Criteria For Myelodysplastic Syndromes Research Articles

Validation and comparison of 5th edition World Health Organization classification (WHO 2022) and International Consensus Classification proposals for MDS-SFB31.

The criteria of myelodysplastic syndromes (MDS) with mutated SFB31 (MDS-SFB31) proposed by the 5th edition of the WHO classification (WHO 2022) and the International Consensus Classification (ICC) need validation. We analysed 125 consecutive MDS cases with SFB31 mutation or ring sideroblasts (RS) ≥15% without excess blasts. We found that SFB31-negative MDS with RS had significantly different clinical features and worse prognosis. According to WHO 2022, the detection of ≥15% RS may substitute for SF3B1 mutation and our analyses support this proposal for similar prognosis of two groups after excluding high-risk genetic features referred by WHO 2022. Patients with variant allele frequency (VAF) <10% SFB31 tend to have briefer survival, supporting the VAF 10% threshold of ICC. Patients with multilineage dysplasia (MLD) had significantly shorter OS than those with single lineage dysplasia. MLD is still a powerful morphological marker of worse outcome in WHO 2022 and ICC-defined MDS-SF3B1.

Efficacy and safety analysis of venetoclax combined with hypomethylating agents for the treatment of higher-risk myelodysplastic syndromes in the real world

Objective: To investigate the efficacy and safety of combining venetoclax (VEN) with hypomethylated drugs (HMA) in the treatment of higher-risk (IPSS-R score >3.5) myelodysplastic syndromes (MDS) . Methods: From March 2021 to December 2022, forty-five MDS patients with intermediate and high risk were treated with VEN in combination with HMAs. Clinical data were collected and analyzed retrospectively, including gender, age, MDS subtype, IPSS-R score, treatment regimen, and efficacy, etc. Kaplan-Meier method and Cox regression model were used to analyze univariate and multivariate of survival prognosis. Results: ①Forty-five patients with MDS, including ninety-one percent were classified as high or very high risk. According to the 2023 consensus proposal for revised International Working Group response criteria for higher-risk MDS, the overall response rate (ORR) was 62.2% (28/45), with the complete response rate (CR) was 33.3% (15/45). For twenty-five naïve MDS, the ORR was 68% (17/25) and the CR rate was 32% (8/25). In nonfirst-line patients, the ORR and CR were 55% (11/20) and 35% (7/20) respectively. The median cycle to best response was 1 (1-4). ②With a median followup of 189 days, the median overall survival (OS) time was 499 (95% confidence interval, 287-711) days, and most patients died from disease progression. Responders had a significantly better median OS time than nonresponders (499 days vs 228 days, P<0.001). Multifactor analysis revealed that IPSS-R score and response to treatment were independent prognostic factors for OS; the presence of SETBP1 gene mutations was associated with a longer hospital stay (51.5 days vs 27 days, P=0.017) . Conclusions: There is clinical benefit of venetoclax in combination with hypomethylated agents in patients with higher-risk MDS, but adverse events such as severe hypocytopenia during treatment should be avoided.

A Phase 2 Study of Canakinumab in Patients with Lower-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia

Background Myelodysplastic syndromes (MDS) lie on a continuum of myeloid neoplastic progression between clonal hematopoiesis (CH) and acute myeloid leukemia (AML). Interleukin 1 beta (IL-1β)-induced inflammasome activation is a mechanism of cancer initiation and progression. Given that IL-1β upregulation induces aberrant myeloid differentiation of hematopoietic stem and progenitor cells (HSPCs), we hypothesize that IL-1β plays a critical role in MDS pathogenesis, and targeting IL-1β signaling will overcome aberrant MDS HSPCs' myeloid skewing. Here, we report final results of a phase 2 study evaluating the safety and efficacy of canakinumab, an IL-1β inhibitor, in patients with lower-risk MDS or chronic myelomonocytic leukemia (CMML). Methods We conducted a single center, open-label phase 2 trial at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged ≥ 18 with IPSS-R ≤ 3.5 MDS/CMML who have previously been treated were included in the study. Patients received 300 mg of canakinumab on day 1 of a 4-week cycle. The primary objective was to determine the clinical activity of canakinumab in MDS/CMML patients. Response was assessed using the modified International Working Group 2006 criteria for MDS (Cheson et al. 2006). Secondary objectives were to evaluate the safety profile including rate of transfusion independence (TI), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). All patients who received 1 dose of study drug were included in the analyses. This study is registered with ClinicalTrials.gov (NCT04239157). Findings Between August 2020 and May 2023, 27 patients were enrolled in the phase 2 portion of this study, and 2 patients failed screening. The median age was 74 years with 15 (60%) male patients; 20 patients (80%) were post-hypomethylating agent failure with a median number of prior lines of therapy of 2 (1-5). Transfusion dependency was observed in 24 patients (96%) prior to canakinumab initiation. Fourteen (56%) patients showed normal karyotype. IPSS-R stratification revealed an intermediate-2 risk in 12 (48%) patients and a high risk in one (4%). The most common mutations were SF3B1 (40%), TET2 (32%), DNMT3A (28%), and RUNX1 (24%). IPSS -M risk score was calculated for 24 cases showing one (4%) very low (VL), four (16%) low (L), 14 (16%) moderate low (ML), eight (32%) moderate high (MH), five (20%) high (H), and two (8%) very high (VH) risk categories. Canakinumab was well tolerated and no drug-related toxicities were observed. One death due to sepsis, which was deemed not treatment-related, occurred on the study drug. Out of 23 evaluable patients, the overall response rate was 17·4%, with erythroid and platelet hematological improvement (HI-E and HI-P, respectively) confirmed in 3 (13.0%) patients and 1 (4.3%) patient, respectively. Thirteen patients had stable disease (56·5%) and 6 (26·1%) progressed during therapy, 1 of which transformed to AML (Fig. 1). TI was achieved in 3 patients (median DoR 8·53 months (95% CI 0·41-16·1) and 2 of them maintained TI for over 12 months. With a median follow-up time of 22·6 months (95% CI 15·0-29·4), median OS was 17·3 months (95% CI 14·3-not estimable). We performed separate univariate analyses to evaluate any associations between the IPSS-M and OS/PFS. The median OS in patients with higher-risk MDS by IPSS-M (MH, H, VH) was 15·0 months vs 29·4 months in the lower-risk disease by IPSS-M (VL, L, ML) group (p=0·12). Interestingly, statistically significant findings were observed with 1-year PFS when stratifying patients into higher vs lower risk MDS by IPSS-M (64·3% vs 100·0%, respectively; p=0·022, Fig. 2). Conclusion In this cohort of MDS patients who had experienced multiple lines of prior therapy and exhibited high-molecular-complexity, canakinumab showed limited efficacy (HI 17.3%). Nevertheless, canakinumab showed a good safety profile and yielded sustained long-term responses in patients with single somatic driver mutation in TET2 or DNMT3A. This suggests that clonal complexity, and therefore disease burden, may be a determining factor in response to canakinumab. Therefore, we have amended the protocol of a phase 1/2 clinical trial evaluating the safety and activity of canakinumab in clonal cytopenia of unknown significance (CCUS) and low-molecular complexity MDS patients. Our results will clarify the role of IL-1β signaling in MDS initiation and progression.

