RARE DISEASE
Refractory anemia with excess blasts in transformation
Refractory anemia with excess blasts in transformation
Refractory anemia with excess blasts in transformation
Synonyms: RAEB-t
Synonyms: RAEB-t
Synonyms: RAEB-t
Drug discovery
0
drugs
With orphan designations
Overview
Refractory anemia with excess blasts in transformation (RAEB-t) is a high-risk myelodysplastic syndrome (MDS) subtype characterized by 20-29% bone marrow blasts, ≥5% peripheral blasts, or Auer rods [1][9][16]. It carries significant risk of progression to acute myeloid leukemia (AML) and demonstrates distinct biological features from AML, including increased apoptosis [4][16]. Now classified as MDS with increased blasts-2 (MDS-IB2) per WHO criteria, it requires differentiation from AML [9][16].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
717 drug discovery papers about Refractory anemia with excess blasts in transformation, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
717 drug discovery papers about Refractory anemia with excess blasts in transformation, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2025-08-18 | Features of hematopoietic progenitor cell functioning in patients with myelodysplastic syndrome treated with lenalidomide
The stem cell pool is the primary site of malignant transformation, so studying progenitor cells in hematopoietic disorders is one of the most important ways to uncover the pathogenesis of malignant hemoblastoses. Myelodysplastic syndrome (MDS) is a hematologic disease characterized by genomic instability and heterogeneity. Treatment of MDS in the early stages of the disease (RAEB I) is limited to immunomodulators, one of which is lenalidomide. The drug is known to inhibit the proliferation of malignant cells by suppressing abnormal cloning and promoting apoptosis of Del(5q) cells. However, the extent of lenalidomide’s effect on the hematopoietic system in MDS has not yet been fully established. It is believed to enhance cellular immunity mediated by T cells and natural killer cells, and to inhibit the secretion of pro-inflammatory cytokines. The purpose of this study was to investigate the specific features of hematopoietic progenitor cell functioning under the influence of the immunomodulatory drug lenalidomide in patients with RAEB I. The study evaluated peripheral blood parameters and colony- and cluster-forming abilities of bone marrow hematopoietic progenitor cells cultured in semi-liquid agar. The study showed that the action of lenalidomide extends not only to the immune system, but also affects the closest descendants of the hematopoietic stem cells — hematopoietic progenitor cells — stimulating colony formation in 24% of bone marrow cultures and promoting the proliferation of all three blood lineages in the peripheral blood. These findings highlight the need to continue exploring therapeutic approaches for MDS that target early stages of hematopoiesis.
2024-04-14 | Role of reactive oxygen species in myelodysplastic syndromes
Abstract Reactive oxygen species (ROS) serve as typical metabolic byproducts of aerobic life and play a pivotal role in redox reactions and signal transduction pathways. Contingent upon their concentration, ROS production not only initiates or stimulates tumorigenesis but also causes oxidative stress (OS) and triggers cellular apoptosis. Mounting literature supports the view that ROS are closely interwoven with the pathogenesis of a cluster of diseases, particularly those involving cell proliferation and differentiation, such as myelodysplastic syndromes (MDS) and chronic/acute myeloid leukemia (CML/AML). OS caused by excessive ROS at physiological levels is likely to affect the functions of hematopoietic stem cells, such as cell growth and self-renewal, which may contribute to defective hematopoiesis. We review herein the eminent role of ROS in the hematological niche and their profound influence on the progress of MDS. We also highlight that targeting ROS is a practical and reliable tactic for MDS therapy. Graphical Abstract
2023-10-26 | Glutathione promotes the synergistic effects of venetoclax and azacytidine against myelodysplastic syndrome‑refractory anemia by regulating the cell cycle
Azacitidine is a DNA methyltransferase inhibitor that has been used as a singular agent for the treatment of myelodysplastic syndrome-refractory anemia with excess blast-1 and -2 (MDS-RAEB I/II). However, recurrence and overall response rates following this treatment remain unsatisfactory. The combination of azacitidine and venetoclax has been used for the clinical treatment of a variety of hematological diseases due to the synergistic killing effect of the two drugs. Venetoclax is a BCL-2 inhibitor that can inhibit mitochondrial metabolism. In addition, azacitidine has been shown to reduce the levels of myeloid cell leukemia 1 (MCL-1) in acute myeloid leukemia cells. MCL-1 is an anti-apoptotic protein and a potential source of resistance to venetoclax. However, the mechanism underlying the effects of combined venetoclax and azacitidine treatment remains to be fully elucidated. In the present study, the molecular mechanism underlying the impact of venetoclax on the efficacy of azacitidine was investigated by examining its effects on cell cycle progression. SKM-1 cell lines were treated in vitro with 0-2 µM venetoclax and 0-4 µM azacytidine. After 24, 48 and 72 h of treatment, the impact of the drugs on the cell cycle was assessed by flow cytometry. Following drug treatment, changes in cellular glutamine metabolism pathways was analyzed using western blotting (ATF4, CHOP, ASCT2, IDH2 and RB), quantitative PCR (ASCT2 and IDH2), liquid chromatography-mass spectrometry (α-KG, succinate and glutathione) and ELISA (glutamine and glutaminase). Venetoclax was found to inhibit mitochondrial activity though the alanine-serine-cysteine transporter 2 (ASCT2) pathway, which decreased glutamine uptake. Furthermore, venetoclax partially antagonized the action of azacitidine through this ASCT2 pathway, which was reversed by glutathione (GSH) treatment. These results suggest that GSH treatment can potentiate the synergistic therapeutic effects of venetoclax and azacitidine combined treatment on a myelodysplastic syndrome-refractory anemia cell line at lower concentrations.
