Lower-risk Myelodysplastic Syndromes Research Articles

Treatment of high risk myelodysplastic syndrome.

The myelodysplastic syndrome (MDS) is considered to be a heterogeneous myeloid malignancy with a common origin in the hematopoietic stem cell compartment, generally divided into lower and higher risk. While treatment goal for lower risk MDS (LR-MDS) is to decrease transfusion burden and transformation into acute leukemia major aim for high risk MDS is to prolong survival and ultimately cure. While novel agents such as luspatercept or imetelstat have recently been approved as new treatment options for LR-MDS, hypomethylating agents (HMA) remain currently the only approved non-transplant option for HR-MDS and is the standard of care for non-transplant-eligible patients. Combinations with other drugs as first-line treatment has to date not proven more efficacious than monotherapy in HR-MDS, and outcome after HMA failure is poor. The only potential cure and standard of care for eligible patients is allogeneic stem cell transplantation (HSCT) and even if the number of transplanted - especially older - MDS patients increased over time due to a better management and donor availability the majority of MDS patients will not be eligible for this curative approach. Current challenges encompass to decrease the relapse risk, the main cause of HSCT failure. This review will summarize current knowledge of options of transplant- and non-transplant treatment approaches for these patients and demonstrate the unmet clinical need for more effective therapies.

Imetelstat for anemia in lower-risk myelodysplastic syndromes: A summary from the Institute for Clinical and Economic Review's California Technology Assessment Forum.

Imetelstat for anemia in lower-risk myelodysplastic syndromes: A summary from the Institute for Clinical and Economic Review's California Technology Assessment Forum.

Successful treatment of low-risk myelodysplastic syndrome-related anemia in patients with chronic kidney disease with daprodustat: A report of two cases.

Anemia is a major clinical manifestation seen in myelodysplastic syndromes (MDS). Treatment options for anemia in low-risk MDS are limited. Especially, oral medication which is uniformly effective for anemia in low-risk MDS is required. Hypoxia-inducible factor (HIF) prolyl hydroxylase (HIF-PH) inhibitors, such as daprodustat, are oral tablets effective for renal anemia. Pharmacological restoration of HIF activity by HIF-PH inhibitors may be beneficial for MDS-related anemia as well. Yet, their efficacy and safety against low-risk MDS are unclear. Here, we report two cases of low-risk MDS complicated with chronic kidney disease whose anemia responded to daprodustat treatment.

A phase 2 clinical trial of luspatercept in non-transfusion-dependent patients with myelodysplastic syndromes.

Luspatercept has shown durable clinical efficacy for the treatment of anemia in transfusion-dependent patients with lower-risk myelodysplastic syndromes (LR-MDS). We report the results of a prespecified primary analysis of a phase 2 trial of luspatercept in non-transfusion-dependent (NTD) Japanese patients with anemia due to LR-MDS. Luspatercept (starting dose 1.0mg/kg) was administered subcutaneously once every 3weeks. The primary endpoint was the proportion of patients who achieved hematological improvement-erythroid (HI-E) response (≥ 1.5g/dL increase in hemoglobin level for 8weeks) without transfusions within the first 24weeks of treatment. At the primary analysis data cutoff, 21 patients had been enrolled/treated; 17 and 10 patients had completed 24 and 48weeks of treatment, respectively. HI-E response occurred within 24weeks in 10 patients (47.6%; 95% confidence interval, 25.7-70.2; P < 0.0001), which was significantly higher than the predefined threshold (10%). By week 48, HI-E response occurred in 12 patients (57.1%) and 17 patients (81.0%) remained NTD. Luspatercept was well tolerated. Three patients (14.3%) had grade 3-4 treatment-related treatment-emergent adverse events. Luspatercept resulted in statistically and clinically significant improvements in hemoglobin levels, and may help delay the need for transfusions in NTD patients with LR-MDS.

