Low Transfusion Burden Research Articles

Experience with luspatercept therapy in patients with transfusion-dependent low-risk myelodysplastic syndromes in real-world clinical practice: exploring the positive effect of combination with erythropoietin alfa.

Luspatercept, an inhibitor of the transforming growth factor beta (TGF-β) pathway, is a novel treatment for anemic patients with lower-risk myelodysplastic syndromes (MDS) with transfusion dependence (TD) who do not respond to erythropoiesis-stimulating agents (ESA) therapy or are not suitable candidates for this treatment. We present real-world experience with luspatercept therapy from two hematology centers in the Czech Republic. By January 2024, 54 MDS patients (33 men, 21 women) with a median age of 74 years (range, 55-95) were treated with luspatercept ± ESA at two Charles University hematology centers in Prague and Hradec Králové. According to the WHO 2016 classification, the cohort included 32 MDS-RS-MLD, seven MDS-MLD, two patients with 5q- + ring sideroblasts (RS), 12 RARS-T, and 1 patient with CMML-0 + RS. SF3B1 mutation data were available for 45 patients. All patients were in the IPSS-R and IPSS-M lower-risk groups (except four IPSS-M high). The median follow-up was 17 months (range, 1-54). All patients were transfusion-dependent. Thirty-five (64.8%) patients had a high transfusion burden (HTB) with ≥ 4 transfusion units (TU)/8 weeks, and 19 (35.2%) had a low transfusion burden (LTB) (< 4 TU/8 weeks). The median time between diagnosis and initiation of luspatercept was 27 months (range, 4-156). ESA were used prior to luspatercept in 45 patients, and luspatercept was used as first-line treatment in nine patients. Thirty-one (61%) patients were treated simultaneously with ESA. Only patients who received luspatercept for ≥ 8 weeks (51 patients) were assessed. We evaluated the achievement of transfusion independence (TI) lasting 8, 12, 16, and 24 weeks. Thirty-two (62.7%) patients achieved TI for ≥ 8 weeks, 31 (60.7%) for ≥ 12 weeks, 29 (56.8%) for ≥ 16 weeks, and 25 (49%) for ≥ 24 weeks. Hematologic improvement (HI) without TI was achieved in six patients (11.7%). Overall, HI + TI was achieved in 38 patients (74.5%). Epoetin alfa was used simultaneously in 31 patients (60.7%). In 21 (55.2%) of all responding patients, concomitant therapy with epoetin alfa led to an improved response, with 16 reaching TI. Thirteen (25.5%) patients were nonresponders. Eight (21%) patients experienced therapy failure and became transfusion-dependent again. Optimal response required a gradual increase in the luspatercept dose to 1.75 mg/kg in up to 35 patients, with 23 responders (TI + HI). Response rates varied by transfusion burden: 79% in LTB and 50% in HTB reached TI. Of RS+ patients, 70% reached TI, while only one out of five RS- patients achieved TI. Among 39 SF3B1-positive patients, 61.6% achieved TI. In the low and very low IPSS-M groups, 86% of patients responded (TI + HI), compared to 62% in the moderate-low group. Luspatercept was well-tolerated, with no adverse events higher than grade II toxicity. We have demonstrated in real-world clinical practice that luspatercept is a very effective agent, even in an unselected, pretreated, significantly TD MDS population. The effect was particularly high in the IPSS-M low and very low groups. We believe that the relatively high response rate in our patients was influenced by the frequent use of a higher dose (1.75 mg/kg) and especially by adding ESA to luspatercept in poorly responding patients.

Transfusion independence after lenalidomide discontinuation in patients with del(5q) myelodysplastic neoplasm: a HARMONY Alliance study.

Lenalidomide (LEN) can induce red blood cell-transfusion independence (RBC-TI) in 60-70% of del(5q) myelodysplastic neoplasm (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN while RBC-transfusion independent. We enrolled 118 patients with IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis, RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment ≥ 12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved again RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients who reached RBC-TI allows prolonged maintenance of TI in a large subset of patients.

Improved Overall Survival Among Luspatercept Responders and Predictors of Response

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

Real-World Retrospective Study of Non-Transfusion Dependent Patients with Myelodysplastic Syndromes Treated with Luspatercept: A Healthcare Claims Database Study