Phase II Study Assessing Safety and Preliminary Efficacy of High Dose Intravenous Ascorbic Acid in Patients with TET2 Mutant Clonal Cytopenias

Background: Clonal cytopenia(s) of undetermined significance ( CCUS) is defined as persistent cytopenias arising in the context of myeloid neoplasm ( MN)-associated somatic mutations ( MT) in hematopoietic stem cells. Patients ( PTs) with TET2MT CCUS have a high probability of progression to MN. To date, no FDA-approved therapies exist for CCUS, and PTs often have similar cytopenias/transfusion needs as those with myelodysplastic syndromes ( MDS). TET2 is an ascorbic acid (AA)-dependent dioxygenase that catalyzes the conversion of 5-methylcytosine ( 5mC) to 5-hydroxymethylcytosine ( 5hmC), providing rationale to study high-dose IV (HI)-AA in TET2MT CCUS. Here we report the final results of this pilot trial. Methods: This is an investigator-initiated, single-institutional, phase II trial assessing the safety and efficacy of HI-AA in PTs with TET2MT CCUS (NCT03418038). PTs≥ 18 years with ≥1 TET2MT with or without additional somatic MTs, without prior treatment, and with any of the following laboratory criteria: (1) hemoglobin ( Hb) ≤10g/dL, (2) absolute neutrophil count ( ANC) ≤1(10^9/L), (3) platelet count ( PLT)≤100 (10^9/L) were eligible. HI-AA (1g/kg, maximum 100g) was given 3 times weekly for 12 weeks. The primary endpoint was hematologic response rates determined by MDS IWG 2018 criteria at week 20. (Platzbecker Blood 2018) and reported as hematologic improvement ( HI)- erythropoietic ( HI-E), platelets ( HI-P), neutrophils ( HI-N). Secondary endpoints include safety and adverse events ( AEs), graded by NCI-CTCAE v4.03. Correlative studies include changes in TET2MT variant allele fraction ( VAF), in vitro colony formation and differentiation, global and sequence-specific DNA methylation/hydroxymethylation, and quantitative 5hmC estimated by IHC in bone marrow biopsy specimens. Results: Ten patients were enrolled, with a median age of 71.4 (range: 65, 79) years, 8 (80%) males. The median number of mutations was 3, with 9 (90%) having co-mutations. All PTs but one [-Y] had normal karyotype. Baseline Hb levels were normal in all but one who was red blood transfusion dependent. Five (50%) PTs were thrombocytopenic, and 5 (50%) PTs had ANC&amp;lt;1 (10^9/L). ( Table). HI-AA was well tolerated with the most common AEs being infusion-related polyuria (40%) and polydipsia (40%, 3 Grade 1, 1 Grade 2). One (10%) PT had constipation and headaches (both Grade 1), and 1 (10%) experienced dyspepsia. No treatment-related Grade 3 or 4 AEs' or deaths were reported. The median follow-up duration was 16.8 months (range: 9.4, 24.1). Overall, no PTs met the criteria for HI. There were no significant differences with regards to median Hb, PLT, and ANC values at baseline, week 20, and 1-year (median Hb: 13.3, 12.5, and 12.7 g/dL, p=0.93; PLT: 97 vs. 120 vs. 92.5X10^9/L, p&amp;gt;0.99, and ANC: 0.9 vs. 1.2 vs. 1.3X10^9/L, p=0.99). By CTCAE grading criteria for cytopenias, 3 (30%) PTs had an improvement in severity of cytopenias, while 2 had worsening. One (10%) PT had an improvement in PLT (baseline vs. week 20: 62 vs 192X10^9/L) but was morphologically deemed to meet criteria for CMML-1 at week 20. Four (40%) PTs met criteria for disease progression (PT_4, 7,8,10); CMML-1- 2 and MDS-2. The median time to progression was 5 months (95% CI: 4.9, unreached). Two PTs had mutational clonal evolution, with 1 (PT_8) acquiring a RUNX1 (VAF: 20%) and 1 (PT_9) acquiring 2 CBL mutations (both VAF:4%) at one-year follow-up. There were no significant differences regarding the clinical characteristics or the TET2 variants between PTs who had stable disease vs. progression. There were no significant differences in TET2 VAF at baseline, week 20, and 1-year (median: 39% vs. 43% vs. 42%, p=0.54). We profiled changes in 5-mC and 5-hmC (Ilumina EpicArray) in PTs pre- and post-IV AA treatment and did not observe global changes. However, we were able to highlight site-specific changes in differentially methylated regions, largely resulting in hypomethylation at enhancer sites and affecting actively transcribed states in PTs with an improvement in cytopenia(s) severity by CTACE criteria ( Figure). Conclusion: We report the final safety and efficacy analysis of HI-AA in PTs with TET2 MT CCUS. The trial data suggest that HI-AA is safe and well tolerated. Although there were no significant responses by IWG MDS criteria, alleviation in severity of cytopenias in a subset of PTs (n=3) along with correlative epigenetic changes in enhancer regions, needs further exploration.

