Int-1 Risk Myelodysplastic Syndromes Research Articles

Effect of Deferasirox Combined with Erythropoietin Versus Erythropoietin Alone on Erythroid Response in Patients with Low- and Int-1-Risk Myelodysplastic Syndromes: Results of the Phase II Kallisto Trial

Background: Many patients with myelodysplastic syndromes (MDS) have anemia at diagnosis. Erythropoiesis-stimulating agents (ESAs), such as recombinant erythropoietin (EPO), remain the first-choice treatment for anemia in most International Prognostic Scoring System (IPSS) lower-risk MDS patients without del(5q). EPO (~40,000-60,000 U/week) yields ∼60% erythroid responses, as defined by the International Working Group (IWG) 2006 response criteria (Cheson et al. Blood 2006), when baseline EPO is low (<500 U/L) and transfusion requirement is absent/limited. Responses to ESAs occur mostly within 8-12 weeks of treatment. Addition of the oral iron chelator deferasirox (DFX) at low doses could lead to synergism, with elimination of free iron and reduction of toxic reactive oxygen species, improving the bone marrow environment, and enhancing hematopoietic function and response to EPO. Here we present results of a randomized, open-label, Phase II pilot study that evaluated low-dose DFX+EPO compared to EPO alone on erythroid response.Methods: Patients with IPSS Low- or Int-1-risk MDS (not secondary to treatment with radiotherapy, chemotherapy, and/or immunotherapy for malignant or autoimmune diseases; duration ≥3 months to <3 years), hemoglobin (Hb) ≥8-<10 g/dL, history of <10 RBC transfusions, serum ferritin >300-<1500 ng/mL, and endogenous EPO <500 U/L were enrolled. Patients were randomized 1:1 to DFX (dispersible tablet [DT; 10 mg/kg/day] or, once available, film-coated tablets [FCT; 7 mg/kg/day]) in combination with subcutaneous EPO (40,000 U/week, escalated to 60,000 U/week after 4 weeks if inadequate erythroid improvement) or EPO for 24 weeks (non-responders to EPO after 12 weeks could switch to DFX+EPO for a further 12 weeks). The primary endpoint was the difference in the proportion of patients achieving an erythroid response according to IWG 2006 response criteria (increase from baseline in Hb ≥1.5 g/dL) within 12 weeks. Secondary endpoints included evaluation of hematological responses, tolerability, and safety over 24 weeks.Results: Enrollment was stopped early because of recruitment issues. 23 MDS patients (mean age 72.9 [range 57.7-82.7] years; 43.5% male) were randomized to DFX+EPO (n=11) or EPO (n=12). Eight (34.8%) patients received prior transfusions (n=2 and n=6 in the DFX+EPO and EPO arms, respectively). Baseline serum ferritin was >500 ng/mL in 7 patients in each arm (n=14, 60.9%). After 12 weeks, 5 patients receiving EPO switched to DFX+EPO. Overall, 5 and 4 patients in the DFX+EPO and EPO arms, respectively discontinued; most commonly (n≥1) due to adverse events (AEs; n=4 and n=2). Median EPO exposure was 91 days in patients receiving EPO only (n=7; median dose 270,400 units/week); 77 days in patients receiving DFX DT+EPO (n=10; 295,227 units/week); 100 days in patients receiving DFX FCT+EPO (n=1; 338,800 units/week); and 161 days in patients who switched to DFX+EPO (n=5; 365,833 units/week). Median DFX exposure was 81 days in patients receiving DFX DT+EPO (median dose 10.3 mg/kg/day); 161 days in patients receiving DFX FCT+EPO (3.4 mg/kg/day); and 77 days in patients who switched to DFX+EPO (9.6 mg/kg/day). After 12 weeks, there were 3 (27.3%) erythroid responders in the DFX+EPO arm and 5 (41.7%) in the EPO arm (Table A). Hematologic improvement within 24 weeks was observed in 5 (45.5%) and 12 (100%) patients randomized to DFX+EPO and EPO treatment, respectively (Table B).The most common AEs (n≥3) over 24 weeks were: gastrointestinal disorders (n=5), and infections/infestations (n=3) in the DFX+EPO arm; musculoskeletal and connective tissue disorders (n=3) in the EPO alone arm; infections/infestations (n=4), general disorders, and administration-site conditions (n=3), and musculoskeletal and connective tissue disorders (n=3) in patients who switched to DFX+EPO. No deaths were reported.Conclusions: In this small Phase II, pilot study combining low-dose DFX (10 mg/kg/day) with EPO for the treatment of anemia in Low and Int-1 risk MDS patients, there was no beneficial effect on erythroid response. The combination was well tolerated, with no new or unexpected AEs. As reported by Meunier et al. (ASH 2016), higher erythroid proliferation rates were observed in vitro with lower (3 µM; ~5 mg/kg/day) vs higher (>5 µM) DFX concentrations. It remains of interest to investigate outcomes with lower DFX doses in combination with EPO, as well as the use of DFX after EPO failure. [Display omitted] DisclosuresGattermann:Takeda Pharmaceutical International Co.: Research Funding; Novartis: Honoraria, Other: Travel support; Celgene: Honoraria. DeBonnett:Novartis: Employment. Azmon:Novartis: Employment.

Clinical Outcomes of Decitabine Treatment for Patients with Lower-Risk Myelodysplastic Syndrome By the International Prognostic Scoring System

IntroductionDecitabine has shown clinical benefits in patients with International Prognostic Scoring System (IPSS) intermediate (INT)-2 or high risk myelodysplastic syndrome (MDS), but the benefits have not been well defined in patients with lower-risk disease group (IPSS low or INT-1). Recently, it was proposed that the prognosis for patients with lower-risk disease is heterogeneous, with a substantial fraction of these patients having poor survival. Therefore, we classified IPSS lower-risk MDS patients using the Lower-Risk Prognostic Scoring System (LR-PSS) and then identified clinical outcomes after decitabine treatment in each subgroup.MethodsTwo observational studies (DIVA [NCT01041846] and DRAMA [NCT01400633]) on the effectiveness of decitabine treatment in patients with IPSS INT-1, 2, or high risk MDS were previously conducted. This analysis included patients with IPSS INT-1 risk disease from these two studies, and the patients were classified into one of the LR-PSS categories (category 1, 2, or 3) classifying patients by clinical variables such as cytogenetic, age, hemoglobin, platelet levels, and bone marrow blast percentage, so that patients with higher scores would be classified into higher risk categories. Patients in each LR-PSS category were divided by response or non-response to decitabine treatment. Overall response rate (ORR) included complete response (CR), partial response, marrow CR with or without hematologic improvement (HI), and stable disease with HI by the modified IWG 2006 response criteria. The overall survival (OS) in each subgroup was calculated and we analyzed differences in survival by response in each category group.ResultsA total of 130 patients were included in this analysis: 12 patients (9.2%) in LR-PSS category 1, 65 (50.0%) in category 2, and 53 (40.8%) in category 3. Patients in LR-PSS category 3 were older, predominantly male, and had more comorbidities. Overall refractory cytopenia with multilineage dysplasia (RCMD) was the most common WHO subtype (53/130, 40.8%), but there was a trend toward more patients with refractory anemia with excess of blasts (RAEB-1) in LR-PSS category 3. Transfusion dependency at baseline was more common in LR-PSS category 3. ORR was observed in 74 patients (56.9%) after decitabine treatment: there was no significant difference in ORR between the LR-PSS groups (category 1, 58.3%; category 2, 56.9%; and category 3, 56.6%, P = 0.9940). Unlike patients in category 1 or 2, those in category 3 showed a significant difference in OS between responders and non-responders (P = 0.0015). A higher platelet count at baseline (≥50 x 109/L) was a favorable predictor of ORR (odds ratio, 2.24; 95% confidence interval [CI], 1.03 to 4.84) and a patient with lower percentage of bone marrow blasts at baseline (<4%) showed significantly lower ORR (odds ratio, 0.26; 95% CI, 0.12 to 0.56). The presence of comorbidities was the only variable significantly associated with OS in Cox proportional hazards regression model (hazard ratio, 0.35; 95% CI, 0.129 to 0.922).ConclusionsDecitabine treatment was effective in patients with lower-risk disease and showed a survival benefit in patients with lower-risk MDS classified as LR-PSS category 3 who responded to treatment. DisclosuresNo relevant conflicts of interest to declare.

