Erythroid Response Research Articles

Treatment of myelofibrosis with refractory anemia with luspatercept: a multicenter Chinese study.

Myelofibrosis is a rare and often fatal hematological neoplasm, and the treatment of myelofibrosis-associated anemia remains suboptimal, with no improved therapies. Luspatercept was shown to display some efficacy in a phase 2 clinical trial for Myelofibrosis with anemia, yet relevant research are limited. Threrfore,data from patients diagnosed with refractory anemic primary or post-essential thrombocythemia/polycythemia vera myelofibrosis, who were treated with luspatercept for at least 9 weeks, were retrospectively collected. Eighteen patients with myelofibrosis treated with luspatercept were enrolled. Median age was 68 years (range, 44-80 years), and 27.8% were males. Ten (55.6%) were transfusion-dependent. Ten (55.6%) were Dynamic International Prognostic Scoring System intermediate-1, and eight (44.4%) were intermediate-2. The median follow-up was 7 (4-16) months. Erythroid response occurred in eight patients (44.4%) at week 12, four patients (30.8%) at week 24, and nine (50%) at the end of follow-up. Patients who were transfusion-dependent and not transfusion-dependent had similar HI-E responses, at different time points (P > 0.05). Patients had a significantly higher hemoglobin level at 12 weeks, 24 weeks, and at the end of follow-up, than at baseline (P = 0.001, P = 0.021, and P = 0.005, respectively). Treatment-related adverse events occurred in five (16.7%) patients, with no serious adverse events. Two (11.1%) patients relapsed at weeks 15 and 31. One patient progressed to acute myeloid leukemia. No patients had died by the end of follow-up. Luspatercept induced a good response in patients with anemic myelofibrosis, with a low relapse rate and good tolerance.

A preliminary study of roxadustat in the treatment of aplastic anemia patients with inadequate erythroid responses

Some aplastic anemia(AA) patients only have partial hematological responses after immunosuppressive therapy. Failure to achieve complete normalization of blood counts, particularly hemoglobin, will reduce their quality of life. This open-label pilot study was conducted to evaluate the efficacy and safety of roxadustat in this setting. A total of 14 patients with AA who had inadequate erythroid response after immunosuppressive therapy were included in the study. The primary efficacy endpoint was hemoglobin response at week 8 after roxadustat treatment. The median duration of roxadustat therapy was 14 (4–30) weeks, with 12 patients receiving roxadustat for ≥ 8 weeks. At week 8, nine patients (9/14, 64.3%) had their hemoglobin rising for at least 15 g/L, with two patients (2/14, 14.3%) achieving normal hemoglobin levels. By the last follow-up, hemoglobin responses were observed in 10 patients (10/14, 71.4%), with 4 patients(4/14, 28.6%) having normal hemoglobin levels. Roxadustat was tapered or discontinued in four responded patients; one relapsed after 12 weeks of tapering, and three maintained their response. Four patients (4/14, 28.6%) experienced mild adverse effects during therapy. Roxadustat is safe and well tolerated by patients with AA. Treatment with the hypoxia-inducible factor prolyl hydroxylase inhibitor improves hemoglobin levels in AA patients with inadequate erythroid responses.

Erythropoietin hyporesponsiveness in non-alcoholic fatty liver disease.

Treatment with erythropoietin (EPO) can correct anaemia in chronic kidney disease (CKD) patients; however, up to 10% exhibit resistance or hyporesponsiveness to EPO. Non-alcoholic fatty liver disease (NAFLD), prevalent liver disease in CKD patients, may limit EPO response because of thrombopoietin deficiency, iron homeostasis disorder and inflammation. Therefore, we hypothesized NAFLD is a risk factor for EPO responsiveness. To test our hypothesis, we evaluated the effect of EPO in healthy rats and rats with NAFLD induced by a high-fat, high-carbohydrate (HFHC) diet. After 12 weeks on the HFHC diet, NAFLD rats showed lower erythroid response to EPO treatment than healthy rats. We, then, determined that the primary cause of EPO hyporesponsiveness could be iron deficiency associated with inflammation, which reduces erythroid cell production. Specifically, the concentrations of hepcidin, ferritin, transferrin and white blood cells in NAFLD rats were 12.8-, 16.4-, 2.51- and 1.40-fold higher than those in healthy rats, respectively. However, erythroid cell types in the bone marrow of NAFLD rats were significantly reduced. In conclusion, our data suggest that NAFLD could be a risk factor for EPO responsiveness, which is attributed to functional iron deficiency associated with inflammation.

Treatment of refractory/relapsed Diamond-Blackfan anaemia with eltrombopag.

Diamond-Blackfan anaemia (DBA) is a rare, inherited bone marrow failure syndrome with a ribosomal defect causing slowed globin chain production with normal haem synthesis, causing an overabundance of reactive iron/haem and erythroid-specific cellular toxicity. Eltrombopag, a non-peptide thrombopoietin receptor agonist, is a potent intracellular iron chelator and induced a robust durable response in an RPS19-mutated DBA patient on another trial. We hypothesized eltrombopag would improve RBC production in DBA patients. We conducted a single-centre, single-arm pilot study (NCT04269889) assessing safety and erythroid response of 6 months of daily, fixed-dose eltrombopag for DBA patients. Fifteen transfusion-dependent (every 3-5 weeks) patients (median age 18 [range 2-56]) were treated. One responder had sustained haemoglobin improvement and >50% reduction in RBC transfusion frequency. Of note, 7/15 (41%) patients required dose reductions or sustained discontinuation of eltrombopag due to asymptomatic thrombocytosis. Despite the low response rate, eltrombopag has now improved erythropoiesis in several patients with DBA with a favourable safety profile. Dosing restrictions due to thrombocytosis may cause insufficient iron chelation to decrease haem production and improve anaemia in most patients. Future work will focus on erythropoiesis dynamics in patients and use of haem synthesis inhibitors without an impact on other haematopoietic lineages.

Successful treatment pure red cell aplasia after ABO major mismatched allogeneic hematopoietic stem cell transplantation with avatrombopag and low dose rituximab.

Pure red cell aplasia (PRCA) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) with ABO major incompatibility is characterized by transfusion dependent anemia. No standard treatment existed for PRCA following allo-HSCT yet. We conducted a retrospective study, and reported our experience with the use of avatrombopag and lower dose rituximab to treat five patients with PRCA subsequent to major ABO-incompatible allo-HSCT. Five cases of PRCA were identified from 72 patients who underwent allo-HSCT with major or bidirectional ABO mismatch. Cumulative incidence at Day +60 was 6.9% (5/72) at our center. All donor and recipient blood groups were A+ and O+ , respectively. In the first three cases we reported, patients received erythropoietin, plasma exchange, and donor lymphocyte infusion, but none of them had any effect. After 4 weeks of treatment with low dose rituximab (100 mg/week) combined with avatrombopag (40 mg/day), favorable outcomes were obtained. According to the aforementioned experience, Cases 4 and 5 were administered low-dose rituximab and avatrombopag in 3 months after transplantation, and erythroid response was observed on 3 weeks after treatment. Our patients tolerated low-dose rituximab and avatrombopag well and experienced rapid efficacy, with a median duration of 3 weeks. Furthermore, no severe infection or thrombocytosis necessitated a dose adjustment. Low-dose rituximab and avatrombopag may be an effective treatment for patients with PRCA after major ABO-incompatible allo-HSCT. The patients should be treated at least 90 days post transplantation if conventional erythropoietin therapy fails.

Outcomes and effect of somatic mutations after erythropoiesis stimulating agents in patients with lower-risk myelodysplastic syndromes.

