure is poor, with median overall survival (OS) of 4-6 months (m) and 2-year survival of 15%. Second-line intensive chemotherapy (IC) can reduce disease burden and serve as a bridge to allogeneic stem cell transplantation. To date, no large-scale study has focused on HMA failure pts and there is no standardized induction regimen. This retrospective, multicenter cohort study compared clinical responses, cumulative incidence of relapse (CIR), and median OS for different induction chemotherapy regimens given after HMA failure in MDS and AML pts.Methods. Pts from 11 centers treated between January 2005 to September 2015 were analyzed. Inclusion criteria was age 18 years or older, diagnosis of higher-risk MDS (IPSS Int-2 or high) or AML, failure to respond or progression of disease after at least 1 HMA cycle, and treatment with an intensive chemotherapy (IC) regimen after HMA failure. Response was evaluated per AML 2003 IWG criteria (CR + CRi), OS was calculated from time of induction to death or last follow-up, CIR was calculated from time of response to IC to relapse or last follow-up. All statistical analyses were adjusted on region (Europe vs US).Results. Of 366 included pts, 203 received 7+3, 56 received intermediate to high-dose Aracytine (IDAC), and 107 received a nucleoside analogue (NA)-based regimen (fludarabine, cladribine, clofarabine). Baseline demographics (sex, age, IPSS cytogenetic risk stratification, and prior number of HMA cycles) were similar between the treatment groups (table1). For the whole cohort, the overall response rate to chemo was 39.6%, 8-week mortality was 7.9%, the median OS was 10m (95%CI [8-12m]) and the cumulative incidence of relapse was 50% at 1 year and 71% at 2 years. In univariate analyses, history of therapy related myeloid neoplasm, adverse cytogenetic risk, and use of 7+3 or NA vs IDAC negatively impacted chance of response. Cytogenetic risk stratification was the only variable that impacted response in multivariate analyses (MVA) (45%, 46%, and 28% for favorable, intermediate, and unfavorable group respectively, p=0.005). Factors associated with significantly shorter median OS in MVA included diagnosis of AML at the time of initiation of HMA (6m vs 11m for AML vs MDS, p=0.006), adverse cytogenetics (15m, 10m, 7m for favorable, intermediate, and unfavorable groups, respectively, p=0.003), prior IC before HMA (8m with vs 11m without IC, p=0.001), and progression of disease at the time of HMA failure (9m with vs 20m without, p<0.001). There was no impact on OS of the induction regimen (Figure 1A). The cumulative incidence of relapse after IC was significantly increased for patients receiving IC before HMA (median CIR of 8m with vs 14m without, p=0.006) and progression at the time of HMA failure (9m with vs 17m without, p=0.05). Allogeneic transplantation was performed in 95 pts (26%), including 53 pts in complete response after induction (37% of responders). In a landmark analysis performed at 6 months after IC, transplanted pts had improved OS vs non-transplanted pts (25m vs 13m, p<0.001, Figure 1B). Moreover, no long-term survival was observed in the cohort of responding patients who were not transplanted.Conclusions. This large cohort of patients treated with IC after HMA failure confirms the relatively dismal outcome of this patient group. No induction strategy is superior for outcomes of interest, nor more toxic. IC-post-HMA is a valid treatment option, with response rates and transplant rates that exceed what is observed with other treatment modalities. The benefit of IC-post-HMA may be maximized by patient selection: non-adverse cytogenetics, no prior exposure to IC, and availability of an allogeneic donor seem to be the key factors. [Display omitted] [Display omitted] DisclosuresKomrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Ades:Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Pleyer:Celgene: Consultancy, Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AOP Orphan Pharmaceuticals: Honoraria. Vey:Sunesis: Honoraria. Almeida:Alexion: Speakers Bureau; BMS: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Shire: Speakers Bureau. Gore:Celgene: Research Funding. Prebet:celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Results of a Phase II Study of Guadecitabine (SGI-110) in Higher Risk MDS, CMML or Low Blast Count AML Patients Refractory to or Relapsing after Azacitidine (AZA) Treatment