A Pilot Multicentric Prospective Study on the Usefulness of Peripheral Blood Immunophenotyping As Erythroid Maturation Response Marker during Luspatercept Treatment in Patients Affected By ß-Thalassemia Major and SF3B1+ Myelodysplastic Syndrome

Introduction Erythropoiesis is a multi-step maturation process; luspatercept proved to be successful on ineffective erythropoiesis acting on the second phase of erythroid maturation reducing the hyper expression of transforming growth factor beta (TGF-beta) ligands via the Smad 2/3 signaling pathway, thus ameliorating the aberrant late stage erythroid maturation featured in the myelodysplastic syndrome (MDS) and thalassemia. MEDALIST and BELIVE studies showed efficacy and safety of Luspatercept in MDS and Thalassemic patients respectively, but, regarding erythroid maturation, a significant correlation has been revealed only between hematological response and the reticulocyte value or medullar erythroblasts counts. In order to avoid for patients extra scheduled bone marrow aspirate , in particular in thalassemic patients, in our pilot study we propose to explore, for the first time, the role of peripheral blood immunophenotyping (IF) as reproducible and more affordable erythroid maturation's marker respect to the medullar immunophenotyping described in the previous published papers. Our hypothesis is that peripheral IF could represent a new tool to detect the ameliorate of inefficacy erythropoiesis during Luspatercept therapy, acting as “minimal residual disease” in patients in response or that loss the response to Luspatercept. Patients, Material and Methods Approval by local Ethic Scientific Commission has be completed. Patients will be enrolling by Hematology Unit and by Hemoglobinophaties Unit from 2 different Institution in Italy (“A. Businco” Oncologic Hospital and “A. Cao” Hemoglobinopathies Hospital). Inclusion criteria: Patients must be affected by MDS with ringed sideroblasts (with or without SF3B1 mutation) very low, low and intermediate revised IPSS stage or affected by ß-thalassemia major; aged ≥ 18 years and able to understand and sign an informant consent; not renal or hepatic failure; EF &amp;gt; 50%. Duration of the study will be scheduled for 1 year. Prevision of 30 patient enrolled in the first 1 year of study. Primary endpoint is to confirm the role of peripheral blood immunophenotyping (IF) as reproducible and affordable erythroid maturation's marker in these setting of patients. Secondary endpoint is to evaluate the role of peripheral IF as “minimal residual disease” in particular during the loss of Lusplatercept response and also the assessments of iron homeostasis in responder's patients. Patients will be assessed for r-IPSS and NGS (only for MDS), endogenous erythropoietin, full blood count and reticulocyte, iron status, transfusion burden in the previous 24 weeks and peripheral IF (centralized in the laboratory of Hematology Unit). All patients will collect these samples at baseline timing and after 12,24,36 and 48 weeks. Peripheral IF is tested by 8-color EuroFlow antibody panels define progressive terminal stages of erythroblasts' maturation (10 health samples have been used as control). Hematological response and Luspatercept's dose escalation are considered as for MEDALIST study criteria for MDS and BELIVE study for thalassemia, as well adverse events. Results At the time of this report 26 patients have been enrolled in the two institution (10 MDS and 16 thalassemic patients). Baseline patients' characteristics are reported in TAB 1 and baseline peripheral blood erythroid maturation (based on centralized IF) are reported in TAB 2 Conclusion Our pilot study aims to explore, for the first time, the role of peripheral blood immunophenotyping (IF) as reproducible and affordable erythroid maturation's marker during Luspatercept therapy in Thalassemic and MDS patients.

