small molecules

2026-07-14 | Venetoclax combined with azacitidine in the treatment of secondary myelodysplastic syndrome following multiple myeloma: a case report and literature review

We conducted a retrospective analysis of the clinical data of a patient with myelodysplastic syndrome (MDS) secondary to stable multiple myeloma (MM), who was treated with a combination of venetoclax and azacitidine at the Fifth People's Hospital of Chengdu. Additionally, we reviewed the relevant literature. The patient, a 74-year-old male, was initially diagnosed with multiple myeloma (IgA-γ, DS IIIA, ISS III, R-ISS II) and achieved a very good partial response (VGPR) following sequential treatments with BCTD, RVD, and PVD regimens, subsequently receiving maintenance therapy with pomalidomide. Despite being in continuous remission, the patient developed secondary myelodysplastic syndrome characterized by refractory anemia with excess blasts-2 (MDS-RAEB-II) 51 months post-initial MM diagnosis. He was then treated with venetoclax in combination with azacitidine. After the first treatment course, the patient achieved morphological partial remission of MDS. However, due to non-adherence to continuous treatment, he ultimately succumbed to a secondary infection.

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2026-04-21 | Survival of myelodysplastic syndrome patients after azacitidine therapy.

BACKGROUND: Although azacitidine monotherapy improves survival in myelodysplastic (MDS) patients, various outcomes have been found regarding cytogenetic and molecular features. METHODS: This retrospective analysis of 80 Thai patients with MDS treated with azacitidine monotherapy evaluated real-world outcomes in Thailand and identified clinical parameters associated with treatment response and survival. Azacitidine was given at 100 mg/day for 7 days, every 28-day cycle. Targeted exome analysis of 25 genes was performed, using a QIAact Myeloid DNA UMI Panel with GeneReader next generation sequencing system. RESULTS: MDS with increased blasts (IB) and low blasts (LB) were observed in 64% and 20%, respectively. The median number of cycles of azacitidine therapy was 11 cycles. The ORR was 59%, patients with MDS-IB2 had the highest ORR (71%) compared to those with MDS-IB1 (47%) or MDS-LB (41%), p = 0.029. A significantly lower ORR was found for MDS patients (27%) with complex karyotypes (CKs), p = 0.016. MDS patients with poor/very poor risk cytogenetics had significantly lower ORR than those without poor/very poor risk cytogenesis 37% versus 65%, p = 0.039. MDS patients with mutated TET2 had lower ORR than those with wild-type TET2, 17% vs. 62% (p = 0.041). The median OS in patients with MDS was 19 months. The median OS was shorter in MDS patients with CKs (p = 0.003), intermediate/higher-risk IPSS-R (p = 0.046), poor- cytogenetic risks (p = 0.028), RUNX1 (p = 0.047) or transcription factor (TF) gene mutations (p = 0.011) than those without CKs, poor risk cytogenetics, RUNX1 and TF gene mutation. CONCLUSIONS: Complex karyotype was associated with poor ORR in MDS patients receiving azacitidine monotherapy, therefore, these patients need to be treated with the combination therapy or other treatment regimens rather than azacitidine monotherapy. CKs, intermediate/higher-risk IPSS-R, poor-cytogenetic risks, mutated RUNX1 and transcription factor gene mutations were associated with poor OS in MDS patients.

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2025-11-26 | PO:21:028 | A difficult case of VEXAS syndrome: management of myelodysplastic syndrome associated with systemic inflammation and infectious complications