Background: Myelodysplastic syndromes (MDS) are common hematologic malignancies in older adults that are characterized by abnormal bone marrow function leading to reduced blood cell production, persistent cytopenias, with a risk that patients may progress to acute myeloid leukemia (AML). Due to the high rate of anemia, many patients with MDS require red blood cell transfusions (RBCT), which, in turn, are associated with a high clinical and economic burden. In the phase 3 randomized COMMANDS and MEDALIST clinical trials, luspatercept reduced the severity of anemia among transfusion-dependent (TD), erythropoiesis-stimulating agent (ESA)-refractory and ESA-naive patients with lower-risk (LR)-MDS (Platzbecker U, et al. Lancet 2023. doi:10.1016/S0140-6736(23)00874-7, Fenaux P, et al. N Engl J Med 2020;382:140-151). However, there are limited real-world data on the use of luspatercept in patients who are non-transfusion dependent (NTD) or have a low transfusion burden. This study aims to describe the real-world clinical outcomes and treatment patterns before and after the initiation of luspatercept in patients with LR-MDS who were NTD before luspatercept initiation, in the USA. Methods:In this retrospective claims-based cohort study, data from the Symphony Health database (Jan 1, 2010 to June 30, 2022) were used to identify adults with a diagnosis of MDS (initial diagnosis on or after Jan 1, 2015) before the first claim for luspatercept (index date). Patients were considered NTD if they had no unique dates with a claim for RBCT during the 8-week period before or on the index date. Patients were excluded if they received chemotherapy or had a diagnosis of refractory anemia with excess blasts or AML during the study period, as they were presumed to have higher-risk MDS. Patients were also excluded if they had a diagnosis of β-thalassemia, myelofibrosis, aplastic anemia, or breast cancer in the 6 months pre-index (baseline period) or prior use of hypomethylating agents (HMAs). Patient demographics and clinical characteristics were assessed during the baseline period, and patients' RBCT status (NTD or TD) was measured for 6 months after the index date. A patient was considered 8-week NTD if they had no RBCT in ≥ 1 rolling 8-week period; 12-week, 16-week, and 24-week NTD patients were defined similarly, using increasing durations of NTD. Administration of other MDS therapies (ie, chemotherapy, ESA, granulocyte colony stimulating factor [G-CSF], HMA, and immunomodulatory imide drug [IMiD ®] agent) was measured pre-index and post-index until the end of clinical activity or data availability (follow-up). Results: Of the 871 eligible patients who received luspatercept 589 (67.6%) were NTD before luspatercept initiation. Among this NTD population, the mean (standard deviation [SD]) age was 74.7 (6.3) years and 57.2% were male. Before luspatercept initiation, 15.3% of patients received 2 treatment classes and 0.8% received ≥ 3 treatment classes. Almost all patients (98.5%) maintained 8-week NTD status in the 6 months after luspatercept initiation. Similarly, 96.8%, 94.1%, and 88.6% of patients maintained NTD status for at least 12, 16, and 24 weeks in the 6 months after luspatercept initiation, respectively (Figure 1). Most patients (64.7%) did not require any additional MDS-related treatments during the study follow-up period, (median [SD] 15.7 [7.4] months). Overall, 77.1% of patients were treated with luspatercept for &amp;gt; 6 months and 68.4% for &amp;gt; 12 months. After luspatercept initiation, patients most commonly received treatment with ESAs or HMAs (14.9%; Figure 2). Conclusion:This is the first real-world evidence study to address luspatercept treatment in patients who were NTD prior to luspatercept treatment, which resulted in positive clinical outcomes and few RBCTs.Almost all patients with LR-MDS who were NTD at luspatercept initiation maintained 8-week NTD status during the 6 months after luspatercept initiation. The majority of patients did not receive a RBCT for a 24-week period after luspatercept initiation. Finally, over three-quarters of the patients remained on luspatercept and two-thirds of patients did not receive additional MDS-related treatments after a median follow-up of 15.7 months.

Overall Survival and Erythroid Response in Patients with Low-Risk Myelodysplastic Neoplasms after First-Line Treatment in a Low-Middle Income Country

Introduction Myelodysplastic neoplasms/syndromes (MDS) are a heterogeneous group of clonal disorders characterized by ineffective hematopoiesis and an increased risk of transformation to acute myeloid leukemia (AML). Current standard risk stratification model, the Revised International Prognostic Scoring System (IPSS-R), classifies patients into lower (≤3.5 points) or higher risk MDS. Lower-risk MDS (LR-MDS) treatment is based on the prevailing cytopenia and intends to improve symptomatic burden and minimize transfusion dependency. Anemia is present in 80-90% of patients with MDS. Throughout most of the course of the disease, patients with MDS have a hemoglobin &amp;lt; 10 g/dL, which leads to a decreased quality of life. Also, 50% of patients with MDS will eventually need red blood cell transfusions. Current options for the active treatment of anemia in LR-MDS are limited and vary among countries. Although erythropoiesis stimulating agents (ESAs) are considered standard of care in the absence of del5q, immunosuppressive therapy (IST) and androgens are still used in low income countries. The present study aims to evaluate whether erythroid responses and overall survival differ in patients with LR-MDS, based on their first-line treatment. Methods This is a retrospective study in patients with LR-MDS at Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, a tertiary care center in Mexico City. Eligible patients were diagnosed between January 2002 and December 2022 according to World Health Organization (WHO) 2016 criteria. Response was assessed according to International Working Group (IWG) 2018 criteria. We defined erythroid response (HI-E) as the sum of the responses achieved within different transfusion burden categories. First line therapy included ESAs, IST (cyclosporine ± eltrombopag), and androgens (mesterolone, danazol). These were compared through bivariate analysis, Kaplan-Meier curves and log-rank test. Results Until December 2022, 109 LR-MDS patients were considered for inclusion. Among them, 29 patients were lost to follow-up, and 25 patients were solely observed without any further therapy. Also, 7 patients who received other therapies were excluded. Ultimately, 48 patients were included in this analysis, 56.3% (n=27) were female, mean age was 62.8 (±15.9) years. Based on WHO 2016 classification, MDS with uni- and multilineage dysplasia was present in 58.3% (n=28) of the patients, while 29.2% (n=14) had hypoplastic MDS. Anemia was present in 89.6% (n=43) of the patients. When evaluating transfusion burden, 37.5% (n=18) of patients were non-transfusion dependent (NTD), 31.3% (n=15) low-transfusion burden (LTB), and another 31.3% (n=15) high-transfusion burden (HTB). ESAs and IST were the most frequently used frontline therapies, each accounting for 41.7% (n=20) of the patients; the remaining 16% (n= 8) received androgens. When comparing baseline characteristics between treatment arms, we found lower hemoglobin values and a greater proportion of severe anemia in ESA-treated patients (p= 0.039, p= 0.036), however, no differences in transfusion burden was observed (p= 0.212). Erythroid response rates were 25% (n=5), 20% (n=4) and 62.5% (n=5) among those treated with ESAs, IST and androgens, respectively (p= 0.071). When assessing HI-E by transfusion burden, no differences were observed between treatment arms except in HTB patients (p= 0.023). Neither time to response, nor duration of response were significantly different between treatment groups ( Table 1). Importantly, 3 of the 4 responders in the IST group received cyclosporine monotherapy, also 50% were hypoplastic MDS. After a median follow up of 47 months (IQR:22.5-85.5), the median overall survival(OS) for the entire cohort was not reached. The 3-year-OS rates for IST, ESA and androgens were 94%, 54% and 50%, respectively (p= 0.018) ( Figure 1). Conclusions In spite of the bias and limitations in the retrospective nature of this study, IST seems to be a valid option in frontline therapy for LR-MDS, since HI-E rates are similar to those observed with ESAs. Additionally, IST group showed a better OS. Results obtained with androgens merit further study and should be interpreted with caution because of the sample size.

