Transfusion Burden Research Articles

Safety and Efficacy of Pegcetacoplan in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria over 48Weeks: 307 Open-Label Extension Study.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by complement-mediated hemolysis and thrombosis. Pegcetacoplan, the first targeted complement component3 (C3) PNH therapy, was safe and efficacious in treatment-naive and pre-treated patients with PNH in five clinical trials. The 307 open-label extension (OLE) study (NCT03531255) is a non-randomized, multicenter extension study of long-term safety and efficacy of pegcetacoplan in adult patients with PNH who completed a pegcetacoplan parent study. All patients received pegcetacoplan. Outcomes at the 48-week data cutoff (week48 of 307-OLE or August 27, 2021, whichever was earlier) are reported. Hemoglobin concentrations, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores, and transfusion avoidance were measured. Hemoglobin > 12g/dL and sex-specific hemoglobin normalization (i.e., male, ≥ 13.6g/dL; female, ≥ 12g/dL) were assessed as percentage of patients with data available and no transfusions 60days before data cutoff. Treatment-emergent adverse events, including hemolysis, were reported. Data from 137 patients with at least one pegcetacoplan dose at data cutoff were analyzed. Mean (standard deviation [SD]) hemoglobin increased from 8.9 (1.22) g/dL at parent study baseline to 11.6 (2.17) g/dL at 307-OLE entry and 11.6 (1.94) g/dL at data cutoff. At parent study baseline, mean (SD) FACIT-Fatigue score of 34.1 (11.08) was below the general population norm of 43.6; scores improved to 42.8 (8.79) at 307-OLE entry and 42.4 (9.84) at data cutoff. In evaluable patients, hemoglobin > 12g/dL occurred in 40.2% (43 of 107) and sex-specific hemoglobin normalization occurred in 31.8% (34 of 107) at data cutoff. Transfusion was not required for 114 of 137 patients (83.2%). Hemolysis was reported in 23 patients (16.8%). No thrombotic events or meningococcal infections occurred. Pegcetacoplan sustained long-term improvements in hemoglobin concentrations, fatigue reduction, and transfusion burden. Long-term safety findings corroborate the favorable profile established for pegcetacoplan. ClinicalTrials.gov identifier, NCT03531255.

Long-Term Follow-Up of Patients Undergoing Thalidomide Therapy for Transfusion-Dependent β-Thalassaemia: A Single-Center Experience.

We evaluated the long-term safety and efficacy of thalidomide in the treatment of transfusion-dependent β-thalassemia (TDT). Fifty patients with TDT were treated with thalidomide and followed-up for 5 years. Thalidomide at a 50 mg dose was administered once a day after dinner. The dose was increased to 150 mg/d after 3 d if well tolerated. After 1 year of treatment, the hemoglobin (Hb) level was stabilized at its maximum, and thalidomide was gradually reduced and maintained at the minimum dose. The hematological response, transfusion dependence, and haemolytic indicators were assessed. At 9 month of follow-up, 38 (76%) patients achieved an excellent response, 1 (2%) a good response, 4(8%) a minor response, and 7(14%) did not show a response. The overall response rate was 86%. At 9 months, the Hb level increased from 79.0 ± 13.2 g/L at baseline to 99.0 ± 13.7g/L (P<0.001). Patients who achieved excellent response continued to show an increase in Hb levels during follow-up. At 48 months, the mean Hb level was 98.99 ± 10.3g/L; 21 patients (84.0%) became transfusion independent. Thalidomide was reduced and maintained to 25 mg/d in three of these patients. Moreover, five patients completed 60 months of follow-up, and with a mean Hb level of 99.8 ± 6.7g/L. During follow-up, grade 1-2 adverse drug reactions were noted; however, no grade 3 or higher adverse event was reported. However, no decrease in hemolytic indicators was observed. Thalidomide was well tolerated in the long term, while it significantly improved Hb levels and reduced the transfusion burden.

Current challenges of blood transfusions in patients with thalassemia in India and future perspectives

The introduction of regular red blood cell transfusions transformed thalassemia major from a fatal childhood disease into a chronic disorder. Thalassemia is highly prevalent in South Asia, including the Indian subcontinent, and blood transfusion remains the cornerstone of management for these patients. But safe blood transfusions still remain a major problem in India. Difficulties in maintaining adequate blood inventory, a lack of a national blood act, and fragmented blood transfusion services are some of the major contributing factors for the delay in blood supply. In most of the blood centers, alloantibody detection facilities and extended red cell antigen typing are unavailable. Awareness is the key to reducing alloimmunization, which limits the effectiveness of transfusions and the potential availability of blood. Patients with thalassemia are also at high risk of transfusion-transmitted infections unless appropriate blood screening is in place. Hence, many patients remain under-transfused, resulting in decreased health and quality-of-life outcomes. Facilities such as leucoreduction and immunohematological monitoring following a blood transfusion are often lacking in India, especially at the sub-district level. Continuous efforts to raise community awareness, regular training of health-care workers, and proper utilization of available resources are essential to ensuring safe blood transfusions for patients with thalassemia. Access to the new treatments at an affordable cost may reduce the blood transfusion burden for thalassemia patients in India.

