Failure Of Erythropoiesis-stimulating Agents Research Articles

Clinical Outcomes and Healthcare Resource Utilization for Patients With Lower-Risk Myelodysplastic Syndromes Treated With Erythropoiesis-Stimulating Agents

IntroductionReal-world studies of lower-risk myelodysplastic syndromes (LR-MDS) are limited. We evaluated treatment patterns, clinical outcomes, and healthcare resource utilization (HCRU) among patients with LR-MDS treated with erythropoiesis-stimulating agents (ESAs) in the United States. Patients and MethodsThis retrospective study included patients with LR-MDS who initiated treatment with ESAs between January 1, 2016 and June 30, 2019. The primary analysis assessed patient demographic and clinical characteristics, treatment patterns, clinical outcomes (hematologic response, transfusion requirements, disease progression), and HCRU (medical encounters, laboratory tests, and medication use). Subgroup analyses of patients repeatedly treated with ESA therapy evaluated selected clinical outcomes and primary ESA failure by SF3B1 mutational status, per recently updated NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). ResultsA total of 142 patients were included with a median follow-up time of 17 months (interquartile range [IQR], 7-33). Median age at ESA initiation was 79 years (IQR, 73-85). Patients were predominantly male (54%), overweight or obese (32% and 23%, respectively), of White race (96%) and non-Hispanic ethnicity (89%). Overall, 57% patients were initially treated with darbepoetin alfa and 43% with epoetin alfa. Clinical outcomes were poor, and there was a significant burden on both the health system and individual patients treated with ESA therapies. Hematologic improvement- erythroid was only seen in 26% of 142 patients treated with ESAs, and 65% of 82 retreated patients experienced primary ESA failure. ConclusionOur results indicate that primary ESA failure is largely unrecognized and that many patients should be considered for alternative treatments.

The ELEMENT-MDS Trial: A Phase 3 Randomized Study Evaluating Luspatercept Versus Epoetin Alfa in Erythropoiesis-Stimulating Agent-Naive, Non-Transfusion-Dependent, Lower-Risk Myelodysplastic Syndromes

Background and Significance: Anemia is a common and debilitating symptom in patients with myelodysplastic syndromes (MDS), frequently leading to dependence on red blood cell (RBC) transfusions. Transfusion-dependent (TD) patients have worse overall survival and quality of life, and repeat transfusions are associated with complications, including iron overload. Erythropoiesis-stimulating agents (ESAs) are the standard treatment for anemia in patients with lower-risk (LR)-MDS, but many patients are ineligible for or refractory to ESAs, and responses are limited. Luspatercept, a late-stage erythroid maturation agent, is approved to treat TD patients with LR-MDS after ESA failure. In the phase 3 COMMANDS study, in ESA-naive patients with LR-MDS requiring transfusions, a significantly higher proportion of patients receiving luspatercept than epoetin alfa achieved RBC transfusion independence for ≥ 12 weeks with concurrent hemoglobin (Hb) increase ≥ 1.5 g/dL (weeks 1-24) (Platzbecker U, et al. Lancet 2023. doi: 10.1016/S0140-6736(23)00874-7). The potential of luspatercept to improve moderately severe chronic anemia and reduce RBC transfusion dependence has not yet been investigated in the majority non-transfusion-dependent (NTD) LR-MDS patient population. Preventing transfusion dependence is crucial for improving LR-MDS patient outcomes. The aim of this actively enrolling, phase 3, randomized, multicenter study is to compare the safety and efficacy of luspatercept versus epoetin alfa in reducing progression to RBC transfusion dependence in ESA-naive, NTD adult patients with anemia due to LR-MDS. Study design and methods: The ELEMENT-MDS study includes a 5-week screening period, a 96-week treatment period, an extension phase, and a post-treatment follow-up period (Figure). Target enrollment is 360 patients with anemia due to Revised International Prognostic Scoring System (IPSS-R) Very low-, Low-, or Intermediate-risk MDS. Eligible patients are ≥ 18 years of age with a confirmed MDS diagnosis, baseline serum erythropoietin (sEPO) levels ≤ 500 U/L, and symptomatic anemia defined as a score of moderate or worse on ≥ 1 Patient Global Impression of Severity (PGI-S) item (fatigue, shortness of breath, weakness, or dizziness). Participants must be RBC transfusion-independent per International Working Group 2018 criteria (no RBC transfusions within 16 weeks prior to randomization) and have baseline Hb ≤ 9.5 g/dL. Patients will be excluded if they have a del(5q) cytogenetic abnormality, unclassifiable MDS or myelodysplastic/myeloproliferative neoplasms, anemia due to reasons other than MDS, bleeding disorders, low absolute neutrophil or platelet counts, uncontrolled hypertension, previous acute myeloid leukemia diagnosis, or history of recent malignancies, among other reasons. Participants will be randomized 1:1 to receive luspatercept or epoetin alfa. Stratification factors include baseline sEPO levels, ring sideroblast status, and IPSS-R risk category. Patients will receive luspatercept once every 3 weeks at a starting dose of 1.0 mg/kg (escalation up to 1.75 mg/kg allowed) or epoetin alfa once a week at a starting dose of 450 IU/kg (escalation up to 1050 IU/kg allowed). The primary endpoint will compare the proportion of patients becoming TD (defined as requiring ≥ 3 RBC units/16 weeks) during any continuous 16-week interval in weeks 1-96. The key secondary endpoint is a Hb increase ≥ 1.5 g/dL sustained for ≥ 16 weeks during weeks 1-48. Additional secondary endpoints include time to RBC transfusion dependence, transfusion-free survival, time to achieve modified hematologic improvement-erythroid response, transfusion independence ≥ 24 weeks, and quality of life assessment. Safety endpoints include type and severity of adverse events and relationship to treatment, overall survival, and progression to high-risk MDS and acute myeloid leukemia. Summary: The results of this phase 3 study will determine the efficacy and safety of luspatercept as a therapy for ESA-naive NTD patients with LR-MDS, who have limited treatment options for anemia. The study is registered at ClinicalTrials.gov (NCT05949684) and EudraCT (2022-500430-29-00).