2023-10-09 | Refining the Diagnosis and Treatment of Myelodysplastic Syndromes
Myelodysplastic syndromes (MDS) constitute a group of heterogeneous hematopoietic disorders characterized by cytopenias, dysplasia of hematopoietic cells and a propensity to transform into acute myeloid leukemia (AML). At the time of diagnosis, nearly all MDS patients have anemia, of whom approximately half require therapeutic interventions. In 20-40% of patients, low levels of neutrophils and thrombocytes are present as well. Due to the heterogeneity of MDS, the diagnosis and treatment of MDS poses considerable challenges. In this thesis, we aimed to improve diagnosis, classification, and treatment using computational and experimental methods. In the first part of this thesis, we focused on improving the diagnosis of MDS. We developed and validated a computational tool that included pre-processing of flow cytometry data, FlowSOM for cell population detection, and a machine-learning classifier. This tool demonstrated an improved performance in comparison to existing diagnostic flow cytometry approaches in terms of accuracy and efficiency. Further, we examined inter-analyst agreement for myeloid progenitor assessment by flow cytometry, and illustrated the efficacy and concordance of both manual and computational approaches for analysis. In the second part, we explored classification and genotype-phenotype associations in MDS, focussing on the association of SF3B1 mutations with bone marrow immunophenotype and natural killer (NK) cells. We identified specific erythroid, myelomonocytic, and progenitor features associated with SF3B1 mutations and in case of co-occurrence with a deletion of chromosomal arm 5q (del(5q)). In the study focussing on SF3B1 mutations and NK cells, we identified associations with certain immunophenotypic profiles and impaired NK cell functionality. Additionally, we extensively characterized stem- and progenitor cells of MDS patients of different risk categories, and identified specific cell surface proteins associated with these risk categories. In the third part, we focused on the treatment of MDS, investigating new treatment regimens, identifying potential therapeutic biomarkers and exploring reasons for the paucity of available agents. We conducted a randomized phase-II study that assessed the efficacy and safety of lenalidomide with or without erythropoietin stimulating agents in lower risk MDS patients, and identified several biomarkers for response. Additionally, the monitoring of therapy response through flow cytometric assessment of MDS-associated dysplasia provided insights into treatment effectiveness in the presence or absence of a del(5q). Lastly, we conducted an analysis of MDS trials over a 20-year period to identify reasons for the paucity of available effective agents for the treatment of MDS. In summary, this thesis provides strategies for improving the clinical management of MDS and offers insights into the pathogenesis. The obtained results may contribute to the development of more effective diagnostic tools, to the refinement of classification strategies, and to the expansion of treatment options for MDS patients.
2023-06-23 | Decitabine in patients with myelodysplastic syndromes: A multi‐center, open‐label, dose comparison trial
The hypomethylating agent decitabine is the standard therapy for intermediate or high risk myelodysplastic syndrome (MDS).In this trial, 191 adult patients with intermediate/high risk MDS (IPSS score ≥ 0.5) randomly received decitabine using a standard regimen (20 mg/m2 /day for 5 consecutive days; n = 94) or an extended regimen with lower daily dose (12 mg/m2 /day for 8 consecutive days; n = 97) every 4 weeks, for a total of 4 cycles.The median follow-up was 14 months (range 2-36). The primary end point of overall response rate in the intent-to-treat analysis was 41.5% and 38.1% in the standard and extended dosing arms, respectively (p = 0.660). Complete remission and marrow complete remission also did not differ between the two arms. Cytopenia was the most frequent adverse event (76.4%). The median duration of neutropenia per cycle did not differ between the two arms during the first two cycles, but significantly shorter in the extended dosing arm in the third cycle (8.5 vs. 15.5 days, p = 0.049) and in the fourth cycle (8 vs. 14 days, p = 0.294).The 5-day 20-mg/m2 /day and 8-day 12-mg/m2 /day decitabine regimens have similar efficacy and safety in patients with intermediate or high risk MDS.
