small molecules

2026-08-26 | Venetoclax in combination with azacitidine induced remission in a cat with relapsed myelodysplastic syndrome following failure of azacitidine monotherapy

Summary Myelodysplastic syndromes (MDS) are rare in cats, and relapse after azacitidine is difficult to manage. A 3‐year‐old, neutered, male British shorthair cat with MDS with refractory anaemia with excess blasts achieved three remissions on azacitidine (35 mg/m 2 subcutaneously for 3–4 days every 21 days), but relapsed with severe cytopenias and splenomegaly. Azacitidine re‐challenge failed, requiring four whole‐blood transfusions in 17 days. Salvage azacitidine (35 mg/m 2 subcutaneously for 5 days) plus venetoclax (360 mg/m 2 orally daily planned for 28 days) induced clinical remission, with notable improvements in appetite and activity, reduced transfusion dependence, and reduced splenomegaly, representing the first reported feline use of this combination. Toxicities were monitored with serial complete blood counts and Veterinary Cooperative Oncology Group's Common Terminology Criteria for Adverse Events grading. Dose‐limiting Grade 4 neutropenia and thrombocytopenia and severe gastrointestinal toxicity with fever occurred during Cycle 2, prompting venetoclax discontinuation and hospitalisation for intensive supportive care and antimicrobials. Survival was 168 days from venetoclax initiation, supporting B‐cell lymphoma 2 inhibition as salvage, while highlighting cautious dosing and frequent monitoring.

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2026-08-25 | CPX-351 plus gemtuzumab ozogamicin in relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome

Outcomes of patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and those with myelodysplastic syndrome (MDS) with increased blasts (IB) who progress after therapy with hypomethylating agents (HMA) are dismal, especially in the absence of targetable genetic aberrations. In this phase 2 pilot trial we treated 50 patients (48 R/R AML and 2 post-HMA MDS-IB) with a combination of CPX351 and gemtuzumab ozogamicin (GO); the median age was 68.7 years (range, 21.5-76.8 years). In patients with AML, 87% had received prior HMA, 83% prior venetoclax, 65% prior chemotherapy and 15% had undergone hematopoietic stem cell transplantation (HSCT). Both patients with MDS had received prior HMA and venetoclax. A composite complete remission (CRc) (CR+CR with incomplete count recovery) was achieved in 9 (19%) patients with AML, 2 of whom were consolidated with HSCT, and one of 2 patients with MDS achieved marrow CR with incomplete platelet recovery. The median event free (EFS) and overall survival (OS) for the whole group was 1.7 and 5.7 months respectively, while in responders it was 6.1 and 9.3 months. Among patients with AML who achieved a CRc the 1-year OS rate was 56%. Overall, 45 (90%) patients had a grade ≥ 3 adverse event (AE) with infections being the most common AE; there were no AE of hepatic sinusoidal obstruction syndrome. The combination of CPX-351+ GO is feasible and led to a CRc rate of 19% in R/R AML but with limited duration of responses and low rates of subsequent HSCT. (NCT03672539)

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2026-08-21 | Gelatinous transformation and concomitant fibrosis of bone marrow in a patient with relapsed myelodysplastic syndrome following unrelated bone marrow transplantation.

Gelatinous transformation of bone marrow (GTBM) is a rare histological condition characterized by deposition of hyaluronic acid-rich gelatinous material, usually accompanied by adipocyte atrophy, reduced reticulin fibers, and hypocellularity. Although most frequently associated with malnutrition and severe weight loss, GTBM has also been reported in hematological malignancies. The coexistence of GTBM and bone marrow fibrosis is rarely described, and its underlying mechanisms remain unclear. We report a 69-year-old woman with myelodysplastic syndrome with excess blasts-1 (MDS-EB-1) harboring a complex karyotype including chromosome 7 abnormalities, classified as very high risk by IPSS-R. She underwent unrelated bone marrow transplantation and achieved complete remission. On day 35, she developed acute skin graft-versus-host disease (GVHD), which resolved with immunosuppressive therapy. Five months later, she presented with pancytopenia, chronic cutaneous GVHD, severe anorexia, 15-kg weight loss, and malnutrition (BMI 11.5 kg/m2). Bone marrow aspiration yielded a dry tap, while biopsy revealed Alcian blue-positive gelatinous material, reticulin fibrosis, and preserved adipocytes. Her disease progressed to acute myeloid leukemia with 50% circulating blasts and was refractory to azacitidine and CPX-351, leading to death from progression. This case illustrates that GTBM and marrow fibrosis can occur simultaneously in relapsed MDS after transplantation, potentially driven by cytokine dysregulation related to neoplastic clones and chronic GVHD.