Clinical outcomes by SF3B1 mutation status in patients (pts) with lower-risk myelodysplastic syndrome (LR-MDS) retreated with erythropoiesis-stimulating agents (ESAs).

7071 Background: Pts with SF3B1-mutated LR-MDS often have a more favorable prognosis versus those with SF3B1 wildtype. A sizeable number of pts with LR-MDS undergo ESA treatment even after experiencing ESA failure in first line. This study evaluated the outcomes of pts with LR-MDS retreated with ESAs in routine clinical practice, stratified by SF3B1 status. Methods: This retrospective cohort study included pts with LR-MDS in the US community setting who initiated ESAs as first-line therapy between January 1, 2016 and June 30, 2019, and were followed through June 30, 2021. Eligible pts discontinued ESAs (treatment gap ≥ 3 wk for epoetin alfa or ≥ 6 wk for darbepoetin alfa) and subsequently reinitiated ESA therapy at least once during follow-up. Ring sideroblasts (RS) ≥ 15% served as a surrogate for pts with unknown SF3B1 mutation status. Outcomes included ESA switches, dose reductions and escalations, ESA failure, and overall survival (OS). Primary ESA failure was defined as no rise in hemoglobin (Hb) ≥ 1.5 g/dL or no decrease in RBC transfusion requirement by 8 wk of treatment. Transfusion-dependent (TD) status was evaluated for pts who were transfusion independent (TI) at baseline. Results: A total of 82 pts with LR-MDS and repeat ESA treatment were included. Median age at start of ESA treatment was 79 y (interquartile range [IQR], 72–85). Diagnosis of MDS-RS, MDS with isolated del(5q), MDS with multilineage dysplasia, and MDS with single lineage dysplasia was reported in 30 (36%), 7 (9%), 9 (11%), and 9 (11%) pts, respectively; 27 (33%) had unknown classification. Median follow-up was 26 mo (IQR, 13–38) with 65% failing ESA therapy by 8 wk. Table shows pts’ SF3B1 mutation status, median OS, pts who had an ESA switch, dose reduction or escalation, experienced ESA failure, and pts who were TI at baseline and became TD during follow-up. Results were similar when RS was not used as a surrogate, and when analyses were limited to pts who were treated with ESAs only throughout follow-up. Conclusions: In this study of pts with LR-MDS retreated with ESAs, primary ESA failure was high with nearly half of TI pts becoming TD during follow-up. OS was poor regardless of SF3B1 status – 2–4 times lower than the remaining life expectancy for a 79-y-old (108 mo for men; 125 mo for women). Although treatment options were limited during the study period, the high primary failure rate suggests that pts with LR-MDS may benefit from alternatives to ESAs. [Table: see text]

Hematologic and transfusion outcomes in patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) receiving luspatercept: Real-world assessment in the community practice setting.

7057 Background: Erythropoiesis-stimulating agents (ESAs) are used as first-line (1L) treatment (tx) for the management of symptomatic anemia in LR-MDS. Luspatercept is approved for pts with LR-MDS with ring sideroblasts (RS) who experience ESA failure and are transfusion dependent. We assessed clinical outcomes of pts with LR-MDS with RS, or MDS/myeloproliferative neoplasms with RS and thrombocytosis, treated with luspatercept in US community practices. Methods: This retrospective, observational cohort study used physician-abstracted chart data from community oncology clinics and included adults diagnosed with LR-MDS (including Very low- to Intermediate-risk IPSS-R status) on/after Jan 1, 2015 who received luspatercept for ≥ 3 months (mos) with ≥ 3 mos of follow-up. Transfusion burden (TB) was defined by number of sessions (ses) received in the 8 weeks (wks) prior to luspatercept tx (baseline) and the lowest number for any consecutive period ≥ 8 wks during wks 1–24 of tx: transfusion independent (TI); low TB (LTB), 1–3 ses; and moderate TB (MTB), 4–5 ses. Results: Of 253 pts, 219 (87%) had 1 tx prior to luspatercept tx and 31 (12%) received ≥ 2. ESAs were used as 1L tx in 210 pts (83%). Median follow-up was 5.7 mos. The most common reason for discontinuing initial MDS tx among patients who received ≥ 1 tx prior to luspatercept was lack of anemia improvement (133/250). At baseline, 21 (8%) pts were TI, 208 (82%) had LTB, and 24 (10%) MTB. Median duration of luspatercept tx was 10.8 mos. During wks 1–24, 20/21 (95%) pts remained TI and 201/232 (87%) pts with LTB/MTB at baseline achieved TI for ≥ 8 wks. The Table shows changes in median hemoglobin (Hb), absolute neutrophil count (ANC), and platelet (plt) count. Conclusions: Most pts with LR-MDS received 1L ESAs and over half discontinued the first tx prior to luspatercept due to lack of anemia improvement, highlighting the need for alternative options to improve clinical outcomes. Consistent with data from the MEDALIST trial, 87% of pts with LTB/MTB who received luspatercept achieved TI for ≥ 8 wks, supporting its clinical benefit in routine clinical practice. [Table: see text]

EE509 Burden of Disease in Low-Risk Myelodysplastic Syndromes in Spain

Myelodysplastic syndromes (MDS) are a group of hematological malignancies characterized by cytopenias and an increased risk of progression to acute myeloid leukemia (AML). Red blood cell transfusions constitute the main supportive care for patients with MDS after failure of Erythropoiesis-stimulating agents. The aim was to assess the disease burden in low-risk MDS (LR-MDS) patients from the Spanish National Health System (NHS) perspective.

