Erythroid Response Research Articles

Therapy-Related Myelodysplastic Syndromes with Isolated Del(5q): Comparative Analysis of Phenotype and Long-Term Survival

Background: Myelodysplastic syndromes (MDS) with chromosome 5q deletion [MDS-del(5q)] is a subcategory of MDS recognized by both the International Consensus (ICC) and World Health Organization (WHO) classification systems. Diagnostic criteria according to ICC-2022 include i) presence of del(5q) alone or with only one other additional cytogenetic abnormality, other than -7/del(7q), ii) absence of multi-hit TP53 mutation, iii) presence of ≥1 cytopenias, iv) presence of bone marrow myeloid dysplasia in ≥1 lineages, v) absence of ≥5% bone marrow blasts, and vi) absence of ≥2% circulating blasts (Arber et al. Blood 2022). We used WHO-2016 diagnostic criteria to identify Mayo Clinic patients with MDS-del(5q) and confirmed a study population that also met ICC-2022 criteria. The main objective of the current study was to describe the phenotype and long-term survival of patients with therapy-related MDS-del(5q) and compare the findings with a cohort of patients with primary MDS-del(5q), sourced from the same database. Methods: The current study was conducted under an institutional review board approved minimum risk protocol that allowed retrospective collection and analysis of data from patients with MDS-del(5q) who were seen at the Mayo Clinic. Diagnosis of MDS-del(5q) was retrofitted to comply with ICC-2022 criteria, with the exception that patients with additional cytogenetic abnormalities were excluded from the current report (Arber et al. Blood 2022). Most patients were treated with lenalidomide, often given at the recommended dose of 10 mg/day x 21-28 days, with dose adjustements at physician discretion. Erythroid response criteria included transfusion independence for at least 8 weeks for transfusion dependent patients and an increase in hemoglobin by 1.5 g/dl lasting for at least 8 weeks, in transfusion independent patients. Transfusion dependency was assigned to those patients who had received at least 3 units of packed red cells in the 8 weeks prior to diagnosis. Conventional statistical methods were applied using JMP Pro 16.0.0 software (SAS Institute, Cary, NC, USA). Results A total of 93 patients (median age 73 years; range 24-89; females 63%) were included in the current study, including primary (n=79) and therapy-related (n=14) MDS-del(5q). Cancer/treatment history for the latter group of patients included prostate cancer/radiotherapy (n=5), thyroid cancer/radiotherapy (n=2), breast cancer/radiotherapy (n=2), bladder cancer/chemotherapy (n=2), colon cancer/chemotherapy (n=1), lung cancer/chemotherapy (n=1), and non-Hodgkin's lymphoma/chemotherapy/radiotherapy (n=1). Median (range) time from radiotherapy/chemotherapy and recognition of MDS-del(5q) was 16 years (1.9-30). Comparison of presenting features for therapy-related vs primary MDS-del(5q) revealed the former to be associated with older age (median 77 vs 72 years; p=0.002), male gender (72% vs 30%; p=0.003), and lesser likelihood of transfusion-dependent anemia, at time of initial diagnosis (28% vs 68%; p=0.03). The two groups were otherwise similar in their leukocyte and platelet counts and mutational landscape, including prevalence of TP53 mutations (25% vs 13%, respectively). All 79 patients with primary vs 10 of the 14 with therapy-related disease received lenalidomide therapy with erythroid response rates of 62% vs 80% (p=0.2) and complete/partial cytogenetic response rates of 13%/10% vs 0/0, respectively (p=0.05); the latter information was available in a subset of 64 patients. After a median follow up of 4.8 years, 38 (41%) deaths and 16 (17%) leukemic transformations were documented; the corresponding figures for therapy related/primary disease were 50%/39% and 14%/18%, respectively (p=0.4 and 0.7). Figure 1 depicts similar (p=0.6) survival data for therapy-related vs primary MDS-del(5q), with corresponding median survival (3-year survival) rates of 6.3 years (60%) vs 7.7 years (63%). Conclusions: The current study describes the circumstances surrounding the development of therapy-related MDS-del(5q) and highlights differences in age and gender distribution, compared to primary MDS-del(5q). The two groups were otherwise similar in their response to lenalidomide therapy, overall survival, and leukemic transformation rates while their similarity in mutation distribution requires validation with higher number of informative cases. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Inhibition of Lysyl Oxidases Synergizes with 5-Azacytidine to Restore Erythropoiesis in Myeloid Neoplasms