A Clinical Study of Tomaralimab (OPN-305), a Toll-like Receptor 2 (TLR-2) Antibody, in Heavily Pre-Treated Transfusion Dependent Patients with Lower Risk Myelodysplastic Syndromes (MDS) That Have Received and Failed on Prior Hypomethylating Agent (HMA) Therapy

A Clinical Study of Tomaralimab (OPN-305), a Toll-like Receptor 2 (TLR-2) Antibody, in Heavily Pre-Treated Transfusion Dependent Patients with Lower Risk Myelodysplastic Syndromes (MDS) That Have Received and Failed on Prior Hypomethylating Agent (HMA) Therapy

A Phase 3 Randomized Placebo (PBO)-Controlled Double-Blind Trial of Darbepoetin Alfa in the Treatment of Anemia in Patients with Low or Intermediate-1 (Int-1) Risk Myelodysplastic Syndromes (MDS)

▪Background: Although erythropoiesis-stimulating agents (ESAs) are recommended in clinical guidelines to treat anemia in patients with lower-risk MDS, ESAs are not widely approved for this indication due to a lack of PBO-controlled trials. Aim: To evaluate the use of darbepoetin alfa (DAR) to treat anemia in patients with IPSS low / int-1 risk MDS in a phase 3 randomized controlled trial (EudraCT2009-016522-14, NCT01362140). Methods: Patients, enrolled from 12/2011 to 8/2014 in 9 European countries, had MDS per WHO 2008 criteria with IPSS low/int-1 risk, anemia [hemoglobin (Hb) ≤10 g/dL], low transfusion burden [<4 units in 2 consecutive 8-week (wk) periods prior to randomization], no previous treatment with ESAs or biologic-response modifiers, and serum EPO ≤500 mU/mL. Patients were randomized 2:1 to 24 wk of SC DAR 500 µg or PBO every 3 wk (Q3W), stratified by IPSS risk, followed by 48 wk of open-label (OL) DAR (dose frequency could be increased to Q2W during that time), and follow-up to assess survival and AML progression for 3 years (ongoing). The dose was withheld for Hb >12 g/dL and decreased if Hb increased by >1.5 g/dL in 3 wk without transfusions. Key endpoints were transfusion incidence from wk 5-24 and erythroid response (HI-E) per IWG 2006 criteria (≥1.5 g/dL Hb increase from baseline sustained for 8 wk without transfusions). Results: Randomized patients [N = 147, 55% male, all Caucasian, median age 74 (min-max: 28-88) years] had median Hb of 9.3 (min-max: 5.5-10.6) g/dL and median baseline EPO level of 69 (min-max: 4.3-497) mU/mL; 50.7% were IPSS low risk and 49.3% int-1 risk, IPSS-R rates were very low: 10%, low: 61%, intermediate: 23%, and high: 3%, IPSS karyotype rates were good: 91% and intermediate: 9%, and WHO classification was RA: 15%, RARS: 14%, RCMD: 44%, del5q: 9%, RAEB-1: 16%, and MDS-U/unknown: 2%. Completion rates for the 24-wk double-blind portion were DAR: 89% (87/98) and PBO: 80% (39/49). Transfusion incidence from wk 5-24 was significantly reduced with DAR [DAR: 36.1% (35/97) vs. PBO: 59.2% (29/49), p = 0.008]. In the 48-wk OL DAR period, 50.8% (64/126) of patients had transfusions. More DAR patients achieved HI-E in the double-blind period [DAR: 14.7% (11/75 evaluable) vs. PBO: 0% (0/35 evaluable), p = 0.016]. All 11 patients with HI-E had baseline EPO ≤100 mU/mL, 4/11 had a dose withheld for Hb >12 g/dL, and 10/11 had no transfusions in the 16 wk prior to randomization (none had transfusions in the 8 wk prior). In the 48-wk OL DAR period, 34.7% (34/98) of patients achieved HI-E; 11/38 (29%) prior PBO arm, 23/87 (26%) prior DAR arm (10 of the prior DAR had HI-E in the 24-wk portion); 6/34 had transfusions in the 16 wk prior to randomization, 30/34 received Q2W dosing at some point, 30/34 had baseline EPO ≤100 mU/mL, and 26/34 had doses withheld. Improved HI-E and transfusion responses were seen with more favorable status for IPSS-R but not IPSS (Figure). In the 48-wk OL DAR period, dose frequency increased from Q3W to Q2W in 81% (102/126) of patients; doses were held or reduced frequently (Table). Safety results from this trial (Table) were consistent with the previous DAR phase 2 MDS trial (Gabrilove BJH 2008, 142:379-393), with similar AML rates observed in PBO and DAR arms. Conclusion/Summary: In this phase 3, randomized, double-blind, PBO-controlled trial in anemic IPSS low/int-1 risk MDS patients, 24 wk of darbepoetin alfa Q3W significantly reduced transfusions and increased HI-E rates with no new safety signals. Most patients met criteria to change to Q2W dosing during the 48-wk OL period, suggesting that Q2W dosing may offer more benefit. The true clinical benefit of darbepoetin alfa may have been underestimated in this trial due to the nature of IWG 2006 HI-E criteria and the trial design (Hb measured Q3W, dose held if Hb >12 g/dL and decreased if Hb increased by >1.5 g/dL); additional ad hoc analyses are underway. [Display omitted] [Display omitted] DisclosuresPlatzbecker:Novartis: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Symeonidis:Amgen Inc.: Research Funding. Oliva:Amgen Inc.: Honoraria; Celgene: Honoraria, Speakers Bureau; La Jolla: Honoraria; Novartis: Speakers Bureau. Goede:Amgen Inc.: Honoraria. Delforge:Amgen Inc.: Honoraria. Mayer:Amgen Inc.: Research Funding. Badre:Amgen Inc.: Employment, Equity Ownership. Gasal:Amgen Inc.: Employment, Equity Ownership. Mehta:Amgen Inc.: Employment, Equity Ownership. Franklin:Amgen Inc.: Employment, Equity Ownership.

A Clinical Study of OPN-305, a Toll-like Receptor 2 (TLR-2) Antibody, in Patients with Lower Risk Myelodysplastic Syndromes (MDS) That Have Received Prior Hypomethylating Agent (HMA) Therapy

▪INTRODUCTION: Alterations of innate immune signaling, including overexpression of TLR2, are common in MDS. Signaling mediated by this receptor results in activation of NF-kB and the histone demethylase JMJD3 (KDM6B) leading to expression of multiple cytokines that can result in inhibition of hematopoiesis. Significant TLR2 overexpression in MDS bone marrow CD34+ cells, especially after HMA therapy, has been reported (Wei, Leukemia 2013). OPN-305 is a fully humanized antagonistic IgG4 kappa monoclonal antibody to TLR2 which significantly increases the formation of erythroid colonies (CFU-E) in BM CD34+ cells isolated from pts with lower-risk MDS in vitro. This data suggested the potential therapeutic value of OPN-305 in patients (pts) with MDS.METHODS: We designed a phase I/II trial of OPN-305 for pts with Low or Int-1 risk MDS by IPSS after failure to prior therapy with a HMA. Pts with isolated del(5q) should have received therapy with lenalidomide. Pts with prior history of AML or alloSCT were excluded from the study. Because, OPN-305 had not been previously used in pts with hematological malignancies, the study had an initial phase of N=10 pts using OPN-305 at a dose of 5 mg/kg every 4 weeks for a maximum of 9 cycles. Therapy could be repeated as long as there was no excess toxicity or progression. If after 16 weeks of therapy, there was no response, azacitidine on a 3 day schedule, could be added to OPN-305. Responses were evaluated following the revised 2006 IWG criteria. This initial cohort allowed evaluation of toxicity, pharmacokinetic analysis, receptor occupancy, and sequential analysis of cytokine profile. Depending on results, dose escalation to 10 mg/kg monthly could be instituted in a second cohort of N=5 pts.RESULTS: At the time of this report, 15 pts have been enrolled, 11 at the initial 5 mg dose and 4 at 10 mg/kg. All pts were evaluable for toxicity and 12 (80%) were evaluable for response. Patient characteristics are shown in Table 1. Median age was 73 years (range 48-87). Three (20%) pts were classified as Low risk and 12 (80%) as Intermediate-1 risk by IPSS. Seven pts had normal karyotype, 2 del(5q), 2 trisomy 8, 1 del(20q), 1 monosomy Y and 2 other single or double abnormalities. Median number of prior therapies was 2 (range 1-4) with a median duration of prior therapies of 28 months (range 4-62) (Figure 1). A total of 13 (87%) pts were transfusion dependent of red cells prior to enrollment. Median follow up is 8 months (1-16). Median number of cycles administered is 5 (2-17) with 5 (33%) pts having received addition of azacitidine after 16 weeks of therapy. A total of 5 (42%) pts developed AEs related to OPN-305. All AEs were grade 1 with gastrointestinal disorders being the most frequent (33%). At this point, no significant drug related toxicity has been documented with no excess infectious complications. Overall response rate in the form of hematological improvement was 50% (6/12) with 2 (17%) pts achieving transfusion independence. A total of 5 (33%) pts remain on study with 3 pts continuing on therapy off study. Three (20%) pts were taken off study due to progression to AML and 4 (27%) due to no response. Half-lives of OPN-305 in serum were >200 h at 5 mg/kg and >300 h at 10 mg/kg (Figure 2A). There was a greater-than-dose proportional increase in mean OPN-305 exposure (AUC) between 5 and 10 mg/kg. PK profiles after repeated dosing at 5 mg/kg in N=2 subjects and pre-dose (trough) levels in other subjects indicated some variability in the potential for accumulation. TLR-2 receptor occupancy in blood PBMCs and bone marrow aspirates was essentially complete in virtually all samples taken after OPN-305 administration (Figure 2B). There is no evidence of treatment related anti-drug antibodies. Compared with baseline, no statistically significant dynamic changes of IL-23, IL-18, IFN-r, IL-10, IL-1β, IL-6, IL-12 (p40), IL-12 (p70) and IL-8 levels where observed after treatment, among responders or non-responders or based on OPN-305 dosing.CONCLUSIONS: Treatment with OPN-305 in pts with previously treated lower-risk MDS was well tolerated with no significant toxicities and 50% ORR. Correlative studies suggest adequate receptor occupancy with no correlation between responses and cytokine levels. Because no effect on cytokine profile, we plan to continue to escalate the dose of OPN-305 and investigate its activity profile in front line therapy. [Display omitted] [Display omitted] [Display omitted] DisclosuresDiNardo:Daiichi Sankyo: Research Funding; Agios: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.