Background: Hypomethylating agents (HMAs) have become the reference treatment of higher risk MDS, but the median survival of about 2 years obtained with AZA remains modest, and median survival after HMA failure is only about 6 months (Prebet et al, JCO 2011). Guadecitabine (GDAC, SGI-110) is a novel HMA dinucleotide of Decitabine and deoxyguanosine, administered SC, which results in extended DAC exposure. In a phase I-II study in AML (Issa, Lancet Oncol, 2015) a dose of 60mg/m2/day for 5 consecutive days was recommended. We designed a national multicenter phase II study evaluating the efficacy of GDAC in higher-risk MDS patients, refractory or relapsing after AZA (NCT02197676). Methods: Main inclusion criteria were (1) IPSS int-2 or high MDS, or CMML with WBC 10%, or AML with 20-30% marrow blasts (2) Refractory to 6 cycles of AZA or relapsing after response, but without overt progression (i.e., greater than doubling of marrow blasts compared to pre AZA values) (3) Age ≥ 18 years (4) Normal liver and renal functions. Patients received GDAC 60mg/m2/d x5 d every 28 d until progression, death or no response after 6 cycles (extended to 9 cycles after the 20 first pts). Global DNA methylation was assessed at baseline and on d 8, 15, 22 and 28 of cycle 1 in blood, and on d 28 of cycles 1 , 3 and 6 in BM and blood ,using bisulfite-converted DNA followed by pyrosequencing technology measuring 3 representative CpG sites of the LINE-1 promoter region. An intent-to-treat analysis was performed on June 2016, with a median FU of 9.6 months Results: Between Aug 2014 and Jan 2016, 56 pts from 13 centers were enrolled, M/F: 37/19, median age 75 years [IQR, 69-76]. 15 patients had primary resistance after 6 cycles of AZA, and 41 patients had relapsed after a response and a median of 13 AZA cycles [IQR 9.75-23]). 15 pts had IWG 2006 progression between onset of AZA and inclusion. At inclusion, WHO classification was RCMD in 2 pts, CMML in 1 pt, RAEB-1 in 11 pts, RAEB-2 in 31 pts and AML in 11 pts; . IPSS was int-1, int-2 and high in 4 (6%), 27 (50%) and 23 (42%) pts, resp. (2NA), and R-IPSS was low, int., high and very high in 1 (2%), 3 (6%), 13 (26%), and 34 (60.7%) pts resp (5NA). 43 (77%) pts were RBC transfusion-dependent (TD) and ECOG was >1 in 5 (9%) pts. The average baseline LINE-1 methylation level in the 45 pts evaluated was 73% in blood and 72% in BM. One pt died before any treatment, and 55 patients received at least one cycle of GDAC, with a median of 3 cycles [IQR, 2-5.5]. 9 pts responded (8 after 3 cycles) with 1 (3%) CR, 2 (5%) CRp, 5 (14%) marrow CR and 1 HI; ie an ORR of 16% (95%CI, 8-28%). Responses were seen in 4/15 (26.6%) primary refractory, and in 5/41 (12.2%) relapsing patients (p=NS). On average, the maximum LINE-1 demethylation occurred during the first cycle on day 8 in blood (median -11.3%), and on day 28 in BM (median -3.1%). Median duration of response was 9 months including so far 2 responses ≥ 1 year (12 and 18 months). 49 SAE occurred in 44 pts, and were mostly hematological, with myelosupression in 35/56 (63%) of pts 49 patients ended the study, because of progression (n=20), death (n=14), investigator or patient decision (n= 8), toxicities (n= 6) and pt withdrawal (n=1). Median OS from inclusion was 6.7 months (IC95% [5.6-11.8]). 33 pts had died, because of MDS progression in 14 (42%), infection in 13 (39.3%), bleeding in 1 (3%), and other causes in 5 (15%) pts (2 UK, 2 general deterioration, 1 heart attack). No significant prognostic factor of response to GDAC, including age, sex, ECOG, TD, baseline Hb, platelet, ANC, marrow blast %, cytogenetics, IPSS, IPSS-R, type of AZA failure (primary or secondary), LINE1 baseline methylation or demethylation rate was found. OS was significantly shorter in pts with high IPSS (HR=2.1, 95%CI, 1.04-4.20, p=0.04), and with very poor IPSS-R cytogenetics (HR=4.3, 95%CI, 2.0-9.1, p=0.0015), the latter remaining prognostic in multivariate analysis. Using the recent prognostic model for MDS pts having failed HMA (Nazha et al, hematologica 2016), that includes ECOG>1, very poor cytogenetics, age, marrow blasts >20%, TD, platelets Conclusion: Response rates with GDAC, in this population of higher risk MDS, CMML or low blast count AML with failure to AZA (and often with IWG 2006 progression) were modest. Tolerance was similar to that of conventional HMA treatment. Disclosures Beyne-Rauzy:Celgene, Novartis: Honoraria. Park:Novartis: Research Funding. Jueliger:astex: Employment. Bevan:astex: Employment. Ades:Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding.

Safety, Efficacy, and Pharmacokinetic Profiles of Intravenous Rigosertib in Japanese Patients with Recurrent/Relapsed or Refractory Myelodysplastic Syndromes: A Multicenter, Open-Label Phase I Clinical Study