Association of Clinical Characteristics at Diagnosis with Outcomes in Patients (Pts) with Lower-Risk Myelodysplastic Syndromes (LR-MDS) Treated with Erythropoiesis Stimulating Agents (ESAs): Findings from a Real-World Medical Chart Review in the US

Introduction: LR-MDS comprise a heterogeneous group of clonal myeloid neoplasms characterized by ineffective hematopoiesis, dysplasia(s), cytopenia(s), and relatively good-risk karyotypic and molecular abnormalities. The primary therapeutic strategy for pts with symptomatic LR-MDS is supportive care with red blood cell (RBC)/platelet transfusions and growth factor support such as treatment with ESAs. However, length of treatment and clinical outcomes vary among pts and are poorly understood in real-world clinical practice, particularly in the context of current guidelines. This medical chart review explores the impact of clinical characteristics at diagnosis on clinical outcomes of pts with LR-MDS treated primarily in community settings. Methods: This was a retrospective, observational, US multisite chart review of adult pts diagnosed with LR-MDS between January 1, 2015 and June 24, 2020. Eligible pts had ≥ 1 year of follow-up after diagnosis unless follow-up was < 1 year due to death. Pts who participated in a clinical trial were excluded. Demographic characteristics assessed included age at diagnosis, sex, and race/ethnicity. Four sets of subgroups were analyzed based on the following clinical characteristics collected at diagnosis: ring sideroblast (RS) status; erythropoietin (EPO) level; cytogenetic risk status; and transfusion burden (TB) level. TB level was defined as the number of RBC transfusion sessions for hemoglobin level < 9 g/dL and/or platelet sessions within the 56 consecutive days immediately prior to diagnosis, where transfusion independence (TI)/low TB was 0-3 RBC transfusion sessions and moderate/high TB was ≥ 4 RBC transfusion sessions. Treatment outcomes included physician-reported disease progression or ESA failure. ESA failure was determined per physician reports and/or calculated based on pre-specified criteria, which included discontinuation or switch of ESA-based therapy and/or increased TB within any consecutive 56-day period during ESA-based treatment. Statistical comparisons of characteristics and outcomes between subgroups were conducted using Fisher's exact or Chi-square tests for categorical data, Wilcoxon tests for continuous data, and log rank tests for Kaplan-Meier estimates. Statistical significance was defined as P ≤ 0.05. Results: Among 338 pts with LR-MDS identified, 23 (6.8%) were RS+, 14 (4.1%) had EPO levels ≥ 500 U/L, 65 (19.2%) had intermediate cytogenetics, and 37 (10.9%) had moderate/high TB at diagnosis. Median age at diagnosis was lower in pts with EPO levels ≥ 500 U/L vs < 500 U/L and in those with moderate/high TB vs TI/low TB. There were no statistically significant differences in race or sex among subgroups. The median follow-up time since diagnosis was longer for pts with RS+ status (50.9 months) vs those with negative/unknown RS status (27.0 months). No statistically significant differences in follow-up time were observed for the other subgroups (Table). A greater proportion of pts with moderate/high TB (94.6%) vs TI/low TB (74.1%) received any first-line (1L) systemic therapy for LR-MDS; no significant differences were observed for the other subgroups. Among those who received any 1L systemic therapy, a greater proportion of pts with disease progression at 1L was observed for those with EPO levels ≥ 500 U/L (50.0%) vs < 500 U/L (21.6%), intermediate (35.2%) vs good/very good (21.9%) cytogenetics, and moderate/high TB (45.7%) vs TI/low TB (22.4%) at diagnosis (Table). A smaller proportion of pts with EPO levels ≥ 500 U/L (14.3%) vs < 500 U/L (63.5%) at diagnosis received an ESA-based therapy at 1L. Among pts who received 1L ESA-based therapy, a greater proportion of pts with moderate/high TB (100%) vs TI/low TB (61.6%) experienced ESA failure. No statistically significant differences in 1L ESA failure were observed for the other subgroups (Table). Conclusions: This real-world medical chart review study in the US community care setting suggests that among pts with LR-MDS who receive 1L systemic therapy, more pts who have EPO levels ≥ 500 U/L, intermediate cytogenetics, and/or moderate/high TB at diagnosis may experience disease progression during treatment than those who do not. These results are in line with previous findings that EPO levels, cytogenetic status, and TB at diagnosis may be important predictors of 1L treatment outcomes. Additional studies with larger sample sizes may be useful to further explore these findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Outcomes of Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS) Treated with Luspatercept: An Evaluation of US Clinical Practice Utilization and Treatment Patterns