Background. This work describes a clinical case of VEXAS syndrome associated with myelodysplastic neoplasm, aiming to highlight the clinical and diagnostic features and the importance of a multidisciplinary approach to optimize treatment and improve the patient's prognosis. Materials and Methods. A 57-year-old male, with a medical history of type 2 diabetes and hypertension, presented between March and June 2024 with marked fatigue, migratory arthralgia in the lower limbs, subcutaneous nodules, an episode of left ear chondritis, and a 20 kg weight loss over 6 months, without fever or apparent infections. Laboratory findings included macrocytic anemia (Hb 6.8 g/dL, MCV 108 fl), without hemolysis, leukocytopenia (WBC 2270/mm³, PMN 1170/mm³), hyperferritinemia (842 µg/L), CRP 111 mg/L, and polyclonal hypergammaglobulinemia. Autoimmune markers (ANA, ENA, ANCA) and HCV/HBV serology were negative. CT scans of the head, chest, and abdomen (August 2024) revealed hepatosplenomegaly. In September, the patient developed a fever with chills, further weight loss, and petechiae at the base of all limbs. PET-CT showed increased lymph node, splenic, and skeletal uptake, while bone marrow biopsy identified myelodysplastic syndrome of the RAEB II subtype, with high IPSS and R-IPSS scores. Microscopic examination noted cytoplasmic vacuoles in granulocytes and blasts. VEXAS syndrome was confirmed by genetic testing identifying a mutation in the UBA1 gene (c.121A>G p.(Met41Val)). The treatment regimen included corticosteroids (methylprednisolone 1 mg/kg/day), with azacitidine as a bridge to transplant. Results. During follow-up, the patient showed a satisfactory clinical and laboratory response to steroid and antineoplastic drugs, with normalization of inflammatory markers, blood count, and regression of clinical manifestations. In January 2025, he was hospitalized for influenza A pneumonia during neutropenia and treated with antivirals, antibiotics, and corticosteroids. The steroid dose was tapered to 10 mg/day of prednisone, maintaining satisfactory clinical and laboratory control. A follow-up chest CT (3 months later) revealed persistent fibrotic changes and ground-glass opacities, consistent with an inflammatory pattern related to the syndrome. Azacitidine therapy resulted in partial remission, and the option of allogeneic stem cell transplantation was contemplated owing to the patient's youth and the poor prognosis linked to myelodysplasia. Conclusions. This case underscores the importance of early recognition of VEXAS syndrome, a rare autoinflammatory disorder that combines systemic inflammatory and hematological manifestations. Genetic diagnosis is essential for confirming the diagnosis and guiding treatment. A multidisciplinary approach, involving immunosuppressive therapy and consideration of allogeneic stem cell transplantation, is the most promising strategy to improve patient’s prognosis. Close clinical and radiological monitoring is crucial to manage infectious and inflammatory complications, optimizing the therapeutic choice and the patient's quality of life.

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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.

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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