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

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

Treatment of refractory or relapsed myelodysplastic neoplasms with luspatercept: a multicenter Chinese study.

Few effective therapies are available to treat patients with relapsed/refractory myelodysplastic neoplasms (MDS). Luspatercept was shown to display good efficacy in a phase 3 clinical trial for lower-risk MDS (LR-MDS) patients, yet real-world data are limited, especially in China. Therefore, data from patients diagnosed as having MDS with low blasts and SF3B1 mutation (MDS-SF3B1) and MDS with SF3B1 mutation and thrombocytosis were retrospectively analyzed. Of the 23 enrolled patients, 17 (73.9%) were males (median age 67years: range 29 to 80years). Previously, a total of 22 (95.7%) patients had received recombinant human erythropoietin (rhEPO), 9 (39.1%) roxadustat, 7 (30.4%) lenalidomide and 3 (13.0%) hypomethylating agents (HMA). The median treatment time was 22.9weeks (9.0-32.4). At week 12, 60.9% (14/23) of the patients achieved a hematologic improvement-erythroid (HI-E) response. Red blood cell transfusion independence (RBC-TI) for ≥ 8weeks was found in 57.1% (8/14) of transfusion-dependent patients. The median hemoglobin concentration was 84g/L, and patients had significantly higher hemoglobin concentrations after 12weeks of treatment (P < 0.001). It is noteworthy that responders had a greater reduction in serum ferritin (P = 0.021). Those with serum EPO < 500IU/L at baseline tended to have a higher HI-E rate (P = 0.081), but only patients in non-transfusion and low transfusion burden (LTB) subgroups had statistical differences (P = 0.024). The most commonly occurring adverse events were blood bilirubin increase (17.4%), fatigue (13.0%) and dizziness (13.0%). Luspatercept was effective and tolerated well in refractory LR-MDS-SF3B1 patients. In particular, baseline non-transfusion and LTB patients exhibited a greater response rate to treatment.

Hematologic and transfusion outcomes in patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) receiving luspatercept: Real-world assessment in the community practice setting.

7057 Background: Erythropoiesis-stimulating agents (ESAs) are used as first-line (1L) treatment (tx) for the management of symptomatic anemia in LR-MDS. Luspatercept is approved for pts with LR-MDS with ring sideroblasts (RS) who experience ESA failure and are transfusion dependent. We assessed clinical outcomes of pts with LR-MDS with RS, or MDS/myeloproliferative neoplasms with RS and thrombocytosis, treated with luspatercept in US community practices. Methods: This retrospective, observational cohort study used physician-abstracted chart data from community oncology clinics and included adults diagnosed with LR-MDS (including Very low- to Intermediate-risk IPSS-R status) on/after Jan 1, 2015 who received luspatercept for ≥ 3 months (mos) with ≥ 3 mos of follow-up. Transfusion burden (TB) was defined by number of sessions (ses) received in the 8 weeks (wks) prior to luspatercept tx (baseline) and the lowest number for any consecutive period ≥ 8 wks during wks 1–24 of tx: transfusion independent (TI); low TB (LTB), 1–3 ses; and moderate TB (MTB), 4–5 ses. Results: Of 253 pts, 219 (87%) had 1 tx prior to luspatercept tx and 31 (12%) received ≥ 2. ESAs were used as 1L tx in 210 pts (83%). Median follow-up was 5.7 mos. The most common reason for discontinuing initial MDS tx among patients who received ≥ 1 tx prior to luspatercept was lack of anemia improvement (133/250). At baseline, 21 (8%) pts were TI, 208 (82%) had LTB, and 24 (10%) MTB. Median duration of luspatercept tx was 10.8 mos. During wks 1–24, 20/21 (95%) pts remained TI and 201/232 (87%) pts with LTB/MTB at baseline achieved TI for ≥ 8 wks. The Table shows changes in median hemoglobin (Hb), absolute neutrophil count (ANC), and platelet (plt) count. Conclusions: Most pts with LR-MDS received 1L ESAs and over half discontinued the first tx prior to luspatercept due to lack of anemia improvement, highlighting the need for alternative options to improve clinical outcomes. Consistent with data from the MEDALIST trial, 87% of pts with LTB/MTB who received luspatercept achieved TI for ≥ 8 wks, supporting its clinical benefit in routine clinical practice. [Table: see text]