Introduction: LR-MDS is characterized by ineffective hematopoiesis, cytogenic and molecular abnormalities, progressive bone marrow failure, ≥ 1 cytopenias, and variable risk of progression to acute myeloid leukemia. Patients (pts) may be classified as having LR-MDS based on an International Prognostic Scoring System (IPSS) score of Low or Intermediate risk and/or an IPSS-Revised (IPSS-R) score of Very Low, Low, or Intermediate risk. Erythropoiesis-stimulating agents (ESAs) are the first line of treatment for most pts with LR-MDS. However, many pts experience ESA failure and have limited subsequent treatment options. Luspatercept is a first-in-class erythroid maturation agent approved by the US FDA in April 2020 for the treatment of anemia following ESA failure and requiring ≥ 2 red blood cell units over 8 weeks in adult pts with LR-MDS with ring sideroblasts (RS) or with MDS/myeloproliferative neoplasms with RS and thrombocytosis. Limited evidence exists on treatment patterns and outcomes among pts with LR-MDS treated with luspatercept in routine clinical practice. The aim of this study was to examine pt characteristics, treatment patterns, and transfusion outcomes among pts with LR-MDS treated with luspatercept in the real-world setting. Methods: This was a retrospective, observational cohort study using physician-abstracted data from the charts of adults diagnosed with LR-MDS on or after January 1, 2015, who received luspatercept treatment in US clinical practice. Pts ≥ 18 years old with LR-MDS who received luspatercept for ≥ 3 months and had ≥ 3 months of follow-up after starting luspatercept (or until death if within 3 months of luspatercept initiation) were included. Pts were classified as having LR-MDS based on their IPSS-R or IPSS scores at diagnosis. Pts who participated in a clinical trial were excluded. All data were summarized using descriptive statistics. Results: A total of 76 eligible pts were included; 52.6% were male, 72.4% were White, and the mean age at luspatercept treatment initiation was 72.0 years (Table 1). Median follow-up time from luspatercept initiation was 5.6 months. Nearly all pts (92.1%) received only 1 line of systemic treatment for LR-MDS before receiving luspatercept. All pts initiated luspatercept treatment at the approved starting dose of 1 mg/kg every 3 weeks, and 75.0% of pts received luspatercept according to the approved US FDA indication. Based on Kaplan-Meier estimates, the median duration of luspatercept treatment was 13.3 months. Twenty-two pts (29.0%) discontinued luspatercept treatment during the follow-up period, of whom 54.5% discontinued on the same dose as their starting dose, ie, 1 mg/kg every 3 weeks (68.2% discontinued at a dose < 1.75 mg/kg) (Table 1). Disease progression to higher-risk MDS was the most common reason for luspatercept discontinuation (n = 10/22, 45.5%). No pts discontinued treatment due to adverse events. At luspatercept initiation, 85.5% of pts had low transfusion burden (TB), of whom 7.7% maintained low TB and 92.3% converted from low TB to transfusion independence (TI) during the first 24 weeks of luspatercept treatment (Table 2). Moderate TB was present in 13.2% of pts at luspatercept initiation, all of whom transitioned to having lower TB during the first 24 weeks of luspatercept treatment. Conclusions: This real-world chart review study showed > 90% of pts with low TB prior to luspatercept initiation achieved TI within the first 24 weeks of luspatercept treatment. All pts with moderate TB prior to luspatercept had a decrease in level of TB within the first 24 weeks of starting luspatercept treatment. The MEDALIST trial showed 38% of pts treated with luspatercept- with IPSS-R Very Low to Intermediate risk reached TI within 24 weeks (Fenaux P, et al. N Engl J Med 2020;382:140-151). The present study suggests that initiating luspatercept for low or moderate TB may have a substantial impact on TB and merits continued attention as experience with luspatercept in clinical practice accumulates. Among those who discontinued luspatercept treatment, more than half discontinued at the starting dose. Luspatercept dose titration in real-world clinical practice may not align with recommended dose increases according to the approved US indication. This discrepancy represents an unmet clinical need and potential area for further clarification and education in the community setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lower-risk myelodysplastic syndromes: Current treatment options for anemia.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological disorders. Treatment options are classified and defined by prognostic risk based on the International Prognostic Scoring System (IPSS) and, more recently, the revised IPSS (IPSS-R). The treatment goal for lower-risk MDS is to correct cytopenias or their consequences, with the goal of maintaining or improving quality of life. Erythropoiesis-stimulating agents (ESAs) play an important role in treating anemia. Individuals with MDS who have a 5q deletion are particularly sensitive to treatment with lenalidomide; however, this comprises the minority of patients with MDS. Luspatercept was recently approved in the United States and the European Union for the treatment of ESA-refractory MDS with ring sideroblasts. Research into new treatment options, especially after ESA failure, is needed. In this review, we will focus on the current therapeutic options for MDS-related anemia.

Analysis of Duration of Response, Exposure-Adjusted Safety and Progression to Acute Myeloid Leukemia (AML) for Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS) Receiving Luspatercept in the MEDALIST Study

Analysis of Duration of Response, Exposure-Adjusted Safety and Progression to Acute Myeloid Leukemia (AML) for Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS) Receiving Luspatercept in the MEDALIST Study

Lower-Risk Myelodysplastic Syndromes: Erythropoiesis-Stimulating Agent Treatment Approaches and Outcomes in the United States

Lower-Risk Myelodysplastic Syndromes: Erythropoiesis-Stimulating Agent Treatment Approaches and Outcomes in the United States

Prognosis of Lower Risk Patients with Myelodysplastic Syndromes without Isolated Del(5q) after Failure of Erythropoiesis-Stimulating Agents. a Multicenter Study By the Hellenic MDS Study Group

