RARE DISEASE
Myelodysplastic neoplasm with increased blasts type 1
Myelodysplastic neoplasm with increased blasts type 1
Myelodysplastic neoplasm with increased blasts type 1
Synonyms: MDS-IB1, RAEB-1, Refractory anemia with excess blasts type 1
Synonyms: MDS-IB1, RAEB-1, Refractory anemia with excess blasts type 1
Synonyms: MDS-IB1, RAEB-1, Refractory anemia with excess blasts type 1
Drug discovery
12
drugs
With orphan designations
Overview
Myelodysplastic neoplasm with increased blasts type 1 (MDS-IB1) is a high-risk subtype of myelodysplastic neoplasms characterized by cytopenias, 5–9% bone marrow blasts (or 2–4% peripheral blood blasts), and uni-/multilineage dysplasia without Auer rods [1][13]. It carries a median survival of 16–18 months and a 25% risk of progression to acute myeloid leukemia (AML) [1][13][16]. Diagnosis requires integration of morphology, cytogenetics, and molecular profiling per WHO 2022 and ICC 2022 classifications [2][4][16].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
356 drug discovery papers about Myelodysplastic neoplasm with increased blasts type 1, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
356 drug discovery papers about Myelodysplastic neoplasm with increased blasts type 1, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2025-11-03 | The efficacy and safety of luspatercept in patients with low-blasts myelodysplastic neoplasms in real world
Abstract Backgroud: Myelodysplastic neoplasms (MDS) are characterized by myelodysplasia and ineffective hematopoiesis leading to refractory cytopenia. Most of MDS patients had anemia at diagnosis requiring red blood cell (RBC) transfusion, which was an independent prognostic factor for poor overall survival of MDS. Therefore, improving anemia is one of the main goals of therapy in LR-MDS patients. Luspatercept, the transforming growth factor-β pathway inhibitor, showed good efficacy in low-risk MDS (LR-MDS) based on clinical trials. Aim: In this study, we analyzed the efficacy and safety of luspatercept in patients with low-blasts MDS (MDS-LB) compared to erythropoiesis-stimulating agents (ESA) in real world. Methods: The study planned to enroll MDS-LB patients newly diagnosed in the Department of Hematology, General Hospital of Tianjin Medical University from June 1st, 2022 to December 30th, 2024. The patients were divided into LR-MDS group (IPSS-R score ≤ 3.5) and HR-MDS group (IPSS-R score > 3.5) based on IPSS-R. The MDS patients in luspatercept group were received luspatercept treatment, as administered subcutaneously every 3 weeks. The starting dose of luspatercept was 1.0 mg per kilogram of body weight (mg/kg). If without erythroid response (HI-E, according to IWG 2018 criteria) and without disease progression after 2 cycles, patients could be received luspatercept with adjustment to a dose of 1.33 mg/kg and then to 1.75 mg/kg. The ESA group were received rhEPO ± roxadustat treatments. The primary end-point was the proportion of patients with HI-E. The key secondary end point was RBC transfusion independence (RBC-TI) for 8 weeks or longer. The adverse events (AE) were defined according to CTCAE 5.0. Results: The data-cutoff was June 30, 2024. A total of 48 MDS-LB were enrolled in this study (Luspatercept group n=27, ESA group n=21).(Table 1) Among luspatercept group, 11 (40.7%) had received treatments combined with ESA (including recombinant human EPO, roxadustat). The results showed that patients treated with luspatercept have a higher HI-E rate than those treated with ESA (73.9% vs. 55%), which might not be affected by SF3B1 mutation, serum erythropoietin level or transfusion burden. After 2 cycles of luspatercept treatment, the median Hb level increased significantly (P<0.05). The patients with first-line treatment, LR-MDS and combined treatments tended to have a higher response rate to luspatercept. The median time to achieve HI-E in luspatercept group was shorter than that of controls (1.5 vs. 5 months, P<0.01). (Table 1, Figure1) There was no serious AE observed. In luspatercept group, the median duration of response (mDOR) of patients received ≥ 3 cycle treatments was higher than that of < 3 cycles group (8 vs. 3 months, P<0.05). (Figure2) The HI-E group tend to have higher population of Treg, and lower concentrations of IL-2, IL-6, TNF-α and IFN-γ compared to non-HI-E group. The serum ferritin (SF), B-type natriuretic peptide (BNP) and C-reactive protein (CRP) levels in HI-E group tended to be lower than that of non-HI-E group. But there was no significant statistical difference between the two groups (all P>0.05). The BNP levels of patients with HI-E after luspatercept treatment were lower than the base-line (P <0.05). (Figure3) It indicated that inflammation factors might affect the response of luspatercept in MDS. Conclusions: This study showed that luspatercept was effective and tolerated well in MDS-LB patients. But inadequate treatments could affect the duration of response. It need to optimize the treatment of luspatercept in further. Key words: MDS-LB, luspatercept, EPO refractory, anemia, immune state
2018-07-23 | The use of immunosuppressive therapy in MDS: clinical outcomes and their predictors in a large international patient cohort
Most studies of immunosuppressive therapy (IST) in myelodysplastic syndromes (MDS) are limited by small numbers and their single-center nature, and report conflicting data regarding predictors for response to IST. We examined outcomes associated with IST and predictors of benefit in a large international cohort of patients with MDS. Data were collected from 15 centers in the United States and Europe. Responses, including red blood cell (RBC) transfusion independence (TI), were assessed based on the 2006 MDS International Working Group criteria, and overall survival (OS) was estimated by Kaplan-Meier methods. Logistic regression models estimated odds for response and TI, and Cox Proportional Hazard models estimated hazards ratios for OS. We identified 207 patients with MDS receiving IST, excluding steroid monotherapy. The most common IST regimen was anti-thymocyte globulin (ATG) plus prednisone (43%). Overall response rate (ORR) was 48.8%, including 11.2% (95% confidence interval [CI], 6.5%-18.4%) who achieved a complete remission and 30% (95% CI, 22.3%-39.5%) who achieved RBC TI. Median OS was 47.4 months (95% CI, 37-72.3 months) and was longer for patients who achieved a response or TI. Achievement of RBC TI was associated with a hypocellular bone marrow (cellularity < 20%); horse ATG plus cyclosporine was more effective than rabbit ATG or ATG without cyclosporine. Age, transfusion dependence, presence of paroxysmal nocturnal hemoglobinuria or large granular lymphocyte clones, and HLA DR15 positivity did not predict response to IST. IST leads to objective responses in nearly half the selected patients with the highest rate of RBC TI achieved in patients with hypocellular bone marrows.
2010-02-01 | Low Dose Alemtuzumab In Vivo Confers An Efficient GvHD Prophylaxis Protocol In Sibling And Matched Unrelated HCT
Despite standard CyA/MTX GvHD prophylaxis, severe acute GVHD occurs after ∼35% of matched sibling HCT. MTX is associated with mucositis, delayed engraftment and pulmonary toxicity. Campath anti-CD52 antibody may reduce GvHD by targeting lymphocytes and dendritic cells. Studies with high doses (100 mg) of the humanized Campath1H (alemtuzumab) revealed increased incidence of relapse and severe viral infections. We report our single centre experience of low dose (20-10 mg) alemtuzumab as GvHD prophylaxis in 26 consecutive matched sibling (n=12), related (1) or unrelated transplantations (13) performed during 1/2007-6/2009. Median pt age was 36y (17-59). Diagnoses were AML(15), ALL(8), MDS-RAEB(1), T-NHL (1), PNH (1). 20 pts were transplanted in CR1 and 6 with advanced disease. Conditioning was BuCy=12, TBI/VP16/Cy=5, Flu/BCNU/Melphalan(FB/M) or FB+Thiotepa=8, HDARA-C+FB/M=1. All pts received peripheral blood stem cells. The first 11 pts received for GvHD prophylaxis iv alemtuzumab 20 mg absolute (10 mg on d-2 and d-1), the next 5 pts received 15 mg (10 mg d-2, 5 mg d-1) and the last 10 pts received total 10 mg alemtuzumab (5 mg on d-2 and d-1). All pts engrafted promptly (WBC>1000/μl on d+14 (9-19), PLT>50000/μl on d+12(7-19)) and revealed complete BM and PB chimerism on d+30, except one with refractory disease. Two patients who discontinued CyA on d+25 (incompliance) and d+30 (refractory disease) experienced steroid/ATG resistant, fatal GvHD. From the remaining pts, none revealed gut or liver aGvHD, whereas 10pts (38.5%) experienced steroid-sensible skin GvHD St I-II between d+12-d+57 (median d+17). 16 pts revealed CMV reactivation but no CMV disease occurred. CyA could be discontinued in all evaluable pts at median on d+120 (25-210). 8 out of 20 evaluable pts (40%) revealed mild skin chronic GvHD, 2 moderate skin cGvHD which resolved with steroids and one extensive skin and liver GvHD. After a median follow up of 323 days (24-902), 17/26 pts are alive (65.4%) and in CR and 9 died (relapse n=6, TRM n=3). From the 6 pts who died due to relapse, 4/6 were at advanced stage (>CR-1) at transplant, 5/6 underwent sibling HCT and 5/6 received the higher (20 mg) Campath dose. Median Karnofsky is 100% and only 1 pt receives steroids for skin cGvHD. In conclusion, in vivo low dose Campath confers an efficient GvHD prophylaxis. Campath 10 mg seems to be the optimal schedule for efficient GvHD prophylaxis without compromising relapse in sibling and matched unrelated HCT.