Background and Objectives: Rigosertib, a novel phosphoinositide 3/polo-like kinase pathway inhibitor, promotes G2/M arrest, selectively induces the apoptosis of cancer cells, and has no impact on normal cells. A Phase I/II study in the U.S. showed that rigosertib was safe and well tolerated in patients (pts) with myelodysplastic syndromes (MDS) or acute myeloid leukemia relapsed after or refractory to treatment with hypomethylating agents. A multicenter, open-label Phase I dose-finding study of rigosertib was conducted to evaluate the safety and preliminary efficacy, and to determine the recommended dose for a Phase II study in Japanese patients with recurrent/relapsed or refractory MDS.Patients and Methods: The key eligibility criteria were as follows: patients withrecurrent/relapsed or refractory MDS; FAB classifications (RA, RARS, RAEB, RABE-t, and CMML), excepting patients at IPSS low- or Int-1 risk with respect to RA; aged 20 years or older, ECOG PS of 0 to 2, no major organ dysfunctions, and written informed consent. Rigosertib (1,200 and 1,800 mg daily) was administered intravenously in one 14-day cycle that consisted of continuous intravenous administration for 72 hours followed by monitoring for 14 days. In principle, intravenous rigosertib was administered in up to cycle 8. The primary endpoint was the dose-limiting toxicity (DLT) in each cohort. The secondary endpoints were as follows: 1) safety as assessed with adverse events (AEs) and laboratory results; 2) the hematological remission rate, the hematological improvement rate, and the cytogenetic response rate¾all of which were assessed according to the International Working Group 2006 criteria; and 3) pharmacokinetics.Results: Between June 2012 and February 2015, a total of 9 pts with a median age of 70 (range: 63 to 84) years and with a 7/2 ratio of male/female were enrolled from 5 medical institutions in Japan, and 3 and 6 pts were eventually assigned to the 1,200 and 1,800 mg cohorts, respectively. According to the FAB classification, 6, 2, and 1 pts were categorized to RAEB, RAEB-t, and RA, respectively. There were 3 pts each in the IPSS Int-1, Int-2, and high-risk risk groups, with 1 and 2 pts in each risk group in the 1,200 and 1,800 mg cohorts, respectively. The median numbers of delivered cycles in the 1,200 and 1,800 mg cohorts were 4 (2 to 4) and 2 (1 to 8), respectively. The median relative dose intensity (RDI) in the 1,200 and 1,800 mg cohorts was 100% (98.2 to 100.0%) and 79% (55.6-100%), respectively; lower RDI in the 1,800 mg cohort was caused by dose delay in the next treatment due to toxicities. A total of 169 AEs developed. The most frequently observed grade 4 hematologic toxicities included neutropenia (3/9, 33%), thrombocytopenia (3/9, 33%), and leukopenia (3/9, 33%). Grade 3 or greater non-hematologic toxicities included grade 4 meningitis (1/9, 11%), grade 4 sepsis (1/9, 11%), grade 3 catheter-related infections (2/9, 22%), grade 3 hyponatremia (2/9, 22%), and grade 3 anorexia (2/9, 22%). DLT was not observed in the 1,200 mg cohort, while 2 pts in the 1,800 mg cohort had 5 DLTs (sepsis and meningitis in one pt, as well as hyponatremia, pustular rash, and hypochloremia in the other pt). Three serious AEs, including grade 4 meningitis, grade 4 sepsis, and grade 3 catheter-related infection, developed in the 1,800 mg cohort. No death occurred during the study period. Stable disease was obtained in 2 pts in the 1,800 mg cohort. Any hematological remission, hematological improvement, and cytogenetic response were not obtained in the two cohorts. In the 1,200 mg cohort, maximum plasma concentration (Cmax) was 5.99 ± 1.50 μg/mL (mean ± SD), and the area under the concentration-time curve (AUC0-∞) was 314.6 ± 142.7 μgŸ·hr/mL. In the 1,800 mg cohort, the Cmax was 6.74 ± 2.39 μg/mL, and the AUC0-∞ was 324.8 ± 83.9 μgŸ·hr/mL. The urinary excretion rates of rigosertib in the 1,200 and 1,800 mg cohorts were 12.7 ± 6.6% and 16.2 ± 4.7%, respectively.Conclusions: This Phase I study showed that intravenous rigosertib of 1,800 mg daily for 72 hours was well tolerated, although remarkable efficacy was not observed. The recommended dose for Japanese patients was determined to be 1,800 mg daily for 3 consecutive days as with a Phase III study in the U.S. Based on these data, Japanese MDS patients started to participate in a global randomized Phase III study to compare rigosertib vs. physicians' choice of treatment. DisclosuresOgura:SymBio Pharmaceuticals: Consultancy, Honoraria; Celltrion, Inc.: Consultancy, Honoraria. Kobayashi:Ariad: Research Funding; Ohtsuka Pharmaceutical: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; SymBio Pharmaceuticals: Research Funding. Kubonishi:SymBio Pharmaceuticals: Research Funding. Hidaka:SymBio Pharmaceuticals: Research Funding. Uchida:SymBio Pharmaceuticals: Research Funding. Takamatsu:SymBio Pharmaceuticals: Research Funding.

Romiplostim in Thrombocytopenic Patients with Low- or Int-1- Risk MDS Results in Reduced Bleeding without Impacting Leukemic Progression: Final Follow-up Results from a Randomized, Double-Blind, Placebo-Controlled Study

Romiplostim in Thrombocytopenic Patients with Low- or Int-1- Risk MDS Results in Reduced Bleeding without Impacting Leukemic Progression: Final Follow-up Results from a Randomized, Double-Blind, Placebo-Controlled Study

P53 Protein Expression Correlates with Adverse Outcome in Low-Risk Myelodysplastic Syndromes

