Regular Red Blood Cell Transfusions Research Articles

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

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

Patients' Preferences for Dosing Frequency and out-of-Pocket Cost Associated with Iron Chelators: A Mixed-Methods Pilot Study in the United States

Patients with sickle cell disease, thalassemia, and other anemias who require regular red blood cell transfusions are at risk of developing iron overload. Excess iron accumulates in tissues and vital organs, such as the liver, heart, and pancreas, causing end organ damage with significant morbidity and higher risk of early mortality. To offset the negative impacts of iron overload, patients are often prescribed iron chelators; however, little is known about what is important to patients when choosing between therapies, including the impact of dosing frequency or cost. The primary objective of our study was to develop and examine the comprehension of a patients' health preference survey regarding the dosing frequency of hypothetical oral iron chelators and the impact of the associated out-of-pocket costs. We hypothesized that patients would prefer iron chelators administered less frequently with some tradeoffs related to cost. The secondary objective was to explore potential reasons for preferring a less frequent dosing schedule to inform a larger-scale online preference study. A stated-preference survey using a direct elicitation approach was developed and tested in one-on-one, semistructured cognitive interviews with eight adults recruited through L&E Research, a market research firm specializing in healthcare. Patients with sickle cell disease, thalassemia major, or other anemias requiring frequent blood transfusions and who have experience with an iron chelator were invited to participate in an online interview. The survey instrument included a trade-off scenario involving a choice between two hypothetical oral iron chelators. Participants were told to assume that the medicines were just as safe and effective as their current iron chelator and could be taken either twice a day or three times a day. The survey also included questions to help explain preferences and understand the impact of out-of-pocket costs on treatment choice. During the interviews, we followed the “think aloud” approach where participants were asked to read the draft survey aloud, provide answers to the questions, and discuss or explain their interpretations of the information and the motivation behind their answers to selected questions. Open-ended, probing interview questions were used to explore participants' responses further. Qualitative data were generated through interview participants' verbatim accounts of their decision-making. The interviewer and the research team interpreted the qualitative data and made notes and observations to refine the survey instrument between interviews in an iterative process of updating and retesting. Quantitative data were generated through responses to the survey questions and were summarized using descriptive statistics. The median age of participants was 39 years old (25th percentile: 37 years; 75th percentile: 44 years), and most identified as female (n=7, 87.5%). Five participants were currently taking an oral iron chelator at the time of the interview, but the length of time on treatment varied from less than 6 months (n=2) to 2-5 years (n=3). When asked to choose a hypothetical oral iron chelator, all participants chose oral tablets that would be taken twice daily. The most common reasons for choosing a less frequent dosing schedule included dislike of taking a lot of pills (n=6), not having to remember to take pills (n=5), and not having to carry as many pills with them (n=4). When asked whether they would still choose oral tablets taken twice daily when the monthly out-of-pocket cost was $50, all but one participant switched to oral tablets taken three times a day. Qualitative data suggested participants accepted the hypothetical context of the preference scenarios, and the survey instrument was generally well understood. Participants also reported several other reasons for preferring a less frequent dosing schedule, which will all be included as response options in the final survey. Although patients indicated a preference for an iron chelator administered less frequently two times a day versus three times a day, choice was affected by the out-of-pocket cost of treatment. The results of our pilot mixed-methods interview study supported patients' comprehension of the health preference survey, which will be administered online to a larger sample to further explore preferences for dosing frequency and out-of-pocket costs of oral iron chelators.

Impact of Genomic Landscape and Mutational Burden on Primary Endpoint Responses in the COMMANDS Study

