High Transfusion Burden Research Articles

Real-world Data From the Swiss Lenalidomide in MDS del(5q) (SLIM)-Registry Identify New Chances and Challenges in Lenalidomide Treatment of Patients With MDS del(5q).

Real-world Data From the Swiss Lenalidomide in MDS del(5q) (SLIM)-Registry Identify New Chances and Challenges in Lenalidomide Treatment of Patients With MDS del(5q).

Red blood cell transfusion burden in myelodysplastic syndromes (MDS) with ring Sideroblasts (RS): A retrospective multicenter study by the Groupe Francophone des Myélodysplasies (GFM).

MDS-RS patients are characterized by chronic anemia and a low risk of Acute Myeloid Leukemia (AML) progression and they generally become Red Blood Cell (RBC) transfusion dependent (TD). We performed a retrospective "real-life" observational study of 6months in 100 MDS-RS TD patients, recruited in 12 French centers, to describe transfusion characteristics, and evaluate the frequency and causes of hospitalizations, health costs, and morbidity, associated with transfusion dependency, in a French population of RBC transfusion-dependent MDS-RS patients. 79% of the patients had high transfusion burden (HTB) and 21% low transfusion burden (LTB). HTB patients had a longer disease duration (6 vs. 3.7 years, p=0.0078), more frequent iron chelation (82% vs. 50%, p=0.0052) and higher serum ferritin (p=0.03). During the 6-month study period, 22% of the patients required inpatient hospitalization, 36% of them for symptomatic anemia requiring emergency RBC transfusion. The 6-month median transfusion costs, including the cost of the day care facility, transportation to and from the hospital, iron chelation, and lab tests, was 16,188€/patient. MDS-RS represents the archetypal type of chronically transfused lower-risk MDS. Most of those patients have a high transfusion burden and thus frequently need visits to the hospital's day care facility, and frequent hospitalizations, with an overall high median treatment cost. Those costs should be compared with costs of new treatments potentially able to avoid RBC transfusion dependence and to reduce the complications of chronic anemia in MDS-RS patients.

Health state utilities for beta-thalassemia: a time trade-off study

BackgroundBeta-thalassemia (BT) is an inherited blood disorder characterized by reduced levels of functional hemoglobin resulting in phenotypes ranging from clinically asymptomatic to severely anemic. Patients with BT may require lifelong regular blood transfusions supported by appropriate iron chelation therapy (ICT). This study aimed to determine how the UK general population values BT health states associated with differing transfusion burden and ICT.MethodsComposite time trade-off (cTTO) methodology was employed to elicit health state utilities in BT. Relevant BT literature related to symptom and quality-of-life impact, including physical, functional, and emotional well-being, and safety profiles of BT treatments were considered when drafting health state descriptions. Eleven health state descriptions were developed and validated by hematologists and patient advocates for clinical accuracy and completeness. 200 individuals from the UK general population participated in the cTTO interviews.ResultsThe mean age of participants was 41.50 years (SD 16.01, range 18–81); 88 (46.8%) were female. Utility values ranged from 0.78 (SD 0.34) for non-transfusion dependent BT with oral ICT to 0.37 (SD 0.50) for high transfusion burden with subcutaneous ICT in transfusion-dependent BT.ConclusionsThis study provides health utilities for a range of BT health states from the UK general population perspective. Importantly, lower transfusion burden and lower burden of anemia were associated with higher utilities. To a lesser extent, differential modes of ICT were found to impact utility valuations in patients with BT. The utilities obtained in this study can be employed as inputs in cost-effectiveness analyses of BT therapies.

Hematopoietic Stem Cells (HSC) and Granulocyte Macrophage Progenitors (GMP) are the Oxidative Stress Targets in Low/Intermediate-1 Risk Myelodysplastic Syndromes.