2025-08-18 | Features of hematopoietic progenitor cell functioning in patients with myelodysplastic syndrome treated with lenalidomide
The stem cell pool is the primary site of malignant transformation, so studying progenitor cells in hematopoietic disorders is one of the most important ways to uncover the pathogenesis of malignant hemoblastoses. Myelodysplastic syndrome (MDS) is a hematologic disease characterized by genomic instability and heterogeneity. Treatment of MDS in the early stages of the disease (RAEB I) is limited to immunomodulators, one of which is lenalidomide. The drug is known to inhibit the proliferation of malignant cells by suppressing abnormal cloning and promoting apoptosis of Del(5q) cells. However, the extent of lenalidomide’s effect on the hematopoietic system in MDS has not yet been fully established. It is believed to enhance cellular immunity mediated by T cells and natural killer cells, and to inhibit the secretion of pro-inflammatory cytokines. The purpose of this study was to investigate the specific features of hematopoietic progenitor cell functioning under the influence of the immunomodulatory drug lenalidomide in patients with RAEB I. The study evaluated peripheral blood parameters and colony- and cluster-forming abilities of bone marrow hematopoietic progenitor cells cultured in semi-liquid agar. The study showed that the action of lenalidomide extends not only to the immune system, but also affects the closest descendants of the hematopoietic stem cells — hematopoietic progenitor cells — stimulating colony formation in 24% of bone marrow cultures and promoting the proliferation of all three blood lineages in the peripheral blood. These findings highlight the need to continue exploring therapeutic approaches for MDS that target early stages of hematopoiesis.
2024-04-14 | Role of reactive oxygen species in myelodysplastic syndromes
Abstract Reactive oxygen species (ROS) serve as typical metabolic byproducts of aerobic life and play a pivotal role in redox reactions and signal transduction pathways. Contingent upon their concentration, ROS production not only initiates or stimulates tumorigenesis but also causes oxidative stress (OS) and triggers cellular apoptosis. Mounting literature supports the view that ROS are closely interwoven with the pathogenesis of a cluster of diseases, particularly those involving cell proliferation and differentiation, such as myelodysplastic syndromes (MDS) and chronic/acute myeloid leukemia (CML/AML). OS caused by excessive ROS at physiological levels is likely to affect the functions of hematopoietic stem cells, such as cell growth and self-renewal, which may contribute to defective hematopoiesis. We review herein the eminent role of ROS in the hematological niche and their profound influence on the progress of MDS. We also highlight that targeting ROS is a practical and reliable tactic for MDS therapy. Graphical Abstract
2023-10-26 | Glutathione promotes the synergistic effects of venetoclax and azacytidine against myelodysplastic syndrome‑refractory anemia by regulating the cell cycle
Azacitidine is a DNA methyltransferase inhibitor that has been used as a singular agent for the treatment of myelodysplastic syndrome-refractory anemia with excess blast-1 and -2 (MDS-RAEB I/II). However, recurrence and overall response rates following this treatment remain unsatisfactory. The combination of azacitidine and venetoclax has been used for the clinical treatment of a variety of hematological diseases due to the synergistic killing effect of the two drugs. Venetoclax is a BCL-2 inhibitor that can inhibit mitochondrial metabolism. In addition, azacitidine has been shown to reduce the levels of myeloid cell leukemia 1 (MCL-1) in acute myeloid leukemia cells. MCL-1 is an anti-apoptotic protein and a potential source of resistance to venetoclax. However, the mechanism underlying the effects of combined venetoclax and azacitidine treatment remains to be fully elucidated. In the present study, the molecular mechanism underlying the impact of venetoclax on the efficacy of azacitidine was investigated by examining its effects on cell cycle progression. SKM-1 cell lines were treated in vitro with 0-2 µM venetoclax and 0-4 µM azacytidine. After 24, 48 and 72 h of treatment, the impact of the drugs on the cell cycle was assessed by flow cytometry. Following drug treatment, changes in cellular glutamine metabolism pathways was analyzed using western blotting (ATF4, CHOP, ASCT2, IDH2 and RB), quantitative PCR (ASCT2 and IDH2), liquid chromatography-mass spectrometry (α-KG, succinate and glutathione) and ELISA (glutamine and glutaminase). Venetoclax was found to inhibit mitochondrial activity though the alanine-serine-cysteine transporter 2 (ASCT2) pathway, which decreased glutamine uptake. Furthermore, venetoclax partially antagonized the action of azacitidine through this ASCT2 pathway, which was reversed by glutathione (GSH) treatment. These results suggest that GSH treatment can potentiate the synergistic therapeutic effects of venetoclax and azacitidine combined treatment on a myelodysplastic syndrome-refractory anemia cell line at lower concentrations.