Background: Myelodysplastic syndromes (MDS)-related anemia leads to significant morbidity, due to impaired oxygen transport and red blood cell transfusion (RBCT)-related iron overload. Erythropoiesis-stimulating agents (ESAs) are used to treat anemia and decrease transfusion burden and are effective in ~ 35% of patients (pts) with lower-risk (LR)-MDS. Luspatercept is approved for pts with LR-MDS refractory/intolerant to ESAs who need regular RBCTs. Primary resistance to ESAs is frequent, and ~ 70% of responders relapse in < 2 years. Baseline (BL) erythropoietin level ≤ 200 U/L and ≤ 2 somatic mutations are prognostic factors for better ESA response. An association of driver gene mutations with deteriorating clinical outcomes is well established in LR-MDS (Papaemmanuil E, et al. Blood 2013;122:3616-3627; Bersanelli M, et al. J Clin Oncol 2021;39:1223-1233; Nazha A, et al. J Clin Oncol 2021;39:3737-3746). The Molecular International Prognostic Scoring System (IPSS-M; Bernard E, et al. NEJM Evidence 2022;1(7):EVIDoa2200008) was developed to improve upon the shortcomings of the Revised IPSS (IPSS-R) and restratified ~ 46% of pts by adding genomic profiling to existing hematologic and cytogenetic parameters. Pts with LR-MDS typically harbor a median of 2-3 driver mutations in genes involved in MDS pathogenesis. Methods: Individual pt bone marrow samples were prepared for sequencing using the Illumina ® DNA prep with enrichment and the xGen™ hybridization capture of DNA libraries. Exon coverage was ≥ 400X for 3% sensitivity. Sequencing libraries were run on the NovaSeq6000 (Illumina ®) system and statistical analyses were conducted using R. A targeted panel of 82 genes was used. Results: At BL, 322/363 pts enrolled in the COMMANDS trial had somatic mutations in ≥ 1 gene; 11 pts did not have mutation data. Most mutations had a variant allele frequency of 3%-50%. In the intent-to-treat (ITT) population, the luspatercept arm did not show any significant differences in BL mutational burden (MB, defined as the number of gene mutations from the myeloid gene panel) between responders (R) and non-responders (NR). Interestingly, R in the ESA arm trended ( P = 0.065) towards lower MB compared with NR. Subgroup analysis revealed that ring sideroblast (RS)− pts in the ESA arm had lower MB at BL (median 1 gene mutation) compared with RS+ pts (2 gene mutations; P = 0.0004). However, no significant difference was observed in the luspatercept arm. In the ITT population (and the RS+ subgroup), compared with ESAs, luspatercept showed robust responses (Figure A) in pts with 1 (63% vs 40%; Fisher's P = 0.040), 2 (70% vs 27%; Fisher's P < 0.001), and 3 (72% vs 40%; Fisher's P = 0.018) gene mutations. However, in the RS− subgroup, luspatercept and ESAs had similar response rates independent of MB. Interestingly, more RS− pts in the luspatercept arm had ≥ 4 gene mutations (12/47 pts [26%]) versus the ESA arm (only 3 pts [6.4%]). Furthermore, these ≥ 4 mutations were in genes associated with shorter leukemia-free survival, overall survival, and progression-free survival. Of the RS− pts in the luspatercept arm, 9/12 were NR, compared to 2/3 in the ESA arm. Luspatercept showed superior clinical benefit in pts with difficult-to-treat mutations (such as ASXL1, TET2 DNMT3A ZRSR2) and favorability in pts with mutations in SRSF2 EZH2, TP53, DTA.SF3B1.n and IDH2. Primary endpoint analysis by IPSS-M (Figure B) also showed superior clinical benefit of luspatercept across risk groups compared with ESAs: Low (75% vs 38%); Moderate low (61% vs 38%); Moderate high (44% vs 21%); and High (36% vs 24%). Conclusion: In pts in the COMMANDS trial,BL MB impacted response to ESAs but not to luspatercept. In both ITT and RS+ pts, luspatercept showed either superior or comparable clinical benefit in pts with LR-MDS with various BL MB. Interestingly, both luspatercept and ESAs had similar clinical benefit across various MB in the RS− subgroup. However, lower MB favored higher responses to ESAs in the RS− subgroup, and higher MB in genes associated with poor prognosis significantly impacted response rates in the luspatercept arm. Despite the presence of these imbalances in BL MB, RS− pts had similar response rates to luspatercept as to ESAs. Pts with LR-MDS with difficult-to-treat mutations also showed superior or favorable clinical benefit with luspatercept. Finally, luspatercept showed superior clinical benefit to ESAs in pts with LR-MDS across all IPSS-M risk groups.

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

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

Long-Term Evaluation of Luspatercept in Erythropoiesis-Stimulating Agent (ESA)-Intolerant/Refractory Patients (pts) with Lower-Risk Myelodysplastic Syndromes (LR-MDS) in the Phase 3 MEDALIST Study