2010-01-22 | Immune Dysregulation in Myelodysplastic Syndrome
Myelodysplastic syndrome (MDS) represents one of the most challenging health-related problems in the elderly. Characterized by dysplastic morphology in the bone marrow in association with ineffective hematopoiesis, pathophysiological causes of this disease are diverse including genetic abnormalities within myeloid progenitors, altered epigenetics, and changes in the bone marrow microenvironment. The concept that T-cell mediated autoimmunity contributes to bone marrow failure has been widely accepted due to hematologic improvement after immunosuppressive therapy (IST) in a subset of patients. Currently, IST for MDS primarily involves anti-thymocyte globulin (ATG)-based regimens in which responsiveness is strongly associated with younger (under 60 years) age at disease onset. In such cases, progressive cytopenia may occur as a consequence of expanded self-reactive CD8(+) cytotoxic T lymphocytes (CTLs) that suppress hematopoietic progenitors. Although most hematologists agree that IST can offer durable hematologic remission in younger patients with MDS, an international clinical study and a better understanding of the molecular mechanisms contributing to the expansion of self-reactive CTLs is crucial. In this review, data accumulated in the US, Europe, and Asia will be summarized to provide insight and direction for a multi-center international trial.
2003-11-03 | Treating patients of myelodysplastic syndrome with antithymocytic globulin—should we be more selective?
We read with interest the article by Steensma et al[1][1] on use of antithymocytic globulin (ATG) for the management of myelodysplastic syndrome (MDS). This study showed a very poor response to ATG therapy with substantial toxicity in all of the 8 MDS patients and suggests that clinicians be more
vaccines
2024-01-08 | Vaccines: a promising therapy for myelodysplastic syndrome
Abstract Myelodysplastic neoplasms (MDS) define clonal hematopoietic malignancies characterized by heterogeneous mutational and clinical spectra typically seen in the elderly. Curative treatment entails allogeneic hematopoietic stem cell transplant, which is often not a feasible option due to older age and significant comorbidities. Immunotherapy has the cytotoxic capacity to elicit tumor-specific killing with long-term immunological memory. While a number of platforms have emerged, therapeutic vaccination presents as an appealing strategy for MDS given its promising safety profile and amenability for commercialization. Several preclinical and clinical trials have investigated the efficacy of vaccines in MDS; these include peptide vaccines targeting tumor antigens, whole cell-based vaccines and dendritic cell-based vaccines. These therapeutic vaccines have shown acceptable safety profiles, but consistent clinical responses remain elusive despite robust immunological reactions. Combining vaccines with immunotherapeutic agents holds promise and requires further investigation. Herein, we highlight therapeutic vaccine trials while reviewing challenges and future directions of successful vaccination strategies in MDS.
2010-01-15 | High-dose RHAMM-R3 peptide vaccination for patients with acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma
Background Recently, we demonstrated immunological and clinical responses to a RHAMM-R3 peptide vaccine in patients with acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma. To improve the outcome of the vaccine, a second cohort was vaccinated with a higher dose of 1,000 μg peptide.Design and Methods Nine patients received four vaccinations subcutaneously at a biweekly interval. Immunomonitoring of cytotoxic CD8+ as well as regulatory CD4+ T cells was performed by flow cytometry as well as by enzyme-linked immunospot (ELISpot) assays. Parameters of clinical response were assessed.Results In 4 of 9 patients (44%) we detected positive immunological responses. These patients showed an increase of CD8+RHAMM-R3_tetramer+/CD45RA+/CCR7−/CD27−/CD28− effector T cells and an increase of R3-specific CD8+ T cells. Two of these patients showed a significant decrease of regulatory T cells (Tregs). In one patient without response Tregs frequency increased from 5 to 16%. Three patients showed clinical effects: one patient with myelodysplastic syndrome RAEB-1 showed a reduction of leukemic blasts in the bone marrow, another myelodysplastic syndrome patient an improvement of peripheral blood counts and one patient with multiple myeloma a reduction of free light chains. Clinical and immunological reactions were lower in this cohort than in the 300 μg cohort.Conclusions High-dose RHAMM-R3 peptide vaccination induced immunological responses and positive clinical effects. Therefore, RHAMM constitutes a promising structure for further targeted immunotherapies in patients with different hematologic malignancies. However, higher doses of peptide did not improve the frequency and intensity of immune responses in this trial. (This study is registered at http://ISRCTN.org as ISRCTN32763606)
2007-11-01 | RHAMM-R3 peptide vaccination in patients with acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma elicits immunologic and clinical responses
Abstract The receptor for hyaluronic acid–mediated motility (RHAMM) is an antigen eliciting both humoral and cellular immune responses in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM). We initiated a phase 1 clinical trial vaccinating 10 patients with R3 (ILSLELMKL), a highly immunogenic CD8+ T-cell epitope peptide derived from RHAMM. In 7 of 10 patients, we detected an increase of CD8+/HLA-A2/RHAMM R3 tetramer+/CD45RA+/CCR7−/CD27−/CD28− effector T cells in accordance with an increase of R3-specific CD8+ T cells in enzyme linked immunospot (ELISpot) assays. In chromium release assays, a specific lysis of RHAMM-positive leukemic blasts was shown. Three of 6 patients with myeloid disorders (1/3 AML, 2/3 MDS) achieved clinical responses: one patient with AML and one with MDS showed a significant reduction of blasts in the bone marrow after the last vaccination. One patient with MDS no longer needed erythrocyte transfusions after 4 vaccinations. Two of 4 patients with MM showed a reduction of free light chain serum levels. Taken together, RHAMM-R3 peptide vaccination induced both immunologic and clinical responses, and therefore RHAMM constitutes a promising target for further immunotherapeutic approaches. This study is registered at http://ISRCTN.org as ISRCTN32763606 and is registered with EudraCT as 2005-001706-37.
small molecules
2025-11-03 | Survival outcomes and mortality-to-incidence ratio (MIR) in refractory anemia with excess blasts: A retrospective overview
Abstract Introduction Myelodysplastic syndrome (MDS) is a heterogeneous clonal disorder of hematopoietic stem cells characterized by dysplasia and restricted maturation resulting in ineffective hematopoiesis and peripheral blood cytopenias. Refractory anemia with excess blasts (RAEB) is a subtype of MDS, defined by the presence of 2%-19% blasts in peripheral blood or 5%-19% blasts in the bone marrow. The purpose of this study is to determine the racial and gender disparities and survival trends in patients with RAEB. Methods We collected RAEB cases from Surveillance, Epidemiology and End Result database Research Plus Data, 17 Registries, Nov 2024 Sub (2000-2022), using the ICD Code 9983/3. The analysis was further stratified based on age, sex, race, year of diagnosis, income, demography and treatment with chemotherapy and radiation therapy. Survival curves were then compared using the Log-Rank test (GraphPad Prism). Results We extracted 12155 cases of refractory anemia with excess blasts. The median age of diagnosis was 74 years. 60.7% of the cases were males, while only 39.3% were females. The neoplasm was most noted in Caucasians (77.1%) and then Hispanics (8.4%), Asians/Pacific Islanders (7.2%), Black (6.6%) and Alaskans/American Indians and unknown race <1% each. Overall median of survival (MoS) was 11 months, with a 1-year OS of 47.4% (CI 95%, 46.5-48.3), 3-year OS of 18.1% (CI 95%, 17.4-18.8), and 5-year OS of 10.97% (CI 95%, 10.4-11.6). MoS were significant for Age: 0-65 years (16 months), 65+ years (10 months) (p <0.0001); Race: Caucasians (11 months), Black (11 months), Hispanics (12 months), Asian/Pacific Islanders (13 months), Alaskan/Native Americans (15 months) (p <0.0001); Income: less than 40,000$ - 70,000$ (10 months), 70K-100K (11 months), 100K+ (14 months); Demography: residents in a metropolitan area (12 months) vs non-metropolitan area (10 months) (p value 0.0003). Treatment based survival analysis showed: chemotherapy (14 months) vs no chemotherapy (8 months) (p <0.0001), XRT (27 months) vs no XRT (11 months). Survival analyses based on gender was insignificant. Mortality-to-Incidence Ratio (MIR) trend was notable for 2000-2005 (96.6%), 2006-2011 (95.5%), 2012-2016 (92.2%), and 2017-2022 (69.3%) (p 0.0001, Logrank test for trend). Conclusion Refractory anemia with excess blasts is a subtype of MDS with a very high mortality. Our analysis revealed that it favors male gender, and Caucasian race. Superior survival outcomes were observed with age less than 65, Asian/Pacific Islanders or Alaskan/Native Americans origin, income above 100K and metropolitan residence. Management with chemotherapy or radiotherapy were also associated with higher survival. No significant association was noted with gender. Further research and analysis is warranted to identify specific targetable mutations to help improve overall survival in this aggressive hematologic malignancy.
2025-05-28 | Phase II study evaluating olutasidenib and azacitidine in patients with IDH1 -mutated higher-risk myelodysplastic syndromes, chronic myelomonocytic leukemia, or advanced myeloproliferative neoplasms.
TPS6586 Background: IDH1 mutations are detected in 3-4% of patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) and approximately 9% of patients with myeloproliferative neoplasms (MPN). IDH1 mutations have been associated with shortened survival and increased rates of transformation to acute myeloid leukemia (AML). Despite the use of IDH1 inhibitors in AML and the recent FDA approval of ivosidenib for relapsed/refractory IDH1 -mutated MDS, no IDH1-directed therapies are approved in MPN or treatment-naïve MDS/CMML, and no combination treatment regimens are commercially available. Olutasidenib, an FDA-approved oral, highly selective, potent inhibitor of mutant IDH1, is well-tolerated, non-cytotoxic and effective, with overall response rates in relapsed/refractory AML of 51% in combination with azacitidine. Olutasidenib alone or with azacitidine demonstrated overall response rates of 86% in treatment-naïve and 47% in relapsed/refractory MDS. We consequently hypothesize olutasidenib to be effective in patients with IDH1 -mutated higher-risk MDS/CMML or advanced MPN. Methods: This multicenter investigator-initiated study under the MDACC-Rigel Research Alliance is a phase II non-randomized study evaluating the efficacy of olutasidenib in combination with azacitidine in patients with IDH1 -mutated higher-risk MDS/CMML or advanced MPN. Patients will be divided into 2 arms: treatment naïve and previously treated. Eligibility includes adult patients with acceptable organ function and confirmed IDH1 mutation with higher-risk MDS/CMML (by International Prognostic Scoring System [IPSS], Revised IPSS [IPSS-R], or Molecular IPSS [IPSS-M] criteria) or advanced MPN (with bone marrow blast percentage ≥ 10%). The primary objective of the study is to determine the overall response rate by International Working Group 2023 criteria (MDS), 2015 MDS/MPN uniform response criteria (CML), and European Leukemia Network 2017 AML criteria (advanced MPN). Secondary objectives include rates of complete remission, safety and tolerability, overall survival, progression-free survival, duration of response, and changes in IDH1 clone size. All patients will receive azacitidine 75 mg/m 2 intravenously or subcutaneously daily on days 1-7 of each treatment cycle and olutasidenib 150 mg orally twice daily. Response assessments will be performed after cycle 1, then every 3 cycles up through cycle 12, then every 12 cycles thereafter. Once off treatment, survival follow-up will occur every 3 months for 3 years. The goal enrollment is 45 patients (25 treatment-naïve and 20 previously-treated with no more than 5 MPN patients in each arm) across 5-6 centers in the United States. The study was activated and enrollment began in January 2025. Clinical trial information: NCT06597734 .