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2026-08-17 | Functional Characterization of Myelodysplastic Syndrome by Multiparameter Flow Cytometry: The Clinical Synergy Between Ki-67 and Bcl-2 and Their Potential Role in Diagnostics and Personalized Therapy

The diagnosis and clinical management of myelodysplastic neoplasms are increasingly challenged by the disease's inherent heterogeneity, particularly with respect to the diagnosis of low-grade variants. While standardized flow cytometric protocols traditionally rely on static biomarkers for lineage assignment, these often fail to capture the dynamic biological behavior of the malignant clone. This review synthesizes studies on the integration of functional biomarkers, specifically the nuclear proliferation marker Ki-67 and the anti-apoptotic protein Bcl-2, into the diagnostic and prognostic workflow. By utilizing high-dimensional multiparameter flow cytometry (MFC) and software-based maturation continuum analysis, the survival and growth kinetics of the myeloid, erythroid, and monocytic lineages can be quantified. These findings redefine myelodysplastic syndromes (MDS) as characterized by a significant decrease in cell-cycle progression and an increase in anti-apoptotic activity during early stages of maturation. Recent studies demonstrate that integrating the erythroid Ki-67 proliferation index as a fifth parameter into the conventional Ogata score dramatically improves diagnostic sensitivity for detecting MDS from 66% to 90% while maintaining 100% specificity. In particular, the sensitivity for detecting low-grade MDS improved from 56% to 91%. Additionally, a reduced erythroid Ki-67 index (≤28%) is a powerful independent predictor of transfusion dependence within 1 year. Beyond diagnostics, the introduction of the Bcl-2:Ki-67 ratio provides a superior metric for biological aggressiveness and a potential predictive tool for precision medicine. A high ratio identifies a quiescent, apoptosis-resistant cell population that is likely refractory to standard chemotherapy but is an ideal candidate for targeted Bcl-2 inhibition with Venetoclax. The integration of functional biomarkers bridges the gap between complex mutational landscapes and clinical manifestations. While digital imaging and artificial intelligence (AI) are beginning to automate blast enumeration and maturation analysis, functional kinetics may provide a necessary biological readout for personalized therapy.

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2026-08-14 | EZH2 Inhibition and Myeloid Risk: A Feature of On-Target Biology

In March 2026, Ipsen voluntarily withdrew the EZH2 inhibitor tazemetostat (Tazverik) from all markets and indications following results from the confirmatory Phase Ib/III SYMPHONY-1 trial demonstrating hematologic second primary malignancies (SPMs) in 5.7% of treated patients, compared with none in the control arm. The most frequently reported SPMs were myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Although this finding may be interpreted as an idiosyncratic liability of a single agent, the biology of EZH2 suggests a broader, target-driven risk. EZH2 functions in a context-dependent manner as both an oncogene and a tumor suppressor. Gain-of-function mutations drive transformation in germinal center B-cell lymphomas, whereas loss-of-function alterations impair hematopoietic stem cell differentiation and are recurrent in myeloid malignancies, including MDS and AML. In selected solid tumor contexts, such as specific subtypes of medulloblastoma, EZH2 loss can likewise promote tumorigenesis. These observations raise concern that chronic pharmacologic inhibition of EZH2 may phenocopy loss-of-function states that initiate myeloid neoplasia. We argue that the withdrawal of tazemetostat exposes a fundamental vulnerability in the development of epigenetic therapies: target validation has focused on tumor-intrinsic effects while underweighting consequences in normal stem cell compartments. This issue is particularly relevant for ongoing Phase III programs in prostate cancer, where prolonged exposure may amplify latency-dependent risks. We propose changes to preclinical safety assessment, trial design, and pharmacovigilance to mitigate predictable, target-mediated toxicities.

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proteins

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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2021-03-01 | Expression of mRNA TNFα and level of protein TNFα after exposure sCD40L in bone marrow mononuclear cells of myelodysplastic syndromes

Cytopenia is the primary phenomenon in myelodysplastic syndrome (MDS) amidst hypercellular bone marrow. The soluble CD40 ligand (sCD40L) is considered as a cytokine that can trigger synthesis of tumor necrosis factor α (TNFα) that promotes apoptosis. The objective of this study is to prove that recombinant human sCD40L (rh-sCD40L) exposure on bone marrow mononuclear cells (BMMC) MDS increases TNFα expression at mRNA level and at protein level.BMMC from MDS patients whom diagnosed and classified using the WHO 2008 criteria, were exposed to rh-sCD40L and antiCD40L. The expressions of TNFα mRNAs were quantified by qRT-PCR, level of TNFα were measured using the ELISA method.Exposure of rh-sCD40L significantly increased the expression of TNFα mRNA. The similar exposure also significantly increased the level of TNFα compared to controls. TNFα mRNA expression on BMMC in MDS samples exposed to rh-sCD40L is 3.32 times compared to TNFα mRNA expression without exposure. level of TNFα in supernatant media exposed to rh-sCD40L in MDS samples was higher than that of control samples which were 44.44 and 4.85 pg/mL, P=0.018.The sCD40L plays a role in increasing the synthesis of TNFα in mRNA level and protein level in BMMC MDS.