Clinical Outcomes of 420 MDS Patients Treated with 5-Azacytidine: Evaluation of Overall Survival, Duration of Treatment and Rate of Discontinuation in a Real Life Study from the Italian MDS Registry of Fondazione Italiana Sindromi Mielodisplastiche (FISM)

▪IntroductionAzacytidine(AZA) is the current standard of care for patients with high-risk myelodysplastic syndrome (MDS) in Europe. AZA has shown a survival advantage when compared with conventional therapies and has also shown activity in IPSS lower-risk patients. However, about 40% of patients do not respond and most patients show a loss of response within 2 years. Treatment options for MDS patients who progressed while on, failed to respond to, or became intolerant tohypomethylatingagents are scarce and it has been shown that overall survival (OS) is extremely short. Objectives of this study were to describe in a cohort of real life MDS patients treated with AZA, the reasons to discontinue treatment, and to evaluate their clinical outcomes.MethodsWe present here the results of a real life study from a large group ofnon selectedpatients recorded in the MDS registry of FondazioneItalianaSindromiMielodisplastiche(FISM). Only patients treated with AZA from January 2009 to June 2014 were considered for the analysis. All types of conventional published schedules of AZA were allowed. The primary end point was the evaluation of OS from start of AZA treatment to the date of death from any cause. Secondary end points were clinical response, cause of discontinuation, salvage treatments and OS from discontinuation of the drug.ResultsBetween January 2009 to June 2014 1799 newly diagnosed MDS patients were enrolled , and 420 received AZA; 271 patients received AZA as 1st line treatment, 115 patients as 2nd line treatment, 34 as a line ≥3rd. Median age was 73 years (IQR: 67-77); 261 patients (62%) were male. WHO diagnosis was RA or RARS (n=27, 6%), RCMD with or without RS (n=62, 15%) AREB-1 (n=126, 30%), AREB 2 (n=190, 45%), other subtypes (n=15, 4%). At start of AZA therapy IPSS score was low in 11 (3%), int-1 in 80 (19%), int-2 in 143 (34%), high in 54 patients (13%), and not available in 132 patients (31%). Forty-three (47%) low and int-1 risk MDS patients had a transfusion-dependent anemia. Patients received a median of 7 courses of treatment (range 3-12). Twenty-four patients (6%) received concomitant erythropoietin therapy. OS at 1 year from beginning of AZA therapy was 73% for the whole cohort (420 pts)(95%CI: 0.69-0.78), and median OS was 23 months, 25 months for patients with IPSS lower-risk MDS and 21 months for those with IPSS higher risk MDS (log-rank test: 0.72). OS after discontinuation of AZA was 8 months. Clinical response was reported according to IWG criteria only in 288/420 patients (69%); 94 patients (33%) achieved a hematological response, that was complete in 35 patients (12%) and partial in 59 (20%), 78 patients (27%) had stable disease while 116 (40%) patients did not respond. Response was achieved after a median of 6 cycles (IQR: 4-11), in both lower and higher risk MDS patients. After a median follow up of 16 months (IQR:7-35) in 97 patients (23%) AZA therapy was still ongoing and in 323 has been discontinued (77%). Interruption of treatment was due to loss of response/worsening of hematological parameters in 24 patients who achieved complete or partial response (7%) and in 20 patients with stable disease (6%). AML evolution was the cause for interruption in 105 cases (32%), death in 28 (9%), toxicity or poor compliance in only 26 (8%), while clinical decision of the treating hematologist determined interruption in 22 cases (7%). In additional 98 patients AZA was discontinued early for reasons not reported by the treating physician (30%). Of the 323 patients who discontinued AZA 10 (3%) were managed with intensive AML-like chemotherapy, 17 (5%) underwent an allogeneic HSCT, 18 (6%) received low-dose chemotherapy, 42 (14%) other treatments and 236 patients (73%) received only transfusions and other supportive therapy.ConclusionsOur data confirm that AZA therapy is effective for MDS patients, both with higher and lower IPSS risk disease. Response rate is consistent with what previously reported and median OS is 23 months. The interesting observation is that at 16 months, 77% of patients had discontinued treatment, either for progression or loss of response (45% of cases) and only in 8% of cases for reported toxicity. As there are few treatment options after AZA interruption, it is important to establish the reasons other than progression yielding to a stop in therapy, in order to avoid too early discontinuation and loss of survival advantage. DisclosuresFinelli:Celgene: Research Funding; Celgene: Other: Speaker fees; Novartis: Other: Speaker fees. Angelucci:Novartis oncology, celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Santini:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Astex: Consultancy; Amgen: Consultancy; Onconova: Consultancy.

Iron Chelation Is Associated with Improved Survival Adjusting for Disease and Patient Related Characteristics in Low/Int-1 Risk MDS at the Time of First Transfusion Dependence: A MDS-CAN Study

Iron Chelation Is Associated with Improved Survival Adjusting for Disease and Patient Related Characteristics in Low/Int-1 Risk MDS at the Time of First Transfusion Dependence: A MDS-CAN Study

53 LUSPATERCEPT INCREASES HEMOGLOBIN AND REDUCES TRANSFUSION BURDEN IN PATIENTS WITH LOW OR INTERMEDIATE-1 RISK MYELODYSPLASTIC SYNDROMES (MDS): PRELIMINARY RESULTS FROM A PHASE 2 STUDY

Introduction. ACE-536, a recombinant fusion protein containing modified activin receptor type IIB and IgG Fc, is being developed for the treatment of anemias due to ineffective erythropoiesis, such as myelodysplastic syndromes (MDS). Patients with MDS often have elevated levels of erythropoietin (EPO) and may be non-responsive or refractory to erythropoiesis-stimulating agents (ESAs). MDS patients have also been shown to have increased serum GDF11 levels (Suragani R et al., Nature Medicine 2014) and increased Smad 2/3 signaling in the bone marrow (Zhou L et al., Blood 2008). ACE-536 binds to ligands in the TGF-s superfamily, including GDF11, inhibits Smad 2/3 signaling, and promotes late-stage erythroid differentiation via a mechanism distinct from ESAs. RAP-536 (murine version of ACE-536) reduced Smad 2 signaling, increased hemoglobin (Hb) levels and decreased bone marrow erythroid hyperplasia in a mouse model of MDS (Suragani R et al., Nature Medicine 2014). In a healthy volunteer study, ACE-536 was well-tolerated and increased Hb levels (Attie K et al., Am J Hematol 2014). Aims. This is an ongoing, phase 2, multicenter, open-label, dose-finding study to evaluate the effects of ACE-536 on anemia in patients with Low or Int-1 risk MDS who have either high transfusion burden (HTB, defined as ≥4 units RBCs/8 weeks prior to baseline) or low transfusion burden (LTB, defined as Methods.Inclusion criteria included Low or Int-1 risk MDS, age ≥ 18 yr, anemia (defined as either being HTB patient or having baseline Hb 500 U/L or nonresponsive/refractory to ESAs, no prior azacitidine or decitabine, and no current treatment with ESA, G-CSF, GM-CSF, or lenalidomide. In the dose escalation phase, ACE-536 was administered by subcutaneous (SC) injection once every 3 weeks in 7 sequential cohorts (n=3-6) at dose levels of 0.125, 0.25, 0.5, 0.75, 1.0, 1.33 and 1.75 mg/kg for up to 5 doses with a 3-month follow-up. An expansion cohort (n=30) is planned, and all patients completing this study may enroll in a 12-month extension study. Results. Preliminary data were available for 26 patients (7 LTB/19 HTB) as of 18 Jul 2014. Median age was 71 yr (range: 27-88 yr), 50% were female, 54% had prior EPO therapy and 15% had prior lenalidomide. 69% were WHO subtype RCMD, and the remaining patients were del(5q), RARS, or RAEB-1. Mean (SD) baseline Hgb for the LTB patients (n=7) was 9.1 (0.4) g/dL. Mean (SD) units RBC transfused in the 8 weeks prior to treatment was 0.9 (1.1) units for the LTB patients and 6.3 (2.4) units for the HTB patients. Two of the 7 LTB patients had an increase in mean Hb ≥1.5 g/dL over 8 weeks compared to baseline. Mean maximum Hb increase in the LTB patients was 0.8, 1.0, 2.2, and 2.7 g/dL in the 0.125 (n=1), 0.25 (n=1), 0.75 (n=3), and 1.75 (n=2) mg/kg dose groups, respectively. Six of the 7 LTB patients achieved RBC transfusion independence (RBC-TI) for ≥8 weeks during the study. Six of the 19 HTB patients had a ≥4 unit or ≥50% reduction in RBC units transfused over an 8-week interval during the treatment period compared to the 8 weeks prior to treatment; five of these 6 patients achieved RBC-TI ≥ 8 weeks during the study (range 71-152 days). Increases in neutrophil count following study drug administration were observed in some patients. ACE-536 was generally well tolerated. No related serious adverse events have been reported to date. The most frequent adverse events regardless of causality were: diarrhea (n=4, grade 1/2), bone pain, fatigue, muscle spasms, myalgia, and nasopharyngitis (n=3 each, grade 1/2). Conclusions. Based on preliminary data in Low or Int-1 MDS patients, ACE-536 administered SC every 3 weeks for up to 5 doses increased Hb levels or decreased transfusion requirement, with a favorable safety profile. These data strongly support further evaluation of longer-term treatment with ACE-536 in patients with MDS. Disclosures Platzbecker:Celgene: Honoraria, Research Funding. Germing:Celgene: Honoraria, Research Funding. Goetze:Celgene Corp: Honoraria; Novartis Pharma: Honoraria. Radsak:Celgene: Research Funding. Hankin:Acceleron Pharma: Employment, Equity Ownership. Wilson:Acceleron Pharma: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership. Attie:Acceleron Pharma: Employment, Equity Ownership.