Background: Pts with LR-MDS receiving luspatercept in the phase 3 MEDALIST trial previously reported durable, long-term red blood cell (RBC) transfusion independence (RBC-TI) (Fenaux P, et al. J Clin Oncol 2022;40[suppl 16]. Abstract 7056). MEDALIST pts were eligible to enroll in a follow-up study to evaluate long-term efficacy and safety. Aims: To report long-term efficacy and safety outcomes in ESA-refractory/intolerant pts with LR-MDS treated with luspatercept in the MEDALIST trial with an additional 26 mo of follow-up from the final MEDALIST data cutoff. Methods: Eligible pts were ≥ 18 y of age; IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with ring sideroblasts; were refractory, intolerant, or unlikely to respond to ESAs, and required regular RBC transfusions. Pts were randomized 2:1 to luspatercept (starting dose 1.0 mg/kg, with titration up to 1.75 mg/kg) or placebo. Efficacy outcomes include RBC-TI ≥ 8 wk and ≥ 16 wk. Cumulative duration of response was determined by Kaplan-Meier (KM) analysis. Rates of longest single and cumulative duration of RBC-TI ≥ 1 y and exposure-adjusted incidence rates (EAIR) of treatment-emergent adverse events (TEAEs) and AEs of special interest (AESIs) were calculated. Rates of high-risk (HR)-MDS and acute myeloid leukemia (AML) progression were calculated from LR-MDS diagnosis to HR-MDS/AML diagnosis, or to last HR-MDS/AML follow-up date for pts who did not progress. Results: As of January 2, 2023, 11 pts remained on luspatercept treatment; 8 pts randomized to luspatercept and none from placebo continued in post-treatment follow-up. The median (range) follow-up time was 39.9 (2.8-76.0) mo for luspatercept arm pts and 38.7 (1.7-68.6) mo for placebo arm pts. The median (range) duration of treatment was 50.9 (5.9-332.9) wk for luspatercept pts and 24.0 (9.0-103.0) wk for placebo pts. Seventy-five of 153 (49.0%) luspatercept pts achieved RBC-TI ≥ 8 wk during the entire treatment period and 53/75 (70.7%) had ≥ 2 response periods with a median cumulative duration of 110.14 wk (95% confidence interval [CI], 53.71-154.14; Figure A). Overall, 31/75 (41.3%) luspatercept pts had the longest RBC-TI duration ≥ 1 y, and 44/75 (58.7%) had a cumulative RBC-TI duration ≥ 1 y. In total, of the 48/153 (31.4%) pts receiving luspatercept who achieved RBC-TI ≥ 16 wk during the entire treatment period, 32/48 (66.7%) had ≥ 2 response periods with a median cumulative duration of 129.29 wk (95% CI, 79.86-240.43). Grade 3/4 treatment-related TEAEs were reported in 14/153 (9.2%; EAIR, 5.3 per 100 pt-y [PYs]) and 3/76 (3.9%; EAIR, 6.6 per 100 PYs) luspatercept and placebo pts, respectively; TEAEs of any grade leading to permanent treatment discontinuation were reported in 24/153 (15.7%; EAIR, 8.6 per 100 PYs) luspatercept and 6/76 placebo pts (7.9%; EAIR, 13.0 per 100 PYs). The most common TEAEs of any grade reported in > 5% of luspatercept pts were fatigue (47/153 [30.7%]; EAIR, 22.1 per 100 PYs; vs placebo, 11/76 [14.5%]; EAIR, 27.1 per 100 PYs), diarrhea (47/153 [30.7%]; EAIR, 23.5 per 100 PYs; vs placebo, 8/76 [10.5%]; EAIR, 18.4 per 100 PYs), asthenia (41/153 [26.8%]; EAIR, 18.8 per 100 PYs; vs placebo, 9/76 [11.8%]; EAIR, 21.5 per 100 PYs), peripheral edema (40/153 [26.1%], EAIR, 17.6 per 100 PYs; vs placebo, 13/76 [17.1%]; EAIR, 32.0 per 100 PYs), and back pain (38/154 [24.7%]; EAIR, 16.8 per 100 PYs; vs placebo, 5/76 [6.6%]; EAIR, 11.7 per 100 PYs; Figure B). During the entire treatment period, 26/44 (59.1%), 9/23 (39.1%), and 12/86 (14.0%) pts who received ≤ 1 mg/kg, 1.33 mg/kg, and 1.75 mg/kg luspatercept, respectively, reported fatigue of any grade. No new progression to HR-MDS or AML events have been reported since the last data cutoff (Santini V et al. Blood 2022;140[suppl 1]:4079-4081). Conclusions: Pts with LR-MDS who received luspatercept for > 2 years longer than in the original MEDALIST study, continued to experience sustained periods of RBC-TI with more than half of pts experiencing cumulative RBC-TI for ≥ 1 year. The long-term safety profile of luspatercept is consistent with previous shorter-term reports, and AEs were mostly lower grade with rates of fatigue decreasing with increasing luspatercept dose. These data demonstrate the long-term efficacy and safety of luspatercept in pts with LR-MDS intolerant/ineligible for ESA treatment.

Evaluation of a prophylactic transfusion program on obstetric outcomes in pregnant women with sickle cell disease: A single centre retrospective cohort study

ObjectiveTo evaluate the effects of a prophylactic transfusion program (TP) on obstetric and perinatal outcomes in pregnant women with sickle cell disease (SCD). MethodsThis retrospective cohort study included all singleton pregnancies among women with SCD in a French university tertiary care center between 1 January 2004 and 31 December 2017. The TP group included patients selected according to the French guidelines who received regular red blood cell transfusions during pregnancy until delivery. The factors associated with TP indication [year of birth, SCD genotype, history of acute chest syndrome and delayed hemolysis transfusion reaction (DHTR) risk score] were taken into account in a propensity score. A composite obstetric adverse outcome was defined associating birth before 34 gestational weeks and/or pre-eclampsia and/or small for gestational age and/or abruption and/or stillbirth and/or maternal death and/or neonatal death. ResultsIn total, 246 pregnancies in 173 patients were analyzed. Twenty-two pregnancies with a history of DHTR were excluded. A higher frequency of TP was found before 2013 [119/148 (80.4%) vs 38/76 (50%); p < 0.001]. Rates of preterm birth before 34 gestational weeks (5.6% vs 19.7%; p = 0.001), vaso-occlusive crisis (36.5% vs. 61.8%; p < 0.001), and acute chest syndrome (6.1% vs. 14.5%; p = 0.04) during pregnancy were decreased significantly in the TP group. Among the groups with and without composite obstetric adverse outcomes, the frequency of TP was 52.6% and 74.7%, respectively [odds ratio (OR) 0.30, 95% confidence interval (CI) 0.09–1.02]. The multivariate analysis shows that the TP was associated with a significant reduction in the risk of composite obstetric adverse outcomes (OR 0.28, 95% CI 0.08–0.97; p = 0.04). ConclusionA red blood cell TP may have an independent protective effect on maternal and perinatal adverse outcomes during pregnancy in women with SCD.

EE287 Healthcare Resource Utilization Among Patients with Transfusion-Dependent Beta-Thalassemia in England

Patients with transfusion-dependent β-thalassemia (TDT) have reduced or absent β-globin production and require regular red blood cell transfusions (RBCTs) for survival. This study aimed to describe the healthcare resource utilization (HCRU) associated with TDT in England.