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2021-02-25 | Role of Plasma Gelsolin Protein in the Final Stage of Erythropoiesis and in Correction of Erythroid Dysplasia In Vitro.

Gelsolin, an actin-remodeling protein, is involved in cell motility, cytoskeletal remodeling, and cytokinesis and is abnormally expressed in many cancers. Recently, human recombinant plasma gelsolin protein (pGSN) was reported to have important roles in cell cycle and maturation of primary erythroblasts. However, the role of human plasma gelsolin in late stage erythroblasts prior to enucleation and putative clinical relevance in patients with myelodysplastic syndrome (MDS) and hemato-oncologic diseases have not been reported. Polychromatic and orthochromatic erythroblasts differentiated from human cord blood CD34+ cells, and human bone marrow (BM) cells derived from patients with MDS, were cultured in serum-free medium containing pGSN. Effects of pGSN on mitochondria, erythroid dysplasia, and enucleation were assessed in cellular and transcriptional levels. With pGSN treatment, terminal maturation at the stage of poly- and ortho-chromatic erythroblasts was enhanced, with higher numbers of orthochromatic erythroblasts and enucleated red blood cells (RBCs). pGSN also significantly decreased dysplastic features of cell morphology. Moreover, we found that patients with MDS with multi-lineage dysplasia or with excess blasts-1 showed significantly decreased expression of gelsolin mRNA (GSN) in their peripheral blood. When BM erythroblasts of MDS patients were cultured with pGSN, levels of mRNA transcripts related to terminal erythropoiesis and enucleation were markedly increased, with significantly decreased erythroid dysplasia. Moreover, pGSN treatment enhanced mitochondrial transmembrane potential that is unregulated in MDS and cultured cells. Our findings demonstrate a key role for plasma gelsolin in erythropoiesis and in gelsolin-depleted MDS patients, and raises the possibility that pGSN administration may promote erythropoiesis in erythroid dysplasia.

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2020-11-26 | Safety and Efficacy of Eltrombopag and Romiplostim in Myelodysplastic Syndromes: A Systematic Review and Meta-Analysis

Many studies indicated that eltrombopag and romiplostim could improve hematopoietic function in patients with myelodysplastic syndromes (MDS), but their toxicity and efficacy were not known. This meta-analysis aimed to investigate the safety and efficacy of eltrombopag and romiplostim in MDS.A full-scale search strategy was used to search relevant published studies in PubMed, Embase, Web of Science, ClinicalTrials.gov and the Cochrane Library until January 2020 using a random-effects model and the pooled risk ratio (RR) with 95% confidence interval as the effect indicator. Statistical analyses were performed using RevMan 5.3.This meta-analysis included eight studies comprising 1047 patients. A lower RR of overall response rate (ORR) (RR: 0.65; 95% CI, 0.47-0.9) and grade ≥3 bleeding events (RR: 0.36; 95% CI, 0.36-0.92) were observed after romiplostim and eltrombopag treatment compared with placebo. The pooled RR for the ORR and grade ≥3 bleeding events were 0.58 (95% CI: 0.41-0.83, P = 0.003) and 0.6 (95% CI: 0.37-0.96, P = 0.03) in eltrombopag, respectively. A lower ORR in intermediate- or high-risk MDS (RR: 0.63; 95% CI: 0.45-0.88, P = 0.006) was observed. No difference in mortality, serious adverse events, platelet transfusion, hematologic improvement, and AML transformation was observed.Thrombopoietin receptor agonists (TPO-RAs) romiplostim and eltrombopag were effective in reducing bleeding events, especially grade ≥3 bleeding events. However, it might reduce the ORR of MDS, especially in eltrombopag treatment group or high-risk MDS group. Due to the limited treatment of MDS and the poor response to the drug, this may be a selection method for MDS combined with fatal bleeding, although further research is needed to confirm the effectiveness of this approach.