Erythropoiesis stimulating agents (ESAs) are the first-line therapy in patients with lower-risk myelodysplastic syndromes (LR-MDS). Some predictive factors for ESAs response have been identified. Type and number of somatic mutations have been associated with prognosis and response to therapies in MDS patients. The objective was to evaluate the outcomes after ESAs in patients with LR-MDS and to address the potential predictive value of somatic mutations in ESAs-treated patients. Multi-center retrospective study of a cohort of 722 patients with LR-MDS included in the SPRESAS (Spanish Registry of Erythropoietic Stimulating Agents Study) study. Retrospective analysis of 65 patients with next generation sequencing (NGS) data from diagnosis. ESAs' efficacy and safety were evaluated in patients receiving ESAs and best supportive care (BSC). To assess the potential prognostic value of somatic mutations in erythroid response (ER) rate and outcome, NGS was performed in responders and non-responders. ER rate for ESAs-treated patients was 65%. Serum erythropoietin (EPO) level <200 U/l was the only variable significantly associated with a higher ER rate (odds ratio, 2.45; p = 0.036). Median overall survival (OS) in patients treated with ESAs was 6.7 versus 3.1 years in patients receiving BSC (p < 0.001). From 65 patients with NGS data, 57 (87.7%) have at least one mutation. We observed a trend to a higher frequency of ER among patients with a lower number of mutated genes (40.4% in <3 mutated genes versus 22.2% in ⩾3; p = 0.170). The presence of ⩾3 mutated genes was also significantly associated with worse OS (hazard ratio, 2.8; p = 0.015), even in responders. A higher cumulative incidence of acute myeloid leukemia progression at 5 years was also observed in patients with ⩾3 mutated genes versus <3 (33.3% and 10.7%, respectively; p < 0.001). This large study confirms the beneficial effect of ESAs and the adverse effect of somatic mutations in patients with LR-MDS.

Efficacy and Safety of Luspatercept +/- Erythropoiesis-Stimulating Agent (ESA) in Patients with Myelodysplastic Syndromes with Ring Sideroblasts (MDS-RS): A French Multicenter Prospective Real-Life Registry

Background EMA has recently approved Luspatercept (LUSPA) for the treatment of anemia in adult patients with RBC transfusion-dependent (TD) very low- to intermediate- risk MDS-RS or MDS/MPN with ringed sideroblasts and thrombocytosis (MDS/MPN-RS-T) having failed an ESA. We designed a French observational registry of patients treated with LUSPA according to this label. In case of primary/secondary failure to LUSPA, we also investigated the effect of adding an ESA to LUSPA. The basis of this combination followed a GFM trial showing that, in non-del 5q lower risk MDS failing an ESA, Lenalidomide + ESA gave better results than Lenalidomide alone (Toma A et al. Leukemia. 2016 Apr;30(4):897-905). In a phase I study (GFM Combola trial), we found no unexpected side effects in the LUSPA -ESA combination (unpublished). Patients and treatment This French multicenter prospective observational registry started when the drug became available (July 2022), with a starting dose of 1 mg/kg SC every 3 weeks (2 infusions) and, in the absence of erythroid response increase to 1.33mg/kg (2 injections) and to 1.75 mg/kg (3 injections). In the absence of response after those 7 infusions, the addition of ESA (30 KU /week during 1 month and, if no response, 60 KU/week during 3 months) was recommended. Results Between July 2022 and January 2023, 108 patients (median age 70 years, 47% males) were included. Median time from diagnosis to LUSPA treatment was 64 months (IQR 40-99). According to WHO 2016, 86% of the patients had MDS-RS, 9% MDS-RS-T, and 5% MDS-EB1 or MDS-MLD (but with &amp;gt; 15% ringed cells and/or SF3B1 mutation). IPSS-R was very low, low, int in 96%, and high in 4%, IPSS-M very low/low/moderate low in 82%. Sixty-six of the 73 (90%) patients tested molecularly had SF3B1 mutation. All patients had received an ESA and 44 (41%) other treatments (1 to 6, median 1). The median duration of LUSPA exposure was 6.5 months (range 0.5-11), and 94% of patients had received at least 2 months of treatment. Erythroid response (HI-E, according to IWG 2018 criteria) to LUSPA alone was currently evaluable in 83 patients; 76 of them were RBC-TD before LUSPA (23 low TB (LTB) (1-5 units /8 weeks) and 53 high TB (HTB) (≥ 6 units /8 weeks)), and 30 (39%) of these achieved RBC-TI with no relapse after a median of 6.5 months (range 4.4-11). All 9 non-TD patients obtained HI-E and were still responders after a median of 8 (range 6.5-9) months. Of the 85 patients evaluable for response to LUSPA alone, 34% and 48% required a dose increase once or twice, respectively. The prognostic value of IPSS-R karyotype, IPSS-R, number of somatic mutations, LTB, HTB, number of treatments before LUSPA, previous lenalidomide exposure, and iron chelation was analyzed for their prognostic value on HI-E. In multivariate analysis, HTB was the only variable statistically associated with lower HI-E (OR 0.19 [95%CI: 0.03-0.91, p=0.047] independently of IPSS-R and number of somatic mutations. At least 1 adverse event (AE) was seen in 38/103(37%) of the patients who received at least 2 doses of LUSPA, and 12 patients presented at least one severe AE (grade 3-4 according to CTCAE 5.0): including dizziness (in 5 patients), asthenia (n=4), peripheral and axial arthralgia (n= 4), headache (n=2), described by the patients as different from those they experienced with anemia. With a median follow-up of 6 months (IQR 5-8), 20 patients (18.5%) had discontinued LUSPA before 6 months of exposure due to severe AE (n=8, 7.4%, asthenia, arthralgia, dizziness, headache), lack of HI-E (n=3), disease progression (n=3), infection (n=3), death from intercurrent disease (n=2), acute coronary syndrome (n=1). After LUSPA failure, 26 patients (24.1%) received a combination of LUSPA and ESA and are currently followed. Efficacy and safety will be presented at the meeting. We also tried to correlate gene expression and GDF-11 levels with response. Results will be available at the meeting. Conclusions In this real-life study, we confirmed the results of LUSPA in MDS-RS reported in the MEDALIST study. We observed a significant number of adverse events attributed to LUSPA, some of which led to treatment discontinuation. The importance of RBC transfusion burden was the only prognostic factor of erythroid response.

Ker-050 Treatment Reduced Iron Overload and Increased Bone Specific Alkaline Phosphatase in Participants with Lower-Risk MDS Supporting Potential to Restore Balance to the Osteohematopoietic Niche

