Lower-risk Myelodysplastic Syndromes Pts Research Articles

Biochemical and Metabolomic Analysis of Glycolytic Activity in Red Blood Cells from Low-Risk Myelodysplastic Syndromes (LR-MDS) Patients and in-Vitro Effect of the Pyruvate Kinase Activator AG-946

Background: Anemia is the most common cytopenia occurring in 80%-85% of patients (pts) with LR-MDS and therapeutic strategies remain limited. Beyond defective maturation, preliminary data has shown decreased glycolytic activity in MDS-RBCs. Glycolytic pathway is the prominent metabolic cascade in RBCs and is currently targeted with PK activators in clinical trials of congenital anaemias which are also marked by ineffective erythropoiesis like MDS. AG946 is an investigational, potent activator of PK with potential to enhance RBC functionality and survival by increasing glycolysis. Aim: Evaluate enzymatic activity of the glycolytic pathway in pts with anemia due to LR-MDS and in-vitro effect of pyruvate kinase (PK) activator (AG946) in RBCs cultures of LR-MDS pts. Methods In part A, 66 anemic pts (i.e., Hb<11 g/dL) diagnosed with MDS according to WHO 2022 were enrolled in the study and sampled for peripheral blood >4 weeks after the last RBC unit to reduce blood donor contamination. The determination of activities of RBC enzymes hexokinase (HK) and PK (the initial and terminal steps of glycolytic pathway), and of ATP levels was performed by standard spectrophotometric method according to Beutler et al, 1984. 2,3DPG levels were tested by (2,3-BPG) ELISA kit (ElisaGenie, IE). In part B, purified RBC or whole blood of 10 LRMDS pts and 5 healthy controls (HC) were incubated for 6 and 24 h at 37°C in presence or absence of AG946 in phosphate-buffered saline containing 1% glucose, 170 mg/L adenine, and 5.25 g/L mannitol (AGAM, pH 7.40). RBC were incubated with 1, 5 and 50 uM of AG946 for up to 24 h, at 37°C. After 6 and 24 h, enzymatic activities (HK, PK) and ATP levels were measured. Additionally, metabolomic analysis was performed by LC-MS on extracts from blood samples for each condition. Results Part A: Pts were mainly elderly males (median age 80yr, range 58-92), and mostly belonged to IPSS-R low (78%) and very low/low groups (85%). PK activity (median 13.7 IU/gHb, 7.5-35.9) was reduced in 35% of cases and HK activity (median 2.3 IU/gHb, 0.8-8.1) was increased in 91%, resulting in an abnormally reduced PK/HK ratio in majority of pts (95%). Notably, ATP levels (median 3.4 umol/gHb, 1.3-6.5) were also reduced in 33/56 tested patients (59%), whilst 2,3DPG levels were close to the upper limit of the normal range (median 389 nmol/gHb, 318-639). Conclusions: Our data demonstrates decreased glycolytic activity in a large cohort of anemic pts with LR-MDS versus HC, with reduced PK activity in 1/3 of cases, decreased PK/HK ratio in nearly all subjects, and reduced ATP in 2/3 of pts. Furthermore, in vitro incubation with AG946 led to an increase in PK activity and PK/HK ratio and stable ATP levels in RBCs of LR-MDS pts across all WHO classifications. Metabolomic analysis confirmed an altered RBC-metabolic status of MDS versus HC at baseline with possible modulation of glycolysis by AG946, further supporting a potential therapeutic role of PK Activation with AG946 in LR-MDS.

Hematological Response to Frontline Treatment in Lower Risk Myelodysplastic Syndromes (LRMDS) Is Associated with Better Overall Survival

Background The majority of LRMDS patients (pts) (70%) do not progress but unfortunately succumb to complications related to cytopenia, namely anemia and red blood cell transfusion dependency (RBC-TD) or their interplay with co-morbidities. RBC-TD is associated with worse outcome reflecting bone marrow failure and long-term sequela of RBC-TD. There is growing evidence that response to treatment and RBC transfusion independence (TI) are associated with favorable outcome. In lieu of 2 recent randomized clinical trials demonstrating efficacy of luspatercept & imetelstat in LRMDS, we assessed the impact of response to sequential lines of treatment in LR-MDS on overall survival (OS) to guide our treatment choices and to determine whether erythroid stimulating agents (ESA) should still be our 1 st line of therapy. Methods We included LRMDS pts (IPSS-R very low & low) from Moffitt Database who received ESA as frontline therapy (FL) and assessed subsequently outcomes with second line (SL) therapy (SOC or clinical trial). We excluded MDS/MPN and del5q pts. We also excluded all pts who eventually progressed to either higher risk MDS or AML to better reflect the majority LRMDS in that disease state. We assessed details of FL and SL. Pts who received FL & SL were then divided into 4 groups based on response to FL and SL therapy: group 1 (no/no), group 2 (no/yes) with response only to SL, group 3 (yes/no) response to FL only, and group 4 (yes/yes) with response to both lines of therapy. Response was defined as hematological improvement (HI) with ≥1.5 g/dl Hgb increase in non-TD pts and RBC-TI in TD pts at baseline for at least for 8 weeks. We compared median OS (mOS) among those groups. Results There were 603 LRMDS pts who met eligibility criteria and received ESA as FL (Table-1); 43% were RBC-TD, mean serum EPO was 132 (n=211 pts), 69% received epoetin, 17% darbepoetin and 14% with G-CSF. HI was observed in 42% of pts with no difference among ring sideroblasts (RS) +/- (46% vs 40%, p =.12). Response was higher among non-RBC-TD (52% vs 31%, p< .001). The median time to start ESA was 1.2 mo (0-249). The median time on ESA therapy was 11 mo (.4-213). 331 pts (55%) received SL which included HMA 43% (n= 142), lenalidomide 39% (n=130), luspatercept 7% (n=24), ATG 2% (n=8), investigational agent 4% (n=14), and other 4% (n=13) . The HI rate was 27% (91/331). No difference in HI based on RS nor RBC-TD was observed. The median duration on SL treatment was 6 mo (.1-93). 170 pts (28%) received 3 rd line of therapy with 7% HI, 88 pts (15%) received 4 th line of therapy with 3% HI and 39 pts (7%) had 5 th line of therapy with 2% HI. Among the 331 pts who received at least FL and SL, pts were divided into 4 groups based on response to (methods, table-2), the mOS was 114 mo among Yes/Yes response group, 103 mo among yes/no group, 97 mo no/yes and 64 mo among no/no ( P=.007; Figure-1). Response to FL was significantly associated with better OS after adjusting for RS (HR .74 ,95% CI .55-.99, p=.043). Conclusions Only half of patients who receive ESA as FL therapy for LRMDS received any subsequent therapies. Response rates were highest with ESA as FL than any SL therapy. HI with FL and/or SL is associated with improved OS. Lack of response to first line of therapy is associated with worse OS. Responses beyond SL were rarely observed. Identifying and moving agents with high HI rate as FL therapy and or selecting option based on predictors of best chance of response to a specific treatment as FL may lead to better overall survival.

IMerge: Results from a phase 3, randomized, double-blind, placebo-controlled study of imetelstat in patients (pts) with heavily transfusion dependent (TD) non-del(5q) lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESA).

7004 Background: Unmet needs remain for red blood cell (RBC) TD pts with LR-MDS R/R or ineligible for ESA. In P2 of the IMerge study (NCT02598661), heavily RBC TD ESA R/R non-del(5q) LR-MDS pts naive to lenalidomide and hypomethylating agents (len/HMA) treated with imetelstat, a telomerase inhibitor, achieved durable and continuous transfusion independence (TI). We report primary data from the P3 study of imetelstat in such pts. Methods: Heavily RBC TD ESA R/R non-del(5q) LR-MDS pts naive to len/HMAs were randomized 2:1 to receive imetelstat 7.5 mg/kg or placebo every 4 wks. Primary endpoint was 8-wk TI; subgroup analyses included IPSS risk, prior transfusion burden and ring sideroblast (RS) status. Secondary endpoints included 24-wk TI, TI duration and hematologic improvement-erythroid (HI-E). Variant allele frequency (VAF) changes were explored. Results: As of Oct 2022, 178 pts were randomized. The primary endpoint was met (Table); 39.8% vs 15.0% of pts receiving imetelstat vs placebo, respectively, achieved 8-wk TI. The rate of 8-wk TI was significantly higher with imetelstat vs placebo across subgroups, including RS negative pts. Median TI duration was significantly longer for imetelstat vs placebo, 51.6 vs 13.3 wks, P < 0.001. Pts receiving imetelstat had significantly higher mean hemoglobin (P < 0.001) and fewer transfusions (P = 0.042) over time than those on placebo. In 3 of 4 genes frequently mutated in MDS, VAF reduction was significantly greater in pts treated with imetelstat than placebo: SF3B1 (P < 0.001), TET2 (P = 0.032), DNMT3A (P = 0.019) and ASXL1 (P = NS). SF3B1 VAF reduction correlated with longer TI duration, P < 0.001. No new safety signals were identified. The most common Grade 3/4 AEs were thrombocytopenia and neutropenia, with similar rates of Grade ≥3 bleeding and infections on imetelstat and placebo. In pts treated with imetelstat, cytopenias were manageable, of short duration, and >80% were reversible to Grade ≤2 within 4 wks. Conclusions: For this LR-MDS pt population, imetelstat demonstrated statistically significant and clinically meaningful efficacy with high 8- and 24-wk TI rates, prolonged TI duration and increased hemoglobin. VAF reduction and its correlation to clinical endpoints support imetelstat’s disease-modifying potential. Safety results were consistent with prior reported experience. Clinical trial information: NCT02598661 . [Table: see text]