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2020-07-01 | Phase 1b Study of IGF-Methotrexate Conjugate in the Treatment of High-grade Myelodysplastic Syndromes

The insulin-like growth factor type 1 receptor (IGF-1R) is overexpressed in myelodysplastic syndrome (MDS) cells, and 765IGF-Methotrexate (IGF-MTX) is a conjugate of methotrexate and a variant of insulin-like growth factor-1 (IGF-1) designed to selectively target cancer cells through binding to IGF-1R. The aim of this study was to determine whether IGF-MTX would be effective to treat MDS.In this phase I clinical trial, two patients with high grade MDS or oligoblastic acute myeloid leukemia (O-AML) that had failed standard therapy were treated with IGF-MTX.No dose-limiting toxicity was observed. Both patients had stable or improved cell counts and CD34+ myelodysplastic cell counts and exceeded their life expectancy (both alive at 1.9 years despite a life expectancy of less than 6 months). Bone marrow blast counts decreased from 22% to 5% in one patient, and from 17% to 16% in the other.In conclusion, IGF-MTX at 0.20 μM equivalents per kg was well tolerated, caused no cytopenia, and produced stable disease and extension of life.

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cell therapies

2026-04-05 | Genomic Landscape and Clinical Outcomes of Advanced Pediatric Myelodysplastic Syndromes.

Pediatric myelodysplastic syndromes (MDS) differ from adult MDS, and their genetic basis is poorly understood. This study characterizes the genomic features and clinical outcomes of advanced pediatric MDS. In this retrospective study, next-generation sequencing was performed on 63 pediatric patients with advanced MDS, including 46 with MDS with excess blasts (MDS-EB) and 17 with MDS-EB in transformation (MDS-EB-T, 2016 WHO classification), to detect somatic and potential germline variants. Mutations in 53 genes were detected in 49 patients (77.8%), with a median of 2 variants per patient (range, 0-8). Alterations in the RAS/MAPK pathway were most common, occurring in 28 patients (44.4%). Monosomy 7 significantly co-occurred with SETBP1, ETV6, and GATA2 mutations (p < 0.01). Time-dependent analyses showed HSCT improved 2-year overall survival (OS, 42.6% vs. 84.5%, p = 0.003) and event-free survival (EFS, 37.3% vs. 58.2%, p = 0.011). In multivariate analyses, HSCT was strongly associated with improved OS and EFS (p < 0.01). PTPN11 mutation remained an independent predictor of poorer OS and EFS (p < 0.05), and MDS-EB-T subtype independently predicted inferior EFS (p < 0.05). In advanced pediatric MDS, HSCT was associated with improved survival, whereas PTPN11 mutations emerged as an adverse prognostic factor.

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2025-11-24 | Hematopoietic cell transplantation for pediatric myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are uncommon in children and present distinct features compared to adults. Allogeneic hematopoietic cell transplantation (HCT) is considered the standard curative treatment for many children with MDS, including all patients with MDS with excess of blasts and those with refractory cytopenia of childhood associated with unfavorable karyotype, severe neutropenia or transfusion dependence. In this article, we reviewed the indications of HCT in pediatric MDS.

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2025-09-09 | Allogeneic hematopoietic stem cell transplantation in patients with germ line DDX41 mutated myeloid malignancies.

Germ line DDX41 mutations (DDX41mut) are identified in ∼5% of myeloid malignancies with an excess of blasts, representing a distinct myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) entity. The disease is associated with better outcomes than DDX41 wild-type (DDX41WT) cases, but patients who do not undergo allogeneic hematopoietic stem cell transplantation (HSCT) may experience late relapse. Because of the recent identification of DDX41mut, data on the post-HSCT outcomes remain limited. In this study, we report the HSCT outcomes of 83 patients with DDX41mut MDS/AML. With a median follow-up of 4.4 years, the 2-year leukemia-free survival (LFS) was 68.6% (95% confidence interval [CI], 57.1-77.6) and the 2-year nonrelapse mortality (NRM) was 21.1% (95% CI, 12.9-30.6). We then assessed the impact of DDX41mut using a pair match analysis performed on patients who underwent a transplantation in AML clinical trials. No significant differences were observed between patients with DDX41mut and those with DDX41WT in terms of LFS at 2 years (hazard ratio, 1.06; 95% CI, 0.59-1.90; P = .84), overall survival, NRM, relapse, or graft-versus-host disease incidence. The cumulative incidence of relapse for DDX41mut showed a trend toward a lower relapse rate during the first year then higher after 1 year. Given the familial nature of the disease, we specifically examined patients who relapsed after HSCT with a related donor and identified 7 cases of DDX41mut donor cell leukemia. In this study, HSCT in patients with DDX41mut AML was not associated with an increased risk for toxicity. However, we observed a potential for later relapse, which could potentially be mitigated by selecting related donors based on DDX41 status.

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2025-08-30 | Conditioning intensity in myelodysplastic patients aged ≥ 50 years undergoing allogeneic hematopoietic cell transplantation (allo-HCT): a study on behalf of the chronic malignancies working party of the EBMT.