ACE-536 Increases Hemoglobin and Reduces Transfusion Burden in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS): Preliminary Results from a Phase 2 Study

▪Introduction. ACE-536, a recombinant fusion protein containing modified activin receptor type IIB and IgG Fc, is being developed for the treatment of anemias due to ineffective erythropoiesis, such as myelodysplastic syndromes (MDS). Patients with MDS often have elevated levels of erythropoietin (EPO) and may be non-responsive or refractory to erythropoiesis-stimulating agents (ESAs). MDS patients have also been shown to have increased serum GDF11 levels (Suragani R et al., Nature Medicine 2014) and increased Smad 2/3 signaling in the bone marrow (Zhou L et al., Blood 2008). ACE-536 binds to ligands in the TGF-ß superfamily, including GDF11, inhibits Smad 2/3 signaling, and promotes late-stage erythroid differentiation via a mechanism distinct from ESAs. RAP-536 (murine version of ACE-536) reduced Smad 2 signaling, increased hemoglobin (Hb) levels and decreased bone marrow erythroid hyperplasia in a mouse model of MDS (Suragani R et al., Nature Medicine 2014). In a healthy volunteer study, ACE-536 was well-tolerated and increased Hb levels (Attie K et al., Am J Hematol 2014).Aims. This is an ongoing, phase 2, multicenter, open-label, dose-finding study to evaluate the effects of ACE-536 on anemia in patients with Low or Int-1 risk MDS who have either high transfusion burden (HTB, defined as ≥4 units RBCs/8 weeks prior to baseline) or low transfusion burden (LTB, defined as <4 units RBCs/8 weeks prior to baseline). Study outcomes include erythroid response (either Hb increase in LTB patients or reduced transfusion burden in HTB patients), safety, tolerability, PK, and PD biomarkers.Methods.Inclusion criteria included Low or Int-1 risk MDS, age ≥ 18 yr, anemia (defined as either being HTB patient or having baseline Hb < 10.0 g/dL in LTB patient), EPO >500 U/L or nonresponsive/refractory to ESAs, no prior azacitidine or decitabine, and no current treatment with ESA, G-CSF, GM-CSF, or lenalidomide. In the dose escalation phase, ACE-536 was administered by subcutaneous (SC) injection once every 3 weeks in 7 sequential cohorts (n=3-6) at dose levels of 0.125, 0.25, 0.5, 0.75, 1.0, 1.33 and 1.75 mg/kg for up to 5 doses with a 3-month follow-up. An expansion cohort (n=30) is planned, and all patients completing this study may enroll in a 12-month extension study.Results. Preliminary data were available for 26 patients (7 LTB/19 HTB) as of 18 Jul 2014. Median age was 71 yr (range: 27-88 yr), 50% were female, 54% had prior EPO therapy and 15% had prior lenalidomide. 69% were WHO subtype RCMD, and the remaining patients were del(5q), RARS, or RAEB-1. Mean (SD) baseline Hgb for the LTB patients (n=7) was 9.1 (0.4) g/dL. Mean (SD) units RBC transfused in the 8 weeks prior to treatment was 0.9 (1.1) units for the LTB patients and 6.3 (2.4) units for the HTB patients.Two of the 7 LTB patients had an increase in mean Hb ≥1.5 g/dL over 8 weeks compared to baseline. Mean maximum Hb increase in the LTB patients was 0.8, 1.0, 2.2, and 2.7 g/dL in the 0.125 (n=1), 0.25 (n=1), 0.75 (n=3), and 1.75 (n=2) mg/kg dose groups, respectively. Six of the 7 LTB patients achieved RBC transfusion independence (RBC-TI) for ≥8 weeks during the study.Six of the 19 HTB patients had a ≥4 unit or ≥50% reduction in RBC units transfused over an 8-week interval during the treatment period compared to the 8 weeks prior to treatment; five of these 6 patients achieved RBC-TI ≥ 8 weeks during the study (range 71-152 days). Increases in neutrophil count following study drug administration were observed in some patients.ACE-536 was generally well tolerated. No related serious adverse events have been reported to date. The most frequent adverse events regardless of causality were: diarrhea (n=4, grade 1/2), bone pain, fatigue, muscle spasms, myalgia, and nasopharyngitis (n=3 each, grade 1/2).Conclusions. Based on preliminary data in Low or Int-1 MDS patients, ACE-536 administered SC every 3 weeks for up to 5 doses increased Hb levels or decreased transfusion requirement, with a favorable safety profile. These data strongly support further evaluation of longer-term treatment with ACE-536 in patients with MDS. DisclosuresPlatzbecker:Celgene: Honoraria, Research Funding. Germing:Celgene: Honoraria, Research Funding. Goetze:Celgene Corp: Honoraria; Novartis Pharma: Honoraria. Radsak:Celgene: Research Funding. Hankin:Acceleron Pharma: Employment, Equity Ownership. Wilson:Acceleron Pharma: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership. Attie:Acceleron Pharma: Employment, Equity Ownership.

Hepcidin and GDF15 Levels during the First 2 Years Follow-up in Patients with Low and Int-1 Risk Myelodysplastic Syndromes (MDS) from the European Leukemianet MDS Registry

Background: The EUMDS registry is a prospective observational registry to collect data on lower risk MDS. 17 Countries and 133 centers are participating. We analyzed serum from 101 patients for ferritin, hepcidin, growth differentiation factor 15 (GDF15) and C-reactive protein (CRP) at six-month intervals in order to evaluate temporal changes in iron metabolism.Objective: To explore hepcidin and GDF15 levels over time in lower risk MDS patients and their relation with WHO2001 subtype, transfusion history and conventional iron parameters.Results: The median age of the study population was 73 years (range 44-95 years). The majority was male: 64%. Distribution according to WHO2001 MDS subtype was RCMD (41%), RARS (25%), RA (14%), RAEB (11%), 5q-syndrome (6%) and RCMD-RS (3%). Table 1 shows iron parameters at registration, 1 year and 2 years follow-up both in transfusion-dependent (TD) and transfusion-independent (TI) patients and stratified according to MDS subtypes: RS (RARS/RCMD-RS) or MDS Other (RA/RCMD/RAEB/5q-syndrome). Serum ferritin was increased in TD patients with a median concentration at registration of 550µg/L and at 2 years 818µg/L, compared to TI patients (median <250µg/L, all time points). During follow-up ferritin was most elevated in patients who received >10 red blood cell (RBC) units: median at registration 1482µg/L - 2 years 1970µg/L. Ferritin correlated significantly with hepcidin (r=0.57; p<0.001) as well as CRP: r=0.27, p<0.001. Median CRP was within reference range (<10mg/L) for both TD and TI patients at registration and during follow-up, but mainly TD patients had elevated CRP levels >50mg/L. Median serum hepcidin levels were elevated in TD patients at registration and remained elevated during follow-up, especially in patients with >10 RBC units transfused (median 27.4nmol/l at registration, 12.8nmol/l at 2 years). Remarkable fluctuation in hepcidin levels occurred in patients with elevated hepcidin during follow-up. Even in the longitudinal cohorts hepcidin fluctuated considerably, maybe due to the interval between the previous transfusion and the measurement of hepcidin or due to diurnal fluctuation. Hepcidin was lowest in MDS RS TI patients and showed a tendency to decrease over time from a median level of 4.4nmol/l at registration to 2.4nmol/l after 2 years, associated with ineffective erythropoiesis. This is supported by the high median GDF15 in these patients. Lowest GDF15 was found in TD patients with ‘MDS Other’ associated with transfusional load. The number of transfused RBC units did not affect the median GDF15 levels.Conclusions: Hepcidin levels were influenced by RBC transfusion history, but hepcidin levels appear to decrease over time in the RS subtype only. Interestingly, increase in hepcidin after transfusions was already visible early in follow-up, depending on the transfusional load and erythropoietic activity of the bone marrow. GDF15 concentration appeared to be most related to MDS subtype, functioning as a marker of ineffective erythropoiesis.Table1:ferritin, hepcidin and GDF15 during-follow-upRegistration1 yr follow-up2 yrs follow-upNMedian(p25-p75)NMedian(p25-p75)NMedian(p25-p75)Ferritin (µg/L)101286 (138 - 558)83287 (149 - 845)66347 (191 - 818)MDS Other: TI53205 (87 - 389)31148 (78 - 288)25202 (71 - 319)MDS Other: TD20479 (279 - 877)29845 (481 - 1538)22841 (323 - 2387)RARS/RCMD-RS: TI25268 (195 - 558)19233 (170 - 323)10319 (222 - 379)RARS/RCMD-RS: TD3610 (108 - 1382)41909 (1206 - 2935)9712 (590 - 1222)Hepcidin (nmol/L)1005.2 (3.0 - 9.9)835.8 (2.7 - 14.0)665.2 (2.5 - 9.9)MDS Other: TI534.6 (2.8 - 8.4)314.4 (2.3 - 8.1)254.2 (2.5 - 6.8)MDS Other: TD2011.1 (4.9 - 21.0)2917.2 (9.2 - 22.3)229.6 (4.5 - 17.1)RARS/RCMD-RS: TI244.2 (2.1 - 6.1)193.5 (1.6 - 5.1)102.4 (1.6 - 3.9)RARS/RCMD-RS: TD39.8 (6.0 - 11.1)49.3 (7.3 - 12.1)95.2 (2.9 - 9.3)TI: 0 RBC units814.5 (2.8 - 8.4)514.0 (2.0 - 7.5)373.1 (2.1 - 6.7)TD: ≤10 RBC units1710.6 (4.7 - 14.9)149.2 (5.3 - 17.2)144.3 (2.4 - 8.7)TD: >10 RBC units227.4 (15.7 - 39.1)1818.1 (12.7 - 24.5)1512.8 (9.3 - 21.3)GDF15 (ng/L)1011945 (1207 - 3611)822467 (1659 - 4318)662582 (1519- 5332)MDS Other: TI531831 (1100 - 3176)311902 (1076 - 2698)251702 (1136 - 3564)MDS Other: TD201452 (1169 - 2789)282583 (1937 - 4493)222556 (1661 - 4050)RARS/RCMD-RS: TI253532 (2124 - 4211)193148 (2195 - 4560)103661 (1986 - 5524)RARS/RCMD-RS: TD32196 (1869 - 2893)42996 (1806 - 5141)95555 (3204 - 7488) DisclosuresHellström-Lindberg:Celgene: Research Funding. Symeonidis:Celgene: Research Funding; Novartis Oncology: Research Funding; Amgen: Research Funding; Novartis Oncology: Consultancy; Amgen: Consultancy. de Witte:Novartis: Research Funding; Novartis: Honoraria; Celgene: Consultancy; Novartis: Consultancy.