Introduction: Limited response rates and frequent relapses during standard of care with hypomethylating agents (HMAs) in myeloid neoplasms (MN) require urgent improvement of this treatment indication. The altered bone marrow (BM) niche in MN is increasingly being recognized as a perspective therapeutic target. Upregulated lysyl oxidase (LOX/LOXL) activity in MN BM contributes to the deposition of aberrant extracellular matrix (ECM). Here, we show in pre-clinical models of MN that the inhibition of niche-associated LOX/LOXL activity in combination with 5-Azacytidine (5-AZA) restores erythropoiesis and reduces disease burden in BM samples of anemic patients with MN. Methods: Primary co-cultures of BM mesenchymal stromal cells (MSCs) and hematopoietic stem and progenitor cells (HSPCs) were established from n=31 anemic MN patients and treated with the pan-LOX/LOXL inhibitor PXS-5505, 5-AZA or PXS-5505 + 5-AZA combination (P+A) for 4 days. The differentiation potential of HSPCs in this co-culture was assessed by colony forming unit (CFU) assays and flow cytometry. In some of the experiments, MSC monolayers were pre-treated with PXS-5505 for 7 days and decellularized to obtain ECM. Subsequently, autologous BM HSPCs were cultured on ECM in the presence of 5-AZA or P+A. Patient-derived xenografts (PDX) were established in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice and treated with 3 cycles of 5-AZA, PXS-5505 (30 mg/kg on alternate days) or the combination of both (P+A). Results: MSCs of MN patients significantly overexpressed LOX/LOXL transcripts as compared to healthy age-matched controls. Remarkably, based on the CFU assay the combination of 5-AZA with the pan-LOX/LOXL inhibitor PXS-5505 improved erythroid differentiation of patient HSPCs that poorly responded to 5-AZA monotherapy. From a total of n=31 anemic patients with advanced-stage myelodysplastic syndromes, myeloproliferative neoplasia and chronic myelomonocytic leukemia, n=20 patients (65%) displayed an erythroid response to P+A combination. Of these, n=11 patients (35%) responded exclusively to P+A, whereas n=9 patients (29%) also concomitantly responded to 5-AZA monotherapy. The comparison of P+A versus 5-AZA monotherapy for improving erythroid response showed a relative risk of 0.45 with 95% confidence interval 0.24-0.80 (p=0.0103). Of note, P+A treatment facilitated differentiation of CD235a+ erythroid progenitors from HSPCs sub-clones with low mutational variant allele frequencies (VAFs). The mechanism of action underlying this drug combination required direct cellular contact of HSPCs with BM stroma components including MSCs and ECM, and is dependent on integrin signaling. Therefore, this novel drug combination represents a genuinely BM microenvironment targeting therapy. We further confirmed these results in vivo using a BM niche-dependent PDX mouse model engrafted with human MN. P+A treatment favored erythroid differentiation of human HSPCs in vivo, showing the directly improved human erythropoiesis in the total BM of PDX mice as well as increased erythroid production after human erythropoietin induction ex vivo. In addition, P+A treatment induced the greatest reduction of disease burden as assessed by decrease of spleen indices, total human engraftment rates, BM fibrosis grades and mutational VAFs. Conclusions: The response to 5-AZA in MN can be potently augmented by concomitant LOX/LOXL inhibition. These results lay out a strong pre-clinical rationale for efficacy of combination treatment of PXS-5505 with 5-AZA especially for anemic and red blood cell transfusion-dependent MN patients, which will be assessed in forthcoming clinical trials.

Hematological Response to Avatrombopag Switch in Thrombopoietin Receptor Agonist-Refractory Aplastic Anemia