Danazol Treatment for Thrombocytopenia in Myelodysplastic Syndromes: Can an "Old-fashioned" Drug be Effective?

Danazol Treatment for Thrombocytopenia in Myelodysplastic Syndromes: Can an "Old-fashioned" Drug be Effective?

Improved benefit of continuing luspatercept therapy: sub-analysis of patients with lower-risk MDS in the MEDALIST study

Red blood cell transfusion independence (RBC-TI) is an important goal in treating lower-risk myelodysplastic syndromes with ring sideroblasts. In the phase 3 MEDALIST study, RBC-TI of ≥ 8 weeks was achieved by significantly more luspatercept- versus placebo-treated patients in the first 24 weeks of treatment. In this post hoc analysis, we evaluated RBC transfusion units and visits based on patients’ baseline transfusion burden level and the clinical benefit of luspatercept treatment beyond week 25 in initial luspatercept nonresponders (patients who did not achieve RBC-TI ≥ 8 weeks by week 25) but continued luspatercept up to 144 weeks. RBC transfusion burden, erythroid response, serum ferritin levels, and hemoglobin levels relative to baseline were evaluated. Through week 25, fewer RBC transfusion units and visits were observed in luspatercept-treated patients versus placebo, regardless of baseline transfusion burden. This continued through 144 weeks of luspatercept treatment, particularly in patients with low baseline transfusion burden. Sixty-eight patients were initial nonresponders at week 25 but continued treatment; most (81%) received the maximum dose of luspatercept (1.75 mg/kg). Sixteen percent achieved RBC-TI for ≥ 8 weeks during weeks 25–48, 26% had reduced RBC transfusion burden, 10% achieved an erythroid response, 44% had reduced serum ferritin, and hemoglobin levels increased an average of 1.3 g/dL from baseline. These data have implications for clinical practice, as transfusion units and visits are less in luspatercept-treated patients through week 25 regardless of baseline transfusion burden, and continuing luspatercept beyond week 25 can potentially provide additional clinical benefits for initial nonresponders. Trial registration: NCT02631070.

Real-World Outcomes of Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS) Treated with Luspatercept: An Evaluation of US Clinical Practice Utilization and Treatment Patterns