Oral Decitabine/Cedazuridine in Patients with Lower Risk Myelodysplastic Syndrome: A Longer-Term Follow-up of from the Ascertain Study

▪Background/Introduction:Lower-risk (IPSS low risk and Int-1) myelodysplastic syndromes (MDS) are typically treated supportively to address cytopenias. DNA methyltransferase inhibitors (DNMTi) such as azacitidine and decitabine (DEC) are FDA-approved for higher risk MDS patients (pts), and while the DEC USPI includes IPSS Int-1 pts, it is not widely used in this population. Approved intravenous (IV) or subcutaneous (SC) regimens require 5-7 days of treatment every month burdening older cancer pts due to daily travel and treatment time and may increase potential risk from pandemic SARS-CoV-2 infection. Because DNMTis are rapidly degraded by cytidine deaminase (CDA) in the gut and liver, oral availability has only been recently possible. A randomized study with CC-486, an oral formulation of azacitidine, in the Int-1 population showed a median overall survival (mOS) of approximately 17 months for both placebo and treated patients (Garcia-Manero, 2021). Oral DEC 35 mg/cedazuridine 100 mg (ASTX727) or DEC-C, is an oral fixed dose combination (FDC) of DEC and the CDA inhibitor cedazuridine (CED) resulting in equivalent exposure (99%; 90% CI 93% to 106%) to standard IV DEC 20 mg/m 2 for 5 days in an intra-patient randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present data on patients with lower risk MDS from that study.Methods:We used a randomized cross over design with pts randomized 1:1 in the first 2 cycles to either Sequence A: (DEC 35 mg/ CED 100 mg in Cycle 1 and IV DEC at 20 mg/m 2 in Cycle 2), or Sequence B (IV DEC in Cycle 1 and oral DEC/CED in Cycle 2). Cycles were repeated every 28 days unless delays were needed, and all patients received oral DEC-C in Cycles 3+ until disease progression or unacceptable toxicity. We conducted an intra-patient comparison of DEC PK (DEC AUC equivalence over 5 days of dosing). Pts were eligible as per the FDA-approved label of IV DEC (MDS pts by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk pts). Clinical endpoints were best response as assessed by an independent expert panel according to IWG 2006 response criteria, transfusion independence (TI), overall survival (OS), and safety.Results:Of the 133 pts treated in ASCERTAIN, 69 had a diagnosis of lower-risk MDS (93% Int-1, 7% LR). Median age was 70.0 years (range 45-87), 65% were male, median weight was 84 kg (range 50-127), median baseline hematologic parameters were: hemoglobin 89 g/L (range 69.8-146.5), WBCs 1.50 X 10 9/L (range 0.11-7.1), platelets (plt) 86 x 10 9/L (range 5-703), bone marrow blasts 4% (range 0-18), cytogenetics: 7 (10.1%) poor-risk, 21 (30.4%) intermediate risk, 37 (53.6%) better-risk, 4 (5.7%) missing or not evaluable. 27(39%) of the pts were RBC transfusion dependent (TD) and 6 (9%) plt TD. 17 (25%) had received prior MDS treatment, 3% prior DNMTi. Pts received a median of 9 cycles of therapy (range 1-28). Treatment-emergent adverse events of CTCAE Gr 3 or higher in >10% of pts, independent of relationship to ASTX727, included cytopenias (neutropenia [59%], thrombocytopenia [58%], anemia [48%], leukopenia [26%]), febrile neutropenia (32%), and pneumonia (19%). Sixteen pts (23%) achieved Complete Response (CR), 18 (26%) had marrow CR (mCR), including 9 (13%) with hematologic improvement (HI). Overall Response rate (ORR; CR + PR+ mCR + HI) was 57%. Of those RBC or plt TD at baseline, 13 (48%) became RBC TI and 4 (67%) became plt TI. With approximately 32 months of median follow up, neither median leukemia-free survival (mLFS) nor mOS had been reached (Figure 1). Twelve pts (17%) went on to allogeneic stem cell transplant.Conclusions:Oral decitabine/cedazuridine given as a FDC in MDS pts produced equivalent PK exposure to 20 mg/m 2 IV DEC; in lower risk MDS pts with treatment indicated, the agent was generally well-tolerated with prolonged treatment and could result in mLFS and mOS which exceeds 32 months. This FDC and other dosing regimens of oral DEC-C should be further studied in this patient population.

IDH Mutations Are Enriched in Myelodysplastic Syndromes Patients with Severe Neutropenia: A Potential Targeted Therapy

IDH Mutations Are Enriched in Myelodysplastic Syndromes Patients with Severe Neutropenia: A Potential Targeted Therapy

Mutational Profile and Analysis of Lower-Risk Myelodysplastic Syndromes (MDS) Patients Treated with Luspatercept: Phase 2 PACE-MDS Study

Background: Management of anemia is a common therapeutic challenge in patients (pts) with MDS. Luspatercept (ACE-536), a fusion protein containing modified activin receptor type IIB, is being developed for treatment of anemia in lower-risk MDS. Luspatercept acts as a ligand trap for GDF11 and other TGF-β family ligands to suppress Smad2/3 signaling, promote late-stage erythroid differentiation, and increase hemoglobin (Hgb) levels (Suragani R, Nat Med, 2014; Attie K, Am J Hematol, 2014). Luspatercept has demonstrated clinical activity in ring-sideroblast positive (RS+,≥15% in bone marrow) MDS pts and comparable responses in non-RS+ pts with EPO<500 U/L. While RS+ pts have distinct clinical and molecular features including SF3B1 splicing mutations, non-RS+ pts have a more heterogeneous population of mutations.Aims: This ongoing, phase 2, multicenter, open-label study followed by a long-term extension (ext) study evaluates the effects of luspatercept in pts with lower-risk MDS. Endpoints include long-term safety and tolerability, erythroid response (IWG HI-E), RBC transfusion independence (RBC-TI,≥8 weeks), and duration of HI-E. New analyses focus on clinical, molecular, and bone marrow morphological features of disease and factors associated with luspatercept response.Methods: Inclusion criteria: MDS IPSS low or int-1, age ≥18 yr, Hgb<10 g/dL (if <4U RBC/8 wks), no prior HMA, no current lenalidomide or erythropoiesis-stimulating agent (ESA). The dose-escalation phase of the study is completed. An expansion cohort was added to this phase 2 study to evaluate response in pts not qualified for the phase 3 MEDALIST trial (for regularly transfused RS+ pts refractory to ESA or EPO>200 U/L). These include pts with low transfusion burden (<4U RBC/8 weeks) and either 1) RS+ with baseline EPO ≤200 U/L or 2) non-RS+ and any EPO level. Non-RS+ pts allowed up to 6U RBC/8 wks. Pts treated every 3 weeks subcutaneously for up to 5 doses (titration up to 1.75 mg/kg) in the base study (NCT01749514) and are then eligible for long-term treatment up to 5 additional years (NCT02268383).Results: Data (as of 13Apr2017) were available for 88 pts treated at therapeutic dose levels (≥0.75 mg/kg) in both the base and ext studies. 88 pts were evaluable for IWG HI-E and 60 pts were evaluable for RBC-TI (baseline transfusions of ≥2 units/8 wks). 75 pts were evaluable for mutational data analysis.Baseline characteristics are shown in Table 1. In pts with mutational data, the most common mutations were SF3B1 (57%), TET2 (39%), DNMT3A (21%), ASXL1 (17%), and SRSF2 (11%). Response by subgroup is shown in Table 2.Responses were observed in both RS+ and non-RS+ pts of various mutational backgrounds. Many pts possessed mutations in multiple genes; pts carrying SF3B1 mutations tended to have increased response rates compared to SF3B1 WT pts. Other commonly observed (>10%) mutations (TET2, DNMT2A, ASXL1, and SRSF2) demonstrated similar responses in pts when either mutated or not. Longer-term data on all pts plus additional exploratory analyses of molecular, cellular, and morphologic parameters and their relationship to response will be presented at the meeting.Luspatercept has been well tolerated, with seven possibly related grade 3 non-serious adverse events (AE): ascites, blast cell count increase, blood bilirubin increase, bone pain, hypertension, platelet count increase, and pleural effusion and four possibly related SAEs as of 15June2017: ataxia, general physical health deterioration, muscle weakness, and myalgia. Related AEs in >2 pts were headache, fatigue, hypertension, bone pain, diarrhea, arthralgia, injection site erythema, myalgia, and peripheral edema.Conclusions: Lower-risk MDS pts treated long-term with luspatercept demonstrated robust and sustained increases in Hgb and decreases in transfusion burden and a high rate of RBC-TI. Encouraging responses were seen across EPO levels up to 500 U/L in both RS+ and non-RS+ patients. The presence of an SF3B1 mutation was associated with a higher response in this initial cohort of pts and responses were also observed in SF3B1 WT pts with mutations typically associated with poor prognosis (e.g., ASXL1). The data support continued study of luspatercept in MDS pts, including aPhase 3 study in regularly-transfused RS+ pts with lower-risk MDS according to IPSS-R (MEDALIST study; NCT02631070; fully enrolled) and a future Phase 3 study planned in first-line lower-risk MDS pts. [Display omitted] DisclosuresPlatzbecker:Acceleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Kiewe:Acceleron: Consultancy, Honoraria, Research Funding. Germing:Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Götze:Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria; Abbvie: Honoraria. Radsak:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Gilead: Other: Travel support; Acceleron: Research Funding. Wilson:Acceleron: Employment, Equity Ownership. Zhang:Acceleron: Employment, Equity Ownership. Rovaldi:Acceleron: Employment, Equity Ownership. Laadem:Celgene: Employment, Equity Ownership. Sherman:Acceleron: Employment, Equity Ownership. Attie:Acceleron: Employment, Equity Ownership. Reynolds:Acceleron: Employment, Equity Ownership. Linde:Acceleron: Employment, Equity Ownership. Giagounidis:Celgene: Consultancy; Acceleron: Consultancy.