BackgroundThe presence of diverse spectrum of mutations in myelodysplastic syndromes (MDS) has largely revolutionized the understanding of the disease. Although certain mutations have doubtful prognostic significance, the adverse impact of TP53 mutation is irrefutable in all publications. We and others have shown the strong correlation between presence of TP53 mutation and overexpression of p53 by immunohistochemistry (IHC). This evidence provides the rationale for the evaluation of p53 overexpression which is available in routine diagnostic workup, as a surrogate marker to predict TP53 mutations. Additionally, we predicted that the overexpression of p53 might be an independent prognosticator, even in the absence of TP53 mutations or RPS14 haploinsufficiency, in low risk MDS.In our study,we analyzed the p53 protein expression in a cohort of 277 'lower risk' MDS patients and compared the clinico-pathological features, overall survival and risk of progression and evolution to AML with respect to p53 IHC status.MethodsThis study enrolled 277 adult low risk MDS patients seen at King’s College Hospital between March 2009 and February 2016. All marrow samples were assessed for p53 expression (intensity and proportion of cells) and scored using a Modified Quick Score (MQS). MQS ≥2 was chosen to define p53-positive staining. The median follow-up was 18.7 months [95% confidence interval (CI), 16.5-21.0 months].ResultsAccording to WHO categories, the predominant group was RCMD (78%). Patients were either IPSS low (n=134, 48%) or int-1 (n=91, 33%). We included 52 (19%) pts for whom the IPSS category was not available, due to the lack or failed cytogenetic data, but these were low-risk WHO categories with no excess of blasts. IPSS-R categories were very low 103 (37%), low 77 (28%), intermediate 38 (14%) and high risk 7 (3%). Overall, 19 (7%) patients progressed to AML and 41 (15%) patients died of which 25 (61%) were disease-related deaths.Of the 277 patients, 148 (53%) showed p53 protein expression with MQS ≥ 2 and were considered "p53-positive" patients (p53+). The p53 stain intensity was negative in 125 (45%), weak in 84 (30%), moderate in 40 (14%) and strong in 28 (11%). Seventy six (28%) patients had >5% p53 staining cells.p53 expression correlated with a higher age at diagnosis (median age 64 vs. 60 years, p=0.01). lower haemoglobin levels (9.8 vs 11 g/dL, p=0.002), but a higher platelets count (139 vs 99 x109/L, p =.003) (Table 1). This significance persisted even on exclusion of patients with 5q- and MDS/MPN. P53+ did not correlate with any cytogenetic risk group or degree of fibrosis.Sequencing data was available in 121 patients with 63 harbouring somatic mutations. Among these patients, only 3 showed the TP53 gene mutation; all of them were classified as positive when assessed for p53 stain (MQS≥2), showing that the nuclear staining reflects underlying TP53 mutations in such cases. Additionally, presence of SF3B1 mutation correlated strongly with p53+ (p=0.02).Patients with p53+ had a significantly shorter OS compared with those with p53- (figure 1a) with 2yr and 4yr survival probability of 87% &68% vs 95% & 90% , respectively (p=0.03 ).Analysis of progression-free survival (progression to AML, cytogenetic evolution, increase of blasts or fibrosis) showed that patients with p53 expression had a significantly shorter PFS compared to patients without p53 expression (Figure 1b): 2yr & 4yr PFS 70% & 54% vs 85% &75% respectively, p=0.01). Multivariate analysis confirmed the independent prognostic value of p53 expression for PFS (p=0.013, HR 2.6, 95% CI 1.2-5.2).ConclusionIn conclusion, our study showed that p53 overexpression by IHC, represented as MQS cutoff ≥ 2, correlates with features of poor prognosis, such as more advanced age at diagnosis, lower haemoglobin levels and shorter overall survival, adversely impacting progression-free survival.p53 IHC in MDS patients may represent an important, easily available, cheap and applicable prognostic tool and it should be considered for auxiliary analysis when determining the therapeutic options for a patient. The p53+ predicts poor outcome, especially disease progression, independent of the TP53 mutation status, indicating an alternate yet undefined pathway for p53 overexpression. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognostic Impact of TS, MTHFR and XRCC1 Genetic Variants in 113 Patients with Myelodysplastic Syndromes

