Treatment Of Low-risk Myelodysplastic Syndromes Research Articles

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

MDS-416 Myelodysplastic Syndromes in Morocco: Evolution over 15 Years

Myelodysplastic syndromes (MDS) are defined in the World Health Organization classification of tumors of hematopoietic and lymphoid tissues as a group of clonal hematopoietic cell diseases characterized by cytopenia, dysplasia in one or more of myeloid cell lines, ineffective hematopoiesis, and an increased risk of progression to acute myeloid leukemia (AML). To determine the incidence of MDS in the pediatric hematology and oncology department of hospital 20 August 1953. Descriptive retrospective study made at the Pediatric Hematology and Oncology Department of hospital 20 August 1953 of the CHU Ibn Rochd Casablanca, including all patients with MDS confirmed on myelogram or BOM, diagnosed between January 2014 and December 2018. Patients with CMML, MDS/MPS border syndromes, or AML were excluded from our study. We found 272 patients diagnosed with MDS over the 15-year period from January 2004 to December 2018. The median incidence of MDS in our study was 19 cases/year, the median age was 59.5 years. According to the age groups, we found that 108 patients (or 40%) represented the age group of young adults (31-60 years), 67 patients (or 25%) represented the age group of elderly subjects (61-74 years), 60 patients (20%) represented the age group of very old subjects (over 75 years). The sex ratio (M/F) is 0.74. We noted that 1% of patients were genetically exposed and 16% of patients were exposed to various risk factors. The history of autoimmune diseases was found in 18% of patients in our series. 91% of patients had clinical signs. Therapeutically, we found that 74% of patients received symptomatic treatment. Fifteen patients in our series received specific treatment. Median survival is 5.63 months Conclusions: Myelodysplastic syndromes present a heterogeneous group of clonal hemopathies characterized by peripheral cytopenias and the risk of progression to acute leukemia. Diagnosis is currently based on bone marrow cytology, but the contribution of cytogenetic and molecular biology seems to go beyond prognostic interest (early diagnosis, prediction of therapeutic response). While the treatment of low-risk myelodysplastic syndromes is based on the correction of cytopenias, that of high-risk myelodysplastic syndromes aims to control the leukemic clone.

Treatment of lower-risk myelodysplastic syndrome

Introduction. We present the recommendations for treatment of the lower-risk myelodysplastic syndromes on behalf of the Serbian myelodysplastic syndromes group. Material and Methods. A literature review was conducted using the following bibliographic databases: Google Scholar, MEDLINE and Kobson. The recommendations for treatment of lower-risk myelodysplastic syndromes are based on expert opinion based on review of the literature and contemporary recommendations for treatment of lower risk myelodysplastic syndromes. Recommendations. Anemia is the most relevant cytopenia in terms of frequency and symptoms in lower-risk myelodysplastic syndromes, and may be treated successfully with erythropoietic stimulating agents, with or without granulocyte growth factor, provided a careful selection is performed on the basis of Revised International Prognostic Scoring System, endogenous erythropoietin levels, and transfusion independence. In case a patient fails erythropoietic stimulating agents treatment, the available options may include lenalidomide, hypomethylating agents, and a rather large number of experimental agents. Chelation therapy is recommended in patients who have received or are anticipated to receive > 20 red blood cell transfusions and those with serum ferritin levels > 2500 ng/mL. Specific therapy for thrombocytopenia has been proposed in experimental clinical trials with thrombomimetic agents that have shown good efficacy, but raised some safety concern. Severe neutropenia is targeted symptomatically with growth factor supportive care. The immunosuppressive treatments are indicated mainly for pancytopenia, hypoplastic lowerrisk myelodysplastic syndromes. Finally, hematopoietic stem cell transplantation is the curative option for younger, good performance (fit) lower-risk patient with poor risk features, according to European Blood and Marrow Transplantation/European Leukemia Net International expert panel and myelodysplastic syndrome-RIGHT group. Conclusion. Treatment of myelodysplastic syndromes is mainly based on resolution of symptoms due to particular cytopenia(s).