Introduction: LR-MDS is characterized by ineffective hematopoiesis, cytogenic and molecular abnormalities, progressive bone marrow failure, ≥ 1 cytopenias, and variable risk of progression to acute myeloid leukemia. Patients (pts) may be classified as having LR-MDS based on an International Prognostic Scoring System (IPSS) score of Low or Intermediate risk and/or an IPSS-Revised (IPSS-R) score of Very Low, Low, or Intermediate risk. Erythropoiesis-stimulating agents (ESAs) are the first line of treatment for most pts with LR-MDS. However, many pts experience ESA failure and have limited subsequent treatment options. Luspatercept is a first-in-class erythroid maturation agent approved by the US FDA in April 2020 for the treatment of anemia following ESA failure and requiring ≥ 2 red blood cell units over 8 weeks in adult pts with LR-MDS with ring sideroblasts (RS) or with MDS/myeloproliferative neoplasms with RS and thrombocytosis. Limited evidence exists on treatment patterns and outcomes among pts with LR-MDS treated with luspatercept in routine clinical practice. The aim of this study was to examine pt characteristics, treatment patterns, and transfusion outcomes among pts with LR-MDS treated with luspatercept in the real-world setting. Methods: This was a retrospective, observational cohort study using physician-abstracted data from the charts of adults diagnosed with LR-MDS on or after January 1, 2015, who received luspatercept treatment in US clinical practice. Pts ≥ 18 years old with LR-MDS who received luspatercept for ≥ 3 months and had ≥ 3 months of follow-up after starting luspatercept (or until death if within 3 months of luspatercept initiation) were included. Pts were classified as having LR-MDS based on their IPSS-R or IPSS scores at diagnosis. Pts who participated in a clinical trial were excluded. All data were summarized using descriptive statistics. Results: A total of 76 eligible pts were included; 52.6% were male, 72.4% were White, and the mean age at luspatercept treatment initiation was 72.0 years (Table 1). Median follow-up time from luspatercept initiation was 5.6 months. Nearly all pts (92.1%) received only 1 line of systemic treatment for LR-MDS before receiving luspatercept. All pts initiated luspatercept treatment at the approved starting dose of 1 mg/kg every 3 weeks, and 75.0% of pts received luspatercept according to the approved US FDA indication. Based on Kaplan-Meier estimates, the median duration of luspatercept treatment was 13.3 months. Twenty-two pts (29.0%) discontinued luspatercept treatment during the follow-up period, of whom 54.5% discontinued on the same dose as their starting dose, ie, 1 mg/kg every 3 weeks (68.2% discontinued at a dose < 1.75 mg/kg) (Table 1). Disease progression to higher-risk MDS was the most common reason for luspatercept discontinuation (n = 10/22, 45.5%). No pts discontinued treatment due to adverse events. At luspatercept initiation, 85.5% of pts had low transfusion burden (TB), of whom 7.7% maintained low TB and 92.3% converted from low TB to transfusion independence (TI) during the first 24 weeks of luspatercept treatment (Table 2). Moderate TB was present in 13.2% of pts at luspatercept initiation, all of whom transitioned to having lower TB during the first 24 weeks of luspatercept treatment. Conclusions: This real-world chart review study showed > 90% of pts with low TB prior to luspatercept initiation achieved TI within the first 24 weeks of luspatercept treatment. All pts with moderate TB prior to luspatercept had a decrease in level of TB within the first 24 weeks of starting luspatercept treatment. The MEDALIST trial showed 38% of pts treated with luspatercept- with IPSS-R Very Low to Intermediate risk reached TI within 24 weeks (Fenaux P, et al. N Engl J Med 2020;382:140-151). The present study suggests that initiating luspatercept for low or moderate TB may have a substantial impact on TB and merits continued attention as experience with luspatercept in clinical practice accumulates. Among those who discontinued luspatercept treatment, more than half discontinued at the starting dose. Luspatercept dose titration in real-world clinical practice may not align with recommended dose increases according to the approved US indication. This discrepancy represents an unmet clinical need and potential area for further clarification and education in the community setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Multiple Episodes of Transfusion Independence with Luspatercept Treatment and the Impact of Dose Escalation in Patients with Lower-Risk Myelodysplastic Syndromes from the MEDALIST Study

Introduction: In the phase 3 MEDALIST trial of luspatercept in lower-risk myelodysplastic syndromes (LR-MDS), 58 of 153 (37.9%) patients who received luspatercept achieved the primary endpoint of red blood cell (RBC) transfusion independence (RBC-TI) ≥ 8 weeks during weeks 1-24, versus 10 of 76 (13.2%) for placebo. Among the primary endpoint responders in the luspatercept arm, 17 (29.3%), 13 (22.4%), and 16 (27.6%) patients experienced 2, 3, or ≥ 4 separate RBC-TI ≥ 8 weeks response events during the entire treatment period, versus 3 (30%) and 1 (10%) patient in the placebo arm, who experienced 2 or 3 response events. (Platzbecker U, et al. Blood 2021;138:1524). The starting dose of luspatercept in the MEDALIST trial was 1.0 mg/kg with up-titration to 1.33 and 1.75 mg/kg allowed in the absence of RBC-TI after ≥ 2 doses at the same dose level, or after a loss of response following a dose reduction. Here, we report the effect of baseline transfusion burden (TB) and luspatercept dose level on response to treatment in patients with LR-MDS from the MEDALIST study. Methods: Eligible patients were ≥ 18 years of age, had LR-MDS requiring RBC transfusions, and were ineligible for, intolerant to, or refractory to erythropoiesis-simulating agents. Patients were stratified by mean baseline TB (mean RBC units/8 weeks assessed over the 16 weeks prior to initiation), as follows: low TB (LTB), > 0 to < 4 RBC units/8 weeks; intermediate TB (ITB), ≥ 4 to < 6 RBC units/8 weeks; and high TB (HTB), ≥ 6 RBC units/8 weeks. The number of individual periods of response (distinct episodes of RBC-TI ≥ 8 weeks) occurring during the entire treatment period was calculated. The treatment period lasted until the earliest of: the last dose date + 20 days; study discontinuation; data cutoff; or death. Time between RBC-TI responses was calculated as: start date of next response minus end date of current response plus 1. Results: As of November 26, 2020, RBC-TI ≥ 8 weeks was observed in 74/153 (48.4%) luspatercept patients and 12/76 (15.8%) placebo patients during the entire MEDALIST treatment period. Many patients experienced multiple distinct periods of RBC-TI ≥ 8 weeks; 52/74 (70.3%) luspatercept responders and 4/12 (33.3%) placebo responders experienced ≥ 2 episodes. The greatest number of response periods reported in a single patient was 10 with luspatercept and 3 with placebo. Overall, 30/39 (76.9%), 14/20 (70.0%), and 8/15 (53.3%) LTB, ITB, and HTB luspatercept responders, respectively, experienced ≥ 2 periods of response; 17/39 (43.6%), 10/20 (50.0%), and 5/15 (33.3%) LTB, ITB, and HTB luspatercept responders, respectively, experienced ≥ 3 periods of response; and 8/39 (20.5%), 3/20 (15.0%), and 0 LTB, ITB, and HTB, luspatercept responders, respectively, experienced ≥ 5 periods of response (Figure). The mean (SD) number of response periods with luspatercept was 3.0 (2.25) for LTB patients, 2.9 (2.0) for ITB patients, and 1.9 (1.03) for HTB patients. The greatest number of response periods reported with luspatercept in a single patient was 10 for LTB patients, 8 for ITB patients, and 4 for HTB patients. The mean (SD) time between RBC-TI response periods with luspatercept was 24.3 (63.16) days for LTB patients, 52.1 (55.91) days for ITB patients, and 32.1 (33.79) days for HTB patients. During the entire treatment period, rates of RBC-TI ≥ 8 weeks response at 1.0 mg/kg decreased with increasing baseline TB, with 94.9% of baseline LTB patients responding compared with 40.0% of baseline HTB patients. Patients who were ITB or HTB at baseline were more likely to respond when receiving 1.75 mg/kg luspatercept, with 50.0% and 46.7% responding, respectively, compared with 35.9% for LTB patients (Table). Conclusions: Patients who were LTB at baseline experienced more periods of RBC-TI response than ITB and HTB patients. LTB patients were more likely to respond to lower doses of luspatercept, whereas almost half of ITB and HTB patients required escalation to the maximum dose level to respond. ITB and HTB patients might be expected to wait longer for a second response to luspatercept than LTB patients. Importantly, many patients experienced multiple RBC-TI response periods with luspatercept, emphasizing the value of measuring cumulative response duration as well as the benefit of continuing luspatercept treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Luspatercept for Treatment of Lower Risk Myelodysplastic Syndromes: Real World Data Replicates Medalist Study Results and Confirms Activity Among Hypomethylating Agents and Lenalidomide Treated Patients