The IL-1β inhibitor canakinumab in previously treated lower-risk myelodysplastic syndromes: a phase 2 clinical trial

In myelodysplastic syndromes (MDS), the IL-1β pathway is upregulated, and previous studies using mouse models of founder MDS mutations demonstrated that it enhances hematopoietic stem and progenitor cells’ (HSPCs’) aberrant differentiation towards the myeloid lineage at the expense of erythropoiesis. To evaluate whether targeting the IL-1β signaling pathway can rescue ineffective erythropoiesis in patients with MDS, we designed a phase 2 non-randomized single-arm clinical trial (NCT04239157) to assess the safety profile and efficacy of the IL-1β inhibitor canakinumab in previously treated lower-risk MDS patients. We enrolled 25 patients with a median age of 74 years; 60% were male, 16% had lower-risk MDS, 84% had intermediate-1 risk MDS according to the International Prognostic Scoring System score, and 80% failed hypomethylating agent therapy. The study met the primary endpoint of defining the clinical activity of canakinumab, and the secondary objective of determining the safety profile, including the rate of transfusion independence, the duration of response, progression-free survival, leukemia-free survival, and overall survival. The overall response rate was 17.4%, with all responses including hematological improvement. Sequential post-hoc prospective single-cell RNA sequencing analyses of HSPCs and bone marrow mononuclear cells at different time points during therapy showed that canakinumab’s on-target effects in hematopoietic populations expressing the IL-1β receptor decreased the TNF-mediated inflammatory signaling pathway but rescued ineffective erythropoiesis only in the context of lower genetic complexity. This study demonstrates that better stratification strategies could target lower-risk MDS patients more effectively.

Rapid growth of acquired UBA1 mutations predisposes male patients to low-risk MDS.

Rapid growth of acquired UBA1 mutations predisposes male patients to low-risk MDS.

Initial Results from the QTc Substudy of the IMerge Phase 3 Trial Demonstrate Clinically Meaningful Efficacy, Manageable Safety, and Absence of Proarrhythmic Risk in Patients with Lower-Risk Myelodysplastic Syndromes Who Received Prior Therapies Beyond Erythropoiesis Stimulating Agents

Initial Results from the QTc Substudy of the IMerge Phase 3 Trial Demonstrate Clinically Meaningful Efficacy, Manageable Safety, and Absence of Proarrhythmic Risk in Patients with Lower-Risk Myelodysplastic Syndromes Who Received Prior Therapies Beyond Erythropoiesis Stimulating Agents

Correlation of Patient-Reported Outcomes with Red Blood Cell Transfusion Reduction and Rise in Hemoglobin in Patients with Lower-Risk Myelodysplastic Syndromes in the IMerge Trial

Correlation of Patient-Reported Outcomes with Red Blood Cell Transfusion Reduction and Rise in Hemoglobin in Patients with Lower-Risk Myelodysplastic Syndromes in the IMerge Trial

Association between Lipid Profile and Molecular Signature of Monocytes in Patients with Lower-Risk MDS

Association between Lipid Profile and Molecular Signature of Monocytes in Patients with Lower-Risk MDS

Targeting of Various Inflammatory Circuits Does Not Ameliorate Ineffective Hematopoiesis: Results of the Lucas and Canfire Studies Investigating IRAK4 or IL-1β Blockade to Target Anemia in Lower-Risk MDS

Targeting of Various Inflammatory Circuits Does Not Ameliorate Ineffective Hematopoiesis: Results of the Lucas and Canfire Studies Investigating IRAK4 or IL-1β Blockade to Target Anemia in Lower-Risk MDS

Bone Marrow-Derived CD57+ NK and NK-like T-Cells Expand in Lower-Risk MDS and Are Implicated in Driving Bone Marrow Failure

Bone Marrow-Derived CD57+ NK and NK-like T-Cells Expand in Lower-Risk MDS and Are Implicated in Driving Bone Marrow Failure

Preliminary Safety and Efficacy of Luspatercept Initiated at Maximum Approved Dose in Patients with Transfusion Dependent Anemia Due to Very Low, Low and Intermediate Risk MDS with Ring Sideroblasts: First Results of the Lusplus Trial

Preliminary Safety and Efficacy of Luspatercept Initiated at Maximum Approved Dose in Patients with Transfusion Dependent Anemia Due to Very Low, Low and Intermediate Risk MDS with Ring Sideroblasts: First Results of the Lusplus Trial

Health-Related Quality of Life of Luspatercept Versus Epoetin Alfa in Red Blood Cell Transfusion-Dependent Lower-Risk Myelodysplastic Syndromes: Results from the Final Datacut of the Phase 3 COMMANDS Study

Health-Related Quality of Life of Luspatercept Versus Epoetin Alfa in Red Blood Cell Transfusion-Dependent Lower-Risk Myelodysplastic Syndromes: Results from the Final Datacut of the Phase 3 COMMANDS Study

Differences in Treatment Decision-Making in Frontline Management of Lower-Risk Myelodysplastic Syndromes between Academic and Community Practice Settings: Results from a Nationwide Survey

Differences in Treatment Decision-Making in Frontline Management of Lower-Risk Myelodysplastic Syndromes between Academic and Community Practice Settings: Results from a Nationwide Survey

Imetelstat, a novel, first-in-class telomerase inhibitor: Mechanism of action, clinical, and translational science.