Background: Iron overload (IO) in myelodysplastic syndromes (MDS) contributes to the deterioration of the osteohematopoietic niche (OHN), where hematopoietic and osteogenic precursors interact to regulate hematopoiesis and bone metabolism. Excess iron exacerbates ineffective hematopoiesis, inflammation, and bone loss via direct effects on resident hematopoietic and osteogenic precursors. Iron chelation therapy (ICT) is associated with improved event-free survival in patients with MDS but does not address the underlying cause of IO and introduces patient burden due to tolerability and cost. KER-050 is an investigational, modified activin receptor type IIA ligand trap designed to inhibit select TGF-β superfamily ligands (activins A, B, GDFs 8, 11) and promote differentiation and maturation of erythroid and megakaryocytic precursors. KER-050 has potential to reduce dependence on red blood cell transfusions and increase iron utilization via erythropoiesis, possibly mitigating IO at its source. As previously reported from an ongoing Phase 2 study (NCT04419649), KER-050 treatment in participants with lower-risk (LR) MDS resulted in rates of modified IWG 2006 Hematological Improvement-Erythroid (HI-E) and transfusion independence (TI) of 51.4% and 42.3%, respectively, with a mean decrease in ferritin (322 ng/mL at Week 24) among HI-E and/or TI responders. KER-050 treatment also demonstrated effects on osteogenic precursors, including prevention of bone loss in a mouse model of MDS and dose-dependent increases in bone specific alkaline phosphatase (BSAP), a marker of bone formation, observed in healthy postmenopausal women. Thus, KER-050 has potential to address the multifaceted pathogenesis of MDS, including IO. Here, we present new data from the ongoing Phase 2 study in MDS, exploring the potential of KER-050 to provide benefit beyond hematologic responses and to ameliorate IO in MDS. Methods: This ongoing Phase 2 study is evaluating KER-050 in participants with LR MDS. Data from exploratory assessments of markers of IO, hematopoiesis, and bone turnover are presented as of a cutoff date of April 3, 2023, for all participants who had received the recommended Part 2 dose (RP2D; 3.75-5 mg/kg q4wks). Results: Baseline ferritin levels in RP2D participants (N=59) were generally elevated, while levels of mean corpuscular hemoglobin and reticulocyte hemoglobin were in the normal range (Table 1). After KER-050 treatment, sustained decreases in serum ferritin were observed among participants with baseline levels ≥1000 ng/mL (Figure 1), likely driven in part by reduced transfusion burden in responders. Concomitant increases observed in soluble transferrin receptor (sTfR; Figure 1) suggest that increased erythropoiesis may also have contributed. Mean decreases in ferritin observed in non-transfused (NT) participants (-228 ng/mL at Week 24, n=7) indicate potential for KER-050 to affect iron homeostasis by mechanisms other than transfusion reduction. In 1 NT participant receiving ICT, the baseline ferritin of 1632 ng/mL decreased to &amp;lt;500 ng/mL over 32 weeks, leading to ICT discontinuation and coinciding with an increase in hemoglobin (Hgb) from 9.2 g/dL at baseline to 11.3 g/dL over the same period. In another NT participant not receiving ICT, ferritin decreased from 1094 ng/mL at baseline to 884 ng/mL and 583 ng/mL at Weeks 24 and 68, respectively, while Hgb gradually increased from 9.94 g/dL at baseline to 10.7 and 12.2 g/dL at Weeks 24 and 68. KER-050 treatment was also associated with increases in BSAP, a new finding in this MDS population that is consistent with prior observations in preclinical and healthy volunteer studies. Despite some heterogeneity, mean increases of 8.47% (n=23) and 10.4% (n=13) were observed at Weeks 24 and 48, respectively; 3 participants with erythroid responses had increases in BSAP of ≥30% at these time points. Summary: Exploratory data indicate potential for KER-050 to drive meaningful decreases in ferritin in participants with LR MDS, particularly among those with IO. While transfusion reduction likely contributes, observations in NT participants highlight the potential for enhancement of erythropoiesis to improve IO, irrespective of transfusions. Observed changes in BSAP suggest that KER-050 is also acting on osteogenic precursors, with the potential to provide functional improvements within the OHN. Updated results will be provided at the presentation.

Luspatercept for the Treatment of Anemia in Non-Transfusion-Dependent β-Thalassemia: Final Safety and Efficacy Data from the BEYOND Trial

Background: Suboptimal anemia management in patients (pts) with non-transfusion-dependent (NTD) β-thalassemia may lead to serious clinical complications. Improvements in hemoglobin (Hb) levels were shown to significantly decrease the risk of developing morbidities (Musallam KM, et al. Ann Hematol 2022;101:203-204; Musallam KM, et al. Ann Hematol 2021;100:1903-1905). There is a need for therapies that increase Hb levels besides red blood cell transfusions (RBCT), which lead to secondary iron overload. Primary and longer-term data from the BEYOND study showed that luspatercept led to significant increases in Hb levels and had a manageable safety profile in pts with NTD β-thalassemia (Taher AT, et al. Lancet Haematol 2022;9:e733-e744; Taher AT, et al. Blood 2022;140[suppl 1];8210-8212). Here we report the final data (up to last patient last visit [LPLV] date Nov 28, 2022), of the phase 2, randomized, double-blind, placebo-controlled BEYOND trial (NCT03342404). Methods: Eligible pts (N = 145) had NTD (defined as receiving ≤ 5 RBC units in the 24 wk before randomization) β-thalassemia or HbE/β-thalassemia, Hb levels ≤ 10 g/dL. Pts were randomized to luspatercept (N = 96; 1.0-1.25 mg/kg) or placebo (N = 49) subcutaneously Q3W for ≥ 48 wk. Pts continued to receive best supportive care when required. Pts who crossed over from placebo to luspatercept were not included in this analysis. Mean Hb increase ≥ 1.0 g/dL (any 12-/24-wk interval) and ≥ 1.5 g/dL from baseline (any 12-wk interval), duration of mean Hb increase ≥ 1.0 g/dL and ≥ 1.5 g/dL from baseline, iron parameters, RBCT, and safety were evaluated up to the LPLV date. Results: As of Nov 28, 2022, 93/134 (69.4%) pts on luspatercept transitioned to the long-term follow-up study (NCT04064060): 66/96 (68.8%) pts in the luspatercept arm and 27/38 (71.1%) pts who crossed over from placebo to luspatercept after study unblinding. A total of 76/96 (79.2%) pts in the luspatercept arm completed 144 wk of treatment (tx), with 55/96 (57.3%) completing 192 wk of tx; 28/96 (29.2%) pts on luspatercept discontinued tx. The median (range) luspatercept tx duration was 202.8 (15.0-242.3) wk (Table) and 61.1 (3.0-138.0) wk with placebo. Pts had a durable increase in Hb ≥ 1.0 g/dL from baseline (by 12-wk interval) through wk 240 of luspatercept tx (Figure). In the luspatercept arm, 91/96 (94.8%) pts had a mean Hb increase ≥ 1.0 g/dL from baseline during any 12-wk interval (Table). The mean (standard deviation [SD]) total duration of mean Hb increase ≥ 1.0 g/dL from baseline (any 12-wk interval) with luspatercept was 1136.0 (491.9) days. The proportion of pts achieving a mean Hb increase ≥ 1.5 g/dL during any 12-wk interval over the entire tx period was 80/96 (83.3%) and 4/49 (8.2%) in the luspatercept and placebo arms, respectively. At baseline, 83/96 and 42/49 pts in the luspatercept and placebo arms, respectively, were RBCT-free. The proportion of pts who remained RBCT-free was 78.1% (75/96) and 57.1% (28/49) in the luspatercept and placebo arms, respectively. For pts who received RBCT, the mean time to first RBCT was 482.0 days with luspatercept and 202.6 days with placebo. The mean change from baseline in serum ferritin (SF) level at wk 96 was +76.45 µg/L with luspatercept (n = 90) and +211.51 µg/L with placebo (n = 35). The mean change from baseline in SF level stabilized with longer luspatercept tx (wk 192: 49.14 µg/L [n = 71]; wk 240: 52.19 µg/L [n = 51]). The mean change from baseline in liver iron content in the luspatercept arm was −1.23 mg/g dry weight (dw) at wk 96 (n = 8) and −0.79 mg/g dw at wk 144 (n = 54). The 10 most frequently reported adverse events (AEs; ≥ 5% of pts) with luspatercept were headache, back pain, bone pain, COVID-19, arthralgia, pyrexia, pain in extremity, fatigue, diarrhea, and hypertension. Rates of serious and grade 3-4 AEs in the luspatercept arm were 24.0% [23/96] and 34.4% [33/96]), respectively. In the luspatercept arm, thromboembolic events were reported in 2/96 pts, extramedullary hemopoietic masses in 10/96 pts (all grade 1-2), and there were no malignancies. Few AEs led to tx discontinuation in the luspatercept arm (5/96 [5.2%]); no new safety signals were identified. Summary: The final results from the BEYOND study show that pts with NTD β-thalassemia treated with luspatercept maintained clinically meaningful and durable erythroid responses. The safety profile of luspatercept was manageable, and extended luspatercept exposure did not raise new safety concerns.

