Red Blood Cell Transfusion Burden Research Articles

Longitudinal Assessment of Transfusion Intensity in Patients With JAK Inhibitor–Naive or –Experienced Myelofibrosis Treated With Momelotinib

PurposeAnemia is a cardinal feature of myelofibrosis often managed with red blood cell (RBC) transfusions, which may contribute to negative prognostic, quality-of-life, and healthcare-related economic impacts. The Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor momelotinib was approved for the treatment of patients with myelofibrosis and anemia based on clinical trial evidence of anemia, spleen, and symptom benefits illustrated using binomial response/nonresponse endpoints. In the present post hoc, descriptive analyses, the impact of momelotinib on RBC transfusion burden over time was further characterized across JAK inhibitor–naive and –experienced patients. MethodsAll RBC units transfused were collected during the baseline and 24-week treatment periods, initially in a single-arm phase 2 study as proof-of-concept analysis, and then versus comparators (ruxolitinib, best available therapy [BAT], and danazol) in the phase 3 SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM studies, respectively. ResultsIn the phase 2 study, mean transfusion requirement changed by −1.5 units/28 days, with 85% of patients (35/41) achieving numeric transfusion reduction. Across SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM, mean transfusion requirements decreased with momelotinib (−0.1, −0.36, and −0.86 units/28 days), while mean requirements with ruxolitinib, BAT, and danazol changed by +0.39, 0, and ‒0.28 units/28 days, respectively. Overall, 87% (185/213), 77% (79/103), and 85% (110/130) of patients had improved or stable transfusion intensities with momelotinib versus 54% (117/216), 62% (32/52), and 63% (41/65) with ruxolitinib, BAT, and danazol. ConclusionThese novel time-dependent transfusion burden analyses demonstrate that momelotinib is associated with anemia-related benefits in most patients and greater transfusion burden reduction versus comparators. Trial registrationClinicalTrials.gov identifiers: NCT02515630, NCT01969838, NCT02101268, NCT04173494.

Luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): primary analysis of a phase 3, open-label, randomised, controlled trial

The preplanned interim analysis of the COMMANDS trial showed greater efficacy of luspatercept than epoetin alfa for treating anaemia in erythropoiesis-stimulating agent (ESA)-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. In this Article, we report the results of the primary analysis of the trial. COMMANDS is a phase 3, open-label, randomised, controlled trial conducted at 142 sites in 26 countries. Eligible patients were those aged 18 years or older, with myelodysplastic syndromes of very low risk, low risk, or intermediate risk (as defined by the Revised International Prognostic Scoring System), who were ESA-naive and transfusion dependent, and had a serum erythropoietin concentration of less than 500 U/L. Patients were stratified by baseline red blood cell transfusion burden, serum erythropoietin concentration, and ring sideroblast status, and randomly allocated (1:1) to receive luspatercept (1·0-1·75 mg/kg body weight, subcutaneously, once every 3 weeks) or epoetin alfa (450-1050 IU/kg body weight, subcutaneously, once a week; maximum total dose 80 000 IU) for at least 24 weeks. The primary endpoint was red blood cell transfusion independence lasting at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), evaluated in the intention-to-treat population. The safety population included all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov (NCT03682536; active, not recruiting). Between Jan 2, 2019, and Sept 29, 2022, 363 patients were screened and randomly allocated: 182 (50%) to luspatercept and 181 (50%) to epoetin alfa. Median age was 74 years (IQR 69-80), 162 (45%) patients were female, and 201 (55%) were male. 289 (80%) were White, 44 (12%) were Asian, and two (1%) were Black or African American. 23 (6%) were Hispanic or Latino and 311 (86%) were not Hispanic or Latino. Median follow-up for the primary endpoint was 17·2 months (10·4-27·7) for the luspatercept group and 16·9 months (10·1-26·6) for the epoetin alfa group. A significantly greater proportion of patients in the luspatercept group reached the primary endpoint (110 [60%] vs 63 [35%]; common risk difference on response rate 25·4% [95% CI 15·8-35·0]; p<0·0001). Median follow-up for safety analyses was 21·4 months (IQR 14·2-32·4) for the luspatercept group and 20·3 months (12·7-30·9) for the epoetin alfa group. Common grade 3-4 treatment-emergent adverse events occurring among luspatercept recipients (n=182) were hypertension (19 [10%] patients), anaemia (18 [10%]), pneumonia (ten [5%]), syncope (ten [5%]), neutropenia (nine [5%]), thrombocytopenia (eight [4%]), dyspnoea (eight [4%]), and myelodysplastic syndromes (six [3%]); and among epoetin alfa recipients (n=179) were anaemia (14 [8%]), pneumonia (14 [8%]), neutropenia (11 [6%]), myelodysplastic syndromes (ten [6%]), hypertension (eight [4%]), iron overload (seven [4%]), and COVID-19 pneumonia (six [3%]). The most common serious treatment-emergent adverse events in both groups were pneumonia (nine [5%] luspatercept recipients and 13 [7%] epoetin alfa recipients) and COVID-19 (eight [4%] luspatercept recipients and ten [6%] epoetin alfa recipients). One death (due to acute myeloid leukaemia) considered to be luspatercept-related was reported at the interim analysis. Luspatercept represents a new standard of care for ESA-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. Significantly more patients had red blood cell transfusion independence and haematological improvement with luspatercept than with epoetin alfa, with benefits observed across patient subgroups. Celgene and Acceleron Pharma.

Can N-acetylcysteine reduce red blood cell transfusion burden in patients with transfusion-dependent β-thalassemia?

Patients with beta-thalassemia major require lifelong and frequent red blood cell transfusions for survival, impacting their quality of life and life expectancy. This treatment approach poses risks of organ damage, iron overload, and increased transfusion-transmitted diseases. N-acetylcysteine (NAC) has been studied for its potential antioxidant effects on hemoglobin stability, aiming to reduce the burden of red blood cell transfusions. To explore this possibility further, we conducted a quasi-experimental study involving 35 individuals with thalassemia major over six months All subjects were already receiving iron chelators and blood transfusions. They were given a daily oral dose of 10 mg/kg NAC for three months. After three months of treatment with NAC, the serum levels of ferritin and liver enzymes (SGOT and SGPT) did not show significant changes (p = 0.35, p = 0.352, and p = 0.686, respectively). However, the red blood cell transfusion burden was significantly reduced in all patients after NAC therapy (p = 0.029), with no corresponding decrease in serum hemoglobin levels (p = 0.931), indicating maintained hemoglobin concentration despite reduced transfusion volume. The study indicates that NAC can effectively decrease the burden of red blood cell transfusions without significant toxicity in these patients. This finding suggests the potential for NAC as a cost-effective and manageable treatment option for these patients. A larger clinical trial with more robust statistical methods could further confirm these results and pave the way for using NAC as a valuable therapeutic agent for managing beta-thalassemia major patients.