Mitapivat: New dawn in pyruvate kinase deficiency and beyond

Mitapivat is the first in class oral allosteric activator of pyruvate kinase enzyme, leading to increased ATP production. Since red blood cells (RBC) rely on anaerobic metabolism, converting phosphoenolpyruvate to pyruvate in Embden– Meyerhof glycolytic pathway is the most important step for ATP production. Deficiency of ATP in patients with pyruvate kinase deficiency (PKD) leads to the destruction of RBCs. In hemoglobinopathies, including thalassemia and sickle cell disease, increased stress and utilization leads to rapid depletion of ATP resources.Phase II DRIVE PK study was the first randomized controlled trial that showed benefits in adult patients without regular transfusion requirement in regards to a rise in hemoglobin ≥1.0 g/dl and improvement in other parameters of hemolysis even with a low 50 mg twice daily dose. Minor adverse effects, including headache, insomnia, and nausea were reported.Subsequent adult studies like ACTIVATE III (non-transfusion-dependent) and ACTIVATE III – T (transfusion-dependent) in patients with PKD showed sustained hemoglobin response in 16/40 (40%) patients. It was tolerated well, and the adverse effect profile was similar to the previous study except for hypertriglyceridemia and hypertension in two patients.Phase I/II trials on patients with thalassemia and sickle cell anemia have also shown promising results in reducing transfusion burden and other disease-related co-morbidities, paving the way for further studies.Mitapivat appears to be a safe, well-tolerated, and effective drug for PKD and other RBC pathologies in adults. Results of ongoing pediatric studies in these settings are awaited to reveal its safety profile in children.

The significance of risk factors for acquiring hepatitis B and C virus infections in children with oncological and hematological diseases and immunodeficiencies

Patients with oncological and hematological diseases are at high risk of nosocomial bloodborne infections (hepatitis B, hepatitis C, and HIV) due to their immunosuppressed condition and highly invasive treatment. The aim of our study is to identify the key risk factors of acquiring bloodborne infections among patients with hematological and oncological diseases and to determine the causes of uneven prevalence of hepatitis B and C among main clinical groups of patients. The study was carried out from 2021 to 2023. The study cohort consisted of 500 patients, with 100 patients in each clinical group: primary immunodeficiencies PID), disorders of the blood and blood-forming organs (BD), hematological malignancies (HM), malignant solid tumors (MST), benign tumors (BT). The median burden of invasive procedures per patient in the patients with HM, MST, BD, BT, and PID amounted to 10.9, 6.2, 5.1, 4.1, and 2.2 invasive interventions a day, respectively. The median infusion/injection burden was 8.3, 4.0, 2.7, 2.7, and 0.6 drugs a day, respectively. The median blood sampling burden amounted to 2.0, 1.7, 1.7, 1.3, and 1.6 samples a day, respectively. The median transfusion burden was 0.14, 0.07, 0.25, 0, and 0 units of transfused blood components a day, respectively. The median surgery burden was 0, 0.15, 0, 0.17, 0 surgical procedures a day, respectively. The medians for other medical procedures in all clinical groups amounted to 0. The patients with PID representing a clinical group of patients with the highest prevalence of hepatitis B and C infections (2.5 % and 2.3 %, respectively) have the lowest level of invasive burden. It should be supposed that the major risk factor of acquiring HBV or HCV among patients with oncological and hematological diseases is the level of immunocompetence together with the impact of risk factors associated with invasive procedures such as blood transfusions, the use of venous catheters (for intravenous administration of drugs and blood sampling), and extensive surgeries.

Значение факторов риска заражения вирусными гепатитами в и с у детей с онкогематологическими заболеваниями и иммунодефицитными состояниями

Patients with oncological and hematological diseases are at high risk of nosocomial bloodborne infections (hepatitis B, hepatitis C, and HIV) due to their immunosuppressed condition and highly invasive treatment. The aim of our study is to identify the key risk factors of acquiring bloodborne infections among patients with hematological and oncological diseases and to determine the causes of uneven prevalence of hepatitis B and C among main clinical groups of patients. The study was carried out from 2021 to 2023. The study cohort consisted of 500 patients, with 100 patients in each clinical group: primary immunodeficiencies PID), disorders of the blood and blood-forming organs (BD), hematological malignancies (HM), malignant solid tumors (MST), benign tumors (BT). The median burden of invasive procedures per patient in the patients with HM, MST, BD, BT, and PID amounted to 10.9, 6.2, 5.1, 4.1, and 2.2 invasive interventions a day, respectively. The median infusion/injection burden was 8.3, 4.0, 2.7, 2.7, and 0.6 drugs a day, respectively. The median blood sampling burden amounted to 2.0, 1.7, 1.7, 1.3, and 1.6 samples a day, respectively. The median transfusion burden was 0.14, 0.07, 0.25, 0, and 0 units of transfused blood components a day, respectively. The median surgery burden was 0, 0.15, 0, 0.17, 0 surgical procedures a day, respectively. The medians for other medical procedures in all clinical groups amounted to 0. The patients with PID representing a clinical group of patients with the highest prevalence of hepatitis B and C infections (2.5 % and 2.3 %, respectively) have the lowest level of invasive burden. It should be supposed that the major risk factor of acquiring HBV or HCV among patients with oncological and hematological diseases is the level of immunocompetence together with the impact of risk factors associated with invasive procedures such as blood transfusions, the use of venous catheters (for intravenous administration of drugs and blood sampling), and extensive surgeries.

The Effect of Oral Iron Chelator Deferiprone on Iron Overload and Oxidative Stress in Patients with Myelodysplastic Syndromes: A Study by the Israeli MDS Working Group

Background: Most patients with lower risk myelodysplastic neoplasms or syndromes (MDSs) become RBC transfusion-dependent, resulting in iron overload, which is associated with an increased oxidative stress state. Iron-chelation therapy is applied to attenuate the toxic effects of this state. Deferiprone (DFP) is an oral iron chelator, which is not commonly used in this patient population, due to safety concerns, mainly agranulocytosis. The purpose of this study was to assess the effect of DFP, on oxidative stress parameters in iron-overloaded RBC transfusion-dependent patients with lower risk MDSs. Methods: Adult lower risk MDS patients with a cumulative transfusion burden of >20 red blood cell units and evidence of iron overload (serum ferritin >1,000 ng/mL) were included in this study. DFP was administered (100 mg/kg/day) for 4 months. Blood samples for oxidative stress parameters and iron overload parameters were done at baseline and monthly: reactive oxygen species (ROS), phosphatidylserine, reduced glutathione, membrane lipid peroxidation, serum ferritin, and cellular labile iron pool. The primary efficacy variable was ROS. Tolerability and side effects were recorded as well. A paired t test was applied for statistical analyses. Results: Eighteen patients were treated with DFP. ROS significantly decreased in all cell lineages: median decrease of 58.6% in RBC, 33.3% in PMN, and 39.8% in platelets (p < 0.01 for all). Other oxidative stress markers improved: phosphatidylserine decreased by 57.95%, lipid peroxidase decreased by 141.3%, and reduced gluthathione increased by 72.8% (p < 0.01 for all). The iron-overload marker and cellular labile iron pool decreased by 35% in RBCs, 44.3% in PMN, and 46.3% in platelets (p < 0.01 for all). No significant changes were observed in SF levels. There were no events of agranulocytosis. All AEs were grades 1–2. Conclusions: Herein, we showed preliminary evidence that DFP decreases iron-induced oxidative stress in MDS patients with a good tolerability profile (albeit a short follow-up period). No cases of severe neutropenia or agranulocytosis were reported. The future challenge is to prove that reduction in iron toxicity will eventually be translated into a clinically meaningful improvement.