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proteins

2023-10-01 | MYELODYSPLASTIC SYNDROME RESPONDING TO THE AZACITIDINE PROTOCOL ASSOCIATED WITH HIGH DOSES OF VITAMINS

To report four patients with Myelodysplastic Syndrome (MDS) who had improvements while on AZAVIT-ABCDEF protocol [Azacytidine associated with Erythropoietin (EPO), Filgrastim (G-CSF) and high doses of vitamins B1, C and D], after signing the consent form. This protocol is registered in the Plataforma Brasil-CAAE: 53015421.0.0000.5463. Methodology: This descriptive study was made through data collection from HSPE's medical records. Case 1: 81-year-old (y.o.) male (M) diagnosed (dx) with MDS-IB2; IPSS-R 7. Complete Blood Count (CBC): Hb 7.3 g/dL, White blood count (WBC) 2090/mm3 ANC 794/mm3 platelets (Ptl): 53000/mm3. Bone Marrow Aspirate (BMA): dysplasia with 11 % blasts. Flow Cytometry (FC): positive for D7, CD13, CD33, CD34, CD71, CD117, CD123, HLA-DR, MPO. FISH: Chromosome 8 trisomy. 47, XY +8[18]/ 46, XY [2]. He received 12 cycles of chemo. His last transfusion was 4 months (mo) after dx. Fourteen mo after dx, CBC: Hb 12.6, WBC 3010 (2/49/12/3/4) Pts 168000. He's been surviving for 14 months. Case 2: 69 y.o. M, diagnosed with MDS-IB2; IPSS-R4.5. CBC: Hb 10.9 g/dL, WBC 3890/mm3 ANC 1594/mm3 Plt 67000/mm3; BMA: dysplasia (11% blasts), FC: CD13, CD33, CD34, CD71, CD117. FISH: Normal.46, XY. He received 8 cycles of Chemo and has no need for transfusion. 10 mo after dx, CBC: Hb12.5 g/dL, WBC 2.840/mm3 Platelets 65000/mm3; He's been surviving for 10 months. Case 3: 73 y.o. M diagnosed with low blasts and ring sideroblasts MDS. IPSS-R: very low risk. He maintained low transfusion requirements while on EPO. 10 years after dx, CBC: Hb 7.2 g/dL, ANC 7978/mm3, Ptl 49000/mm3 while on G-CSF and EPO, this time requiring packed red blood cell (pRBC) transfusions; Ferritin level: 2243 ng/mL. BMA: dysplasia (0.5% blasts) and 46% ringed sideroblasts. FISH: normal; 46, XY. His last pRBC transfusion was in Oct/22. In Aug/23, CBC: Hb 11 g/dL, ANC 5798/mm3, Ptl 79,000/mm3; ferritin:316. He's currently not on EPO or G-CSF. Survival so far: 11 years. Case 4: 70 y.o.Mdiagnosed with MDS-IB1. IPSS-R: very high risk. CBC: Hb 4.9 g/dL, WBC 900/mm3 (ANC 330) / Ptl 11000/mm3. BMA: dysplasia (6.1% of blasts). FC: CD13, CD 33, CD 34, CD 38, CD 45, CD 117, CD 123, HLA-DR. FISH: normal; 46, XY, t(2;4)[7]/XY[14]. His initial transfusion needs were 2 pRBC/month and platelets transfusion once and while; Ferritin level: 952 ng/mL. He's been with no need for transfusion for 17 months. 28 mo after dx, CBD: Hb 7.1 g/dL, WBC 4310/mm3 ANC 2930/mm3, Ptl 20,000/mm3; Survival so far: 28 months. Discussion: MDS is characterized by genetic, epigenetic and metabolic disturbances in hematopoietic cells causing them to increase their proliferation rate and apoptosis and to lose their ability to differentiate. Clonal expansion is influenced by bone marrow's microenvironment and patients may end up dying from the disease due to cytopenia related complications or due to progressive increase in blast counts. That protocol was well tolerated, conferring improvements in cellular aerobic metabolism thereby making possible hematopoietic cells to differentiate. Conclusion: Patients had improvements in their transfusion needs along with better quality of life. Once compared to the IPSS-R at diagnosis, there have been improvements in patients' overall survival, even for high riskMDS. We believe such treatment may be beneficial for MDS and low-risk patients may have longer survival in association with less transfusion of blood components.

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2022-12-08 | Cellular and metabolic characteristics of pre-leukemic hematopoietic progenitors with GATA2 haploinsufficiency.

Mono-allelic germline disruptions of the transcription factor GATA2 result in a propensity for developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), affecting more than 85% of carriers. How a partial loss of GATA2 functionality enables leukemic transformation years later is unclear. This question has remained unsolved mainly due to the lack of informative models, as Gata2 heterozygote mice do not develop hematologic malignancies. Here we show that two different germline Gata2 mutations (TgErg/Gata2het and TgErg/Gata2L359V) accelerate AML in mice expressing the human hematopoietic stem cell regulator ERG. Analysis of Erg/Gata2het fetal liver and bone marrow-derived hematopoietic cells revealed a distinct pre-leukemic phenotype. This was characterized by enhanced transition from stem to progenitor state, increased proliferation, and a striking mitochondrial phenotype, consisting of highly expressed oxidative-phosphorylation-related gene sets, elevated oxygen consumption rates, and notably, markedly distorted mitochondrial morphology. Importantly, the same mitochondrial gene-expression signature was observed in human AML harboring GATA2 aberrations. Similar to the observations in mice, non-leukemic bone marrows from children with germline GATA2 mutation demonstrated marked mitochondrial abnormalities. Thus, we observed the tumor suppressive effects of GATA2 in two germline Gata2 genetic mouse models. As oncogenic mutations often accumulate with age, GATA2 deficiency-mediated priming of hematopoietic cells for oncogenic transformation may explain the earlier occurrence of MDS/AML in patients with GATA2 germline mutation. The mitochondrial phenotype is a potential therapeutic opportunity for the prevention of leukemic transformation in these patients.