Retrospective Real-World Analysis of Baseline Characteristics and Posttreatment Hematologic Outcomes in Patients with Myelofibrosis Receiving Ruxolitinib

Introduction: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by the key hallmarks of constitutional symptoms, splenomegaly, and cytopenias such as anemia and thrombocytopenia. While Janus kinase (JAK) inhibitors have become a mainstay of MF treatment, improving symptom and spleen burden in many patients (pts), some approved JAK inhibitors such as ruxolitinib (RUX) may worsen or fail to adequately address anemia and thrombocytopenia. Dose reduction may mitigate the myelosuppressive effects of RUX, but this strategy and resultant effects on real-world clinical outcomes are not well characterized. Here we describe real-world baseline characteristics and posttreatment hematologic outcomes in a US pt population with MF treated with RUX, including those with red blood cell (RBC) transfusion burden at baseline. Methods: This was a retrospective analysis of adult pts in the US Flatiron Health electronic health record-derived deidentified database with evidence of MF ( International Classification of Diseases, Ninth Revision or Tenth Revision diagnosis) on or after January 1, 2013, and ≥1 administration of an antineoplastic agent; the data cutoff was March 1, 2023. Pts were required to have ≥1 order or administration of RUX after MF diagnosis. Follow-up was from initiation of RUX (index date) to earliest of end of clinical activity, data availability, or death; only pts with index dates in April 2013 or later were included to allow for a 3-month baseline period. Baseline characteristics were summarized at index date (or closest available visit ≤3 months prior) and included demographics, disease characteristics, hematologic measures, transfusion status, and prior treatment. Incidence of anemia, thrombocytopenia, and either anemia or thrombocytopenia (defined as a negative hematologic outcome), based on laboratory values (hemoglobin [Hb] levels &amp;lt;10 g/dL, platelet counts &amp;lt;150×10 9/L) or the presence of diagnostic codes, were evaluated in time-to-event analyses over the follow-up period. Subgroup analyses in pts who were transfusion dependent (TD; ≥4 RBC units transfused in any 8-week period, or ≥1 Hb level &amp;lt;8 g/dL at any point, within the previous 12 weeks) at baseline were also performed. Transfusion status at specific time points during follow-up was summarized. Results: A total of 383 pts with MF treated with RUX in the real-world database met the criteria for analysis. The mean age was 72.0 years, 44.4% were female, and 72.4% were White. A total of 58.2% had primary MF; mean time from diagnosis to index was 8.7 months, and 22.2% had prior non-JAK inhibitor therapy before RUX initiation. Cytopenias were common at baseline; 45.7% had anemia and 24.5% had thrombocytopenia, based on laboratory assessment or diagnostic codes. Among pts with available Hb laboratory values, 13.4% had severe (&amp;lt;8 g/dL) and 38.5% had moderate (≥8 to &amp;lt;10 g/dL) anemia. A total of 20.9% were TD, with a mean 0.6 RBC units transfused per month. In time-to-event analyses, among the 175 pts who did not have either anemia or thrombocytopenia at baseline, 149 (85%) had an incident negative hematologic outcome (ie, anemia or thrombocytopenia) event during follow-up. The 6- and 12-month event rates were 63.5% and 72.7%; median time to event was 2.7 months (95% CI, 2.1-4.9 months) (Figure). In the respective subpopulations without anemia (n=208) or thrombocytopenia (n=289) at baseline, median time to anemia was 3.8 months (95% CI, 2.4-6.7 months), and median time to thrombocytopenia was 10.9 months (95% CI, 7.7-19.7 months); 12-month event rates were 66.8% and 51.8%. At 3 months after index date, 41.3% of pts were TD. Among those who were TD at baseline, 88.8% remained TD after 3 months of RUX treatment, with a mean increase in transfusion intensity of 0.4 units per month. Among pts who were not TD at baseline, 24.4% became TD after 3 months of RUX treatment, with a mean increase in transfusion intensity of 0.6 units per month. Conclusions: This retrospective analysis provides insights into hematologic outcomes under the current first-line treatment paradigm for MF in clinical practice. Many pts who initiated RUX were anemic and/or thrombocytopenic at baseline, and incidences of anemia and thrombocytopenia as well as RBC transfusion burden increased over time. These results highlight the continued need for treatments that address the underlying hematologic burden, including anemia and thrombocytopenia, of pts with MF.

Efficacy and Safety of Luspatercept in Patients with HbE/β-Thalassemia from the BELIEVE Study: A Subgroup Analysis

Background: Thalassemias are a group of inherited blood disorders caused by impaired production of the globin chains of hemoglobin (Hb), resulting in anemia. HbE/β-thalassemia results from the co-inheritance of a specific point mutation in the β-globin gene with a second β-thalassemia mutation. The combination of mutations influences disease severity, ranging from mild to severe, with HbE/β-thalassemia accounting for about half of all cases of severe thalassemia. Patients (pts) with severe disease have higher red blood cell (RBC) transfusion requirements, which can be associated with increased risk of related morbidities. Treatments that can reduce dependence on RBC transfusions are needed to improve pt outcomes. Primary results from the BELIEVE study (NCT02604433) demonstrated the efficacy and safety of luspatercept to treat anemia in transfusion-dependent pts with β-thalassemia across genotypes including HbE (Cappellini MD, et al. HemaSphere 2020;4[S1]:108-109). A subsequent analysis of the final BELIEVE data for pts with β 0/β 0 mutations, a form of severe β-thalassemia, demonstrated similar results with longer treatment in this subgroup (Sheth S, et al. Blood 2022;140 [S1]:1946-1948). The aim of this post hoc sub-analysis was to investigate the efficacy and safety of longer-term luspatercept treatment in pts in the BELIEVE trial with HbE/β-thalassemia. Methods: The BELIEVE trial included adult pts with β-thalassemia or HbE/β-thalassemia (compound heterozygous β-thalassemia with mutation and/or multiplication of α-globin genes allowed) who required regular RBC transfusions (6-20 RBC units in the 24 wk before randomization with no transfusion-free period &amp;gt; 35 days). Pts were randomized 2:1 to receive luspatercept (1.0-1.25 mg/kg) or placebo subcutaneously every 3 wk and evaluated for response (defined as reduction in RBC transfusion burden ≥ 33% or ≥ 50% from baseline during any 12-wk interval over the entire study) and safety. Data were evaluated up to the final pt visit (Jan 5, 2021). Results: The BELIEVE trial enrolled 336 pts, 52 (15.5%) of whom had HbE/β-thalassemia; 31 were randomized to the luspatercept group of the overall intent-to-treat (ITT) population (13.8%; N = 224). At baseline, pts receiving luspatercept with HbE/β-thalassemia were similar in age compared with the overall ITT population (median 32 y vs 30 y, respectively) and had similar transfusion burden (median 13.0 units vs 14.0 units over 24 wk), but had higher median fetal Hb (6.1% vs 5.1%), higher median serum ferritin (2087.0 vs 1441.3 μg/L), and higher median liver iron content (10.8 vs 6.1 mg/g dry weight). The median (range) duration of luspatercept treatment for pts with HbE/β-thalassemia was similar to the overall ITT population (157.7 [51.0-207.1] wk vs 153.6 [1.7-215.0] wk). A similar proportion of pts with HbE/β-thalassemia as in the overall ITT population achieved ≥ 33% reduction in transfusion burden (83.9% vs 77.2%) and ≥ 50% reduction in transfusion burden (61.3% vs 50.0%) over any 12-wk interval with luspatercept treatment (Figure A). Median total duration of ≥ 33% reduction in transfusion burden response was longer for HbE/β-thalassemia pts versus the overall ITT population (722.0 days vs 586.0 days). In the HbE/β-thalassemia subgroup, 67.6% of pts experienced ≥ 1 treatment-emergent adverse event (TEAE) related to treatment versus 60.5% of pts in the overall luspatercept safety population. The proportion of pts experiencing grade ≥ 3 treatment-related TEAEs was 25.8% in the HbE/β-thalassemia subgroup and 12.1% in the overall safety population. Treatment-related TEAEs resulted in discontinuation of luspatercept in 6.5% and 9.0% of the HbE/β-thalassemia and overall safety populations, respectively. No treatment-related TEAEs resulted in death in either group (Figure B). Summary: The HbE/β-thalassemia sub-group of the BELIEVE study had rates of response that were consistent with the larger ITT population. Furthermore, pts with HbE/β-thalassemia experienced a longer median total duration of response compared with the overall ITT population with a similar safety profile. Additional evaluation of the efficacy and safety of luspatercept in a larger population of HbE/β-thalassemia pts would be valuable as the number of pts in this sub-analysis was small, yet these results suggest that luspatercept is as safe and effective for this subgroup of pts as for the wider β-thalassemia population.