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.

Next-generation therapy for lower-risk MDS.

Myelodysplastic syndromes (MDS) are malignant myeloid neoplasms characterized by ineffective clonal hematopoiesis leading to peripheral blood cytopenia and a variable risk of transformation to acute myeloid leukemia. In lower-risk (LR) MDS, as defined by prognostic scoring systems recently updated with the addition of a mutation profile, therapeutic options aim to reduce cytopenia, mainly anemia. Although options for reducing the transfusion burden have recently been improved, erythropoiesis-stimulating agents (ESAs), lenalidomide, hypomethylating agents, and, more recently, luspatercept have shown efficacy in rarely more than 50% of patients with a duration of response often far inferior to the patient's life expectancy. Nevertheless, several new therapies are currently under investigation aiming at improving cytopenia in patients with LR-MDS, mostly by targeting different biological pathways. Targeting ligands of the transforming growth factor β pathway has led to the approval of luspatercept in LR-MDS with ring sideroblasts or SF3B1 mutation, potentially replacing first-line ESAs in this population. Here, we also discuss the evolving standard of care for the treatment of LR-MDS and explore some of the most promising next-generation agents under investigation.

Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial

Unmet medical needs remain in patients with red blood cell transfusion-dependent (RBC-TD) lower-risk myelodysplastic syndromes (LR-MDS) who are not responding to or are ineligible for erythropoiesis-stimulating agents (ESAs). Imetelstat, a competitive telomerase inhibitor, showed promising results in a phase 2 trial. We aimed to compare the RBC transfusion independence (RBC-TI) rate with imetelstat versus placebo in patients with RBC-TD LR-MDS. In phase 3 of IMerge, a double-blind, placebo-controlled trial conducted in 118 sites including university hospitals, cancer centres, and outpatient clinics in 17 countries, patients (aged ≥18 years) with ESA-relapsed, ESA-refractory, or ESA-ineligible LR-MDS (low or intermediate-1 risk disease as per International Prognostic Scoring System [IPSS] criteria) were randomly assigned via a computer-generated schedule (2:1) to receive imetelstat 7·5 mg/kg or placebo, administered as a 2-h intravenous infusion, every 4 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Randomisation was stratified by previous RBC transfusion burden and IPSS risk group. Patients, investigators, and those analysing the data were masked to group assignment. The primary endpoint was 8-week RBC-TI, defined as the proportion of patients without RBC transfusions for at least 8 consecutive weeks starting on the day of randomisation until subsequent anti-cancer therapy, if any. Primary efficacy analyses were performed in the intention-to-treat population, and safety analyses were conducted in patients who received at least one dose of trial medication or placebo. This trial is registered with ClinicalTrials.gov (NCT02598661; substudy active and recruiting). Between Sept 11, 2019, and Oct 13, 2021, 178 patients were enrolled and randomly assigned (118 to imetelstat and 60 to placebo). 111 (62%) were male and 67 (38%) were female. 91 (77%) of 118 patients had discontinued treatment by data cutoff in the imetelstat group versus 45 (75%) in the placebo group; a further one patient in the placebo group did not receive treatment. Median follow-up was 19·5 months (IQR 12·0-23·4) in the imetelstat group and 17·5 months (12·1-22·7) in the placebo group. In the imetelstat group, 47 (40% [95% CI 30·9-49·3]) patients had an RBC-TI of at least 8 weeks versus nine (15% [7·1-26·6]) in the placebo group (rate difference 25% [9·9 to 36·9]; p=0·0008). Overall, 107 (91%) of 118 patients receiving imetelstat and 28 (47%) of 59 patients receiving placebo had grade 3-4 treatment-emergent adverse events. The most common treatment-emergent grade 3-4 adverse events in patients taking imetelstat were neutropenia (80 [68%] patients who received imetelstat vs two [3%] who received placebo) and thrombocytopenia (73 [62%] vs five [8%]). No treatment-related deaths were reported. Imetelstat offers a novel mechanism of action with durable transfusion independence (approximately 1 year) and disease-modifying activity for heavily transfused patients with LR-MDS who are not responding to or are ineligible for ESAs. Janssen Research & Development before April 18, 2019, and Geron Corporation thereafter.

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.

Improved Overall Survival Among Luspatercept Responders and Predictors of Response

Introduction Luspatercept (luspa) is a first-in-class erythroid-maturation agent approved for red blood cells transfusion dependent (RBC-TD) lower risk myelodysplastic syndrome (LR-MDS) with ring sideroblast (RS) based on MEDALIST clinical trial. We aimed to explore impact of luspa on overall survival (OS) and predictors of response in a large cohort of pts treated with luspa, collected from Moffitt Cancer Center (MCC) and from Fondazione Italiana Sindromi Mielodisplastiche (FISiM). Methods We evaluated all pts with LR-MDS-RS treated with luspa from MCC cohort since FDA approval, and from a multicenter observational trial of FISiM for pts treated on a compassionate use program . Baseline RBC transfusion burden (TB) was defined as: non-transfusion dependent (NTD) (0 units in 8 weeks prior luspa), low TB (LTB) (1-5 units/8 weeks ) and high TB (HTB) (≥ 6 units/8 weeks). A hematological response (HI) was defined as an (i) objective Hgb increase of &amp;gt; 1.5 g/dl in NTD, and (ii) RBC-TI with Hgb increase of 1.5 g/dl, or RBC-TI without Hgb 1.5 g/dl increase, or &amp;gt;50% reduction in RBC TB among RBC-TD. Somatic mutation (MT) data were available for 137 pts. Results Between January 2020 and March 2023, 331 pts were treated with Luspa (Table-1). The median age was 69 years; 308 pts (93%) had MDS-RS, 86,1% were intermediate, low or very low risk MDS by R-IPSS and 82% (105/128) were moderate low (ML), low (L) or very low (VL) by IPPS-M. SF3B1 MT was detected in 86.3% (120/139) with a median VAF of 37.7. The mean Hgb level was 7.97 g/dl and 93.7% were RBC-TD. Majority had prior erythroid stimulating agents (ESA) (93.6%). In the MCC cohort 42.9% (52/121) had prior hypomethylating agents (HMA) therapy, and 31.4% (38/121) had prior lenalidomide (len). With a median follow up of 14.6 mos from starting luspa treatment, the median OS was not reached (NR) among responders to luspa compared to 24.5 mos for non-responders (p &amp;lt;.001) (Figure-1). The median OS benefit was more pronounced among pts with RBC-TI and Hgb&amp;gt; 1.5 g/dl increase compared to other categories of response. In the NTD group at baseline, the median OS among luspa responders was NR compared to 22.7 mos among non-responders (P&amp;lt; .001). In the LTB group at baseline median OS was NR as well among luspa responders compared to 29.9 mos in non-responders (p=.002) and finally among HTB group at baseline, the median OS among luspa responders was 35.4 mos compared to 21.2 mos in non-responders (p=.007). In multivariable analysis adjusting for IPSS-M and baseline RBC-TD, response to luspa was independently associated with improved OS, HR .39 (95% CI .18-.83), p= .015 The overall HI rate to luspa was 40.6% (134/330) (Table-1), 85% of pts needed dose escalation, HI correlated with baseline RBC-TB where 80% (16/20) NTD, 60.2% (65/108) LTB and 41.8% HTB (77/184) achieved HI respectively, p&amp;lt; .001. By IPSS-M, there was a trend for lower HI with higher risk disease (100% in VL, 60.3% in L, 36.7% in ML, 56.3% in MH, 16.7% in H risk pts, p=.051). There was a mild trend for higher response among SF3B1 MT pts compared to wild type, 54% (64/119) versus 42% (8/19), p=.34.The segregation of SF3B1 MT cases into three independent groups based on IPSS-M, showed that HI rate was better in SF3B1 β ( SF3B1 and any gene from BCOR, BCORL1, NRAS, RUNX1, SRSF2 or STAG2) and SF3B1 α (as any other mutant) than SF3B1 5q(concomitantpresence with isolated del5q): 50% (7/14), 58.8% (57/97), and 0% (0/5) respectively, p=.03. Among SF3B1 5qpts, 4 had been treated with len before luspa and only 1 had achieved an HI with prior len. Among pts with SF3B1 MT, we observed a trend for higher response in pts with the hotspot K700E, 62.7% (37/59) vs 47.4% (27/57) in non-K700E, p=.097. In pts with SF3B1 MT, divided by median VAF, we observed a trend for better HI with VAF was &amp;gt;38, 63.5% (33/52) vs 45.3% (24/53), p=.062. Among responders, the median duration of response was 14.1 mos. As of last follow up, 85% pts (191/224) discontinued treatment. Reason of discontinuation was lack of response in 126 pts, loss of response in 26 patients and adverse events in 6 pts. The most common reported adverse events were fatigue (n=10), GI symptoms (n=4), shortness of breath and arthralgia (1 each). Conclusions Our RWD in the largest luspa treated cohort demonstrates OS benefit to luspa response. Low baseline RBC-TB dependency, lower risk IPSS-M, SF3B1 MT, SF3B1-K700E mutation and SF3B1 α co-mutations correlated with higher response rates. Our data emphasizes the impact of RBC-TI in LR-MDS.

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.

Real-World Impact of Luspatercept on Patients with Myelodysplastic Syndromes Requiring Red Blood Cell Transfusions and with Prior Exposure to Erythropoietin-Stimulating Agents: A United States Healthcare Claims Database Study

Background: Myelodysplastic syndromes (MDS) are among the most common hematologic cancers in older US adults. MDS are characterized by abnormal bone marrow function leading to impaired production of blood cells, persistent cytopenia, and variable risk of progression to acute myeloid leukemia (AML). Since anemia is a common complication of MDS, many patients (pts) become dependent on red blood cell transfusions (RBCTs) and erythropoiesis-stimulating agents (ESAs) are the standard of care for patients with lower-risk MDS. In a randomized, double-blind, placebo-controlled phase 3 MEDALIST clinical trial, luspatercept, a first-in-class erythroid maturation agent, was shown to reduce the severity of anemia among transfusion-dependent (TD) pts with lower-risk MDS with ring sideroblasts (RS) status and who were refractory to prior ESA treatment (Fenaux P, et al. N Engl J Med 2020; 382:140-151). However, real-world evidence regarding the effect of luspatercept on transfusion burden among pts with MDS requiring RBCTs and with prior ESA exposure is currently limited. Aim: To describe clinical outcomes and MDS-related treatment patterns before and after the initiation of luspatercept among real-world pts with lower-risk MDS in the USA who required RBCTs before luspatercept initiation and were previously exposed to ESAs. Methods:In this retrospective claims-based cohort study, data from Symphony Health, a nationally representative database, (Jan 1, 2010 to June 30, 2022) were used to identify adults with ≥1 claim with a diagnosis of MDS (initial diagnosis on or after Jan 1, 2015) before the first claim for luspatercept (index date). Pts were considered TD at luspatercept initiation if they had ≥1 claim for RBCT in the 8 weeks before index date, and ESA-exposed if they had ≥1 ESA claim at any point before or at luspatercept initiation. Pts with chemotherapy treatments, with a diagnosis for refractory anemia with excess blasts, or with AML during the study period were excluded as they were presumed to have higher-risk MDS. Pts were also excluded if they had prior use of hypomethylating agents (HMAs) or a diagnosis for β-thalassemia, myelofibrosis, aplastic anemia, or breast cancer in the 6 months prior to index date (baseline period). Pt demographics and clinical characteristics were assessed during the baseline period. Pts' RBCT status (transfusion independent [TI] or TD) was measured in the 6 months after index date. A pt was considered 8-week TI if they had 0 RBCT in ≥1 rolling 8-week period in the 6 months after index date. 12-week, 16-week, and 24-week TI pts were defined similarly, using increasingly longer periods without RBCT. Pts' use of MDS-related treatment classes (ie, chemotherapy, ESAs, granulocyte-colony stimulating factor [G-CSF], HMA, and immunomodulatory imide drug [IMiD] agent) was measured before and after index date until end of data availability or clinical activity (follow-up). Results:The population comprisedof240 pts with MDS who were TD and had ESA exposure before luspatercept initiation. The mean (standard deviation [SD]) age was 75.4 (5.4) years and 56.7% were male. About one fifth of pts received ≥2 treatment classes before luspatercept initiation (2: 17.5%; 3+: 1.7%). Most pts (64.2%) achieved 8-week TI in the 6 months after luspatercept initiation. Similarly, 53.8%, 43.3%, and 29.6% of pts achieved 12-, 16-, and 24-week TI in the 6 months after luspatercept initiation, respectively (Figure 1). The percentage of pts achieving 8-, 12-, 16-, and 24-week TI was numerically higher among pts with positive RS status than those with negative/unknown RS status (Figure 1). Most pts (64.2%) did not require any additional MDS-related treatments during the study follow-up period (mean (SD) 15.6 (7.3) months). The most common treatment classes used after luspatercept initiation were ESA (22.5%) and HMA (16.3%; Figure 2). Conclusions:The findings of this real-world study strongly corroborate clinical trial results, showing that luspatercept is highly effective in reducing transfusion dependence among ESA-exposed pts with lower-risk MDS who were TD before luspatercept initiation. In this study, over half of pts achieved 8-week and 12-week TI status during the follow-up period, and more than a quarter did not require any RBCT over a 24-week period. Further, most pts treated with luspatercept did not require any additional MDS-related treatments during the follow-up period.

Durable Continuous Transfusion Independence (TI) with Imetelstat in IMerge Phase 3 for Patients with Heavily Transfused Non-Del(5q) Lower-Risk Myelodysplastic Syndromes (LR-MDS) Relapsed/Refractory (R/R) to or Ineligible for Erythropoiesis-Stimulating Agents (ESAs)

CONCLUSIONS MDS are serious life-threatening hematologic malignancies in which a heterogeneous group of clonal disorders results in ineffective hematopoiesis. An unmet need remains for new therapies for patients (pts) with LR-MDS who are red blood cell transfusion dependent (RBC-TD) and R/R to or ineligible for ESAs. Imetelstat, an oligonucleotide, is a first-in-class telomerase inhibitor that targets cells with high telomerase activity by direct binding to the RNA template of telomerase. In the IMerge phase 3 trial, imetelstat produced higher rates of TI for ≥8 weeks, ≥24 weeks, and ≥1 year (39.8%, 28.0%, and 17.8%) than placebo (15.0%, 3.3%, and 1.7%) in pts with non-del(5q) LR-MDS that was RBC-TD, R/R to/ineligible for ESAs, and naïve to lenalidomide or hypomethylating agents (HMAs; Platzbecker et al. EHA 2023. Abstr S165). We report characteristics and clinical benefit for pts with sustained TI for ≥1 year from this trial. IMerge (MDS3001, NCT02598661) is a global, double-blind, randomized, placebo-controlled, phase 3 trial of imetelstat in RBC-TD, ESA-R/R, non-del 5(q) lenalidomide/HMA-naïve LR-MDS. The primary end point was 8-week TI rate; secondary end points included safety, 24-week TI, duration of response, hematologic improvement, and MDS response. Exploratory end points included assessment of cytogenetic response and mutational status with clinical response. The proportion of pts with&amp;gt;1-year TI and other binary end points, were summarized with percentage and 95% 2-sided exact Clopper-Pearson CI. The Kaplan-Meier method was used to estimate the distribution of TI. Of 118 pts receiving imetelstat, 21 (17.8%; 95% CI, 11.4-25.9) achieved ≥1-year sustained TI, representing 45% of ≥8-week TI (21 of 47 pts) and 64% of ≥24-week TI (21 of 33 pts); of 60 pts receiving placebo plus supportive care, 1 (1.7%; 95% CI, 0-8.9) achieved ≥1-year TI. Of the ≥1-year TI imetelstat responders, 15/21 (71.4%) had ring sideroblasts, as did the 1 placebo pt. The median prior RBC transfusion burden was 6 U over 8 weeks (range, 4-9 U) for the imetelstat group and 5 U for the placebo pt. Additional baseline characteristics are in the table. Pts received imetelstat for a median of 101.1 weeks (range, 75.1-163.9 weeks) and a median of 24 cycles (range, 18-41 cycles). The median duration of TI for imetelstat ≥1-year TI responders was 123 weeks (95% CI, 80.4 to not evaluable); the median increase in hemoglobin during the longest TI interval was 5.18 g/dL (range, 2.67-13.76 g/dL) for the imetelstat group vs 1.67 g/dL for the placebo pt. After a median follow-up of 125 weeks, none of the patients with ≥1 year TI on either arm progressed to acute myeloid leukemia (AML). Of the pts receiving imetelstat, 7 had an abnormal karyotype at baseline, of which 6 had reduction in the cytogenetic abnormal clones (4 with cytogenetic complete response and 2 with cytogenetic partial response by independent review committee). Mutation data were available for 18 pts receiving imetelstat, all with SF3B1 mutations present at baseline, and multiple of these pts concurrently had TET2, DNMT3A, ASXL1, or JAK2 mutations. The maximal reduction ranged from −6% to −100% in SF3B1 variant allele frequency (VAF) in these pts, and 13 of 18 (72.2%) achieved ≥50% VAF reduction, including 7 with complete elimination of the VAF. Reduction in other concurrent mutations was also observed in these pts. Safety was consistent with that previously reported; most frequent adverse events were reversible grade 3 or 4 thrombocytopenia and neutropenia. At the time of data cutoff (May 10, 2023), 13 pts receiving imetelstat and the pt receiving placebo were ongoing (Figure); of the 8 who discontinued treatment, 7 had loss of response, and 1 was due to adverse event. Analyses for progression-free and overall survival were not evaluable as of this cutoff date (insufficient follow-up). Treatment with imetelstat resulted in ≥1-year sustained, continuous TI in 17.8% of pts in the IMerge phase 3 trial. In this ESA-R/R/ineligible population with a high prior transfusion burden, a reduction to 0 RBC transfusions for ≥1 year represents an opportunity to achieve relief from iron overload and other transfusion associated complications, and decreased demand on already limited blood product supply. Furthermore, durable TI and meaningful reductions in mutational burden suggest imetelstat may have disease-modifying activity.

Safety and Preliminary Efficacy of DFV890 in Adult Patients with Myeloid Diseases: A Phase 1b Study

Background and Significance: Patients (pts) with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) have a high unmet medical need, with limited standard-of-care therapeutic approaches, particularly after failure of response to first-line agents, and with allogeneic hematopoietic transplant as the only potential curative option. Through the production of interleukin (IL)-1β and IL-18, the NLRP3 inflammasome has been implicated as a major driver of inflammation associated with acute and chronic inflammatory diseases. The NLRP3 pathway is activated in hematopoietic stem and progenitor cells and in the marrow microenvironment in myeloid neoplasms such as MDS and CMML contributing to ineffective hematopoiesis and clonal progression (Hamarsheh 2020; Basiorka 2016). DFV890, a small molecule NLRP3 inhibitor, blocks IL-1β and IL-18 secretion and pyroptotic cell death in response to a wide variety of NLRP3-dependent danger signals, both in vitro and in vivo. Therefore, DFV890 may disrupt the smoldering inflammation and provide disease-modifying benefits to pts by improving hematopoiesis. Study Design and Methods: This is an open-label, phase 1b, multicenter study with a randomized dose-optimization part and a dose-expansion part consisting of two groups evaluating DFV890 in pts with very low, low, or intermediate risk MDS (LR-MDS) per revised International Prognostic Scoring System (IPSS-R) criteria and low or intermediate-1 risk CMML (LR-CMML) per CMML-specific Prognostic Scoring System (CPSS) criteria (NCT05552469). Eligible pts must be 18 years of age, with an Eastern Cooperative Oncology Group performance status ≤2, candidates for serial bone marrow assessments who are willing to undergo a bone marrow aspirate/biopsy during the trial, and meet one of the following: (a) IPSS-R-defined LR-MDS who failed to respond to or did not tolerate erythropoiesis-stimulating agents (ESAs) or luspatercept or hypomethylating agents (HMAs) and pts with del 5q who failed to respond to or did not tolerate lenalidomide; (b) CPSS-defined LR-CMML who failed to respond to or did not tolerate hydroxyurea or HMAs. Key exclusion criteria include treatment with systemic antineoplastic or any experimental therapies within 28 days (or 5 half-lives, whichever longer); unresolved treatment-related toxicities prior to the first dose of study treatment; previous treatment with agents targeting the NLRP3 inflammasome and the IL-1 pathways; prior use (≤1 week or 5 half-lives, whichever is longer) of hematopoietic colony-stimulating growth factors, thrombopoietin mimetics or ESAs; and concomitant medications, known to modulate cytochrome P450 enzymes. DFV890 is administered orally twice daily (bid) for a minimum of 24 weeks (6 cycles of treatment [1 cycle=28 days]) until treatment discontinuation. In the dose-optimization part, pts are randomized to receive either low dose or high dose bid and stratified by indications. The recommended dose (RD) determined from this part is further explored in the dose-expansion part to confirm safety and tolerability of DFV890 and explore preliminary efficacy. The primary objective is to assess safety (incidence and severity of adverse events, and dose-limiting toxicities) and tolerability to then determine the optimal RD for DFV980. Secondary objectives include assessment of DFV890 pharmacokinetics, evaluation of the preliminary efficacy of DFV890 on transfusion burden, and hematologic improvement: time to onset of transfusion independence; duration of response, best overall response, overall response rate, progression-free survival, and time to progression; and reduction in spleen volume (for CMML). Key exploratory objectives include patient perceptions of tolerability as measured by patient-reported outcomes; and determination of genetic characteristics and potential predictive markers of efficacy and/or resistance. The study is currently enrolling in Singapore, Hong Kong, and the USA with plans to treat approximately 80 pts. The first patient first visit was achieved on May 8, 2023.

Effect of Luspatercept on Erythropoiesis and Fetal Hemoglobin in β-Transfusion-Dependent Thalassemia Patients: A Real-Life Experience

Background: Luspatercept is the first erythropoiesis-stimulating agent approved for transfusion-dependent β-thalassemia (TDT). In the BELIEVE trial, more than 70% of the patients had a hematological response defined as a reduction of ≥33% of transfusion burden in any 12-week interval. In our experience, some patients have a clinical benefit even if a response as defined by the clinical trial is not reached. Indeed, several aspects remain to be addressed, including its specific effects on erythropoiesis. Fetal hemoglobin (HbF) has been hypothesized as a potential marker in response evaluation. However, no results have been published, excluding an abstract presentation by Cappellini MD et al. at the European Hematology Association meeting in 2019, showing a greater HbF increase in responders vs. non-responders. Aim: This study aims to evaluate the effect of luspatercept on erythropoiesis and the hemoglobin (Hb) fractions in patients with β-TDT treated with luspatercept in a real-life setting at our Center in Milan, Italy. Methods: Inclusion criteria: age ≥18 years, β-TDT eligible for treatment with luspatercept, and signed informed consent. Exclusion criteria: unwilling to participate in the study. We assessed hematological parameters, Hb fractions, and erythropoiesis markers at baseline and over the treatment period of up to 48 weeks (Dose16). We also extracted mRNA from reticulocytes (RET) from peripheral blood at fixed doses and analyzed the expression of a panel of genes involved in erythropoiesis. We evaluated hematological variables dividing the patients into three groups of responses defined: Full responder (FR): reduction of transfusion burden ≥33% and ≥2 units of blood in any 12-week intervalIntermediate responder (IR): patients with a reduction in transfusion burden ≥25% and &amp;lt;33% in any 12-week intervalNon-responder (NR): reduction of the transfusion burden &amp;lt;25%. Statistical analysis at baseline was performed using Kruskal-Wallis test. We fitted linear random intercept regression models to evaluate time trends of hematological variables. Results: Thirty-seven patients have been enrolled in the study. 3/37 have been excluded from the analysis because they developed adverse events leading to drug interruption before completing 12 weeks of treatment. We herein present the data of the 29/34 subjects who reached at least 12 weeks of treatment as of July 20, 2023. The median age was 41 yrs (range 19-63 yrs), 15 were females (52%). 8/29 (28%) had a β0/β0 genotype; 12/29 (41%) patients underwent splenectomy. Twelve patients had a FR, 6 an IR, and 11 were NR. We found that the baseline median absolute value of HbF (g/dL) was different in the three groups (NR: 0.21, range 0.09-0.34; IR: 0.37, range 0.14-1.52; FR: 0.95, range 0.31-1.65, p=0.009) (Figure 1). In all subjects, HbF increased over time. However, the increase was different in the three groups (p-interaction: 0.0001). In the linear regression model (Figure 2), the HbF absolute increase per week was 0.004 g/dL (95% confidence interval (CI): 0.002-0.006) among NR, 0.015 (CI: 0.008-0.022) in the IR group and 0.03 g/dL (CI: 0.02-0.04) in the FR group. EPO baseline value was similar in the three groups, but unexpectedly we observed different increases over time (p-interaction: 0.0001). In the IR and FR groups, the regression slopes were 6.66 U/L (CI: 3.11-10-21) and 9.42 U/L (CI: 5.53-13.31) per week, respectively. In the NR group, there was no EPO increase. Interestingly, the baseline value of erythroblasts (EB) was different between the three groups, with FR having the highest value. EB increased in both IR and FR, with the IR group displaying a steeper increase and finally reaching the FR group. Preliminary results on gene expression in RET showed an upregulation of GATA-1 and its target genes involved in erythroid differentiation and heme biosynthesis, as shown in the murine model (Martinez PA et al. 2019), irrespective of the response group. Conclusions: Our findings identify baseline HbF as a possible predictor of response. Also, the HbF trend could represent a marker of response to luspatercept in β-TDT patients. Furthermore, HbF can be useful in identifying patients in the IR group with the best chance of becoming responders in long-term treatment. Our preliminary results also suggest that luspatercept acts by enhancing erythropoiesis and leads to an increase in EPO levels and EB. Studies on more patients are needed to confirm these findings.

Efficacy and Safety Is Maintained in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria Receiving Pegcetacoplan for up to 3 Years

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by complement-mediated hemolysis and thrombosis. Pegcetacoplan, the first complement component 3 (C3) inhibitor for PNH, increased hemoglobin (Hb) levels in complement component 5 inhibitor (C5i)-experienced and -naive adult patients with PNH in 2 phase 3 clinical trials (PEGASUS [NCT03500549] and PRINCE [NCT04085601], respectively). This integrated analysis of data from the pivotal phase 3 trials and the subsequent open-label extension (study 307; NCT03531255) evaluated the long-term efficacy and safety of pegcetacoplan for PNH treatment. Methods: For this integrated analysis, baseline was defined as the initiation of pegcetacoplan, regardless of when in the trials this occurred. Patients initially received pegcetacoplan 1080 mg subcutaneously twice weekly; dose escalations to once every 3 days or 3 times weekly were permitted. Efficacy was evaluated from baseline up to Weeks 132 (2.5 years, PRINCE) and 156 (3 years, PEGASUS) by Hb, lactate dehydrogenase (LDH; upper limit of normal [ULN] 226 IU/L), absolute reticulocyte count (ARC), and indirect bilirubin values; Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores; and transfusion avoidance rates (percentages of patients who did not require a transfusion during treatment). Safety was assessed by incidence of adverse events (AEs) and serious AEs (SAEs) during pegcetacoplan monotherapy for up to 3 years. Results: Of the 133 patients in the phase 3 trials (PEGASUS, 80; PRINCE, 53), 114 enrolled in the extension study (PEGASUS, 64; PRINCE, 50). At least 75% had received a transfusion in the year before enrolling in PEGASUS or PRINCE. Prior to pegcetacoplan initiation, mean (SD) Hb levels were 8.95 (1.09) g/dL in PEGASUS, 9.27 (1.44) g/dL in PRINCE, and 9.08 (1.24) g/dL in the total population; median (interquartile range) LDH levels were 217.0 (184.8, 276.5) IU/L in PEGASUS, 1964.0 (1409.0, 2503.3) IU/L in PRINCE; and mean (SD) FACIT-Fatigue scores were 31.6 (11.7) in PEGASUS, 36.6 (10.0) in PRINCE, and 33.6 (11.3) in the total population. After pegcetacoplan initiation, mean Hb levels markedly improved from baseline and remained stable through Weeks 132 (2.5 years, PRINCE) and 156 (3 years, PEGASUS) ( Figure). Median LDH rapidly decreased and stabilized below the ULN ( Figure). Improvements in ARC and indirect bilirubin were similarly maintained. Average FACIT-Fatigue scores increased (indicating less fatigue) rapidly and were maintained near the general population norm of 43.6. Annual transfusion avoidance ranged from 71%-79% in PEGASUS and 80%-86% in PRINCE, with 52% of patients from PEGASUS avoiding transfusion for up to 3 years of pegcetacoplan treatment and 67% of patients from PRINCE avoiding transfusion for up to 2.5 years. Overall, &amp;gt;92% patients had compliance rates of at least 95%. Over 3 years, most patients experienced an AE; SAEs were reported in 50.0% of patients, with 4.5% experiencing a SAE deemed related to pegcetacoplan. Overall, 17 patients discontinued pegcetacoplan due to an AE; of those, 9 discontinued due to a hemolytic disorder, 7 of which discontinued within 1 year of starting pegcetacoplan. Over 3 years, 4 (3.0%) deaths occurred, none were deemed related to pegcetacoplan; 3 (2.3%) patients experienced a thrombotic event (in the context of multiple associated comorbidities or discontinuation of pegcetacoplan) and no cases of meningitis were reported. Overall, no new or unexpected safety findings were identified. Conclusions: Rapid improvements in Hb, LDH, ARC, indirect bilirubin, and FACIT-Fatigue values were observed and maintained up to 3 years in C5i-experienced patients and up to 2.5 years in C5i-naive patients. The transfusion burden was significantly reduced. No new safety findings were identified. This analysis demonstrates sustained efficacy and continued safety of long-term pegcetacoplan for patients with PNH, regardless of prior C5i treatment.

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.

Cost-Effectiveness of Sutimlimab Versus Standard-of-Care in Transfusion Dependent Patients with Primary Cold Agglutinin Disease in the United States

Introduction: Primary cold agglutinin disease (CAD) is an autoimmune hemolytic anemia characterized by the presence of cold-reactive antibodies that lead to red blood cell destruction at low temperatures. Patients with CAD who are transfusion-dependent experience the burden of increased health resource utilization and reduced quality-of-life. The standard-of-care (SOC) in patients with primary CAD has included chemoimmunotherapy, transfusion support, and cold avoidance. Sutimlimab is a humanized monoclonal antibody that selectively inhibits C1-mediated hemolysis. It is the only FDA-approved therapeutic for patients with cold agglutinin disease regardless of history of transfusion, with approval based on two phase 3 clinical studies. The cost-effectiveness of this expensive therapeutic in the care of patients with either transfusion-independent or transfusion-dependent primary CAD is not known. We sought to fill this gap by determining the cost-effectiveness of sutimlimab versus standard-of-care for the transfusion-dependent patient population with primary CAD. Methods: For this independent analysis free of industry influence, we built a Markov state transition model of adult patients with transfusion-dependent primary CAD to determine the cost-effectiveness of sutimlimab versus SOC, over a lifetime time-horizon and across accepted willingness-to-pay thresholds in US dollars per quality-adjusted life-year (QALY). For transition probabilities, we employed phase 3 study data (NCT03347396) with descriptive statistics informing the documented pre- versus on-sutimlimab clinical benefit, including the decrement in hemolytic anemia severity and transfusion burden. For SOC, we assumed that all patients undergo the costs and risks of chemoimmunotherapy with bendamustine-rituximab, followed by rituximab monotherapy and subsequent treatment with mycophenolate mofetil, with all patients remaining dependent on transfusion care. Health resource utilization costs for SOC were further supplemented with country- and disease-specific real-world costs over a median of 42.8 and 33.0 months of follow-up after incident primary CAD diagnosis across two claims databases. These costs were assessed from the highest of 1) annualized cost quartile and 2) the worst ordinal category of hemolytic anemia severity (defined as hemoglobin &amp;lt;8 g/dL) across all of 1) hospitalizations, 2) emergency visits, 3) outpatient services, and 4) blood transfusions. We assumed no loss of sutimlimab efficacy and no discontinuation off sutimlimab due to adverse events. Age- and sex-adjusted, disease-specific mortality was employed. Effectiveness was calculated in QALYs and was informed directly from trial-specific utilities. The primary outcome was the incremental cost-effectiveness ratio (ICER) or the incremental net monetary benefit (iNMB), if the intervention was found to be cost-saving. The secondary outcome was a scenario analysis for patients with a body weight of &amp;lt;75 kilograms that mandate lower dosing per-kilogram sutimlimab dosing, as per the FDA package insert. We concluded by conducting deterministic and probabilistic sensitivity analyses, capturing uncertainty in all parameters simultaneously over 10,000 Monte Carlo simulations. Results: In the base-case analysis, treatment with sutimlimab versus SOC accrued 5.60 and 4.79 QALYs at costs of $9.52 and $7.67 million, respectively, with the ICER for sutimlimab treatment being $2,280,000/QALY [95% credible interval 960,000-13,900,000]. In the scenario analysis for patients with lower body weight (i.e., lower sutimlimab dosing), the ICER was $1,910,000/QALY. Model results were sensitive to sutimlimab cost. In a probabilistic sensitivity analysis, SOC was favored over sutimlimab in 100% of 10,000 iterations. An exploratory threshold analysis showed that the mortality hazard with sutimlimab would need to decrease by 201% for sutimlimab to become cost-effective. Conclusion: Sutimlimab is conventionally cost-ineffective compared to SOC in transfusion-dependent patients with CAD. Distributional cost-effectiveness analysis (DCEA) to potentially justify sutimlimab as an equitable therapeutic option despite cost-ineffectiveness in the United States context is needed.