Reduced intensity conditioning (RIC) is usually used for patients with myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (allo-HCT), particularly in the elderly or those with comorbidities. The impact of conditioning intensity on patients' outcome remains controversial with clinicians' subjective opinion/ experience remaining a major guide in choosing the intensity. Here, we compare RIC versus MAC in a large EBMT retrospective study in MDS patients aged ≥50 years undergoing allo-HCT between 2014 and 2018. Among the 1393 included patients, 922 (66%) were males, and the median age at transplant was 62.8 (50.0-77.9) years. The majority of patients (n = 884; 64.3%) had MDS with excess blasts. IPSS-R recorded was very low/low (n = 598, 43%), intermediate (n = 352, 25%), and high/very high (n = 443, 32%). Karnofsky index was ≥90 in 916 (69.3%) patients, and HCT-CI ≥ 3 in 292(27.3%) patients. A RIC regimen was used in 1053 (75.5%) patients. Median follow-up was 27.9 months (IQR: 26.4-30.6). Both uni- and multi-variable analyses did not show any significant association between conditioning intensity and outcomes. This study highlights a lack of association between RIC/MAC regimens and outcomes in allo-HCT MDS patients. Our results support the recently published systematic review and meta-analysis, where evidence for using one conditioning regimen over another remains weak.

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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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antibodies

2026-09-25 | ATM mutations in myelodysplastic neoplasms, acute myeloid leukemia, and myeloproliferative neoplasms: a systematic review

Ataxia Telangiectasia Mutated (ATM), a central kinase in the DNA damage response, is recurrently altered across these disorders, including myelodysplastic neoplasms (MDS), acute myeloid leukemia (AML), and myeloproliferative neoplasms (MPN), yet its clinical significance remains underrecognized. We conducted a PROSPERO-registered systematic review (CRD420251142673) to evaluate the prognostic and biological impact of ATM alterations in MDS, AML, and MPN. Ten studies met inclusion criteria. In MDS, ATM alterations showed consistent downregulation, hypermethylation, and a predominance of oncogenic missense mutations, with methylation significantly enriched in cases progressing to AML. In AML, reduced ATM gene expression, often driven by miR-100 or miR-181a, was associated with increased blast proliferation, while the ATM genetic variant rs3092856 correlated with chemoresistance and inferior survival. Evidence in MPN/CML, although limited, suggests that ATM polymorphisms, such as rs228593, rs3092856 (C4138T), -5144A>T (rs228589), c.5753G>C, c.346A>G, c.4060C>A, and the germline variant L2307F, contribute to disease susceptibility and adverse prognostic stratification. Collectively, current evidence supports ATM alterations as clinically relevant biomarkers in myeloid malignancies, although their functional role in disease pathogenesis remains incompletely understood.. Rather than establishing ATM merely as a prognostic marker, future efforts should prioritize the characterization of ATM-related therapeutic vulnerabilities and integrate ATM status into treatment-oriented molecular panels to guide precision-based interventions in myeloid diseases.

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2024-11-05 | The Bispecific Innate Cell Engager AFM28 Can Leverage AML Patient's NK Cells in Addition to Allogeneic NK Cells, Enabling Elimination of CD123+ Leukemic Stem and Progenitor Cells in AML and MDS