Treatment Outcome of Patients with Myelodysplastic Syndromes (MDS) in Regular Care: Incidence of IPSS Risk Groups and Different Therapies in the German Outpatient MDS Registry

The international prognostic scoring system (IPSS) for MDS patients (pts) receiving supportive care predicts a median overall survival of 68.4 months (mo), 42 mo, 14.4 mo and 4.8 mo according to the subgroups low, Int-1, Int-2, and high-risk, respectively. In July 2009, we established the German outpatient MDS registry with the aim to describe diagnostic procedures, treatment and course of disease of MDS pts in the community outpatient setting. In this analysis we evaluate the incidence of the IPSS subgroups, the frequencies of different therapies and the outcome, respectively.Methods: Newly diagnosed pts with MDS confirmed by bone marrow biopsy who gave informed consent were registered in an online database (IoStudy®). Baseline characteristics and diagnostics as well as a quarterly update of the course of disease were documented.Results: From July 2009 to March 2014 (56 mo) 1368 pts from 78 institutions were registered. Mean age was 73.5 years (y) (min-max 26.5 - 94.3 y, median 74.5 y) and 41% were women. 1,262 pts (92.3%) were evaluable for follow-up with a mean observation time (OT) of 21.7 mo (median: 19 mo). At diagnosis, IPSS risk classification was available in 898/1,262 (71%) pts. OT, overall survival (OS), number of pts (N) with epigenetic and iron-chelation therapy (ICT) over the entire term and the need of transfusions (tx) per quarter (Q) are given according to risk groups and treatment in the table. The figure shows the estimated Kaplan-Meyer-Plot for the IPSS risk groups. 180/1,315 pts (13.7%) received ICT, whereas 1,035 did not (86.3%). Median OS was 51 (95% confidential interval (CI) 44.7-57.3) and 49 mo (95% CI 43.7-54.3) (p = 0,281) for those with and without ICT, respectively.Conclusion: In the community outpatient setting in Germany, epigenetic therapy is used in a relative high proportion of pts with int-2 risk (57.1%) and high risk MDS (63.5%) at diagnosis, as well as in a substantial minority of patients with low-risk (6.7%) and int-1 risk (28.9%) MDS at progression. In the higher risk groups, transfusion need decreased more than 10% over time and overall survival was substantially longer than predicted by the IPSS. This may be considered as an empirical evidence for the efficacy of the new therapeutic options in regular care.Supported by Celgene, Munich, and Novartis, Erlangen, Germany [Display omitted] [Display omitted] DisclosuresSteinmetz:Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Severin:Novartis: Research Funding; Celgene: Research Funding. Germing:Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Schmitz:Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau. Gattermann:Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

Incidence of Atrx Mutations in Myelodysplastic Syndromes (MDS)

INTRODUCTIONAcquired α-thalassemia MDS (ATMDS) is an acquired syndrome characterized by a somatic point mutation or splicing defect in the ATRX gene in patients with myeloid disorders, primarily MDS. No large series have assessed its incidence in these pathologies. The ATRX protein is a chromatin-remodeling factor that may act as a transcriptional cofactor and plays an important role in the epigenetic regulation of gene expression (1). The unusual microcytosis in the context of MDS is due to a reduced synthesis of α-globin related to a dramatic down regulation of α-globin gene expression by inactivating mutation in the ATRX gene (2). We tried to better determine the frequency of ATRXmutations in a MDS registry and a clinical trial cohort.METHODSWe first used next-generation sequencing (NGS) on samples from 80 patients included in GFM-AZA-EPO-2008-01 study, a phase II study of azacitidine combined to EPO in IPSS low and int-1 risk MDS patients resistant to EPO. All coding exons of ATRXwere sequenced using the following methodology: Library preparation was performed using the Ion Ampliseq™ Library kit 2.0-384 LV (Life Technologies®). Template-positive Ion Sphere Particles™ were prepared using the Ion OneTouch™ 200 Template Kit v2 (Life Technologies®). Sequencing was performed with the Ion PGM™ 200 Sequencing Kit and the Ion 318™ Chip on the Personal Genome Machine® (PGM™) platform (Life Technologies®). Data files were independently analysed using two softwares: Torrent Browser™ (Life Technologies®) and SeqNext™ (JSI® Medical Systems).We then focused on the GFM registry, started in 2003, which includes 2980 MDS patients (at diagnosis regardless of the MDS type) and searched by direct Sanger method for mutations in the ATRXgene in MDS with unexplained microcytosis (MCV lower or equal to 80), ie without iron deficiency, inflammatory disease or history of inherited hemoglobinopathy.RESULTSNGS of ATRX gene in the 80 patients included in GFM-AZA-EPO-2008-01 study found no mutation. Of the 2980 patients in the GFM register, 139 had MCV below 80, unexplained in 58 of them. Out of these 58 patients, 14 had available material for ATRX gene sequencing by Sanger method. 2/14 patients were already known to have ATMDS, a RCMD and a CMML. In the remaining 12 patients, a mutation was found in 4 cases: a missense mutation in exon 9, a missense mutation in exon 4, a deletion in intron 9 with a frame shift and an addition in exon 1. Those mutations, to our knowledge, had not yet been described in ATMDS.Therefore, of 2980 patients with MDS, we described 6 ATMDS (5 males, 1 female), ie an incidence of 6/2980 or 0.2%. However, 6/14 or 43% of patients with unexplained microcytosis had a mutation of ATRXand only 14/58 patients with unexplained microcytosis could be sequenced, suggesting an incidence closer to 6x58/14/2980 or 0.8%. There was no recurrent mutation. Of the 6 patients (median age was 76 years), 1 had RCUD, 1 CMML, 1 RAEB-2 and 3 RAEB-1. All karyotypes were different: favorable (n=2), intermediate (n=3) and poor (n=1) and IPSS was low (n=1), int-1 (n=3) and high (n=1). Median survival was 31.5 months. In the CMML patient, microcytosis was found 7 years before diagnosis. In the other 5 patients, microcytosis was discovered concomitantly with MDS. In 4 patients, microcytosis disappeared during the disease course. 2 patients died from AML progression, 2 from other causes and 2 were still alive.CONCLUSIONOur data confirm the low frequency of ATRX mutations in MDS: 0% in an unselected clinical trial cohort of 80 lower risk MDS, 0.2 to 0.8% in a multicenter registry of 2980 MDS and 42% of MDS with unexplained microcytosis in this same registry. We also confirmed that these mutations can be found in all types of MDS. Larger studies are required to determine the prognostic value of these rare and non recurrent ATRXmutations. 1.Law MJ. Cell. 2010.2.Steensma DP, Blood. 2005 DisclosuresNo relevant conflicts of interest to declare.