2025-05-28 | Comparing myeloablative and reduced-intensity conditioning for allogeneic PBSCT in MDS with increased blasts.
e18573 Background: Myelodysplastic syndrome with increased blasts (MDS-IB) is a complex hematologic malignancy characterized by ineffective hematopoiesis and a high risk of transformation to acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a potentially curative treatment option for these patients, but the optimal conditioning regimen remains a subject of ongoing debate. This retrospective study aims to compare the outcomes of patients with MDS-IB who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) using either MAC or RIC regimens between 2015 and 2023. Methods: We identified 53 patients with MDS-IB1 and MDS-IB2 who underwent allogeneic PBSCT. They received MAC (FBT or FB4) with fludarabine 50 mg/m2/day, day -6 to day -2, busulfan 3.2 mg/kg/day, day -5 to day -2, +/- TBI 200 cGy/day on day -1 and day 0. Or reduced intensity conditioning (FB2) with fludarabine 30 mg/m2/day day -6 to day -2, busulfan 3.2 mg/kg/day day -3 and day -2. The endpoints were progression-free survival (PFS) and overall survival (OS) at 2-years. Kaplan Meier method was used to study survival estimates, log-rank test was used to compare those estimates. Results: The median age at diagnosis was 63.8 years. Most patients had underlying MDS-IB2 (62%), and 79% of patients received their transplant from matched unrelated donors. Only 21% of patients received MAC with either FB4 or FBT, while the rest received RIC. The median follow-up was 9.7 months. 2-year PFS was 87.5% for the MAC group versus 48.9% for RIC group (p-value 0.099). The 2-year overall survival (OS) was 54.5% in the MAC group compared to 35.7% in the RIC (p-value = 0.737). Conclusions: Our institutional 2-year analysis showed a non-significant difference in PFS and OS between the conditioning regimens in MDS patients with increased blasts. This lack of statistical significance could be related to the small sample size and retrospective analysis. However, prospective review and multicenter analysis with a larger sample size may be warranted to validate the choice of conditioning regimen in this group of patients.
2025-02-19 | Effect of pre-transplant cytoreductive therapy on the outcomes of patients with MDS or secondary AML evolving from MDS undergoing allo-HSCT: a secondary analysis of an RCT
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative therapy for patients with myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia evolving from MDS (sAML) [ 1 ]. Multiple factors are reported to influence the prognosis of patients with MDS and sAML undergoing allo-HSCT, including prognostic stratification, disease status, conditioning regimen and pre-transplant therapy [ 2 , 3 ]. Our randomized controlled trial (RCT) has shown that granulocyte-colony stimulating factor, decitabine, busulfan and cyclophosphamide (G-DAC-BuCy) conditioning is a better choice than busulfan and cyclophosphamide (BuCy) conditioning for patients with MDS-refractory anemia with excess blasts (RAEB) or sAML undergoing allo-HSCT [ 4 ].
2024-11-05 | A Phase 1, Multicenter, Open-Label, Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Clinical Activity of Orally Administered LP-108 (Lacutoclax) As Monotherapy and in Combination with Azacitidine in Subjects with Relapsed or Refractory Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML)
Background: LP-108 (Lacutoclax) is a potent inhibitor of BCL-2. We explore the toxicity and tolerability of LP-108 as monotherapy and combined with azacitidine (Aza) in patients with relapse/refractory Acute Myeloid Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML) and high-risk refractory/relapsed Myelodysplastic syndrome (MDS) (EudraCT 2021-001402-29, NCT04139434). Description and aims of the trial: This is a First -in-human (FIH), Phase 1, multicenter, open-label study with dose-escalation of only lacutoclax phase (Phase 1a) and a cohort expansion phase (Phase 1b) combined with Aza. Inclusion criteria were AML, RAEB 1and 2, MDS with IPSS-R>4.5 and CMML with ≥5% of blasts in bone marrow, refractory or relapsed to previous treatment. The primary objective is to characterize safety and tolerability, to define maximum tolerability dose (MTD) recommended phase 2 dose (RP2D) and asses the pharmacokinetics of lacutoclax as monotherapy and combined with Aza. The secondary objective were Overall Response Rate (ORR) the Complete Remission (CR), minimal residual disease (MRD), complete remission with incomplete blood count recovery (CRi), morphologic leukemia free state (MLFS), partial remission (PR), the same in MDS (ORR, CR, PR and marrow CR), progression free survival (PFS), duration of response (DOR), event free survival (EFS) and overall survival (OS). The phase 1 was designed with two arms, monotherapy (Arm 1) and combination therapy with Aza (Arm 2) in a classic 3+3 in order to determine the MTD/OBD and RP2D starting with a dose of 100 mg q d in a 28 daily dosing schedule. Dose Limiting Toxicity (DLT) was described as any extra hematological toxicity ≥3 during the first 28 days of induction or prolonged grade 4 pancytopenia not due to active leukemia beyond 42 days. Adverse events were graded according to the NCI-CTCAE version 5.0. Results: A total of 44 patients (18 Female, 26 Male) were screened. A total of 32 patients were enrolled due to 12 patients deemed screen failures. The median age of the patients was 70 years (40-88 years). The patient population previous diagnosis were AML (20), CMML (4) and MDS (8). The median number of previous lines of therapy were 2 (1-7). Total patients enrolled in the Arm 1 (monotherapy) were 20, and 12 patients were enrolled in Arm 2. Within Arm 1 the dose was increased from 100mg/day (7 patients) to 200 mg/4 patient then to 400 mg/day (4 patients) and finally up to 600 mg/day (3 patients). In Arm 2 (combination therapy) the dose was increase from 100 mg/day (4 patients), 200 mg/day (5 patients) and 400 mg/day (3 patients). No new TAE's of special interest were found. The number serious TAE's >3 were 5 (25%). In Arm 2 100% of the patients experience some type of AE. No TAE's that implies DLT were not seen. The more frequent AE's were gastrointestinal (vomiting 65%), hematological (thrombocytopenia 65%) and increase bilirubin (25%). COVID 19 was only detected in 1 patient. We observed 4 CRc, 1PR and 2MFLS and 2 patients with improvement in its MDS status. Conclusions: Lacutoclax is safe with no apparent extra hematological toxicities and appears as a new anti BCL-2 agent in patients with refractory myeloid malignancies. This agent had encouraging efficacy as both monotherapy and in combination with azacitidine.
oligonucleotides
2023-07-27 | MicroRNA-765 is upregulated in myelodysplastic syndromes and induces apoptosis via PLP2 inhibition in leukemia cells
Epigenetic studies, particularly research on microRNA (miRNA), have flourished. The abnormal expression of miRNA contributes to the development of hematologic malignancies. miR-765 has been reported to inhibit cell proliferation by downregulating proteolipid protein 2 (PLP2), which causes apoptosis. We investigated miR-765 dysregulation in myelodysplastic syndromes (MDS).We compared the expression profiles of miR-765 in 65 patients with MDS and 11 controls. Cell proliferation and apoptosis assays were performed to determine the in vitro effects of miR-765 on leukemia cells transfected with the miR-765 mimic. Reverse transcription quantitative PCR (RT-qPCR) and western blotting were performed to examine the targets of miR-765.We found that miR-765 levels were upregulated 10.2-fold in patients with MDS compared to controls. In refractory cytopenia with multilineage dysplasia, the percentage of patients with elevated miR-765 levels was significantly higher than in other forms of MDS. Experiments with leukemia cells revealed that transfection with a miR-765 mimic inhibited cell proliferation and induced apoptosis. RT-qPCR and western blotting demonstrated that the target of miR-765 was PLP2.These findings imply that upregulation of miR-765 induces apoptosis via downregulation of PLP2 and may have a role in MDS pathogenesis.
2023-02-20 | A miRNA screening identifies miR-192-5p as associated with response to azacitidine and lenalidomide therapy in myelodysplastic syndromes
Abstract Background miRNAs are small non-coding RNAs that regulate gene expression and are linked to cancer development and progression. miRNA profiles are currently studied as new prognostic factors or therapeutic perspectives. Among hematological cancers, myelodysplastic syndromes at higher risk of evolution into acute myeloid leukemia are treated with hypomethylating agents, like azacitidine, alone or in combination with other drugs, such as lenalidomide. Recent data showed that, during azacitidine and lenalidomide therapy, the concurrent acquisition of specific point mutations affecting inositide signalling pathways is associated with lack or loss of response to therapy. As these molecules are implicated in epigenetic processes, possibly involving miRNA regulation, and in leukemic progression, through the regulation of proliferation, differentiation and apoptosis, here we performed a new miRNA expression analysis of 26 high-risk patients with myelodysplastic syndromes treated with azacitidine and lenalidomide at baseline and during therapy. miRNA array data were processed, and bioinformatic results were correlated with clinical outcome to investigate the translational relevance of selected miRNAs, while the relationship between selected miRNAs and specific molecules was experimentally tested and proven. Results Patients’ overall response rate was 76.9% (20/26 cases): complete remission (5/26, 19.2%), partial remission (1/26, 3.8%), marrow complete remission (2/26, 7.7%), hematologic improvement (6/26, 23.1%), hematologic improvement with marrow complete remission (6/26, 23.1%), whereas 6/26 patients (23.1%) had a stable disease. miRNA paired analysis showed a statistically significant up-regulation of miR-192-5p after 4 cycles of therapy (vs baseline), that was confirmed by real-time PCR analyses, along with an involvement of BCL2, that was proven to be a miR-192-5p target in hematopoietic cells by luciferase assays. Furthermore, Kaplan–Meier analyses showed a significant correlation between high levels of miR-192-5p after 4 cycles of therapy and overall survival or leukemia-free survival, that was stronger in responders, as compared with patients early losing response and non-responders. Conclusions This study shows that high levels of miR-192-5p are associated with higher overall survival and leukemia-free survival in myelodysplastic syndromes responding to azacitidine and lenalidomide. Moreover, miR-192-5p specifically targets and inhibits BCL2, possibly regulating proliferation and apoptosis and leading to the identification of new therapeutic targets.