Background: Several studies have suggested that genetic variability related with single nucleotide polymorphisms (SNPs) of the BER system, DNA synthesis and folate-metabolizing pathway genes could modulate DNA repair capacity. Moreover, these genes are supposed to be related to cancer risk. However, the prognostic impact of the association of individual and/or combined genetic variants in patients with myelodysplastic syndromes (MDS) remains undetermined.Methods: We genotyped 113 MDS patients, 54 with IPSS low/int-1 receiving only best supportive care (BSC group) and 59 with IPSS int-2/high treated with azacitidine (AZA-group), for the following polymorphisms: XRCC1 194 and 399, APE1 148, XRCC3 241, TS5'-UTR (2R/3R and G/C) and 3'-UTR (6bp+/6bp-), MTHFR 677 and 1298. Genomic DNA was analyzed by High Resolution Melting assay and restriction digests of PCR products. Overall survival (OS) was calculated using the Kaplan-Meier estimate probabilities, and differences between survival curves were analyzed by the log-rank test. Multivariate analyses were performed using the Cox method.Results: For all the target genes, the distribution of genotypes was consistent with the Hardy-Weinberg equilibrium. Among the baseline characteristics analyzed (age, sex, diagnosis according to WHO, hemoglobin) there was no statistically significant difference in the genotype distribution of studied polymorphisms. In the BSC group, the variants XRCC1 399 GG [Hazard ratio (HR)=7.07; p=0.02], -6/-6 of TS3'-UTR (HR=4.65; p=0.05), 2R/3G, 3C/3G, 3G/3G of TS5'-UTR (HR=11.44; p=0.02) and TT of MTHFR 677 (HR=67.12; p<0.001), were associated with a statistically significant adverse clinical outcome compared to variant alleles (Table 1). This is consistent with the enzymatic activity reduction attributed to these genetic variants. Multivariable regression model analysis was also performed in the AZA group for the same genetic variants. We found similar results for the association between XRCC1 399 GG(HR=5.71 p=0.002), TS3'-UTR +6/+6(HR=0.097 p=0.004), MTHFR 677 TT (HR=8.58 p<0.001) and survival, but not for SNPs in TS5'-UTR (Table 2). Finally, we performed an exploratory analysis to investigate the combined effect of the unfavorable genotypes on survival. In the BSC group, the 3-year OS was 33% for those patients with ≥2 variant alleles, as compared to 62.5%, and 100%, respectively, for those with 2 or 0/1 variant alleles. The predictive role of the adverse genotypes combination on survival was confirmed also in the AZA group, suggesting that patients with a higher number of genetic variants had a shorter survival. Interestingly, when we compared survival of patients with adverse genotypes between BSC and AZA groups, we did not find any statistically significant difference between the 2 groups (Kaplan-Meyer and Log-rank test). Therefore, we speculated that azacitidine could give a survival advantage to patients with unfavorable genetic variants, independently from IPSS at diagnosis.Conclusion: Our study reveals, for the first time, an associations between genetic variants in TS, MTHFR and XRCC1 genes, BSC, azacitidine and survival in MDS patients. If confirmed, they could represent new prognostic markers able to provide guidance for clinical management of MDS patients. In particular, the presence of adverse genotypes could represent a biomarker to treat patients with low-risk IPSS with azacitidine, if confirmed on larger series. Further studies with larger population are needed to validate these associations, especially in SNPs with low variant allele frequency.Table 1GeneGenotypeHazard risk95,0% CI forHazard Risk Lower95,0% CI forHazard Risk Upperp valueXRCC1 399[G/G]versus[A/G-A/A]7,0721,29538,6190,024TS5'-UTR[3G/3G, 3G/3C, 2R/3G]versus[2R/2R, 2R/3C, 3C/3C]11,4471,33098,5440,026TS3'-UTR[Del/Del]versus[Del/Ins, Ins/Ins]4,6530,94622,8740,058MTHFR 677[T/T]versus[C/T-C/C]67,1256,409703,081<0,001Table 2GeneGenotypeHazard risk95,0% CI forHazard Risk Lower95,0% CI forHazard Risk Upperp valueXRCC1 399[G/G]versus[A/G-A/A]5,7131,90417,1420,002TS3'-UTR[Ins/Ins]versus[Ins6/del6, del6/del6]0,0970,0190,4790,004MTHFR 677[T/T]versus[C/T-C/C]8,5872,74926,828<0,001 DisclosuresFinelli:Celgene: Other: Speaker, Research Funding; Novartis: Other: Speaker; Janssen: Other: Speaker.

A Phase II Study of the Efficacy and Safety of an Intensified Schedule of Azacitidine (AZA) in Intermediate-2 and High Risk MDS Patients: A Study By the Groupe Francophone Des Myelodysplasies (GFM)