Deep immunophenotypic analysis of the bone marrow progenitor cells in myelodysplastic syndromes

BackgroundDiagnosis of myelodysplastic syndromes (MDS) is often challenging and requires integration of clinical, morphologic, cytogenetics and molecular information. Flow cytometry immunophenotyping (FCIP) can support the diagnosis by demonstration of numerical and immunophenotypic abnormalities of progenitor and maturing myelomonocytic and erythroid populations. We have previously shown that comprehensive immunophenotypic analysis of the progenitor population is valuable in the diagnosis of MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). This study was designed to improve the analysis method and confirm its value in a larger cohort of patients. MethodsFCIP of bone marrow samples from 105 patients with cytopenia(s) (with or without leukocytosis) and clinical concern for MDS or MDS/MPN was performed using a single-tube/10-color/13-marker assay. A modified analysis approach was used to obtain 11 progenitor parameters and 2 myelomonocytic parameters. ResultsSignificantly higher number of abnormalities were identified in MDS and MDS/MPN cases when compared to cytopenic patients not meeting the diagnostic criteria for MDS (Non-MDS). A FCIP score that combined the 13 parameters showed a sensitivity of 89.8% and specificity of 93.5% for the diagnosis of MDS and MDS/MPN. The sensitivity was 100% for both MDS/MPN and higher-risk MDS, and 81.3% for lower-risk MDS. ConclusionThis study confirms that detailed immunophenotypic analysis of the progenitor population is powerful in the diagnosis of MDS and MDS/MPN. The combination of markers used in the panel allowed for evaluation of two relatively new parameters, namely myeloid progenitor heterogeneity and stem cell aberrancy, which improved the sensitivity of the assay for lower-risk MDS.

A phase I study of MEK inhibitor selumetinib in combination with azacitidine in patients with higher-risk chronic myeloid neoplasia.

TPS7084 Background: Myelodysplastic syndrome (MDS), Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), and MDS/MPN overlap syndromes present significant clinical challenges for patients deemed transplant ineligible, and who are relapsed or refractory to conventional therapies. RAS-pathway activating mutations in myeloid malignancies are associated with a proliferative phenotype and contribute to disease progression. Cooperation between RAS-dependent signaling and epigenetic dysregulation provides the basis for rationally designed combination studies. Selumetinib (AZD6244) is a potent, selective, orally bioavailable, and non-ATP competitive small molecule inhibitor of MEK1/2, downstream of RAS. Methods: This is an investigator-initiated, Phase I, open-label dose-escalation study of selumetinib in combination with azacitidine for patients with higher risk MDS, MDS/MPNs, and myelofibrosis. The trial will enroll patients with high-risk myeloid neoplasms that meet disease-specific criteria for MDS or MPNs and who require treatment. This phase I study follows a 3+3 dose-escalation design, with three planned dose levels across two different cohorts (A and B). The dose of azacitidine 75 mg/m2 will remain stable, with three planned selumetinib dose levels (50 mg, 75 mg, and 100mg, respectively) across the two cohorts. Azacitidine will be given on days 1-7 followed by selumetinib from days 7-21 of 28 day cycles. Cohort A includes subjects with MDS with relapsed/refractory disease requiring therapy and MDS/MPN overlap syndromes; Cohort B includes subjects with myelofibrosis refractory or intolerant to JAK inhibitor therapy or ineligible for ruxolitinib treatment given baseline cytopenias (thrombocytopenia &lt; 50,000/uL, anemia &lt; 9 g/dL, and/or red cell transfusion dependent). The trial has an enrollment goal of 18 to 24 subjects, and treatment will continue indefinitely if the patient continues to derive benefit. Dose escalation will proceed independently within both cohorts. Cohort A is nearing completion of enrollment and cohort B is actively enrolling. The primary objective is to determine the maximum tolerated dose of selumetinib in combination with azacitidine. Select secondary and exploratory objectives include describing the preliminary clinical response rates and observing relationships between the presence of RAS activating mutations, RAS pathway activation, and clinical response. Clinical trial information: NCT03326310 .

SF3B1 mutations in myelodysplastic syndromes: A potential therapeutic target for modulating the entire disease process.

Myelodysplastic syndromes (MDS) are clonal hematologic malignancies characterized by ineffective hematopoiesis and dysplasia of the myeloid cell lineage and are characterized by peripheral blood cytopenia and an increased risk of transformation to acute myeloid leukemia (AML). Approximately half of the patients with MDS have somatic mutations in the spliceosome gene. Splicing Factor 3B Subunit 1A (SF3B1), the most frequently occurring splicing factor mutation in MDS is significantly associated with the MDS-RS subtype. SF3B1 mutations are intimately involved in the MDS regulation of various pathophysiological processes, including impaired erythropoiesis, dysregulated iron metabolism homeostasis, hyperinflammatory features, and R-loop accumulation. In the fifth edition of the World Health Organization (WHO) classification criteria for MDS, MDS with SF3B1 mutations has been classified as an independent subtype, which plays a crucial role in identifying the disease phenotype, promoting tumor development, determining clinical features, and influencing tumor prognosis. Given that SF3B1 has demonstrated therapeutic vulnerability both in early MDS drivers and downstream events, therapy based on spliceosome-associated mutations is considered a novel strategy worth exploring in the future.

Fetal hemoglobin level predicts lower-risk myelodysplastic syndrome.