2019-05-29 | Role of 4‑aminobutyrate aminotransferase (ABAT) and the lncRNA co‑expression network in the development of myelodysplastic syndrome
IncRNAs play an important role in the regulation of gene expression. The present study profiled differentially expressed lncRNAs (DELs) and mRNAs (DEMs) in myelodysplastic syndrome (MDS) to construct a 4‑aminobutyrate aminotransferase (ABAT)‑DEL‑DEM co‑expression network in MDS development using the Agilent human BeadChips and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and network analyses. Compared with controls, there were 543 DELs and 2,705 DEMs in MDS patients, among which 285 (52.5%) DELs were downregulated and 258 (47.5%) DELs were upregulated, whereas 1,521 (56.2%) DEMs were downregulated and 1,184 (43.70%) DEMs were upregulated in MDS patients. The ABAT‑DEL‑DEM co‑expression network contained six DELs that were co‑expressed with ABAT in MDS. The GO analysis revealed that the co‑expression network mainly participated in response to organic cyclic compound, cell proliferation, cell part morphogenesis, regulation of cell proliferation and enzyme‑linked receptor protein signaling pathways, while the KEGG database showed that the co‑expression network was involved in various pathways, such as phagosome and metabolic pathways. Furthermore, the expression of a selected DEL (lncENST00000444102) and ABAT was shown to be significantly downregulated in MDS patients, and in SKM‑1 and THP‑1 cells. The selected lncENST00000444102 was then overexpressed and ABAT expression was knocked down in the MDS cell lines using lentiviral transfection. In addition, lncENST00000444102 overexpression reduced the viability and increased the apoptosis of MDS cells, ABAT expression was upregulated by lncENST00000444102.
2019-05-06 | MicroRNA-661 upregulation in myelodysplastic syndromes induces apoptosis through p53 activation and associates with decreased overall survival
MicroRNA (miRNA) dysregulation contributes to myelodysplastic syndromes (MDS), and apoptosis is one of the pathogenic features of MDS. We investigated the dysregulation of miRNA expression and its biological significance in MDS. We compared the expression profiles of miRNAs encoded by chromosome 8 in 65 patients with MDS and 11 controls, and analyzed the in vitro effect of the upregulated miRNA expression. We found that compared to the controls, miR-661 was upregulated by 5.28-fold in patients with MDS. Patients with high miR-661 expression showed significantly decreased overall survival. In vitro study results demonstrated that transfection with a miR-661 mimic induced apoptosis through the activation of p53. These findings suggest that high miR-661 expression can be associated with decreased overall survival and recapitulates apoptosis, the characteristic feature of MDS.
2017-09-11 | The U2AF homology motif kinase 1 (UHMK1) is upregulated upon hematopoietic cell differentiation
Abstract UHMK1 (KIS) is a nuclear serine/threonine kinase that possesses a U2AF homology motif and phosphorylates and regulates the activity of the splicing factors SF1 and SF3b155. Mutations in these components of the spliceosome machinery have been recently implicated in leukemogenesis. The fact that UHMK1 regulates these factors suggests that UHMK1 might be involved in RNA processing and perhaps leukemogenesis. Here we analyzed UHMK1 expression in normal hematopoietic and leukemic cells as well as its function in leukemia cell line. In the normal hematopoietic compartment, markedly higher levels of transcripts were observed in differentiated lymphocytes (CD4 + , CD8 + and CD19 + ) compared to the progenitor enriched subpopulation (CD34 + ) or leukemia cell lines. UHMK1 expression was upregulated in megakaryocytic-, monocytic-and granulocytic-induced differentiation of established leukemia cell lines and in erythrocytic-induced differentiation of CD34 + cells. No aberrant expression was observed in patient samples of myelodysplastic syndrome (MDS), acute myeloid (AML) or lymphoblastic (ALL) leukemia. Nonetheless, in MDS patients, increased levels of UHMK1 expression positively impacted event free and overall survival. Lentivirus mediated UHMK1 knockdown did not affect proliferation, cell cycle progression, apoptosis or migration of U937 leukemia cells, although UHMK1 silencing strikingly increased clonogenicity of these cells. Thus, our results suggest that UHMK1 plays a role in hematopoietic cell differentiation and suppression of autonomous clonal growth of leukemia cells.
other
2023-04-12 | Acute myeloid leukemia cells and MSC-derived exosomes inhibiting transformation in myelodysplastic syndrome
Abstract Aims To investigate the mechanism of exosomes role in the transformation of MDS to AML. Methods Exosomes in culture supernatants of MDS and AML cell lines, were extracted by ultrafiltration and identified in three ways: morphology, size and exosome surface marker proteins. Exosomes from AML cell lines were then co-cultured with MDS cell lines and their effects on the proliferation, cycle, differentiation, apoptosis and cell microenvironment of MDS cell lines were analysed by CCK-8 assay and flow cytometry. Furthermore, exosomes from MSC were extracted for further authentication. RESULTS The transmission electron microscopy, nanoparticle tracking analysis, Western blotting and flow cytometry methods all showed that ultrafiltration is a reliable method for extracting exosomes. Exosomes from AML cell lines inhibit the proliferation of MDS cell lines, block cell cycle progression and promote apoptosis and cell differentiation. It also leads to increased secretion of tumour necrosis factor-α (TNF-α) and reactive oxygen species (ROS) in MDS cell lines. In addition, MSC-derived exosomes were found to inhibit the proliferation of MDS cell lines, arrest cell cycle progression, promote apoptosis, and inhibit differentiation. CONCLUSION In this study, we explored that exosomes of AML cell line origin affect the apoptosis of MDS cell lines via the TNF-α/ROS-Caspase3 pathway, thereby influencing the conversion of MDS to AML. Additional, MSC-derived exosomes inhibited the transformation of MDS to AML.
2018-01-26 | Long-term follow-up for up to 5 years on the risk of leukaemic progression in thrombocytopenic patients with lower-risk myelodysplastic syndromes treated with romiplostim or placebo in a randomised double-blind trial
Background Treatment options for thrombocytopenia in myelodysplastic syndromes are scarce. As described previously in a randomised phase 2 study (n=250), 58 weeks of romiplostim treatment in patients with International Prognostic Scoring System (IPSS)-defined lower-risk (low-risk or intermediate-1 risk) myelodysplastic syndromes led to reduced platelet transfusions (p<0·0001) and increased International Working Group-defined haematological improvement–platelet rates (p<0·0001) versus placebo. However, the study drug was discontinued because of the potential risk for progression to or incorrect diagnosis or treatment for acute myeloid leukaemia, based on an acute myeloid leukaemia interim hazard ratio (HR) of 2·5; the subsequent 58-week acute myeloid leukaemia HR was 1·2 (95% CI 0·4–3·8). Methods This study is a 5-year follow-up of a phase 2, multicentre, double-blind trial of romiplostim treatment in patients with lower-risk myelodysplastic syndromes. Eligible patients were recruited at 109 centres in North America, Europe, Russia, and Australia, were aged 18–90 years, and had platelets of 20 × 109 per L or less with or without a history of bleeding or 50 × 109 platelets per L or less with a history of bleeding. Patients were randomly assigned by interactive voice response system with stratification by baseline platelet count (≥20 × 109 per L or <20 × 109 per L) and IPSS risk (low or intermediate-1) to receive either placebo or 750 μg romiplostim subcutaneously once per week for 58 weeks. The primary outcomes for this long-term follow-up were survival and progression to acute myeloid leukaemia. Progression to acute myeloid leukaemia was defined as either 20% blasts or more after 4 weeks from romiplostim discontinuation; as per pathology; or by initiation of antileukaemia treatment. The primary outcome was assessed per protocol in all patients with available data. This study is registered with ClinicalTrials.gov, NCT00614523. Findings Patients were recruited from July 21, 2008, to Dec 16, 2010. 167 patients were assigned to receive romiplostim treatment and 83 were assigned to receive placebo. 210 (84%) of 250 patients entered the 5-year long-term follow-up (139 patients in the romiplostim group and 83 in the placebo group). At the end of follow-up, proportions of patients with acute myeloid leukaemia (20 [12%] of 167 in the romiplostim group vs nine [11%] of 83 in the placebo group; HR 1·06 [95% CI 0·48–2·33]; p=0·88) and proportions who died (93 [56%] vs 54 [54%]; HR 1·03 [0·72–1·47]; p=0·89) were not significantly different between the two groups. Interpretation Following the decision to stop the study drug, 5-year long-term follow-up HRs for transformation to acute myeloid leukaemia and HRs for death did not differ between patients treated with romiplostim and those treated with placebo, indicating that use of romiplostim is probably not associated with any increased risk of acute myeloid leukaemia or death, despite initial concerns. Funding Amgen Inc.