▪Background: Although azacitidine (AZA) improves survival over conventional treatments in higher risk MDS (Lancet Oncol, 2009), median overall survival (OS) with AZA is only about 2 years, the CR+PR rate about 30%, and further improvements are needed. Gene hypomethylation appears to be a major mechanism of action of AZA but, with the typical 7 days of administration every 28 days, reversal of gene hypomethylation is seen at the end of each cycle (Braiteh F, Clin Cancer Res 2008), suggesting that increasing the number of treatment days could improve AZA results. This trial tested the hypothesis that an AZA regimen with more days of drug administration (ie using the standard daily dose of 75 mg/m2, but during 5 days every 14 days) could increase the response rate, and that this improvement could translate into better OS.Methods: Patients (pts) aged 18-75 years with ECOG performance status (PS) of 0-2 and no major comorbidities preventing administration of an intensified regimen of AZA, with IPSS int-2 or high MDS, CMML with WBC < 13,000/mm3 and marrow blasts > 10% , or AML with 20-30% marrow blasts (ie EU label for AZA) who had received no prior treatment for their MDS/AML except ESAs could be included. Treatment consisted of AZA 75mg/m2/d for 5 days every 14 days for 4 cycles (AZA-14, cycles 1-4). Patients achieving CR or PR then received 4 cycles of AZA 75mg/m2/d during 5 days every 21 days (AZA-21, cycles 5 to 8) followed by classical cycles of AZA 75mg/m2/d for 7 days every 28 days, to be continued until progression/relapse or toxicity arose. This schedule corresponded to a 30% increase in the number of days of AZA during the first 3 months of treatment. Patients not obtaining CR or PR after the initial 4 cycles of AZA-14 received 4 additional cycles of AZA 14 (cycles 5 to 8). Patients not obtaining CR, PR or HI after 8 cycles of AZA-14 were excluded from the trial. The primary endpoint was response after 4 and 8 cycles (IWG 2006 criteria). Median [IQR] are reported unless specified.Results: 27 patients were included, of whom 1 was excluded for consent withdrawal. 26 patients (M/F: 19/7, median age 66) enrolled between 2011 and 2013, were thus analyzed, including 1 ARSI, 2 RCMD, 3 RAEB1, 13 RAEB2, 2 CMML and 5 AML (with 20 to 30% marrow blasts). Karyotype (IPSS) was favorable in 11 pts, intermediate in 6 patients and unfavorable in 9 pts. Median marrow blast was 13.5% (IQR 9.7-18.0), baseline platelet count was 72.5 G/l (43.5-177.0) including 69% with platelet<50 G/L, baseline Hb level was 9.8 g/dl (8.9-10.6), and baseline ANC was 1.2 G/l (0.6-2.3). IPSS was int-1 in 1, int-2 in 16 patients and high in 9 patients. With a median follow-up of 20 months, 342 cycles were administered (median 12/patient, including 23 (88%) patients who received 6 or more cycles). Cycle 2 was performed at a median of 14 (14-14) days after cycle 1 and had to be delayed beyond d15 in only 1 patient. Cycles 3 and 4, scheduled at d28 and d42, were slightly delayed in many pts (and were administered at a median of d35 and d51 from AZA onset). 1 pt terminated the study before cycle 4. Regarding toxicity, 25 SAEs (grade 3-4) were reported in 16 patients, including 21 infectious events, 1 being lethal.After 4 cycles, 1 achieved CR, 6 PR, 7 marrow CR, 5 stable disease with HI (overall response rate 19/26=73.1%). Overall, after 8 cycles, the ORR was 22/26 (85%), including 4 CR, 6 PR, 11 mCR and 1 stable disease with HI. Median survival was 21 months, while one and 2-year overall survival rates were 73%[95CI: 58%;92%] and 41%[95CI: 25%;66%], respectively.No prognostic factors for OS, including IPSS (p=0.63), bone marrow blast % (p=0.24), sex (p=0.42), IPSS cytogenetic group (p=0.30) and PS (p=0.64) was found.Conclusion: In this population of relatively "fit" Higher risk MDS, an intensified schedule of AZA seems feasible without obvious increase in toxicity compared to the classical 7 day schedule of azacitidine. Cycles were delayed in a limited proportion of patients and no extra toxicities were observed. Both the ORR of 85% and the 73% overall survival at 1 year are encouraging. DisclosuresGuerci-Bresler:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; PFIZER: Speakers Bureau. Legros:ARIAD: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Fenaux:Novartis: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

Azacitidine (AZA) Combined with Idarubicin in Higher Risk MDS - Results of a Phase I/II Study By the Groupe Francophone Des Myelodysplasies (GFM)

Background: Hypomethylating agents, especially AZA, have become the reference treatment of higher risk MDS, but the median survival of about 2 years obtained with AZA remains modest, and must be further improved. In addition, AZA yields only about 30% of marrow responses (including CR+PR+marrow CR). Intensive chemotherapy combining Idarubicin (IDA) and AraC yields 30 to 50 % CR in higher risk MDS (Beran and all, cancer 2001) and IDA, as single agent, induces about 30% CR in elderly AML patients (Carella, haematologica 1990). We designed a phase I/II study evaluating the safety and efficacy of the combination of AZA and IDA (1 day during each AZA cycle) in higher risk MDS patients (NCT01305135).Methods: Main Inclusion criteria were: (1) IPSS int-2 or high MDS, or CMML with WBC < 13 G/l and marrow blasts > 10%, or AML with 20-30% marrow blasts (2) Age ≥ 18 years (3) Performance Status (PS) <=2 (4) no prior treatment, except ESAs. Patients received AZA 75 mg/m2/d SC x7d every 4 weeks combined, on day 8 of each cycle (for the first 9 cycles), with IDA 5 mg/m2 (IV) in a first cohort of 10 patients, escalated to 10 mg/m2 IV in a second cohort of 10 patients, followed by an extension study in 21 patients with the IDA 10 mg/m2 schedule. The primary endpoint of the study was response after 6 cycles according to IWG 2006 criteria.Results: Between Dec 2010 and Jan 2014, 41 patients (from 13 centers) were enrolled, including 13 women and 28 men with a median age of 74 years [IQR 70; 76]. At inclusion, WHO classification was RCMD in 1 pt, CMML in 2 pts, RAEB-1 in 10 pts, RAEB-2 in 13 pts, AML in 12 pts and unclassified MDS in 3 pts. Median marrow blast % was 9.5 [IQR: 6-19.9] and karyotype according to IPSS was favorable in 12 (29%), intermediate in 9 (22%) and unfavorable in 18 pts (44%) (2 cytogenetic failures). IPSS was int-2 and high in 56% and 44%, respectively. PS was 0 in 39%, 1 in 55% and 2 in 6% pts.10 patients received 5 mg/m2 of idarubicin (cohort 1) and 31 received 10 mg/m2 (cohort 2). 375 cycles of AZA were administered (219 of them with AZA+IDA, as IDA was used only for the first 9 cycles), with a median number of 6 cycles/patient (median 6 in the IDA 5 mg/m2 cohort and 4 in the 10 mg/m2 cohort (p=0.9).Of the 41 patients enrolled, 20(48.8%, 95%CI: 32.9-64.9) achieved response (6 CR, 7 PR, 4 mCR and 3 stable disease with HI) with no difference between the two cohorts (50% vs 48%) and a marrow response rate (CR + PR + mCR) of 41,5%. Thirteen of the 22 patients with abnormal karyotype were evaluable for cytogenetic response: 5 achieved cytogenetic response (4 complete, 1 partial), 1 in cohort 1 and 4 in cohort 2. With a median follow up of 14 months, 9 of the 20 responders had relapsed. Median response duration was 11 months [3.2-42.7], with no difference between the two cohorts.Median OS was 14.3 months [IC95%: 12.5; NA] and 2y OS was 24.8%, with no significant difference between the 2 cohorts (p=0.43).By univariate analysis no baseline parameter including gender, karyotype, marrow blast %, IPSS and IDA dosage (5 or 10 mg/m2), had any significant impact on response or survival.45 SAEs were reported in 26 patients, including febrile neutropenia (n=25), bleeding (n=7) and 2 non-clinically significant reductions in left ventricular ejection fraction (1 transient, and 1 persisting without symptoms). The number of infections per cycle [9/85 (10%) in the IDA 5 mg/m2 arm and 38/281 (14%) in the IDA 10 mg/m2 arm] and the number of bleeding events (9% vs 17%) did not significantly differ between the two cohorts.Conclusion: In our experience, Idarubicin (on day 8 of each cycle) can be combined to Azacitidine without any additional toxicity. The marrow response rate obtained with the combination (41.5%) may be higher than with AZA alone. We are currently comparing in higher risk MDS patients this AZA-IDA combination versus AZA alone (and other combinations of AZA with other drugs) in a prospective randomized GFM trial. DisclosuresSebert:Celgene: Research Funding. Fenaux:Celgene: Research Funding.