The relationship between fetal hemoglobin (HbF) levels and disease prognosis in patients with myelodysplastic syndrome (MDS) is unclear. This study aimed to clarify the relationship between HbF level and the prognosis of MDS. To this end, data from 217 patients diagnosed with MDS between April 2006 and August 2020 at Ebina General Hospital were analyzed retrospectively. The primary endpoint was leukemia-free survival (LFS) for 5years after diagnosis. HbF levels were significantly higher in patients with MDS than in control patients without MDS (n = 155), with a cut-off value of 0.4%. Higher-risk patients had a similar prognosis regardless of HbF level, but lower-risk patients had longer LFS at intermediate HbF levels. Although prognosis based on pre-treatment HbF levels did not differ significantly among azacitidine-treated patients, prognosis tended to be better in lower-risk patients with intermediate HbF levels. Multivariate analysis showed that the intermediate HbF category correlated with LFS, independently of MDS lower-risk prognostic scoring system (LR-PSS)-related factors. This study is the first to assess the association between HbF levels and the new World Health Organization 2016 criteria for MDS, demonstrating the significance of HbF levels in the prognosis of MDS.

Predictors of Disease Progression and Survival in Patients with Myelodysplastic Syndrome Secondary to Inherited Bone Marrow Failure Syndromes

Introduction Inherited bone marrow failure syndromes (IBMFSs) are rare genetic disorders characterized by abnormal hematopoiesis resulting in cytopenias, risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Once patients develop MDS, the only cure is hematopoietic stem cell transplant (HSCT). Proceeding to HSCT before transformation to advanced MDS or AML leads to better outcomes (Smith et al., PBC 2013). The rate of disease progression from early MDS to advanced MDS or AML is variable and risk factors for progression in IBMFS patients are unknown. We hypothesized that certain variables could predict the likelihood of progression, and that the type of disease progression may impact overall survival (OS). Methods Data were collected from patients prospectively enrolled in the Canadian Inherited Marrow Failure Registry (CIMFR), a Canadian collaboration including >95% of pediatric IBMFS patients. Patients were diagnosed with a specific syndrome or unclassified IBMFS (ucIBMFS) based on published criteria. Diagnostic criteria for pediatric MDS defined by Cada et al. (Haematologica 2015) were used, patients with refractory cytopenia (RC) with or without dysplasia or ringed sideroblasts were included. Patients with refractory cytopenia with excess blasts (RCEB) were excluded. MDS progression was defined as 1 or more of: a new cytogenetic abnormality, more advanced cytopathology, worse cytopenias requiring HSCT. Variables evaluated included: involvement of specific organ systems, hematologic parameters within 3 months of cytogenetic clones/MDS diagnosis, type of mutation (as per Waespe et al., Genomic Medicine 2017). Univariate Cox Proportional Hazard modelling was used to estimate association with specific variables and disease progression, Kaplan-Meier analysis was used for survival evaluation. Results Between January 1, 2001 and November 30, 2018, 601 patients were enrolled in the CIMFR, and during this time 59 (9.8%) developed cytogenetic clones/MDS. Four did not meet the pre-defined criteria for IBMFS, 9 had RCEB at diagnosis with MDS and 1 did not have data available; these were excluded from our cohort of 45 patients. Twelve (26%) patients with clones/MDS had Fanconi Anemia (FA), 13 (28.3%) had Shwachman-Diamond Syndrome (SDS), 5 (10.8%) had ucIBMFS, 15 (33.3%) had other IBMFSs. The most common cytogenetic finding at diagnosis was -7/-7q (n=10, 22%). Patients who developed clones/MDS had significantly worse OS compared to those without clones/MDS (HR 3, 95% CI 2-6, p<0.0001). Among patients who developed clones/MDS, 22 (48.9%) underwent HSCT. Twenty one clones/MDS patients (46.7%) had disease progression, with a median time to progression of 7.9 months (1.2-131.4). The majority (68.4%) developed progression within one year of clones/MDS diagnosis. Nine (42.8%) developed more advanced cytopathology, 9 (42.8%) a new cytogenetic abnormality and 5 (23.8%) worsening cytopenias. Most patients with FA (67%) had disease progression, compared to 38.5% of patients with SDS. Mutation types (classified as more vs less deleterious) were similar between the groups with and without progression. The evaluated hematologic parameters (MCV, hemoglobin, platelets and neutrophils within 3 months of diagnosis) were not predictive of disease progression. Patients with disease progression, when compared to those without, were more likely to have congenital malformations of the skin (14.3% vs 0%), cardiovascular system (28.6% vs 4.2%) and kidneys (14.3% vs 4.2%). No specific system involvement predicted disease progression, although congenital malformations of the cardiovascular system had a HR of 2.63 (95% CI 0.93-7.42). Conclusion Development of MDS has a significant adverse impact on the OS of IBMFS patients, with disease progression typically occurring within the first year after MDS diagnosis. Patients with FA have a high risk of disease progression. Hematologic parameters were not predictive of the risk of disease progression, however, the presence of congenital cardiovascular anomalies is suggestive of increased risk of disease progression and warrants further investigation. Our study is limited by the rare nature of IBMFSs and MDS and the collection of additional data will help to guide treatment decisions for this high-risk patient population. Acknowledgment The authors thank Mr. Bryan Maguire for his statistical analysis of data related to this work.