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2016-12-07 | Erythropoiesis‐stimulating agents significantly delay the onset of a regular transfusion need in nontransfused patients with lower‐risk myelodysplastic syndrome

Abstract Background The EUMDS registry is an unique prospective, longitudinal observational registry enrolling newly diagnosed patients with lower‐risk myelodysplastic syndrome ( MDS ) from 17 European countries from both university hospitals and smaller regional hospitals. Objective The aim of this study was to describe the usage and clinical impact of erythropoiesis‐stimulating agents ( ESA s) in 1696 patients enrolled between 2008 and 2014. Methods The effects of ESA s on outcomes were assessed using proportional hazards models weighting observations by propensity to receive ESA treatment within a subset of anaemic patients with or without a regular transfusion need. Results ESA treatment (median duration of 27.5 months, range 0–77 months) was administered to 773 patients (45.6%). Outcomes were assessed in 897 patients (484 ESA treated and 413 untreated). ESA treatment was associated with a nonsignificant survival benefit ( HR 0.82, 95% CI: 0.65–1.04, P = 0.09); this benefit was larger amongst patients without prior transfusions ( P = 0.07). Amongst 539 patients for whom response to ESA treatment could be defined, median time to first post‐ ESA treatment transfusion was 6.1 months (IQR: 4.3–15.9 months) in those transfused before ESA treatment compared to 23.3 months (IQR: 7.0–47.8 months) in patients without prior transfusions ( HR 2.4, 95% CI: 1.7–3.3, P < 0.0001). Responding patients had a better prognosis in terms of a lower risk of death ( HR 0.65, 95% CI: 0.45–0.893, P = 0.018), whereas there was no significant effect on the risk of progression to acute myeloid leukaemia ( HR 0.71, 95% CI: 0.39–1.29, P = 0.27). Conclusion Appropriate use of ESA s can significantly delay the onset of a regular transfusion need in patients with lower‐risk MDS .

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2016-03-29 | Effect of IL-7 and IL-15 on T cell phenotype in myelodysplastic syndromes

Aberrant T cell phenotype is one of the characteristics of myelodysplastic syndromes (MDS). In this study, we detected an increased concentration of IL-15 in the plasma of MDS patients (n = 20) compared with that in the plasma of healthy controls (n = 20). In MDS patients, reduced naïve CD4+ and CD8+ T cells [16.11 ± 6.56 vs. 24.11 ± 7.18 for CD4+ T cells (p < 0.001) and 13.15 ± 5.67 vs. 23.51 ± 6.25 for CD8+ T cells (p < 0.001)] were observed. The reduced naïve and increased effector memory T cells were significantly correlated with IL-15 plasma level. Then, the effect of IL-15 and IL-7 was tested in vitro. Peripheral blood mononuclear cells from MDS were treated for 15 days with IL-15. This treatment significantly decreased naïve CD4+ (p < 0.001) and CD8+ (p < 0.001) T cells and correspondingly increased terminal memory CD4+ and CD8+ T cells (p < 0.001). Treatment with IL-7 increased naïve CD4+ (p < 0.05) and CD8+ (p < 0.001) T cells. Our results indicated that exposure to high levels of IL-15 may be involved in the T cell phenotype conversion observed in MDS. IL-7 may be one of the promising therapeutic candidates for recovering the effector immune compartment in MDS patients.

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2012-08-20 | A randomized controlled trial of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving decitabine

Patients with myelodysplastic syndrome (MDS) receiving hypomethylating agents commonly develop thrombocytopenia. This double-blind study evaluated the efficacy and safety of romiplostim, a peptibody protein that increases platelets, in patients with MDS receiving decitabine. Patients received romiplostim 750 μg (n = 15) or placebo (n = 14) and decitabine. Median platelet counts at the beginning of each decitabine cycle trended lower in placebo-treated than in romiplostim-treated patients. Bleeding events occurred in 43% of placebo-treated and 27% of romiplostim-treated patients, and platelet transfusions were administered to 57% of placebo-treated and 47% of romiplostim-treated patients. Overall clinical therapeutic response was achieved by 21% of placebo-treated and 33% of romiplostim-treated patients. Treatment was generally well tolerated. Progression to acute myeloid leukemia (AML) occurred in one patient per group. Adding romiplostim to decitabine treatment is well tolerated and may be beneficial, as indicated by trends toward higher platelet counts at the beginning of each treatment cycle and lower platelet transfusion rates and percentages of patients with bleeding events.