Introduction: Acute myeloid leukemia (AML) and high-risk myelodysplastic neoplasms (HR-MDS) remain challenging hematological malignancies with poor long-term outcomes. Novel strategies targeting leukemic stem and progenitor cells (LSPCs) are crucial to improve durable remissions. In that regard, CD123 expressed on LSPCs and leukemic blasts has emerged as a promising therapeutic target. We have demonstrated the preclinical efficacy of the bispecific CD123/CD16A innate cell engager AFM28 against CD123+ leukemic cells mediated by natural killer (NK) cells including its favorable safety outcome in cynomolgus monkey studies. Here, we investigated whether AFM28 alone could be preclinically effective by leveraging AML patient-derived NK cells to target autologous leukemic cells in addition to its potential in combination with allogeneic NK cell therapy. Moreover, we explored the preclinical effects of AFM28 on hematopoietic progenitors and LSPC derived from AML and HR-MDS patients. Methods: To assess the activity of AFM28 against leukemic blasts and LSPC, primary bone marrow (BM)-derived mononuclear cells (MNCs) of AML (n=5) and HR-MDS (n=5) patients were co-cultured with allogeneic NK cells from healthy donors in the presence of AFM28 for 24 h, followed by flow cytometric analysis of CD123+ leukemic cells including LSPCs defined as CD123+CD34+CD38−CD117+ cells. Colony forming unit (CFU) assays were performed using CD34+ MNCs derived from AML patients (n=5), HR-MDS patients (n=5) and healthy donors (n=5) after exposure to allogeneic NK cells and AFM28. In ex vivo assays, freshly drawn blood of newly diagnosed AML patients (n=7) was treated with AFM28 for 24 h with or without additional allogeneic NK cells. Results: In an autologous setting, AFM28 demonstrated activity against primary leukemic blasts in ex vivo cultures of fresh whole blood derived from untreated first diagnosis AML patients, indicating that AFM28 has the potential to arm AML patient's endogenous NK cells for anti-leukemic activity. Responder samples (n=3) showed a mean lysis of 76% (range 59-90%), while non-responders (n=4) exhibited a mean lysis of 7% (range 0-22%). The addition of healthy allogeneic NK cells could convert non-responders to responders and enhanced the overall anti-leukemic activity to 89% (range 77-100%) in previous responders and 66% (range 18-99%) in previous non-responders. Moreover, AFM28 induced the elimination of 98% of LSPCs (range 95-99%) in cultures using BM-MNCs of AML and HR-MDS patients supplemented with allogeneic NK cells. Depletion of LSPCs was corroborated by the concentration-dependent reduction in leukemic colony formation of AML (57-75% reduction) and HR-MDS BM-MNCs samples (57-64%), whereas colony formation of healthy BM-MNCs samples was only modestly affected (6-39%). Hence, AFM28 demonstrated specificity for leukemic cells while largely sparing healthy hematopoietic progenitors. Conclusion: This study highlights the potent efficacy of AFM28 in targeting CD123+ leukemic cells including LSPCs of AML and HR-MDS patients. Our results demonstrate that AFM28 monotherapy has the potential to mediate anti-leukemic activity by leveraging the endogenous innate immunity in some AML patients. The anti-leukemic activity of AFM28 may be further increased in combination with allogeneic NK cell immunotherapy to improve responses in patients with low numbers and/or hypofunctional NK cells.

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2024-11-05 | An Open-Label, Multicenter, Phase Ib Study of the Anti-TIM3 Monoclonal Antibody BC3402 in Combination with Azacitidine in Patients with Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

Background: BC3402 is a monoclonal antibody (mAb) targeting the T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), a member of the TIM family, which was originally identified as a receptor expressed on interferon-γ-producing CD4+ and CD8+ T cells. Recent studies have shown that TIM3 is part of a module that contains multiple co-inhibitory receptors (checkpoint receptors), which are co-expressed and co-regulated on dysfunctional or ‘exhausted’ T cells in chronic viral infections and cancer. To date, BC3402 has demonstrated a favorable safety profile, pharmacokinetic (PK) characteristics and activity as a single agent in treating patients (pts) with solid malignances. This is the first report on an ongoing phase Ib study of BC3402 in combination with azacitidine (AZA) in pts with higher-risk MDS or CMML. Method: This Phase Ib, open-label, multicenter, dose escalation and expansion study evaluated the safety, PK, pharmacodynamics, and preliminary activity of BC3402 combined with AZA in pts with higher-risk MDS (intermediate-, high-, or very high-risk by IPSS-R) or CMML. Three dose-schedules of BC3402 are being evaluated (10 mg/kg every 4 weeks (Q4W), 10 mg/kg every 2 weeks (Q2W) and 20 mg/kg Q2W) combined with AZA at a fixed dose of 75 mg/m2/day on Days 1-7 every 28 days. An accelerated titration design was used in the first dose level followed by a standard “3+3” design. A recommended phase 2 dose (RP2D) is being selected for dose expansion. Disease assessments are performed by IWG 2006 criteria for MDS and CMML. Results: As of the data cut-off date (June 7th, 2024), 10 pts (7 MDS, 3 CMML) were enrolled including 8 pts in the dose escalation part (10 mg/kg Q4W [1], 10 mg/kg Q2W [3], and 20 mg/kg Q2W [4]) and 2 pts in the dose expansion part. DLT has not been observed and 20 mg/kg Q2W has been determined to be the RP2D. All pts experienced treatment-related adverse event (TRAE), with 9 pts (9/10, 90%) experiencing Grade ≥ 3 TRAEs. The most common (incidence≥25%) TRAEs are neutrophil count decreased (90%), white blood cell decreased (90%), platelet count decreased (90%), anemia (50%), and lymphocyte count decreased (30%). All of the TRAEs were manageable. Of the 3 treatment naïve MDS pts treated with BC3402 10 mg/kg Q2W, two pts had complete remissions (CRs). Of the 6 pts treated with BC3402 20 mg/kg Q2W, one treatment naïve MDS and two treatment naïve CMML pts had CRs giving an overall CR rate of 71.4% (5/7) among the total of 7 treatment naïve pts. The duration of treatment for these CR pts are range from 6.3 to 11.4 months, all of whom are still receiving study treatment. Conclusion: BC3402 at dose range up to 20 mg/kg Q2W combined with AZA demonstrated promising anti-tumor efficacy (CR rate: 71.4%) in treatment naïve MDS and CMML patients and AEs were manageable. Given the CR rate of ~16% with AZA monotherapy in this patient population, the current data supports further evaluation of BC3402 in combination with AZA for pts with treatment naïve MDS and CMML. Clinical trial information: NCT05970822.