ATG combined with CsA is the first-line treatment for patients with SAA who cannot choose HLA-matched HSCT because of various conditions. The HR rate is only approximately 60-80%, and the CR is not high. The lack of residual HSC in patients is an important reason for this unsatisfactory effect. RhTPO/TPO-RA combine with HSC membrane receptors to promote their proliferation and differentiation, expand multipotent hematopoietic progenitor cells in vivo. Studies have found that TPO-RA eltrombopag (EPAG) combined with IST can significantly increase the HR rate and improve the quality of the HR. From 40-50% hematologic improvement can also be obtained with refractory SAA. However, TPO-RA treatment is ineffective in some patients. Avatrombopag (APAG) acts on the transmembrane region of the TPO receptor, has a stronger effect than EPAG, and has no obvious liver toxicity. We analyzed the efficacy and safety of IST combined with rhTPO and/or EPAG in patients with SAA of switching to APAG. We retrospectively analyzed the data of 10 patients who were hospitalized between January and December 2021. All patients have been diagnosed with V/SAA. They received IST combined with rhTPO/TPO-RA treatment, failed to obtain a HR, and were converted to APAG. The patients were treated with IST for at least 6 months, combined with rhTPO and/or EPAG for at least 3 months, and did not get HR. None of the patients included in this study was suitable for undergo allogeneic HSCT. APAG was administered orally at a dose of 40 mg/day once a day for at least 6 months.The efficacy criteria for refractory SAA were defined as follows: one-line response included platelet response (HI-P), neutrophil response (HI-N), and erythroid response (HI-E). The 2-line HR could be a combination of any two of the aforementioned one-line responses. A trilineage response was defined as a patient with simultaneous platelet, erythroid, and neutrophil responses, and the quality of the trilineage response was the same as that of the initial treatment with SAA/TDNSAA. Ten patients were included in the study, with a median age of 54 (14-68) years, including five males and five females. All patients received IST for a median of 8.5 (6-40) months. Four patients received rhTPO for 1-2 months followed by EPAG for 2-8 months. Six patients received only EPAG for 3-4 months. All the patients received rhTPO/TP-RA for a median of 3.5 (3-10) months. Five patients with PNH clones were positive by flow cytometry, and there was no hemolytic or biochemical evidence of hemolysis. Two patients had clonal chromosomal abnormalities: one with 47,XY; +8 [2/20] and the other with 45,XY; -Y [10/20]. Ten patients were converted to APAG treatment for a median of 6 (6-10) months. After 3 months of follow-up , seven patients obtained a HR (7/10, 70%), of which two patients obtained a HI-P and HI-N, and five patients (5/10, 50%) obtained a three-line HR (1-CR, 3-GPR, 1-PR). Seven patients (7/10, 70%) obtained HR after 6 months of follow-up, of which one patient obtained HI-P/N and six patients (6/10, 60%) obtained three-line HR (3-CR, t2-GPR, 1-PR). The patient with two-line HR further improved after 8 months of APAG, reaching a three-line blood cell response to PR. At the end of the last follow-up, the HR rate of all patients with APAG conversion therapy was 70%, and all of them achieved three-line blood cell responses (4-CR, 1-GPR, 2-PR). During the follow-up period, no APAG-related adverse events of grade 2 or above were found in any patient, no thrombotic events occurred, and no fibrous tissue hyperplasia was found in the bone marrow pathology review after 6 months of treatment. Among the five patients with PNH clones before APAG conversion therapy, three patients did not change significantly. Otherwise one patient's granulocyte PNH clone decreased from 16.2% at baseline to 6.3%, and the other patient's PNH clone increased from 9.8% at baseline to 19.6%, whereas there was no symptomatic hemolysis in all patient. One patient (1/10, 10%) with normal chromosomal before therapy get a new clonal chromosomal abnormality after 3 months. It was 46XX, t(X;4 )(p11.4;q21) [4/20]; the HR was assessed as GPR. In conclusion, patients with SAA refractory to TPO-RA, drug conversion therapy can be based on the safety, pharmacological, and pharmacodynamic characteristics of TPO-RA drugs. Therefore, APAG is a better choice for switch therapy in these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Evolution of Somatic Mutations in Patients with Del(5q) MDS Early Treated with Lenalidomide in the Sintra-Rev Clinical Trial: Safe and Effecitive Approach?

INTRODUCTION Lenalidomide (LEN) is the election treatment in del(5q) MDS, approved only in case of RBC transfusion dependency (TD). Only scarce retrospective data exploring LEN in non-TD setting are available, suggesting a benefit. SintraRev is the first randomized clinical trial evaluating LEN in del(5q) MDS with anemia but without TD. While efficacy has been confirmed in this trial, safety regarding clonal evolution and disease progression has not been addressed in this early treatment context. METHODOLOGY SintraRev is a phase III multicenter clinical trial in low-risk del(5q) MDS patients with anemia without TD. Patients were randomized (2:1) in a double-blind design to LEN (5mg/day continuously) vs placebo (PCB) for 2 years of treatment and 2 years of follow-up (FU). In addition to clinical results, we aimed to study the role of molecular profiling in this early therapeutic approach (LEN use prior to TD) in both arms during FU (baseline, week 12 and the last available FU). Next-generation sequencing (NGS) was performed in available samples. Sequential samples were collected before treatment initiation and then every 6 months until last FU. A capture-based NGS panel targeting 65 myeloid genes was used. Libraries were prepared following manufacturer's instructions (Twist BioScience) and run on Illumina sequencers. Mutations were considered at coverage of 2000x and >5% variant allele frequency (VAF). RESULTS Sixty-one patients were included in SintraRev with a median FU of 60.6 (32.3-73.9) months. A total of 47 patients (29 LEN, 18 PCB) had NGS data. At baseline, 32%, 36% and 32% of patients had 0, 1 and ≥2 mutations, respectively. More frequently mutated genes were SF3B1 (25.5% of patients) and TP53 (21%). No differences were observed regarding SF3B1 (p=0.74), TP53 (p=0.48) and DAT (DNMT3A, ASXL1 and TET2, p=1.0) mutations between groups. Furthermore, no differences in neither median number of mutations per patient (1: 0-4) nor VAF were found between LEN and PCB initially (p>0.05). At week 12, median VAF of mutations was significantly lower in the LEN group as compared to baseline (1.84% vs 9%, respectively p<0.01, n=21), but remaining stable in the PCB arm (18% w12 vs 17% baseline, p=0.594). Interestingly, in the long-term FU (median 22.4 months - 3.03 to 68.77) an increase in median VAF (from 17% to 29%, p<0.001, n=13) was observed in PCB arm (Fig 1). Clonal evolution among LEN & PCB patients during treatment was different, with a reduction in predominating clones in LEN arm, while remaining stable in the PCB group (Fig 2). In the long-term FU, both PCB & LEN showed acquisition of additional mutations (20% PCB & 22.7% LEN, p=1.0). Nevertheless, all these new mutations in the LEN group were acquired several months after loss of response to treatment or LEN discontinuation. Interestingly, dynamics of mutations under LEN treatment did not affect DAT mutations, which remained stable when cytogenetic response (CyR) was achieved. In this way, 87,5% of DAT mutations showed an independent behavior from the clone with 5q deletion. However, most SF3B1 (62,5%) and TP53 mutations (100%) were affected by LEN treatment in parallel with the disappearance of the del(5q) clone at the time of CyR. In this regard, responses were not affected by the persistence of DAT mutations (>80% of erythroid response, ER, and CyR) and interestingly, SF3B1mut patients achieved 100% of ER and CyR. In contrast, only 20% of TP53mut patients achieved ER and 60% CyR. AML evolution occurred in 13.8% and 22.2% patients in LEN & PCB arms, respectively (p=0.43). In patients transforming to AML, 50% had TP53mut in LEN while no TP53 mutations were found in PCB AML progression. No differences were found regarding median time to AML between the two groups (25.87 months, p=0.2). CONCLUSIONS MDS patients showing 5q deletion and without TD early treated with LEN did not showed more clonal evolution than the same set of patients in PCB arm. In fact, the acquisition of additional mutations in LEN patients was observed after loss of response or LEN discontinuation. Interestingly, molecular responses were confirmed in LEN patients by reduction of mutation's median VAF at week 12. Dynamic evolution of DAT alterations was not affected by LEN treatment, suggesting a role as CHIP-associated mutations. In contrast, most SF3B1 and TP53 mutations were modified in parallel with the del(5q) clone at the time of CyR. The maintenance of CHIP-related mutations did not affect either ER or CyR. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Luspatercept in Adult Patients with Transfusion-Dependent Anemia Due to Very Low, Low and Intermediate Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts, Who Had an Unsatisfactory Response to or Are Ineligible for Erythropoietin-Based Therapy: A Retrospective Multicenter Study By Fondazione Italiana Sindromi Mielodisplastiche (FiSiM ETS)