EE58 Healthcare Resource Utilization Among Patients with Transfusion-Dependent Beta-Thalassemia in Italy

Patients with transfusion-dependent β-thalassemia (TDT) require regular red blood cell transfusions (RBCTs) for survival. This study sought to understand the healthcare resource utilization (HCRU) among patients with TDT in Italy.

Management of luspatercept therapy in patients with transfusion-dependent β-thalassaemia.

Patients with transfusion-dependent β-thalassaemia require lifelong, regular red blood cell transfusions for survival; however, frequent blood transfusions are associated with an increased risk of iron overload, transfusion-transmitted disease and alloimmunization, as well as reduced quality of life. Luspatercept, an erythroid maturation agent that promotes late-stage erythroid maturation independently of erythropoietin, has demonstrated efficacy in reducing transfusion burden in patients with transfusion-dependent β-thalassaemia. In this review, we discuss treatment initiation, ongoing evaluation, dose adjustment and management of adverse events in transfusion-dependent patients with β-thalassaemia receiving luspatercept, and we provide guidance on how to determine whether patients are deriving clinical benefit.

Defining Pathological Iron Status in Children with Thalassemia

The purpose of this review is to summarize the recent knowledge that has been gathered, allowing a better understanding of iron status in children with thalassemia. Children with thalassemia major typically have severe anemia during the first two stages of life and receive regular red blood cell (RBC) transfusions. The results show that individuals with thalassemia major who are overtly or inadequately transfused have significant body changes that affect physical growth retardation, hostility, weak musculature, leg muscle fitness, extramedullary development of hematopoiesis, and bone expansion, as seen in some developing countries. Cases of thalassemia intermedia occur late and have mild anemia, and cannot tolerate regular blood transfusions. Treatment for thalassemia major includes regular red blood cell transfusions, iron chelating drugs, and bone marrow surgery. In addition, spleen scanning may be necessary in some cases. Also, a bone marrow transplant is the only definitive treatment currently available. The prognosis for patients with beta-thalassemia has improved most over the past 25 years, mostly due to recent medical advances in blood transfusions, iron-chelating drugs, and bone marrow transplants. However, heart disease (heart disease) has been found to remain the leading cause of death in iron-related cases.

Effect of Luspatercept on Red Blood Cell (RBC) Transfusion Burden, Iron Chelation Therapy (ICT), and Iron Overload in Adults with Transfusion-Dependent β-Thalassemia (TDT) from the BELIEVE Trial: A Long-Term Analysis

Effect of Luspatercept on Red Blood Cell (RBC) Transfusion Burden, Iron Chelation Therapy (ICT), and Iron Overload in Adults with Transfusion-Dependent β-Thalassemia (TDT) from the BELIEVE Trial: A Long-Term Analysis

Clinical and Economic Outcomes in Patients with Transfusion-Dependent β-Thalassemia and Patients with Sickle Cell Disease with Recurrent Vaso-Occlusive Crises Receiving Hematopoietic Stem Cell Transplants in the United States

Background: Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are inherited blood disorders caused by mutations in the β-globin gene, resulting in abnormal, reduced, or absent expression of hemoglobin. TDT is characterized by ineffective red blood cell production that leads to chronic anemia, need for regular red blood cell transfusions (RBCTs), and organ complications. SCD is characterized by sickle-shaped red blood cells that cause vaso-occlusive crises (VOCs), hemolysis, and end-organ damage. Hematopoietic stem cell transplant (HSCT) is currently the only curative option for patients with TDT and patients with SCD. There is limited research on the frequency and outcomes of HSCT in these two patient populations. This study describes the economic and clinical outcomes for a combined population of patients with TDT and patients with SCD with recurrent VOCs who received HSCTs in the United States. Methods: This retrospective cohort study used administrative claims from the MerativeTM Commercial, Medicare, and Multi-State Medicaid Databases to identify patients with ≥1 inpatient or ≥2 outpatient claims for β-thalassemia or SCD between March 1, 2010, and March 1, 2019. Eligible patients with TDT were required to have ≥8 discrete RBCTs in any 12-month period on or after the date of the earliest qualifying β-thalassemia claim. At least 3 days between service dates of RBCT claims were required to be considered discrete RBCTs. Patients with TDT were required to have 1 year of continuous enrollment after their first transfusion to be included. Eligible patients with SCD with recurrent VOCs were required to have ≥2 diagnosed VOCs per year in any 2 consecutive years after and including the first qualifying SCD claim. A VOC was defined as inpatient or outpatient claim of acute chest syndrome, priapism, SCD crisis, or splenic sequestration; at least 3 days between VOC claims were required to be considered discrete VOCs. Eligible patients with SCD with recurrent VOCs were required to have 24 months of continuous enrollment before the second VOC in the second consecutive year and 12 months of continuous enrollment after. Patients with TDT and patients with SCD who met the above criteria and received an HSCT were included in the analysis set. Patients receiving HSCT were identified utilizing relevant procedure codes. The index date was the date of transplant. Patients were followed from the index date to the earliest of end of enrollment, death, or end of study period (March 1, 2020). Demographics were assessed at the index date, and clinical complications, healthcare resource utilization, and costs were descriptively summarized in the post-index period. Costs were based on paid amounts of adjudicated claims and patient cost-sharing and included costs in the 10 days before the index date to account for pre-transplant healthcare services associated with the transplant. Results: Two hundred thirty-four and 3500 patients met the criteria for TDT and SCD with recurrent VOCs, respectively, for a total of 3734 patients. Of that total, 62 patients (1.66%) underwent a transplant and were therefore included in the analysis cohort. Mean patient age at the index date was 12.6 years, and 46.8% were female. A proportion of transplant patients experienced graft versus host disease (GvHD) (37/62; 59.7%), unspecified HSCT complications (33/62; 53.2%), or bone marrow transplant rejection or failure (6/62; 9.7%) post-transplant. Average length of stay for the index HSCT admission was 42 days; in the first year post-transplant, patients averaged 58.3 days in the hospital. Total costs in the first 100 days and 1 year post-transplant were $442,752 and $623,301, respectively. Inpatient costs accounted for 93.7% and 88.7% of costs at 100 days and 1 year, respectively. Conclusions: This retrospective cohort study suggests that only a small proportion of patients with TDT and patients with SCD with recurrent VOCs receive HSCTs. Many patients who undergo transplants experience clinical complications, including graft failure and GvHD, and substantial economic burden. Given the limited utilization and potential safety risks of HSCT, additional curative treatment approaches are needed for patients with TDT and patients with SCD with recurrent VOCs.