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2024-10-01 | SJÖGREN-LARSSON SYNDROME ASSOCIATED WITH MYELODYSPLASTIC SYNDROME: A CASE REPORT

Introduction: The Sjögren-Larsson Syndrome (SSL) is a rare autoimmune disease that causes glandular inflammation, normally in salivary and lacrimal glands. It can be classified as primary, when it is isolated, or secondary, when it is concomitant with other syndromes. Several studies correlate immune diseases with bone-marrow neoplasias, between them, the Myelodysplastic neoplasms (MDS). MDS is a heterogeneous group of hematologic diseases characterized by cytopenias in one or more hematologic lineages. Also, immunological disorders and chronic immunological stimulation are shown to be a trigger to ineffective hematopoiesis in patients with genetic predisposition. This report aims to describe MDS diagnosis in a patient with a rare immune disease and to demonstrate the complications associated with this condition. Case report: A 76-year-old woman, diagnosed with secondary SSL and autoimmune hemolytic anemia (AHAI), mastectomized, returned to a follow-up declaring fatigue and indisposition. The hematologic perfil showed: direct coombs positive, reticulocytes 8.0%, hemoglobin 7.7 g/dL, leukocytes 1280, platelets 318,000, homogeneous nuclear ANA 1/640, hypergammaglobulinemia, anti-SSA 240.0 and Schirmer positive. She was submitted to multiple treatments with antihistamines and immunosuppressants, but had infectious complications and hospital admissions. In 2023, it was indicated a splenectomy due to refractory disease and she started to be followed up by a hematologist, who suggested treatment with rituximab (500 mg in two sections with intervals of 14 days) as an alternative to active AHAI secondary to SSL. The treatment showed a good clinical result with the hemoglobin increased to 10,6 g/dL. However, at the end of 2023, the patient was unable to undergo a new pulse therapy of mabthera due to changes in the follow-up examinations of previously treated breast adenocarcinoma. A new biopsy showed multiple adenopathy attributed to the SSL itself. In 2024, a new bone marrow aspirate was taken which showed dyserythropoiesis, dysgranulopoiesis, 2% blasts and, in the cytogenetics test, 47,XX,+14[4]/46,XX[16]. In this context, the patient was diagnosed with MDS with a low percentage of blasts (MDS-LB). Discussion: The immunological dysregulation and hyperactivation of T and B lymphocytes will destroy self-antigens present in the epithelium of the exocrine glands, characterizing SSL, and in the erythrocytes, as in AHAI, leading to the release of hemoglobin into the plasma and dysfunction in gas transport. Studies show that autoimmune manifestations can lead to secondary diseases in bone marrow and MDS is one of them. Recently, studies linked UBA1 somatic mutations as the recurrent cause of clinically complex diagnoses with overlapping hematologic features. This new disease entity is known as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. VEXAS syndrome is frequently associated with hematological disorders, around 30-50% of these patients have concurrent MDS. Interestingly, the 14 trisomy finding has been associated with hematologic neoplasias and MDS overlap syndromes. In addition, it is crucial to confirm UBA1 mutation to VEXAS-associated diagnoses in this context of inflammatory clinical presentation. The correct diagnosis of MDS overlap syndromes is essential because their prognosis differs from isolated disorders and may require specific treatments due to unique molecular vulnerabilities.

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2024-05-06 | Multiple autoimmune disorders refractory to glucocorticoids after allogeneic hematopoietic stem cell transplantation: a case report and review of the literature.

We report here the case of a 50-year-old man who was first diagnosed with myelodysplastic syndrome with excess blasts-2 (MDS-EB-2) and underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 2019, resulting in complete remission. However, he was diagnosed in 2021 with several autoimmune disorders, including autoimmune hepatitis (AIH), Hashimoto's thyroiditis (HT), and autoimmune hemolytic anemia (AIHA). This is referred as multiple autoimmune syndrome (MAS), which is a rare occurrence after allo-HSCT, as previously noted in the literature. Despite being treated with glucocorticoids, cyclosporine A, and other medications, the patient did not fully recover. To address the glucocorticoid-refractory MAS, a four-week course of rituximab (RTX) at a weekly dose of 100mg was administered, which significantly improved the patient's condition. Thus, this case report underscores the importance of implementing alternative treatments in patients with post-transplant autoimmune diseases, who are glucocorticoid-refractory or glucocorticoid-dependent, and highlights the effectiveness of RTX as second-line therapy.