Luspatercept in the treatment of lower-risk myelodysplastic syndromes.

Transforming growth factor beta (TGF-β) signaling pathway is key to hematopoiesis regulation. Increased activation of this pathway contributes to ineffective terminal erythroid differentiation in myelodysplastic syndromes (MDS). Luspatercept is a novel fusion protein that traps TGF-β ligands preventing them from binding to Type II TGF-β receptors, thereby decreasing phosphorylated SMAD2/3 resulting in the downstream effect of promoting erythropoiesis. Seminal clinical trials using luspatercept, PACE-MD and MEDALIST, demonstrated impressive efficacy in the treatment of transfusion-dependent anemia in intermediate risk or lower MDS had led to the US FDA approval for this indication. This review summarizes luspatercept mechanisms of action, efficacy/safety data supporting its use and ongoing clinical trials in MDS.

Prise en charge des syndromes myélodysplasiques en 2019 : mise au point

Myelodysplastic syndromes are a heterogeneous group of clonal myeloid disorders characterized by peripheral cytopenias and an increased risk of progression to acute myeloid leukemia. Inflammatory, auto-immune or syndromic symptoms can make the diagnosis difficult. Diagnosis is currently based on bone marrow cytology but cytogenetics and molecular features are currently overpassing their initial prognostic function (allowing early diagnosis and prediction of therapeutic response). The prognostic classification is based on the Revised International Prognostic Scoring System, which also provides guidance for therapeutic management. The treatment of low-risk myelodysplastic syndromes is based on the correction of cytopenias (erythropoiesis stimulating agents, transfusions, lenalidomide, etc.), whereas in high-risk group, the goal is the control of the leukemic clone (hypomethylating agents, allograft of hematopoietic stem cell transplantation). Other molecules are used to manage complications of cytopenias or transfusion (anti-infectious prophylaxis and treatments, martial chelation). New molecules are being studied with some interesting results (luspatercept, venetoclax). This article aims to provide an update on the knowledge that an internist should know for the practical management of myelodysplastic syndromes in 2019.

Efficacy and safety of lenalidomide for the treatment of acute myeloid leukemia: a systematic review and meta-analysis.

BackgroundLenalidomide is effective for the treatment of low-risk myelodysplastic syndromes with deletion 5q abnormalities. However, whether lenalidomide leads to a significant improvement in treatment response and overall survival (OS) in cases of acute myeloid leukemia (AML) remains controversial. A systematic review and a meta-analysis were performed to evaluate the efficacy and safety of lenalidomide in the treatment of AML.MethodsClinical studies were identified from the Cochrane Central Register of Controlled Trials, PubMed, Embase, and ClinicalTrials.gov. Efficacy outcomes included overall response rate (ORR), complete remission (CR), and OS. Safety was evaluated based on the incidence of grade 3 and 4 treatment-related adverse events (AEs).ResultsEleven studies were included in our meta-analysis; collectively these studies featured 407 AML patients. Pooled estimates for overall ORR and CR were 31% (95% CI: 26%–36%) and 21% (95% CI: 16%–27%), respectively. Thrombocytopenia, anemia, neutropenia, and infection were the most common grade 3 and 4 AEs.ConclusionLenalidomide may have some clinical activity in AML, but the population that would benefit from lenalidomide and incorporating lenalidomide into combination drug strategies need to be better defined.