Myelodysplastic Syndromes (MDS) are a heterogenous group of clonal hematopoietic stem cell malignancies. Previous studies showed that Reactive Oxygen Species (ROS) play a role in the pathogenesis and clinical evolution of MDS, contributing to Hematopoietic Stem and Progenitor Cells (HSPC) genetic instability. Less is known about ROS levels in the various sub-populations of MDS HSPC and how they correlate with clinical data in MDS patients. Our study aims to analyze ROS levels in MDS Hematopoietic Stem Cells (HSC), common myeloid progenitors (CMP), Granulocyte Macrophages Progenitors (GMP) and megakaryocyte-erythrocyte progenitors (MEP); afterwards, we looked at the relationship between ROS levels and clinical data. thirty-eight MDS and 27 Normal Bone Marrow (NBM) samples were collected; ROS levels were analyzed via multicolor flow cytometry. In both NBM and MDS, HSC showed much higher ROS levels than progenitors (3 to 4 folds, p < 0.0001); HSC ROS were significantly more elevated in MDS-no excess blasts versus MDS with excess blasts and versus NBM. GMP from MDS-no excess blasts showed higher ROS compared to NBM GMP. The 3 MDS with Ringed Sideroblasts (RS) showed more elevated ROS in HSC and GMP compared to the not RS low/intermediate-1 MDS; the 2 monosomy 7 patients displayed higher ROS levels in each subpopulation compared to the normal karyotype MDS; the only del(5q) patient did not show relevant differences in ROS levels compared to the median of the normal karyotype MDS ROS. The 9 high transfusion burden patients exhibited higher ROS in HSC and GMP compared to NBM HSC and GMP. These data were not confirmed in low transfusion burden (n:2) and non-transfused patients (n:26). In low/intermediate-1 MDS, a direct correlation between ferritin values and ROS levels in progenitors, but not in HSC, was detected. Interestingly, low/intermediate-1 risk patients that are no longer responding to recombinant human erythropoietin (rh-EPO) showed higher ROS levels in GMP and HSC. Our data showed that ROS can play a role in the pathogenesis and maintenance of low and intermediate-1 risk MDS clone; ROS status can be influenced by several clinical factors as ferritin levels and rh-EPO treatment. In this scenario, high ROS levels can contribute to genetic instability and influence progression to AML. Further biological studies are needed to elucidate ROS role in MDS pathogenesis and analyze the possible benefit of antioxidant drugs added to the standard MDS treatments.

Monitoring of Plasma Ferritin Levels after Blood Transfusions in Patients with Myelodysplastic Syndromes

Background: The majority of patients with myelodysplastic syndromes (MDS) needs regular blood transfusions and becomes transfusion dependent. Blood transfusions temporarily alleviate anemia-related symptoms, but can be accompanied by adverse events, like iron overload. In MDS patients with >20 blood transfusions and plasma ferritin levels >1000 µg/L, (inter)national guidelines advise iron chelation therapy (ICT) to reduce potential organ damage due to transfusion-mediated iron overload. The aim of this study was to determine the adherence to these guidelines, to determine to what extent plasma ferritin levels were monitored in daily practice and which patient-related factors contributed to monitoring plasma ferritin levels during the transfusion period.Methods: We performed an observational, retrospective, population-based study, using the Hemobase registry, in MDS patients diagnosed between 2005 and 2017. The Hemobase registry is a population-based registry for all hemato-oncological patients diagnosed since 2005 in Friesland, a province of the Netherlands with approximately 650.000 inhabitants. It provides detailed clinical information on diagnosis and follow-up in daily clinical practice. Clinical information on blood transfusions, plasma ferritin measurements, treatment with ICT, and patient-related factors as age, comorbidities (according to the Charlson Comorbidity Index (CCI)) and revised international prognostic scoring system (IPSS-R) risk category was collected from electronic health records. Information about all distributed blood transfusions was available from the laboratory systems. RBC units were administered to patients according to and following national guidelines. Transfusion dependence was defined according to the International Working Group (IWG) 2018 guidelines: low transfusion burden (LTB) or high transfusion burden (HTB). LTB was defined as 3-7 transfusions in a period of 16 weeks; HTB was defined as ≥8 transfusions in a period of 16 weeks. MDS patients with International Prognostic Scoring System (IPSS-R) (very) low and intermediate were categorized as low-risk MDS, and patients with IPSS-R (very) high as high-risk MDS. Logistic regression analyses were performed to analyze the likelihood of monitoring plasma ferritin levels for patients of different subgroups: age >80 years vs. ≤80 y, CCI score ≥2 vs. <2, and IPSS-R high vs. low risk MDS.Results: A total of 237 out of 292 MDS patients (81.1%) received at least one transfusion. Plasma ferritin levels were measured at least once in 55.3% (n=131) of these patients (Table 1 and Figure 1). During the first 20 transfusions, plasma ferritin measurements were present in 114 of 237 patients (48.1%). After >20 transfusions, plasma ferritin measurements were present in 51 of 121 patients (42.1%). Age, comorbidities and IPSS-R score were not associated with the likelihood of monitoring plasma ferritin levels. 112 patients were eligible for ICT (i.e. plasma ferritin levels >1000 µg/L or >20 transfusions). ICT was given to 22.3% (n=25) of these patients. Five patients received ICT whilst not fulfilling the criteria according to the guideline. During ICT, plasma ferritin levels were monitored in 60.0% of patients with ICT.Conclusions: In conclusion, in this population-based study, plasma ferritin levels were measured, irrespective of age, comorbidities and IPSS-R score, in 55% of MDS patients with transfusions. ICT was not given to all eligible patients and during ICT, monitoring of plasma ferritin levels was not performed in all cases. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Characterizing Iron Overload By Age in Patients Diagnosed with Pyruvate Kinase Deficiency - a Descriptive Analysis from the Peak Registry

Characterizing Iron Overload By Age in Patients Diagnosed with Pyruvate Kinase Deficiency - a Descriptive Analysis from the Peak Registry

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.

Large Population Dataset Linkage to Understand Evolving Practice in Red Cell and Platelet Transfusion and Clinical Outcomes in Patients with Myelodysplastic Syndromes (MDS): A 15-Year Study

Aim: Transfusions are frequently administered for anemia and thrombocytopenia in MDS. However, evidence to guide transfusion remains sparse, along with data about real-world MDS transfusion practices, transfusion-related outcomes and changes over time with increasing access to disease-modifying therapies. In Australia, from 2011, 5-azacitidine was funded through the Pharmaceutical Benefit Scheme (PBS) for patients with IPSS classification intermediate-2 or high-risk MDS, or Chronic Myelomonocytic Leukemia-2 (CMML-2). Australian Patient Blood Management (PBM) guidelines were also first published in 2011. We aimed to characterise red blood cell (RBC) and platelet transfusion practices, and transfusion-related outcomes of MDS and CMML patients over a 15 year period, and explore whether access to disease-modifying therapies or the introduction of PBM guidelines impacted on transfusion requirements.Methods: Retrospective longitudinal cohort study including all patients with MDS/CMML admitted to hospitals in Victoria, Australia's second most populous state, from 2002-2017. Data linkage from the Victorian Admissions Episode Dataset (VAED) (contains data from all public and private hospital admissions in Victoria, including all transfusion episodes), the Victorian Cancer Registry and the Victorian Death Index was performed. We analysed transfusion episodes and outcome events (cardiac ischemia/failure, transfusion reactions, bleeding).Results: 6771 patients with a diagnosis of MDS/CMML reported to the Cancer Registry were included (5970 MDS; 801 CMML). The cohort was elderly (>50% aged 70y and over) and predominantly male (male 61%; female 39%). The majority of patients had a low number of comorbidities (Charlson Comorbidity Score: 60% low (0-2); 32% moderate (3-5); 8% high (≥6)).Of the 179 patients on 5-azacitidine, 38 (21.2%) commenced prior to 2011 and 141 (78.8%) from 2011 onwards. Patients on 5-azacitidine were more likely to be RBC transfusion dependent (TD) (defined as 2 or more RBC transfusions within 16 weeks) (77.7.1% vs 49.9%, p<0.001) and receive platelet transfusions (54.2% vs 28.6%, p<0.001).During the study period, the patients had a total of 142,765 hospital admissions. 66,068 (46.3%) admissions involved RBC transfusion, with median 3 admissions (IQR 1-10) per patient and median 14 days (IQR 14-33) between transfusions. 3433 (50.7%) of patients were RBC transfusion-dependent (TD). Comparing pre-and post-2011, the proportion of admissions involving RBC transfusion, median number of RBC transfusion admissions per patient, and rates of RBC-TD decreased (table 1). Cardiac events were common, and more frequent in RBC-TD patients (acute cardiac ischemia 14.6% vs 10.3%, p<0.001; acute cardiac failure 27.3% vs 14.1%,p<0.001).10,049 (7.0%) admissions involved platelet transfusion. Platelet transfusion admissions increased over time (table 1). Median time between platelet transfusions was 7 days (IQR 4-16). 2436 patients (36.0%) experienced bleeding, including 51.3% of platelet-transfused patients. The commonest bleeding site was gastrointestinal (n=1388, 20.5%). Intracranial bleeding occurred in 175 patients (2.6%). 300 patients (4.4%) died from bleeding complications, with higher bleeding-related mortality in platelet-transfused patients (7.0% vs 3.4%, p<0.001) and RBC-TD patients (5.2% vs 4.0%, p=0.001).Conclusion: This study highlights the high transfusion burden in MDS patients, and related adverse cardiac and bleeding outcomes and mortality. RBC transfusion requirements reduced over time but platelet transfusions increased. This may be related to changing availability or use of MDS therapies, or clinical transfusion decision-making practices, or both - although national PBM guidelines do not specify a particular hemoglobin threshold for chronically transfused MDS patients, clinicians may be extrapolating from recommendations for restrictive transfusion thresholds in other settings (e.g. critical care, perioperative transfusion). These data will help design future MDS transfusion trials, which should include quality-of-life and health economics outcomes, given the burden of transfusion on these elderly patients. [Display omitted] DisclosuresShortt: Amgen: Research Funding; Astex: Research Funding; BMS: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Wood: Amgen, Celgene, Gilead, Janssen, Novartis, Sanofi, Takeda: Research Funding; Abbvie, Amgen, Antengene, Bristol-Myers Squibb, Celgene, Gilead, GSK, Janssen, Novartis, Sanofi, and Takeda.: Other: The Australian and New Zealand Myeloma and Related Diseases Registry (MRDR) has received funding from Abbvie, Amgen, Antengene, Bristol-Myers Squibb, Celgene, Gilead, GSK, Janssen, Novartis, Sanofi, and Takeda. .

A Phase 2, Open-Label, Ascending Dose Study of Ker-050 for the Treatment of Anemia in Patients with Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

A Phase 2, Open-Label, Ascending Dose Study of Ker-050 for the Treatment of Anemia in Patients with Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

Patterns of transfusion burden in an unselected population of patients with myelodysplastic syndromes: A population-based study.

BackgroundIneffective hematopoiesis in patients with myelodysplastic syndromes (MDS) often results in transfusion dependence. The burden of frequent transfusions in the real‐world MDS population is largely unknown.Study design and methodsAn observational, retrospective, population‐based study, using the HemoBase registry, was performed including all patients diagnosed with MDS between 2005 and 2017 in Friesland, a province in the Netherlands with approximately 650,000 inhabitants. Detailed clinical information was collected from the electronic health records. Transfusion burden was classified according to the International Working Group 2018 criteria: not transfusion dependent, low (LTB), or high transfusion burden (HTB). Univariate and multivariable regression analyses were performed.ResultsOf 292 patients, 136 (46.6%) had a HTB of ≥8 units/16 weeks and 17 (5.8%) had a LTB of 3–7 units/16 weeks. This was present in all types of MDS patients, but patients aged 75–84 years (odds ratio [OR] 4.02, 95% confidence interval [CI]: 1.84–8.82), high‐risk MDS patients (OR 2.88, 95% CI: 1.08–7.68) and MDS‐EB‐2 patients (OR 7.07, 95% CI: 2.17–22.90) were particularly at risk for a HTB.DiscussionThis study provides a reliable estimate of the transfusion burden in real‐world MDS patients, with almost half of the patients having a HTB. A HTB was observed in all MDS subtypes and both low‐ and high‐risk MDS. Therefore, we conclude that the entire MDS population might benefit from novel agents that reduce the transfusion need and that might have beneficial effects on patient outcomes and healthcare utilization outcomes.

A Simple Tool for the Prediction of Azacytidine Treatment Failure in Patients with Myelodysplastic Syndrome

Introduction:The development of a tool to predict the sensitivity of MDS patients to azacytidine has great clinical applicability. Furthermore, a tool that is able to dynamically predict response to azacytidine while on therapy would be of utility to the clinician who must determine when the efficacy of the drug has been lost. Goal: The purpose of this work was to evaluate clinical and laboratory parameters to develop markers of ineffective hematopoiesis that correlate with the development of resistance to azacytidine in MDS patients. Methods: We conducted a retrospective cohort study of all patients with MDS with Int-2/hi risk IPSS score treated with 5-azacytidine at the London Health Science Centre between January 2008 and December 2014. The study was approved by the institutional Research Ethics Board. Relevant data, including bone marrow aspirate and biopsy, cytogenetics, peripheral blood counts, transfusion frequency, and azacytidine dosing and administration were extracted from the electronic patient record. Response to azacytidine, as assessed by IWG 2006 criteria, was recorded and time to treatment failure was calculated. The parameter representative of ineffective erythropoiesis was derived using an ROC curve generated by comparing the RDW during time periods of low red blood cell transfusion burden to time periods of high transfusion burden. Parameters representative of ineffective hematopoiesis in each of the megakaryocytic and granulocytic lineages were derived using ROC curves generated by comparing changes in each of the respective counts during time periods with effective erythropoiesis and known azacytidine treatment response (based on bone marrow blast counts and cytogenetic profile), and time periods with effective erythropoiesis and proven treatment failure. The parameter for ineffective erythropoiesis was defined as hemoglobin Results: The characteristics of all MDS patients included in the cohort is summarized in Table 1. There was a total of 97 patients in the cohort, with 74 patients receiving greater than 3 treatment cycles and having sufficient response data for the derivation of hematopoietic parameters. The presence of ineffective erythropoiesis after the 3rd cycle of azacytidine had a significant correlation with the time to treatment failure (Figure 1). The median time to treatment failure of MDS patients was 144 days for patients with ineffective erythropoiesis after 3 cycles of azacytidine, while it was 418 days for patients with effective erythropoiesis. The parameters for ineffective megakaryopoiesis and ineffective granulopoiesis after 3 cycles of azacytidine had no correlation with time to treatment failure. There were 25 patients who attained response to azacytidine beyond 6 cycles and who had proven treatment failure based on either increasing blast count or cytogenetic evolution along with sufficient peripheral blood count data corresponding to the time of treatment failure. Among these patients, the development of ineffective granulopoiesis followed by the development of ineffective megakaryopoiesis had a positive predictive value of 87% for disease progression. Conclusion: The presence of ineffective erythropoiesis after 3 cycles of azacytidine was the strongest predictor of azacytidine treatment failure in Int-2/Hi IPSS MDS patients. The earliest peripheral blood markers of disease progression after initial response reflect the development of ineffective granulopoiesis followed by ineffective megakaryopoiesis, with effective erythropoiesis preserved. Download : Download high-res image (207KB) Download : Download full-size image Disclosures Lazo-Langner: Daiichi Sankyo: Research Funding; Alexion: Research Funding; Bayer: Honoraria; Pfizer: Honoraria.

Health-related quality of life (HRQoL) in patients (pts) with myelodysplastic syndromes (MDS) in the Connect Myeloid Disease Registry.

7040 Background: At diagnosis, disease risk and transfusion burden (TB) can impact HRQoL in pts with MDS. The impact of disease status and higher transfusion requirements on HRQoL has not been well studied. We used data from the Connect Myeloid Disease Registry, an ongoing, prospective, observational cohort study that includes adult pts with lower-risk (LR) and higher-risk (HR) MDS, to investigate factors influencing baseline (BL) and subsequent HRQoL. Methods: BL and Month 6 (M6) data from pts enrolled from Dec 12, 2013 to Mar 6, 2020 (data cutoff) were analyzed. Pts were stratified by International Prognostic Scoring System (IPSS) risk (LR, HR), treatment (Tx) within 45 days post-enrollment (no Tx, best supportive care [BSC], active Tx), and TB 16 weeks post-BL (non-transfusion dependent [NTD], low TB [LTB]; 1−3 transfusions, high TB [HTB]: ≥4 transfusions). Pts completed EQ-5D, FACT-An trial outcome index (TOI), and FACT-Fatigue (FACT-F) questionnaires at BL and quarterly thereafter. Clinically meaningful change, based on minimally important differences, was defined as a change of ±0.07 for EQ-5D, ±6 for FACT-An TOI, and ±3 for FACT-F. Results: At data cutoff, 830 (489 LR, 341 HR) pts were enrolled. Median age was 74 years. 278 pts received no initial Tx, 161 BSC, and 378 active Tx. At BL, 470 were NTD, 197 LTB, and 163 HTB. Of 670 pts still on-study at M6, 462 completed the questionnaires at both BL and M6. At BL , clinically meaningful differences were observed in FACT-An TOI and FACT-F scores, but not EQ-5D, between LR- and HR-MDS and the Tx subgroups . From BL to M6, no clinically meaningful changes were observed in mean scores for each questionnaire. For the TB subgroups, meaningful differences were observed at BL in FACT-An TOI and FACT-F scores, but not EQ-5D (Table). From BL to M6, meaningful decreases in scores were reported by 26%, 30%, and 35% of NTD, LTB, and HTB pts in EQ-5D, 41%, 43%, and 48% for FACT-An TOI, and 40%, 42%, and 48% for FACT-F; increases were reported by 19%, 19%, and 20% pts for EQ-5D, 31%, 32%, and 39% for FACT-An TOI, and 30%, 39%, and 40% for FACT-F. Conclusions: This preliminary analysis suggests that pts with HR-MDS, and transfusion-dependent pts, generally had worse HRQoL at BL, providing further support to initiating active Tx in pts with TB. Possible limitations of the analysis are lower completion rates in pts with more severe disease, and EQ-5D may not capture changes in these subgroups at M6. A longer follow-up may help delineate the impact of Tx on HRQoL assessments in pts with MDS. Clinical trial information: NCT01688011. [Table: see text]

A high transfusion burden following an ambulatory-allogeneic hematopoietic cell transplantation using reduced-intensity conditioning is associated with adverse outcomes

ObjectivesAmbulatory allogeneic hematopoietic cell transplantation (allo-HCT) after reduced-intensity conditioning (RIC) is a cost-effective option for hematology patients. Data on the impact of transfusion burden in this setting are scarce; we analyzed this retrospectively. MethodsA study of 177 HLA-identical and haploidentical allo-HCT recipients on an outpatient basis was conducted between 2013 and 2019. Packed red blood cell (PRBC) and platelet transfusions were documented from days 0–100 after HCT. ResultsA total of 121 patients (68.4%) required transfusion while 56 (31.6%) did not. In the multivariate analysis, a lower disease-free (DFS) and overall survival (OS) were documented for patients that received ≥9 total blood products (p = 0.018) (p = 0.014), those who required hospitalization (p = 0.001) (p < 0.001), had acute graft-versus-host disease (p = 0.016) (p = 0.004), and a high/very high Disease-Risk-Index (p = 0.002; p = 0.004), respectively. Transfusion of ≥5 PRBC units was associated with a lower OS (p = 0.027). The cumulative incidence of transplant-related mortality at two years for an HLA-identical transplant was 9.5% and for haploidentical, it was 27.1% (p = 0.027); this last group had significantly more transfusion demands than HLA-identical recipients (p = 0.029). ConclusionIncreased blood product utilization is an independent predictor of decreased survival in ambulatory RIC allo-HCT recipients. Further evidence leading to individualized guidelines to transfuse in this complex scenario is needed.