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antibodies

2026-05-06 | Case Report: Use of mirvetuximab soravtansine in a patient with platinum-resistant ovarian cancer and concomitant PARP-inhibitor-related myelodysplastic syndrome.

Response rates in platinum-resistant ovarian cancer remain low (16-30%) and decline with subsequent lines of therapy. Mirvetuximab soravtansine (MIRV), an antibody-drug conjugate targeting folate receptor alpha (FRα), has demonstrated clinically meaningful activity in FRα-positive disease. We report a 65-year-old patient with heavily pretreated, FRα-positive ovarian cancer who developed therapy-related myelodysplastic syndrome with increased blasts (MDS-IB2, DNMT3A-mutated) during therapy with MIRV in combination with carboplatin having received prior PARPi maintenance therapy. Azacitidine treatment induced complete hematologic remission. Following progression of the ovarian cancer disease, MIRV was reintroduced concurrently with ongoing azacitidine. This strategy resulted in seven months of sustained disease control of the ovarian cancer without evidence of MDS worsening. In fact, after three cycles of azacitidine, a follow-up bone marrow biopsy showed no residual MDS. This case demonstrates that MIRV can be safely and effectively administered alongside azacitidine, providing clinically meaningful tumor control without compromising hematologic outcomes. These findings support the concurrent management of ovarian cancer and therapy-related MDS as a viable and underutilized treatment approach in a highly challenging clinical setting.

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2024-07-19 | Prognostic significance of GATA2 in patients with MDS/AML: a systematic review and meta-analysis.

GATA2 deficiency syndrome is a heterogeneous disorder characterized by a high risk of developing myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML). We conducted a meta-analysis of the literature to explore the prognostic significance of GATA2 mutations in patients diagnosed with MDS/AML, as previous studies have yielded conflicting findings regarding the impact of GATA2 mutations on patient outcomes. We conducted a comprehensive literature search of databases such as PubMed, Embase, the Cochrane Library, and the Web of Science to obtain studies on the prognostic significance of GATA2 mutations in patients with MDS/AML that were published through January 2024. We extracted the hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS), disease-free survival (DFS), and event-free survival (EFS). The meta-analysis was conducted by choosing either a fixed-effect model or a random-effect model, depending on the variability observed among the studies. A total of 13 cohort studies were included in the final meta-analysis, including 2714 patients with MDS, of whom 644 had GATA2 mutations. The results revealed that GATA2 mutations had an adverse impact on OS (HR = 1.54, 95% CI = 1.08-2.18, P = 0.02) and EFS (HR = 1.32, 95% CI = 1.01-1.72, P = 0.04), but no significant effect on DFS (HR = 1.21, 95% CI = 0.89-1.64, P = 0.23). GATA2 mutations were associated with a significantly shorter OS in MDS patients (HR = 2.56, 95% CI = 1.42-4.06, P = 0.002) but not in AML patients (HR = 1.08, 95% CI = 0.92-1.26, P = 0.37). Our meta-analysis revealed that GATA2 mutations are associated with unfavourable outcomes in patients with MDS/AML. Furthermore, patients harbouring these mutations should be prioritized for aggressive therapeutic interventions.

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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.

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2017-10-04 | Functional expression of Tim-3 on blasts and clinical impact of its ligand galectin-9 in myelodysplastic syndromes