Phase I Study of TQB3455, a Selective Inhibitor of IDH2 with Favorable Safety and More Potent Efficacy to IDH2-R172K Mutation, for Acute Myeloid Leukemia and Myelodysplastic Syndrome

Introduction: Approximately 15% of patients with acute myeloid leukemia (AML) and 5% of patients with myelodysplastic syndrome(MDS) harbor IDH2 mutations (mIDH2). Enasidenib (ENA), the first selective IDH2 inhibitor, was associated with impressive response rates in relapsed/refractory (R/R) AML and was approved by FDA in 2017. TQB3455, a novel selective inhibitor of IDH2, different from ENA, showed stronger inhibitory activity against IDH2-R172K in vitro, and also demonstrated potent antileukemic activity in humans. The current analysis is the first to evaluate the safety and clinical efficacy of TQB3455 monotherapy in pts with mIDH2-positive AML or MDS. Methods: This multicenter, phase 1, open-label, dose-escalation/expansion study enrolled AML or MDS pts with mIDH2, who were RR or not candidate for standard treatment, estimated survival ≥12w and ECOG performance status＜2. Prior allogeneic hematopoietic stem cell transplantation is prohibited. TQB3455 is administered continuously as oral tablets QD in 28-day cycles. Dose levels are 25mg, 50mg, 75mg, 100mg, 150mg, and 300mg.Dose escalation followed a modified 3+3 design. Once the recommended phase 2 dose (RP2D) is determined, subjects will be enrolled into expansion cohort. Primary objectives include safety, tolerability, maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Safety was assessed by treatment-emergent adverse event (TEAE) reporting and TEAEs were graded per CTCAE version 5.0. DLT was defined as any Grade ≥4 hematologic toxicity or Grade ≥3 non-hematologic toxicity（alopecia excluded）occurring within the first 28 days after initiation of treatment. Secondary objectives include pharmacokinetics (PK), preliminary efficacy per International Working Group (IWG) response criteria for AML and MDS. Fisher's exact test was used to assess the association between categorical variables. Results: As of May 31, 38 pts were enrolled in the study and had received at least one dose of TQB3455, 35 with AML and 3 with MDS. Baseline characteristics are detailed in Table 1. Pts received daily TQB3455 doses of 25mg(n=1), 50mg(n=1), 75mg(n=3), 100mg(n=3), 150mg(n=7), 300mg(n=1). When the dose escalated to 300mg, the patient experienced a DLT of pneumonia, then the dose was switched back to 150mg. The 150mg cohort was expanded to 7 evaluable patients and 1 patient experienced a DLT of differentiation syndrome. Therefore, the RP2D of TQB3455 was identified as 100 mg daily. 22 additional pts were enrolled on this dose during the expansion phase. Safety analysis was performed in all patients. The most frequent Grade 3-4 TEAEs in all regimens were 25mg(n=1, 100%), 50mg(n=1, 100%), 75mg(n=2, 66.67%), 100mg(n=13, 68.42%), 150mg(n=7, 87.50%) and 300mg(n=1, 100%). The most frequent TEAEs were pancytopenia(Table 2). 24 pts discontinued treatment, primarily due to progressive disease or relapse (n=17, 44.74%), adverse events (n=1, 2.63%), withdrawal by patient (n=3, 7.89%) or death (n=2, 5.26%). Efficacy was analyzed only in patients with AML. Three pts was not evaluable for response due to withdrawal by patients before the first efficacy evaluation. Of the 32 evaluable pts, overall response rate (ORR) was 40.63 %, including 12 pts (37.5%) in complete remission(CR) or CR with incomplete hematologic recovery (CRi), 1 pts (3.13%) in partial remission (PR). TQB3455 shows more powerful inhibitory effects on IDH2-R172K rather than IDH2-R140Q/W mutation (ORR, 66.67% vs 25.00%, p=0.03; CR, 41.67% vs 15.00%, p=0.12). The presence of FLT3 and/or RAS co-mutations at study entry was significantly associated with lack of response (ORR, 10% vs 45.46%; CR, 10% vs 31.82%). Median duration of response was 9.17 months (95% CI 7.39-not reached). After a median follow up of 5.49 months, the median overall survival (mOS) was 7.43 months (95% CI 5.55- not reached). Conclusion: TQB3455 is well-tolerated for myeloid malignancy at the R2PD of 100 mg qd. It also yield high rates of clinical response in pts with mIDH2AML. Patients with IDH2-R172K mutation fared much better than IDH2-R140Q/W with regard to response, this is in line with outcome of TQB3455 in vitro but different from previous reports of ENA. These encouraging findings have prompted further studies of TQB3455 combination therapy in patients with mIDH2 AML and MDS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 1, First-in-Human, Dose-Escalation Study of MGD024, a CD123 x CD3 Bispecific Dart® Molecule, in Patients with Relapsed or Refractory CD123-Positive (+) Hematologic Malignancies