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

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

Luspatercept, a two-edged sword in beta-thalassemia-associated paravertebral extramedullary hematopoietic masses (EHMs).

Paravertebral extramedullary hematopoietic masses (EHMs) account for up to 15% of extramedullary pseudotumors in beta-thalassemia (BT) and are most likely related to compensatory hematopoiesis. In most cases, pseudotumors are incidentally detected, as the majority of patients are asymptomatic. Since June 2020, luspatercept is approved for the treatment of patients with BT who require regular red blood cell transfusions. Data addressing the safety and efficacy of luspatercept in patients with BT-associated EHMs are pending. To date (May 2022), paravertebral EHMs were observed in two asymptomatic patients out of currently 43 adult patients with BT registered at the Adult Hemoglobinopathy Outpatient Unit of the University Hospital Essen, Germany. In one of them, a paravertebral EHM was diagnosed more than 10 years prior to referral. Throughout observation time, treatment with luspatercept was associated with a clinically significant reduction in transfusion burden while allowing to maintain a baseline hemoglobin concentration of ≥10 g/dL aiming to suppress endogenous (ineffective) erythropoiesis associated with BT. Considering the rarity of paravertebral EHMs in BT, luspatercept might potentially represent a novel therapeutic option for these often-serious disease-associated complications. However, appropriate follow-up investigations are recommended to detect (early) treatment failures secondary to an undesired luspatercept-associated erythroid expansion.

Long-term utilization and benefit of luspatercept in patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) from the MEDALIST trial.

7056 Background: Luspatercept was previously shown to improve anemia in the phase 3 MEDALIST trial of pts with LR-MDS ineligible, intolerant, or refractory to erythropoiesis-stimulating agents (ESAs). Here, we report the long-term clinical value of luspatercept treatment (Tx) in pts from the MEDALIST study including dosing and rates of progression to acute myeloid leukemia (AML) and high-risk MDS (HR-MDS). Methods: Eligible pts were ≥ 18 y of age, had LR-MDS requiring regular red blood cell (RBC) transfusions, and were ineligible/intolerant or refractory to ESAs. Pts were randomized 2:1 to subcutaneous luspatercept or placebo every 3 wk for 24 wk. The primary endpoint was RBC transfusion independence (RBC-TI) ≥ 8 wk during wk 1–24. MEDALIST pts were eligible for enrollment into the long-term follow-up study. Median duration of Tx and cumulative duration of response were determined by Kaplan–Meier (KM) analysis. Total person-years for pts at risk of HR-MDS/AML progression was calculated from LR-MDS diagnosis to HR-MDS/AML diagnosis, or to last HR-MDS/AML follow-up date for pts who did not progress. Results: As of January 15, 2021, the median duration of Tx was 11.70 (95% CI, 8.97–16.33) mo for luspatercept pts and 5.52 (95% CI, 5.52–5.59) mo for placebo pts. Of those enrolled in MEDALIST, 106/153 (69.3%) pts receiving luspatercept and 64/76 (84.2%) receiving placebo escalated to the maximum dose of 1.75 mg/kg. During the entire Tx phase, RBC-TI ≥ 8 wk was observed in 74/153 (48.4%) and 12/76 (15.8%) pts in the luspatercept and placebo arms, respectively, with a median cumulative duration of response of 80.7 (95% CI, 53.71–154.14) wk and 21.0 (95% CI, 10.86–NE) wk, respectively. During the entire Tx period, RBC-TI ≥ 16 wk was observed in 48/153 (31.4%) and 6/76 (7.9%) pts in the luspatercept and placebo arms, respectively (Table). Among pts randomized to luspatercept, 13/153 (8.5%) progressed to HR-MDS/AML during the entire Tx period, compared with 5/76 (6.6%) for placebo. The total person-years for pts randomized to luspatercept at risk of progressing to HR-MDS/AML was 401.7 y vs 190.9 y for placebo. Conclusions: Pts receiving luspatercept had an extended period of clinical benefit and &gt; 50% of pts continued to receive luspatercept for &gt; 1 y, the majority of whom underwent dose escalations to achieve an optimal response. Pts experienced durable responses with luspatercept, with a median cumulative duration of RBC-TI response of approximately 20 mo. Pts receiving luspatercept also appeared to have a longer time to HR-MDS/AML progression than those receiving placebo.[Table: see text]