antibodies
2025-11-03 | The efficacy and safety of luspatercept in patients with low-blasts myelodysplastic neoplasms in real world
Abstract Backgroud: Myelodysplastic neoplasms (MDS) are characterized by myelodysplasia and ineffective hematopoiesis leading to refractory cytopenia. Most of MDS patients had anemia at diagnosis requiring red blood cell (RBC) transfusion, which was an independent prognostic factor for poor overall survival of MDS. Therefore, improving anemia is one of the main goals of therapy in LR-MDS patients. Luspatercept, the transforming growth factor-β pathway inhibitor, showed good efficacy in low-risk MDS (LR-MDS) based on clinical trials. Aim: In this study, we analyzed the efficacy and safety of luspatercept in patients with low-blasts MDS (MDS-LB) compared to erythropoiesis-stimulating agents (ESA) in real world. Methods: The study planned to enroll MDS-LB patients newly diagnosed in the Department of Hematology, General Hospital of Tianjin Medical University from June 1st, 2022 to December 30th, 2024. The patients were divided into LR-MDS group (IPSS-R score ≤ 3.5) and HR-MDS group (IPSS-R score > 3.5) based on IPSS-R. The MDS patients in luspatercept group were received luspatercept treatment, as administered subcutaneously every 3 weeks. The starting dose of luspatercept was 1.0 mg per kilogram of body weight (mg/kg). If without erythroid response (HI-E, according to IWG 2018 criteria) and without disease progression after 2 cycles, patients could be received luspatercept with adjustment to a dose of 1.33 mg/kg and then to 1.75 mg/kg. The ESA group were received rhEPO ± roxadustat treatments. The primary end-point was the proportion of patients with HI-E. The key secondary end point was RBC transfusion independence (RBC-TI) for 8 weeks or longer. The adverse events (AE) were defined according to CTCAE 5.0. Results: The data-cutoff was June 30, 2024. A total of 48 MDS-LB were enrolled in this study (Luspatercept group n=27, ESA group n=21).(Table 1) Among luspatercept group, 11 (40.7%) had received treatments combined with ESA (including recombinant human EPO, roxadustat). The results showed that patients treated with luspatercept have a higher HI-E rate than those treated with ESA (73.9% vs. 55%), which might not be affected by SF3B1 mutation, serum erythropoietin level or transfusion burden. After 2 cycles of luspatercept treatment, the median Hb level increased significantly (P<0.05). The patients with first-line treatment, LR-MDS and combined treatments tended to have a higher response rate to luspatercept. The median time to achieve HI-E in luspatercept group was shorter than that of controls (1.5 vs. 5 months, P<0.01). (Table 1, Figure1) There was no serious AE observed. In luspatercept group, the median duration of response (mDOR) of patients received ≥ 3 cycle treatments was higher than that of < 3 cycles group (8 vs. 3 months, P<0.05). (Figure2) The HI-E group tend to have higher population of Treg, and lower concentrations of IL-2, IL-6, TNF-α and IFN-γ compared to non-HI-E group. The serum ferritin (SF), B-type natriuretic peptide (BNP) and C-reactive protein (CRP) levels in HI-E group tended to be lower than that of non-HI-E group. But there was no significant statistical difference between the two groups (all P>0.05). The BNP levels of patients with HI-E after luspatercept treatment were lower than the base-line (P <0.05). (Figure3) It indicated that inflammation factors might affect the response of luspatercept in MDS. Conclusions: This study showed that luspatercept was effective and tolerated well in MDS-LB patients. But inadequate treatments could affect the duration of response. It need to optimize the treatment of luspatercept in further. Key words: MDS-LB, luspatercept, EPO refractory, anemia, immune state
2018-07-23 | The use of immunosuppressive therapy in MDS: clinical outcomes and their predictors in a large international patient cohort
Most studies of immunosuppressive therapy (IST) in myelodysplastic syndromes (MDS) are limited by small numbers and their single-center nature, and report conflicting data regarding predictors for response to IST. We examined outcomes associated with IST and predictors of benefit in a large international cohort of patients with MDS. Data were collected from 15 centers in the United States and Europe. Responses, including red blood cell (RBC) transfusion independence (TI), were assessed based on the 2006 MDS International Working Group criteria, and overall survival (OS) was estimated by Kaplan-Meier methods. Logistic regression models estimated odds for response and TI, and Cox Proportional Hazard models estimated hazards ratios for OS. We identified 207 patients with MDS receiving IST, excluding steroid monotherapy. The most common IST regimen was anti-thymocyte globulin (ATG) plus prednisone (43%). Overall response rate (ORR) was 48.8%, including 11.2% (95% confidence interval [CI], 6.5%-18.4%) who achieved a complete remission and 30% (95% CI, 22.3%-39.5%) who achieved RBC TI. Median OS was 47.4 months (95% CI, 37-72.3 months) and was longer for patients who achieved a response or TI. Achievement of RBC TI was associated with a hypocellular bone marrow (cellularity < 20%); horse ATG plus cyclosporine was more effective than rabbit ATG or ATG without cyclosporine. Age, transfusion dependence, presence of paroxysmal nocturnal hemoglobinuria or large granular lymphocyte clones, and HLA DR15 positivity did not predict response to IST. IST leads to objective responses in nearly half the selected patients with the highest rate of RBC TI achieved in patients with hypocellular bone marrows.
2010-02-01 | Low Dose Alemtuzumab In Vivo Confers An Efficient GvHD Prophylaxis Protocol In Sibling And Matched Unrelated HCT
Despite standard CyA/MTX GvHD prophylaxis, severe acute GVHD occurs after ∼35% of matched sibling HCT. MTX is associated with mucositis, delayed engraftment and pulmonary toxicity. Campath anti-CD52 antibody may reduce GvHD by targeting lymphocytes and dendritic cells. Studies with high doses (100 mg) of the humanized Campath1H (alemtuzumab) revealed increased incidence of relapse and severe viral infections. We report our single centre experience of low dose (20-10 mg) alemtuzumab as GvHD prophylaxis in 26 consecutive matched sibling (n=12), related (1) or unrelated transplantations (13) performed during 1/2007-6/2009. Median pt age was 36y (17-59). Diagnoses were AML(15), ALL(8), MDS-RAEB(1), T-NHL (1), PNH (1). 20 pts were transplanted in CR1 and 6 with advanced disease. Conditioning was BuCy=12, TBI/VP16/Cy=5, Flu/BCNU/Melphalan(FB/M) or FB+Thiotepa=8, HDARA-C+FB/M=1. All pts received peripheral blood stem cells. The first 11 pts received for GvHD prophylaxis iv alemtuzumab 20 mg absolute (10 mg on d-2 and d-1), the next 5 pts received 15 mg (10 mg d-2, 5 mg d-1) and the last 10 pts received total 10 mg alemtuzumab (5 mg on d-2 and d-1). All pts engrafted promptly (WBC>1000/μl on d+14 (9-19), PLT>50000/μl on d+12(7-19)) and revealed complete BM and PB chimerism on d+30, except one with refractory disease. Two patients who discontinued CyA on d+25 (incompliance) and d+30 (refractory disease) experienced steroid/ATG resistant, fatal GvHD. From the remaining pts, none revealed gut or liver aGvHD, whereas 10pts (38.5%) experienced steroid-sensible skin GvHD St I-II between d+12-d+57 (median d+17). 16 pts revealed CMV reactivation but no CMV disease occurred. CyA could be discontinued in all evaluable pts at median on d+120 (25-210). 8 out of 20 evaluable pts (40%) revealed mild skin chronic GvHD, 2 moderate skin cGvHD which resolved with steroids and one extensive skin and liver GvHD. After a median follow up of 323 days (24-902), 17/26 pts are alive (65.4%) and in CR and 9 died (relapse n=6, TRM n=3). From the 6 pts who died due to relapse, 4/6 were at advanced stage (>CR-1) at transplant, 5/6 underwent sibling HCT and 5/6 received the higher (20 mg) Campath dose. Median Karnofsky is 100% and only 1 pt receives steroids for skin cGvHD. In conclusion, in vivo low dose Campath confers an efficient GvHD prophylaxis. Campath 10 mg seems to be the optimal schedule for efficient GvHD prophylaxis without compromising relapse in sibling and matched unrelated HCT.
2010-01-22 | Immune Dysregulation in Myelodysplastic Syndrome
Myelodysplastic syndrome (MDS) represents one of the most challenging health-related problems in the elderly. Characterized by dysplastic morphology in the bone marrow in association with ineffective hematopoiesis, pathophysiological causes of this disease are diverse including genetic abnormalities within myeloid progenitors, altered epigenetics, and changes in the bone marrow microenvironment. The concept that T-cell mediated autoimmunity contributes to bone marrow failure has been widely accepted due to hematologic improvement after immunosuppressive therapy (IST) in a subset of patients. Currently, IST for MDS primarily involves anti-thymocyte globulin (ATG)-based regimens in which responsiveness is strongly associated with younger (under 60 years) age at disease onset. In such cases, progressive cytopenia may occur as a consequence of expanded self-reactive CD8(+) cytotoxic T lymphocytes (CTLs) that suppress hematopoietic progenitors. Although most hematologists agree that IST can offer durable hematologic remission in younger patients with MDS, an international clinical study and a better understanding of the molecular mechanisms contributing to the expansion of self-reactive CTLs is crucial. In this review, data accumulated in the US, Europe, and Asia will be summarized to provide insight and direction for a multi-center international trial.
2003-11-03 | Treating patients of myelodysplastic syndrome with antithymocytic globulin—should we be more selective?
We read with interest the article by Steensma et al[1][1] on use of antithymocytic globulin (ATG) for the management of myelodysplastic syndrome (MDS). This study showed a very poor response to ATG therapy with substantial toxicity in all of the 8 MDS patients and suggests that clinicians be more
vaccines
2024-01-08 | Vaccines: a promising therapy for myelodysplastic syndrome
Abstract Myelodysplastic neoplasms (MDS) define clonal hematopoietic malignancies characterized by heterogeneous mutational and clinical spectra typically seen in the elderly. Curative treatment entails allogeneic hematopoietic stem cell transplant, which is often not a feasible option due to older age and significant comorbidities. Immunotherapy has the cytotoxic capacity to elicit tumor-specific killing with long-term immunological memory. While a number of platforms have emerged, therapeutic vaccination presents as an appealing strategy for MDS given its promising safety profile and amenability for commercialization. Several preclinical and clinical trials have investigated the efficacy of vaccines in MDS; these include peptide vaccines targeting tumor antigens, whole cell-based vaccines and dendritic cell-based vaccines. These therapeutic vaccines have shown acceptable safety profiles, but consistent clinical responses remain elusive despite robust immunological reactions. Combining vaccines with immunotherapeutic agents holds promise and requires further investigation. Herein, we highlight therapeutic vaccine trials while reviewing challenges and future directions of successful vaccination strategies in MDS.