Background The interleukin-3 receptor alpha chain CD123 is overexpressed in a number of hematologic malignancies and is particularly upregulated in leukemia stem cells, which are believed to serve as a reservoir for relapse (El Achi Cancers 2020). Several investigational agents targeting CD123 with diverse mechanisms of action including bispecific T-cell engagers, antibody-drug conjugates, and Chimeric Antigen Receptor (CAR) T-cell therapies, are being investigated in these malignancies, with many showing preliminary clinical anticancer activity (El Achi Cancers 2020). Of note, the CD123-directed therapy tagraxofusp has now become the standard of care (SoC) for blastic plasmacytoid dendritic cell neoplasm (BPDCN) (Pemmaraju NEJM 2019). MGD024 is an investigational, second-generation CD123 × CD3 DART molecule that can simultaneously bind CD123 on malignant cells and CD3 on T cells, targeting CD123+ leukemic cells for recognition and elimination by CD3+ T lymphocytes as effector cells. MGD024 was engineered to minimize cytokine release syndrome (CRS), while maintaining antitumor activity. This new construct permits intermittent intravenous (IV) dosing due to a longer half-life (Alderson ASH 2021) compared with the first-generation DART molecule flotetuzumab, a continuous-infusion molecule that showed preliminary single-agent activity in refractory acute myeloid leukemia (AML) (Uy Blood 2021). Moreover, preliminary in vitro and in vivo data supported MGD024 clinical investigation as a single agent or in combination with SoC in patients with CD123+ hematologic malignancies (Alderson ASH 2021). Study Design and Method This is a Phase 1, first-in-human, dose-escalation study (CP-MGD024-01; NCT05362773) of MGD024 in patients with the following relapsed or refractory hematologic malignancies: AML, myelodysplastic syndrome (MDS), classical Hodgkin's lymphoma (cHL), chronic myeloid leukemia (CML), B-cell acute lymphoid leukemia (B-ALL), hairy cell leukemia (HCL), advanced systemic mastocytosis (ASM), and BPDCN. Eligible patients must have CD123+ malignant cells by flow cytometry or immunohistochemistry, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and no history or current evidence of any condition, therapy, or laboratory abnormality that may confound trial results. Primary objectives are to assess the safety, tolerability, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) or maximum administered dose (if no MTD is defined) and identify a recommended Phase 2 dose and schedule of MGD024. Secondary objectives include pharmacokinetics, immunogenicity, preliminary assessment of MGD024 clinical activity, and preliminary evaluation of safety/efficacy of tocilizumab in the management of MGD024-induced CRS. Patients receive MGD024 via intermittent intravenous infusion for approximately one year or until discontinuation for unacceptable toxicity or disease progression, whichever occurs first. The dose escalation begins with an accelerated titration phase (1+3 design) and converts to a conventional 3+3 design after the first patient experiences a DLT or a Grade ≥2 nonhematologic adverse event (AE) considered at least possibly related to MGD024 during Cycle 1, whichever occurs first. Safety assessments are based on AEs occurring from the first dose until 30 days after the last dose or until starting another anticancer therapy. Response assessments are performed after Cycle 1, then after every even numbered cycle starting with Cycle 2 until progression or discontinuation, whichever occurs first, and at the end of treatment visit. Response evaluation is determined using modified European LeukemiaNet (ELN) 2017 criteria for ALM and ALL; International Working Group (IWG) 2006 criteria for MDS; Lugano 2014 criteria for cHL; ELN 2020 criteria for CML; 2017 consensus criteria for HCL; IWG-Myeloproliferative Neoplasms Research and Treatment (MRT) & European Competence Network on Mastocytosis (ECNM) 2013 criteria for ASM; and modified criteria from Pemmaraju NEJM 2019 for BPDCN. Patients benefitting from MGD024 may continue to receive MGD024 after completion of the study treatment period, at physician discretion.

Cox Proportional Hazards Deep Neural Network Identifies Peripheral Blood Complete Remission (PB-CR) to be at Least Equivalent to Morphologic CR in Predicting Outcomes of Patients Treated with Azacitidine - a Prospective Cohort Study By the AGMT

Background Myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) are multiclonal diseases demonstrating considerable biologic, phenotypic, genetic, and clinical overlap. In recognition of this continuum, these diseases are often treated similarly. Achievement of complete remission (CR)/CR-incomplete (CRi) is deemed the major outcome associated with improved overall survival (OS), and is often used as primary endpoint in clinical AML trials, whereas red blood cell transfusion independence is often the endpoint used in MDS trials. Expert opinions questioning these endpoints are cumulating [Sekeres M, Leukemia 2019, 570; Kim N, BJH 2021, 1137; Chandhok N, Leuk Lymphoma 2022, 1], as are reports indicating that achievement of CR/CRi may not be necessary for prolonged OS in patients treated with azacitidine [Pleyer L, Annals Hematol 2014, 1825; Schuh AC, ASH 2015, P575; Pleyer L, ASH 2015, P3752; Pleyer L, ASH 2019, P3387]. All response criteria for MDS, CMML and AML require bone marrow evaluations (BME), which are only performed in ~50% of patients outside of clinical trials [Dinmohamed A, Leuk Res 2015, 177; Pleyer L, ASH 2019, P3387], indicating the real-world need for internationally accepted response endpoints that do not necessitate repeated BME. We thus introduced peripheral blood CR (PB-CR), defined as Hb ≥11.0 g/dL, PLT ≥100 and <450 G/L, ANC ≥1.0 G/L, WBC ≥1.5 and <10.0 G/L, monocytes ≤1.0 G/LPB blasts=0%, no growth factors, no transfusions). In 1441 patients treated with azacitidine, multivariate survival modelling adjusted for 17 baseline covariates, indicated that PB-CR is at least as good a predictor of OS as CR [Pleyer L, ASH 2019, P3387]. Aims To compare the predictive value of CR or CR/CRi versus PB-CR. Methods Data from 1441 patients receiving 13971 cycles of azacitidine included in the Austrian Azacitidine Registry NCT01595295 was used for expanded analyses. The endpoints OS, time to next treatment (TTNT) and time on treatment (TOT) were defined as described previously [Pleyer L, Lancet Haematology 2021, e135]. Only data from patients who had a BME during treatment, and for whom all 17 baseline variables remaining in the final Cox model [Pleyer L, ASH 2019, P3387] were available, were analyzed (n=624). DeepSurv, a Cox proportional hazards model parametrized by a deep neural network [Katzman J, BMC Med Res Meth 2018, 24], was used to assess the predictive value of CR, CR/CRi and PB-CR. The network architecture is depicted in Fig 1. To assess whether CR or CR/CRi has greater predictive value than PB-CR, model performance was evaluated on randomly corrupted (i.e. destroyed) data. Either CR, CR/CRi or PB-CR responses were randomly permutated 1000 times, thus removing the information content from the respective variable and allowing investigation of the resulting drop in model performance using the concordance index (C-index). The average validation C-index for each response type of the corrupted datasets was generated with 5-fold cross-validation (Fig 2), stratified by sex, age </≥75 years and diagnosis. Validation C-index pairs for each of the 1000 permutations were compared by Wilcoxon signed-rank test. Bonferroni-correction for multile testing was performed. Results Random permutations of the PB-CR response resulted in signficantly higher performance loss than random permutations of the response types CR or CR/CRi, indicating that PB-CR has significantly more information content than either CR or CR/CRi. The C-indices with "intact PB-CR and permutated CR (or CR/CRi) were significantly higher than for "intact CR (or CR/CRi) and permutated PB-CR", with p<0·0001 for the endpoints TOT, TTNT and OS (Fig 3). Results remained consistent irrespective of the choice of inner network architectures. Conclusions In the largest cohort of azacitidine treated patients reported to date, survival modelling with a neural Cox regression revealed a higher information content for PB-CR as compared to either CR or CR/CRi for all time-to-event endpoints analyzed. Presence of PB-CR can thus identify patients with adequate response to non-intensive therapies without repeated BM assessments. Incorporation of PB-CR as secondary endpoint in clinical trials would be ideal to confirm these results. We aim to analyse whether these findings can be recapitulated in MDS, CMML and AML patients receiving other treatments and welcome collaborations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Transfusion Patterns during Early Follow-up Predict Overall Survival Independently of IPSS-M in Patients with Myelodysplastic Syndromes