Extended Abstract: Treatment of Lower-Risk Myelodysplastic Syndromes

Extended Abstract: Treatment of Lower-Risk Myelodysplastic Syndromes

Treatment of low-risk myelodysplastic syndromes

New progress of treatment of low-risk myelodysplastic syndromes (MDS) reported in the 58th American Socienty of Hematology (ASH) Annual Meetings was reviewed. Anemia is a single common symptom of low-risk MDS, and erythropoietic-stimulating agents (ESA) may be effective. The dose and duration of erythropoietic-stimulating agents (ESA) are critical to determine efficacy. If the treatment of ESA failed, the available options may include lenalidomide (approved for del5q positive cases), hypomethylating agents and a rather large number of experimental agents. The choice for the second-line treatment must consider the biologic, cytogenetic and molecular-identified characteristics of individual patient, as well as frailty and comorbidities. Other cytopenias rarely appear alone. Thrombomimetic agents for thrombocytopenia has been proposed in clinical trials, but there were some safety issues. Although neutropenia is targeted symptomatically with growth factor supportive care, the immunosuppressive therapy is indicated mainly for pancytopenic and hypoplastic low-risk MDS. Finally, hematopoietic stem cell transplantion is the curative option also for low-risk MDS, but it should be carefully evaluated to balancing toxicity and the possibility of survival advantage. Key words: Myelodysplastic syndromes; Low-risk; American Society of Hematology Annual Meeting

Treatment of low-risk myelodysplastic syndromes.

The majority of myelodysplastic syndrome (MDS) patients belong to the International Prognostic Scoring System (IPSS) and IPSS-revised (IPSS-R) lower-risk categories. Their precise diagnostics and prognostic stratification is often a challenge, but may ensure the optimization of therapy. The availability of diverse treatment options has significantly improved the quality of life and survival of this group of patients. Anemia is the most relevant cytopenia in terms of frequency and symptoms in lower-risk MDS, and may be treated successfully with erythropoietic stimulating agents, provided a careful selection is performed on the basis of IPSS-R, endogenous erythropoietin levels, and transfusion independence. Doses and duration of therapy of erythropoietic-stimulating agents (ESAs) are critical to determine efficacy. In case a patient fails ESA treatment, the available options may include lenalidomide (approved for del5q positive cases), hypomethylating agents, and a rather large number of experimental agents, whose clinical trials should be offered to a larger number of MDS patients. The choice for second-line treatment must take into account biologic, cytogenetic, and molecular-identified characteristics of individual patients, as well as frailty and comorbidities. Other cytopenias are less frequently presenting as isolated. Specific therapy for thrombocytopenia has been proposed in experimental clinical trials with thrombomimetic agents that have shown good efficacy, but raised some safety concern. Although neutropenia is targeted symptomatically with growth factor supportive care, the immunosuppressive treatments are indicated mainly for pancytopenic, hypoplastic lower-risk MDS; they are not widely used because of their toxicity, despite the fact that they may induce responses. Finally, hematopoietic stem cell transplant is the curative option also for lower-risk MDS and timing should be carefully evaluated, balancing toxicity and the possibility of survival advantage. Finally, even when considered suitable for lower-risk MDS, transplant application is limited to the rarer fit and younger MDS patient.

Lenalidomide – A Brief Review of its Use in Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are a heterogeneous group of blood diseases mainly affecting older people. Deletion of the long arm of chromosome 5 (del[5q]) is reported in approximately 10–15 % of all MDS cases. Lenalidomide is an immunomodulatory, anti-cytokine and anti-angiogenic agent, which leads to red blood cells transfusion independence in patients of lower risk MDS with del(5q). This review briefly describes role of lenalidomide in treatment of lower-risk MDS with del(5q) as well as non-del-5q MDS. Recent evidence also suggest a potential role of lenalidomide in combination with other agents for treatment of higher-risk MDS

Clinical efficacy analysis of recombinant human erythropoietin in the treatment of lower-risk myelodysplastic syndromes