Introduction: Luspatercept, TGF-B fusion trap protein, is a first in class erythroid maturating agent approved by FDA for treatment of red blood cell transfusion dependent (RBC-TD) lower risk myelodysplastic syndromes (LR-MDS) with ring sideroblasts (RS) based on the MEDALIST clinical trial. Red blood cell transfusion independence (RBC-TI) was observed in 38% of 153 patients (pts) treated with luspatercept compared to 13% of 76 pts in the placebo group. We present to our knowledge first real-world data (RWD) in a large cohort of pts treated at our center with luspatercept for LR-MDS. More importantly, we address impact of prior therapies on response namely hypomethylating agents (HMA) as the original clinical trials excluded HMA treated pts. Methods We identified all pts treated at Moffitt Cancer Center with luspatercept since the FDA approval. Baseline RBC transfusion burden (TB) was defined as: non- transfusion dependent (NTD) (0 units in 8 weeks prior luspatercept), low TB (LTB) (1-5 units /8weeks) and high TB (HTB) (≥ 6 units /8 weeks). A hematological response (HI) was defined as an (i) objective Hgb increase of > 1.5 g/dl in NTD, and (ii) RBC-TI with Hgb increase of 1.5 g/dl, or RBC-TI without Hgb 1.5 g/dl increase, or >50% reduction in RBC transfusion burden among RBC-TD. Results Between February 2020 and December 2021, 114 pts were treated with luspatercept. Table-1 summarizes baseline characteristics in comparison to Medalist trial, the median age was 70 years. Seventy-three pts (67%) had MDS-RS subtype, 91% were intermediate or lower risk MDS by R-IPSS. SF3B1 mutation (MT) was detected in 71% (80/112). The mean Hgb level was 7.90 g/dl and 47% were RBC HTB transfusion dependent. The median serum erythropoietin (epo) level at time of referral was 122 U/L (19% > 500 U/L) (n=77). Majority had prior erythroid stimulating agents (ESA) (89%) with 29% hematological response to prior ESA, 59 pts (53%) had prior HMA therapy, and 42 patients (47%) had prior lenalidomide (len). The overall HI rate to luspatercept was 39.5% (45/114). Table-2 summarizes detailed responses. HI correlated with baseline RBC-TB where 69% (9/13) NTD, 47% (21/47) LTB and 25% HTB (13/53) achieved HI respectively, p=.004. Almost 55% of pts needed dose escalation, 62 pts received 1.33 mg/kg and 63 pts received 1.75 mg among whom 40% (25 pts) demonstrated response to higher doses. Based on RBC-TB, 75% (6/8) NTD patients achieved HI with highest dose escalation, 40% (10/25) LTB pts achieved HI with dose escalation and 30% (9/30) HTB pts achieved response with dose escalation. Among responders, the median duration of response was 15.6 months (2.6-27.3). As off last follow up, 56 pts (49%) discontinued treatment. Reason of discontinuation was lack of response in 47 pts, loss of response in 4 patients and adverse events in 5 pts (58 pts are still on therapy). The most common captured adverse events were fatigue (n=8), GI (n=4), shortness of breath and arthralgia (1 each). The response rates were higher among SF3B1 MT pts compared to wild type, 48% (34/80) compared to 16% (5/32), p=.002. The response rate among pts with RS subtypes versus non-RS were 49% versus 28% respectively, p=.05. Among 14 pts with MDS/MPN-RS-T the HI rate was 79%. HI for pts with serum epo < 500 U/L, was 48% (30/62) compared to 13% 2/15) for those with serum epo > 500, p=.01. Majority of pts with high serum epo level were RBC HTB at baseline 67% (10/15). The HI rate was 30% (18/60) after HMA failure compared to 50% (27/54) in HMA naïve pts, (p=.03). More pts post HMA failure were RBC-HTB 62% compared to 30% in HMA naïve. The luspatercept HI among RBC-LTB HMA failure pts was 39% compared to 54% in HMA naïve LTB, however, it was 24% among HTB HMA failure compared to 25% among HMA naïve HTB. The HI rate was 33% (15/46) for len failure pts compared to 43% (29/67) naïve patients, (p=.3). In multivariable analysis both SF3B1 mutation status and baseline RBC TB independently correlated with luspatercept response but not HMA failure. Conclusions Our RWD confirms luspatercept clinical benefit and safety profile observed in the MEDALIST trial. Responses are dose dependent with 1/3 of patients who were dose escalated responding. Low baseline RBC-TB dependency and SF3B1 MT correlated with higher response rates. Luspatercept retained activity after HMA or lenalidomide failure however a trend of lower responses observed correlated with RBC-HTB among those patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