Mutations in Histone Modulators Are Associated with Prolonged Survival during Azacitidine Therapy

Early therapeutic decision-making is crucial in patients with higher-risk MDS where median survival is only around one year. Azacitidine prolongs survival for these patients (Fenaux et al, Lancet Oncology 2009) but clinically relevant biomarkers remain to be identified. We evaluated retrospectively, the impact of clinical parameters and mutational profiles in 134 consecutive patients treated with a median number of 7 cycles of Azacitidine (range 1-45), in accordance to European guidelines. The vast majority (n=114) had higher-risk disease i.e. MDS with IPSS int-2 or high, AML with multilinear dysplasia and 20-30% blasts or CMML-II. We combined an initial cohort from Karolinska University Hospital (n=89) with a validating cohort from King's College Hospital, London (n=45). Studied endpoints were response, as defined by the IWG criteria, and survival. Since prolonged survival is the main goal for this cohort of patients, we believe that survival is the most relevant endpoint, supported by the fact that even non-responding patients have a survival benefit from Azacitidine (Gore et al, Haematologica, 2013).While neither clinical parameters nor mutations had a significant impact on response rate, both karyotype and mutational profile were strongly associated with survival from the start of treatment, see Table 1 and Figure 1-2. IPSS high-risk cytogenetics was negatively associated with survival (median 20 vs 10 months; p<0.001), whereas mutations in histone modulators (ASXL1, EZH2, MLL) were associated with prolonged survival (22 vs 12 months, p=0.001). This positive association was present in both cohorts and remained highly significant in the multivariate cox model. Importantly, patients with mutations in histone modulators lacking high-risk cytogenetics showed a survival of 29 months (response rate 73%) compared to 10 months (response rate 49%) in patients with the opposite pattern, see Figure 3. While TP53 was negatively associated with survival in the univariate analysis, neither RUNX1-mutations nor the number of mutations, previously reported as negative prognostic markers, appeared to influence survival in this cohort. In contrast, disease duration and cellularity showed a weak negative correlation with survival. We propose a model combining histone modulator mutational screening with cytogenetics in the clinical decision-making process for higher-risk MDS eligible for treatment with Azacitidine.Table 1Variables associated with survival. Univariate analyses used the log-rank test. The cox model included all listed variables except response rate in a multivariate analyses.Estimated median survival (months)Univariate p-valueCox regression p-valueHazard ratio (95% CI)Response rate: CR / mCR vs PR/HI vs SD/PD20 vs 20 vs 10<0.001IPSS cytogenetic risk group: Favorable vs Int vs Adverse20 vs 20 vs 10<0.001<0.001*3.00 (1.9-4.7)Disease duration ≥ 4 months: Yes vs No14 vs 170.440.05**1.01 (1.00-1.02)Marrow blasts ≥ 11%: Yes vs No14 vs 140.7Cellularity ≥ 70%: Yes vs No14 vs 200.20.021.013 (1.002-1.023)**ANC ≥ 1.3: Yes vs No14 vs 170.32Platelets ≥ 60: Yes vs No17 vs 120.07Transfusion dependent: Yes vs No13 vs 170.43Therapy related: Yes vs No17 vs 140.44Number of mutations: 0 vs 1 vs ≥ 217 vs 12 vs 170.64Epigenetic mutation: Yes vs No19 vs 120.03DNA methylation mutation: Yes vs No14 vs 140.64Histone modulator mutation: Yes vs No22 vs 120.0010.0070.499 (0.3-0.83)Splicing factor mutation: Yes vs No13 vs 170.31ASXL1 mutation: Yes vs No29 vs 120.03TET2 mutation: Yes vs No13 vs 160.45EZH2 mutation: Yes vs No20 vs 140.37SF3B1 mutation: Yes vs No13 vs 160.35RUNX1 mutation: Yes vs No17 vs 140.76SRSF2 mutation: Yes vs No20 vs 140.5TP53 mutation: Yes vs No9 vs 17<0.001*Comparing adverse cytogenetics vs the other groups. ** Disease duration, marrow blasts, cellularity, ANC and TPK were analyzed as a continuous variable in the cox model [Display omitted] [Display omitted] [Display omitted] DisclosuresMcLornan:Novartis: Research Funding, Speakers Bureau. Jädersten:Celgene: Other: speakers fee. Kulasekararaj:Alexion: Consultancy. Mufti:Celgene: Consultancy, Other: Speakers fee. Hellström-Lindberg:Celgene Corporation: Research Funding.