Overall Survival and Erythroid Response in Patients with Low-Risk Myelodysplastic Neoplasms after First-Line Treatment in a Low-Middle Income Country

Introduction Myelodysplastic neoplasms/syndromes (MDS) are a heterogeneous group of clonal disorders characterized by ineffective hematopoiesis and an increased risk of transformation to acute myeloid leukemia (AML). Current standard risk stratification model, the Revised International Prognostic Scoring System (IPSS-R), classifies patients into lower (≤3.5 points) or higher risk MDS. Lower-risk MDS (LR-MDS) treatment is based on the prevailing cytopenia and intends to improve symptomatic burden and minimize transfusion dependency. Anemia is present in 80-90% of patients with MDS. Throughout most of the course of the disease, patients with MDS have a hemoglobin &amp;lt; 10 g/dL, which leads to a decreased quality of life. Also, 50% of patients with MDS will eventually need red blood cell transfusions. Current options for the active treatment of anemia in LR-MDS are limited and vary among countries. Although erythropoiesis stimulating agents (ESAs) are considered standard of care in the absence of del5q, immunosuppressive therapy (IST) and androgens are still used in low income countries. The present study aims to evaluate whether erythroid responses and overall survival differ in patients with LR-MDS, based on their first-line treatment. Methods This is a retrospective study in patients with LR-MDS at Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, a tertiary care center in Mexico City. Eligible patients were diagnosed between January 2002 and December 2022 according to World Health Organization (WHO) 2016 criteria. Response was assessed according to International Working Group (IWG) 2018 criteria. We defined erythroid response (HI-E) as the sum of the responses achieved within different transfusion burden categories. First line therapy included ESAs, IST (cyclosporine ± eltrombopag), and androgens (mesterolone, danazol). These were compared through bivariate analysis, Kaplan-Meier curves and log-rank test. Results Until December 2022, 109 LR-MDS patients were considered for inclusion. Among them, 29 patients were lost to follow-up, and 25 patients were solely observed without any further therapy. Also, 7 patients who received other therapies were excluded. Ultimately, 48 patients were included in this analysis, 56.3% (n=27) were female, mean age was 62.8 (±15.9) years. Based on WHO 2016 classification, MDS with uni- and multilineage dysplasia was present in 58.3% (n=28) of the patients, while 29.2% (n=14) had hypoplastic MDS. Anemia was present in 89.6% (n=43) of the patients. When evaluating transfusion burden, 37.5% (n=18) of patients were non-transfusion dependent (NTD), 31.3% (n=15) low-transfusion burden (LTB), and another 31.3% (n=15) high-transfusion burden (HTB). ESAs and IST were the most frequently used frontline therapies, each accounting for 41.7% (n=20) of the patients; the remaining 16% (n= 8) received androgens. When comparing baseline characteristics between treatment arms, we found lower hemoglobin values and a greater proportion of severe anemia in ESA-treated patients (p= 0.039, p= 0.036), however, no differences in transfusion burden was observed (p= 0.212). Erythroid response rates were 25% (n=5), 20% (n=4) and 62.5% (n=5) among those treated with ESAs, IST and androgens, respectively (p= 0.071). When assessing HI-E by transfusion burden, no differences were observed between treatment arms except in HTB patients (p= 0.023). Neither time to response, nor duration of response were significantly different between treatment groups ( Table 1). Importantly, 3 of the 4 responders in the IST group received cyclosporine monotherapy, also 50% were hypoplastic MDS. After a median follow up of 47 months (IQR:22.5-85.5), the median overall survival(OS) for the entire cohort was not reached. The 3-year-OS rates for IST, ESA and androgens were 94%, 54% and 50%, respectively (p= 0.018) ( Figure 1). Conclusions In spite of the bias and limitations in the retrospective nature of this study, IST seems to be a valid option in frontline therapy for LR-MDS, since HI-E rates are similar to those observed with ESAs. Additionally, IST group showed a better OS. Results obtained with androgens merit further study and should be interpreted with caution because of the sample size.

Durable Clinical Benefit with Ker-050 Treatment: Findings from an Ongoing Phase 2 Study in Participants with Lower-Risk MDS

Background: In myelodysplastic syndromes (MDS), defects occur at multiple stages of hematopoiesis. Available Erythropoiesis Stimulating or Erythroid Maturation Agents (ES/EMAs) target early or late stages of erythropoiesis, respectively, and are only effective in subsets of patients. For patients with high transfusion burden (HTB) who have diminished erythropoietic capacity and a worse prognosis, ES/EMAs show limited efficacy and durability of response (DOR). KER-050 is an investigational, modified activin receptor type IIA ligand trap designed to inhibit select TGF-β superfamily ligands (activins A, B, GDFs 8, 11) that is being evaluated in diseases with ineffective hematopoiesis (IH), including MDS and myelofibrosis. Preclinical studies demonstrated that KER-050 increased erythropoiesis and thrombopoiesis and acted on early- and late-stage erythropoietic and megakaryocyte progenitors. By eliciting effects on hematopoiesis across multiple differentiation stages and cell lineages, KER-050 has the potential to address the complex nature of IH and to provide robust and sustained hematological improvement in patients with MDS who have limited treatment options, including those with HTB or non-ring sideroblast (RS) MDS. Methods: Analyses evaluating KER-050 at the recommended Part 2 dose (RP2D; 3.75 - 5 mg/kg q4wk) in participants with lower-risk (LR), RS+ or non-RS MDS from an ongoing Phase 2 study (NCT04419649) are presented as of a data cutoff date of April 3, 2023. The primary endpoint evaluates the safety and tolerability of KER-050. Secondary endpoints of modified IWG 2006 Hematological Improvement-Erythroid (HI-E) and transfusion independence (TI) ≥8 weeks are presented for participants who received ≥24 weeks of treatment or discontinued. DOR and changes in hematological parameters for participants with ongoing TI are presented for the first time. Results: At baseline, most participants receiving KER-050 at the RP2D (74.6%) required regular transfusions (≥2 RBC units/8 weeks); 52.5% of RP2D participants had HTB (≥4 RBC units/8 weeks) and 20.3% had ≥8 RBC units/8 weeks (Table 1). The median treatment duration was 166 days (range 6 to 649). Most participants (89.8%) had at least 1 treatment-emergent adverse event (TEAE), and 32.2% had TEAEs considered treatment-related (Table 1). The most frequently observed TEAEs in ≥15% of participants were fatigue (22.0%), nausea and diarrhea (18.6% each), epistaxis (16.9%), and COVID-19 and dyspnea (15.3% each). A minority of participants (10.2%) had TEAEs that led to treatment discontinuation. Consistent with prior data, rates of TI for ≥8 weeks were similar regardless of baseline transfusion burden or RS status (Table 1). Among TI responders, 72.7% maintained TI for ≥24 weeks (data not shown), and the median DOR was not yet evaluable as more than half (6/11) had ongoing TI as of the cutoff date (Figure 1). Five of the 6 (83.3%) participants with ongoing TI had HTB at baseline, including one participant with a baseline transfusion burden of 11 RBC units/8 weeks, and all 3 responders with ongoing TI for &amp;gt;60 weeks. One participant with HTB and non-RS MDS had ongoing TI for &amp;gt;72 weeks with a steady increase in hemoglobin from 8.4 to 11.8 g/dL. Erythroid responses were not at the expense of other cell lineages, as levels of platelets and neutrophils generally did not decrease (Figure 1). In fact, 44.1% of participants overall experienced a sustained (≥8 weeks) mean increase in platelet count of ≥30 x 10 9 within the first 24 weeks. Sustained decreases in ferritin were observed in parallel with increases in soluble transferrin receptor (Table 1), and for 3 participants, iron chelator therapy (ICT) was able to be discontinued. Investigation into changes in serum ferritin and ICT with KER-050 treatment will continue as cohorts of participants with MDS and iron overload are enrolled. Summary: Updated findings from this ongoing Phase 2 study in LR MDS continue to show that KER-050 is generally well-tolerated and has potential to elicit sustained hematological improvements in a broad population of participants with LR MDS, including those with HTB. New data reveal an encouraging DOR, with observed preservation or improvement of multilineage hematopoiesis and sustained decreases in ferritin manifesting clinically with discontinuation of ICT. The study is ongoing and an update with the latest data will be provided at the time of presentation.