INTRODUCTIONMost anemic non-del(5q) lower risk myelodyplastic syndromes (MDS) patients are treated with erythropoiesis stimulating agents (ESAs). Second-line treatments, including hypomethylating agents (HMA), lenalidomide (LEN) and other drugs, may be used after ESA failure in some countries, but their effect on disease progression, transformation to acute myeloid leukemia (AML), and overall survival (OS) is unknown. We analyzed MDS patients' outcome after primary or secondary failure of treatment with ESAs as a first-line treatment option. METHODSThis retrospective study included 1065 non-del(5q) lower risk (low or intermediate-1 IPSS risk) MDS patients, registered in the Hellenic National MDS Registry, treated with ESAs. Extensive biostatistical analysis performed in this study included Kaplan-Meier survival analysis. The level of statistical significance was set at a probability value of less than 0.050 (P <0.050). RESULTSBaseline patient characteristics are presented in Table 1. 848 (79.6%) of 1065 MDS patients included in this study were first treated with ESAs. Erythroid response (HI-E) to ESAs was 26.3%, and the median response duration was 21 months. Stable disease (SD) was achieved by 139 (19.4%) MDS patients, while 204 (28.4%) patients receiving ESA had progression of disease (PD) or primary treatment failure. Moreover, 353 (41.6%) MDS patients relapsed after an initial response. Primary failure to ESA was associated with a higher risk of transformation to AML, as well as poorer prognostic outcome regarding OS. The 5-year cumulative incidence of AML transformation in patients with primary and secondary failure was 32.2% and 16.1% respectively (P <0.001). In a median follow-up time period of 28 months, the mean survival from ESA failure was 40 and 80 months for primary refractory patients and relapsing patients, respectively (P <0.001). The estimated mean time to transformation to AML patients with primary failure to ESA treatment was 71.2 months (95% confidence interval [CI] = 63.0-79.3) vs. 104.6 months (95% CI = 99.6-109.6) for those having a secondary failure (P <0.001) (Figure 1a). The estimated mean OS for patients with primary failure to ESA treatment was 40.1 months (95% CI = 34.5 - 45.6) vs. 79.9 months (95% CI = 73.9-85.9) for those having a secondary failure (P <0.001) (Figure 1b). Out of 412 patients who received a second-line treatment, 48 received HMAs, 22 were treated with LEN and 176 had other treatments. CONCLUSIONSThe data of this large, multicenter, retrospective cohort of non-del(5q) lower-risk MDS patients, treated with ESAs, show that patients not responding to ESAs, as first-line treatment, are at a higher risk of transformation to AML and have poorer OS, compared to those who initially respond to ESAs but lose response thereafter. This information combined with other parameters, predictive a worse outcome (eg IPSS-R, duration of ESAs response) can be used in future clinical studies, distinguishing candidate patients for a more intensive treatment. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Stanozolol for the treatment of anemic lower-risk myelodysplastic syndromes without del(5q) after failure of epoetin alfa: findings from a retrospective study.

Options for anemic lower-risk myelodysplastic syndromes (MDS) without del(5q) after failure of erythropoiesis-stimulating agents (ESAs) are very limited. The effectiveness of second-line treatments is uncertain. We retrospectively reviewed the clinical effectiveness and overall survival (OS) of lower-risk MDS without del(5q) patients exclusively treated with stanozolol (STZ) after failure of epoetin alfa. The response was defined according to the 2006 International Working Group (IWG) criteria. Fifty-six patients were included. The median follow-up time was 55 months (range: 5-156 months). Twenty-seven patients (48.2%) achieved hematologic improvement-erythroid response (HI-E). Higher response rates were observed in patients with lower IPSS-R scores (≤3.5, P = 0.008) and hypocellular bone marrow (P = 0.002). In univariate Cox analysis, HI-E was the strongest factor associated with better OS (P = 0.0003). In multivariate Cox, HI-E, age ≤ 50, and transfusion independence (TI) at the onset of STZ were factors associated with better OS. The estimated 5-year OS was 88.6% (68.7-96.2%) and 33.8% (14.9-54.0%) in responders and non-responders (P < 0.01), respectively. The most common side effects included masculinization and liver damage, but they were manageable with supportive measures and dose adjustments. STZ may be considered an alternative treatment in lower-risk MDS after failure of epoetin alfa.

Response to Erythropoiesis Stimulating Agents in Patients with WHO-Defined Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T)