2010-01-15 | High-dose RHAMM-R3 peptide vaccination for patients with acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma
Background Recently, we demonstrated immunological and clinical responses to a RHAMM-R3 peptide vaccine in patients with acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma. To improve the outcome of the vaccine, a second cohort was vaccinated with a higher dose of 1,000 μg peptide.Design and Methods Nine patients received four vaccinations subcutaneously at a biweekly interval. Immunomonitoring of cytotoxic CD8+ as well as regulatory CD4+ T cells was performed by flow cytometry as well as by enzyme-linked immunospot (ELISpot) assays. Parameters of clinical response were assessed.Results In 4 of 9 patients (44%) we detected positive immunological responses. These patients showed an increase of CD8+RHAMM-R3_tetramer+/CD45RA+/CCR7−/CD27−/CD28− effector T cells and an increase of R3-specific CD8+ T cells. Two of these patients showed a significant decrease of regulatory T cells (Tregs). In one patient without response Tregs frequency increased from 5 to 16%. Three patients showed clinical effects: one patient with myelodysplastic syndrome RAEB-1 showed a reduction of leukemic blasts in the bone marrow, another myelodysplastic syndrome patient an improvement of peripheral blood counts and one patient with multiple myeloma a reduction of free light chains. Clinical and immunological reactions were lower in this cohort than in the 300 μg cohort.Conclusions High-dose RHAMM-R3 peptide vaccination induced immunological responses and positive clinical effects. Therefore, RHAMM constitutes a promising structure for further targeted immunotherapies in patients with different hematologic malignancies. However, higher doses of peptide did not improve the frequency and intensity of immune responses in this trial. (This study is registered at http://ISRCTN.org as ISRCTN32763606)
2007-11-01 | RHAMM-R3 peptide vaccination in patients with acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma elicits immunologic and clinical responses
Abstract The receptor for hyaluronic acid–mediated motility (RHAMM) is an antigen eliciting both humoral and cellular immune responses in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM). We initiated a phase 1 clinical trial vaccinating 10 patients with R3 (ILSLELMKL), a highly immunogenic CD8+ T-cell epitope peptide derived from RHAMM. In 7 of 10 patients, we detected an increase of CD8+/HLA-A2/RHAMM R3 tetramer+/CD45RA+/CCR7−/CD27−/CD28− effector T cells in accordance with an increase of R3-specific CD8+ T cells in enzyme linked immunospot (ELISpot) assays. In chromium release assays, a specific lysis of RHAMM-positive leukemic blasts was shown. Three of 6 patients with myeloid disorders (1/3 AML, 2/3 MDS) achieved clinical responses: one patient with AML and one with MDS showed a significant reduction of blasts in the bone marrow after the last vaccination. One patient with MDS no longer needed erythrocyte transfusions after 4 vaccinations. Two of 4 patients with MM showed a reduction of free light chain serum levels. Taken together, RHAMM-R3 peptide vaccination induced both immunologic and clinical responses, and therefore RHAMM constitutes a promising target for further immunotherapeutic approaches. This study is registered at http://ISRCTN.org as ISRCTN32763606 and is registered with EudraCT as 2005-001706-37.
small molecules
2025-11-03 | Survival outcomes and mortality-to-incidence ratio (MIR) in refractory anemia with excess blasts: A retrospective overview
Abstract Introduction Myelodysplastic syndrome (MDS) is a heterogeneous clonal disorder of hematopoietic stem cells characterized by dysplasia and restricted maturation resulting in ineffective hematopoiesis and peripheral blood cytopenias. Refractory anemia with excess blasts (RAEB) is a subtype of MDS, defined by the presence of 2%-19% blasts in peripheral blood or 5%-19% blasts in the bone marrow. The purpose of this study is to determine the racial and gender disparities and survival trends in patients with RAEB. Methods We collected RAEB cases from Surveillance, Epidemiology and End Result database Research Plus Data, 17 Registries, Nov 2024 Sub (2000-2022), using the ICD Code 9983/3. The analysis was further stratified based on age, sex, race, year of diagnosis, income, demography and treatment with chemotherapy and radiation therapy. Survival curves were then compared using the Log-Rank test (GraphPad Prism). Results We extracted 12155 cases of refractory anemia with excess blasts. The median age of diagnosis was 74 years. 60.7% of the cases were males, while only 39.3% were females. The neoplasm was most noted in Caucasians (77.1%) and then Hispanics (8.4%), Asians/Pacific Islanders (7.2%), Black (6.6%) and Alaskans/American Indians and unknown race <1% each. Overall median of survival (MoS) was 11 months, with a 1-year OS of 47.4% (CI 95%, 46.5-48.3), 3-year OS of 18.1% (CI 95%, 17.4-18.8), and 5-year OS of 10.97% (CI 95%, 10.4-11.6). MoS were significant for Age: 0-65 years (16 months), 65+ years (10 months) (p <0.0001); Race: Caucasians (11 months), Black (11 months), Hispanics (12 months), Asian/Pacific Islanders (13 months), Alaskan/Native Americans (15 months) (p <0.0001); Income: less than 40,000$ - 70,000$ (10 months), 70K-100K (11 months), 100K+ (14 months); Demography: residents in a metropolitan area (12 months) vs non-metropolitan area (10 months) (p value 0.0003). Treatment based survival analysis showed: chemotherapy (14 months) vs no chemotherapy (8 months) (p <0.0001), XRT (27 months) vs no XRT (11 months). Survival analyses based on gender was insignificant. Mortality-to-Incidence Ratio (MIR) trend was notable for 2000-2005 (96.6%), 2006-2011 (95.5%), 2012-2016 (92.2%), and 2017-2022 (69.3%) (p 0.0001, Logrank test for trend). Conclusion Refractory anemia with excess blasts is a subtype of MDS with a very high mortality. Our analysis revealed that it favors male gender, and Caucasian race. Superior survival outcomes were observed with age less than 65, Asian/Pacific Islanders or Alaskan/Native Americans origin, income above 100K and metropolitan residence. Management with chemotherapy or radiotherapy were also associated with higher survival. No significant association was noted with gender. Further research and analysis is warranted to identify specific targetable mutations to help improve overall survival in this aggressive hematologic malignancy.
2025-05-28 | Phase II study evaluating olutasidenib and azacitidine in patients with IDH1 -mutated higher-risk myelodysplastic syndromes, chronic myelomonocytic leukemia, or advanced myeloproliferative neoplasms.
TPS6586 Background: IDH1 mutations are detected in 3-4% of patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) and approximately 9% of patients with myeloproliferative neoplasms (MPN). IDH1 mutations have been associated with shortened survival and increased rates of transformation to acute myeloid leukemia (AML). Despite the use of IDH1 inhibitors in AML and the recent FDA approval of ivosidenib for relapsed/refractory IDH1 -mutated MDS, no IDH1-directed therapies are approved in MPN or treatment-naïve MDS/CMML, and no combination treatment regimens are commercially available. Olutasidenib, an FDA-approved oral, highly selective, potent inhibitor of mutant IDH1, is well-tolerated, non-cytotoxic and effective, with overall response rates in relapsed/refractory AML of 51% in combination with azacitidine. Olutasidenib alone or with azacitidine demonstrated overall response rates of 86% in treatment-naïve and 47% in relapsed/refractory MDS. We consequently hypothesize olutasidenib to be effective in patients with IDH1 -mutated higher-risk MDS/CMML or advanced MPN. Methods: This multicenter investigator-initiated study under the MDACC-Rigel Research Alliance is a phase II non-randomized study evaluating the efficacy of olutasidenib in combination with azacitidine in patients with IDH1 -mutated higher-risk MDS/CMML or advanced MPN. Patients will be divided into 2 arms: treatment naïve and previously treated. Eligibility includes adult patients with acceptable organ function and confirmed IDH1 mutation with higher-risk MDS/CMML (by International Prognostic Scoring System [IPSS], Revised IPSS [IPSS-R], or Molecular IPSS [IPSS-M] criteria) or advanced MPN (with bone marrow blast percentage ≥ 10%). The primary objective of the study is to determine the overall response rate by International Working Group 2023 criteria (MDS), 2015 MDS/MPN uniform response criteria (CML), and European Leukemia Network 2017 AML criteria (advanced MPN). Secondary objectives include rates of complete remission, safety and tolerability, overall survival, progression-free survival, duration of response, and changes in IDH1 clone size. All patients will receive azacitidine 75 mg/m 2 intravenously or subcutaneously daily on days 1-7 of each treatment cycle and olutasidenib 150 mg orally twice daily. Response assessments will be performed after cycle 1, then every 3 cycles up through cycle 12, then every 12 cycles thereafter. Once off treatment, survival follow-up will occur every 3 months for 3 years. The goal enrollment is 45 patients (25 treatment-naïve and 20 previously-treated with no more than 5 MPN patients in each arm) across 5-6 centers in the United States. The study was activated and enrollment began in January 2025. Clinical trial information: NCT06597734 .