Background: Patients with lower-risk myelodysplastic syndromes (MDS) who develop red blood cells (RBC) transfusion-dependent anemia, experience worse quality of life and shorter survival. Therapeutic strategies after failure of erythropoiesis stimulating agents (ESAs) are limited. Regulatory approval of luspatercept in lower-risk MDS with ring sideroblasts (MDS-RS) offers a novel approach for the treatment of transfusion-dependent anemia in this subset of patients. However, data about luspatercept effectiveness in a real-world clinical setting are lacking. Here we report the results of a multicenter retrospective study including patients who were treated with luspatercept within the Italian compassionate use program. Methods: Eligible patients were ≥ 18 years old, had MDS-RS (2016 WHO classification), met criteria for very low, low, or intermediate IPSS-R risk; were receiving regular RBC transfusions (≥2 units/8 weeks in the 16 weeks before study entry); were refractory to or unlikely to respond to ESAs. Primary end point was transfusion independence (TI) for 8 weeks or longer during weeks 1 through 24; key secondary end point was TI for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48. Other secondary end points included erythroid response (defined by the IWG 2006 criteria), progression to acute myeloid leukemia (AML) and safety analyses. Exploratory analyses were performed to identify predictive factors for treatment response. Results: 184 patients who were enrolled in the Italian luspatercept compassionate use program between December 2020 and December 2021 were analyzed in this study. Median age at enrollment was 74 years (range, 31-88), median time since diagnosis was 43 months, and median time since onset of transfusion-dependence was 23 months. Overall, 123 (66.8%) patients had at least one comorbidity requiring ongoing treatment, 39 (21.2%) had at least three. Baseline median transfusion burden was 6 RBC units every 8 weeks (range, 2-25). At the time of data analysis (June 30, 2022), 130 (73.4%) patients completed at least 24 weeks of treatment. Median time on treatment was 301.5 days, and median follow-up time was 376 days. During the first 24 weeks of the trial, 59 (32%) patients had TI for 8 weeks or longer. The percentage of patients achieving TI increased to 38.6% in the first 48 weeks of the trial. Median duration of TI was 27.9 weeks. Focusing on secondary endpoints, 36 patients (19.6%) had TI for 12 weeks or longer during the first 24 weeks, 52 (28.3%) had TI for 12 weeks or longer considering the first 48 weeks of the trial. A reduction ≥ 4 RBC units/8 weeks during weeks 1-24 was seen in 66 patients (40.2%). Four (2.2%) patients evolved to AML. Serious adverse events were recorded in 27 (15.2%) patients and led to study discontinuation in 5 (2.8%). Overall, treatment was discontinued in 72 (40.7%) patients, mainly for lack of benefit (table 1) The maximum approved dose (1.75 mg/kg) of luspatercept was administered at least once in 144 (81%) patients. Among patients who achieved TI for 8 weeks or longer in the first 48 weeks, luspatercept dose (mg/kg) at response was 1, 1.33 and 1.75 in 31 (46.3%), 18 (29.9%) and 18 (29.9%%) patients, respectively. Logistic regression analysis showed that higher baseline transfusion burden was significantly associated with a lower probability of achieving TI. We identified 3 group of patients stratified according to baseline transfusion burden (group 1, ≤4 units/8 weeks; group 2, 5 to 7 units/8 weeks, group 3, ≥8 units/8 weeks) with a significantly different probability to achieve both the primary endpoint (51.9%, 35.2% and 16.7%, respectively, P<0.01) and the key secondary endpoint (30.8%, 24.1% and 9%, respectively, P<0.01). Patients with higher transfusion burden had higher luspatercept doses at first response (table 2). In patients with low probability to achieve TI (group 2 and 3), a reduction in transfusions equal or greater than 4 units/8 weeks was achieved in 66 (46.2%). Conclusion: Luspatercept was effective for the treatment of transfusion-dependent anemia in MDS-RS in a real-life setting. The benefit extended beyond the achievement of TI and produced a significant reduction in the number of RBC transfusions. Higher baseline transfusion burden was associated with a reduced probability to achieve TI; in these patients, the reduction of transfused RBC units appears a more reliable treatment target. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