Background: Myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) was formally included as a unique WHO-defined entity in the 2016, iteration of the classification of hematological neoplasms (under MDS/MPN overlap syndromes). Patients with MDS/MPN-RS-T have features of MDS-RS-single lineage dysplasia (SLD), persistent thrombocytosis (platelet count ≥450x109/L), with proliferation of large atypical megakaryocytes. Anemia, including red blood cell transfusion dependency (RBC-TD) is a major problem. While extensive studies have documented erythroid response rates (ERR) to erythropoiesis stimulating agents (ESA) in MDS and MDS-RS-SLD, the data in MDS/MPN-RS-T is less clear. We carried out this study to asses ERR in ESA treated patients with MDS/MPN-RS-T. Methods: After approval by the IRB, patients with 2016, WHO-defined MDS/MPN-RS-T were included in the study. The bone marrow (BM) morphology, cytogenetics and BM RS% were retrospectively reviewed. All study patients underwent next generation sequencing for 29 myeloid-relevant genes, obtained on BM mononuclear cells, at diagnosis, or at first referral, by previously described methods (Patnaik et al., BCJ 2016). Treatment details, including the type of ESA used, dose administered, side effects and reason for discontinuation were retrospectively abstracted. Erythroid responses were assessed using the 2006, international working group (IWG) MDS and the 2015, IWG MDS/MPN response criteria. Results: Forty seven patients with MDS/MPN-RS-T were identified, of which 37 (79%) patients received ESA treatment at any time point during their disease course; median age 73 years (range, 52-93), 46% male.The hemoglobin at diagnosis (HB) and baseline erythropoietin (EPO) levels were 9.1 gm/dL (range, 6.6-12.1) and 39 IU/L (range, 8-500), respectively. Ten (29%) patients were RBC-TD at baseline. None of the 37, ESA-treated patients were on concomitant cyto-reductive therapy for thrombocytosis. Twenty (54%) patients were treated with erythropoietin-a, 13 (35%) with darbepoetin, and 4 (11%) with both sequentially. Median doses were 40,000 IU weekly (range, 20,000-80,000) for erythropoietin-a and 200 mcg every 2 weeks (range, 100-500), for darbepoetin. Median treatment duration was 14 months (range, 1-173) and causes for discontinuation included; ESA failure/loss of response in 20 (54%), sustained HB rise in 1 (3%) and other causes, including adverse events in 4 (11%) patients. With regards to safety, the following events were considered potentially ESA related; treatment emergent hypertension in 2 (5%), venous thromboembolism, ischemic stroke and splenic infarction in 1 (3%) patient each, respectively. All patients with thrombotic/ischemic events had been on low dose aspirin prophylaxis. Erythroid responses by the IWG MDS and MDS/MPN response criteria were assessable in 35 (95%) patients: with 16 (46%) meeting criteria for an erythroid response, by both assessment systems. The median duration of ER was 20 months (range, 2-172). In comparison to ESA non-responders, those that responded were more likely to have baseline EPO levels ≤44 IU/L (ROC analysis; median, 28 vs 112 IU/L; p=0.0080), while there was a trend for inferior responses associated with RBC-TD (p=0.0857). Age, gender, baseline white blood cell and platelet counts, type of ESA used, BM RS %, JAK2V617F, SF3B1, DNMT3A, TET2 and ASXL1 mutational status did not impact ESA response (Table 1). On a univariate survival analysis (OS), survival was not significantly different between ESA responders vs non-responder (median OS, 76 vs 45 months; p=0.2929). After ESA failure, 7 (19%) patients received hypomethylating agents (HMA), while 5 (14%) received lenalidomide. There were no erythroid responses to HMA, while 1 of 3 (33%) assessable lenalidomide treated patients achieved a morphological complete response. Conclusion: Erythropoiesis stimulating agents are effective first line therapies for the management of anemia in patients with MDS/MPN-RS-T, with 46% achieving an erythroid response (median duration of response of 20 months). Low baseline endogenous EPO level (&lt;44 IU/L) was the best predictor of response, with a trend towards an inferior response in the presence of RBC-TD. In the context of clonal thrombocytosis, potentially related thrombotic/ischemic events were documented in 8% of patients. Disclosures Al-Kali: Astex Pharmaceuticals, Inc.: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

The fraction of CD117/c-KIT-expressing erythroid precursors predicts ESA response in low-risk myelodysplastic syndromes.

Compelling evidence has emerged for the relevance of flow cytometry (FC) in the diagnostic work-up of myelodysplastic syndromes (MDS) but due to technical issues, the erythroid lineage has been under investigated, specifically in the therapeutic context. Using the "no red cell lysis" method developed to set up the RED-score, we specifically quantified the fraction of CD117/c-KIT-expressing erythroid precursors in a cohort of 144 MDS patients and studied the correlation with response to erythropoiesis-stimulating agents (ESA) in a sub cohort of 63 low-risk MDS patients. We confirmed the previously reported increase in CD117/c-KIT-expressing erythroid precursors in a subset of MDS patients and demonstrated a strong association between a cut off of CD117/c-KIT-expressing erythroid precursors ≥3% and ESA response (P = 0.001), independent of red blood cell requirement. From our observations, we hypothesized that a decrease in CD117/c-KIT-expressing erythroid precursors could be a mechanism of ESA failure. Moreover, the fraction of CD117/c-KIT-expressing erythroid precursors was correlated with progression-free survival in low-risk MDS patients (P = 0.018). In vitro, we demonstrated in an EPO dependent cell line that CD117/c-KIT expression is necessary for cell survival under EPO stimulation. The quantification of the CD117/c-KIT-expressing erythroid precursors could be proposed as a new theranostic and prognostic marker in MDS treated by ESA. Future studies will be required to determine whether modulating CD117/c-KIT expression and signaling could be used to improve anemia in MDS. © 2019 International Clinical Cytometry Society.

Transfusion Independence in Lower-Risk, Non-del5(q) Myelodysplastic Syndromes (LR-MDS) Among Patients (pts) Initiating Hypomethylating Agents (HMAs) While Receiving Red Blood Cell (RBC) Transfusions