Most cancers and neoplastic progenitor cells have elevated telomerase activity and preservation of telomeres that promote cellular immortality, making telomerase a rational target for the treatment of cancer. Imetelstat is a first-in-class, 13-mer oligonucleotide that binds with high affinity to the template region of the RNA component of human telomerase and acts as a competitive inhibitor of human telomerase enzymatic activity. Pharmacokinetics, pharmacodynamics, exposure-response analyses, efficacy, and safety of imetelstat have been evaluated invitro, invivo, and clinically in solid tumor and hematologic malignancies, including lower-risk myelodysplastic syndromes (LR-MDS) and myeloproliferative neoplasms. Imetelstat was approved in the United States in June 2024 for the treatment of adult patients with LR-MDS with transfusion-dependent anemia requiring four or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents, with a recommended dosing regimen of 7.1 mg/kg administered via 2-h intravenous infusion every 4 weeks. In the pivotal trial, significantly more patients treated with imetelstat versus placebo achieved ≥8-week and ≥24-week red blood cell-transfusion independence, and imetelstat was associated with a manageable safety profile characterized primarily by short-lived and manageable neutropenia and thrombocytopenia. This mini-review summarizes the mechanism of action, pharmacokinetic and pharmacodynamic characteristics, clinical development, and clinical efficacy and safety data of imetelstat.

Prognostic impact of 'multi-hit' versus 'single-hit' TP53 alteration in patients with acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases.

While there is clear evidence to suggest poorer outcome associated with multi-hit (MH) TP53 mutation (TP53MT) compared to a single-hit (SH) mutation in lower-risk myelodysplastic syndrome (MDS), data are conflicting in both higher-risk MDS and acute myeloid leukemia (AML). We conducted an in-depth analysis utilizing data from ten US academic institutions to study differences in molecular characteristics and outcomes of SH (N=139) versus MH (N=243) TP53MT AML. Complex cytogenetics were more common in MH than in SH TP53MT AML (P<0.001); whereas ASXL1 (P<0.001), RAS (P<0.001), splicing factor (P=0.003), IDH1/2 (P=0.001), FLT3 ITD (P<0.001) and NPM1 (P=0.005) mutations clustered significantly with SH TP53MT AML. Survival after excluding patients who received best supportive care alone was dismal but not significantly different between patients with SH or MH disease (event-free survival: 3.0 vs. 2.20 months, respectively, P=0.22; overall survival: 8.50 vs. 7.53 months, respectively, P=0.13). In multivariable analysis, IDH1 mutation and allogeneic hematopoietic stem cell transplantation as a time-dependent covariate were associated with superior event-free survival (hazard ratio [HR]=0.44, 95% confidence interval [95% CI]: 0.19-1.01, P=0.05 and HR=0.34, 95% CI: 0.18-0.62, P<0.001) and overall survival (HR=0.24, 95% CI: 0.08-0.71, P=0.01 and HR=0.28, 95% CI: 0.16-0.47, P<0.001). Complex cytogenetics (HR=1.56, 95% CI: 1.01-2.40, P=0.04) retained an unfavorable significance for overall survival. Our analysis suggests that MH TP53MT is less relevant in independently predicting outcomes in patients with AML than in those with MDS.

Síndromes mielodisplásicos y leucemia mielomonocítica crónica

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal diseases of hematopoietic progenitor cells. They are characterized by hypercellular bone marrow and ineffective hematopoiesis, which leads to the onset of cytopenia, morphological abnormalities, and a greater tendency to progress to acute myeloblastic leukemia (AML). Due to the highly variable clinical course, it is recommended that prognostic indexes be established to help identify progression to AML and make treatment decisions. However, when starting treatment, not only does the prognostic index have an influence, but age, comorbidities, Eastern Cooperative Oncology Group (ECOG) functional status, and the social environment must also be taken into account. Unlike high-risk MDS, where the goal of treatment is to modify the natural history of the disease and prolong overall survival, in low-risk MDS, the main goal is to improve cytopenia and quality of life with as little toxicity as possible.