A Phase I/II, Intra-Patient Dose-Escalation Study of Bitopertin, a Selective Inhibitor of GlyT1 and Heme Synthesis, for Steroid-Refractory Diamond-Blackfan Anemia

Background: Diamond-Blackfan anemia (DBA) is a heritable bone marrow failure disorder characterized by macrocytic anemia with reticulocytopenia and bone marrow erythroid hypoplasia, usually presenting within the first two years of life. Treatment consists of systemic corticosteroids. Treatment failure or steroid intolerance occurs in approximately half of all cases, necessitating chronic transfusions, which carry the risks of iron overload and infections. Hematopoietic cell transplant remains the sole curative therapy for DBA. In cases where a causative mutation can be identified, with rare exceptions, the affected genes encode ribosomal proteins (RPs), defining DBA as prototypic haploinsufficient ribosomopathy. Erythrocyte hemoglobinization requires balanced heme synthesis and globin translation. Various in vitro and animal models suggest that RP insufficiency results in reduced ribosomal biogenesis, disrupting this balance and leading to excess of heme, resulting in toxicity to developing erythroid cells and premature termination of erythroid differentiation. Bitopertin is an investigational, orally administered, inhibitor of the GlyT1 glycine transporter. Outside the central nervous system (CNS), GlyT1 is expressed almost exclusively on developing erythrocytes. By reducing intracellular glycine, a rate-limiting substrate for heme synthesis, bitopertin slows heme synthesis and thus we hypothesize rebalances hemoglobin synthesis. In preclinical DBA models, bitopertin rescues erythropoiesis. The drug was originally developed for CNS indications, and has been shown to exhibit a favorable safety profile in prior studies with cumulative enrollment of over 4,000 patients and healthy volunteers. It is currently under clinical investigation for the treatment of erythropoietic protoporphyria. Study Design and Methods: This is a phase I/II, intra-patient dose-escalation study of bitopertin for steroid-refractory DBA, conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, Maryland. Subjects visit the NIH for initial evaluation and eligibility assessment and at the primary endpoint, with interim follow-up conducted via telehealth and local laboratory assessments. Subjects must be 18 years of age or and older, diagnosed with DBA and with clinically significant anemia (hemoglobin &amp;lt; 9/dL and/or requiring 2 units PRBC per 8 weeks). They must have relapsed and/or steroid refractory disease or be intolerant of systemic steroids, and be without significant comorbidities. Ongoing transfusions and chelation therapy are allowed, but other DBA-directed therapy, most notably steroids and growth factors, are not. Each subject will take oral bitopertin daily, escalating the dose monthly (5 mg, 10 mg, 20 mg, 40mg, and 60 mg) until reaching either the study maximum dose of 60 mg, the minimum effective dose (MED), or the maximum tolerated dose (MTD). Subjects will be followed for 8 months (32 weeks), including a minimum of 4 months (16 weeks) at the final dose (MED, MTD or study maximum). Response will be assessed on an ongoing basis and will be defined as an increase in hemoglobin ≥by 1.5 g/dL and/or a reduction in the units of PRBC transfusions by ≥50% from baseline. Furthermore, a robust response will be defined as a hemoglobin ≥10 g/dL and transfusion independence for 8 weeks. Patients with response (robust or non) by the 8-month primary endpoint will be allowed to continue extended therapy for 3 additional years. The primary endpoint is erythroid response. Secondary endpoints include safety as defined by the toxicity profile over 8 months of therapy and on extended therapy, relapse, survival, clonal evolution, health-related quality of life, and ancillary laboratory studies including the impact of bitopertin upon erythroid cell dynamics. The study employs a minmax design. A minimum of 15 patients will be enrolled. If the minimum efficacy threshold is met or surpassed (≥13% response rate), an additional 10 patients will be enrolled. Status: This study has been granted an FDA IND (165778) and is open for enrollment. It is monitored under the NIH Institutional Review Board (001528-H) and is registered with the U.S. National Library of Medicine (NCT05828108). Funding: This study is supported by the NHLBI Division of Intramural Research and in part through a Cooperative Research and Development Agreement (CRADA) with Disc Medicine, Inc. (Watertown, MA).

Efficacy and Safety of Luspatercept in Patients Enrolled in the BELIEVE Trial: Data from the Phase 3b Long-Term Rollover Study

Background: Ineffective erythropoiesis and anemia are pathognomonic features of β-thalassemia, leading to red blood cell (RBC) transfusion dependence in patients with more severe genotypes and consequently increased morbidity and mortality. The phase 3 BELIEVE study showed that luspatercept reduces transfusion burden in transfusion-dependent patients with a manageable safety profile (Cappellini MD, et al. HemaSphere 2022;6[S3]:171-172; Viprakasit V, et al. HemaSphere 2022;6[S3]:2664-2665). Patients who continued to benefit from luspatercept at completion of the BELIEVE study or who needed to complete post-treatment follow-up could roll over to the phase 3b long-term follow-up study (LTFU; NCT04064060) to continue receiving treatment or complete post-treatment follow-up, respectively. Patients receiving luspatercept were monitored for continued efficacy and safety. Methods: The aim of this analysis was to evaluate long-term safety and efficacy of luspatercept in patients who rolled over to the LTFU study. This analysis included patients randomized to luspatercept during BELIEVE (luspatercept group) and those randomized to placebo who crossed over to receive luspatercept after unblinding (crossover group). Response was defined as ≥ 33% reduction from baseline in RBC transfusion burden during any 12-week interval over the entire treatment period of the combined studies. The data cutoff was Jan 2, 2023. Results: At the closure of the BELIEVE trial, 127/224 (56.7%) patients from the luspatercept group and 67/92 (72.8%) patients from the crossover group had transitioned to the LTFU study with the intention to continue luspatercept. At data cutoff, treatment was ongoing for 138 patients, 90 in the luspatercept group and 48 in the crossover group. Median (range) total treatment duration over the combined studies was 229.1 (1.7-336.1) weeks for the luspatercept group and 221.2 (6.1-230.7) weeks for the crossover group; 98 patients had completed 288 weeks (&amp;gt; 5 years) of treatment at data cutoff, all of whom had been randomized to luspatercept. In the luspatercept group, 180/224 (80.4%) patients had achieved response, continuing the trend showing an increasing proportion of responders with longer duration of treatment observed at previous data cutoffs (Figure A). Response in the crossover group was similar with 71/92 (77.2%) responders. Patients in the luspatercept and crossover groups had median (range) reductions in transfusion burden of −17.75% (−100.0 to 33.3) and −19.05% (−100.0 to 20.8), respectively, from baseline to week 145-192, equating to mean reductions of 6.78 RBC units (SD 7.27; n = 120) and 6.85 RBC units (SD 6.78; n = 50), respectively. Liver iron concentration in the luspatercept group was reduced with long-term treatment at each timepoint compared with the baseline (mean decrease of 2.80 mg/g dry weight [dw] at week 144 from median 8.97 [range, 1.1-31.9] at baseline [n = 24]; mean decrease of 0.45 mg/g dw at week 192 from median 7.75 [1.4-35.5] at baseline [n = 27]; mean decrease of 1.48 mg/g dw at week 240 from median 5.65 [1.0-42.0] at baseline [n = 20]). Mean changes from baseline in overall serum ferritin levels (last 24-week level for each patient prior to their efficacy cutoff) were −376.27 μg/L for luspatercept and +43.09 μg/L for crossover. In the combined studies up to data cutoff, 59.4% of luspatercept patients and 47.8% of crossover patients discontinued treatment. The most frequent reason for treatment discontinuation was the patient's personal decision to withdraw (luspatercept: 23.7% in BELIEVE and 33.5% in the combined studies; crossover: 14.1% in BELIEVE and 28.3% in the combined). Discontinuation due to an adverse event (AE) in the combined studies was similar to experience from BELIEVE (luspatercept: 10.3% BELIEVE and 12.5% combined; crossover: 4.3% BELIEVE and 7.6% combined). One patient (0.4%) discontinued luspatercept and transitioned to a commercially available treatment. The frequency of treatment-emergent AEs in the combined studies was also consistent with previous experience from the BELIEVE trial (Figure B). Summary: These long-term data from the LTFU study show that erythroid responses and safety results in both the luspatercept and crossover groups were consistent with previous clinical experience from the BELIEVE trial. Patients receiving long-term luspatercept treatment experience durable clinical benefit with no new safety concerns.