2023-10-09 | Refining the Diagnosis and Treatment of Myelodysplastic Syndromes
Myelodysplastic syndromes (MDS) constitute a group of heterogeneous hematopoietic disorders characterized by cytopenias, dysplasia of hematopoietic cells and a propensity to transform into acute myeloid leukemia (AML). At the time of diagnosis, nearly all MDS patients have anemia, of whom approximately half require therapeutic interventions. In 20-40% of patients, low levels of neutrophils and thrombocytes are present as well. Due to the heterogeneity of MDS, the diagnosis and treatment of MDS poses considerable challenges. In this thesis, we aimed to improve diagnosis, classification, and treatment using computational and experimental methods. In the first part of this thesis, we focused on improving the diagnosis of MDS. We developed and validated a computational tool that included pre-processing of flow cytometry data, FlowSOM for cell population detection, and a machine-learning classifier. This tool demonstrated an improved performance in comparison to existing diagnostic flow cytometry approaches in terms of accuracy and efficiency. Further, we examined inter-analyst agreement for myeloid progenitor assessment by flow cytometry, and illustrated the efficacy and concordance of both manual and computational approaches for analysis. In the second part, we explored classification and genotype-phenotype associations in MDS, focussing on the association of SF3B1 mutations with bone marrow immunophenotype and natural killer (NK) cells. We identified specific erythroid, myelomonocytic, and progenitor features associated with SF3B1 mutations and in case of co-occurrence with a deletion of chromosomal arm 5q (del(5q)). In the study focussing on SF3B1 mutations and NK cells, we identified associations with certain immunophenotypic profiles and impaired NK cell functionality. Additionally, we extensively characterized stem- and progenitor cells of MDS patients of different risk categories, and identified specific cell surface proteins associated with these risk categories. In the third part, we focused on the treatment of MDS, investigating new treatment regimens, identifying potential therapeutic biomarkers and exploring reasons for the paucity of available agents. We conducted a randomized phase-II study that assessed the efficacy and safety of lenalidomide with or without erythropoietin stimulating agents in lower risk MDS patients, and identified several biomarkers for response. Additionally, the monitoring of therapy response through flow cytometric assessment of MDS-associated dysplasia provided insights into treatment effectiveness in the presence or absence of a del(5q). Lastly, we conducted an analysis of MDS trials over a 20-year period to identify reasons for the paucity of available effective agents for the treatment of MDS. In summary, this thesis provides strategies for improving the clinical management of MDS and offers insights into the pathogenesis. The obtained results may contribute to the development of more effective diagnostic tools, to the refinement of classification strategies, and to the expansion of treatment options for MDS patients.
2023-06-23 | Decitabine in patients with myelodysplastic syndromes: A multi‐center, open‐label, dose comparison trial
The hypomethylating agent decitabine is the standard therapy for intermediate or high risk myelodysplastic syndrome (MDS).In this trial, 191 adult patients with intermediate/high risk MDS (IPSS score ≥ 0.5) randomly received decitabine using a standard regimen (20 mg/m2 /day for 5 consecutive days; n = 94) or an extended regimen with lower daily dose (12 mg/m2 /day for 8 consecutive days; n = 97) every 4 weeks, for a total of 4 cycles.The median follow-up was 14 months (range 2-36). The primary end point of overall response rate in the intent-to-treat analysis was 41.5% and 38.1% in the standard and extended dosing arms, respectively (p = 0.660). Complete remission and marrow complete remission also did not differ between the two arms. Cytopenia was the most frequent adverse event (76.4%). The median duration of neutropenia per cycle did not differ between the two arms during the first two cycles, but significantly shorter in the extended dosing arm in the third cycle (8.5 vs. 15.5 days, p = 0.049) and in the fourth cycle (8 vs. 14 days, p = 0.294).The 5-day 20-mg/m2 /day and 8-day 12-mg/m2 /day decitabine regimens have similar efficacy and safety in patients with intermediate or high risk MDS.
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