Expanding on Current Definitions of Hematologic Improvement in MDS, CMML and AML: Landmark Analyses of 1301 Patients Treated with Azacitidine in the Austrian Registry of Hypomethylating Agents By the AGMT-Study Group

Expanding on Current Definitions of Hematologic Improvement in MDS, CMML and AML: Landmark Analyses of 1301 Patients Treated with Azacitidine in the Austrian Registry of Hypomethylating Agents By the AGMT-Study Group

Assessment of Longer-Term Efficacy and Safety in the Phase 3, Randomized, Double-Blind, Placebo-Controlled MEDALIST Trial of Luspatercept to Treat Anemia in Patients (Pts) with Revised International Prognostic Scoring System (IPSS-R) Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions

Assessment of Longer-Term Efficacy and Safety in the Phase 3, Randomized, Double-Blind, Placebo-Controlled MEDALIST Trial of Luspatercept to Treat Anemia in Patients (Pts) with Revised International Prognostic Scoring System (IPSS-R) Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions

Danazol Treatment for Thrombocytopenia in Lower-Risk Myelodysplastic Syndromes: A Pilot Real Life Experience

Background: Severe thrombocytopenia is an uncommon event in patients (pts) with lower-risk MDS, but it may significantly affect the prognosis. No specific pharmacological approaches other than hypometilating agents (not licensed in Europe in lower-risk MDS), able to improve platelet count in this setting, are currently available. Trials testing efficacy and safety of Eltrombopag are ongoing (Oliva 2017). Few data were reported about danazol, an attenuated androgen, that seems to have also some effectiveness in this still unmet need (Wattel 1994; Chan 2002). Aims: To assess the efficacy and safety of danazol in improving the platelet count in low risk MDS pts with severe thrombocytopenia. Methods: We retrospectively reviewed 35 thrombocytopenic MDS pts treated with danazol. The initial and maximal dose was 600 mg/day for all pts, modulated according to response and toxicity. The response was evaluated according to IWG response criteria (Cheson 2006). The outcome was strictly observed every 3 months (mo) up to the 12th mo, and the platelets average number in each observation moment was described. The time to response, the response rate and the enduring of response were also recorded. Results: Of the 35 pts, according to 2016 WHO classification, 4 pts were MDS-ULD; 19 were MDS-MLD (3 of them with medullar hypocellularity), 7 were MDS-EB1 and 5 were affected by MDS/MPN. At baseline the platelet count was lower than 20x10^3/mL in 11 pts, the median was 23x10^3/mL . At starting time of danazol therapy the IPSS-R cytogenetic class of risk was very low in 2 cases, low in 28 cases, intermediate in 3 cases and very high in 1 case. Cytogenetic was not available in one patient. In the 30 MDS pts, the IPSS-R was "very low" in 1 patient, "low" in 16, "intermediate" in 7, "high" in 4 and "very high" in 1. In 1 case it was not evaluable due to the lack of cytogenetics. Two pts were not included in the analysis because they were treated for less than 3 mo (in 1 case danazol was withdraw to permit the beginning of another therapy and in 1 case due to death for other neoplastic disease). The response rate was 63,6% (21 responders on 33 evaluable). Median time to response was 3.5 mo (range 0.3 - 12.4 mo); the average response time was 5.09 mo. In the first year of treatment, the platelet count (evaluated at baseline, 3, 6, 9 and 12 mo) changed in a significant way (F test after repeated measures ANOVA: p Conclusion: Even if the mechanism of action of danazol in pts with MDS is unclear, this series confirms its efficacy to improve platelet count in the most of MDS pts with severe thrombocytopenia. The response was often clinically significant. It may not be immediate but seems to be reachable after 3-6 mo of treatment. A responsive patient has a good probability to maintain a long-lasting response. The toxicity profile of this drug is acceptable. Waiting for more effective options, danazol may be a good therapeutic option for these pts. Disclosures Riva:Jannsen and Cilag: Consultancy; Novartis: Consultancy; Celgene: Consultancy. Reda:Celgene: Consultancy; Janssen and Cilag: Consultancy; Gilead: Consultancy; ABBVIE: Consultancy. Molteni:AMGEN: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Celgene: Consultancy; Janssen and Cilag: Consultancy.

Safety and Efficacy, Including Event-Free Survival, of Deferasirox Versus Placebo in Iron-Overloaded Patients with Low- and Int-1-Risk Myelodysplastic Syndromes (MDS): Outcomes from the Randomized, Double-Blind Telesto Study