FORTITUDE: A Phase 2 Open-Label Study in Progress to Evaluate Etavopivat for the Treatment of Anemia in Patients with Lower-Risk Myelodysplastic Syndromes

Background: Most patients with lower-risk myelodysplastic syndrome (LR-MDS) develop anemia and a high proportion of patients become dependent on red blood cell (RBC) transfusions. MDS-related anemia is associated with low hemoglobin (Hb) levels, iron overload and poor quality of life. Erythropoiesis-stimulating agents and other drugs, including lenalidomide, luspatercept and imetelstat (an investigational product), can lead to RBC transfusion independence and improve Hb levels in many patients; however, responses are generally transient and novel treatments are needed for this population. Etavopivat is an investigational, once-daily, selective erythrocyte pyruvate kinase (PKR) activator in development for the treatment of sickle cell disease (SCD) and anemia in patients with LR-MDS. In a phase 1 study in adult and adolescent patients with SCD by Saraf et al. HemaSphere. (2022), etavopivat 400 mg once daily was considered well tolerated and showed sustained Hb increases up to 12 weeks for most patients. Additional studies in healthy volunteers and patients with SCD support an acceptable safety profile together with improved RBC health and function during continuous treatment with etavopivat. In patients with LR-MDS, ineffective hematopoiesis may be due, in part, to insufficient ATP production, leading to increased erythroid lineage apoptosis. By activating PKR, etavopivat may improve RBC health and function by stimulating energy production (increasing ATP levels), increasing Hb levels (decreasing anemia), and decreasing erythroid lineage apoptosis. Aims:Describe the design of a multicenter, open-label, phase 2 study (FORTITUDE; NCT05568225) evaluating hematologic improvements in patients with very low-, low- and intermediate-risk MDS during treatment with etavopivat. Study design:Key eligibility criteria include age ≥18 years; very low-, low- and intermediate-risk MDS per the Revised International Prognostic Scoring System; and anemia defined by mean Hb &amp;lt;10.0 g/dL and &amp;lt;3 RBC transfusions &amp;lt;16 weeks prior to first dose for non-transfusion-dependent (NTD) patients or ≥3 units of RBCs for anemia &amp;lt;16 weeks prior to first dose for transfusion-dependent (TD) patients. Key exclusion criteria include MDS associated with del 5q cytogenetic abnormality and known TP53 abnormality, history of acute myeloid leukemia, and an absolute neutrophil count &amp;lt;0.5 × 10 9/L. Additional exclusion criteria include prior treatment with azacitidine; decitabine; erythropoietin, other hematopoietic growth factor treatment or lenalidomide within 30 days of Day 1 or anticipated to be required during the study; and luspatercept within 30 days of Day 1 for NTD patients and within 16 weeks of Day 1 for TD patients. Patients will receive etavopivat 400 mg once daily for at least 48 weeks. Treatment may be continued beyond 48 weeks in patients demonstrating clinical benefit. The primary objective of the study is to assess hematologic improvements based on an erythroid response over any continuous period ≥8 weeks within 24 weeks on etavopivat treatment in patients with LR-MDS. The primary endpoint will be based on the combined incidence of: ≥1.5 g/dL increase in Hb from baseline maintained for ≥8 consecutive weeks for NTD patients; absence of any transfusion for ≥8 consecutive weeks for low transfusion-burden patients; and reduction by ≥50% of RBC units for ≥8 consecutive weeks for high transfusion-burden patients. Safety, tolerability, pharmacokinetic, and pharmacodynamic properties of etavopivat will be evaluated. FORTITUDE is open for enrollment in Canada, France, Germany, and the USA. Planned enrollment includes approximately 15 patients in each of the three transfusion requirement-based groups (Figure). Statistical analysis: The primary endpoint (pooled incidence) will be tested with a one-sided Fisher's exact test at the significance level of 0.025 where 0.2 is the assumed null proportion. Summary:Etavopivat is a novel, investigational, once-daily, selective PKR activator with the potential to improve RBC health and lifespan. This phase 2 study will assess the safety of etavopivat and its impact on Hb levels and RBC transfusion burden in patients with LR-MDS and anemia.

Efficacy and Safety of Luspatercept Versus Epoetin Alfa in Erythropoiesis-Stimulating Agent (ESA)-Naive Patients (Pts) with Transfusion-Dependent (TD) Lower-Risk Myelodysplastic Syndromes (LR-MDS): Full Analysis of the COMMANDS Trial