Eltrombopag restores proliferative capacity and adipose-osteogenic balance of mesenchymal stromal cells in low-risk myelodysplastic syndromes

In low-risk myelodysplastic syndromes (MDS), the proinflammatory signaling is excessive, and the proliferation and differentiation potentials of mesenchymal stromal cells (MSCs) are strongly impaired. Eltrombopag (ELT) has been demonstrated recently effective and relatively safe in low-risk MDS with severe thrombocytopenia. However, its impact on the MDS-MSCs has not been investigated in any detail. Here, for the first time, we investigated the changes induced by ELT in MSCs’ viability, proliferation, apoptosis, senescence, multilineage differentiation properties, and stem cell support capacity in low-risk MDS patients. We demonstrated that ELT may act on improving the impaired inflammatory profile and reactivating the downregulated canonical WNT signaling pathway in low-risk MDS, and also restoring the self-renewal capacity and the balance in adipose-osteogenic differentiation of MDS-MSCs.

Efficacy of Epoetin Alfa in Managing Symptomatic Anaemia in Low-Risk Myelodysplastic Syndromes: A Retrospective Analysis.

Background Myelodysplastic syndromes (MDS) are clonal myeloid disorders characterised by ineffective haematopoiesis, leading to anaemia that often requires dependence on red blood cell (RBC) transfusions. Epoetin alfa (Eprex®) is now a mainstay in the management of symptomatic anaemia in low-risk MDS patients, reducing transfusion dependence and improving the quality of life in this patient group. Objective This retrospective study aimed to assess the efficacy of epoetin alfa in treating symptomatic anaemia in low-risk MDS patients, focusing on transfusion independence and its relationship with baseline erythropoietin (EPO) levels and haemoglobin (Hb) response. Methods Data from 56 patients with low-risk MDS treated with epoetin alfa at Norfolk and Norwich University Hospital,Norwich, United Kingdom, between 2018 and 2023 were retrospectively analysed. Baseline EPO levels, transfusion history, Hb response, and the duration of transfusion independence were assessed. Statistical analyses were performed to evaluate the correlation between baseline characteristics and treatment outcomes. Results Among the patients, 98.2% had baseline EPO levels below the 500 IU/L threshold, with a median EPO level of 74.3 IU/L. Following an eight-week trial of 30,000 units of epoetin-alfa, 41.1% of patients showed improved Hb levels, 41.1% maintained stable Hb levels, and 17.9% experienced a decline. A significant correlation was found between lower baseline EPO levels (<250 IU/L) and a positive treatment response (p = 0.0065). Additionally, patients who required fewer transfusions before treatment had longer durations of transfusion independence (correlation coefficient = -0.40, p = 0.015). Dose escalation to 60,000 units provided a benefit to 53.3% of patients with initially stable Hb levels. The average duration of transfusion independence was 8.1 months, and patients with improved Hb levels had the longest periods of transfusion independence (p = 0.005). Conclusion Epoetin alfa is an effective therapy for managing symptomatic anaemia in low-risk MDS patients. This study highlights its efficacy and provides valuable predictive information, particularly showing that patients with lower baseline EPO levels are more likely to respond to treatment. While prior transfusion dependence did not significantly predict response to therapy in this cohort, it was associated with the duration of transfusion independence.

Treatment of lower-risk myelodysplastic syndromes.

Myelodysplastic neoplasms (MDS) involve clonal hematopoiesis and cellular dysplasia, driven by genetic and epigenetic alterations. Spliceosome mutations and epigenetic dysregulation underscore the intricate pathogenesis of MDS. The bone marrow microenvironment, stromal dysfunction, chronic inflammation, and immune dysregulation contribute to disease progression. This complex pathogenesis underscores the necessity for targeted therapies, offering a personalized medicine approach, particularly in lower-risk patients. The development of risk scores like the International Prognostic Scoring System (PISS), its revision IPSS-R, and the incorporation of molecular genetics in IPSS-M have refined the diagnostic and prognostic framework of MDS. These scoring systems facilitate tailored treatment strategies and better prognostication, especially for lower-risk MDS patients. The progression from IPSS to IPSS-R and now to IPSS-M epitomizes the shift towards personalized medicine in MDS management. In this review we discuss recent developments and positive phase III studies in lower-risk MDS. The review concludes by proposing a treatment algorithm for LR-MDS and highlighting ongoing trials in this heterogeneous patient population.