Background: HMAs were approved in the U.S. for treatment of MDS in 2004 (azacitidine) and 2006 (decitabine), and are used for upfront management higher risk disease and in LR-MDS at progression or after failure or low likelihood to respond to erythropoiesis stimulating agents (ESAs). Clinical trial data suggest that 24-50% of LR-MDS pts achieve RBC transfusion independence (TI) from prior transfusion dependence (TD) with HMA therapy. Response among older pts with LR-MDS treated with HMA in a real-world setting is unclear. We have previously shown that survival of higher risk MDS pts treated with HMAs in real-life setting is much shorter than clinical trial data. We therefore examined rates of achieving TI in LR-MDS pts receiving HMAs.Methods: We identified adults >65 years old diagnosed with LR-MDS (WHO categories RA, RARS, and RCMD) in 2004-2013 from the Surveillance Epidemiology and End Results Medicare claims data. Exclusion criteria include: pts with MDS diagnosed on autopsy report or death certificate, absence of continuous Medicare Part A and B coverage or presence of HMO enrollment from 12 months prior to diagnosis through death or end of study (12/31/2014). Pts had to initiate at least one cycle of HMA, defined as 3 to 10 doses of HMA within 28 days. A gap in treatment between 14 to 28 days indicates a new cycle. Pts were assessed for their transfusion status each week throughout the study period. We measured weekly transfusion status based on receipt of RBC transfusions (observed in Medicare claims) during the current and prior 7 weeks (8 weeks total). Transfusion status was defined as: transfusion receiving (TR), pts received at least one transfusion in each period; TD, patient received ≥2 transfusions over 8 weeks, with ≥2 transfusions ≥2 weeks apart; TI, no transfusions within the 8-week period. We required pts to be at least TR at HMA initiation. We censored observations one month prior to death and 4 weeks after the end of the last HMA cycle. TI duration is defined as number of weeks between last transfusion before achieving TI and first transfusion after TI. TI ends the week that the pt receives a transfusion. Time to achieve TI as well as duration of TI were assessed with Kaplan-Meier and Cox models, adjusting for patient's demographics, health status at HMA initiation, prior hospitalization for bleeding and infection, and prior erythropoiesis-stimulating agent and transfusion use. Analysis was also conducted among the subset of pts who were TD at time of first HMA.Results: Among 336 pts with LR-MDS who initiated HMA while RBC TR, median age was 76 years (interquartile range [IQR]: 71-81) and 87.2% were non-Hispanic white. Median time to HMA initiation from diagnosis of MDS was 44.3 (IQR: 13-117) weeks. 136 (40.5%) pts achieved RBC TI, with median time of 23 (95% confidence interval [CI]: 18-28) weeks (Figure 1a). Multivariate Cox model showed pts receiving ≥3 transfusions in the 8 weeks before HMA initiation were less likely to achieve TI (HR: 0.46, p<.01). Geographic region of residence also affected time to TI, with pts in the Northeast and West having lower probability of achieving TI compared to pts in the Midwest (hazard ratio [HR]: 0.44, 95% CI: 0.24-0.80 and HR: 0.56, 0.36-0.87 respectively). Medicaid dual coverage also had a positive association with achieving TI (HR: 1.92, p=.03). Median TI duration was 50 (95% CI:26-76) weeks (Figure 1b). Among 192 pts who were TD at HMA initiation, 64 (33.3%) achieved TI, with a median time to TI of 32 (95% CI: 24-71) weeks. Median TI duration was 60 (95% CI: 23-87) weeks. TD pts of older age (>85 years) showed a higher tendency of losing TI over younger pts (age 66-69) (HR: 4.50, p=.04).Conclusions: Achieving TI is an important quality of life outcome for MDS pts. Our results indicate that a substantial portion of HMA recipients who were RBC TD or TR at initiation achieved TI status, with slightly shorter time to achieve TI for those who initiated while TR compared to TD, and no significant difference in duration of TI. Our results are limited by inability to assess for lenalidomide use and lack of ascertainment of reason of HMA initiation (progression of LR-MDS versus ESA failure). Observed rates of achieving RBC TI in LR-MDS pts utilizing HMA were consistent with clinical trials. DisclosuresZeidan:Celgene: Consultancy; Gilead: Consultancy; Pfizer: Consultancy; Incyte: Employment; Abbvie: Consultancy; Ariad: Consultancy, Speakers Bureau; Agios: Consultancy; Novartis: Consultancy. Huntington:Celgene: Consultancy; Bayer: Consultancy; Janssen: Consultancy. Podoltsev:Pfizer: Membership on an entity's Board of Directors or advisory committees; Sunesis Pharmaceuticals: Research Funding; Pfizer: Research Funding; Celator: Research Funding; Astellas Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; Celgene: Research Funding; Genentech: Research Funding; LAM Therapeutics: Research Funding; Daiichi Snakyo: Research Funding; Boehringer Ingelheim: Research Funding. Gore:Celgene: Consultancy, Research Funding. Ma:Celgene: Consultancy; Incyte: Consultancy. Davidoff:Celgene: Research Funding.

Outcome of Lower-Risk Patients With Myelodysplastic Syndromes Without 5q Deletion After Failure of Erythropoiesis-Stimulating Agents.

Purpose Most anemic patients with non-deleted 5q lower-risk myelodysplastic syndromes (MDS) are treated with erythropoiesis-stimulating agents (ESAs), with a response rate of approximately 50%. Second-line treatments, including hypomethylating agents (HMAs), lenalidomide (LEN), and investigational drugs, may be used after ESA failure in some countries, but their effect on disease progression and overall survival (OS) is unknown. Here, we analyzed outcome after ESA failure and the effect of second-line treatments. Patients and Methods We examined an international retrospective cohort of 1,698 patients with non-del(5q) lower-risk MDS treated with ESAs. Results Erythroid response to ESAs was 61.5%, and median response duration was 17 months. Of 1,147 patients experiencing ESA failure, 653 experienced primary failure and 494 experienced relapse after a response. Primary failure of ESAs was associated with a higher risk of acute myeloid leukemia (AML) progression, which did not translate into an OS difference. Of 450 patients (39%) who received second-line treatment, 194 received HMAs, 148 received LEN, and 108 received other treatments (MISC), whereas 697 received RBC transfusions only. Five-year AML cumulative incidence was 20.3%, 20.3%, and 11.3% for those receiving HMAs, LEN, and MISC, respectively ( P = .05). Five-year OS for patients receiving HMA, LEN, and MISC was 36.5%, 41.7%, and 51%, respectively ( P = .21). In a multivariable analysis adjusted for age, sex, revised International Prognostic Scoring System score, and progression at ESA failure, there was no significant OS difference among the three groups. Conclusion In this large, multicenter, retrospective cohort of patients with non-del(5q) lower-risk MDS treated with ESAs, none of the most commonly used second-line treatments (HMA and LEN) significantly improved OS. Early failure of ESAs was associated with a higher risk of AML progression.

Trends in Clinical Investigation for Myelodysplastic Syndromes.