Introduction: ESAs are an established treatment (tx) for pts with TD LR-MDS and endogenous serum erythropoietin (sEPO) levels ≤ 500 U/L; however, eligible pts often do not respond, or the response duration is limited. Luspatercept is approved in the US and EU to treat anemia due to LR-MDS after ESA failure. The preplanned interim analysis of the phase 3 COMMANDS trial (NCT03682536), comparing luspatercept with epoetin alfa in ESA-naive TD pts with anemia due to LR-MDS (with or without ring sideroblasts [RS]) showed for the first time the superiority of another therapy over ESAs in improving red blood cell transfusion independence (RBC-TI) rates (Platzbecker U, et al. Lancet 2023. doi:10.1016/S0140-6736[23]00874-7). Here we report the full efficacy and safety analysis of the COMMANDS trial. Methods: Eligible pts were ≥ 18 y of age, had Revised International Prognostic Scoring System-defined LR-MDS with &amp;lt; 5% bone marrow blasts, sEPO &amp;lt; 500 U/L, and were TD (received 2-6 RBC U/8 wk for ≥ 8 wk before randomization). Pts were randomized 1:1 to luspatercept (1.0-1.75 mg/kg) subcutaneously (SC) Q3W, or epoetin alfa (450-1050 IU/kg) SC Q1W for ≥ 24 wk and stratified by baseline RBC transfusion burden (&amp;lt; 4 vs ≥ 4 RBC U/8 wk), RS status (RS+ vs RS−), and sEPO (≤ 200 vs &amp;gt; 200 U/L). The primary endpoint was the achievement of RBC-TI ≥ 12 wk with a concurrent mean hemoglobin (Hb) increase ≥ 1.5 g/dL (wk 1-24). Key secondary endpoints (wk 1-24) included achievement of RBC-TI ≥ 12 and for 24 wk and hematologic improvement-erythroid (HI-E) ≥ 8 wk. Other endpoints included duration of RBC-TI ≥ 12 wk, progression to acute myeloid leukemia (AML), and safety. Results: As of Mar 31, 2023, 182 pts were randomized to luspatercept and 181 to epoetin alfa, with a median (range) tx duration of 51.3 (3-196) and 37.0 (1-202) wk and median (range) follow-up of 17.2 (1-46) and 16.9 (0-46) months, respectively. The primary endpoint was achieved by110 (60.4%) pts in the luspatercept arm versus 63 (34.8%) in the epoetin alfa arm ( P &amp;lt; 0.0001). Subgroup analysis of the primary endpoint response showed that response rates achieved with luspatercept versus epoetin alfa, respectively, were greater for SF3B1-mutated and non-mutated pts (Table), greater for pts with baseline sEPO ≤ 200 U/L and with baseline sEPO &amp;gt; 200 to &amp;lt; 500 U/L (Table), and greater for RS+ pts (Table). The response rates were comparable between tx arms for RS− pts (Table). RBC-TI ≥ 12 wk was achieved by 124 (68.1%) and 88 (48.6%) pts in the luspatercept and epoetin alfa arms, respectively, RBC-TI for 24 wk by 87 (47.8%) and 56 (30.9%) pts, and HI-E ≥ 8 wk by 135 (74.2%) and 96 (53.0%) pts. The median (95% CI) duration of RBC-TI ≥ 12 wk was longer with luspatercept versus epoetin alfa (128.1 wk [108.3-not estimable (NE)] versus 89.7 wk [5.9-157.3]; HR, 0.534; Figure), and longer for clinically relevant subgroups, including RS+ and RS−. The median duration of tx was longer in the luspatercept arm compared with the epoetin alfa arm (51.3 versus 37.0 wk). Five (2.7%) and 6 (3.3%) pts in the luspatercept and epoetin alfa arms, respectively, progressed to AML. Overall, 178 (97.8%) and 165 (92.2%) pts receiving luspatercept and epoetin alfa reported tx-emergent adverse events (TEAEs) of any grade; 107 (58.8%) and 88 (49.2%) pts reported grade 3/4 TEAEs, respectively. The most common any-grade TEAEs in either arm (≥ 10% of pts) were diarrhea (17.6% luspatercept vs 14.0% epoetin alfa), COVID-19 (14.8% vs 15.6%), asthenia (13.7% vs 16.2%), and anemia (12.1% vs 10.6%). TEAEs of interest were reported by 105 (57.7%) and 81 (45.3%) pts receiving luspatercept and epoetin alfa, respectively, with asthenia including fatigue, malaise, and lethargy (30.8% vs 24.6%), hypertension (15.9% vs 9.5%), malignancies and premalignant disorders (14.3% vs 12.8%), kidney toxicity (8.8% vs 6.7%), and injection site reactions (6.6% vs 2.2%), occurring in &amp;gt; 5% pts. In both tx arms, rates of on-tx deaths (8.2% for luspatercept and 7.2% for epoetin alfa) and post-tx deaths (13.2% and 13.4%) were similar. Conclusions: Results of this full analysis confirm the findings from the interim analysis; RBC-TI duration and erythroid responses achieved with luspatercept are superior compared with epoetin alfa. Luspatercept safety results were consistent with previous MDS studies. These data show that luspatercept could represent a new standard of care for pts with TD LR-MDS.

Efficacy and safety results from the COMMANDS trial: A phase 3 study evaluating luspatercept vs epoetin alfa in erythropoiesis-stimulating agent (ESA)-naive transfusion-dependent (TD) patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS).

7003 Background: Most pts with LR-MDS have limited responses to ESAs, thus there is an unmet need to treat anemia and reduce TD. Here we report interim results from the open-label, randomized phase 3 COMMANDS trial (NCT03682536) comparing the efficacy and safety of luspatercept vs epoetin alfa in ESA-naive pts with LR-MDS. Methods: Eligible pts were ≥ 18 years old with IPSS-R-defined LR-MDS with or without RS, &lt; 5% bone marrow blasts, sEPO levels &lt; 500 U/L, required RBC transfusions (defined as 2–6 RBC units/8 weeks [wk] for ≥ 8 wk immediately prior to randomization), and were ESA naive. Pts were randomized 1:1 to receive subcutaneous luspatercept (starting dose 1.0 mg/kg, titration up to 1.75 mg/kg) once every 3 wk or epoetin alfa (starting dose 450 IU/kg, titration up to 1050 IU/kg) weekly for ≥ 24 wk. Primary endpoint was achievement of RBC transfusion independence (TI) ≥ 12 wk within the first 24 wk, with a mean hemoglobin increase ≥ 1.5 g/dL. Secondary endpoints included achievement of hematologic improvement-erythroid (HI-E) response ≥ 8 wk per IWG 2006 criteria, RBC-TI 24 wk and ≥ 12 wk, and safety. Results: As of Aug 31, 2022, 178 pts received luspatercept and 176 epoetin alfa, with median treatment durations of 41.6 and 27.0 wk, respectively. Baseline pt characteristics were balanced across treatment arms. Of 301 pts included in the efficacy analysis, 86 (58.5%) pts receiving luspatercept vs 48 (31.2%) epoetin alfa achieved the primary endpoint of RBC-TI ≥ 12 wk with concurrent mean Hb increase ≥ 1.5 g/dL within the first 24 wk ( P &lt; 0.0001). HI-E ≥ 8 wk was achieved by 109 (74.1%) luspatercept and 79 (51.3%) epoetin alfa pts ( P &lt; 0.0001 ). Within the first 24 wk of treatment, RBC-TI 24 wk and ≥ 12 wk was achieved by 70 (47.6%) and 98 (66.7%) luspatercept pts, respectively, vs 45 (29.2%) and 71 (46.1%) epoetin alfa pts ( P = 0.0006 and 0.0002). Treatment-emergent adverse events (TEAEs; any grade) were reported by 164 (92.1%) luspatercept and 150 (85.2%) epoetin alfa pts; 8 (4.5%) and 4 (2.3%) pts discontinued due to TEAEs. Treatment-related AEs were reported by 54 (30.3%) luspatercept and 31 (17.6%) epoetin alfa pts. AML progression was reported in 4 (2.2%) luspatercept and 5 (2.8%) epoetin alfa pts. Overall rates of death were comparable between arms during treatment and post-treatment (32 [18.0%] luspatercept, 32 [18.2%] epoetin alfa pts). Conclusions: Compared with epoetin alfa, luspatercept led to clinically meaningful and statistically significant improvements in RBC-TI and erythroid response, as well as duration of response. Luspatercept safety results were consistent with previous findings. These data show, for the first time, superiority of an innovative therapy over ESAs in ESA-naive pts with TD LR-MDS. Luspatercept could represent a new standard of care for pts with TD LR-MDS. Clinical trial information: NCT03682536 .

Danazol Treatment for Thrombocytopenia in Myelodysplastic Syndromes: Can an "Old-fashioned" Drug be Effective?

Danazol Treatment for Thrombocytopenia in Myelodysplastic Syndromes: Can an "Old-fashioned" Drug be Effective?