Prospective validation of a biomarker-driven response prediction model to romiplostim in lower-risk myelodysplastic neoplasms – results of the EUROPE trial by EMSCO

The EUROPE phase 2 trial investigated the predictive value of biomarkers on the clinical efficacy of single agent romiplostim (ROM) treatment in patients with lower-risk myelodysplastic neoplasms (LR-MDS) and thrombocytopenia within the ‘European Myelodysplastic Neoplasms Cooperative Group‘ (EMSCO) network. A total of 77 patients with LR-MDS and a median platelet count of 25/nl were included, all patients received ROM at a starting dose of 750 μg by SC injection weekly. Thirty-two patients (42%) achieved a hematologic improvement of platelets (HI-P) with a median duration of 340 days. Neutrophil (HI-N) and erythroid (HI-E) responses were observed in three (4%) and seven (9%) patients, respectively. We could not confirm previous reports that HI-P correlated with baseline endogenous thrombopoietin levels and platelet transfusion history, but SRSF2 mutation status and hemoglobin levels at baseline were significantly linked to HI-P. Sequential analysis of variant allelic frequency of mutations like SRSF2 did not reveal an impact of ROM on clonal evolution in both responders and non-responders. In summary, our study confirms the safety and efficacy of ROM in LR-MDS patients and may allow to better define subgroups of patients with a high likelihood of response.

Ferritin Increase in Hemochromatosis Subjects After Discontinuing Their Regular Maintenance Treatment: A Longitudinal Analysis Performed During the COVID-19 Imposed Hospital Lockdown.

Ferritin Increase in Hemochromatosis Subjects After Discontinuing Their Regular Maintenance Treatment: A Longitudinal Analysis Performed During the COVID-19 Imposed Hospital Lockdown.

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

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

Phase II trial of luspatercept with or without hydroxyurea for the treatment of patients with myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis or unclassifiable with ring sideroblasts.

TPS7080 Background: Myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) are classified as a distinct category under the World Health Organization (WHO) classification of myeloid neoplasms. MDS/MPN with RS and thrombocytosis (MDS/MPN-RS-T) and MDS/MPN, unclassifiable with &gt; 15% bone marrow ring sideroblasts (MDS/MPN-U-RS) have similar clinical and pathological characteristics with symptomatic or transfusion-dependent anemia as the predominant morbidity. Luspatercept has been approved in myelodysplastic syndromes with ring sideroblasts (MDS-RS) and MDS/MPN overlap syndromes, based on the phase 3 MEDALIST clinical trial which primarily included MDS-RS patients with an objective erythroid response rate of approximately 40 per cent. In this trial, some MDS-RS patients also experienced an increase in neutrophil and platelet counts. This raises a safety concern for MDS/MPN patients with elevated platelet or WBC counts such as MDS/MPN-RS-T and MDS/MPN-U-RS. Previous studies have shown clinical and biological differences between MDS-RS and MDS/MPN-RS-T, with the latter group at a significantly elevated risk for thrombotic events. Additionally, several MDS/MPN-RS-T patients are on hydroxyurea which may blunt the erythroid response of luspatercept. Therefore, it is imperative to establish the safety and efficacy of luspatercept in this patient group. Methods: This is an investigator-initiated, prospective, phase II study of luspatercept in MDS/MPN overlap neoplasms with ring sideroblasts and thrombocytosis or unclassifiable with ring sideroblasts with 2 arms; hydroxyurea-independent (cohort A) and hydroxyurea-dependent (cohort B). Hydroxyurea and/or aspirin use is allowed as per investigator discretion. The primary goal is to study the efficacy and safety of luspatercept in MDS/MPN-RS-T or MDS/MPN-U-RS with symptomatic anemia. The primary endpoint is to assess erythroid response rate as per the 2015 International Working Group MDS/MPN response criteria. Secondary endpoints include response duration, time to acute myeloid leukemia (AML) transformation, thrombosis rate, AML-free and overall survival. Inclusion criteria include newly diagnosed or relapsed/refractory adult patients with WHO-defined diagnosis of MDS/MPN-RS-T or MDS/MPN-U-RS with symptomatic or transfusion-dependent anemia and unlikely to respond (EPO level &gt; 200 IU/L) or intolerant to erythropoiesis stimulating agent (ESA) therapy. Prior therapy with lenalidomide, hypomethylating agents or immunosuppressive therapy is allowed. The overall plan is to enroll 54 patients across the three Mayo Clinic sites, Minnesota, Arizona and Florida. Enrollment to the trial began in January 2022 with 1 patient enrolled at the time of abstract submission. Clinical trial information: NCT05005182.