T-cell immunoglobulin mucin-3 (Tim-3), an inhibitory immune checkpoint receptor, is highly expressed on acute myeloid leukemia cells and its ligand galectin-9 is reported to drive leukemic progression by binding with Tim-3. However, it remains unclear whether the Tim-3-galectin-9 pathway is associated with the pathophysiology of myelodysplastic syndromes (MDS). Thus, we investigated the expression and function of Tim-3 and the clinical impact of its ligand galectin-9 in MDS. Tim-3 expression levels on MDS blasts by CD45/side-scatter or CD34/CD45 gating were increased as MDS progressed to the advanced stage. Tim-3 expression in the MDS blasts was upregulated in the presence of the cell culture supernatant of human stromal cells or the MDS-related cytokine transforming growth factor-β1. The proliferation of Tim-3+ MDS blasts was inhibited by the blockade of anti-Tim-3 antibody. Furthermore, plasma levels of galectin-9 were elevated as MDS progressed to the advanced stage in 70 MDS/acute leukemia transformed from MDS patients and was a prognostic factor in 40 MDS patients. Our data demonstrated that the Tim-3-galectin-9 pathway is associated with the pathogenesis and disease progression of MDS. These findings provide new insight into potential immunotherapy targeting the galectin-9-Tim-3 pathway in MDS.

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2017-06-10 | Influence of TNF and IL6 gene polymorphisms on the severity of cytopenias in Argentine patients with myelodysplastic syndromes

Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematologic disorders characterized by cytopenia(s) and predisposition to leukemic progression. An immune dysregulation and an aberrant bone marrow microenvironment seem to be key elements in the physiopathological process of MDS. In order to evaluate a possible association between susceptibility and clinic-pathologic features, we genotyped 153 MDS patients for functional cytokine polymorphisms: TNF (−308 G/A), IFNG (+874 A/T and +875 CAn), IL6 (−174 G/C), and TGFB1 (+869 C/T and +915 G/C). The frequency of TNF and IL6 polymorphisms was different between patients and healthy controls (n = 131), suggesting a relatedness to MDS susceptibility in our population. Furthermore, the presence of each or both high-producing genotypes [TNF: p = 0.048, odds ratio (OR): 3.979; IL6: p = 0.001, OR: 6.835; both: p = 0.010, OR: 6.068] and thrombocytopenia at platelet counts of <50,000/μL (p = 0.004, OR: 4.857) were independently associated with an increased risk of manifesting a hemoglobin level of <8 g/dL at diagnosis. In particular, a severe bicytopenia was more frequently observed in patients with the TNF (high)_IL6 (high) combined genotype (p = 0.004, OR: 8.357), who consistently became transfusion dependent earlier (2.9 vs. 34.6 months; p = 0.001); and this likelihood was more evident in patients with lower bone marrow blast counts. The contribution of the remaining functional polymorphisms to the disease phenotype was less relevant. Our results demonstrate that TNF and IL6 gene polymorphisms, as underlying host features, are likely to play a key role in influencing the severity of the cytopenias in MDS and they may be instrumental for tailoring cytokine-target therapies.

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cell therapies

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.

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2024-05-09 | Clinical and Genomic-Based Decision Support System to Define the Optimal Timing of Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Myelodysplastic Syndromes

Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only potentially curative treatment for patients with myelodysplastic syndromes (MDS). Several issues must be considered when evaluating the benefits and risks of HSCT for patients with MDS, with the timing of transplantation being a crucial question. Here, we aimed to develop and validate a decision support system to define the optimal timing of HSCT for patients with MDS on the basis of clinical and genomic information as provided by the Molecular International Prognostic Scoring System (IPSS-M). We studied a retrospective population of 7,118 patients, stratified into training and validation cohorts. A decision strategy was built to estimate the average survival over an 8-year time horizon (restricted mean survival time [RMST]) for each combination of clinical and genomic covariates and to determine the optimal transplantation policy by comparing different strategies. Under an IPSS-M based policy, patients with either low and moderate-low risk benefited from a delayed transplantation policy, whereas in those belonging to moderately high-, high- and very high-risk categories, immediate transplantation was associated with a prolonged life expectancy (RMST). Modeling decision analysis on IPSS-M versus conventional Revised IPSS (IPSS-R) changed the transplantation policy in a significant proportion of patients (15% of patient candidate to be immediately transplanted under an IPSS-R-based policy would benefit from a delayed strategy by IPSS-M, whereas 19% of candidates to delayed transplantation by IPSS-R would benefit from immediate HSCT by IPSS-M), resulting in a significant gain-in-life expectancy under an IPSS-M-based policy (P = .001). These results provide evidence for the clinical relevance of including genomic features into the transplantation decision making process, allowing personalizing the hazards and effectiveness of HSCT in patients with MDS.