Improved benefit of continuing luspatercept therapy: sub-analysis of patients with lower-risk MDS in the MEDALIST study

Red blood cell transfusion independence (RBC-TI) is an important goal in treating lower-risk myelodysplastic syndromes with ring sideroblasts. In the phase 3 MEDALIST study, RBC-TI of ≥ 8 weeks was achieved by significantly more luspatercept- versus placebo-treated patients in the first 24 weeks of treatment. In this post hoc analysis, we evaluated RBC transfusion units and visits based on patients’ baseline transfusion burden level and the clinical benefit of luspatercept treatment beyond week 25 in initial luspatercept nonresponders (patients who did not achieve RBC-TI ≥ 8 weeks by week 25) but continued luspatercept up to 144 weeks. RBC transfusion burden, erythroid response, serum ferritin levels, and hemoglobin levels relative to baseline were evaluated. Through week 25, fewer RBC transfusion units and visits were observed in luspatercept-treated patients versus placebo, regardless of baseline transfusion burden. This continued through 144 weeks of luspatercept treatment, particularly in patients with low baseline transfusion burden. Sixty-eight patients were initial nonresponders at week 25 but continued treatment; most (81%) received the maximum dose of luspatercept (1.75 mg/kg). Sixteen percent achieved RBC-TI for ≥ 8 weeks during weeks 25–48, 26% had reduced RBC transfusion burden, 10% achieved an erythroid response, 44% had reduced serum ferritin, and hemoglobin levels increased an average of 1.3 g/dL from baseline. These data have implications for clinical practice, as transfusion units and visits are less in luspatercept-treated patients through week 25 regardless of baseline transfusion burden, and continuing luspatercept beyond week 25 can potentially provide additional clinical benefits for initial nonresponders. Trial registration: NCT02631070.

Efficacy and Safety of Luspatercept in the Treatment of β-Thalassemia: A Systematic Review.

β-thalassemia is characterized by the faulty generation of hemoglobinresulting in an elevated α/β globin ratio; this led to several patients needing red blood cell (RBC) transfusionsfor the rest of their lives. Luspatercept is an erythroid maturation test for treating various types of anemia, including β-thalassemia. It inhibits the Smad2/3 cascade and treats β-thalassemia by downregulating the transforming growth factor-beta (TGF-β) pathway. Luspatercept was evaluated in randomized controlled trials (RCTs). However, there is still limited data. Therefore, the study aims to review the current literature to assess the efficacy of luspatercept in cure β-thalassemia and its safety. From 2015 to 2022, searches were undertaken in PubMed, Google Scholar, and Cochrane. Only RCTs published in English were eligible for inclusion. The Cochrane Collaboration tool for bias assessment was used to analyze the quality of the publications. Our search strategy revealed 94 publications, of which 12 full-text papers were read and five were chosen for this review.All five trials included 1161 participants. Of whom, 153 (13.18%) entered phase 2, and 1008 (86.82%) entered phase 3. Two articles included 153 participants, of whom 70 (45.75%) were transfusion-dependent beta-thalassemia (TD) and 83 (54.25%) were non-transfusion-dependent beta-thalassemia (NTD) of phase 2. Three articles included 1008 participants, of whom 672 (66.67%) were given luspatercept and 336 (33.33%) were given a placebo. All participants in RCTs were 18 years of age or older. In phase 2, 0.2 to 1.25 mg/kg of luspatercept was given, and in phase 3, 1.0 to 1.25 mg/kg of luspatercept was given once every three weeks. In beta-thalassemia patients, luspatercept was more effective than a placebo and well tolerated. The high dose has shown promising results in the erythroid response, measured by a drop in blood transfusions or an average rise in hemoglobin levels. Luspatercept might make patients less likely to need RBC transfusions, improve their clinical results, and improve their quality of life. Adverse events were hyperuricemia, arthralgia, dizziness, influenza hypertension, and bone pain, but they were manageable.

Erythroid Response in Patients with Non-Transfusion-Dependent β-Thalassemia Treated with Luspatercept: Long-Term Data from the BEYOND Trial

Introduction: Long-term, untreated anemia in patients with non-transfusion-dependent (NTD) β-thalassemia can lead to serious clinical complications. Several studies have shown that increasing hemoglobin (Hb) levels by ≥ 1 g/dL can significantly decrease the risk of developing morbidities (Musallam KM, et al. Ann Hematol 2022;101:203-204; Musallam KM, et al. Ann Hematol 2021;100:1903-1905). Although there are no available treatments for NTD β-thalassemia-associated anemia, previous studies showed that luspatercept improved erythropoiesis leading to a decrease in transfusion burden in pts with transfusion-dependent β-thalassemia, and durably increased Hb levels in pts with NTD β-thalassemia (Cappellini MD, et al. N Engl J Med 2020;382:1219-1231; Taher AT, et al. HemaSphere 2021;5[Suppl 2]. Abstract S101). Here, we report the long-term efficacy update of luspatercept in patients with NTD β-thalassemia in the BEYOND trial (NCT03342404). Methods: Eligible patients (N = 145) with NTD β-thalassemia or HbE/β-thalassemia (defined as receiving 0-5 RBC units in the 24 weeks [wk] prior to randomization) and Hb levels ≤ 10 g/dL were randomized to luspatercept (1.0-1.25 mg/kg) or placebo subcutaneously for ≥ 48 wk. Assessment groups were based on patient assignment at randomization: patients in the luspatercept arm were assessed while remaining on treatment and patients in the placebo arm were assessed up to discontinuation or crossover to luspatercept. Mean change from baseline in Hb was assessed for continuous 12-wk intervals up to wk 144. Erythroid response was defined as mean Hb change from baseline of ≥ 1 g/dL and was assessed over rolling 12-wk intervals. The incidence of RBC transfusions (events and units) was also assessed. Results: As of September 22, 2021, 83 (86.5%) patients in the luspatercept arm and 16 (32.7%) in the placebo arm completed ≥ 96 wk of treatment. Moreover, 72 (75.0%) patients in the luspatercept arm completed ≥ 120 wk of treatment. The median (range) treatment duration was 150.1 (15.0-185.4) wk in the luspatercept arm and 61.1 (3.0-138.0) wk in the placebo arm. Patients in the luspatercept and placebo arms received a median (range) of 42.0 (3.0-61.0) doses and 20.0 (1.0-46.0) doses per patient, respectively. Mean (standard error [SE]) Hb change from baseline in the luspatercept arm was 1.28 (0.069) g/dL during wk 1-12 and 1.48 (0.078) g/dL during wk 13-24, and the increase was maintained among patients remaining on study through all time points. Improvements in Hb levels from baseline were nominally significant versus placebo at assessed 12-wk intervals up to wk 96 (Figure). The proportion of patients experiencing an erythroid response during any 12-wk interval increased from 91.7% (88/96 patients) at the primary data cutoff date (September 14, 2020), to 93.8% (90/96 patients) at the current data cutoff date. Among responders, the proportion of patients in the luspatercept arm with more than one 12-wk rolling response increased from 35.2% (31/88 patients) to 61.1% (55/90 patients) between the primary and current data cutoff dates, and the mean (standard deviation [SD]) total duration of erythroid response among patients with at least one 12-wk rolling response also increased, from 611.1 (243.3) to 873.1 (363.4) days. During wk 1-96, a smaller proportion of patients in the luspatercept arm compared to the placebo arm (10.4% [10/96 patients] vs 32.7% [16/49 patients]) had ≥ 2 RBC transfusions. During the same period, the mean number of transfusion events (0.4 vs 1.3) and RBC units transfused (0.7 vs 2.2) per patient was lower in the luspatercept arm than in the placebo arm. During wk 97-144, the mean number of transfusion events and units per patient in the luspatercept arm remained stable (0.2 events and 0.2 units, respectively). Conclusions: Long-term luspatercept treatment resulted in sustained and significantly improved Hb levels in patients with NTD β-thalassemia. The duration of erythroid response increased with an additional year of luspatercept treatment. Few patients required RBC transfusions and the cumulative incidence of RBC transfusions remained low and relatively stable through 144 wk. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal