Transfusion-dependent Myelodysplastic Syndromes Research Articles

New therapy options for myelodysplastic syndrome—all for all or targeted?

SummaryThe OeGHO-Frühjahrstagung 2024 took place in Vienna. Thereby one session was dedicated specifically to the field of myelodysplastic syndrome (MDS). Just a few days before the meeting, the European Medicines Agency approved luspatercept for transfusion-dependent low-risk MDS patients in the first line. It was therefore more current than ever to discuss the future significance of this therapy for our patients in the low-risk field. In addition, there are other new substances in the pipeline; some of which already have mature phase III data (e.g., imetelstat), which have already led to the approval by the US Food and Drug Administration.

Combination Therapy with Luspatercept and the Ferroportin Inhibitor Vamifeport Is Superior to Either Drug Alone in Improving Anemia and Reducing Myeloid Skewing in MDS

Background: Patients with myelodysplastic syndromes (MDS) are prone to develop iron overload as a consequence of ineffective erythropoiesis and chronic transfusion therapy. Although iron overload is a common feature in MDS, it has remained unclear whether and how iron excess is detrimental for MDS pathophysiology. Recently, we have shown that iron restriction by the oral ferroportin (FPN) inhibitor vamifeport improves anemia and reduces myeloid skewing, being of benefit for MDS as single treatment. Luspatercept is a recombinant fusion protein acting as TGF-β superfamily ligands trap which has recently gained FDA approval for the treatment of anemia in transfusion-dependent low-risk MDS patients. Luspatercept promotes erythropoietin (EPO)-independent maturation of late-stage erythroid cells, resulting in increased hemoglobin and red blood cells (RBCs) count. However, this drug - due to a lack of improvement in myeloid skewing and AML evolution - is considered a non-disease-modifying therapy. Aims: In this study we investigated the effect of a combined therapy using luspatercept and the FPN inhibitor vamifeport in a preclinical MDS mouse model, with the hypothesis that both drugs could have additive effects with further benefit for the disease. Methods: To this end, we administered the FPN inhibitor vamifeport in NUP98-HOXD13 MDS mice for 3 months (0.5 mg/ml into drinking water), combined with luspatercept for the last 2 months (5 mg/kg twice a week, subcutaneous injection), starting at 3 months of age. Mice receiving the combined treatment were compared to those untreated or receiving single treatments. Results: At steady-state MDS mice develop anemia, neutropenia and lymphopenia, together with an iron overload phenotype, hallmarked by inappropriately low hepcidin levels, elevated serum iron and transferrin saturation, non-transferrin-bound iron (NTBI) formation and tissue iron deposition. Vamifeport administration in MDS mice reduced serum iron and NTBI formation and prevented tissue iron loading, either as a single or combined treatment with luspatercept. Luspatercept and vamifeport, as single-agent treatment, ameliorated anemia and the maturation of bone marrow and splenic RBCs in MDS mice. The combined therapy further improved anemia compared to the treatments with either drugs alone, as suggested by the higher hemoglobin levels, hematocrit and RBC count, and the decreased number of early erythroid precursors, sign of more effective erythropoiesis. Importantly, vamifeport, but not luspatercept, significantly altered myeloid skewing in MDS, revealing a major role of the iron status in myeloid expansion. Myeloid bias, monitored as percentage of CD11b + Gr1 + myeloid cells in the bone marrow was attenuated by iron restriction in vamifeport-treated MDS mice compared to control and luspatercept-treated MDS animals. The combined treatment merkedly reduced myeloid skewing in MDS mice, similarly to the single vamifeport treatment. Furthermore, the number of immature cKit + myeloid blasts in the peripheral blood of MDS animals were decreased by vamifeport alone and in combination with luspatercept, but not by luspatercept alone. Finally, splenomegaly was reduced in MDS mice treated with vamifeport alone or in combination with luspatercept, confirming that iron restriction improves ineffective erythropoiesis and limits myeloid skewing. Overall, the combination therapy with vamifeport and luspatercept showed superior effects in improving anemia and myeloid bias as compared to single treatments. Conclusion: In conclusion, our results show that iron restriction by vamifeport enhances the erythroid maturation action of luspatercept, likely by improving iron utilization in erythroid cells and ameliorating their survival. Furthermore, vamifeport improves the myeloid skewing in the MDS model, suggesting disease-modifying activity as single agent as well as combined therapy with luspatercept. Together, these data prove that combo therapies aimed at restricting iron and boosting erythroid maturation may offer additive beneficial effects in MDS and provide pre-clinical evidence for combining iron restriction and TFG-β superfamily ligand-trap approaches as more effective therapeutic strategies for the treatment of MDS.

Net Clinical and Quality of Life Benefit of Luspatercept in Transfusion-Dependent MDS: A Win Ratio Analysis Using Data from the Phase 3 MEDALIST Study

Background: Patients with transfusion-dependent (TD) myelodysplastic syndromes (MDS) often experience various anemia-related symptoms and functional impairments. Treatments reducing red blood cell (RBC) transfusion burden could impact these symptoms and/or functions to varying degrees depending on patients' conditions at baseline and warrants the use of composite endpoints, including both clinical outcomes and patient-reported outcomes (PROs) to fully capture these benefits. However, conventional statistical approaches may not satisfactorily assess composite outcomes, especially when the components of the composite outcomes have different types of scales and/or degrees of importance to stakeholders. The win ratio (WR) approach, one of the generalized pairwise comparison methods commonly used for assessing treatments in cardiovascular diseases, offers hierarchical structure, statistical power, and flexibility to address these challenges. Objective: This exploratory analysis used the WR approach to assess the net benefit of luspatercept vs. placebo on composite clinical/PRO endpoints using data from the MEDALIST study. Methods: Four different WR scenarios were performed, in each of which every possible patient-to-patient pair between the luspatercept and placebo arms was compared on a set of relevant clinical/PRO endpoints in a pre-specified order of assumed priority from patients' perspectives, accompanied with a pre-determined rule to assign a win, loss, or tie for luspatercept in each pairwise comparison on each endpoint. If a win or loss could not be determined on a given endpoint, then the next endpoint in the hierarchy was evaluated until a win or loss occurred. Otherwise, if all pre-specified endpoints were evaluated, a tie was assigned. The scenarios considered two clinical endpoints: RBC-transfusion independence [TI] ≥8 weeks over Weeks 1-24 and RBC-TI over Weeks 1-24. PRO endpoints included changes from baseline to the end of Week 24 in five key domains of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), categorized as improvement (≥10-point improvement), stable (10 > change >-10), or worsening (≥10-point worsening). Improvement was considered a better outcome than stable and worsening, and stable was considered better than worsening when determining a win or loss for luspatercept on each of the PRO endpoints. The four different scenarios of composite clinical/PRO endpoints and their order of priority, shown in the Table were pre-specified for assessment . The WR (nominal 95% CI, p-value) for luspatercept on each scenario of the composite clinical/PRO endpoints was calculated as the total number of pairs with a win divided by the total number of pairs with a loss. A WR >1 indicates that luspatercept is more favorable than placebo. Results: 153 patients randomized to the luspatercept arm were compared to 76 patients randomized to the placebo arm, for a total of 11,628 pairwise comparisons within each WR analysis. In all four scenarios, WRs were nominally statistically significantly in favor of luspatercept ( Table). Most wins favoring luspatercept were attributed to wins on the clinical endpoint. Among those pairs who tied on the clinical endpoint, the luspatercept arm experienced more wins (or tied) in almost all of the five PRO endpoints. WRs were similar whether PRO endpoints were prioritized over others or not. Conclusions: The analysis findings indicate that, for two randomly selected patients with low-risk TD MDS, the odds that the patient treated with luspatercept would have a better outcome (if not tied) than the patient with placebo, is significantly higher than 1, ranging between 1.51 to 1.90. The analysis also shows that when multiple clinical and PRO endpoints, especially with different importance to stakeholders, are considered to provide a comprehensive treatment benefit, WR can be a useful and valuable approach for making this evaluation.

Prevalence and treatment of anemia and secondary iron overload in patients with a myelodysplastic syndrome: real-world data from a multicenter cohort study.

anemia is the most common finding in patients with a myelodysplastic syndrome (MDS). Repetitive red blood cell (RBC) transfusions and disease-related low hepcidin levels induce secondary iron overload. Real-world data on the prevalence and treatment strategies of anemia and secondary iron overload in MDS patients, is limited. three years of data on MDS diagnosis, anemia and ferritin management was collected in 230 MDS patients from seven non-academic hospitals in the Netherlands. Descriptive statistics and linear mixed models were used to analyze the data. transfusion dependent (TD) patients (n=49) needed 1-3 RBC transfusions per month. Serum hemoglobin remained stable in both TD and transfusion-independent (TI) patients over 3 years. In the TD patients, serum ferritin increased 63 pmol/L/month. Overall, 19 (39%) were diagnosed with secondary hemochromatosis, of which 13 (68%) received chelation therapy with a heterogeneous response. mean hemoglobin remains stable over time in both TD and TI MDS patients. Approximately 40% of TD patients develop secondary hemochromatosis. Treatment and monitoring of secondary hemochromatosis as well as the response on chelation therapy varies substantially.

Duality of Nrf2 in iron-overload cardiomyopathy.

Cardiomyopathy deeply affects quality of life and mortality of patients with b-thalassemia or with transfusion-dependent myelodysplastic syndromes. Recently, a link between Nrf2 activity and iron metabolism has been reported in liver ironoverload murine models. Here, we studied C57B6 mice as healthy control and nuclear erythroid factor-2 knockout (Nrf2-/-) male mice aged 4 and 12 months. Eleven-month-old wild-type and Nrf2-/- mice were fed with either standard diet or a diet containing 2.5% carbonyl-iron (iron overload [IO]) for 4 weeks. We show that Nrf2-/- mice develop an age-dependent cardiomyopathy, characterized by severe oxidation, degradation of SERCA2A and iron accumulation. This was associated with local hepcidin expression and increased serum non-transferrin-bound iron, which promotes maladaptive cardiac remodeling and interstitial fibrosis related to overactivation of the TGF-b pathway. When mice were exposed to IO diet, the absence of Nrf2 was paradoxically protective against further heart iron accumulation. Indeed, the combination of prolonged oxidation and the burst induced by IO diet resulted in activation of the unfolded protein response (UPR) system, which in turn promotes hepcidin expression independently from heart iron accumulation. In the heart of Hbbth3/+ mice, a model of b-thalassemia intermedia, despite the activation of Nrf2 pathway, we found severe protein oxidation, activation of UPR system and cardiac fibrosis independently from heart iron content. We describe the dual role of Nrf2 when aging is combined with IO and its novel interrelation with UPR system to ensure cell survival. We open a new perspective for early and intense treatment of cardiomyopathy in patients with b-thalassemia before the appearance of heart iron accumulation.

Effects of Ker-050 on Iron Metabolism: Exploratory Analyses from an Ongoing Phase 2 Study in Patients with Myelodysplastic Syndromes

Background: Iron overload (IO) is an important clinical consequence of transfusion-dependent myelodysplastic syndromes (MDS). For patients with high transfusion burden (HTB), limited treatment options are available to effectively treat anemia and reduce transfusion dependence. Transfusion dependence is an independent predictor of poor prognosis in MDS. It is associated with IO and elevated ferritin, a marker of intracellular iron storage that also predicts poor prognosis in MDS. When adjusting for transfusion burden, each 500 µg/L increase in ferritin above 1000 µg/L is associated with a 30% greater risk of death (Malcovati et al. 2006). IO also disrupts osteoprogenitors and erythroid precursors within the osteohematopoietic niche, leading to abnormal bone turnover and ineffective erythropoiesis (Bulycheva 2015). While iron chelators have shown some efficacy in managing IO, they introduce toxicities and have little effect on transfusion burden. Unmet need remains for treatments that effectively address anemia, IO, and reduce transfusion dependence in patients with MDS, especially those with HTB. KER-050 is designed to alter signaling of TGF-β superfamily ligands, restoring balance to the osteohematopoietic niche, and promoting differentiation of erythroid and megakaryocytic precursors. It is a modified activin receptor type IIA ligand trap that inhibits TGF-β superfamily ligands, including activins A and B and growth and differentiation factors (GDFs) 8 and 11. To date, clinical data indicate that KER-050 induces sustained increases in reticulocytes and hemoglobin. Preliminary findings also show potential for KER-050 to induce erythroid response and reduce transfusion burden in patients with MDS, including those with HTB (Tan et al., 2022). KER-050 may also impact iron metabolism and this presentation explores the effects of KER-050 on indices of IO. Methods: This Phase 2 study is evaluating KER-050 in participants with very low- to intermediate-risk MDS. Data presented are from Part 1 Dose Escalation which included 16 weeks of KER-050 treatment across 5 cohorts (0.75 to 5 mg/kg). Iron chelator therapy was permitted at the discretion of the investigator provided patients had been on a stable dose for 8 weeks prior to C1D1. Markers of IO and hematopoiesis were assessed as exploratory endpoints over the 16-week treatment period. Analyses presented evaluate the effect of KER-050 on these markers. Baseline markers of bone turnover were also assessed. Results: A total of 31 patients were enrolled in Part 1 Dose Escalation; 26 were transfusion dependent, 18 with HTB (≥ 4 RBC units in 8 weeks prior to day 1). Seven HTB patients (38.9%) received iron chelator therapy. Baseline differences were noted in measures of iron status, erythropoiesis and bone turnover for non-transfused (NT), low transfusion burden (LTB), and HTB patients (Table 1). HTB patients had the highest baseline serum iron and ferritin levels. Preliminary findings indicate that KER-050 treatment was associated with decreases in serum ferritin for patients both with and without iron chelator therapy. Patients achieving transfusion independence (TI) experienced a 39.5% reduction (mean change: -619.4 ng/ml, range: -2118.4 to +243 ng/mL) in serum ferritin at Week 12 that was generally sustained at Week 16 and 20 (Figure 1). Similarly, over the same time period, serum iron and transferrin saturation (TSAT) decreased by 4.03 µmol/L (8.38%) and 5.3%, respectively, in patients achieving TI. Soluble transferrin receptor (sTfR) increased by 32.2% and remained elevated at subsequent visits. Summary: Preliminary data from the 16-week Dose Escalation in this ongoing phase 2 study reveal differences in baseline iron biomarkers indicative of increasing iron overload with increasing transfusion burden. While nearly half of HTB patients received iron chelator therapy, this group had markedly elevated ferritin compared to NT and LTB patients at baseline. KER-050 treatment was associated with reductions in serum ferritin, irrespective of the use of iron chelation. Patients achieving TI experienced decreases in ferritin, iron and TSAT concurrent with increases in sTfR that were generally maintained through follow-up. The data suggest that, in addition to improving hematopoiesis and transfusion burden in MDS patients, KER-050 may reduce iron overload, a serious clinical complication impacting the survival of these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lessons from the European and Israel National MDS Registry

On behalf of the Israeli MDS working group and EUMDS Registry/ XIII Eurasian Hematology Oncology Congress (EHOC) 2022. The myelodysplastic syndromes (MDS) are a group of clonal stem cell diseases with cytopenias and a tendency to transform to leukemia. Despite the progress, there is still lack of real world data about the disease. In 2008, top European experts launched the EUMDS Registry. In this project, including 19 countries and 150 sites, epidemiological, clinical and lab data on newly diagnosed MDS patients, are collected and analyzed. As of today, 3300 patients have been recruited. In 2012, the Israel MDS group joined the project. We have contributed data on 360 patients, # 4 in the contributors. This project led to more than 100 abstracts in international meetings and 40 publications in first line journals. We will mention some of these studies. de Swart et al. summarized data on the first 1000 patients, validated the IPSS-R prognostic classification, showing its superiority on IPSS (de Swart L. BJH 2015). Another study, focusing on Quality of life (QoL) of LR-MDS patients revealed that these patients suffer from depression, anxiety, pain, discomfort and mobility difficulties, compared to controls (Stauder R, Leukemia 2018) The effects of Erythroid Stimulating Agents (ESAs,) was evaluated: Garelius et al. showed that ESA administration delays RBC transfusion dependency (Garelius HK. J Intern Med 2017). Since in most countries ESA is given to transfusion-dependent MDS patients, it might change the paradigm. Recently, we demonstrated that ESA treatment, is associated with improved outcomes and overall survival (Garelius HK. EHA 2022; submitted). Since prognostic factors are often determined at disease presentation, it was important to develop dynamic parameters. We showed that a rapid decline > 25% in the platelet count within 6 months is an adverse prognostic marker (Itzykson R. Bl Adv 2018) A study focusing on the mutational status was presented at ASH 2021 showing that LR-MDS patients can be grouped into 3 clusters, with a correlation to the clinical status (Malcovati L. ASH 2021) The Israeli group, independently and as a part of the EUMDS, was involved in several projects. Oster et al. suggested a non-invasive calculator to assess the probability of or excluding MDS diagnosis, based on patient characteristics, avoiding BM examination (Oster HS. Bl Adv 2021). We also investigated the correlation between Hb level and QoL. This correlation was found to be partial, and the decrease in QoL was not linear. This suggests that other factors other than Hb might play a role in determining QoL (Haring Y. ASH 2021). We recently presented data on lymphoid aggregates in BM biopsies, suggesting a possible association with poor prognosis (Book-Rabinowitz. Int MDS Symposium, Toronto 2021; submitted). In summary , the EUMDS registry is a platform of a scientific project, and an example of international collaboration. Such projects, especially in relatively uncommon diseases, allow collection of enough data to allow meaningful conclusions that might change paradigm and improve patient care. We call all participants of this meeting to join us and improve the quality of this wonderful important project.

Impact of Lenalidomide Treatment on Overall Survival in Patients With Lower-Risk, Transfusion-Dependent Myelodysplastic Syndromes.

For patients with lower-risk (LR) myelodysplastic syndromes (MDS), overall survival (OS) is rarely a primary clinical trial endpoint. Treatments such as lenalidomide can reduce red blood cell (RBC) transfusion burden (TB) and serum ferritin, but the long-term impact on OS remains undetermined. Data from 3 trials evaluating lenalidomide in patients with LR-MDS (the phase 2 MDS-003 and phase 3 MDS-004 trials in del[5q]; the phase 3 trial MDS-005 in non-del[5q] patients) were pooled. Predictors of OS were assessed by multivariate analysis using time-dependent models for TB and RBC transfusion independence (RBC-TI), and a landmark analysis of RBC-TI at 17 weeks. Separate analyses using MDS-004 and MDS-005 data determined the relationship between OS and serum ferritin. Median follow-up for MDS-003, MDS-004, and MDS-005 was 3.2, 3.0, and 1.7 years, respectively. In multivariate analyses, transfusion of ≥6 RBC units over 8 weeks was a significant predictor of shorter OS vs. 0 units in the time-dependent TB model (hazard ratio [HR] 4.65; 95% confidence interval [CI] 3.32-6.52; P < .0001). RBC-TI achievement was associated with prolonged OS in the time-dependent (HR 0.48; 95% CI 0.37-0.62; P < .0001) and landmark model (HR 0.57; 95% CI 0.44-0.75; P < .0001). Increased serum ferritin was associated with shorter OS (P < .0001). This analysis of prospective trial data in patients with LR-MDS confirms lenalidomide may improve OS by reducing TB and serum ferritin. OS should be considered as an endpoint in future lower risk MDS clinical trials.

New treatment for myelodysplastic syndromes: luspatercept and oral hypomethylating agents

Several novel myelodysplastic syndromes (MDS) treatment drugs are being developed, and luspatercept and oral hypomethylating medicines have already been licensed in the United States and other countries. Luspatercept is a ligand trap that inhibits SMAD2/3 signals by combining the extracellular domain of the activin type IIA receptor with the human immunoglobulin G1 Fc domain. In the phase 2 study for low-risk MDS, the hematological improvement-erythroid (HI-E) was found in 63% of patients, and in the phase 3 study for transfusion-dependent low-risk MDS with ring sideroblasts, 38% of patients achieved transfusion independence. A combination of oral decitabine with oral cedazuridine, an inhibitor of cytidine deaminase, which metabolizes decitabine, demonstrated pharmacological equivalence with intravenous decitabine and has overall response rates of 60% and 43% for high-risk MDS in phase 2 and 3 trials, respectively. Furthermore, oral azacitidine and its combination with oral cedazuridine have been under development.

Predictors of cardiovascular events and all-cause of death in patients with transfusion-dependent myelodysplastic syndrome.

Cardiovascular disease (CVD) involves the second cause of death in low-risk myelodysplastic syndrome (MDS) population. Prospective study to characterise the CVD and to identify predictors for the combined event (CE) cardiovascular event and/or all-cause mortality in transfusion dependent low-risk MDS patients. Thirty-one patients underwent a cardiac assessment including biomarkers and cardiac magnetic resonance (cMR) with parametric sequences (T1, T2 and T2* mapping) and myocardial deformation by feature tracking (FT) and were analysed for clonal hematopoiesis of indeterminate potential mutations. Cardiac assessment revealed high prevalence of unknown structural heart disease (51% cMR pathological findings). After 2·2 [0·44] years follow-up, 35·5% of patients suffered the CE: 16% death, 29% cardiovascular event. At multivariate analysis elevated NT-proBNP ≥ 486pg/ml (HR 96·7; 95%-CI 1·135-8243; P = 0·044), reduced native T1 time < 983ms (HR 44·8; 95%-CI 1·235-1623; P = 0·038) and higher left ventricular global longitudinal strain (LV-GLS) (HR 0·4; 95%-CI 0·196-0·973; P = 0·043) showed an independent prognostic value. These variables, together with the myocardial T2* time < 20ms, showed an additive prognostic value (Log Rank: 12·4; P = 0·001). In conclusion, low-risk MDS patients frequently suffer CVD. NT-proBNP value, native T1 relaxation time and longitudinal strain by FT are independent predictors of poor cardiovascular prognosis, thus, their determination would identify high-risk patients who could benefit from a cardiac treatment and follow-up.

British Society for Haematology guidelines for the management of adult myelodysplastic syndromes.

British Society for Haematology guidelines for the management of adult myelodysplastic syndromes.

Abdominal Distention in a Patient on Peritoneal Dialysis.

A 66-year-old Caucasian man with a failing cardiac transplant, transfusion-dependent myelodysplastic syndrome, and ESKD from calcineurin inhibitor toxicity on peritoneal dialysis (PD) was admitted with complaints of acute onset of shortness of breath after suspected aspiration, and progressive abdominal distention. Physical examination revealed crepitations in the right lung base and distended abdomen that was dull on percussion in the flanks, as well as bilateral inguinal hernias. Chest x-ray confirmed right lower lobe patchy pneumonitis consistent with aspiration along with mild cardiomegaly. Because his symptoms persisted despite antibiotics and achieving daily ultrafiltration in excess of 1 L with PD, a computed tomography (CT) abdomen scan with oral contrast was performed that showed extensive …

Patient and physician perceptions about blood transfusions in the myelodysplastic syndromes

BackgroundLittle is known about the shared decision-making between patients with transfusion-dependent (TD) myelodysplastic syndromes (MDS) and their physicians about the benefits, risks, and alternatives to reduce the need for blood transfusions. Methods and MaterialsWe conducted interviews and two cross-sectional surveys of MDS patients and MDS physicians in the US about the use of blood transfusions and disease-modifying therapies (DMTs). Responses from 157 MDS patients and 109 MDS physicians were analyzed. ResultsThe TD-MDS patient cohort had a median age of 69 years and a greater proportion of lower IPSS risk. The MDS physicians primarily practiced in large centers, evenly distributed between academic and community hospitals. There was a high level of independence and generally positive quality of life among patients, who were mostly concerned about effectiveness of blood transfusions and iron overload. MDS patients with shorter duration of disease (less than 5 years) were primarily concerned with transfusion reaction, while MDS patients with longer duration of disease were primarily concerned with iron overload. Approximately half of TD-MDS patients stated they had not discussed alternatives to reduce the need for blood transfusions with their physician. Patients with longer duration of disease were more likely to have a discussion with their physician about alternatives to blood transfusions. Physicians stated that they administered blood transfusions as primary therapy for MDS when it was patient preference, advanced age of patient, frailty, lower risk MDS, significant comorbidities, or failed prior treatments. ConclusionsWhile quality of life seemed generally positive in TD-MDS patients, there were differing perceptions about blood transfusions between patients and physicians. In the future, appraisal and optimization of the informed consent process between MDS patients and physicians are needed.

A Systematic Literature Review on the Burden of Illness in Lower-Risk Transfusion-Dependent Myelodysplastic Syndromes

Introduction: Anemia occurs in 80-90% of patients with myelodysplastic syndromes (MDS), nearly half of whom are red blood cell (RBC) transfusion dependent (TD) at diagnosis. The presence of anemia, transfusion dependency, and the resulting complications exacerbate the burden of MDS. Patients with lower-risk MDS have longer overall survival (OS) than patients with higher-risk MDS; however, TD status and higher transfusion load significantly reduce OS. Treatment of lower-risk TD MDS aims to achieve RBC transfusion independence (TI), hematologic improvements and alterations in erythroid response according to IWG 2006 criteria, and improved health-related quality of life (HRQoL). To evaluate these points, we performed a systematic literature review (SLR) to assess the burden experienced by adult patients with RBC TD anemia in lower-risk MDS. Methods: Embase®, MEDLINE®, and the Cochrane Library were systematically searched from inception to March 2019 to identify observational studies reporting on the HRQoL, clinical, and epidemiological burden as well as treatment patterns for adult patients with lower-risk MDS who were RBC TD. Conference proceedings from the last 2 years were searched to identify recent data not yet published as a full text article. Only English language articles and conference abstracts were included. References were screened at the title/abstract and full-text levels by 2 independent reviewers, with methodology following Cochrane guidelines. Results: Database searches yielded 1,175 records. After removing duplicates, 837 abstracts were reviewed, with 152 publications progressing to full-text review. Ten studies met the eligibility criteria. Two additional records were identified from hand searching (Figure). Many studies reported on mixed MDS patient populations, where only a subset were lower-risk and TD, limiting the amount of data available. Nine studies were from the USA or EU5 (France Germany, Italy, Spain, United Kingdom) as well as 1 international study encompassing Europe, the USA, and Australia. The majority of studies defined risk status using the International Prognostic Scoring System (IPSS) risk score, with only 1 study reporting both IPSS and Revised-IPSS (IPSS-R) score. Where reported, patients were mostly older (mean age &gt; 70 years). Burden data were sparse, with few outcomes reported across multiple studies (Table). One study from Italy (mean age 72 years) reporting EuroQoL 5-dimension Visual Analogue Scale data indicated that patients with TD MDS had worse scores (53.0) compared with patients aged 65-74 years in the general Italian population (67.8). Clinical data indicated a variable OS rate across studies conducted in Spain and France, as well as in the 1 international study, with a 2-year OS rate of 73.2% and 4-year OS rates ranging from 27.6% to 73%. The data consistently reported that patients with TD MDS had shorter OS than patients with TI MDS. Differences in timepoints for assessment, types of treatments, and RBC transfusion load increased the variation in OS data. TI was defined as a transfusion-free period of ≥ 56 days, or 8 weeks, in most studies. Median time to reach TI (when reported) ranged from 32-97 weeks, although the prolonged length of time it took to reach TI and the proportion of patients achieving TI indicated an extensive time on treatment. Similar conclusions were drawn in 3 studies that compared OS in patients who became TI with those who remained TD. Epidemiology data were limited to mortality data, and no data were available on morbidity, incidence, or prevalence of disease. Mortality data provided an incomplete picture; deaths were reported as overall mortality or non-leukemic deaths, obscuring mortality rates specifically associated with lower-risk TD MDS. Treatment patterns were reported in 3 studies; erythropoiesis-stimulating agents and hypomethylating agents were the most common treatments reported. Conclusions: Data on the burden of illness in patients with lower-risk MDS with TD anemia were limited and reported inconsistently across studies. Despite this heterogeneity, HRQoL outcomes had a trend toward worse scores in patients with TD MDS than in the general population. OS rate at 2 and 4 years indicated worse prognosis in patients with TD MDS compared with the general population. To better understand the burden of illness, further robust observational studies are needed to close the evidence gaps in this population. Disclosures Deshpande: Evidera: Employment; Celgene Corporation: Consultancy. Turner:Evidera: Employment; Celgene Corporation: Consultancy. Byrnes:Evidera: Employment. Pelligra:Celgene Corporation: Research Funding; Evidera: Employment. Rines-MacEachern:Evidera: Employment. Chitnis:Celgene Corporation: Consultancy; Evidera: Employment. Kulasekararaj:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Achilleon: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akari Therapeutics: Consultancy. Tang:Celgene Corporation: Employment, Equity Ownership. Morison:Celgene Corporation: Employment. Oliva:Apellis: Consultancy; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Speakers Bureau.

Intermittent Transfusion Independence Is Associated with Improved Overall Survival in Patients with Transfusion Dependent MDS

Intermittent Transfusion Independence Is Associated with Improved Overall Survival in Patients with Transfusion Dependent MDS

Differing Perceptions between Myelodysplastic Syndrome (MDS) Patients and Providers Regarding Blood Transfusions

Background: According to claims-based studies, a minority of MDS patients receive disease-modifying therapy. Unfortunately, these studies are limited by design in describing the shared decision-making process between MDS patients and their physicians in choosing supportive care, such as blood transfusions. Therefore, we surveyed and interviewed transfusion-dependent (TD) MDS patients and MDS physicians about the choice and use of supportive care, blood transfusions, and chemotherapy. Methods: Nearly 300 TD-MDS patients and MDS physicians were surveyed or interviewed under an IRB exempt protocol (WIRB). Semi-structured interviews of 15 patients and 10 providers were conducted between July and December of 2018 to inform survey development. Patients and providers within the AAMDSIF database were then invited via email and social media to participate in anonymous surveys. Survey respondents were entered into a lottery to receive a $50 gift card. Each interviewed patient was offered a $25 gift card and each provider interviewee was offered a $50 gift card. Survey 1 queried MDS patients who self-reported they had been TD, defined as 2 or more blood transfusions within a 2-month timespan, at some time since 2014. Between September 2018 and February 2019, 157 TD-MDS patients responded. Primary variables of interest included patient age, sex, use of disease-modifying therapies, use of chelating agents, and frequency of blood transfusions. Survey 2 queried providers who regularly manage TD-MDS patients (n=109). Nominal and ordinal variables were tested for possible association by the Goodman-Kruskal tau statistic. Results: Demographics and baseline disease characteristics of TD-MDS patients are shown in Table 1. In brief, the patient cohort had a median age of 69 years (range, 36-83), male 51%, and a greater proportion of low and low-intermediate IPSS risk. Nearly half of patients were unaware of their IPSS risk group. The majority (57%) of patients were TD within the past 2 months of answering the survey. Two-thirds of patients received care from an MDS specialist. MDS providers practiced in academic medical centers (61%), community hematology/oncology specialty practices (17%), community urban hospitals (10%), community suburban hospitals (5%), and rural community hospitals (4%), with some providers practicing in multiple locations. On a monthly basis, the majority (85%) of providers cared for up to 10 patients with TD-MDS. The highest ranked patient concerns about blood transfusions were transfusion reaction and iron overload. Concern for the more common risk of bacterial infection ranked 5th and was least often selected as the most important concern to patients. Approximately half of patients reported use of an iron chelating agent. On qualitative interview, most patients did not recall a discussion with their physician regarding the risks of blood transfusions, despite providers reporting they regularly educate patients and ask for informed consent. Further, although 98% of patients visited their MDS care provider at least quarterly, 48% stated they had not discussed alternatives to blood transfusion with their provider. Many patients held the sentiment there was "no choice to be made" in receiving blood transfusions. While providers said blood transfusions as primary management of MDS was rare, they reported they would recommend transfusions as stand-alone therapy in settings of patient preference for supportive therapy only, failure of ESAs, patient desire for transfusion-only therapy, and older patient age. Most patients (65%) ranked their quality of life positively, with 6% ranking excellent. The majority (58%) of patients drove themselves to their transfusion clinic, and 54% of patients traveled greater than 10 miles to these visits. Older age significantly associated with higher transfusion frequency (G-Test = 31.318, χ2 df = 18, p-value = 0.02644), but not with use of disease-modifying therapy. The presence of comorbidities was not associated with either transfusion frequency or active therapy. No significant association was found between patient income and either transfusion frequency, BMT, or administration of HMAs. Conclusions: MDS patients and physicians hold differing perceptions about the choice to receive and risks of receiving blood transfusions. Appraisal and optimization of the informed consent process between TD-MDS patients and physicians are needed. Disclosures No relevant conflicts of interest to declare.

Assessment By MRI T2*of Iron Accumulation and Removal in Transfusion Dependent MDS Patients

Introduction: Transfusion dependency in Myelodysplastic syndrome (MDS) patients is associated with shortened over-all survival and leukemia-free survival; however, it is not clear whether this detrimental effect is mediated by transfusional iron overload itself or whether the need for RBC transfusion is a surrogate marker of disease severity. Additionally, despite the negative effects of anemia and transfusion dependence on disease outcomes and patient quality of life, the clinical impact of iron overload in MDS remains controversial. Overall, the most common non-leukemic cause of death in MDS is heart failure. Recent T2* cardiac MRI (CMR) studies have shown that cardiac iron accumulation in MDS patients is variable and infrequent. T2* CMR is noninvasive, robust and the best available modality for assessing iron organ quantification. The current study assessed iron overload in transfusion dependent MDS patients using ferritin levels combined with myocardial and liver iron quantification using T2* CMR. The study monitored iron accumulation dynamics while on iron chelation therapy. Methods: We collected retrospectively clinical data in 18 RBC transfusion dependent MDS patients that had a CMR in our institution; some of the patients have serial scans. All scans were obtained using a 1.5 T scanner (Signa HDx ver 15 GE). Scans interpretation was performed using a dedicated workstation (Medis Medical imaging version 7.6, the Netherlands) for left ventricular ejection fraction measurement and T2* investigation as previously described. T2* values were recorded in milliseconds and converted to mg/gr dry tissue of myocardial liver and pancreatic tissue. Results: Ten of 18 patients were chelated. During the study period 4 patients have died from pneumonia, brain tumor, complications of Allo BMT and transformation to AML. Demographic data and prognostic score of MDS are shown in table 1. Before the first CMR, patients were treated with median of 48 PC (14-145) with median ferritin levels 1691.3ng/ml (269.4-3730ng/ml). In Table 2 we show iron accumulation in the first CMR. Iron accumulation in the heart was seen in 2 patients. The results are shown as severity of accumulation and not absolute numbers, as normal and abnormal range is different in the different organs. Seven patients had yearly serial CMR done, 6 of them were treated with iron chelation. We found iron accumulation in the heart in 4 of them. In table 3 we show example of a patient that was treated with chelation. Another patient, that had decrease ejection fraction with only moderate accumulation in the heart in CMR, improved her heart function with chelation. During the study period all patients continue to be transfusion dependent except 1 patient that became transfusion independent. She was transfused with 182 PC with maximal ferritin of 6926ng/ml. She was chelated with deferiprone and then with desferal. She is now transfusion independent for a year. Conclusion: Blood transfusion dependency in MDS patients, leads to high ferritin levels and evidences in CMR of iron accumulation in parenchymal orangs including the heart. During the study 4 patients had evidence of iron accumulation in the heart with 2 of them with severe accumulation that improved with iron chelation. Liver and pancreas accumulation was seen in 12 and 8 patients accordingly. Prospective studies documenting the correlation between chelation therapy and improvement in organ damage and survival are needed. Disclosures No relevant conflicts of interest to declare.