Myelodysplastic Syndromes with Isolated 20q Deletion: A New Clinical-Biological Entity?

Aims: To define the peculiar features of patients with the deletion of the chromosome 20 long arm (del20q), data from 69 patients with myelodysplastic syndromes (MDSs) and isolated del20q, followed by the Gruppo Romano-Laziale Sindromi Mielodisplastiche (GROM-L) and Ospedale Torrette of Ancona, were collected and compared with those of 502 MDS patients with normal karyotype (NK-MDS). Results: Compared to the NK-MDS group, patients with del20q at diagnosis were older (p = 0.020) and mainly male (p = 0.006). They also had a higher rate of bone marrow blast < 5% (p = 0.004), a higher proportion of low and int-1 risk according to IPSS score (p = 0.023), and lower median platelet (PLT) count (p < 0.001). To date, in the del20q cohort, 21 patients (30.4%) received no treatment, 42 (61.0%) were treated with erythropoiesis-stimulating agents (ESA), 3 (4.3%) with hypomethylating agents, and 3 (4.3%) with other treatments. Among 34 patients evaluable for response to ESA, 21 (61.7%) achieved stable erythroid response according to IWG 2006 criteria and 13 (38.2%) were resistant. Nine patients (13.0%) progressed to acute myeloid leukaemia (AML) after a median time from diagnosis of 28 months (IR 4.1–51.7). The median overall survival (OS) of the entire cohort was 60.6 months (95% CI 54.7–66.4). the 5-year cumulative OS was 55.9% (95% CI 40.6–71.2). Conclusion: According to our results, we hypothesize that MDSs with isolated del 20q may represent a distinct biological entity, with peculiar clinical and prognostic features. The physio-pathological mechanisms underlying the deletion of the chromosome 20 long arm are still unclear and warrant future molecular analysis.

Response Assessment to Erythropoietin-Zeta (Epo-Alpha Biosimilar) Therapy in Low-Risk Myelodysplastic Syndromes.

Background. This prospective observational study aimed to verify the efficacy of erythropoietin zeta in the treatment of patients with low-risk myelodysplastic syndrome. Methods. Patients with low/int-1 IPSS risk and serum erythropoietin level below 500 U/L were enrolled. Treatment consisted of erythropoietin zeta 40,000 U subcutaneously once a week. The primary endpoint was the erythroid response. According to Simon’s two-stage statistical design, 36 patients were recruited. The median age was 75 years (range 56–83 years), male/female ratio was 1.1/1, median baseline serum erythropoietin was 57.9 U/L (range 9.4–475 U/L). 53% of patients had low-risk disease, while the remaining had Int-1 risk. Results. After 8 weeks, a significant response (rise in Hb levels of at least 1.5 g/dL) was achieved in 18 patients (50%) out of 36. However, 17 patients did not improve; 8/17 patients pursued the 40,000 U weekly schedule of erythropoietin zeta, and 4/8 (50%) of them reached the erythroid response after 16 weeks. Nine patients underwent dosage doubling (40,000 U twice per week), and 5/9 (55%) of them achieved the erythroid response. Conclusion. Compared with data from the literature, this prospective study revealed that EPO-zeta is a safe and effective therapeutic option in low-risk MDS patients.

Deferasirox in the management of iron overload in patients with myelofibrosis treated with ruxolitinib: The multicentre retrospective RUX-IOL study.

Deferasirox (DFX) is used for the management of iron overload (IOL) in many haematological malignancies including myelofibrosis (MF). The 'RUX-IOL' study retrospectively collected 69 MF patients treated with ruxolitinib (RUX) and DFX for IOL to assess: safety, efficacy in term of iron chelation response (ICR) and erythroid response (ER), and impact on overall survival of the combination therapy. The RUX-DFX therapy was administered for a median time of 12.4months (interquartile range 3.1-71.2). During treatment, 36 (52.2%) and 34 (49.3%) patients required RUX and DFX dose reductions, while eight (11.6%) and nine (13.1%) patients discontinued due to RUX- or DFX-related adverse events; no unexpected toxicity was reported. ICR and ER were achieved by 33 (47.8%) and 32 patients (46.4%) respectively. Thirteen (18.9%) patients became transfusion-independent. Median time to ICR and ER was 6.2 and 2months respectively. Patients achieving an ER were more likely to obtain an ICR also (p=0.04). In multivariable analysis, the absence of leukocytosis at baseline (p=0.02) and achievement of an ICR at any time (p=0.02) predicted improved survival. In many MF patients, the RUX-DFX combination provided ICR and ER responses that correlated with improved outcome in the absence of unexpected toxicities. This strategy deserves further clinical investigation.