S123: SAFETY AND EFFICACY OF EARLY-START DEFERIPRONE IN INFANTS AND YOUNG CHILDREN WITH BETA-THALASSEMIA (START STUDY)

Background: Patients with beta-thalassemia may need regular red blood cell transfusions in infancy.1 In the absence of iron chelation therapy, frequent transfusions cause iron to accumulate, which can lead to morbidity, organ damage, and death. However, in very young children, current practice is to delay chelation therapy until receipt of 10–20 transfusions, or until serum ferritin (SF) has reached 1000 μg/L, due to concerns over excessive iron depletion with deferoxamine.1,2 Unfortunately, this delay may increase the risk of iron accumulation in endocrine glands where toxicities could later manifest.3 Aims: START (NCT03591575) evaluated the safety and efficacy of the oral iron chelator deferiprone (DFP) in children with transfusion-dependent beta-thalassemia who did not yet meet the criteria for starting chelation therapy per standard practice. Methods: Infants and children receiving regular blood transfusions (2 minimum) and whose SF level was between 200–600 μg/L were randomly assigned 1:1 to DFP oral solution or placebo until SF exceeded 1000 μg/L at 2 consecutive visits or 12 months of therapy. DFP was initiated at 25 mg/kg/d and increased to 50 mg/kg/d after 2 weeks; based on iron load, DFP was increased to 75 mg/kg/d. Efficacy was assessed by monthly SF measurements to monitor iron load. The primary endpoint was the percentage of patients in each group with SF <1000 μg/L. All patients provided informed consent or assent. Results: The study enrolled 64 patients; 32 per group. The mean (SD) age was 3.03 (2.42) years in the DFP group and 2.63 (1.70) years in the placebo group; participants were 62.5% and 65.6% male in the DFP and placebo groups, respectively. There were no group statistical differences in the baseline demographics. The primary reason for withdrawal was SF levels that exceeded 1000 μg/L at 2 consecutive visits, which occurred in 25% of patients receiving DFP vs 63% of patients receiving placebo (P=0.0051). After completing 12 months of treatment, 65.6% of patients receiving DFP had a SF level <1000 mg/L vs 37.5% receiving placebo (P=0.0446). The percentage of patients who reached the 1000 mg/L SF threshold increased more rapidly in the placebo group vs the DFP group, and the difference in rates between the 2 groups was significant (P=0.0407). A summary of adverse events (AEs) is shown in Table 1. There were no significant group differences in the number of overall AEs (P=1.0000), serious AEs (P=0.4258), or the number of AEs that were considered to be at least possibly related to the study treatment (P=1.0000). Two patients receiving DFP withdrew from the study due to AEs: 1 patient experienced agranulocytosis and 1 patient experienced neutropenia of moderate severity and both patients recovered. Conclusions: Initiation of DFP chelation therapy at a lower threshold of SF values than currently recommended was safe and efficacious in preventing iron overload in most transfusion-dependent children. After 12 months of treatment, the number of patients with a SF level <1000 μg/L was significantly higher in the DFP group vs the placebo group. Moreover, there were significantly more patients who withdrew due to elevated SF levels in the placebo group (62.5%) vs the DFP group (25%). The safety and tolerability profile of DFP administered for up to 12 months in infants and young children was comparable to the profile established in older age groups and there were no instances of iron depletion.

Clinical, Cytogenetic, and Molecular Characteristics Analysis in Myelodysplastic Syndromes with Elevated Ferritin Levels