▪Background: MDS comprise a group of disorders characterized by bone marrow (BM) failure, cytogenetic and molecular alterations, and progression to acute myeloid leukemia (AML). Most lower-risk MDS patients (pts) eventually need chronic red blood cell (RBC) transfusions because of impaired hematopoiesis, resulting in iron overload (IO) that damages organ function and contributes to shortened survival. Though iron chelation therapy (ICT) has been consistently shown to improve outcomes in lower-risk MDS pts, most studies had limitations (eg retrospective analyses, registry studies, pts not stratified by performance status). As such, a prospective, controlled study of ICT and survival in Low/Intermediate (Int-1)-risk MDS pts was needed.Aims: TELESTO (NCT00940602) was a Phase II randomized, double-blind study that evaluated event-free survival (EFS) and safety of deferasirox (DFX) vs placebo (PBO) in Low/Int-1-risk MDS pts.Methods: Eligible pts were aged ≥18 yrs, had IPSS Low/Int-1-risk MDS (confirmed by BM examination within 6 months of study entry), serum ferritin (SF) >1000 ng/mL, transfusion history of 15-75 pRBC units, without cardiac, liver and renal abnormalities. Pts were randomized 2:1 to DFX (dispersible tablets; 10-40 mg/kg/day based on dosing guidelines) or PBO. Primary objective was to evaluate DFX and PBO for EFS, measured by a composite primary endpoint of time to first non-fatal event (related to cardiac and liver function and transformation to AML) or death, whichever occurred first; events were confirmed by an independent adjudication committee. With a planned sample size of 210 pts, no hypotheses were planned to be tested; statistical tests are exploratory, P values associated with treatment effect are nominal.Results: 225 pts were randomized to DFX (n=149) or PBO (n=76); 72.4% had Int-1 MDS, 60.9% were male, mean age was 61.0 yrs; baseline characteristics were balanced, but more pts in the DFX arm were aged ≥75 yrs (25.5% vs 17.1%). DFX and PBO pts received a mean of 20.28 and 20.27 international units of pRBC transfusions 6 months prior to randomization. Median time on treatment was longer with DFX vs PBO (587.5 vs 370.5 days); 43.9% and 25.0% of DFX and PBO pts received treatment for ≥2 yrs. Median EFS was prolonged by 349 days with DFX (1440 days; 95%CI 1167-1559) vs PBO (1091 days; 95%CI 820-1348): 36.4% risk reduction in EFS with DFX (P=0.015 [Figure 1]). Estimated EFS at 3 yrs was 61.5% (95%CI 52.2-69.6) with DFX and 47.3% (95%CI 31.8-61.3) with PBO. Events that occurred first with DFX (n=62; 41.6%) and PBO (n=37; 48.7%) included: worsening cardiac function (1.3 vs 2.6%); hospitalization for congestive heart failure (0.7 vs 3.9%); liver function impairment (0.7 vs 1.3%); progression to AML (6.7 vs 7.9%); death (32.2 vs 32.9%). Robustness of the positive treatment effect with DFX was confirmed by various sensitivity analyses, including censoring pts with premature treatment discontinuation and subsequent ICT.Median overall survival (OS) was 1907 days (95%CI: 1440-not estimable) with DFX and 1509 days (95%CI 1095-1804) with PBO; HR 0.832 (95%CI 0.54-1.28, P=0.200). ICT after study treatment discontinuation may have diluted any potential OS difference. SF declined over time with DFX and increased in the PBO arm (Figure 2).Most frequently reported AEs (≥20% in either arm) were diarrhea, pyrexia, upper respiratory tract infection, cough and increased blood creatinine. After adjustment for exposure, rates were: diarrhea (24.7 vs 23.9%), pyrexia (21.8 vs 18.7%), upper respiratory tract infection (16.7 vs 22.7%), cough (12.6 vs 11.3%) and increased blood creatinine (15.9 vs 0.9%) in the DFX and PBO arms, respectively. Most frequently reported severe AEs (≥5% in either arm) were anemia, pyrexia, thrombocytopenia and lung infection. When adjusted for the different exposure time, the rate of all severe AEs per 100 pt-yrs was overall comparable.Summary/conclusions: TELESTO is the first prospective, randomized study in Low/Int-1-risk MDS pts with IO to show ICT with DFX provides clinical benefit across multiple tissues, leading to longer EFS (including cardiac and liver events and transformation to AML) vs PBO. The safety profile was as expected, consistent with previous studies of DFX in adult MDS pts with IO. Considering the current treatment landscape, it is unlikely that a similar, randomized trial can be performed. These results support the use of DFX in Low/Int-1-risk MDS pts with IO. [Display omitted] DisclosuresAngelucci:Celgene: Honoraria, Other: Chair DMC; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Roche Italy: Other: Local (national) advisory board; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol. Rodriguez:Novartis: Speakers Bureau. Dong:Novartis: Employment. Ghosh:Novartis: Employment. Bornstein:Novartis: Employment.

PD-L1 Blockade with Atezolizumab in Higher-Risk Myelodysplastic Syndrome: An Initial Safety and Efficacy Analysis

PD-L1 Blockade with Atezolizumab in Higher-Risk Myelodysplastic Syndrome: An Initial Safety and Efficacy Analysis

Clinical and Molecular Characteristics of DDX41-Mutated Patients in a Large Cohort of Sporadic MDS/AML

Background:MDS and AML are mostly found in elderly patients. However, even in this population there is increasing evidence of predisposing genetic conditions, which have been underdiagnosed so far. Identifying inherited predisposition to myeloid disorders can be crucial especially in the context of hematopoietic stem cell transplantation (HSCT).Germline mutations in the DEAD/H-box helicase gene DDX41 have been identified in families with multiple cases of MDS or AML but also in sporadic cases. We aimed to analyze the prevalence and clinical features of DDX41-related myeloid malignancies within an unselected cohort of pts diagnosed with MDS or AML (MDS/AML).MethodsBetween March 2017 and June 2018, mutation screening was performed in 842 consecutive pts with a diagnosis of MDS/AML in a single center at Hôpital Saint-Louis, Paris. DNA was obtained from bone marrow or peripheral blood. Targeted sequencing of all exons of a panel of 80 genes recurrently mutated in myeloid malignancies was performed using custom capture-based library preparation (Agilent SureSelect) and Illumina sequencing. Sanger sequencing was performed on selected pts' cultured skin fibroblasts to check for the putative germline origin of the variants.ResultsWe identified a DDX41 gene variant in 36 unrelated pts (4% of 842). We focused on the 32 pts having at least one DDX41 variant with a variant allele frequency (VAF) ranging from 40 to 60% highly suggestive of a germline origin, which was subsequently confirmed in all available cases (N=7). Sixteen variants were classified as pathogenic or likely pathogenic based on major predicted changes in protein sequence while the 16 others were missense variants of unknown significance (VUS), which scored deleterious in most algorithms (Figure 1A). An additional, likely somatic DDX41 mutation (VAF < 40%) was present in 18 of 32 pts (56%). Overall, 22 pts could be unambiguously considered as having a DDX41-related malignancy based on the presence of a major disturbing mutation and/or a second DDX41 mutation, while 10 pts had a single VUS. Twenty-six variants were newly described, including a recurrent one, G173R found in 5 pts, all having a second DDX41 mutation.Median age of the 32 patients was 70 years (35-88). Only 4 pts (12%) had a familial history of hematologic disorders. According to revised WHO classification, 4 (12.5%) had MDS-MLD, 8 MDS-EB (25%), 12 AML (37.5%), 6 MDS/MPN (18.7%), one 5q syndrome and one aplastic anemia. Strikingly, 15/32 (47%) pts had a history of cytopenia several years before blastic evolution and the 5 pts with G173R presented with hypoplastic MDS or initially isolated cytopenias, suggesting a specific functional effect of this mutation. Karyotype was normal in 16 pts (44%), complex in one, 12 pts had an isolated abnormality, and three had cytogenetic failure. Additional driver mutations were identified in most (27/32,84%) pts (Figure 1B), but we noticed that they were less frequent and at lower VAF in pts having both germline and somatic DDX41 mutations as compared to pts with a single variant (median 1.5 vs 3 mutations, median VAF 7% vs 29.5%, p<0.001). This suggests distinct oncogenic pathways, with DDX41 double-hit oncogenesis being relatively independent of other oncogenic drivers.Seven low-risk MDS pts were untreated, 7 received ESA and 5 (71%) responded. Ten high-risk MDS/AML pts received a hypomethylating agent and 8 (80%) achieved hematological response. Nine AML pts received intensive chemotherapy, with a complete response rate of 100% (7/7, 2 ongoing) and 5 of them had HSCT, all of them being alive with tolerable toxicity. Five pts died, median OS was 87 months, and 2-y OS was 89%. No difference on OS was observed between single and double-DDX41 mutated pts.Conclusions:DDX41 germline variant carriers represent a significant part of MDS/AML pts, the vast majority presenting without familial history. The predicted change in protein and/or the presence of a second somatic mutation strongly support the causality of the germline variant in most pts. By contrast with previous reports, pts frequently presented a phase of cytopenia before overt malignancy. Finally, outcome regarding response to treatment and OS in this DDX41-mutated cohort appeared relatively favorable. DisclosuresPeffault De Latour:Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Fenaux:Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Impact of Erythropoietic Stimulating Agents on Mutational Composition in Patients with Low-Risk Myelodysplastic Syndromes