First Single-Center Experience with Luspatercept Therapy in Low-Risk Myelodysplastic Syndrome (LR-MDS) Patients with Transfusion Dependence Refractory to Erythropoietin Therapy

Introduction: In the treatment of low-risk myelodysplastic syndromes (MDS) patients, anemia is the predominant problem. A recent breakthrough in the therapy of anemia in low-risk MDS patients are drugs involved in TGFβ pathway blockade. Luspatercept is a recombinant fusion protein derived from human activin receptor type IIB. It binds TGFβ superfamily ligands and inhibits the SMAD2/3 pathway leading to potentiation of red cell line differentiation and proliferation. Luspatercept was approved last year by the FDA and EMEA in the treatment of anemic low-risk MDS patients with ring sideroblasts (MDS-RS-MLD, MDS-RS-SLD) and/or SF3B1 mutated patients who are not eligible for erythropoiesis-stimulating agents (ESA) or for patients who failed on this therapy. Luspatercept showed high clinical activity for the treatment of anemia in the phase 2 trial (PACE-MDS) and subsequently in the phase 3 trial (MEDALIST). It has led to transfusion independence (TI) in about 40 % of patients. Methods: From January 2021 to July 2022, 27 patients were treated with luspatercept at the hematology department of Charles University Hospital in Prague, Czech Republic. The median age of the patients was 77 years (range 57-89) with a male to female ratio 17:10. WHO 2016 diagnosis were: MDS-RS-MLD (N = 23) and MDS/MPN-RS-T (N = 4). Median of IPSS-R was 2.5 (range 1-4). Median of IPSS-R cytogenetic score scaled from 0-2 with the median of 1. Median follow-up was 7.8 months (range 1-38). Luspatercept was administered in subcutaneous injections once every 3 weeks with an initial dose of 1 mg/kg. Dose escalation was done according to the level of response to 1.33 and 1.75 mg/kg. The median number of cycles administered was 7 (2-17). Transfusion dependency before luspatercept initiation ranged from 2 transfusion units (TU)/8 weeks to 12 TU/8 weeks, 11 patients had low transfusion burden (LTB), 16 high transfusion burden (HTB). Baseline erythropoietin (EPO) level was 374 IU/l in average (range 150-770) and ferritin level was 1307 μg/l in average (range 234-3832). 9 patients received chelation therapy. 22 patients were tested for SF3B1 mutation with 21 positive results (95.5 %) using Sanger sequencing (N = 3) or NGS approach (N = 18). Isolated mutation of SF3B1 was present in 8 patients (44 %). The most frequent mutations besides SF3B1 were TET2 (N = 8; 44 %), ASXL1 (N = 3; 17 %), DNMT3A and RUNX1 (N = 2; 11 %). Average mutations count per one patient was 1.7 (range 0-5). We did not observe any TP53 mutation. Results: There were 24 evaluable patients in terms of response. Thus far 11 (45 %) patients have responded by achieving TI, 5 (20 %) patients have had a reduction in transfusion dependence (HI, according to IWG criteria 2006), 8 (33 %) patients have not responded. One patient progressed to the higher risk MDS, and one transformed to acute myeloid leukemia. Median duration of response was 7.4 months (range: 0.7-31.8). Median number of cycles to achieve response was 4. Eleven patients responded to the basic dose 1 mg/kg, 2 additional patients on the dose 1.33 mg/kg and 2 more on the dose 1.75 mg/kg. There were differences in response according to transfusion burden, in LTB group achieved TI 8 patients and HI 1 patient, in HTB group we observed TI in 3 patients and HI in 4 patients. In 9 patients, we added ESA to luspatercept therapy, as they act both at different levels of erythropoiesis, which led to the improvement of response in 5 cases. In general, patients with lower initial baseline EPO level were better responders. We did not observe decrease in ferritin level during therapy. There was no significant effect of mutation burden on patient's OS, although patients with single mutated SF3B1 achieved better ORR (75 %), than patients bearing mutations in multiple genes (ORR = 40 %). There were no adverse effects of Grade II or more. Conclusion: In conclusion, luspatercept is certainly the next major step in the treatment of anemia in MDS patients. The advantage of the drug is very good tolerance and easy administration. We observed better responses in patients bearing single mutation in SF3B1, patients with LTB and lower initial baseline EPO levels. The higher response rate in our follow-up may be influenced by the combination with ESA and rapid dose escalation. This work was supported by the following grants: grant AZV 2021-2024 NU21-08-00312, Grant AZV 2019-2023 NV19-08-00144, UNCE/MED/016