Durable Hematological and Major Cytogenetic Response in a Patient with Isolated 20q Deletion Myelodysplastic Syndrome Treated with Lenalidomide

Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder characterized by ineffective hematopoiesis. It is characterized by peripheral blood cytopenia and significant risk of progression to acute myeloid leukemia result. Deletion of the long arm of chromosome 20 (20q deletion) is present in 3–7% of patients with MDS. Lenalidomide is an immunomodulatory agent with antiangiogenic activity. It is FDA approved for the treatment of anemia in patients with low or int-1 risk MDS with chromosome 5q deletion with or without additional cytogenetic abnormalities. Study of lenalidomide in patients with MDS without 5q deletion but other karyotypic abnormalities demonstrated meaningful activity in transfusion dependent patients; however, response of patients with isolated 20q deletion to lenalidomide is not known. We are reporting a patient with 20q deletion MDS treated with lenalidomide after he failed to respond to azacytidine; to our knowledge this is the first report of a patient with isolated 20q deletion treated with lenalidomide.

P-295 Azacytidine 75 mg/m2 ×5 day in high-risk myelodisplastic syndromes and acute myeloid leukemia refractory/relapsed patients

Background: In higher-risk patients with myelodysplastic syndromes (MDS), the DNA methyltransferase inhibitors produce responses in 20% to 30% of patients and azacitidine (AZA) has demonstrated a survival advantage when comparedwith conventional therapies. Introduction: AZA is increasingly used in low-risk patients failing to respond to recombinant human erythropoietin (r-EPO) and in acute myeloid leukaemia patients (AML) with low marrow blast count or considered not fit for intensive chemotherapy. Purpose:We report a retrospective review on AZA treatment of MDS and AML patients in the common clinical practice of an Italian region (Liguria). Materials and Methods: Of 67 patients who started therapy only 46 patients received at least 4 courses of therapy, and were therefore considered evaluable for response and included in the study. Median age was 74 years (56-84), male/female ratio was 25/21. Nine patients (19%) had untreated AMLwithmarrow blasts ranging from 25 to 41%. MDS patients had RA or RARS (n.7, 19%), AREB-1 (n. 13, 35%), AREB 2 (n. 15, 40%), other forms (n. 2, 5%). In MDS patients the IPSS score was low/int-1 in 18 pts, int-2/high in 13 pts, not assessed in 7 pts. Twenty-six patients had a transfusion-dependent anaemia and the median number of packed erythrocyte units transfused weekly was 1 (range 1-2). All low and int-1 risk MDS patients had transfusion dependent anaemia and were unresponsive to r-EPO. Results: After a median of 8 courses (range 4-44) 26 patients (63%) achieved a haematological response (CR in 26%, PR in 24%, HI in 6,5%) whereas 20 (43,5%) were unresponsive. According to diagnosis and IPSS score responders were 6 (66,6%) among AML patients (CR 1, PR 4, HI 1), 10 (55,5%) in low/int-1 risk MDS patients and 7 (54%) among int-2/high risk MDS patients (CR 4, PR 3). Response was achieved after a median of 5 (range 3-6), 3 (range 2-12) and 5 (range 1-12) AZA courses in AML, low/int-1 risk and int-2/high risk MDS patients, respectively. Grade 1-2 myelotoxicity was commonly observed but no life threatening infections were reported. Eight-teen patients concomitantly received r-EPO therapy. Response lasted a median of 16 months (range 4-40) and median survival was 6 months in AML patients (4-9) and 23 months (6-48) in MDS patients. Conclusions: These preliminary data confirm efficacy and feasibility of AZA therapy in the common clinical practice, for both AML and all risk MDS patients.

Outcome of Patients with Lower-Risk Myelodysplastic Syndrome (MDS) After Azacitidine (AZA) Treatment Failure.

AbstractAbstract 2815▪▪This icon denotes a clinically relevant abstract Background:Azacitidine has emerged as the standard of care for treatment of higher risk MDS based upon results of the AZA-001 study. Several groups reported poor outcomes after AZA failure in patients with int-2 or high risk International Prognostic Scoring System (IPSS) risk groups with a median overall survival (OS) ranging from 4–8 months (mo). In the USA, AZA is approved for all FAB types and risk groups and is as first or second line therapy for anemia after erythroid stimulating agents in low /int-1 risk non-deletion 5q MDS and is the treatment of choice for thrombocytopenia. The outcome of patients with lower risk myelodysplastic syndrome (MDS) after AZA failure has not been characterized. We report our experience in a large cohort of low/int-1 (lower risk) MDS patients after AZA failure. Methods:Patients were identified through the Moffitt Cancer Center (MCC) MDS database. Individual charts were reviewed and relevant clinical data was extracted. Patients with low or intermediate-1 (int-1) risk disease as defined by IPSS who had received AZA treatment were identified. These patients were also risk stratified based on Global MD Anderson Score (MDAS). The primary objective was to estimate OS in these patients after AZA failure. AZA failure was defined as failure to respond after 4 or more treatment courses, loss of response, or disease progression while on therapy. All responses were defined according to the International Working Group (IWG) 2006 criteria. The Kaplan–Meier method was used to estimate median overall survival. Results:Two hundred eighty MDS patients with low/int-1 IPSS risk who had received AZA treatment were identified. Most patients (81%) were greater than 60 years of age (median, 69 years), and 90% of AZA treated patients were RBC transfusion dependent. Refractory cytopenia with multilineage dysplasia (RCMD) was the most common WHO subtype (44%), and 81% of patients had good risk cytogenetics (Table-1).The median time from MDS diagnosis to AZA treatment was 12.3 months; median number of AZA cycles received was six. At the time of AZA treatment, 241 patients (86 %) were risk stratified as int-1 versus 39 patients (14 %) who were stratified as low risk IPSS. The IWG 2006 responses to AZA treatment included 4% CR (n=10 ), 1% marrow CR (n=2), 4% PR (n=10), 27% Hematological improvement (HI) (n=75), whereas 52% (n=146) had stable disease with no HI (n=146) and 10% had progressive disease (n=10); 6 patients (2%) died on therapy, and responses were missing in 2 patients (<1%). The overall best response (HI or better) was 36%.The median OS for the entire cohort after AZA failure was 18.5 months (95% CI [13.5–23.5 mo], Figure 1A). The median OS for patients with low risk IPSS disease from time of AZA failure was 46 months versus 15 mo for int-1 patients (p<0.005, Figure 1B). When utilizing MDAS, median OS was 33.3 months for low risk patients, 21 months for int-1, 11 months for int-2, and 7.5 months for poor risk patients (p=0.005). Conclusions:To our knowledge this is the first report describing the outcome of lower risk MDS patients after AZA treatment failure. Outcome is particularly poor for those patients with int-1 risk MDS, with a median OS of 15 mo. Global MDAS identified patients upstaged to int-2 or high risk with less than one year OS. There is unmet need for effective novel therapies for lower risk MDS patients after AZA failure.Table 1Baseline characteristicsVariableN (%)N=280Age>60227 (81%)GenderMale74 (64%)WHO subtypeRA26 (9%)RARS33 (12%)RCMD123 (43%)Del5 q9 (3%)RAEB-155 (20%)RAEB-26 (2%)MDS-U7 (3%)CMML8 (3%)MDS/MPN-U13 (5%)IPSSDiagnosis Prior AZALow61 (22%) 39 (14%)Int-1219 (78%) 241 (86%)MDASLow47 (17%)Int-1159 (57%)Int-261 (22%)High13 (5%)CytogeneticsGood227 (81%)Intermediate43 (15%)Poor8 (3%) [Display omitted] Disclosures:List:Celgene: Consultancy. Komrokji:Celgene: Speakers Bureau.

Very High Rate of Leukemic Transformation and Poor Survival in Patients with Lower Risk Myelodysplastic Syndrome (MDS) Who Dynamically Acquire FLT3 Molecular Alteration (FLT3m): Study of 290 MDS Patients with Sequential Mutation Analysis