▪Background:Chronic anemia is most often the presenting symptom and major issue for patients (pts) with low-risk myelodysplastic syndrome (LR-MDS). Erythropoietic stimulating agents (ESAs) are the initial therapy for many LR-MDS pts and can predictably yield benefit in pts with low transfusion burden and a low erythropoietin (EPO) level. (Hellstrom-Lindberg, 2013). However, only about 40-50% of pts respond to erythropoietin (ESAs). We posit that improvement of the predictive algorithm for response to ESA therapy might be optimized with inclusion of molecular mutation informatics. If validated, the model could inform those pts with risk of ESA treatment failure and thus favor alternative approaches such as hypomethylating therapy (Thus, sparing unnecessary pt exposure, cost and time to an ineffective agent, as well as delay to delivery of a possibly more effective therapy). Furthermore, the impact of EPO stimulation/treatment on the clonal dynamics of LR-MDS is not yet well understood nor described. Thus, we analyzed molecular profiles of LR-MDS pts in order to identify mutations associated with ESA failure and the subsequent clonal alterations post ESA exposure.Methods:Of 394 pts who had LR-MDS based on International Prognostic Scoring System (IPSS) criteria, and were treated at Cleveland Clinic from 2002-2015, we studied 49 primary cases with clinical and mutational data. Next generation targeted deep sequencing was performed for a panel of 60 genes that are known to be commonly mutated in myeloid malignancies. ESA response was assessed in the first 8 weeks of treatment according to International Working Group (IWG) criteria (Cheson, 2006). We further studied clonal alterations upon ESA treatment in a small subset of patients who had sequential samples during the course of treatment.Results: Median age of 50 pts was 76 yrs (range, 45-87) and 56% were male. 28% had MDS with single lineage dysplasia, 21% had MDS with ringed sideroblasts, 38% had MDS with multilineage dysplasia, 6% had isolated del(5q), and 7% had MDS-unclassifiable. 65% had normal cytogenetics at diagnosis and 44% had low EPO level at baseline. 43% of pts responded to ESA therapy. Mutations commonly found in our cohort included SF3B1 (25% in responders vs 22% in non-responders), U2AF1 and DNMT3A (15% in responders vs 11% in non-responders), ASXL1 (10% in responders vs 15% in non-responders), and TET2 (10% in responders vs 11% in non-responders). In 20 responders, 2 cases had CBL2 mutation, while 2 other cases harbored JAK2 mutation, which were not detected in non-responders. In 27 non-responders, NGS identified EZH2, ETV6, and RUNX1 mutations in 2 individual cases while one case harbored both ETV6 and RUNX1 mutations. None of these mutations were found in responders. Of interest, among 8 patients who had low baseline EPO level without response to ESA, 3 patients harbored RUNX1 mutation. Serial analysis of eight cases revealed genomic diversity that may give insight to prognostic models for EPO response. For example, we found in one case who had a U2AF1, CBL mutations prior to starting ESA, at the time of evolution to AML this pt had acquired additional mutations involving RUNX1, IDH1, and GPR98. Additional cases with high risk mutations at presentation including EZH2, ASXL1, DNMT3A, U2AF1did not respond and evolved to secondary acute myeloid leukemia (sAML).Conclusions: Evaluation of the mutational spectrum in LR-MDS patient, revealed insight into clonal dynamics that may be determinants of EPO responsiveness. We found in our cohort that LR-MDS individuals harboring RUNX1 and ETV6 mutations did not respond to ESA directed therapy and were noted to evolve to high risk MDS or sAML. Notably, pts with SF3B1 mutations can respond to ESA therapy but not all pts appear to reliably do so. These mutational data will inform a future algorithm to help predict ESA responsive patients in LR-MDS that will require prospective validation. DisclosuresCarraway:Novartis: Membership on an entity's Board of Directors or advisory committees; Baxalta: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees.

Characterization of Myelodysplastic Syndromes (MDS) with T-Cell Large Granular Lymphocyte Proliferations (LGL)

▪Introduction:MDS include a spectrum of hematopoietic stem cell malignancies characterized by bone marrow failure and dysplastic morphology. LGL is a clonal proliferation of cytotoxic T cells, which manifest as neutropenia, anemia, and thrombocytopenia and is associated with autoimmune disorders. LGL in association with MDS has been previously reported. However, clinicopathological features, prognostic, and predictive factors in those patients diagnosed with both LGL and MDS is not well studied.Methods:We identified patients at Moffitt Cancer Center (MCC) diagnosed with MDS who were previously tested for the presence of LGL clonal populations by peripheral blood flow cytometry at time of first visit. An LGL population was defined by the standard flow cytometry immunophenotype and clonality confirmed by T-cell receptor gamma and beta gene rearrangement.. Next Generation sequencing data was available for 151 patients. Recurrent somatic gene mutations were compared between patients with an LGL clone and those without.Results:Of the 675 patients with MDS tested for LGL in the database, 206 (30.5%) had an LGL clonal population. The mean LGL absolute cell count in the peripheral blood was 335/µL. Table-1 summarizes the baseline characteristics of the two groups.There was no difference in response to azacitidine therapy. Among 50 patients with LGL clone who received azacitidine with available data on response, the rate of hematological improvement or better (HI+) was 38%. The (HI+) was 28% among 105 patients evaluable for response without LGL clone. P .14The median overall survival (OS) was for patients with no LGL clone was 65 months (mo) compared to 46 mo (p .024). The median OS for lower risk MDS patients (low/int-1 by International Prognostic Scoring System [IPSS]) was 68 mo versus 97 mo for those with or without LGL proliferation, respectively (P .005). In higher risk MDS, there was no difference in median OS between those with or without LGL expansion, respectively (20 mo versus 16 mo, p .7). The median OS for patients with very low/ low Revised-Internatinal Prognostic Scoring System (R-IPSS) was 96 mo if LGL proliferation was detected compared to 128 mo if it was not, (p value .016). For intermediate R-IPSS the median OS was 65 mo and 41 mo with or without LGL proliferation (p .16). Finally, for high/very high R-IPSS the median OS was 18 and 16 mo with or without LGL proliferation, (p .84) In cox regression analysis the presence of an LGL clone was independently prognostic for OS after adjusting for age and R-IPSS, Hazard ratio 1.3, p = .05. Somatic gene mutation data were available for 151 patients; there was no statistically significant difference in the distribution of any mutation except IDH-2 (Table-2). The most common somatic mutations observed among patients with LGL clone were SF3B1 19%, TET-2 16%, U2AF1 13%, IDH-2 13%, RUNX-1 13%, and ASXL-1 10%. In patients without an LGL clone the most common somatic mutations were TET-2 26%, ASXL-1 20%, DNMT3A 16%, TP53 13%, SF3B1 12%.Conclusion:An LGL clone is demonstrable in approximately 30% of patients with MDS in association with advancing age. The presence of LGL proliferation was associated with worse OS in lower risk MDS pts. Although the spectrum of somatic gene mutations were similar, the presence of IDH-2 mutation and absence of DNMT3A or TP53 gene mutationscharacterized LGL+ cases. [Display omitted] [Display omitted] DisclosuresRoe:Celgene: Speakers Bureau; Alexion: Speakers Bureau; Seattle Genetics: Speakers Bureau. Sweet:Pfizer: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Incyte Corporation: Research Funding; Karyopharm: Honoraria, Research Funding. Sokol:Seattle Genetics: Consultancy; Spectrum: Consultancy. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy.

Impact of Somatic Gene Mutations on Response to Lenalidomide (LEN) in IPSS Lower-Risk Myelodysplastic Syndromes (MDS) Patients (Pts) without Del(5q) and Ineligible for or Refractory to Erythropoiesis-Stimulating Agents (ESAs)