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2025-12-19 | Molecular Characterization of MECOM Rearrangements in Two Cases with Myelodysplastic Syndrome and t(2;3)(p23;q26.2).

MECOM rearrangements are frequently observed in myeloid neoplasms and associated with poor prognosis. Among the genomic alterations leading to MECOM rearrangements, t(2;3)(p13∼p25;q26.2) accounts for approximately 13% of reported cases. However, the precise DNA breakpoints of this translocation have not been previously reported, nor has the mechanism by which it alters MECOM expression been fully elucidated. In this report, we describe two cases with myelodysplastic syndromes (MDS) and t(2;3)(p23;q26.2). Our genomic characterization of these two t(2;3) translocations provided insights into the molecular mechanism of MECOM activation. Case 1 is a 44-year-old female who presented with new anemia and thrombocytopenia. She was treated with azacitidine. After two allogeneic stem cell transplants, her disease relapsed with rapid progression to acute myeloid leukemia (AML). The patient passed away 1 year after progression to AML and 8 years after initial diagnosis. Case 2 is a 75-year-old female who was incidentally found to have macrocytic anemia with rare circulating blasts. She remained asymptomatic from anemia and did not require transfusions or treatment. Her disease progressed to MDS with excess blasts 3 years later. Patient was treated with azacitidine. Fifteen months later, her disease further progressed to AML. She passed away 5 months later and four and a half years after initial diagnosis. DNA sequencing analysis of these two cases revealed that the t(2;3)(p23;q26.2) breakpoints were within the regulatory regions of ZFP36L2 and THADA on chromosome 2 and the proximity of MECOM on chromosome 3, creating a novel regulatory configuration for MECOM. Notably, the translocation breakpoints differed by 270 kb on chromosome 2 and 93 kb on chromosome 3, resulting in distinct translocated regulatory elements with varying sizes and proximities to MECOM. These structural differences may influence the level of MECOM upregulation and contribute to variation in disease severity and progression. Our findings highlighted that, despite cytogenetic similarity, different t(2;3) translocations may exert distinct regulatory effects depending on the precise breakpoint locations. Thus, molecular characterization of MECOM rearrangements is critical for understanding disease pathogenesis and prognosis in myeloid neoplasms and may lead to the development of novel treatment.

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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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2023-12-21 | CircZBTB46 predicts poor prognosis and promotes disease progression of myelodysplastic syndromes and acute myeloid leukemia.

Circular RNAs (circRNAs) have been recently identified as important regulators of various diseases, especially cancer. However, the roles of circRNAs in hematologic malignancies have been rarely reported. This study aimed to identify a specific circRNA expression profile in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and to evaluate the biological roles of circRNA in MDS and AML for understanding their clinical significance. Reverse transcription-quantitative PCR was performed to validate the expression of circZBTB46. Kruskal-Wallis test, Kaplan-Meier curves, and the Cox regression model were employed to analyze the clinical significance of circZBTB46. Two specific shRNAs as well as an expression lentiviral vector of circZBTB46 were constructed to identify the biological function of circZBTB46. The impact of circZBTB46 on leukemia cell proliferation, cell cycle distribution, and apoptosis was confirmed using cell viability assay and flow cytometry analysis. The expression of circZBTB46 gradually increased in patients with higher-risk MDS and AML, as compared to controls. CircZBTB46 expression was significantly correlated with important clinical parameters of MDS, including WHO classification, absolute neutrophil count (ANC), marrow blast, IPSS karyotype, IPSS/IPSS-R risk groups, and AML transformation. CircZBTB46 expression was also associated with ANC, marrow blast, cytogenetic risk groups, FLT3-ITD mutation, and treatment response in AML patients. Furthermore, circZBTB46 overexpression was significantly correlated with shorter overall survival (OS, P = 0.0342, median survival time 18.5 vs. 45.4 months) and leukemia-free survival (LFS, P = 0.0421) in MDS, also with the shorter OS in AML (P = 0.0293, median survival time 11.6 vs. 16.9 months). Functional studies revealed that silencing circZBTB46 expression significantly inhibited proliferation and induced apoptosis in SKM-1, THP-1, and K562 cell lines, while rescue experiments alleviated the siRNA-mediated growth inhibition and apoptosis in these leukemic cells. The present data suggested the essential oncogenic role of circZBTB46, as a progression and survival indicator in both MDS and AML.

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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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