Red Blood Cell Transfusion Burden in Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS): A Retrospective Multicenter Study By the Groupe Francophone Des Myélodysplasies (GFM)

Background: MDS-RS are associated with a low risk of Acute Myeloid Leukemia (AML) progression and prolonged survival in most cases, but recurring anemia whose treatments, including Erythropoiesis Stimulating Agent (ESA), Lenalidomide, hypomethylating agents (HMAs), Luspatercept, and experimental drugs generally have transient effect and/or are not widely available. MDS-RS patients thus eventually have regular Red Blood Cells (RBC) transfusion dependency (TD) associated with mean low hemoglobin levels, and chronic anemia responsible for reduced quality of life, cardiovascular complications, and iron overload with organ dysfunction. We performed a retrospective observational study to describe transfusion characteristics and costs, along with clinical events, in a French population of RBC TD MDS-RS patients. Methods: Adult RBC-TD patients with MDS-RS from 12 hematology departments of the GFM were included. The number of RBC concentrates transfused was assessed over the last 6 months (during which no other treatment than transfusions was received), and patients categorized in low transfusion burden (LTB: 3 to 7 RBC/16 weeks) and high transfusion burden (HTB: ≥8 RBC concentrates /16 weeks). Data about iron chelation, full time hospitalization (differing from day care facility stays for programmed transfusions), causes of hospitalization, treatment of anemia before inclusion and transfusion costs was collected. Results: 100 patients MDS-RS were included, with a median time from diagnosis of 5 years (1 to 21 years). Median age was 78 years (57 to 99). Patients had received a median of 2 lines of treatment (including an ESA in 97% of them). 21% had LTB and 79% HTB. HTB patients had a longer disease duration, more frequent iron chelation (82% versus 50% in LTB patients, p=0.0052) and higher serum ferritin at inclusion (median 1958 µg/l versus 1176 µg/l, p=0.03). During the 6-month study period, 22% of the patients required full time hospitalization (in addition to day care facility for transfusions), including 25% of patients with HTB and 15% with LTB, and 43% during overall disease follow-up. Causes of full time hospitalization (figure) were symptomatic anemia (41%), general condition degradation (5%) or cardiac disease (8%), to both of which anemia potentially contributed, infection (23%), bleeding (8%), pulmonary (2%), 13% for other reasons. 15 HTB patients versus 1 LTB patient were hospitalized for symptomatic anemia. The 6-months average transfusion costs, including cost of the day care facility for RBC transfusion, transportation to and from the hospital, lab tests and iron chelation were $21459/patient, excluding costs of full-time hospitalization for complications. The average cost in HTB and LTB patients was $22829 and $7586/patient, respectively. Conclusion: Most MDS-RS patients currently become RBC-TD, often during several years, and most have high transfusion burden. The average cost of RBC transfusions and iron chelation was $21459/ 6 months. During this short observation time, 22% of the patients required full time hospitalization, due to complications of anemia in at least 50% of the cases, which also increased costs (comparison with rates of hospitalization in an age and sex matched general population will be presented). Poor quality of life associated with chronic anemia should also be taken into account in those RBC-TD patients. Widely available treatments, capable of avoiding RBC transfusion dependence and improving mean hemoglobin levels, are required in those MDS-RS patients. Disclosures Cony-Makhoul: BMS: Speakers Bureau; Incyte Biosciences: Speakers Bureau; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Cluzeau:Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Stamatoulas Bastard:Takeda: Consultancy; Pfizer: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria. Fenaux:Jazz: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Park:Pfizer: Other: Travel expenses; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees.

Efficacy and Safety of Luspatercept Treatment in Patients with Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T): A Retrospective Analysis from the Medalist Study

Efficacy and Safety of Luspatercept Treatment in Patients with Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T): A Retrospective Analysis from the Medalist Study

MDS-179: Clinical Benefit of Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS) and High Transfusion Burden (HTB) in the Phase 3 MEDALIST Study