▪Background: Somatic gene mutations occur in the majority of MDS pts; specific mutations and high mutation frequency have prognostic relevance (Papaemmanuil et al. Blood. 2013;122:3616-27). Evaluation of somatic mutations may support the diagnosis of MDS and guide treatment (Tx) selection. The phase 3 randomized MDS-005 study compared LEN and placebo (PBO) Tx in red blood cell transfusion-dependent (RBC-TD) non-del(5q) lower-risk MDS pts ineligible for or refractory to ESAs. Deletions in chromosome 5q are associated with a high response rate to LEN in MDS pts; however, no mutations have been definitively associated with a predictable clinical response to LEN in non-del(5q) MDS.Aim:To investigate the relationship between somatic gene mutations detected by targeted next-generation sequencing (NGS) and response and overall survival (OS) in lower-risk non-del(5q) MDS pts treated with LEN in the MDS-005 study.Methods: Eligible pts were: RBC-TD (≥ 2 units packed RBCs/28 days 112 days immediately prior to randomization) with International Prognostic Scoring System defined Low-/Intermediate-1-risk non-del(5q) MDS; ineligible for ESA Tx (serum erythropoietin > 500 mU/mL); or unresponsive or refractory to ESAs (RBC-TD despite ESA Tx with adequate dose and duration). 239 pts were randomized 2:1 to oral LEN 10 mg once daily (5 mg for pts with creatinine clearance 40-60 mL/min) or PBO. DNA was isolated from bone marrow mononuclear cells or whole blood collected at screening from a subset of pts who gave informed consent for this exploratory biomarker analysis and had adequate tissue for analysis. Targeted NGS of 56 genes was performed at Munich Leukemia Laboratory; average sequencing coverage was 2,000-5,000-foldand the variant allele frequency detection cutoff was 3%. Target regions varied by gene, including all exons to hotspots. For association tests, mutant variants (heterozygous or homozygous) were scored as 1 (mutant) or 0 (wildtype) for gene-level analyses. A Fisher exact test was used to test association of mutation status with response. Median OS was calculated by the Kaplan-Meier method. Hazard ratios and 95% confidence intervals were determined by a non-stratified Cox proportional hazards model. A log-rank test was used to test treatment effect with OS for single gene mutation status.Results: The biomarker cohort included 198 of 239 pts (83%; LEN n = 130, PBO n = 68). At least 1 mutation was detected in 30/56 (54%) genes and 173/198 (87%) pts. The most frequently mutated genes were SF3B1 (59%), TET2 (33%), ASXL1 (23%), and DNMT3A (14%); the most frequent co-mutations were SF3B1/TET2 (23%), SF3B1/DNMT3A (10%), SF3B1/ASXL1 (10%), and TET2/ASXL1 (9%) (Figure). Of 116 pts with SF3B1 mutations, 115 (99%) had ≥ 5% ring sideroblasts. The 56-day RBC transfusion-independence (RBC-TI) response rate was significantly lower in LEN-treated ASXL1 mutant pts vs wildtype pts (10% vs 32%, respectively; P = 0.031). At 168 days, the RBC-TI response rate was still lower in LEN-treated ASXL1 mutant pts vs wildtype pts (7% vs 22%); however, the difference was not significant (P = 0.101). LEN-treated DNMT3A mutant pts had a higher 56-day RBC-TI response rate vs wildtype pts (44% vs 25%); however, this difference did not reach significance (P = 0.133) due to the small sample size. RBC-TI response rate with LEN was similar regardless of total number of mutations per pt. Higher numbers of mutations were significantly associated (P = 0.0005) with worse median OS. Mutation in any of the genes associated with a negative prognosis reported by Bejar et al. (N Engl J Med. 2011;346:2496-506) was also significantly associated (P = 0.0003) with worse median OS.However, OS was not significantly different in LEN- vs PBO-treated pts based on any single gene mutation status.Conclusions: In this group of lower-risk RBC-TD non-del(5q) MDS pts, somatic mutations in genes recurrently mutated in myeloid cancers were detected in 87% of pts. SF3B1 mutations (alone or in combination) were most frequent and not associated with response to LEN. ASXL1 mutant pts had a significantly lower LEN response rate vs wildtype pts, whereas DNMT3A mutant pts had a trend for improved LEN response. Median OS was influenced by mutations, but not significantly modified by LEN. Determining predictive clinical markers for Tx response in non-del(5q) MDS pts remains challenging; nevertheless, there is a significant need to identify pt subsets who may be responsive to LEN Tx. [Display omitted] DisclosuresSantini:Novartis: Consultancy, Honoraria; Amgen: Other: advisory board; Onconova: Other: advisory board; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Astex: Other: advisory board. Fenaux:Celgene, Janssen, Novartis, Astex, Teva: Research Funding; Celgene, Novartis, Teva: Honoraria. Giagounidis:Celgene Corporation: Consultancy. Platzbecker:Janssen-Cilag: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding. Zhong:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene Corporation: Employment, Equity Ownership. Mavrommatis:Discitis DX: Membership on an entity’s Board of Directors or advisory committees; Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership. Hoenekopp:Celgene Corporation: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties, Research Funding.

Safety of Lenalidomide (LEN) 10mg in Non-Del(5q) Versus Del(5q) in the Treatment of Patients (Pts) with Lower-Risk Myelodysplastic Syndromes (MDS): Pooled Analysis of Treatment-Emergent Adverse Events (TEAEs)

▪Introduction: Anemia represents the main therapeutic challenge in pts with lower-risk MDS (Fenaux P, Adès L. Blood. 2013;121:4280-6). Prospective studies evaluating LEN for the treatment of red blood cell transfusion-dependent pts showed significant clinical activity in both non-del(5q) and del(5q) International Prognostic Scoring System-defined lower-risk MDS (Raza A, et al. Blood. 2008;111:86-93; Santini V, et al. Blood. 2014;124:abstract 409; List A, et al. N Engl J Med. 2006;355:1456-65; Fenaux P, et al. Blood. 2011;118:3765-76). Hematologic adverse events (AEs) are common, but manageable, with LEN treatment (Giagounidis A, et al. Ann Hematol. 2008;87:345-52). However, there has been no direct comparison of safety profiles in non-del(5q) and del(5q) pts. This pooled analysis compared the incidence of AEs in LEN-treated lower-risk MDS pts with or without del(5q).Methods: This retrospective analysis of pooled data from 7 prospective clinical trials compared the incidence of AEs in LEN-treated lower-risk MDS pts with or without del(5q). The non-del(5q) group included 416 pts from 4 studies: MDS-005 (n = 160), MDS-002 (n = 215), MDS-001 (n = 24), and PK-002 (n = 17). The del(5q) group included 243 pts from 5 studies: MDS-003 (n = 148), MDS-004 (n = 69), MDS-007 (n = 11), MDS-001 (n = 8), and PK-002 (n = 7). A TEAE was defined as an AE that began or worsened in severity on or after the first dose of LEN through to 28 days after the last dose of LEN. Pts received the recommended starting dose of 10 mg LEN for ≥ 1 cycle; in study MDS-005, pts with impaired creatinine clearance (CrCl; ≥ 40 to < 60 mL/min) had a LEN 5 mg starting dose in order to achieve a similar area under the curve as pts with normal CrCl who were receiving LEN 10 mg.Results: Among the LEN-treated lower-risk MDS pts with or without del(5q) in this pooled analysis, the most commonly reported TEAEs (any grade) occurring in ≥ 5% of pts were hematologic: neutropenia [49.3% vs 73.7% for non-del(5q) vs del(5q), respectively], thrombocytopenia (37.3% vs 64.2%), and anemia (16.8% vs 20.2%). Overall, 84.6% of non-del(5q) pts and 96.3% of del(5q) pts experienced grade 3-4 hematologic TEAEs, including neutropenia [45.2% vs 72.0% for non-del(5q) and del(5q), respectively], thrombocytopenia (31.3% vs 52.7%), and anemia (11.8% vs 12.8%) (Table). Non-hematologic TEAEs were similar for both non-del(5q) and del(5q) pts, except deep-vein thrombosis (1.2% vs 4.9%, respectively) and hypertension (0.2% vs 3.7%). Acute myeloid leukemia was reported as a TEAE in 3 non-del(5q) and 9 del(5q) pts. Bleeding events (any grade) occurring concurrently with grade 3-4 thrombocytopenia were observed in 20.7% of non-del(5q) and 24.4% of del(5q) pts. Infection (any grade) occurring concurrently with grade 3-4 neutropenia was observed in 33.6% of non-del(5q) and 54.0% of del(5q) pts. Analysis of grade 3-4 hematologic TEAEs for pts receiving long-term (> 12 months) LEN treatment by time of onset (0 to 6, > 6 to 12, and > 12 to 18 months) showed that onset rates of grade 3-4 neutropenia during the first 6 months were higher versus rates at > 6 to 12 months for non-del(5q) (42.9% vs 19.5%, respectively) and del(5q) pts (65.4% vs 21.3%). Rates decreased similarly for thrombocytopenia in non-del(5q) (13.0% vs 5.2%) and del(5q) pts (40.4% vs 6.6%). At > 12 to 18 months, onset rates of neutropenia and thrombocytopenia for non-del(5q) pts were 15.6% and 9.1%, respectively; rates for del(5q) pts during this period were 23.5% and 4.4%.Grade 3-4 TEAEs resulted in discontinuation of LEN in 27.4% of non-del(5q) and 20.6% of del(5q) pts (Table); however, the criteria for discontinuation differed between studies.Conclusions: In this analysis of pooled data from 7 studies, the safety profiles of LEN-treated lower-risk MDS pts were similar between non-del(5q) and del(5q) pts. Neutropenia and thrombocytopenia were the most common TEAEs in both groups; however, the frequency of these TEAEs was lower in non-del(5q) pts. Among non-del(5q) and del(5q) pts receiving long-term treatment with LEN, onset rates of thrombocytopenia and neutropenia were lower at > 6 to 12 months versus the first 6 months of treatment. In summary, TEAEs in lower-risk MDS pts with or without del(5q) treated with LEN 10 mg for ≥ 1 cycle are predictable, well characterized, and clinically manageable. [Display omitted] DisclosuresAlmeida:Shire: Speakers Bureau; Bristol Meyer Squibb: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy. Off Label Use: Lenalidomide used to treat MDS patients without del(5q). Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Giagounidis:Celgene Corporation: Honoraria. Hellström-Lindberg:Celgene Corporation: Research Funding. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Skikne:Celgene Corporation: Employment, Equity Ownership. Hoenekopp:Celgene International: Employment, Equity Ownership. Séguy:Celgene International: Employment. Zhong:Celgene Corporation: Employment, Equity Ownership. Fenaux:CELGENE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding.