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

Association of Clinical Characteristics at Diagnosis with Outcomes in Patients (Pts) with Lower-Risk Myelodysplastic Syndromes (LR-MDS) Treated with Erythropoiesis Stimulating Agents (ESAs): Findings from a Real-World Medical Chart Review in the US

Introduction: LR-MDS comprise a heterogeneous group of clonal myeloid neoplasms characterized by ineffective hematopoiesis, dysplasia(s), cytopenia(s), and relatively good-risk karyotypic and molecular abnormalities. The primary therapeutic strategy for pts with symptomatic LR-MDS is supportive care with red blood cell (RBC)/platelet transfusions and growth factor support such as treatment with ESAs. However, length of treatment and clinical outcomes vary among pts and are poorly understood in real-world clinical practice, particularly in the context of current guidelines. This medical chart review explores the impact of clinical characteristics at diagnosis on clinical outcomes of pts with LR-MDS treated primarily in community settings. Methods: This was a retrospective, observational, US multisite chart review of adult pts diagnosed with LR-MDS between January 1, 2015 and June 24, 2020. Eligible pts had ≥ 1 year of follow-up after diagnosis unless follow-up was < 1 year due to death. Pts who participated in a clinical trial were excluded. Demographic characteristics assessed included age at diagnosis, sex, and race/ethnicity. Four sets of subgroups were analyzed based on the following clinical characteristics collected at diagnosis: ring sideroblast (RS) status; erythropoietin (EPO) level; cytogenetic risk status; and transfusion burden (TB) level. TB level was defined as the number of RBC transfusion sessions for hemoglobin level < 9 g/dL and/or platelet sessions within the 56 consecutive days immediately prior to diagnosis, where transfusion independence (TI)/low TB was 0-3 RBC transfusion sessions and moderate/high TB was ≥ 4 RBC transfusion sessions. Treatment outcomes included physician-reported disease progression or ESA failure. ESA failure was determined per physician reports and/or calculated based on pre-specified criteria, which included discontinuation or switch of ESA-based therapy and/or increased TB within any consecutive 56-day period during ESA-based treatment. Statistical comparisons of characteristics and outcomes between subgroups were conducted using Fisher's exact or Chi-square tests for categorical data, Wilcoxon tests for continuous data, and log rank tests for Kaplan-Meier estimates. Statistical significance was defined as P ≤ 0.05. Results: Among 338 pts with LR-MDS identified, 23 (6.8%) were RS+, 14 (4.1%) had EPO levels ≥ 500 U/L, 65 (19.2%) had intermediate cytogenetics, and 37 (10.9%) had moderate/high TB at diagnosis. Median age at diagnosis was lower in pts with EPO levels ≥ 500 U/L vs < 500 U/L and in those with moderate/high TB vs TI/low TB. There were no statistically significant differences in race or sex among subgroups. The median follow-up time since diagnosis was longer for pts with RS+ status (50.9 months) vs those with negative/unknown RS status (27.0 months). No statistically significant differences in follow-up time were observed for the other subgroups (Table). A greater proportion of pts with moderate/high TB (94.6%) vs TI/low TB (74.1%) received any first-line (1L) systemic therapy for LR-MDS; no significant differences were observed for the other subgroups. Among those who received any 1L systemic therapy, a greater proportion of pts with disease progression at 1L was observed for those with EPO levels ≥ 500 U/L (50.0%) vs < 500 U/L (21.6%), intermediate (35.2%) vs good/very good (21.9%) cytogenetics, and moderate/high TB (45.7%) vs TI/low TB (22.4%) at diagnosis (Table). A smaller proportion of pts with EPO levels ≥ 500 U/L (14.3%) vs < 500 U/L (63.5%) at diagnosis received an ESA-based therapy at 1L. Among pts who received 1L ESA-based therapy, a greater proportion of pts with moderate/high TB (100%) vs TI/low TB (61.6%) experienced ESA failure. No statistically significant differences in 1L ESA failure were observed for the other subgroups (Table). Conclusions: This real-world medical chart review study in the US community care setting suggests that among pts with LR-MDS who receive 1L systemic therapy, more pts who have EPO levels ≥ 500 U/L, intermediate cytogenetics, and/or moderate/high TB at diagnosis may experience disease progression during treatment than those who do not. These results are in line with previous findings that EPO levels, cytogenetic status, and TB at diagnosis may be important predictors of 1L treatment outcomes. Additional studies with larger sample sizes may be useful to further explore these findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

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

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

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

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

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

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

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