Long-term safety and erythroid response with luspatercept treatment in patients with β-thalassemia.

β-thalassemia is a hereditary blood disorder resulting in ineffective erythropoiesis and anemia. Management of anemia with regular blood transfusions is associated with complications including iron overload. Here, we report long-term safety and efficacy results of the first clinical study of luspatercept in β-thalassemia, initiated in 2013, enrolling adults with both nontransfusion-dependent (NTD) and transfusion-dependent (TD) β-thalassemia. The objective was to report long-term safety data, for up to 5 years of treatment, for 64 patients with TD or NTD β-thalassemia, and long-term efficacy data for a subset of 63 patients with β-thalassemia who received high-dose luspatercept (0.6-1.25 mg/kg): 31 NTD and 32 TD patients. The study was a phase 2, noncontrolled, open-label trial comprising a dose-finding base phase and a 5-year extension phase. Endpoints include safety; erythroid response over a continuous 12-week period [NTD: hemoglobin increase from baseline ⩾1.0 or ⩾1.5 g/dl; TD: red blood cell (RBC) transfusion burden reduction, ⩾20%, ⩾33%, or ⩾50%]; and changes in biomarkers of ineffective erythropoiesis, iron metabolism parameters, Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) scores, and 6-min walking distance. Median duration of luspatercept exposure for NTD and TD patients was 910 days (range, 40-1850) and 433 days (range, 21-1790), respectively. Seventeen of 31 (54.8%) NTD patients achieved a mean hemoglobin increase of ⩾1.5 g/dl and 19 of 32 (59.4%) TD patients achieved ⩾50% reduction in RBC transfusion burden, during any continuous 12-week period. Median cumulative duration of response was 1126 days (range, 127-1790) for NTD patients and 909 days (range, 87-1734) for TD patients. The most common treatment-related adverse events of any grade were bone pain, headache, and myalgia. Long-term assessment of patients with β-thalassemia showed luspatercept was associated with sustained increases in hemoglobin levels in NTD patients and sustained transfusion burden reductions in TD patients. (ClinicalTrials.gov Identifiers: NCT01749540 and NCT02268409). Long-term safety and erythroid response with luspatercept treatment in patients with β-thalassemia Background: β-thalassemia is a genetic blood disorder caused by mutations in the β-globin gene, which encodes one of the proteins that comprise hemoglobin, a key constituent of red blood cells. Patients with β-thalassemia experience anemia, the main treatment for which is blood transfusions. Long-term repeated blood transfusions lower patients' quality of life, use hospital resources, and the resulting accumulation of excess iron can cause organ failure and decrease life expectancy. The severity of the anemia experienced by patients with β-thalassemia varies; patients with transfusion-dependent β-thalassemia require regular blood transfusions, compared with those with nontransfusion-dependent β-thalassemia who require infrequent transfusions, or even none at all, to manage their symptoms. Luspatercept (Reblozyl®) is an agent that stimulates the production of red blood cells and is used to treat anemia caused by β-thalassemia. However, the long-term effects of luspatercept treatment on patients with β-thalassemia are not known.Objective: In this study, we report the long-term safety of luspatercept in 64 adult patients with either transfusion-dependent or nontransfusion-dependent β-thalassemia, and the long-term efficacy of high-dose luspatercept (0.6-1.25 mg/kg) in a subset of 63 patients.Results: The average time period that patients were treated with luspatercept was 910 days for nontransfusion-dependent β-thalassemia and 433 days for transfusion-dependent β-thalassemia. We report that in patients with nontransfusion-dependent β-thalassemia, luspatercept treatment was associated with sustained increases, just over 3 years, in hemoglobin levels. Likewise, in transfusion-dependent β-thalassemia, luspatercept treatment was associated with a sustained reduction, 2.5 years, in the amount of blood transfusion required to manage their anemia. Long-term treatment with luspatercept was not associated with any new side effects compared with previous short-term treatment studies. The most common side effects were headache (27 patients), bone pain (20 patients), and muscle pain (14 patients) with more than 90% of these patients experiencing these side effects as mild severity.Conclusion: The results of this study show that in patients with either transfusion-dependent or nontransfusion-dependent β-thalassemia, luspatercept provides lasting reduction in anemia with mostly mild and predictable side effects.

Prediction of Response to Erythropoiesis Stimulating Agents in Low-Risk Myelodysplastic Syndromes.