Background: Patients with LR-MDS and anemia who have HTB have very few treatment options and represent a patient population with significant clinical unmet need. Aims: To evaluate the clinical benefit of luspatercept in HTB patients with LR-MDS from the MEDALIST trial. Methods: Eligible patients were aged ≥18 years; had IPSS-R-defined LR-MDS with ring sideroblasts (RS); were refractory, intolerant, or unlikely to respond to erythropoiesis-stimulating agents (serum erythropoietin > 200 U/L); and had anemia requiring regular RBC transfusions. All patients provided informed written consent. 229 patients were randomized 2:1 to luspatercept (starting dose 1.0 mg/kg; titration up to 1.75 mg/kg allowed) or placebo subcutaneously every 3 weeks. HTB was defined as ≥6 RBC units transfused/8 weeks. Results: 153 patients were randomized to luspatercept and 76 to placebo; 66 and 33 had HTB at baseline, respectively. As of 01 JULY, 2019, 23/66 (34.8%) and 12/66 (18.2%) luspatercept-treated HTB patients achieved a ≥50% and ≥75% reduction in RBC units transfused over at least 24 weeks compared to baseline, respectively, versus 3/33 (9.1%; P=0.0063) and 1/33 (3.0%; P=0.0363) HTB placebo patients. 6/66 (9.1%) luspatercept-treated HTB patients and 1/33 (3.0%) placebo-treated HTB patient achieved RBC-transfusion independence (RBC-TI) ≥ 8 weeks in Weeks 1–24 (P=0.2699). Median (range) time to achieve RBC-TI was 50.0 days (1.0–100.0) with luspatercept; median (range) duration of longest RBC-TI episode in luspatercept-treated patients was 42.6 weeks (8.4–81.1). Mean number of transfusion events in Weeks 1–24 was 9.2 for luspatercept-treated patients versus 12.4 in the placebo arm (hazard ratio [95% confidence interval] 0.794 [0.660–0.956]). 65/66 (98.5%) luspatercept- and 29/33 (87.9%) placebo-treated HTB patients reported ≥1 treatment-emergent adverse event (TEAE); 11/66 (16.7%) and 3/33 (9.1%) patients, respectively, reported ≥1 TEAE leading to discontinuation. 28/66 (42.4%) luspatercept- and 15/33 (45.5%) placebo-treated patients reported ≥1 serious TEAE. The incidence of grade 3–4 TEAEs in HTB patients was similar between treatment arms (53.0% for luspatercept vs 54.5% for placebo). Conclusions: HTB patients with LR-MDS with RS receiving luspatercept had clinically significant reductions in RBC transfusion burden and reduced number of transfusion events. Luspatercept was well tolerated in HTB patients, consistent with the overall study population.

MDS-171: Effects of Luspatercept on Serum Ferritin in Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS) with Ring Sideroblasts (RS) in the Phase 3 MEDALIST Trial

Background: Iron overload, resulting from RBC transfusions or ineffective erythropoiesis, is associated with significant morbidity in MDS. Aims: To assess changes from baseline in serum ferritin (SF) and iron chelation therapy (ICT) use in the MEDALIST trial patients ( NCT02631070 ). Methods: Patients (IPSS-R-defined lower-risk MDS with RS; ≥18 years; unsatisfactory response to or ineligible for EPO-based therapy; required regular RBC transfusions) had luspatercept (1.0 mg/kg, titration up to 1.75 mg/kg) or placebo administered subcutaneously every 3 weeks. Results: Of 153 luspatercept-treated patients, 87 (56.9%) had low and 66 (43.1%) high baseline RBC transfusion burden (LTB and HTB; Conclusion: Luspatercept treatment resulted in SF decreases, particularly in HTB patients and those with high baseline SF who experienced significant RBC transfusion reduction. Overall, ICT use was reduced with luspatercept.

Clinical benefit of luspatercept in patients (pts) with lower-risk MDS (LR-MDS) and high transfusion burden in the phase III MEDALIST study.

7554 Background: Anemic pts with LR-MDS and high baseline RBC transfusion burden (HTB) have very few treatment options and constitute a pt population with significant clinical unmet need. In this secondary analysis of the MEDALIST trial (NCT02631070), we sought to evaluate the clinical benefit of luspatercept in this pt population. Methods: MEDALIST is a randomized, placebo (PBO)-controlled, phase 3 study evaluating the efficacy and safety of luspatercept in pts with anemia due to LR-MDS with ring sideroblasts (RS) (Fenaux &amp; Platzbecker et al. NEJM. 2020;382:140-51). Pts were aged ≥ 18 years; had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS; were refractory, intolerant, or unlikely to respond to erythropoiesis-stimulating agents (serum erythropoietin &gt; 200 U/L); and had anemia requiring regular RBC transfusions (≥ 2 units/8 weeks in the 16 weeks prior to randomization). 229 pts were randomized 2:1 to luspatercept (starting dose 1.0 mg/kg; titration up to 1.75 mg/kg allowed) or PBO subcutaneously every 3 weeks. HTB was defined as ≥ 6 RBC units transfused/8 weeks. Results: 153 pts were randomized to luspatercept and 76 to PBO. As of July 1, 2019, 23/66 (34.8%) and 12/66 (18.2%) HTB pts receiving luspatercept achieved a ≥ 50% and ≥ 75% reduction from baseline in RBC transfusion burden over ≥ 24 weeks, respectively, vs 3/33 (9.1%; P = 0.0063) and 1/33 (3.0%; P = 0.0363) pts receiving PBO. 6/66 (9.1%) luspatercept-treated HTB pts and 1/33 (3.0%) PBO-treated HTB pt achieved RBC-transfusion independence (TI) ≥ 8 weeks in Weeks 1–24 ( P = 0.2699). The median (range) time to achieve RBC-TI with luspatercept was 50.0 days (1.0–100.0) and median (range) duration of RBC-TI in the luspatercept arm was 42.6 weeks (8.4–81.1). Mean number of transfusion events in Weeks 1–24 was 9.2 in the luspatercept arm vs 12.4 in the PBO arm (hazard ratio [95% confidence interval] 0.794 [0.660–0.956]). 65/66 (98.5%) luspatercept- and 29/33 (87.9%) PBO-treated HTB pts reported ≥ 1 treatment-emergent adverse event (TEAE); 11/66 (16.7%) and 3/33 (9.1%) pts, respectively, reported ≥ 1 TEAE leading to discontinuation. 28/66 (42.4%) luspatercept- and 15/33 (45.5%) PBO-treated pts reported ≥ 1 serious AE. Incidence of grade 3–4 TEAEs in HTB pts was similar between arms (53.0% luspatercept vs 54.5% PBO). Conclusions: Luspatercept treatment resulted in clinically significant reductions in transfusion burden and reduced number of transfusion events in HTB pts with LR-MDS with RS, with an acceptable safety profile consistent with the overall population. Clinical trial information: NCT02631070 .