IntroductionMyelodysplastic syndromes (MDS), a heterogeneous group of acquired clonal hematopoietic stem cell disorders, is characterized by peripheral cytopenia and has a high tendency to progress to acute myeloid leukemia (AML). Serum ferritin (SF) level is a well-known indicator of iron stores and inflammation. Elevated SF levels is common in patients with MDS and appear to be largely related to regular red blood cell (RBC) transfusions. However, some patients with MDS showed high SF levels at the time of diagnosis, even before receiving RBC transfusions, although the exact mechanisms is unclear. The impact of SF elevation without RBC transfusion has not been well characterized. In this study, we assessed cytogenetic, molecular, and clinical characteristics of patients with MDS and SF elevation.MethodsPatients with newly diagnosed MDS who visited our hospital between Jan 2011 and Jan 2020 were included in this study. Patients were defined as high-SF-MDS when SF values were >350 ng/mL (patients with <350 ng/mL were defined as low-SF-MDS). Patients with autoimmune diseases, active infections, hemophagocytic syndromes, and RBC transfusion were excluded. Baseline characteristics were compared using Fisher's exact test for categorical variables and the Mann-Whitney test for continuous variables. The log-rank test was used for the overall survival (OS) analysis. The cumulative incidence of AML progression was estimated and compared using Gray's method. In next-generation sequencing (NGS) analysis, 68 genes associated with myeloid malignancy were analyzed using DNA extracted from bone marrow samples.ResultsAmong the 112 patients with MDS, SF value were available for 87 patients. This study analyzed 28 women and 59 men with a median age of 69 years (range: 28-87 years). The median follow-up period was 540 days (range: 3-3618 days). A total of 17 patients died during the observational period (until Apr 2021). Patients were diagnosed with MDS with single lineage dysplasia (MDS-SLD, n = 9), MDS with multilineage dysplasia (MDS-MLD, n = 26), MDS with ring sideroblasts with SLD (MDS-RS-SLD, n = 5), MDS-RS-MLD (n = 6), MDS with excess blasts 1 (MDS-EB1, n = 25), MDS-EB2 (n = 13), MDS with isolated del(5q) (n=1), and MDS, unclassifiable (MDS-U, n = 2). The median SF value was 263 ng/mL (range: 3-1,245 ng/mL); 31 patients were classified as high-SF-MDS and 56 were classified as low-SF-MDS. The Proportion of MDS subtypes differed significantly between the groups (P=0.004, Table1). Compared to low-SF-MDS, MDS-EB1/2 (51.6% vs. 39.3%) and MDS-RS-SLD/MLD (22.6% vs. 1.8%) was more common in high-SF-MDS. In the laboratory data analysis, high-SF-MDS patients showed low Hb levels, high RBC distribution width values, and high bone marrow RS percentages. In patients with high-SF-MDS, as well as MDS-RS, the presence of bone marrow RS was also observed in seven out of 11 patients with MDS-EB1/2 (median 8%, range 2-19%). Complex karyotype ( was more common in patients with high-SF-MDS (46.4% vs. 16.0%, P=0.007) than those with low-SF-MDS. Trisomy 8 and del (5q) were also frequently detected among those with high-SF-MDS. Patients with high-SF-MDS had worse 2-year overall survival (OS) than those with low-SF-MDS. To clarify the molecular characteristics of high-SF-MDS in more detail, NGS analysis was performed on 11 patients with high-SF-MDS whose samples were available. Ten gene mutations were detected in eight patients. Interestingly, five among 11 patients harbored TP53 mutation; the median variant allele frequency was 53.9% (range, 39.7-64.1%). Subsequently, SF3B1 gene mutation was detected in three patients; and two of them also harbored TP53 mutation. Other gene mutations, RUNX1, STAG2, SRSF2, ASXL1, ATM, DNMT3A, BCOR, and DDX41 were detected in one patient each. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Safety and Efficacy of Early-Start Deferiprone in Infants and Young Children with Beta-Thalassemia (START study)

▪Background: Patients with beta-thalassemia may need to start receiving regular red blood cell transfusions as early as infancy. In the absence of iron chelation therapy, frequent transfusions cause iron to accumulate in the body, which can lead to morbidity, organ damage, and death. However, in very young children, current practice is to delay chelation therapy until receipt of 10-20 transfusions, or until the patient's serum ferritin (SF) level has reached 1000 μg/L, due to concerns over excessive iron depletion observed with the parenteral iron chelator deferoxamine. Unfortunately, this delay may increase the risk of iron accumulation in endocrine glands such as the pancreas, pituitary, and thyroid, where toxicities could manifest later in life. The START study (NCT03591575) evaluated the safety and efficacy of the oral iron chelator deferiprone (DFP) in children with transfusion-dependent beta-thalassemia who did not yet meet the criteria for starting chelation therapy as per standard practice.Methods: Infants and children who had started on a regular blood transfusion regimen, received a minimum of 2 transfusions, and whose SF level was between 200 and 600 μg/L were randomly assigned 1:1 to receive either (DFP) oral solution or a matching volume of placebo until their SF levels exceeded 1000 μg/L at 2 consecutive visits or they completed 12 months of therapy, whichever occurred first. The dosage of DFP was initiated at 25 mg/kg/day and increased to 50 mg/kg/day after 2 weeks; based on iron load, the dosage was then increased to 75 mg/kg/day for some patients. All adverse events (AEs) were reported and assessed for causality. Efficacy was assessed by monthly SF measurements to monitor iron load, with the primary efficacy endpoint being the percentage of patients in each group whose SF was still below the 1000 μg/L threshold. Once withdrawn, the patients were to receive standard chelation therapy, as recommended by their primary care physician.Results: The study enrolled 64 patients; 32 in each group. The mean (SD) age was 3.03 (2.42) years in the DFP group and 2.63 (1.70) years in the placebo group; the participants were 62.5% and 65.6% male in the DFP and placebo groups, respectively. There were no statistical group differences in the baseline demographics. The primary reason for withdrawal was SF levels that exceeded 1000 μg/L at 2 consecutive visits, which occurred in 25% of patients receiving DFP compared with 63% of patients receiving placebo (P=0.0051). After completing 12 months of treatment, 65.6% of patients receiving DFP had a SF level <1000 mg/L compared with 37.5% receiving placebo (P=0.0446). The percentage of patients who reached the 1000 mg/L SF threshold increased more rapidly in the placebo group compared with the DFP group, and the difference in rates between the 2 groups was significant (P=0.0407). A summary of adverse events (AEs) is shown in Table 1. There were no significant group differences in the number of overall AEs (P=1.0000), serious AEs (P=0.4258), or the number of AEs that were considered to be at least possibly related to the study treatment (P=1.0000). Two patients receiving DFP withdrew from the study due to AEs: 1 patient experienced agranulocytosis and 1 patient experienced neutropenia of moderate severity and both patients recovered.Conclusions:Initiation of DFP chelation therapy at a lower threshold of SF values than currently recommended was safe and efficacious in preventing iron overload in most transfusion-dependent children. After 12 months of treatment, the number of patients below the SF threshold was significantly higher in the DFP group compared with the placebo group. Moreover, there was a significant difference in the number of patients who withdrew due to elevated SF levels in the placebo group (62.5%) compared with the DFP group (25%). The safety and tolerability profile of DFP administered for up to 12 months in infants and young children was comparable to the profile established in older age groups and there were no instances of iron depletion.Disclosures:This study was sponsored by Chiesi Global Rare Diseases, and medical writing support was provided by Kelsey Hodge-Hanson, PhD, of Oxford PharmaGenesis Inc., Newtown, PA, and funded by Chiesi. [Display omitted] DisclosuresFradette: Chiesi Canada Corp: Current Employment. Lee: Chiesi Canada Corp: Current Employment. Temin: Chiesi Canada Corp: Current Employment. Tricta: Chiesi Canada Corp: Current Employment. Rozova: Chiesi Canada Corp: Current Employment. Hamdy: Novartis: Honoraria; Roche: Honoraria; NovoNordisk: Honoraria; Bayer: Honoraria; Takeda: Honoraria; Amgen: Honoraria; ApoPharma: Honoraria.