Feasibililty of Azacitidine As Bridge to Allogeneic Stem Cell Transplantation in Patients with Higher-Risk MDS or Low-Blast Count AML: Results of the BMT-AZA Multicenter Prospective Study

Background Allogeneic SCT remains the only curative option in myelodysplastic syndromes (MDS). We prospectively evaluated in a multicenter phase 2 GITMO (Italian Bone Marrow Transplantation Group) trial, the feasibility of allogeneic stem cell transplantation (ASCT, primary protocol end-point) after induction treatment with azacitidine (Vidaza, Celgene). According to the protocol, patients had to perform at least 4 and up to 12 cycles of azacitidine as induction treatment before ASCT. Patients not eligible for ASCT could continue treatment until disease progression.Methods Between November 2010 and September 2014, 102 patients were enrolled by 20 Italian hematology centers. Nine patients never started treatment due to progressive disease (PD, n=2), refusal (n=3), or unknown causes (n=4). Of remaining 93 patients, 70 had with IPSS Int-2/High-risk MDS, 15 WHO-defined acute myeloid leukemia (AML) and 8 chronic myelomonocytic leukemia (CMML). There were 32 females and 61 males with median age 59 yrs (range 21-66.5 yrs). At treatment start, ECOG performance status was: 0 in 66 patients, 1 in 17 and 2 in 10 patients, while MDS HCT-index was: low (0) in 43 patients, intermediate (1-2) in 31 and high (>2) in 18 patients. All 93 patients started azacitidine s.c. at the standard dose of 75 mg/sqm/day, 7 days/month, at a median of 0.8 months (range 0-105 months) from initial MDS diagnosis.Results At response assessment after a median of 4.5 cycles (range 1-11), 25% of patients (n=19) achieved complete remission (CR), 3% marrow-CR (n=2), 14% partial remission (PR, n=11), 9% hematologic improvement (HI, n=7), 35% had stable disease (SD, n=27) and 14% PD (n=11). ASCT was performed in 48 patients (52%), after a median of 4.5 azacitidine cycles (range: 1-11). Data on ASCT are presently available for 45 patients, transplanted with bone marrow (n=10 pts) or peripheral blood stem cells (n=35 pts) from an HLA-identical donor (sibling in 11, and MUD in 34 cases). Forty-five patients did not receive ASCT due to: disease relapse or progression (n=16, 35%), adverse events (n=12, 27%), refusal (n=5, 11%), or other causes (n=12, 27%).At a median follow-up of 18.5 months (range 0.2-31.5), 43 patients are alive (25 received ASCT), and 50 patients died. Causes of death are reported in Table 1. Median overall survival (OS) for the whole patient cohort was 13.4 months (95% CI: 10.9-18.6, Figure 1). Disease status after azacitidine was predictive of significantly improved survival for patients in CR/PR/HI, compared to SD or PD (n=77 patients who completed at least 4 cycles, Figure 2). ASCT considered as time-dependent covariate was associated to a significantly longer survival (p=0.008, HR 0.4, 95% CI: 0.2-0.8). Stratification of MDS according to IPSS and karyotype was not associated to survival.Conclusions Our study shows that allogeneic transplantation following azacitidine is feasible in HR-MDS/CMML and AML, with about 50% of patients being able to undergo HSCT. These data favourably compare with previous studies in MDS on ASCT preceded by conventional chemotherapy. Disease status at the time of HSCT confirms its significant prognostic role for survival, also in the context of hypomethylating treatment, where stabilization of disease also represents a therapeutic target. Disease relapse or progression remain the major causes of death indicating the need for other strategies aimed at improving disease control in MDS. [Display omitted] [Display omitted] [Display omitted] DisclosuresVoso:Celgene: Honoraria, Research Funding. Off Label Use: Azacitidine used as induction treatment before allogeneic stem cell transplantation in MDS. Finelli:Janssen: Other: Speaker; Novartis: Other: Speaker; Celgene: Other: Speaker, Research Funding.