Myelodysplastic syndrome (MDS) paradigms have been dramatically changed over the last 10 years by major breakthroughs on both pathophysiologic and therapeutic aspects. It is currently a field of intense clinical investigation as new challenges have emerged in both low-risk and high-risk populations. In low-risk MDS, long-term control of anemia is a major issue, and second-line treatments after failure of erythropoiesis-stimulating agents are warranted. Several promising therapies are available, and there are many open questions on how to select the most adapted agent and/or sequence of agents in a specific individual. For high-risk MDS patients, improvement of frontline treatment (namely hypomethylating agents) and identification of valid treatments for relapsed/refractory patients are of paramount importance. This review attempts to define these challenges, summarize the results of the most recent and promising investigational strategies in the field, and to describe the future directions.

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.

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.

An Open-Label, Phase 2, Dose-Finding Study of Sotatercept (ACE-011) in Patients with Low or Intermediate-1 (Int-1)-Risk Myelodysplastic Syndromes (MDS) or Non-Proliferative Chronic Myelomonocytic Leukemia (CMML) and Anemia Requiring Transfusion

Introduction: Anemia, a hallmark of MDS, is challenging to treat, particularly after failure of erythropoiesis-stimulating agents (ESAs). Sotatercept (ACE-011) is a novel and first-in-class activin type IIA receptor fusion protein that acts on late-stage erythropoiesis to increase mature erythrocyte release into the circulation (Carrancio et al. Br J Haematol 2014;165:870-82). Treatment with sotatercept stimulated erythropoiesis and significantly increased hemoglobin (Hb) levels in healthy volunteers (Sherman et al. J Clin Pharmacol 2013;53:1121-30), supporting its clinical development for the treatment of anemia in patients (pts) with lower-risk MDS. Methods: The primary objective of this phase 2, open-label, dose-finding study is to determine a safe, tolerable, and effective dose of sotatercept resulting in erythroid hematological improvement (HI-E; modified IWG 2006 criteria) in pts with anemia and IPSS-defined Low or Int-1-risk MDS or non-proliferative CMML (white blood cells 500 mIU/mL). Pts received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks. ClinicalTrials.gov identifier: NCT01736683. Results: As of May 22, 2014, a total of 54 MDS pts were enrolled: 7, 6, 21, and 20 in the sotatercept 0.1, 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Median age was 71 years (range 56–86) and median time from diagnosis was 4 years (range 0–31); most pts were male (70%). Pts received a median of 6 RBC units (range 0–18) in the 8 weeks prior to treatment start. Forty-five pts (83%) received ≥ 4 RBC units in the 8 weeks prior to treatment start (high transfusion burden; HTB), and 9 pts (17%) received 500 mIU/mL. Of the 53 pts evaluable for efficacy, HI-E was observed in 21 pts (40%) overall: 0, 4 (67%), 8 (40%), and 9 pts (45%) in the sotatercept 0.1, 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Nineteen of 44 HTB pts responded with a ≥ 4 RBC units/8 weeks transfusion burden reduction; duration of transfusion response appeared to be dose-dependent. Five HTB pts achieved RBC-TI ≥ 8 weeks, with RBC-TI duration ranging from 59–345+ days. Eight of 9 LTB pts showed Hb increases, not influenced by transfusion, ranging from 1.3–3.8 g/dL. Of these, 2 pts had a Hb increase ≥ 1.5 g/dL sustained for ≥ 8 weeks. Pts with Hb > 11.0 g/dL were subject to dose delay per protocol, which may have impacted Hb increase sustainability. RBC-TI ≥ 8 weeks was achieved in 6 LTB pts. Increases in platelet and neutrophil levels were seen in pts with baseline thrombocytopenia and pts with baseline neutropenia, respectively. Sotatercept was generally well tolerated. Twenty pts (37%) reported ≥ 1 suspected treatment-related adverse event (AE); fatigue (11%), headache (9.3%), decreased appetite (7.4%), and nausea (7.4%) were the most common. Of 35 pts (65%) who discontinued treatment, 28 discontinued due to lack of therapeutic effect and 4 due to AEs. Of those AEs leading to discontinuation, 3 were suspected to be treatment-related: 1 pt with grade 2 hemolytic anemia, 1 pt with grade 3 hypertension, and 1 pt with grade 2 muscular weakness in the sotatercept 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Other reasons for discontinuation were withdrawal of consent (n = 2; 4%) and pt decision (n = 1; 2%). Conclusions: Sotatercept was well tolerated in lower-risk MDS pts at the dose levels tested, with promising evidence of clinical activity in this largely HTB cohort of ESA-refractory, anemic, lower-risk MDS pts. Further exploration of higher sotatercept dose levels and longer-term treatment is planned. PF and AFL contributed equally to this abstract as senior co-authors. Disclosures Komrokji:Celgene Corporation: Consultancy, Research Funding. Off Label Use: Sotatercept (ACE-011) is an investigational agent that is being assessed for efficacy and safety in myelodysplastic syndromes.. Garcia-Manero:Celgene Corporation: Research Funding. Ades:Novartis: Research Funding; Celgene Corporation: Research Funding. Laadem:Celgene Corporation: Employment, Equity Ownership. Vo:Celgene Corporation: Employment. Prebet:Celgene Corporation: Honoraria. Boyd:US Oncology: Research Funding. Sekeres:Celgene: Membership on an entity9s Board of Directors or advisory committees; Amgen Corporation: Membership on an entity9s Board of Directors or advisory committees; Boehringer-Ingelheim Corporation: Membership on an entity9s Board of Directors or advisory committees. Beyne-Rauzy:Novartis: Research Funding; Celgene: Research Funding. Zou:Celgene: Employment. Attie:Acceleron Pharma: Employment. Sherman:Acceleron Pharma: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding. List:Celgene: Consultancy.