2025-05-28 | Comparing myeloablative and reduced-intensity conditioning for allogeneic PBSCT in MDS with increased blasts.
e18573 Background: Myelodysplastic syndrome with increased blasts (MDS-IB) is a complex hematologic malignancy characterized by ineffective hematopoiesis and a high risk of transformation to acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a potentially curative treatment option for these patients, but the optimal conditioning regimen remains a subject of ongoing debate. This retrospective study aims to compare the outcomes of patients with MDS-IB who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) using either MAC or RIC regimens between 2015 and 2023. Methods: We identified 53 patients with MDS-IB1 and MDS-IB2 who underwent allogeneic PBSCT. They received MAC (FBT or FB4) with fludarabine 50 mg/m2/day, day -6 to day -2, busulfan 3.2 mg/kg/day, day -5 to day -2, +/- TBI 200 cGy/day on day -1 and day 0. Or reduced intensity conditioning (FB2) with fludarabine 30 mg/m2/day day -6 to day -2, busulfan 3.2 mg/kg/day day -3 and day -2. The endpoints were progression-free survival (PFS) and overall survival (OS) at 2-years. Kaplan Meier method was used to study survival estimates, log-rank test was used to compare those estimates. Results: The median age at diagnosis was 63.8 years. Most patients had underlying MDS-IB2 (62%), and 79% of patients received their transplant from matched unrelated donors. Only 21% of patients received MAC with either FB4 or FBT, while the rest received RIC. The median follow-up was 9.7 months. 2-year PFS was 87.5% for the MAC group versus 48.9% for RIC group (p-value 0.099). The 2-year overall survival (OS) was 54.5% in the MAC group compared to 35.7% in the RIC (p-value = 0.737). Conclusions: Our institutional 2-year analysis showed a non-significant difference in PFS and OS between the conditioning regimens in MDS patients with increased blasts. This lack of statistical significance could be related to the small sample size and retrospective analysis. However, prospective review and multicenter analysis with a larger sample size may be warranted to validate the choice of conditioning regimen in this group of patients.
2025-02-19 | Effect of pre-transplant cytoreductive therapy on the outcomes of patients with MDS or secondary AML evolving from MDS undergoing allo-HSCT: a secondary analysis of an RCT
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative therapy for patients with myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia evolving from MDS (sAML) [ 1 ]. Multiple factors are reported to influence the prognosis of patients with MDS and sAML undergoing allo-HSCT, including prognostic stratification, disease status, conditioning regimen and pre-transplant therapy [ 2 , 3 ]. Our randomized controlled trial (RCT) has shown that granulocyte-colony stimulating factor, decitabine, busulfan and cyclophosphamide (G-DAC-BuCy) conditioning is a better choice than busulfan and cyclophosphamide (BuCy) conditioning for patients with MDS-refractory anemia with excess blasts (RAEB) or sAML undergoing allo-HSCT [ 4 ].
2024-11-05 | A Phase 1, Multicenter, Open-Label, Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Clinical Activity of Orally Administered LP-108 (Lacutoclax) As Monotherapy and in Combination with Azacitidine in Subjects with Relapsed or Refractory Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML)
Background: LP-108 (Lacutoclax) is a potent inhibitor of BCL-2. We explore the toxicity and tolerability of LP-108 as monotherapy and combined with azacitidine (Aza) in patients with relapse/refractory Acute Myeloid Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML) and high-risk refractory/relapsed Myelodysplastic syndrome (MDS) (EudraCT 2021-001402-29, NCT04139434). Description and aims of the trial: This is a First -in-human (FIH), Phase 1, multicenter, open-label study with dose-escalation of only lacutoclax phase (Phase 1a) and a cohort expansion phase (Phase 1b) combined with Aza. Inclusion criteria were AML, RAEB 1and 2, MDS with IPSS-R>4.5 and CMML with ≥5% of blasts in bone marrow, refractory or relapsed to previous treatment. The primary objective is to characterize safety and tolerability, to define maximum tolerability dose (MTD) recommended phase 2 dose (RP2D) and asses the pharmacokinetics of lacutoclax as monotherapy and combined with Aza. The secondary objective were Overall Response Rate (ORR) the Complete Remission (CR), minimal residual disease (MRD), complete remission with incomplete blood count recovery (CRi), morphologic leukemia free state (MLFS), partial remission (PR), the same in MDS (ORR, CR, PR and marrow CR), progression free survival (PFS), duration of response (DOR), event free survival (EFS) and overall survival (OS). The phase 1 was designed with two arms, monotherapy (Arm 1) and combination therapy with Aza (Arm 2) in a classic 3+3 in order to determine the MTD/OBD and RP2D starting with a dose of 100 mg q d in a 28 daily dosing schedule. Dose Limiting Toxicity (DLT) was described as any extra hematological toxicity ≥3 during the first 28 days of induction or prolonged grade 4 pancytopenia not due to active leukemia beyond 42 days. Adverse events were graded according to the NCI-CTCAE version 5.0. Results: A total of 44 patients (18 Female, 26 Male) were screened. A total of 32 patients were enrolled due to 12 patients deemed screen failures. The median age of the patients was 70 years (40-88 years). The patient population previous diagnosis were AML (20), CMML (4) and MDS (8). The median number of previous lines of therapy were 2 (1-7). Total patients enrolled in the Arm 1 (monotherapy) were 20, and 12 patients were enrolled in Arm 2. Within Arm 1 the dose was increased from 100mg/day (7 patients) to 200 mg/4 patient then to 400 mg/day (4 patients) and finally up to 600 mg/day (3 patients). In Arm 2 (combination therapy) the dose was increase from 100 mg/day (4 patients), 200 mg/day (5 patients) and 400 mg/day (3 patients). No new TAE's of special interest were found. The number serious TAE's >3 were 5 (25%). In Arm 2 100% of the patients experience some type of AE. No TAE's that implies DLT were not seen. The more frequent AE's were gastrointestinal (vomiting 65%), hematological (thrombocytopenia 65%) and increase bilirubin (25%). COVID 19 was only detected in 1 patient. We observed 4 CRc, 1PR and 2MFLS and 2 patients with improvement in its MDS status. Conclusions: Lacutoclax is safe with no apparent extra hematological toxicities and appears as a new anti BCL-2 agent in patients with refractory myeloid malignancies. This agent had encouraging efficacy as both monotherapy and in combination with azacitidine.
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2023-07-27 | MicroRNA-765 is upregulated in myelodysplastic syndromes and induces apoptosis via PLP2 inhibition in leukemia cells
Epigenetic studies, particularly research on microRNA (miRNA), have flourished. The abnormal expression of miRNA contributes to the development of hematologic malignancies. miR-765 has been reported to inhibit cell proliferation by downregulating proteolipid protein 2 (PLP2), which causes apoptosis. We investigated miR-765 dysregulation in myelodysplastic syndromes (MDS).We compared the expression profiles of miR-765 in 65 patients with MDS and 11 controls. Cell proliferation and apoptosis assays were performed to determine the in vitro effects of miR-765 on leukemia cells transfected with the miR-765 mimic. Reverse transcription quantitative PCR (RT-qPCR) and western blotting were performed to examine the targets of miR-765.We found that miR-765 levels were upregulated 10.2-fold in patients with MDS compared to controls. In refractory cytopenia with multilineage dysplasia, the percentage of patients with elevated miR-765 levels was significantly higher than in other forms of MDS. Experiments with leukemia cells revealed that transfection with a miR-765 mimic inhibited cell proliferation and induced apoptosis. RT-qPCR and western blotting demonstrated that the target of miR-765 was PLP2.These findings imply that upregulation of miR-765 induces apoptosis via downregulation of PLP2 and may have a role in MDS pathogenesis.
2023-02-20 | A miRNA screening identifies miR-192-5p as associated with response to azacitidine and lenalidomide therapy in myelodysplastic syndromes
Abstract Background miRNAs are small non-coding RNAs that regulate gene expression and are linked to cancer development and progression. miRNA profiles are currently studied as new prognostic factors or therapeutic perspectives. Among hematological cancers, myelodysplastic syndromes at higher risk of evolution into acute myeloid leukemia are treated with hypomethylating agents, like azacitidine, alone or in combination with other drugs, such as lenalidomide. Recent data showed that, during azacitidine and lenalidomide therapy, the concurrent acquisition of specific point mutations affecting inositide signalling pathways is associated with lack or loss of response to therapy. As these molecules are implicated in epigenetic processes, possibly involving miRNA regulation, and in leukemic progression, through the regulation of proliferation, differentiation and apoptosis, here we performed a new miRNA expression analysis of 26 high-risk patients with myelodysplastic syndromes treated with azacitidine and lenalidomide at baseline and during therapy. miRNA array data were processed, and bioinformatic results were correlated with clinical outcome to investigate the translational relevance of selected miRNAs, while the relationship between selected miRNAs and specific molecules was experimentally tested and proven. Results Patients’ overall response rate was 76.9% (20/26 cases): complete remission (5/26, 19.2%), partial remission (1/26, 3.8%), marrow complete remission (2/26, 7.7%), hematologic improvement (6/26, 23.1%), hematologic improvement with marrow complete remission (6/26, 23.1%), whereas 6/26 patients (23.1%) had a stable disease. miRNA paired analysis showed a statistically significant up-regulation of miR-192-5p after 4 cycles of therapy (vs baseline), that was confirmed by real-time PCR analyses, along with an involvement of BCL2, that was proven to be a miR-192-5p target in hematopoietic cells by luciferase assays. Furthermore, Kaplan–Meier analyses showed a significant correlation between high levels of miR-192-5p after 4 cycles of therapy and overall survival or leukemia-free survival, that was stronger in responders, as compared with patients early losing response and non-responders. Conclusions This study shows that high levels of miR-192-5p are associated with higher overall survival and leukemia-free survival in myelodysplastic syndromes responding to azacitidine and lenalidomide. Moreover, miR-192-5p specifically targets and inhibits BCL2, possibly regulating proliferation and apoptosis and leading to the identification of new therapeutic targets.
2019-05-29 | Role of 4‑aminobutyrate aminotransferase (ABAT) and the lncRNA co‑expression network in the development of myelodysplastic syndrome
IncRNAs play an important role in the regulation of gene expression. The present study profiled differentially expressed lncRNAs (DELs) and mRNAs (DEMs) in myelodysplastic syndrome (MDS) to construct a 4‑aminobutyrate aminotransferase (ABAT)‑DEL‑DEM co‑expression network in MDS development using the Agilent human BeadChips and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and network analyses. Compared with controls, there were 543 DELs and 2,705 DEMs in MDS patients, among which 285 (52.5%) DELs were downregulated and 258 (47.5%) DELs were upregulated, whereas 1,521 (56.2%) DEMs were downregulated and 1,184 (43.70%) DEMs were upregulated in MDS patients. The ABAT‑DEL‑DEM co‑expression network contained six DELs that were co‑expressed with ABAT in MDS. The GO analysis revealed that the co‑expression network mainly participated in response to organic cyclic compound, cell proliferation, cell part morphogenesis, regulation of cell proliferation and enzyme‑linked receptor protein signaling pathways, while the KEGG database showed that the co‑expression network was involved in various pathways, such as phagosome and metabolic pathways. Furthermore, the expression of a selected DEL (lncENST00000444102) and ABAT was shown to be significantly downregulated in MDS patients, and in SKM‑1 and THP‑1 cells. The selected lncENST00000444102 was then overexpressed and ABAT expression was knocked down in the MDS cell lines using lentiviral transfection. In addition, lncENST00000444102 overexpression reduced the viability and increased the apoptosis of MDS cells, ABAT expression was upregulated by lncENST00000444102.
2019-05-06 | MicroRNA-661 upregulation in myelodysplastic syndromes induces apoptosis through p53 activation and associates with decreased overall survival
MicroRNA (miRNA) dysregulation contributes to myelodysplastic syndromes (MDS), and apoptosis is one of the pathogenic features of MDS. We investigated the dysregulation of miRNA expression and its biological significance in MDS. We compared the expression profiles of miRNAs encoded by chromosome 8 in 65 patients with MDS and 11 controls, and analyzed the in vitro effect of the upregulated miRNA expression. We found that compared to the controls, miR-661 was upregulated by 5.28-fold in patients with MDS. Patients with high miR-661 expression showed significantly decreased overall survival. In vitro study results demonstrated that transfection with a miR-661 mimic induced apoptosis through the activation of p53. These findings suggest that high miR-661 expression can be associated with decreased overall survival and recapitulates apoptosis, the characteristic feature of MDS.
2017-09-11 | The U2AF homology motif kinase 1 (UHMK1) is upregulated upon hematopoietic cell differentiation
Abstract UHMK1 (KIS) is a nuclear serine/threonine kinase that possesses a U2AF homology motif and phosphorylates and regulates the activity of the splicing factors SF1 and SF3b155. Mutations in these components of the spliceosome machinery have been recently implicated in leukemogenesis. The fact that UHMK1 regulates these factors suggests that UHMK1 might be involved in RNA processing and perhaps leukemogenesis. Here we analyzed UHMK1 expression in normal hematopoietic and leukemic cells as well as its function in leukemia cell line. In the normal hematopoietic compartment, markedly higher levels of transcripts were observed in differentiated lymphocytes (CD4 + , CD8 + and CD19 + ) compared to the progenitor enriched subpopulation (CD34 + ) or leukemia cell lines. UHMK1 expression was upregulated in megakaryocytic-, monocytic-and granulocytic-induced differentiation of established leukemia cell lines and in erythrocytic-induced differentiation of CD34 + cells. No aberrant expression was observed in patient samples of myelodysplastic syndrome (MDS), acute myeloid (AML) or lymphoblastic (ALL) leukemia. Nonetheless, in MDS patients, increased levels of UHMK1 expression positively impacted event free and overall survival. Lentivirus mediated UHMK1 knockdown did not affect proliferation, cell cycle progression, apoptosis or migration of U937 leukemia cells, although UHMK1 silencing strikingly increased clonogenicity of these cells. Thus, our results suggest that UHMK1 plays a role in hematopoietic cell differentiation and suppression of autonomous clonal growth of leukemia cells.
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2023-04-12 | Acute myeloid leukemia cells and MSC-derived exosomes inhibiting transformation in myelodysplastic syndrome
Abstract Aims To investigate the mechanism of exosomes role in the transformation of MDS to AML. Methods Exosomes in culture supernatants of MDS and AML cell lines, were extracted by ultrafiltration and identified in three ways: morphology, size and exosome surface marker proteins. Exosomes from AML cell lines were then co-cultured with MDS cell lines and their effects on the proliferation, cycle, differentiation, apoptosis and cell microenvironment of MDS cell lines were analysed by CCK-8 assay and flow cytometry. Furthermore, exosomes from MSC were extracted for further authentication. RESULTS The transmission electron microscopy, nanoparticle tracking analysis, Western blotting and flow cytometry methods all showed that ultrafiltration is a reliable method for extracting exosomes. Exosomes from AML cell lines inhibit the proliferation of MDS cell lines, block cell cycle progression and promote apoptosis and cell differentiation. It also leads to increased secretion of tumour necrosis factor-α (TNF-α) and reactive oxygen species (ROS) in MDS cell lines. In addition, MSC-derived exosomes were found to inhibit the proliferation of MDS cell lines, arrest cell cycle progression, promote apoptosis, and inhibit differentiation. CONCLUSION In this study, we explored that exosomes of AML cell line origin affect the apoptosis of MDS cell lines via the TNF-α/ROS-Caspase3 pathway, thereby influencing the conversion of MDS to AML. Additional, MSC-derived exosomes inhibited the transformation of MDS to AML.
2018-01-26 | Long-term follow-up for up to 5 years on the risk of leukaemic progression in thrombocytopenic patients with lower-risk myelodysplastic syndromes treated with romiplostim or placebo in a randomised double-blind trial
Background Treatment options for thrombocytopenia in myelodysplastic syndromes are scarce. As described previously in a randomised phase 2 study (n=250), 58 weeks of romiplostim treatment in patients with International Prognostic Scoring System (IPSS)-defined lower-risk (low-risk or intermediate-1 risk) myelodysplastic syndromes led to reduced platelet transfusions (p<0·0001) and increased International Working Group-defined haematological improvement–platelet rates (p<0·0001) versus placebo. However, the study drug was discontinued because of the potential risk for progression to or incorrect diagnosis or treatment for acute myeloid leukaemia, based on an acute myeloid leukaemia interim hazard ratio (HR) of 2·5; the subsequent 58-week acute myeloid leukaemia HR was 1·2 (95% CI 0·4–3·8). Methods This study is a 5-year follow-up of a phase 2, multicentre, double-blind trial of romiplostim treatment in patients with lower-risk myelodysplastic syndromes. Eligible patients were recruited at 109 centres in North America, Europe, Russia, and Australia, were aged 18–90 years, and had platelets of 20 × 109 per L or less with or without a history of bleeding or 50 × 109 platelets per L or less with a history of bleeding. Patients were randomly assigned by interactive voice response system with stratification by baseline platelet count (≥20 × 109 per L or <20 × 109 per L) and IPSS risk (low or intermediate-1) to receive either placebo or 750 μg romiplostim subcutaneously once per week for 58 weeks. The primary outcomes for this long-term follow-up were survival and progression to acute myeloid leukaemia. Progression to acute myeloid leukaemia was defined as either 20% blasts or more after 4 weeks from romiplostim discontinuation; as per pathology; or by initiation of antileukaemia treatment. The primary outcome was assessed per protocol in all patients with available data. This study is registered with ClinicalTrials.gov, NCT00614523. Findings Patients were recruited from July 21, 2008, to Dec 16, 2010. 167 patients were assigned to receive romiplostim treatment and 83 were assigned to receive placebo. 210 (84%) of 250 patients entered the 5-year long-term follow-up (139 patients in the romiplostim group and 83 in the placebo group). At the end of follow-up, proportions of patients with acute myeloid leukaemia (20 [12%] of 167 in the romiplostim group vs nine [11%] of 83 in the placebo group; HR 1·06 [95% CI 0·48–2·33]; p=0·88) and proportions who died (93 [56%] vs 54 [54%]; HR 1·03 [0·72–1·47]; p=0·89) were not significantly different between the two groups. Interpretation Following the decision to stop the study drug, 5-year long-term follow-up HRs for transformation to acute myeloid leukaemia and HRs for death did not differ between patients treated with romiplostim and those treated with placebo, indicating that use of romiplostim is probably not associated with any increased risk of acute myeloid leukaemia or death, despite initial concerns. Funding Amgen Inc.
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Drug Discovery Landscape
12 orphan drug designations for Myelodysplastic neoplasm with increased blasts type 1.
12 orphan drug designations for Myelodysplastic neoplasm with increased blasts type 1.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Bexmarilimab | antibodies | EMA | Faron Pharmaceuticals Oy | |
bexmarilimab | antibodies | FDA | Faron Pharmaceuticals Ltd. | |
sonrotoclax | small molecules | FDA | BeOne Medicines USA, Inc. | |
co-packaged combination of azacitidine and cedazuridine | small molecules | FDA | Taiho Oncology, Inc. | |
selective dual small molecule inhibitor of IRAK1 and IRAK4 | small molecules | FDA | Rigel Pharmaceuticals, Inc. | |
6-((6-aminopyridin-2-yl)methyl)-4-methyl-2-(1H-pyrazol-3-ylmethyl)-4,6-dihydro-5H-[1,3]thiazolo[5',4':4,5]pyrrolo[2,3-d] pyridazin-5-one | small molecules | FDA | Agios Pharmaceuticals, Inc. | |
Pevonedistat | small molecules | EMA | Takeda Pharma A/S | |
Rigosertib sodium | small molecules | EMA | Onconova Europe GmbH | |
Allogeneic umbilical cord blood cells-derived CD133+ cells ex vivo expanded [StemEX] | cell therapies | EMA | Regulatory Resources Group Limited | |
Lintuzumab | antibodies | EMA | [INACTIVE] Seagen U.K. Limited | |
Val-Leu-Gln-Glu-Leu-Asn-Val-Thr-Val | peptides | EMA | [INACTIVE] Accelsiors CRO & Consultancy Services GmbH | |
Lenalidomide [Revlimid] | small molecules | EMA | Celgene Europe B.V. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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