Non-Requirement to Blood Transfusion in a Patient With Myelodysplastic Syndrome Following the Oral Administration of β-D-Mannuronic Acid: A Case Report

Myelodysplastic Syndromes (MDSs) is a heterogeneous group of hematologic neoplasms that causes cytopenia and dysplasia in one or more major bone marrow cell lines. The patients with this syndrome develop clinical complications associated with progressive bone marrow destruction leading to an increased risk for acute myelogenous leukemia. In the treatment of this syndrome, repeated infusion of Red Blood Cells (RBCs) may lead to iron overload, which is associated with a reduction in the survival rate of patients. In this paper, we report a case with MDS whose risk of dependence on blood transfusion was interstitial and received 4 units of packed RBCs once every 4 weeks. He had enrolled in our current clinical trial of β-D-mannuronic acid (M2000) in Iranian MDS patients. This 68-year-old man was treated with M2000, 500-mg capsule every 12 hours for 3 months. After 3 months of treatment, he experienced a non-requirement to blood transfusion following a hemoglobin increase of more than 2.5 g/dL in his blood sample. Moreover, the patient’s life quality was improved. This case report showed that M2000 drug might be an effective treatment for transfusiondependent MDS patients (Clinical trial identifier; IRCT20130622013739N11).

Treatment of Lymphoid and Myeloid Malignancies by Immunomodulatory Drugs.

Thalidomide and its derivatives (lenalidomide, pomalidomide, avadomide, iberdomide hydrochoride, CC-885 and CC-90009) form the family of immunomodulatory drugs (IMiDs). Lenalidomide (CC5013, Revlimid®) was approved by the US FDA and the EMA for the treatment of multiple myeloma (MM) patients, low or intermediate-1 risk transfusion-dependent myelodysplastic syndrome (MDS) with chromosome 5q deletion [del(5q)] and relapsed and/or refractory mantle cell lymphoma following bortezomib. Lenalidomide has also been studied in clinical trials and has shown promising activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Lenalidomide has anti-inflammatory effects and inhibits angiogenesis. Pomalidomide (CC4047, Imnovid® [EU], Pomalyst® [USA]) was approved for advanced MM insensitive to bortezomib and lenalidomide. Other IMiDs are in phases 1 and 2 of clinical trials. Cereblon (CRBN) seems to have an important role in IMiDs action in both lymphoid and myeloid hematological malignancies. Cereblon acts as the substrate receptor of a cullin-4 really interesting new gene (RING) E3 ubiquitin ligase CRL4CRBN. This E3 ubiquitin ligase in the absence of lenalidomide ubiquitinates CRBN itself and the other components of CRL4CRBN complex. Presence of lenalidomide changes specificity of CRL4CRBN which ubiquitinates two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos), and casein kinase 1α (CK1α) and marks them for degradation in proteasomes. Both these transcription factors (IKZF1 and IKZF3) stimulate proliferation of MM cells and inhibit T cells. Low CRBN level was connected with insensitivity of MM cells to lenalidomide. Lenalidomide decreases expression of protein argonaute-2, which binds to cereblon. Argonaute-2 seems to be an important drug target against IMiDs resistance in MM cells. Lenalidomide decreases also basigin and monocarboxylate transporter 1 in MM cells. MM cells with low expression of Ikaros, Aiolos and basigin are more sensitive to lenalidomide treatment. The CK1α gene (CSNK1A1) is located on 5q32 in commonly deleted region (CDR) in del(5q) MDS. Inhibition of CK1α sensitizes del(5q) MDS cells to lenalidomide. CK1α mediates also survival of malignant plasma cells in MM. Though, inhibition of CK1α is a potential novel therapy not only in del(5q) MDS but also in MM. High level of full length CRBN mRNA in mononuclear cells of bone marrow and of peripheral blood seems to be necessary for successful therapy of del(5q) MDS with lenalidomide. While transfusion independence (TI) after lenalidomide treatment is more than 60% in MDS patients with del(5q), only 25% TI and substantially shorter duration of response with occurrence of neutropenia and thrombocytopenia were achieved in lower risk MDS patients with normal karyotype treated with lenalidomide. Shortage of the biomarkers for lenalidomide response in these MDS patients is the main problem up to now.

Genomic Biomarkers Predict Response/Resistance to Lenalidomide in Non-Del(5q) Myelodysplastic Syndromes

Genomic Biomarkers Predict Response/Resistance to Lenalidomide in Non-Del(5q) Myelodysplastic Syndromes