Improvement of Patient-Reported Outcomes Among Heavily Pretreated Patients with Lower-Risk Myelodysplastic Syndromes and High Transfusion Burden Treated with Imetelstat on the IMerge Phase 3 Trial

CONCLUSIONS Transfusion-dependent anemia and related fatigue are commonly associated with lower-risk myelodysplastic syndromes (LR-MDS) and frequently not improved with therapy. Patients with symptoms associated with anemia have an impaired quality of life and inferior overall survival. In IMerge (NCT02598661), the phase 3, randomized, global trial of patients with LR-MDS and a red blood cell transfusion burden of ≥4 U, imetelstat-treated patients had a significantly higher transfusion independence rate than those treated with placebo and showed sustained improvement in patient-reported fatigue via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (Sekeres et al. EHA 2023. P732). Here, we assess the impact of imetelstat on several patient-reported outcomes (PROs) relevant to LR-MDS. Functional Assessment of Cancer Therapy-Anemia (FACT-An; 55 items) and Quality of Life in Myelodysplasia Scale (QUALMS; 38 items) were the main questionnaires used. Analyses included symptom-specific derived scores for the following parameters: dyspnea, measured by 1 FACT-An and 1 QUALMS item; physical function and systemic symptoms, by 3 FACT-An items each; pain, by 2 FACT-An items; and bleeding, by 1 QUALMS item. Higher scores indicated improvement. QUALMS total score and physical burden score were also analyzed. Psychometric analyses were conducted using blinded interim data to document the measurement properties of these item sets and define the scores that would be used to specify PRO end points in IMerge; all analyses were exploratory and were conducted in the intention-to-treat (ITT) population. The overall effect of imetelstat on each score was evaluated from the repeated measurement mixed model (RMMM) comparing the least-squares means (LSMs) of change in score estimated in the 2 treatment groups using all available data while on treatment up to cycle 30. A positive mean change in the dyspnea score was observed throughout the treatment, up to cycle 24, in the imetelstat group but not in the placebo group (Figure). The RMMM analysis showed an overall change in dyspnea score from baseline of 0.53 (by LSM with 95% CI, 0.241-0.825) with imetelstat versus −0.40 (by LSM with 95% CI, −0.794 to 0.003) with placebo, with a significant difference between the treatment groups (LSM difference, 0.93; 95% CI, 0.446-1.411; P &amp;lt; .001; Table). The model-based mean change estimates for each score showed that, despite having high transfusion burden at baseline, patients in the imetelstat group did not experience more deterioration in any of the other outcomes than those in the placebo group (Table). In addition, the QUALMS composite scores suggested significantly improved health outcomes with imetelstat versus placebo based on RMMM. LSM difference was 4.66 (95%CI, 0.862-8.461; P = .016) and 6.34 (95% CI, 1.771-10.913; P = .007) for QUALMS total and QUALMS physical burden, respectively (Table). Findings from multiple validated PRO questionnaires consistently show that patients with red blood cell transfusion-dependent LR-MDS enrolled into the IMerge randomized trial who were treated with imetelstat reported improved fatigue, dyspnea, and QUALMS composite scores (total and physical burden) compared with those in the placebo group. These data indicate that, in addition to improving transfusion burden in patients with LR-MDS, imetelstat targets multiple core symptoms of LR-MDS simultaneously, also improving PROs.

Characterization and Management of Cytopenias after Imetelstat Treatment in the IMerge Phase 3 Trial of Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS)

CONCLUSIONS Imetelstat, an oligonucleotide and a first-in-class telomerase inhibitor, selectively targets malignant hematopoietic stem and progenitor cells with high telomerase activity by direct binding to the RNA template. In patients with MDS the on-target effects of imetelstat are associated with the development of hematologic treatment-emergent adverse events (TEAEs). In the IMerge phase 3 trial, among patients treated with imetelstat, 68% experienced grade 3-4 neutropenia, and 62% had grade 3-4 thrombocytopenia; however, clinical consequences of grade 3-4 infection or bleeding were similar in patients treated with imetelstat and placebo (Platzbecker et al. EHA 2023. Abstr S165). Here, we report additional data on the occurrence and management of cytopenias after treatment with imetelstat. IMerge phase 3 trial (NCT02598661) is a multicenter study involving 178 patients with a median age of 72 years with red blood cell (RBC) transfusion dependency and LR-MDS relapsed/refractory to or ineligible for erythropoiesis-stimulating agents. Patients were randomized 2:1 to receive either imetelstat or placebo and stratified by prior RBC transfusion burden (4-6 or &amp;gt;6 U) and by International Prognostic Scoring System risk group. The safety population included all patients who received ≥1 dose of study drug and comprised 118 patients treated with imetelstat and 59 with placebo. TEAEs of neutropenia and thrombocytopenia with imetelstat treatment were more prevalent in cycles 1-3 (68.6% and 62.7% respectively), and their frequency decreased over time: 42.7% and 48.5% in cycles 4-6, 36.8% and 44.7% in cycles 7-12, and 31.3% and 37.5% in cycle 13 and beyond. Based on laboratory assessment, neutrophil and platelet counts decreased from baseline levels in patients treated with imetelstat versus those treated with placebo (91.5% and 95.8% vs 47.5% and 33.9%, respectively). Neutropenia decreased to a maximum of grade 4 and 3 in 55 and 29 of imetelstat-treated patients, respectively, and &amp;gt;80% of cytopenia events stabilized to grade ≤2 within 4 weeks (Figure). The median time to grade 4 neutropenia was 5.0 weeks (range,1.1-90.3 weeks) for the imetelstat group vs 23.0 weeks (range, 23.0-23.0 weeks) for the placebo group. Similarly, median time to grade 4 thrombocytopenia was 5.2 weeks (range, 2.0-29.9 weeks) with imetelstat vs 35.5 weeks (range, 28.0-43.0 weeks) with placebo. It is noteworthy that among 47 patients who achieved the primary end point of 8-week RBC transfusion independence with imetelstat, 34 (72.3%) and 28 patients (59.6%) had grade 3-4 neutropenia and grade 3-4 thrombocytopenia, respectively. In the imetelstat group, 3 patients had grade 3-4 neutropenia concurrent with grade 3-4 infections, and no patients experienced grade 3-4 thrombocytopenia associated with grade 3-4 bleeding events. There were no grade 5 cytopenias for either imetelstat or placebo groups. In the imetelstat group, cytopenias were managed with protocol-specified treatment delays and dose adjustments. Dose reductions due to neutropenia and thrombocytopenia occurred in 39 patients (33.1%) and 27 patients (22.9%), respectively. Of imetelstat-treated patients, 6 (5.1%) discontinued treatment due to neutropenia (1 case, grade 4; all others, grade 3), and 4 (3.4%) discontinued due to thrombocytopenia (1 case, grade 2; 3 cases, grade 3). In addition to dose reductions and discontinuation of imetelstat, thrombocytopenia and neutropenia were managed by cycle delays in 46.6% and 50.8% of patients, by platelet transfusions in 17.8% of patients, and by concomitant therapy with growth factor support (mostly during cycles 2-4) in 34.7% of patients. Similar patterns of imetelstat dose modifications were seen in a pooled phase 2 and phase 3 safety analysis of IMerge. In the IMerge phase 3 trial, thrombocytopenia and neutropenia were the most common and most frequently reported grade 3-4 AEs during treatment cycles 1-3. However, these AEs were generally transient, reversible, and manageable through treatment delays and dose adjustments, allowing for patients to remain on treatment and continue to experience clinical benefit. Moreover, occurrence of grade 3-4 cytopenias in responders suggests that these TEAEs do not affect the efficacy of imetelstat.

Efficacy and Safety of Roxadustat for Treatment of Anemia in Patients with Lower-Risk Myelodysplastic Syndrome (LR-MDS) with Low Red Blood Cell (RBC) Transfusion Burden: Results of Phase III Matterhorn Study

Presented on behalf of all MATTERHORN (FGCL-4592-082) study investigators Introduction: For patients (pts) with LR-MDS, anemia poses a major clinical challenge, with limited response to first-line erythropoietin (EPO)-stimulating agents (ESAs) and a median duration of response ≤2 years. Further, pts with RBC transfusion dependence (≥2 packed RBC [pRBC] units every 8 weeks [Q8W]) are less likely to respond to ESAs. Anemia treatments with novel mechanisms of action enabling transfusion independence (TI) are needed to reduce frequent RBC transfusion burden. Roxadustat is a first-in-class, hypoxia-inducible factor prolyl hydroxylase inhibitor for treatment of anemia with chronic kidney disease. In the MATTERHORN (NCT03263091) dose-selection stage, roxadustat was well-tolerated, and 37.5% of pts (9/24) with LR-MDS and low RBC transfusion burden ([LTB] 1 pRBC unit Q8W for two consecutive 8-week periods or 2-4 pRBC units Q8W) achieved TI. In the MATTERHORN double-blind stage, TI response rate and safety of roxadustat were further assessed. Methods: MATTERHORN is an ongoing, double-blind, Phase III, randomized, placebo (PBO)-controlled trial. Eligible adult pts (≥18 years of age) had very low-, low-, or intermediate-risk primary MDS per Revised International Prognostic Scoring System (IPSS-R) classification (&amp;lt;5% bone marrow blasts); hemoglobin (Hb) ≤10.0 g/dL at baseline (BL); and LTB. Prior ESA use (&amp;gt;8 weeks before randomization) was permitted. Pts were randomized 3:2 to roxadustat or PBO, then stratified by serum EPO concentration (≤200 or 200-400 mIU/mL), IPSS-R risk, and transfusion burden. Pts received oral roxadustat (starting dosage: 2.5 mg/kg three times weekly based on the dose-selection stage) or PBO with best supportive care (BSC; per institutional criteria, including RBC transfusion) for a 52-week treatment period, followed by a 4-week follow-up period. Primary efficacy endpoint was percentage of pts with TI (the absence of RBC transfusion) for ≥56 consecutive days during the first 28 treatment weeks (TI responder). The percentage of pts with TI and mean Hb increase of ≥1.0 and ≥1.5 g/dL (averaged over 8 weeks) compared with BL pretransfusion Hb was also assessed (to be reported separately). Safety (including treatment-emergent adverse events [TEAEs] and serious TEAEs) was evaluated throughout the study. Results: As of the final 28-week interim analysis of the double-blind stage (data cutoff: April 24, 2023), 140 pts (82 roxadustat, 58 PBO) were randomized and treated. Across arms, median age was 71.5 years (range, 26-96), 59.3% (83/140) were male, and 80.0% (112/140) were white. Most pts (72.1% [101/140]) had IPSS-R low-risk disease and a transfusion burden of 2-4 pRBC units Q8W (92.1% [129/140]). Median (range) BL transfusion burden was 2.5 (1-10) pRBC units. Seventy pts (50.0%) received prior ESAs (98.6% [69/70] were ESA-refractory). Eighty-four pts (41/82 [50.0%] roxadustat, 43/58 [74.1%] PBO) completed 28 weeks of treatment, and 15 pts (6/82 [7.3%] roxadustat, 9/58 [15.5%] PBO) were continuing treatment. Median (range) treatment duration was 24.1 (1.1-28.0) weeks for the roxadustat arm and 28.0 (0.1-28.0) weeks for the PBO arm. A greater percentage of pts in the roxadustat arm compared with the PBO arm were TI responders (47.5% vs. 33.3%). However, this difference did not reach statistical significance ( p=0.22; figure). Percentages of pts with TEAEs of any grade, serious TEAEs, and TEAEs leading to treatment discontinuation were similar across arms (table). Six deaths occurred on study (roxadustat: pneumonia [n=2], acute myocardial infarction and ischemic stroke [n=1], multiorgan failure [n=1]; PBO: urosepsis [n=1], disease progression [n=1]). Three pts (all in roxadustat arm) progressed to acute myeloid leukemia. The study was terminated by the sponsor and is currently being completed. Conclusions: Despite not meeting the primary endpoint, roxadustat plus BSC was well-tolerated, and a high percentage of pts with LR-MDS and LTB were TI responders. The high TI response rate in the PBO arm, historically poor outcomes in pts with ESA-refractory disease, and the inclusion of pts who were not transfusion-dependent (1 pRBC unit Q8W) may have contributed to the lack of a statistically significant difference in TI response rates between arms. MATTERHORN outcomes highlight the continued unmet need for effective and safe therapies that reduce RBC transfusion burden in LR-MDS.

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.

Longitudinal Assessment of Transfusion Intensity in Patients with JAK Inhibitor-Naive or -Experienced Myelofibrosis Treated with Momelotinib in the Phase 3 Simplify-1 and Momentum Trials

Introduction: Anemia is a cardinal feature of myelofibrosis (MF), along with splenomegaly and constitutional symptoms. Red blood cell (RBC) transfusions, often used to manage anemia in patients (pts) with MF, are a negative prognostic factor for overall survival and are associated with diminished quality of life and increased healthcare-related economic burden. Momelotinib (MMB), a Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor, has demonstrated clinically meaningful and durable improvements in anemia, splenomegaly, and symptoms. Prespecified anemia endpoints in MMB phase 3 studies prioritized achievement of a strict transfusion independence response, defined as no transfusions for ≥12 wk immediately before the end of wk 24, with all hemoglobin levels ≥8 g/dL. Longitudinal analysis of transfusion intensity (units per 28 days) in a phase 2 trial of MMB in pts with transfusion-dependent MF demonstrated a reduction in transfusion burden in most (85%) pts (Harrison C, et al. EHA 2023). Here, we further characterize the impact of MMB and comparators on transfusion burden in pts with JAK inhibitor-naive and -experienced MF from the phase 3 SIMPLIFY-1 and MOMENTUM trials. Methods: This analysis evaluated time-dependent transfusion burden in pts enrolled in the phase 3 SIMPLIFY-1 (NCT01969838) and MOMENTUM (NCT04173494) trials. SIMPLIFY-1 included pts with JAK inhibitor-naive MF randomized (1:1) to receive MMB or ruxolitinib (RUX). In MOMENTUM, pts with symptomatic (Myelofibrosis Symptom Assessment Form Total Symptom Score ≥10), anemic (hemoglobin &amp;lt;10 g/dL), JAK inhibitor-experienced MF were randomized (2:1) to receive MMB or danazol (DAN). All RBC units transfused were collected during the 24-wk randomized treatment period of each study and during the 84 days before receipt of randomized treatment on study for baseline assessment. Time-dependent transfusion burden was quantified by number of RBC units administered, in a tabular display of baseline- and treatment-period intensity. Pts were grouped jointly based on the baseline- and treatment-period intensity of RBC units per 28 days into ordinal bins: exactly zero units, &amp;gt;0 to 1 unit, &amp;gt;1 to 2 units, &amp;gt;2 to 3 units, &amp;gt;3 to 4 units, and &amp;gt;4 units. Results: In SIMPLIFY-1 (JAK inhibitor-naive pts), 150 of 213 evaluable pts (70%) in the MMB arm and 163 of 216 evaluable pts (76%) in the RUX arm required zero units of RBC transfusion per 28 days at baseline. Of pts who required zero units of transfusion at baseline, a higher proportion in the MMB arm (142 of 150 [95%]) maintained a requirement of zero RBC transfusions during randomized treatment of 24 wks vs the RUX arm (93 of 163 [57%]). Overall, the mean RBC transfusion burden per 28 days declined 0.10 units (SD, 0.701) from baseline to randomized treatment in the MMB arm and increased 0.39 units (SD, 1.016) in the RUX arm. Using ordinal bins, 87% of pts in the MMB arm maintained (144 [67.6%]) or improved (41 [19.2%]) RBC transfusion intensity during randomized treatment compared with baseline vs 54% in the RUX arm (maintained, 94 [43.5%]; improved, 23 [10.6%]) (Figure). In MOMENTUM (JAK inhibitor-experienced pts), most pts had some transfusion requirement at baseline, with 26 of 130 (20%) in the MMB arm and 11 of 65 (17%) in the DAN arm requiring zero units of RBC transfusion per 28 days. During randomized treatment, a higher proportion of pts in the MMB arm (46 of 130 [35%]) required zero units of RBC transfusion vs the DAN arm (11 of 65 [17%]), including a higher proportion of those who had zero RBC transfusion requirement at baseline who maintained zero RBC transfusion requirement during randomized treatment (MMB, 92%; DAN, 64%). The mean RBC transfusion burden per 28 days declined 0.86 units (SD, 1.748) from baseline to randomized treatment in the MMB arm and declined 0.28 units (SD, 1.584) in the DAN arm. Using ordinal bins, 85% of pts in the MMB arm maintained (25 [19.2%]) or improved (85 [65.4%]) RBC transfusion intensity compared with baseline vs 63% in the DAN arm (maintained, 7 [10.8%]; improved, 34 [52.3%]). Conclusions: These data demonstrate that MMB was associated with better maintenance of RBC transfusion intensity and zero RBC transfusion status vs RUX in pts with MF who were JAK inhibitor naive and showed greater reduction in RBC transfusion burden from baseline vs DAN in pts with MF who were JAK inhibitor experienced. Across both trials, ≥85% of pts treated with MMB maintained or improved transfusion intensity.

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.

Impact of Delayed Cord Clamping on Red Blood Cell Transfusion and Related Outcomes in Very Low Birth Weight Infants.

Delayed cord clamping (DCC) for 30 to 60 seconds after birth facilitates placental transfusion, increases blood volume, and decreases red blood cell (RBC) transfusion in preterm infants. Study objective was to determine (1) RBC transfusion burden over a 5-year period, (2) impact of DCC practice on RBC transfusions, and (3) association of RBC transfusion on outcomes in very low birthweight (VLBW) preterm infants. A retrospective medical chart review was performed in 787 VLBW infants between 2016 and 2020. Demographic factors, DCC status, number of RBC transfusions, and neonatal outcomes were determined in eligible infants. Adjusted association between DCC, RBC transfusion, and outcomes were determined using logistic and linear regression methods. Of the 538 eligible VLBW infants, 62% (N = 332) received RBC transfusions. Proportion receiving RBC transfusion were significantly higher for infants <1,000 g (N = 217, 65.4%) and gestational age (GA) <29 weeks (N = 256, 77.1%) than larger (1,001-1,250 g, N = 77, 23.2% and 1,251-1,500 g, N = 38, 11.4%) and older GA ≥ 29 weeks' infants (N = 76, 22.9%, p < 0.05). Of the 81/538 (15.1%) who received DCC, 48 (59.2%) received no RBC transfusion (p < 0.001). In multivariable logistic regression analysis, preterm infants with DCC were 55% less likely to receive RBC transfusions as compared with infants with no DCC. At any given GA, the number of RBC transfusions in preterm infants with DCC was 25% lower as compared with infants without DCC (p < 0.05). Transfusion was associated with 8-fold increased odds for bronchopulmonary dysplasia and 4-fold increased odds for medical and surgically treated patent ductus arteriosus compared with no transfusion. There was no significant association of transfusion with neonatal sepsis, laser treated retinopathy of prematurity, necrotizing enterocolitis, and intraventricular hemorrhage. DCC was significantly associated with reduced RBC transfusion, but fewer preterm infants received DCC. Further research is needed to explore the feasibility of providing neonatal resuscitation during DCC in preterm infants. · Delayed cord clamping significantly reduced the need for RBC transfusions.. · Fewer very preterm infants received DCC.. · Future research is needed to explore feasibility of neonatal resuscitation during DCC..

Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial

Erythropoiesis-stimulating agents (ESAs) are the standard-of-care treatment for anaemia in most patients with lower-risk myelodysplastic syndromes but responses are limited and transient. Luspatercept promotes late-stage erythroid maturation and has shown durable clinical efficacy in patients with lower-risk myelodysplastic syndromes. In this study, we report the results of a prespecified interim analysis of luspatercept versus epoetin alfa for the treatment of anaemia due to lower-risk myelodysplastic syndromes in the phase 3 COMMANDS trial. The phase 3, open-label, randomised controlled COMMANDS trial is being conducted at 142 sites in 26 countries. Eligible patients were aged 18 years or older, had a diagnosis of myelodysplastic syndromes of very low risk, low risk, or intermediate risk (per the Revised International Prognostic Scoring System), were ESA-naive, and required red blood cell transfusions (2-6 packed red blood cell units per 8 weeks for ≥8 weeks immediately before randomisation). Integrated response technology was used to randomly assign patients (1:1, block size 4) to luspatercept or epoetin alfa, stratified by baseline red blood cell transfusion burden (<4 units per 8 weeks vs ≥4 units per 8 weeks), endogenous serum erythropoietin concentration (≤200 U/L vs >200 to <500 U/L), and ring sideroblast status (positive vs negative). Luspatercept was administered subcutaneously once every 3 weeks starting at 1·0 mg/kg body weight with possible titration up to 1·75 mg/kg. Epoetin alfa was administered subcutaneously once a week starting at 450 IU/kg body weight with possible titration up to 1050 IU/kg (maximum permitted total dose of 80 000 IU). The primary endpoint was red blood cell transfusion independence for at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), assessed in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The COMMANDS trial was registered with ClinicalTrials.gov, NCT03682536 (active, not recruiting). Between Jan 2, 2019 and Aug 31, 2022, 356 patients were randomly assigned to receive luspatercept (178 patients) or epoetin alfa (178 patients), comprising 198 (56%) men and 158 (44%) women (median age 74 years [IQR 69-80]). The interim efficacy analysis was done for 301 patients (147 in the luspatercept group and 154 in the epoetin alfa group) who completed 24 weeks of treatment or discontinued earlier. 86 (59%) of 147 patients in the luspatercept group and 48 (31%) of 154 patients in the epoetin alfa group reached the primary endpoint (common risk difference on response rate 26·6; 95% CI 15·8-37·4; p<0·0001). Median treatment exposure was longer for patients receiving luspatercept (42 weeks [IQR 20-73]) versus epoetin alfa (27 weeks [19-55]). The most frequently reported grade 3 or 4 treatment-emergent adverse events with luspatercept (≥3% patients) were hypertension, anaemia, dyspnoea, neutropenia, thrombocytopenia, pneumonia, COVID-19, myelodysplastic syndromes, and syncope; and with epoetin alfa were anaemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19 pneumonia, and myelodysplastic syndromes. The most common suspected treatment-related adverse events in the luspatercept group (≥3% patients, with the most common event occurring in 5% patients) were fatigue, asthenia, nausea, dyspnoea, hypertension, and headache; and none (≥3% patients) in the epoetin alfa group. One death after diagnosis of acute myeloid leukaemia was considered to be related to luspatercept treatment (44 days on treatment). In this interim analysis, luspatercept improved the rate at which red blood cell transfusion independence and increased haemoglobin were achieved compared with epoetin alfa in ESA-naive patients with lower-risk myelodysplastic syndromes. Long-term follow-up and additional data will be needed to confirm these results and further refine findings in other subgroups of patients with lower-risk myelodysplastic syndromes, including non-mutated SF3B1 or ring sideroblast-negative subgroups. Celgene and Acceleron Pharma.

Effect of Luspatercept in β-Thalassemia Patients with β0/β0 Genotype: A Subgroup Analysis of the BELIEVE Study

Introduction: β-thalassemia is an inherited hemoglobinopathy caused by mutations in the HBB gene that encodes β-globin. Patients (pts) homozygous for mutations that severely reduce or silence expression of HBB (β0/β0 genotype) do not produce any functional β-globin, resulting in an imbalance of globin chains, ineffective erythropoiesis, and severe anemia. Pts with a β0/β0 genotype require frequent, lifelong red blood cell (RBC) transfusions to address their anemia. However, regular RBC transfusions are associated with increased risk of morbidities and mortality. As such, interventions that can reduce dependence on RBC transfusions are important for improving outcomes in this pt population. Results from the phase 3 BELIEVE study showed that a higher percentage of pts with transfusion-dependent β-thalassemia who received luspatercept experienced reductions in RBC transfusion burden than pts receiving placebo in the first 48 weeks (wk) of the study (Cappellini MD, et al. N Engl J Med 2020;382:1219-1231) and the efficacy of luspatercept has been shown to persist with longer-term treatment (Cappellini MD, et al. HemaSphere 2022;6 [Suppl 3]. Abstract 270). The aim of this post-hoc sub-analysis was to investigate the long-term efficacy of luspatercept in pts with β0/β0 genotypes from the BELIEVE trial. Methods: Pts ≥ 18 years of age with β-thalassemia or hemoglobin E/β-thalassemia (compound β-thalassemia mutation and/or multiplication of α-globin genes allowed) and requiring regular RBC transfusions (6-20 RBC units in the 24 wk prior to randomization, no transfusion-free period > 35 days) were randomized 2:1 to receive luspatercept (1.0-1.25 mg/kg) or placebo subcutaneously every 3 wk. Response was defined as ≥ 33% or ≥ 50% reduction from baseline in RBC transfusion burden during any 12- or 24-wk interval over the entire study period. Genotyping was performed if this information was not included in the pt's medical history. Results: Of the 336 pts enrolled in the BELIEVE study, 103 had a β0/β0 genotype. HBB mutations represented in the β0/β0 subgroup were: c.17_18delCT; c.20delA; c.25_26delAA; c.27dupG; c.52A>T; c.84_85insC; c.92G>A; c.92+1G>A (IVS1-1); c.92+1G>T (IVS1-1); c.92+2T>G; c.93-15T>G (IVS1-116); c.112delT; c.114G>A; c.118C>T; c.126_129delCTTT; c.135delC; c.217dupA; c.315+1G>A (IVS2-1); c.315+1G>T (IVS2-1); c.316-2A>C (IVS2-849); and deletion of HBB. In the intent-to-treat (ITT) population, 224 pts received luspatercept, 68 of whom had a β0/β0 genotype. Median (range) duration of treatment for pts receiving luspatercept was 153.57 (1.7-215.0) wk. In the ITT luspatercept population, 173 (77.2%) pts achieved ≥ 33% reduction in RBC transfusion burden and 112 (50.0%) pts achieved ≥ 50% reduction in RBC transfusion burden during any 12-wk interval over the entire study period (Figure 1A). For pts with a β0/β0 genotype, 52 (76.5%) achieved ≥ 33% reduction in RBC transfusion burden and 36 (52.9%) achieved ≥ 50% reduction during any 12-wk interval. Transfusion burden reductions of ≥ 33% and ≥ 50% over any 24-wk interval were reported in 116 (51.8%) and 53 (23.7%) pts in the ITT population, respectively. Of the pts with a β0/β0 genotype, 36 (52.9%) achieved ≥ 33% reduction and 11 (16.2%) achieved ≥ 50% reduction in RBC transfusion burden during any 24-wk interval. Responses in the β0/β0 subgroup were also evaluated by splenectomy status (n = 40 splenectomized and n = 28 non-splenectomized pts). Of the splenectomized pts, 34 (85.0%) achieved ≥ 33% reduction in RBC transfusion burden and 27 (67.5%) ≥ 50% reduction during any 12-wk interval; 18 (64.3%) and 9 (32.1%) non-splenectomized pts, respectively, achieved these responses (Figure 1B). Over any 24-wk interval, 24 (60.0%) and 8 (20.0%) splenectomized pts achieved ≥ 33% reduction and ≥ 50% reduction in RBC transfusion burden, respectively. For non-splenectomized pts, reductions in RBC transfusion burden of ≥ 33% and ≥ 50% were reported in 12 (42.9%) and 3 (10.7%) pts, respectively. Conclusion: Pts with a β0/β0 genotype in the BELIEVE trial experienced similar reductions in RBC transfusion burden with luspatercept as the overall ITT luspatercept population. Furthermore, greater proportions of splenectomized pts with a β0/β0 genotype achieved reductions in RBC transfusion burden than β0/β0 pts who were not splenectomized. These longer-term data demonstrate the efficacy of luspatercept in a pt population with more severe disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Management of MDS with Isolated Del(5q) Patients in the European MDS (EUMDS) Registry: A Report on 197 Cases

Background 'MDS with isolated del(5q) is a specific WHO 2016 subtype of MDS with characteristic morphological genomic features, and response of anemia to the immunomodulatory agents lenalidomide (LEN). LEN is approved in this indication, although Erythropoiesis Stimulating Agents (ESA) and red blood cell transfusion (RBCT) are still regarded first line options for anemia management. We analysed the characteristics and outcome of 197 MDS with del(5q) patients in the prospective international EUMDS registry. Methods Patients included in EUMDS registry are diagnosed and treated according to local or national recommendations. Treatment options (LEN, ESA, RBCT only) are thus in part influenced by local routines and reimbursement systems. Patient follow-up is recorded electronically every 6 months ("visit") in a central database. Standard descriptive methods and time to event analyses were used to examine differences in baseline factors by diagnosis, treatment response and overall survival (OS). Results Of 2469 EUMDS patients, 197 (8%) met criteria for 'MDS with isolated del(5q)'. Median follow-up was 4.3 yrs (3.8 years for all EUMDS patients). 77% were female, and median age was 73y. In comparison to the EUMDS patients lacking del(5q), patients with MDS with isolated del(5q) were lower risk at diagnosis (IPSS and IPSS-R, p<0.001), had lower Hb and higher platelet count (both p<0.001),and were more likely to have been transfused at registration (p=0.05) as well as during follow up (p<0.001). To date, 168/197 patients received one or more active interventions. First line treatment was RBCT in 96 patients and ESA in 55 patients. In total, 92 patients received LEN, 17 as 1st line, 41 as 2nd line and 34 as 3rd line treatment. Median time on treatment was 369.5 days. Mean baseline serum epo (sEPO) (available for 108/197 patients) was 317.8 IU/ L, compared with 148.9 IU/L for all EUMDS Registry patients. Of 92 patients who received LEN, 29 also received anti-coagulants and 24 patients received concurrent ESAs. As 26 patients were not transfused prior to starting LEN, it is difficult to make comparisons between treated and non-treated groups. Fifty patients were transfusion dependent before LEN. Of there, 76% have responded. Response duration was longer in patients treated with LEN prior to the initiation of regular RBCT (88% vs 60%). Response rates varied depending on transfusion dose-density prior to initiation of LEN and were highest in del(5q) patients with low RBCT burden. Response duration to LEN was broadly comparable to previously published clinical trial data, namely 4.5 study intervals (maximum of 27 months) in patients without prior RBCT vs. 3 intervals (maximum of 18 months) in patients with prior RBCT. Compared with RBC transfusion dose density interval before starting LEN (mean 1.059), dose density interval decreased in the first visit after starting LEN (mean 0.867). Haemoglobin levels increased from 8.8 g/dL before LEN, to 10.3g/dL at visit after starting LEN. No difference in OS or disease progression (to higher risk MDS or AML) was noted for patients treated with LEN vs. not ( OS - adjusted Hazard Ratio, age and sex, 95% Confidence Interval: 0.67 [95% CI:0.35-1.29], LEN treatment as a time-dependent variable). Conclusion EUMDS is uniquely placed to describe 'real-world’ management of patients with 'MDS with isolated del(5q)’ from diagnosis. Response rate to LEN therapy appeared to be higher, and response duration longer in patients with no prior RBCT. More than half of transfusion dependent patients will respond to LEN.

Long-term safety and erythroid response with luspatercept treatment in patients with β-thalassemia.

β-thalassemia is a hereditary blood disorder resulting in ineffective erythropoiesis and anemia. Management of anemia with regular blood transfusions is associated with complications including iron overload. Here, we report long-term safety and efficacy results of the first clinical study of luspatercept in β-thalassemia, initiated in 2013, enrolling adults with both nontransfusion-dependent (NTD) and transfusion-dependent (TD) β-thalassemia. The objective was to report long-term safety data, for up to 5 years of treatment, for 64 patients with TD or NTD β-thalassemia, and long-term efficacy data for a subset of 63 patients with β-thalassemia who received high-dose luspatercept (0.6-1.25 mg/kg): 31 NTD and 32 TD patients. The study was a phase 2, noncontrolled, open-label trial comprising a dose-finding base phase and a 5-year extension phase. Endpoints include safety; erythroid response over a continuous 12-week period [NTD: hemoglobin increase from baseline ⩾1.0 or ⩾1.5 g/dl; TD: red blood cell (RBC) transfusion burden reduction, ⩾20%, ⩾33%, or ⩾50%]; and changes in biomarkers of ineffective erythropoiesis, iron metabolism parameters, Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) scores, and 6-min walking distance. Median duration of luspatercept exposure for NTD and TD patients was 910 days (range, 40-1850) and 433 days (range, 21-1790), respectively. Seventeen of 31 (54.8%) NTD patients achieved a mean hemoglobin increase of ⩾1.5 g/dl and 19 of 32 (59.4%) TD patients achieved ⩾50% reduction in RBC transfusion burden, during any continuous 12-week period. Median cumulative duration of response was 1126 days (range, 127-1790) for NTD patients and 909 days (range, 87-1734) for TD patients. The most common treatment-related adverse events of any grade were bone pain, headache, and myalgia. Long-term assessment of patients with β-thalassemia showed luspatercept was associated with sustained increases in hemoglobin levels in NTD patients and sustained transfusion burden reductions in TD patients. (ClinicalTrials.gov Identifiers: NCT01749540 and NCT02268409). Long-term safety and erythroid response with luspatercept treatment in patients with β-thalassemia Background: β-thalassemia is a genetic blood disorder caused by mutations in the β-globin gene, which encodes one of the proteins that comprise hemoglobin, a key constituent of red blood cells. Patients with β-thalassemia experience anemia, the main treatment for which is blood transfusions. Long-term repeated blood transfusions lower patients' quality of life, use hospital resources, and the resulting accumulation of excess iron can cause organ failure and decrease life expectancy. The severity of the anemia experienced by patients with β-thalassemia varies; patients with transfusion-dependent β-thalassemia require regular blood transfusions, compared with those with nontransfusion-dependent β-thalassemia who require infrequent transfusions, or even none at all, to manage their symptoms. Luspatercept (Reblozyl®) is an agent that stimulates the production of red blood cells and is used to treat anemia caused by β-thalassemia. However, the long-term effects of luspatercept treatment on patients with β-thalassemia are not known.Objective: In this study, we report the long-term safety of luspatercept in 64 adult patients with either transfusion-dependent or nontransfusion-dependent β-thalassemia, and the long-term efficacy of high-dose luspatercept (0.6-1.25 mg/kg) in a subset of 63 patients.Results: The average time period that patients were treated with luspatercept was 910 days for nontransfusion-dependent β-thalassemia and 433 days for transfusion-dependent β-thalassemia. We report that in patients with nontransfusion-dependent β-thalassemia, luspatercept treatment was associated with sustained increases, just over 3 years, in hemoglobin levels. Likewise, in transfusion-dependent β-thalassemia, luspatercept treatment was associated with a sustained reduction, 2.5 years, in the amount of blood transfusion required to manage their anemia. Long-term treatment with luspatercept was not associated with any new side effects compared with previous short-term treatment studies. The most common side effects were headache (27 patients), bone pain (20 patients), and muscle pain (14 patients) with more than 90% of these patients experiencing these side effects as mild severity.Conclusion: The results of this study show that in patients with either transfusion-dependent or nontransfusion-dependent β-thalassemia, luspatercept provides lasting reduction in anemia with mostly mild and predictable side effects.

Advancing the care of β-thalassaemia patients with novel therapies.

The β-thalassaemias are a group of inherited disorders of haemoglobin synthesis characterised by chronic anaemia of varying severity. Currently available conventional therapies in thalassaemia have many challenges and limitations. A better understanding of the pathology of β-thalassaemia has led to the development of new treatment options, most of which are currently in clinical trials. These could have the potential of reducing red blood cell transfusion burden, raising haemoglobin levels, and improving patients' overall quality of life. In this review, we will provide an overview of the novel therapeutic approaches that are currently under development to advance the care of β-thalassaemia patients.

Luspatercept Improves Quality of Life and Reduces Red Blood Cell Transfusion Burden in Patients with Non-Transfusion-Dependent β-Thalassemia in the BEYOND Trial

Luspatercept Improves Quality of Life and Reduces Red Blood Cell Transfusion Burden in Patients with Non-Transfusion-Dependent β-Thalassemia in the BEYOND Trial

A Phase 2a Study Evaluating the Safety and Pharmacokinetics (PK) of Luspatercept in Pediatric Patients with Transfusion-Dependent β-Thalassemia (TDT)

A Phase 2a Study Evaluating the Safety and Pharmacokinetics (PK) of Luspatercept in Pediatric Patients with Transfusion-Dependent β-Thalassemia (TDT)

Phase 1/2 Study of Oral TP-0184 for the Treatment of Anemia in Adults with Low- or Intermediate-Risk Myelodysplastic Syndromes

Patients with anemia due to lower-risk myelodysplastic syndromes (MDS) have limited treatment options. The transforming growth factor β (TGF-β) pathway has been implicated in contributing to ineffective hematopoiesis in patients with MDS. Members of the TGF-β superfamily include activin receptor-like kinase 2 (ALK2) and ALK5. ALK2 signaling plays a key role in modulating hepcidin, an important regulator of iron homeostasis (and thus erythropoiesis). Increased levels of hepcidin have been linked to anemia in patients with chronic inflammation and cancer, including multiple myeloma (Maes K, et al. Blood. 2010;116:3635-44). The role of hepcidin in MDS-related anemia is unknown and needs to be explored. ALK5 signaling through SMAD2/3 phosphorylation is constitutively active in bone marrow precursor cells from patients with MDS (Zhou L, et al. Blood. 2008;112:3434-43). Inhibition of ALK5 suppresses phosphorylation of SMAD2 in MDS hematopoietic progenitor cells and stimulates hematopoiesis in cells derived from patients with MDS. Collectively, these data suggest that blockade of the TGF-β-SMAD2/3 signaling pathway with an ALK5 inhibitor has the potential to benefit patients with anemia due to MDS.TP-0184 is a small-molecule, dual inhibitor of ALK2 and ALK5. In vitro, TP-0184 inhibits downstream signaling from ALK2 by reducing the phosphorylation of SMAD1/5/8 and blocks hepcidin expression (Peterson PW, et al. Blood. 2017;130 [suppl_1]: 937). Ex vivo, TP-0184 inhibits downstream signaling from ALK5 by reducing SMAD2/3 phosphorylation (data on file). By inhibiting both the ALK2 and ALK5 signaling pathways, TP-0184 may reduce ineffective erythropoiesis in patients with MDS.An open-label, single-arm, phase 1/2 study (NCT04623996) is being undertaken to evaluate the preliminary safety and efficacy of TP-0184 in treating anemia in adults (aged ≥18 years) with MDS. To be eligible, patients must have low- or intermediate-risk MDS (de novo or secondary) per the Revised International Prognostic Scoring System and have relapsed, exhibited an inadequate response to, or been refractory, resistant, or intolerant to treatment with an erythropoiesis-stimulating agent. Patients may have low or high red blood cell transfusion burden, must exhibit adequate major organ function, and must have an Eastern Cooperative Oncology Group performance status of 0-2. Key exclusion criteria include the presence of concomitant severe cardiovascular disease, such as congestive heart failure, myocardial infarction, angina, and/or uncontrolled cardiac arrhythmia; history of stroke, deep venous thrombosis, or pulmonary or arterial embolism; presence of clinically significant anemia due to iron, vitamin B12, or folate deficiencies, autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding; and prior allogeneic or autologous stem cell transplant.In this study, TP-0184 will be administered orally once daily for 24 weeks. The primary and secondary endpoints of each study phase are summarized in the table. Recruitment is ongoing, with approximately 30 patients targeted for enrollment in phase 1 and 10-60 patients targeted for enrollment in phase 2. In phase 1, increasing dose levels of TP-0184 ranging from 20 to 270 mg will be evaluated, with 1-6 patients dosed at each level. Dose escalation will be performed using a two-parameter Bayesian logistic regression model. Determination of the recommended phase 2 dose (RP2D) will be informed by the maximum tolerated or maximum administered dose in phase 1. In phase 2, the efficacy of TP-0184 at the RP2D will be monitored using Bayesian posterior probability to optimize enrollment with Bayesian stopping rules. Bayesian monitoring of responses will be started after the first 10 enrolled patients are evaluable for efficacy. [Display omitted] DisclosuresVerma: Medpacto: Research Funding; Curis: Research Funding; Eli Lilly: Research Funding; Stelexis: Consultancy, Current equity holder in publicly-traded company; Novartis: Consultancy; Acceleron: Consultancy; Celgene: Consultancy; Stelexis: Current equity holder in publicly-traded company; Throws Exception: Current equity holder in publicly-traded company; Incyte: Research Funding; GSK: Research Funding; BMS: Research Funding. Brunner: Celgene, Forty Seven Inc, Jazz: Other: Advisory Board; Novartis, Celgene, Takeda, AstraZeneca: Research Funding. Pennock: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. McMullen: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Wade: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Yang: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Xie: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Whatcott: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Foulks: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Melear: Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; TG Therapeutics: Speakers Bureau.