Introduction:Erythropoiesis stimulating agents (ESAs) represents the principal treatments for anemia in patients with lower-risk myelodysplastic syndromes (MDS). Pre-treatment erythropoietin (EPO) level and previous blood transfusion requirement are the two major predictors for response to ESAs. However, most evidence was derived from Western countries whereas there have been limited data in patients with Asian background. Methods:We retrospectively collected data on patients with low-risk MDS who received ESAs. Erythroid response was evaluated according to IWG 2006 criteria. MDS subtypes, r-IPSS, baseline hemoglobin (Hb), ESAs dosage and erythropoietin level were reviewed from medical records. Gene mutations were analyzed in patients’ blood or bone marrow at diagnosis by 40-gene myeloid panel targeted sequencing. Clinical and laboratory parameters were compared between erythroid responder and non-responder groups. Results:A total of 47 patients were recruited in the study. The median age at diagnosis of the patients in this cohort was 77 years (IQR, 70-83) and 44.7% were male. The median revised international prognostic scoring system (R-IPSS) score of patients was 2.5. Response rate to ESAs was 46.8% (22/47). Median EPO level in responders was significantly lower than non-responders (27.7 vs. 59.1 U/L, p=0.02). Median ESAs dosage in responder group was 30,000 units per week. Cytogenetic abnormalities were detected in 27.3% and 24% of the responder and non-responder groups, respectively. Of 22 patients with available 40 gene mutation targeted sequencing, ASXL1, IDH2 and TET2 represented the 3 most common mutations and were found in 22%, 22% and 17%, respectively. There were no differences in cytogenetic abnormalities and gene mutations between groups. Patients who responded to ESAs showed a higher 5-year overall survival (OS) compared to non-responders (5-year OS 75% vs. 60.9%; p=0.008). Conclusion:We conclude that a low serum EPO level is a predictive factor for responsiveness to ESAs in Asian patients with low-risk MDS.

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

CLI120-001 Phase Ib Study of RVU120(SEL120) in Patients with AML and High Risk MDS: Updated Safety/Efficacy Results from Initial Dose Escalation

CLI120-001 Phase Ib Study of RVU120(SEL120) in Patients with AML and High Risk MDS: Updated Safety/Efficacy Results from Initial Dose Escalation

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)

Trial in Progress: A Phase 2, Open-Label Study Evaluating the Safety and Efficacy of the PKR Activator Etavopivat (FT-4202) in Patients with Thalassemia or Sickle Cell Disease

Trial in Progress: A Phase 2, Open-Label Study Evaluating the Safety and Efficacy of the PKR Activator Etavopivat (FT-4202) in Patients with Thalassemia or Sickle Cell Disease

MDS-279: Efficacy and Safety of Luspatercept in Patients with Anemia: A Systematic Review

Context: Luspatercept is an erythroid maturation agent that has been shown to improve anemia by influencing late-onset erythropoiesis. Objective: To determine safety and efficacy of luspatercept in patients aged >18 years of age and diagnosed with either myelodysplastic syndrome or beta-thalassemia. Design: Systematic review. Methods: A literature search was performed on PubMed, Embase, clinicaltrials.gov, Web of Science, and Cochrane using the MeSH terms “anemia” and “Immunoglobulin fc fragments” from database inception until 4/20/2021. After screening 420 articles, 2 randomized clinical trials (RCT, N=565) and 2 phase II trials (N=122) were included. Results: In 4 clinical trials (N=687), subcutaneous luspatercept (0.125 mg/dl to 1.75 mg/dl) was administered every 21 days for at least 48 weeks or 5 cycles to treat anemia in beta-thalassemia (N=288) and MDS (N=211) patients. The median pre-transfusion hemoglobin level was 7.6 g/dl in MDS patients and 10 g/dl in beta-thalassemia patients. Median red cell transfusion burden varied between 14 RBC units/24 weeks to 8 RBC units/8 weeks. Cappellini et al. and Piga et al. (N=400) showed >33% reduction in RBC transfusion burden in 71% (n=159/224) of patients (vs 29.5% with placebo) and >20% reduction in 80% (n=51/64) of patients with beta-thalassemia. Platzbecker et al. and Fenaux et al. (N=287) showed more than 4 RBC unit reduction/8 weeks in 47% (n=100/211) of patients with MDS treated with luspatercept (vs 21% with placebo). High-dose-treated patients had a mean increase in Hb ranging from 0.36 g/dl to 1.52 g/dl. The most common side effects included headache, back pain, bone pain, fatigue, and diarrhea in 19.6% (n=98), 19.4% (n=97), 13% (n=65), 9% (n=45), and 7.4% (n=37), respectively. More than grade 3 adverse effects were bone pains, hyperuricemia, and back pain in 6.4% (n=32), 1.2% (n=6), and 0.6% (n=3), respectively. Conclusion: Luspatercept showed better efficacy than placebo in beta-thalassemia and MDS patients to treat anemia and was well-tolerated by these patients. High-dose luspatercept has shown promising results in terms of erythroid response, measured as either a reduction in transfusion burden or a mean increase in hemoglobin levels. A number of clinical trials are ongoing to assess its efficacy in myelofibrotic disorders to further extend its usage.