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

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

A Systematic Review and Meta-Analysis of the Effect of Iron Chelation Therapy on Survival in Patients with Lower Risk Myelodysplastic Syndrome

Background: Anemia is the most common cytopenia among patients with myelodysplastic syndromes (MDS) often necessitating regular red blood cell (RBC) transfusions. As a result, most patients develop iron overload (IO). RBC transfusion dependency and IO have been associated with worse clinical outcomes, including inferior overall survival (OS), in MDS patients. While iron chelation therapy (ICT) is recommended by most clinical guidelines and experts for select MDS patients, the use of ICT remains controversial in the absence of published, randomized controlled trials. To evaluate the impact of ICT on survival among lower risk MDS patients, we performed a systematic review and meta-analysis (SRMA) of the literature.Methods: We conducted an SRMA according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines. PubMed and Embase electronic databases were searched through October 2016 with search terms “MDS” OR “myelodysplastic syndrome” AND “iron chelation” OR “iron chelating” OR “iron overload” AND “survival” OR “death” AND “study” OR “trial.” Additionally, the Cochrane Library, the World Health Organization (WHO) International Clinical Trials Registry, and abstracts from recent American Society of Hematology annual meetings (years 2014-2016) were searched. One study, published in 2014, had an updated analysis in 2017 that was used for the current analysis. Information abstracted included data relating to study and patient characteristics, outcome measures (mortality and progression to acute myeloid leukemia [AML]), and measures of effect (calculated odds, hazard ratios [HRs], and confounding variables for adjustment). A Random Effects model was used to compute an adjusted HR (aHR) among the different studies. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of studies. Study heterogeneity was assessed using the Cochran Q and the I2 statistic. Publication bias was assessed through visual examination of a funnel plot and with the Egger's test for small-study effects.Results: Of the 331 records screened, 23 were assessed for eligibility, and 9 were included (Figure 1). Of these 9 studies, 6 were considered to be of high quality based on the NOS. All 9 were observational studies (4 prospective and 5 retrospective); 8 were identified as including patients with the International Prognostic Scoring System (IPSS)-defined low and intermediate-1 risk MDS. In these 8 studies, ICT was associated with an overall lower risk of mortality (aHR 0.43; 95% confidence interval [CI] 0.30-0.60; p < 0.01) (Figure 2). The pooled estimate of the ratio of median unadjusted survival times was 2.02 (95% CI 1.64-2.49), indicating that the median OS for patients receiving ICT was approximately twice that for patients who did not receive ICT. There was evidence of significant heterogeneity across studies for this outcome measure with I2 = 64% and Cochran's Q statistic = 19.8 (p = 0.006). Although the direction of effects did not change, heterogeneity was significant in prospective studies (I2 = 73%; Cochran's Q statistic = 7.4, p = 0.02), but not in retrospective studies (I2 = 9.8%; Cochran's Q statistic = 4.4, p = 0.35). In the 2 studies that reported on benefits of adequate chelation, any degree of chelation was found to confer a survival benefit, but this was to a lesser degree than the survival benefit accrued by those who received higher adequate doses. ICT seemed to decrease the risk of progression to AML (odds ratio 0.526; 95% CI 0.37-0.74; p < 0.001) in the studies that reported on this outcome (Figure 3); these studies displayed no significant heterogeneity. The impact of ICT on end organ damage could not be assessed due to non-uniform reporting of studies.Conclusions: This SRMA suggests a significant reduction in the adjusted risk of mortality among IPSS low and intermediate-1 risk MDS patients treated with ICT. Furthermore, our analysis suggests that ICT is associated with delayed progression to AML, although the causality of these associations cannot be established based on this study. Randomized controlled studies are needed to confirm these findings. [Display omitted] DisclosuresBallas:Novartis: Honoraria, Speakers Bureau. Zeidan:AbbVie, Otsuka, Pfizer, Gilead, Celgene, Ariad, Incyte: Consultancy, Honoraria; Takeda: Speakers Bureau; Otsuka: Consultancy.