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2024-01-31 | Single-unit unrelated cord blood transplantation versus HLA-matched sibling transplantation in adults with advanced myelodysplastic syndrome: A registry-based study from the adult MDS working group of the Japanese society for transplantation and cellular therapy.

Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potential curative therapeutic modality for advanced myelodysplastic syndrome (MDS). Within HCT, the advancement of cord blood transplantation (CBT) procedures has resulted in a drastic expansion of CBT as a donor source for MDS. However, data comparing matched sibling donors (MSDs) HCT with CBT for advanced MDS, which was defined as refractory anemia with an excess of blasts (RAEB)-1 and RAEB-2 according to the World Health Organization classification at the time of HCT, have not been explored. We retrospectively compared survival and other posttransplant outcomes in 999 adult patients with advanced MDS after receiving allogeneic HCT in Japan between 2011 and 2020, using either MSD (n = 331) or single-unit unrelated cord blood (UCB) (n = 668). In the multivariate analysis, there were no significant differences in overall survival (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.90-1.34; P = 0.347), disease-free survival (HR, 1.01; 95% CI, 0.84-1.23; P = 0.845), relapse (HR, 0.88; 95% CI, 0.68-1.15; P = 0.370), or non-relapse mortality (HR, 1.15; 95% CI, 0.87-1.50; P = 0.310) between MSD recipients and UCB recipients. UCB was significantly associated with lower neutrophil (HR, 0.28; 95% CI, 0.24-0.33; P < 0.001) and lower platelet (HR, 0.29; 95% CI, 0.23-0.36; P < 0.001) recovery compared to MSD. UCB was significantly associated with a lower incidence of chronic graft-versus-host disease (GVHD) (HR, 0.57; 95% CI, 0.44-0.75; P < 0.001) and extensive chronic GVHD (HR, 0.46; 95% CI, 0.32-0.67; P < 0.001) compared to MSD. Similar results were observed after adjusting for differences between MSD and UCB recipients by propensity score matching analysis. Our study demonstrated that single CBT and MSD HCT had similar survival outcomes for adult patients with advanced MDS despite the lower hematopoietic recovery in CBT recipients and higher chronic GVHD in MSD recipients.

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2023-06-02 | Case Series Using Salvage Haplo-Identical Stem Cells for Secondary Transplantation

In order to expand the donor pool and accessibility of the transplant procedure, it was necessary to introduce haplo-identical stem cell transplants in the Fundeni Clinical Institute from 2015. Even if the Romanian population is an ethnically compact white population, many of the patients referred for bone marrow transplant lack a suitable donor. Hematopoietic stem cell transplant from a haplo-identical donor is an alternative option for those patients without an HLA (Human Leucocyte Antigen)-matched donor (sibling or matched unrelated). This procedure was used also as a salvage option for those who experienced engraftment failure or the rejection of the first stem cell graft. In this case series, we present three such cases, with a haplo-transplant used as a salvage protocol (after an engraftment failure or rejection of the first transplanted cells). The patients we present were diagnosed with AML (acute myeloid leukemia) with MDS (myelodysplastic syndrome), MDS-RAEB 2 (myelodysplastic syndrome-refractory anemia with excess blasts 2), and SAA (severe aplastic anemia). In two of the three cases, the engraftment failure may have been due to the conditioning Fludarabine/Busulfan/Cyclophosphamide (Flu/Bu/CFA) used, combined with marrow grafts. In all three cases, the second transplant was of haplo-identical peripheral blood stem cells using Melphalan/Fludarabine (Mel/Flu) conditioning, the cells engrafted properly and the patients experienced complete chimerism, and two of them are alive with an excellent quality of life.

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2023-04-21 | Successful allogeneic hematopoietic stem cell transplantation for myelodysplastic neoplasms complicated with secondary pulmonary alveolar proteinosis and Behçet's disease harboring GATA2 mutation.