AbstractAbstract 3802 Background and Aims:Molecular alterations of FLT3, in particular internal tandem duplication (ITD) in the juxtamembrane domain or point mutation in the tyrosine kinase domain (TKD), are found in approximately 30% of acute myeloid leukemia (AML). In contrast, FLT3 molecular alteration (FLT3m) is not commonly detected in MDS patients with reported incidence of 0.6–6%. Limited data is available for its prognostic significance in MDS, especially when it is dynamically acquired during the follow up. The aims of this study were to evaluate: 1) the incidence of dynamic acquisition of FLT3m in lower risk MDS patients; 2) the association between FLT3m acquisition and other molecular/cytogenetic aberrations and 3) the prognostic impact of dynamic FLT3m acquisition on AML transformation and survival. Methods:We analyzed 290 patients with low and intermediate-1 (Int-1) risk MDS by IPSS (lower risk MDS), who were tested for FLT3m by semi-quantitative DNA-based PCR capillary electrophoresis assay on at least two occasions (at time of diagnosis and at least once thereafter) between 1/2000 and 1/2010. Result:Median age of the analyzed cohort was 64 years (range, 23–91), and 62% were female. Seventy five (26%) patients were IPSS low risk and 215 (74%) were int-1 risk. RAEB was the most frequent WHO diagnosis (N = 107, 37%), followed by RCMD (N = 78, 27%) and RA (N = 74, 26%). Sixty three percent (N = 183) of the patients had diploid cytogenetics at diagnosis. FLT3m was detected in total of 15 (5%) patients, of which 4 (1%, ITD = 3 and TKD = 1) were detected at initial diagnosis and 11 (4%, ITD = 9 and TKD = 2) were acquired during the follow up. Median time to FLT3m acquisition was 10 months (range, 1–53). Positive statistical association was observed between acquisition of FLT3m and NPM1 mutation (P = 0.004), while negative association was observed against RAS mutation (P = 0.013). Statistical association was not observed between FLT3m acquisition and other covariates that include: age, WHO classification, initial bone marrow blast, cytogenetics, cytogenetic evolution, and molecular mutations other than NPM1 and RAS. Eight (73%) patients with FLT3m acquisition had diploid cytogenetics at diagnosis while 3 had abnormal karyotype at the beginning: inv(3)(q21q26.2), del(11)(q13q23) and dup(2)(p15p23), respectively. Of those 8 patients whose initial cytogenetics were diploid, 4 acquired cytogenetic evolution (of which 3 acquired trisomy 8) concomitantly with FLT3m acquisition. Other 2 patients acquired NPM1 mutation and another patient acquired NRAS mutation in addition to FLT3m. There was only 1 patient whom we could not identify any other genetic alterations accompanied by FLT3m acquisition. After median follow-up duration of 31 months (range, 2–147), 75 [26%] patients transformed to AML in the entire cohort. Median transformation free survival (TFS) and OS of the entire cohort were 34 months (range; 1–147) and 36 months (range; 2–147), respectively. Strikingly, all 11 patients who acquired FLT3m experienced AML transformation (100%), with a median time to transformation of 11 months (range; 4–53). Acquisition of FLT3m was detected prior to transformation in 3 patients and at the time of transformation in 7 patients. One patient acquired FLT3m after the transformation. Log-rank test showed that median TFS and OS were both significantly shorter in the FLT3m acquired group than in the non-acquired group (Figure: TFS = 11 vs. 35 months; OS = 13 vs. 38 months, both P < 0.001). By fitting FLT3m acquisition and cytogenetic evolution as time-dependent covariates, Cox proportional hazard regression showed that age > 60 years (vs. ≤ 60, HR = 1.5, P = 0.008), having cytogenetic evolution (vs. no, HR = 5.3, P < 0.001), and FLT3m acquisition (vs. no, HR = 3.4, P < 0.001) independently predicted worse TFS. Conclusion:Approximately 4% of patients with lower risk MDS acquired FLT3 molecular alteration during their follow-up, and acquisition of such alteration was strongly associated with AML transformation (100%), with significant impact on TFS. Additionally, in 88% of the patients who acquired FLT3m and transformed to AML, other molecular and cytogenetic aberrations were accompanied, that may account for the classical “2-hit” model of AML transformation. This result supports the importance of monitoring for FLT3 mutation in lower risk MDS patients upon or even before disease progression, especially in the new era of FLT3 inhibitors. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Results from a 1-year, open-label, single arm, multi-center trial evaluating the efficacy and safety of oral Deferasirox in patients diagnosed with low and int-1 risk myelodysplastic syndrome (MDS) and transfusion-dependent iron overload

The majority of patients with myelodysplastic syndrome (MDS) present with anemia and will become dependent on regular transfusions of packed red blood cells (PRBC) with the risk of iron overload (IOL). Liver iron content best reflects the total body iron content, and measurement of liver iron concentration (LIC) by MRI is a validated tool for detection, but data in MDS is rather limited. Here we present the results of a multi-center trial evaluating the efficacy and safety of deferasirox (DFX) in low and intermediate-1 risk MDS patients with transfusion-dependent IOL. Three patients with transfusion frequency of > 4 units PRBC per month were initially treated with 30mg/kg/day while in 46 patients with a lower transfusion burden deferasirox was initiated at 20mg/kg/day, due to patient related reasons one patient received DFX in a dose of 6mg/kg/day only. LIC was measured by MRI at baseline and end of study using the method by St. Pierre et al. The intention to treat population consisted of 50 MDS patients (28 male; 22 female) with a median age of 69years who were treated with DFX for a median duration of 354days. Mean daily dose of DFX was 19mg/kg/day. Median serum ferritin level (SF) at baseline was 2,447ng/mL and decreased to 1,685ng/mL (reduction by 31%) at end of study (p = 0.01). In 7 (13%) patients the initially chosen dose had to be increased due to unsatisfactory efficacy of chelation therapy. For 21 patients, LIC measurement by liver MRI was performed at baseline and for 19 of these patients at the end of study: mean LIC decreased significantly from 16,8mg/g dry tissue weight (± 8.3mg/g dry tissue weight) at study entry to 10,8mg/g dry tissue weight (± 10.4mg/g dry tissue weight) at end of study (p = 0.01). Of all patients exposed to the study drug (n = 54), 28 (52%) did not complete the 12month study period most commonly due to AEs in 28% (n = 15) and abnormal laboratory values in 7% (n = 4), respectively. The most common adverse events (≥ 10% of all patients) with suspected drug relationship were diarrhea (n = 25, 46%), nausea (n = 13, 24%), upper abdominal pain (n = 8, 15%), serum creatinine increase (n = 16, 30%) and rash (n = 5, 9%). Adverse events making dose adjustments or interruption of study drug necessary occurred in 33 patients (61%). Hematologic improvement according to IWG criteria (2006) was observed in 6 patients (11%). Initiation of treatment of IOL with DFX depending on the transfusion burden yields sufficient reduction of excess iron indicated by serum ferritin levels and most importantly by liver MRI. The safety profile of DFX was comparable to previous observations.

Acquisition of Cytogenetic Abnormalities (CA) Is a Very Poor Prognostic Feature in Patients (pts) with Low and Intermediate-1 (int-1) Risk Myelodysplastic Syndromes (MDS),

Abstract 3802 Background and Aim:The impact of the CA on prognosis and transformation into acute myeloid leukemia among pts with low and int-1 risk MDS is not known. The aims of the study were to assess the impact of CA on the natural history of pts with lower risk MDS and to identify factors associated with its development. Methods:We reviewed 721 pts clinical records of low and intermediate risk MDS pts from 2000–2010 and conducted a retrospective analysis of all pts with at least two consecutive cytogenetic analysis (365 patients, 51%). The acquisition of CA was defined by structural change or gain in at least 2 metaphases and loss in 3 metaphases, or otherwise confirmed by FISH. Cox proportional hazards regression models were fit to assess the association between transformation-free survival (TFS) or overall survival (OS) and pt characteristics. The acquisition of CA was fitted in the Cox model as a time-dependent covariate. The association between the acquisition of CA and pt characteristics was assessed through univariate and multiple logistic regression models. Results:CA was detected in 107 pts (29%) after a median follow-up of 34 months (mos). CA was observed in a median number of 4 metaphases (range, 2–30). At diagnosis, 21% and 79% of pts who acquired CA were low-and int-1risk MDS; 50% were diploid, 22% harbored chromosome 5 /7 abnormalities. At the time of acquisition of CA, the median percentage of bone marrow blasts was 4% (range, 0% to 89%), the median WBC, hemoglobin and platelets were 3.1 × 109/L, 9.5 g/dL, and 65 × 109/L, respectively; pts were low, int-1, int-2, and high-risk MDS in 3%, 42%, 26%, 29%, respectively. The median TFS and OS were 31 (95% CI: 27– 37) and 34 (95% CI: 30 – 44) mos respectively. Assessing CA as time-dependent covariate, patients with CA had a worse TFS and OS, with a median TFS and OS of 16 and 18 mos compared to 56 and 60 mos, respectively in pts without CA. Based on the multivariable Cox model and after adjusting for effects of all other covariates, pts who had acquired CA had an increased risk of transformation (HR=1.46; p-value = 0.01) or death (HR=1.50; p-value = 0.01). By multivariate analysis, female pts with prior chemotherapy had an increased risk of developing CA (OR= 5.26; p-value <0.0001). 96 pts had history of previous malignancy treated with chemotherapy +/− radiation therapy. Of those, 34 (35%) patients acquired CA. Median time from previous chemotherapy to the acquisition of CA was 61 mos (range, 11 to 180). Pts previously treated who did not acquire CA had similar outcomes to those who had never been treated and did not develop CA, while those who did develop CA whether they were previously treated or not had worse TFS and OS. Conclusion:CA occurs at a rate of 29% of pts with lower risk MDS, more common among pts with previously treated malignancy, and has a significant impact on TFS and OS, possibly reflecting genomic instability in the natural history of MDS. Disclosures:Cortes:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Phase 1 Dose-Escalation/Expansion Study of the p38/Tie2 Inhibitor ARRY-614 in Patients with IPSS Low/Int-1 Risk Myelodysplastic Syndromes