Disparities in receipt of complete diagnostic evaluation to confirm myelodysplastic syndromes.

7555 Background: A complete diagnostic evaluation (CDE), including bone marrow (BM) biopsy, cytogenic testing, FISH panel, and/or flow cytometry, is widely accepted as a prerequisite for histopathologic confirmation of MDS. Earlier reports have raised concerns regarding accuracy of MDS diagnosis in population registries that do not require confirmatory tests for disease reporting. We queried Medicare files to analyze the extent of use of, and factors associated with CDE for diagnosing MDS. Methods: The study population included Medicare patients with at least one inpatient or two outpatient claims for MDS within a 12-month period during the years 2012 and 2013. Variables included age, sex, race, morphologic MDS categories, cytopenias (isolated or any combination), transfusion burden, comorbididities, as well as county-level characteristics (income, educational attainment, rurality, and availability of internal medicine subspecialists). Classification and regression tree (CART) and multivariable logistic regression analysis were used to identify combinations of factors associated with receipt of CDE. Results: Our study population included 45,067 MDS patients, of whom only 68.6% received CDE that included BM biopsy and/or chromosomal studies. The percent of patients undergoing CDE was significantly lower among those 85 years of age or older (56.1%); women (63.7%); Blacks (64.2%); patients with isolated anemia (60.3%); and those who were transfusion independent (p &lt; 0.001 for all comparisons). On the other hand, CDE was significantly higher among patients with the category of MDS with excess blasts (89.4%); those presenting with pancytopenia (92.2%); and those with high transfusion burden (80%). There was little variation by comorbidity burden, county level characteristics, or availability of subspecialists. In CART analysis, 80% of patients presenting with any two or more cytopenias received CDE. In multivariable analysis, advanced age, female sex, Black race, higher comorbidity burden and availability of subspecialists were associated with a lower likelihood to receive CDE, while patients with MDS with excess blasts, and with any &gt; 2 cytopenias were more likely to receive CDE ( P&lt; .0001). Conclusions: Nearly one third (31%) of MDS patients in the Medicare database lack CDE especially BM biopsy. Disparities in CDE can be corrected through proper physician education and stringent registry reporting to avoid such high diagnostic inaccuracies, leading to potential missed treatment opportunities.

PSY7 A CONCEPTUAL FRAMEWORK FOR ECONOMIC EVALUATION OF BETA-THALASSEMIA

To establish a conceptual framework to aid in the economic evaluation of the treatment of beta-thalassemia (BT) to assess cost-effectiveness, long-term effects, and resource use. An economic conceptual framework was developed from a US payer perspective using literature and clinical rationale. Efficacy and safety outcomes, health states, technical assumptions, economic endpoints, and costs were considered. Key value drivers were identified to help optimize future economic models. Different sets of assumptions were considered and tested using a Markov model. The model framework and clinical rationale were validated by expert hematologists. A lifetime horizon was modeled because patients with BT often require lifelong red blood cell transfusions (RBCTs). In addition to disease pathology, RBCTs lead to iron loading and contribute to significant morbidity (e.g. increased long-term complications, complication costs, reduced quality of life) and early mortality. A lifetime horizon further permitted the use of age-related increases for complication rates and captured the long-term outcomes of key therapies (curative or otherwise). Six health states were modeled to capture the patient lifetime journey: transfusion-independence, low transfusion burden, medium transfusion burden, high transfusion burden, treatment discontinuation, and mortality. These health states enabled the inclusion of response status defined in terms of transfusion burden and treatment discontinuation. The cost of iron chelation therapy was a key driver across health states, increasing costs with greater transfusion burden. Drug costs, routine care, complication(s), adverse events, mortality, and indirect costs were also key drivers. This conceptual model framework permitted the reporting of results in incremental costs per QALY, LY, and responder. This conceptual framework can be used to perform future economic evaluations of the treatment of BT, to capture long-term effects, complications, and mortality, and to provide researchers and policymakers with the appropriate tools for informed decision-making.