Myelodysplastic neoplasms (MDS) are defined by cytopenia and morphologic dysplasia originating from clonal hematopoiesis. They are also frequently complicated with diseases caused by immune dysfunction, such as Behçet's disease (BD) and secondary pulmonary alveolar proteinosis (sPAP). MDS with both BD and sPAP is extremely rare, and their prognosis is poor. In addition, haploinsufficiency of the hematopoietic transcription factor gene GATA2 is recognized as a cause of familial MDS and is frequently complicated by sPAP. Herein, we report a case of MDS combined with both BD and sPAP in association with GATA2 deficiency in a Japanese woman. Because she developed progressive leukopenia and macrocytic anemia during BD treatment at the age of 61, she underwent a bone-marrow examination and was diagnosed with MDS. She subsequently developed sPAP. At the age of 63, she underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Since allo-HSCT, she has maintained complete remission of MDS as well as the symptoms of BD and sPAP. Furthermore, we performed whole exome sequencing and identified the GATA2 Ala164Thr germline mutation. These findings suggest that patients with MDS, BD and sPAP should be considered for early allo-HSCT.

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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.

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2023-07-31 | LncRNA PCSK1N-202 regulates CD34 + hematopoietic cells proliferation in MDS patients via PIM2/HIF-1alpha

Abstract Background Myelodysplastic syndromes (MDS) are characterized by malignant clonal hematopoietic stem cells with high-risk of progression to acute myeloid leukemia (AML). Results In this study,we explore the role of PIM2/HIF-1alpha in the proliferation of CD34 + cells in MDS patients. We investigate the profile of lncRNA derived from the bone marrow CD34 + cells in MDS patients and AML secondary to MDS (sAML) patients. We found 1173 lncRNAs (648 upregulated/525 downregulated) and 326 mRNAs (125 upregulated/201 downregulated) significantly deregulated in sAML compared to those in MDS patients (|logFC| > 1, p value < 0.05). Of these, lncRNA PCSK1N-202 predicted as targeted-regulator to PIM2.RT-PCR showed that the level of PCSK1N-202 was upregulated in AML and MDS patients and positive related with PIM2.For further demonstrated the regulation of PCSK1N-202 to PIM2,RNA fluorescence in situ hybridization indicated that PCSK1N-202 was distributed in the nucleus and cytoplasm which as well as PIM2.For functional study, SKM-1 cell was transfected with LV- PCSK1N-202 ,which induced the decline of PIM2 and HIF-1α followed with decreased of cell proliferation and increased of apoptosis. Conclusion In conclusion, the upregulation of PCSK1N-202 transcript may through PIM2 / HIF-1α regulate the proliferation of CD34 + cells in MDS.

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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.

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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.

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2020-06-01 | Identification and validation of prognosis-related DLX5 methylation as an epigenetic driver in myeloid neoplasms.

Abstract The deregulated DLX gene family members DLX1/2/3/4/5/6 ( DLXs ) caused by DNA methylation has been demonstrated in various cancers with therapeutic target value. However, the potential role of DLXs methylation in myeloid neoplasms such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) remains to be elucidated. Clinical significance of DLXs methylation/expression was analyzed in patient with AML and MDS. The functional roles of DLXs were determined in vitro. In the identification stage, we found that lower DLX5 expression was correlated with prognosis in AML among all DLXs analyzed by The Cancer Genome Atlas datasets. In the validation stage, we revealed that reduced DLX5 expression was frequently occurred, and was also correlated with promoter hypermethylation in AML evaluated by targeted bisulfite sequencing. Epigenetic studies also showed that DLX5 promoter DNA methylation was associated with its expression. By quantitative polymerase chain reaction, we also validated that DLX5 hypermethylation was frequent event in both AML and MDS, and also correlated with MDS transformation to leukemia. Moreover, DLX5 hypermethylation was associated with lower rate of complete remission and shorter time of leukemia‐free/overall survival, and was also confirmed by Logistic/Cox regression analysis. Functional studies revealed the antiproliferative and pro‐apoptotic effects of DLX5 in MDS‐derived AML cell‐line SKM‐1. Finally, bioinformatics analysis demonstrated that DLX5 functioned in leukemogenesis may be through the association with PI3K/Akt signaling pathway. Collectively, our findings demonstrated that DLX5 methylation, negatively correlated DLX5 expression, was a potential prognostic and predictive indicator in patients with AML and MDS, which could also act as an epigenetic driver in myeloid neoplasms.

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