To investigate the efficacy and impact factors in lower-risk [International prognostic scoring system (IPSS) low or intermediate-1 risk] myelodysplastic syndrome (MDS) patients treated with recombinant human erythropoietin (rhEPO) alone or in combination with recombinant human granulocyte colony- stimulating factor (rhG-CSF). A total of 52 consecutive lower-risk MDS patients received subcutaneous injection of rhEPO alone or in combination with rhG-CSF at least 8 weeks, the rhEPO dose would be reduced slowly to stop or kept at minimum to maintain the response when the best efficacy achieved and maintained for 4 weeks. Their clinical features, efficacy, survival and the predictors of efficacy were analyzed retrospectively. The overall response rate was 51.9% (27/52) with 33.3%(9/27) achieving complete remission (CR) and 66.7%(18/27) achieving erythroid response (HI-E). In multivariate analysis, sEPO level (less than 500 U/L), BFU-E count (more than 25/10⁵ BMMNC), intermediate and high doses rhEPO±rhG-CSF therapy were independent predictors of better response. The median therapy period was 8(2-45) months and the median efficacy duration was 37(6-94) months (38 months for CR, 36 months for HI-E). Ten of the 27 responsive patients relapsed and 40% of them had disease progressions. Hemoglobin levels and karyotype affect response duration. Median overall survival was 47(6-114) months on a 37(6-114) months median follow-up. In multivariate analysis, ages (less than 60 years old), karyotype (good or intermediate) and response to rhEPO±rhG-CSF therapy may have a favorable survival impact on MDS. rhEPO, alone or in combination with rhG-CSF, is a useful drug for the treatment of anemia in lower-risk MDS patients and has favorable impact on life expectancy.

Valproic acid for the treatment of low-risk myelodysplastic syndromes: A case report and a review of the literature

Myelodysplastic syndromes are heterogeneous myeloid neoplasms ranging from indolent conditions with a near-normal life expectancy to forms approaching acute myeloid leukemia. Here we report a 51-year-old woman with depression and severe obesity who was diagnosed with an International Prognostic Scoring System low-risk myelodysplastic syndrome, presenting mainly with thrombocytopenia, treated with escalating dose of valproic acid as a single agent. After two years of treatment her platelet count is almost normal and the tolerance to therapy is good. It is already known that valproic acid could be used in high-risk myelodysplastic syndromes and acute myeloid leukemia, mainly in association with other drugs, but its role in low-risk myelodysplastic syndrome is not well established yet.

Optimal sequencing of treatments for patients with myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are characterized by chronic cytopenias and a high risk of transformation to acute myeloid leukemia. To date, only allogeneic stem cell transplantation has shown curative potential in MDS. The heterogeneous nature of MDS, and the paucity of randomized studies make individual therapeutic decisions, still largely based on the international prognostic scoring system, difficult. In lower-risk MDS, recent advances include demonstration of a possible survival advantage with erythropoiesis stimulating agents, the role of lenalidomide in cases with del 5q (which lead to its approval in the treatment of lower-risk MDS with del 5q by the Food and Drug Administration), and recognition of the importance of iron overload on prognosis. In higher-risk patients, progress has come from the use of reduced intensity conditioning allogeneic SCT in elderly patients, and from results obtained with the hypomethylating agents azacytidine and decitabine, leading to their approval for the treatment of symptomatic MDS by the Food and Drug Administration. In particular, results of a phase III trial show a significant survival benefit for azacytidine over conventional treatments in higher-risk MDS. This is the first time a drug demonstrates a survival impact in higher-risk MDS. We review these recent advances in this paper.

Evolving trends in the treatment of low‐risk myelodysplastic syndromes: immunomodulation and beyond—9th European Hematology Association Congress Geneva, Switzerland, 10–13 June 2004

The 9th European Hematology Association Congress, held in Geneva, Switzerland, from 10 through 13 June 2004, offered a number of educational programmes that focused on myelodysplastic syndromes (MDS). This report will summarize the material presented at the educational symposium entitled 'Evolving Trends in the Treatment of Low-Risk MDS: Immunomodulation and Beyond'. The overview of the presentations includes a comparative review of the classification systems for MDS; a discussion of treatment strategies and management issues for patients in lower risk disease categories; a description of a novel class of immunomodulators, the IMiDs((R)), and a presentation of updated data from clinical trials of the IMiD compound, lenalidomide, in the treatment of MDS.

Treatment of low-risk myelodysplastic syndromes with high-dose daily oral cholecalciferol (2000–4000 IU vitamin D3)

Treatment of low-risk myelodysplastic syndromes with high-dose daily oral cholecalciferol (2000–4000 IU vitamin D 3 )