Long-Term Outcome of Myelodysplastic Syndromes (MDS) Patients Treated with Erythropoiesis Stimulating Agents (ESAs)

Background: The majority of MDS patients (pts) have anemia and are treated initially with ESAs. Particularly for lower-risk MDS pts (International Prognostic Scoring System (IPSS) Low and Int-1), once ESAs are no longer effective, treatment options are limited to drugs commonly used for higher-risk MDS, such as hypomethylating agents, or off-label use of immunomodulatory drugs. As a result, most pts receive only transfusion support post-ESA, representing a pt group with an unmet medical need frequently targeted for drug development, for whom long-term outcome is unknown.Methods: We studied pts diagnosed with lower-risk MDS from 1997-2014 at MDS CRC institutions and treated with ESAs (epoetin alpha (epo) or darbepoetin (darb)). The best response to treatment was categorized per International Working Group 2006 response criteria (hematological improvement (HI), complete response (CR), or partial response (PR)). The primary endpoint was overall survival (OS) at the time of ESA failure, defined as cessation of treatment due to relapse or refractoriness; a secondary endpoint was time to AML transformation or death, from time of response (for responders) or failure (for nonresponders) determination. Descriptive statistics were used for baseline characteristics. The Kaplan Meier method was used to estimate OS and a log rank analysis was used to compare response categories. Cox regression analysis was performed for multivariable analysis.Results: Of 206 patients included in analyses, median age was 71.6 years (range: 25.3-88.1), 36% were female, 5% were African-American, and 11% had t-MDS. WHO categories included RA (14%), RARS (16%), RCMD (42%), MDS-u (6%), del (5q) (4%), RAEB-1 (9%), RAEB-2 (2%), RARS-T (2%), MDS/MPN-u (3%), and CMML-1 (2%), with pts classified as IPSS Low (39%), Int-1 (61%), or IPSS-R Very Low (16%), Low (55%), Intermediate (26%), and High (4%). IPSS cytogenetic risk groups were Good (72%), Intermediate (22%), and Poor (6%). Baseline median hemoglobin was 9.4 g/dl (range: 5.5-14.2), serum epo level was 97.2 (range: 14.2-3899.0), and 11% were transfusion-dependent. Treatment included darb (59%) and epo (41%) at median doses of 300 mcg (range: 100-500) and 40,000 units (range: 5,000-80,000), respectively. Pts remained on therapy for a median of 30.4 weeks (range: 0.0-447.7) and had a median follow-up of 28.4 months (95% confidence interval (CI): 24.5, 45.4). First treatments following ESA failure included azacitidine (41.7%), decitabine (10.2%), lenalidomide (16.6%), experimental drugs (3.1%), other growth factors (13.6%), ATG and/or other immunosuppressants (8%), chemotherapy (0.1%) , transplant (0.1%) and others (6.6%). The overall response rate (ORR) to ESAs was 18.8%, with 0% achieving CR; 0.1% PR; and 18.7% HI. Responses for epo were 17.3% and for darb were 19.8% (p=.67 for difference). For both ESAs, 81.2% of patients had disease refractory to treatment: 69.4% with stable disease and 12% with progressive disease with no significant differences between epo and darb by responder status. Median response duration for epo and darb were 21.9 weeks (range: 3.0 - 447.7) and 39.1 weeks (range: 0.0 - 350.7) respectively (p=0.045). Median survival from the date of diagnosis was 28.4 months (95% CI: 24.5, 45.4), and from ESA failure was 23.9 months (95% CI: 19.9, 33.0): 21.6 months (95% CI: 15.6, 39.2) for epo and 28.8 months (95% CI: 21.2, 39.7) for darb (p=0.99) (Figure). Median time to AML transformation or death was 17.4 Months (95% CI: 14.1, 22.9): 25.4 months for responders and 16.8 months for non-responders (p=.069). For patients who received ESAs for a minimum of 4 months (39% of pts for epo and 61% for darb), ORR was 16.5%, and median survival from ESA failure was 23.0 months (95% CI: 14.7, 33.0): 22.3 months (95% CI: 13.1, NA) for epo and 24.7 months (95% CI: 14.3, 39.7) for darb (p=0.87).Conclusion: In this large, but uncontrolled cohort, response rates were similar for lower-risk MDS patients treated with epo and darb, though duration was longer for darb. There was a trend for improved outcomes in patients who responded to ESAs. Lower-risk MDS patients treated with ESAs have an OS of less than 2 years from the time of failure, and can thus be considered a high-risk MDS group for whom subsequent therapies are not standardized, representing an unmet medical need. [Display omitted] DisclosuresSekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Komrokji:Incyte: Consultancy, Honoraria, Research Funding; Novartis: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Speakers Bureau.

Outcome of Lower Risk Non Del 5q MDS after Failure of Erythropoiesis Stimulating Agents (ESA), and Impact of Post-ESA Treatment on Survival: A Retrospective European Study

▪Background: Most non-del 5q lower risk MDS patients (pts) are first treated with ESA, with about 50% (generally transient) responses, and second line treatments (TX) including hypomethylating agent (HMA), Lenalidomide (LEN) and investigational drugs are then often proposed, but their effect on overall survival (OS) is unknown. In a previous work on 253 such pts, we found worse OS with early failure to ESA, i.e. primary resistance (RES) or relapse (REL) < 6 months after ESA onset (Kelaidi, Leukemia, 2013), but only few pts had received, after ESA failure, TX other than RBC transfusions.In the present study, we gathered non-del 5q lower risk MDS treated with ESA from several EU MDS cooperative groups, and analyzed their outcome after ESA failure, and the effect of second line TX on survival.Methods: 1611 IPSS low and int-1 (lower risk) non del 5q MDS pts included in the French (GFM), Italian (FISM), Spanish (GESMD), Greek, Düsseldorf and Munich registries between 1997 and 2014, and treated by ESA were studied. Survival was assessed from failure of ESA (i.e. from primary failure evaluated after 12 to 24 weeks of ESA treatment, or from relapse after a response). Progression at ESA failure was defined upon progression to a higher IPSS-R class at ESA failure as compared with ESA onset.Results: At ESA onset, the 1611 pts were reclassified by IPSS-R in 16% very low, 54% low, 13% int, 6% high, 1% very high and 10% ND. HI-E (using IWG 2006 criteria) to ESA treatment was 66.9%, and the median duration of response was 15 months. The cohort of 1038 pts with ESA failure included 521 RES and 517 REL. Median OS was 4.2 years in REL and 3.7 years in RES pts (p=0.56), and no significant difference was seen, even after restricting the analysis to very low and low IPSS-R pts (p=0.81), or when analyzing "early" vs "late" failures, with cut-off points at 6 or 12 months, as we previously reported (Kelaidi, Leukemia, 2013).336 (32%) pts received second line treatment (TX2) other than RBC transfusions, including HMA in 88 pts, LEN in 169 pts, and other TX (OT) in 79 pts (including 11 chemotherapy, 17 thalidomide, 11 immunosuppressors (ATG, cyclosporine), or investigational drugs), with response rates of 46%, 39% and 33% respectively (p=0.4). 87 pts had a third line TX (mostly a new drug, but also 7 pts who received HMA after LEN, and 33 pts LEN after HMA).Pts treated with LEN as TX2 were younger (median age 70 vs 75 for BSC, and 70 for HMA p<10-4), had more RARS (67% vs 28% for BSC and 27% for HMA, p<10-4), while pts treated with HMA as TX2 had more RAEB-1 (34% vs 10% for BSC and 12% for LEN, p<10-4) and more high and very high IPSS-R at onset of TX2 (48% vs 4.6% for BSC and 3.1% for LEN, p<10-4).Median OS for pts receiving BSC, LEN, HMA and OT as TX 2 was 4.3y, 3.7y (HR 1.1 [0.81-1.50] p=0.5), 2.1y (HR 1.59 [1.12-2.72], p=0.01) and 2.2y (HR1.17 [0.81-1.68], p=0.41) respectively (Figure). However, in a multivariate analysis adjusted on age, gender, and IPSS-R progression at ESA failure, OS difference became not significant. Analysis of AML progression in the different TX2 groups is currently being finalized.C onclusion: In this large multicenter retrospective cohort of non-del 5q lower risk MDS pts having failed ESA treatment, OS from failure was similar in RES and REL pts, contrary to our previous smaller experience. About 1/3 of the pts received second line treatments other than RBC transfusion, mainly LEN or HMA. However, none of those treatments was able to improve OS compared to BSC. Newer treatments are required in this situation, possibly including allogeneic SCT in younger pts. [Display omitted] DisclosuresPark:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Celgene: Research Funding. Off Label Use: Lenalidomide in non del 5q MDS. Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Cony-Makhoul:BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Cheze:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wattel:PIERRE FABRE MEDICAMENTS: Research Funding; CELGENE: Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; NOVARTIS: Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Fenaux:Amgen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Effect of Lenalidomide (LEN) Exposure on AML-Free Survival and Overall Survival in LEN-Treated Patients (Pts) with IPSS Low- or Intermediate-1-Risk Myelodysplastic Syndromes (MDS) with Del(5q)