Abstract 118 Background:Myelodysplastic syndromes (MDS) are characterized by excess elaboration of myelosuppressive cytokines contributing to increased apoptotic loss of hematopoietic precursors, the hallmark of lower-risk MDS. p38a MAP kinase (MAPK) is a key downstream convergence point and effector of hematopoietic inhibitory cytokines and death receptors in hematopoietic precursors and stromal elements. The actions of Tie2 complement this regulatory axis by promoting cytokine production and altering cellular quiescence. ARRY-614 is a small-molecule inhibitor of both p38 MAPK and Tie2 that may improve hematopoiesis in lower-risk MDS patients (pts). Methods:This Phase 1 study was designed to determine the maximum tolerated dose (MTD) of ARRY-614 and evaluate safety, pharmacokinetics (PK), preliminary efficacy (International Working Group [IWG] 2006) and pharmacodynamic (PD) effects. Eligible pts had International Prognostic Scoring System (IPSS) risk group Low or Int-1 MDS, and had either received prior therapy or were not eligible or refused treatment. ARRY-614 was administered in 28-day cycles. A standard 3+3 dose escalation design was used and an expansion cohort at the MTD in red blood cell (RBC) transfusion-dependent (TD) pts was evaluated. Results:Forty-five pts with Low (n = 11) or Int-1 (n = 34) risk MDS were enrolled with a median age of 72 years (range 47–84). All but one pt had disease refractory to and/or relapsed from prior therapy with a median of 3 prior regimens (range 0–10); 82% received hypomethylating agents (HMAs), 49% received erythropoietin (EPO)-stimulating agents and 40% received lenalidomide. As of July 2011, 7 pts remain on study.ARRY-614 was administered in a fasting state at doses of 400–1200 mg once daily (QD) and 200–300 mg twice daily (BID), and under fed conditions at 400 mg QD. Dose-limiting toxicities (DLTs) reported at QD doses included single events of Grade (Gr) 3 diarrhea (400 mg QD fasting), Gr 3 macular skin rash (1200 mg QD) and Gr 3 QTc prolongation (400 mg QD fed). Due to the high number of capsules required per dose, the maximum administered QD dose was 1200 mg; the MTD was not reached. The 300 mg BID dose was dose limiting due to 5/7 pts with DLTs of Gr 3 rash (n = 2), Gr 3 asthenia and jitteriness (n = 1), Gr 3 allergic reaction to study medicine (n = 1), and Gr 3 muscle weakness with Gr 3 elevated AST/ALT (n = 1); therefore BID dosing was discontinued. The most common (≥ 10% of pts) treatment-related adverse events (AEs) across all dose cohorts included rash (29%), diarrhea (22%), dry skin (13%) and QTc prolongation (11%). The median duration of treatment was 16 wks (range 1–76).ARRY-614 exposure was dose proportional, but high inter-pt variability was observed. The median Tmax was 3 hours and the t1/2was ∼ 8 hours; both parameters were consistent across all doses evaluated.Plasma EPO was elevated at baseline in pts with erythroid response (471 ± 285 U/L, n = 4) and decreased by 92 ± 4% overall. In non-responding pts, baseline EPO was 984 ± 315 U/L (n = 41) and 68 ± 22% maximal decrease was observed. In 68% (13/19) of pts that were above 500 U/L at baseline, EPO was suppressed below 500 U/L during time on study supporting a drug effect in these pts as well.Eight of 43 evaluable pts experienced hematological improvement (HI) per IWG 2006 criteria. HI responses (duration 8 to 80 wks) occurred in all lineages (4 HI-erythroid, 5 HI-neutrophil and 4 HI-platelet) including 5 bi-lineage responses and some pts had a reduction in platelet transfusions. All IWG 2006 responders failed prior treatment with ≥ 1 HMA. At doses ≥ 900 mg QD, 6 of 18 evaluable pts achieved HI in one or more lineage. Conclusions:ARRY-614 has shown encouraging preliminary multi-lineage hematologic activity as a single agent in a heavily pretreated pt population. At the QD doses studied to date, it has demonstrated an acceptable safety profile. Correlative studies of preliminary drug activity with PD analyses from bone marrow samples are ongoing (final results to be presented). Given the variable but dose-proportional drug exposure, a new oral formulation with improved PK profile will be evaluated in MDS pts starting 4Q2011. Because ARRY-614 has promising preliminary activity, additional investigation in this lower-risk MDS population who have received prior treatment with HMAs is warranted. In addition, the treatment-related reductions in plasma EPO suggest that combination treatment with recombinant EPO may optimize erythroid response. Disclosures:List:Array BioPharma: Consultancy. Winski:Array BioPharma: Employment. Bell:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Maloney:Array BioPharma: Employment. Ptaszynski:Array BioPharma Inc.: Consultancy. Kantarjian:Array BioPharma: Research Funding.

Phase 1 Dose-Ranging Study of Oral Ezatiostat Hydrochloride (Telintra®, TLK199) in Combination with Lenalidomide (Revlimid®) in Patients with Non-Deletion(5q) Low to Intermediate-1 Risk Myelodysplastic Syndrome (MDS)

Abstract 2778 Introduction:Lenalidomide is approved for the treatment of del(5q) MDS in US and Japan. In Low to Intermediate-1 (Int-1) risk non-del(5q) MDS, lenalidomide treatment is less effective with a lower response rate (25%) and shorter response duration [Raza A. et al, Blood, 2008.111,1]. Ezatiostat, a glutathione S-transferase P1-1 (GST P1-1) inhibitor, activates Jun kinase, promoting the growth and maturation of hematopoietic progenitors while inducing apoptosis in malignant cells. Based on the novel mechanism of action, response rates, non-overlapping toxicities, and tolerability observed in a single agent ezatiostat Phase 2 study in MDS, a study of the combination of ezatiostat and lenalidomide was conducted to determine the safety and efficacy of ezatiostat with lenalidomide in non-del(5q) Low to Int-1 risk MDS. Methods: In this multicenter Phase 1 dose-ranging study, ezatiostat was given at a starting dose of 2000 mg in combination with lenalidomide at 10 mg, days 1–21 of a 28-day cycle. In stage 1, 3–6 patients in a standard 3+3 design were treated before escalation to the ezatiostat/lenalidomide 2500/10 mg dose level. Treatment was given until lack of MDS response or unacceptable toxicity. Hematologic improvement-erythroid (HI-E) rates were determined by the MDS International Working Group (IWG; 2006) criteria. Results: Eighteen pts (median age 73 yrs; range 57–82; 72% male), with World Health Organization classifications: 4 refractory anemia (RA), 2 RA with excess blasts-1, 4 refractory cytopenia with multilineage dysplasia (RCMD), 5 RCMD with ring sideroblasts, 2 MDS-unclassified, 1 MDS/myeloproliferative disorder-U were enrolled. Thirteen pts (72%) were Int-1 risk, 5 (28%) Low risk; 4 pts (22%) had abnormal cytogenetics. Twelve RBC transfusion-dependent pts (67%) required a median of 6 units (range 4–10)/8-weeks. Two pts (11%) were platelet transfusion dependent. A total of 67 treatment cycles were given (median 3.5 cycles/pt [range 1–11]) and only 6 cycles (9%) required dose reductions and 8 (12%) dose delays. Two of 6 pts reported DLTs (Grade 3 diarrhea and Grade 3 rash) at 2500/10 mg, with 9 additional pts receiving the recommended combination dose of 2000/10 mg. Eleven of 18 pts were evaluable (4 at 2500/10 mg and 7 at 2000/10 mg), and 3 pts are still on therapy with insufficient treatment duration to be evaluable. The HI-E rate was 43% (3/7; 95% CI, 10%–82%) for pts at the recommended 2000/10 mg dose and 6 pts are continuing therapy at the time of analysis. Three of 8 (38%; 95% CI, 9%–76%) RBC transfusion-dependent evaluable pts achieved transfusion independence including 1 responder who did not respond to prior lenalidomide. In responders, the median increase in hemoglobin level was 3.4 g/dL (from 7.9 g/dL). In 2 of 4 thrombocytopenic pts, a HI-platelet (HI-P) response was observed. A bilineage (HI-E and HI-P) response in 2 of 4 pts with anemia and thrombocytopenia was reported. One RBC and platelet transfusion-dependent pt who had a poor response to prior anti-thymocyte globulin treatment achieved complete RBC and platelet transfusion independence. The combination was generally well tolerated with no unexpected toxicities. Most common treatment-related non-hematologic adverse events (AEs) were Grades 1 and 2 including: fatigue (6%, 28%), swelling (0%, 11%), anorexia (11%, 6%), rash (0%, 6%), skin odor (11%, 6%), nausea (39%, 11%), diarrhea (22%,17%), vomiting (28%,17%), upper abdominal pain (5.6%, 5.6%), and constipation (11%, 0%). Grade 3 events were rash (11%), nausea (6%), diarrhea (17%), and vomiting (6%). Most common hematologic-related AEs were Grades 1 and 2 thrombocytopenia (11%, 6%) and neutropenia (0%, 11%). Grade 3–4 AEs were thrombocytopenia (11%, 17%), neutropenia (17%, 11%), anemia (6%, 6%), and febrile neutropenia (11%, 0%). Conclusions: Ezatiostat is the first GST P1-1 inhibitor to cause clinically significant reductions in RBC and platelet transfusions, including RBC and platelet transfusion independence. Since ezatiostat is non-myelosuppressive, it is a good candidate for combination with lenalidomide and in this study, the combination was well tolerated. Interestingly, ezatiostat may also have the potential to enhance lenalidomide’s efficacy. The recommended doses of this combination regimen for future studies is the ezatiostat/lenalidomide 2000/10 mg. Disclosures:Off Label Use: Lenalidomide was used off-label in patients with non-del5q MDS. Mulford:Celgene: Speakers Bureau. Brown:Telik, Inc.: Employment, Equity Ownership. Meng:Telik, Inc.: Employment, Equity Ownership. Lyons:Incyte: Research Funding; Telik: Research Funding; Alexion: Consultancy, Honoraria; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Sekeres:Celgene: Consultancy, Honoraria, Speakers Bureau. Mesa:NS Pharma: Research Funding; Astra Zeneca: Research Funding; SBio: Research Funding; Lilly: Research Funding; Incyte: Research Funding; Celgene: Research Funding.