Introduction: The efficacy and safety of LEN in red blood cell (RBC) transfusion-dependent pts with International Prognostic Scoring System (IPSS)-defined Low- or Intermediate-1-risk MDS and del(5q) was assessed in 2 large pivotal trials; protocol-defined dose modifications due to adverse events were required in the majority of LEN-treated pts (MDS-003 [List A, et al. N Engl J Med. 2006;355:1456-65] and MDS-004 [Fenaux P, et al. Blood. 2011;118:3765-76]). Previously we have shown that achievement of cytogenetic response (CyR) with LEN is associated with LEN dose and with achieving RBC transfusion-independence and improved acute myeloid leukemia (AML)-free survival. The current analysis evaluates the impact of actual LEN exposure, including induction-type dosing in Cycle 1 and subsequent dose reductions for LEN-associated cytopenias, and CyR on AML-free survival and overall survival (OS) in lower-risk MDS pts with del(5q) treated in the MDS-003 and MDS-004 studies.Methods: This analysis includes pooled data from pts who were treated with LEN in MDS-003 and MDS-004. Pts received LEN at one of the following starting doses and schedules: 5 mg/day, days 1-28 (MDS-004); 10 mg/day, days 1-21 (MDS-003 and MDS-004); or 10 mg/day, days 1-28 (MDS-003); all given in 28-day cycles. LEN dose reductions related to adverse events (NCI CTCAE v3.0) of grade ≥ 3 (MDS-003) or grade 4 thrombocytopenia or neutropenia (MDS-004) were predefined in the study protocols. Full dose modification guidelines for MDS-004 have been published previously (Fenaux P, et al. Blood. 2011;118:3765-76). Dose interruptions were not considered. AML-free survival and OS were estimated by the Kaplan-Meier method with differences evaluated by the log-rank test. Univariate and multivariable Cox proportional hazards models were used to identify predictive factors for AML-free survival and OS. CyR and LEN dose reduction were analyzed as time-varying covariates.Results: Among the 286 LEN-treated pts from MDS-003 and MDS-004, median total doses in Cycle 1 were 245, 210, 280, and 140 mg in the 10 mg (MDS-003: 10 mg × 28 days), 10 mg (MDS-003: 10 mg × 21 days), 10 mg (MDS-004: 10 mg × 21 days), and 5 mg (MDS-004: 5 mg × 28 days) treatment groups, respectively. Median total times on LEN were 364, 385, 510, and 273 days, respectively, and median times to first dose reduction were 53, 63, 54, and 63 days across the treatment groups, respectively. AML-free survival and OS were significantly longer in pts who received > 210 mg versus ≤ 210 mg in Cycle 1 of therapy (log-rank P = 0.0005 and P = 0.0002, respectively). In multivariable analyses, higher total LEN dose in Cycle 1, analyzed as a continuous variable, was significantly associated with improved AML-free survival (hazard ratio [HR] 0.97; P = 0.033) and OS (HR 0.97; P = 0.036) (Table). Sensitivity analyses showed total dose in Cycles 1-3 to be significant, but total dose in Cycle 1 was a better predictor. In the same model, the occurrence of LEN dose reduction was significantly associated with improved AML-free survival (HR 0.54; P < 0.001) and OS (HR 0.56; P = 0.001) (Table) and was strongly associated with longer duration on study (P < 0.001).Conclusions: In this pooled analysis of LEN-treated pts with MDS and del(5q) from the pivotal MDS-003 and MDS-004 trials, the total cumulative LEN dose actually received in Cycle 1 was a significant predictor of AML-free survival and OS; this is likely mediated through clone suppression, evidenced by the association with CyR. Long-term outcomes were significantly improved in LEN-treated pts who had received early cumulative exposure using 10 mg daily and longer duration through dose modifications. These findings support the use of LEN 10 mg as the recommended induction starting dose, and the importance of dose reductions as required to maximize treatment duration and optimize response and survival outcomes in these pts with lower-risk MDS with del(5q). [Display omitted] DisclosuresSekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. List:Celgene Corporation: Honoraria, Research Funding. Fenaux:Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Sugrue:Celgene Corporation: Employment, Equity Ownership.

P53 Mutant Independently Impacts Risk: Analysis of Deletion 5q, Lower-Risk Myelodysplastic Syndromes (MDS) Patients Treated with Lenalidomide (LEN) in the MDS-004 Study

▪Introduction: Refined risk-classification of patients (pts) with MDS allows for improved treatment selection for individual pts. The Revised International Prognostic Scoring System (IPSS-R) has recently been validated as a prognostic tool in lower-risk MDS pts with deletion 5q [del(5q)], who were treated with LEN in the MDS-004 study (Sekeres et al. Blood Cancer J 2014; in press). P53 nuclear protein expression, as assessed by immunohistochemistry (IHC), predicted overall survival (OS) and risk of progression to acute myeloid leukemia (AML) in lower-risk MDS pts with del(5q) (Saft et al. Haematologica 2014;99:1041-9). This analysis evaluated the prognostic value of adding p53 IHC to IPSS-R to predict OS and AML progression in pts with lower-risk MDS with del(5q).Methods: In a subset of 85 pts from MDS-004 with bone marrow (BM) biopsies available, p53+ staining (≥ 1% IHC+++ BM cells) was visualized by IHC. Twenty-four pts had missing IPSS-R scores; 1 due to lack of baseline cytogenetic data and 23 because of missing exact BM blast percentage. Thus, 61 pts (42 initially treated with LEN and 19 with placebo) had IPSS-R and p53 IHC data available; 89% of pts in the placebo group crossed over to LEN 5 mg at Week 16. The IPSS-R Very Low and Very High risk groups with < 5 pts were combined with the Low and High risk groups, respectively. AML-free survival (AFS), OS, and time to AML progression within p53 IHC status (p53+ vs p53−), and IPSS-R risk groups were characterized by the Kaplan-Meier method with differences evaluated by the log-rank test.Results: Of 61 pts, 38% were p53+. There was a linear increasing trend in the proportion of pts with p53+ across IPSS-R risk groups from Very Low/Low, Intermediate to High/Very High (29%, 47% and 63%, respectively; Cochran-Armitage trend test P = 0.050). The 3 IPSS-R risk groups significantly predicted AFS and OS (log-rank P < 0.001 for both AFS and OS), but not time to AML progression (P = 0.335). Overall, AFS, OS, and time to AML progression differed significantly between p53+ versus p53− pts (23.9 vs 47.9 months for median AFS, P = 0.003; 27.0 vs 50.6 months for median OS, P = 0.005; and 44.3 months vs not reached [NR] for median time to AML progression,P = 0.003). In the IPSS-R Very Low/Low risk group (n = 38), AFS, OS, and time to AML progression were significantly worse in p53+ versus p53− pts (20.1 vs 63.1 months for median AFS, P = 0.011; 28.4 vs 76.8 months for median OS, P = 0.031; and 65.2 months vs NR for median time to AML progression, P = 0.014). Results for all IPSS-R risk groups in pts with p53 and IPSS-R data are presented in the Figure. The lack of significant differences between p53+ versus p53− pts in the Intermediate and High/Very High risk groups is likely due to the small sample size of these groups.Conclusions: In this exploratory subset analysis of lower-risk MDS pts with del(5q), p53 IHC status in the IPSS-R Very Low/Low risk group significantly impacted AFS, OS, and AML progression. These data support the addition of p53 mutational analysis to prognostic risk assessment which should help inform the selection of appropriate treatment for individual MDS pts with del(5q). These results need to be validated in a large sample set, which will be accomplished as part of the ongoing efforts to include prognostic molecular mutations in future updates of IPSS-R [Display omitted] [Display omitted] [Display omitted] DisclosuresShiansong Li:Celgene Corporation: Employment, Equity Ownership. Greenberg:Celgene: Research Funding; Onconova: Research Funding; GSK: Research Funding; Novartis: Research Funding; KaloBios: Research Funding. Sekeres:Amgen Corp.: Membership on an entity’s Board of Directors or advisory committees; Boehringer-Ingelheim Corp.: Membership on an entity’s Board of Directors or advisory committees; Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees. Dreyfus:Novartis: Honoraria; Celgene: Honoraria. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding. Swern:Celgene: Employment, Equity Ownership. Sugrue:Celgene: Employment, Equity Ownership. Hellstrom-Lindberg:Celgene: Research Funding.