Background: The cumulative red blood cells (RBC) transfusion burden is known to impact outcomes in myelodysplastic syndromes (MDS) but doesn't accurately predict prognosis during the early disease phase. Here we aimed to assess the prognostic value of early changes in transfusion patterns in addition to the recent IPSS-M scoring system. Methods: We gathered diagnostic biobank samples from adult patients (pts) with MDS and registered in the Karolinska Institute's biobank (KI) and the National Swedish MDS Biobank (NB) between 2003-2017 and 2013-2017, respectively. DNA targeted sequencing (152 genes) was performed (Bernard et al., NEJM Evid, 2022). Clinical data was retrieved through pts’ charts (KI) and the Swedish cancer registry (NB). Pts were treated according to Nordic/EU guidelines and most common therapies for lower-risk MDS and higher-risk MDS were erythropoietin and azacytidine, respectively. Transfusion data was obtained from the SCANDAT registry. Pts were followed with regards to RBC transfusion until censored due to death, transformation to acute myeloid leukemia (AML-t), allogenic stem cell transplantation (allo-SCT), or end of follow-up on the 31st of August 2018, whichever occurred first. As per the IWG hematological response criteria for MDS (Platzbecker et al., Blood 2019), transfusion states (TS) were categorized every 4 months (m) as transfusion dependent (TD) or transfusion free (TF) during the past 4 m period. Lower-risk MDS (LR) was defined as IPSS-M very low, low and moderate low, and higher-risk MDS (HR) as IPSS-M very high, high and moderate high at diagnosis (Bernard et al., NEJM Evid, 2022). Landmark analyses of overall survival (OS) were performed with the Kaplan-Meier method for estimating probabilities of OS over time. Multivariable analyses were conducted using Cox proportional hazards model. Results: We gathered a cohort of 688 pts with MDS from KI (n=424) and 33 other clinics in Sweden (NB, n=264). Median age at diagnosis was 74 years (y) old (range 19-93). The male:female ratio in the cohort was 1.4. At diagnosis, 63% of the pts were TF. Out of 646 pts evaluable by the IPSS-M score at diagnosis 54% had LR. Most frequently mutated genes in the cohort were TET2, SF3B1, ASXL1, DNMT3A, RUNX1, TET2, TP53 (66% TP53 multihit), U2AF1, STAG2, ZRSR2. Changes between TS (transitions) preferentially occurred within a year after diagnosis (panel A) with a median time for occurrence of transfusion-related transitions of 1.0 y (range 0.33-8.37). Based on this finding, we assessed whether TS at 8 m landmark impacted prognosis. We observed that there was a significant difference in OS since landmark between TF pts compared with TD pts at landmark 8 m and across IPSS-M categories (panel B). LR pts who were TD at 8 m, had a median OS of 3.2 y (95% CI: 2.2-4.0) versus 6.9 y (95% CI: 5.6-8.9) for LR pts who were TF (P<0.0001). Similarly, median OS was 0.8 y (95% CI: 0.6-1.1) in HR and TD pts while it was 2.4 y (95% CI: 2.1-3.1) in HR and TF pts at landmark 8 m (P<0.0001). Interestingly, OS for LR pts who were TD didn't significantly differ from HR pts who were TF at 8 m. Overall, pts TD at 8 m had more gene mutations compared to TF pts (median 5 [1;13] and 4 [1;16], respectively, P=0.0084). Moreover, studying specific genetic subgroups of MDS, TS at 8 m distinguished subsets of pts with adverse or favorable outcomes within SF3B1-mutated LR pts. In this population, the median OS in pts TF at 8 m was 8.4 y (95% CI: 6.5-13.1) compared to 3.2 y (95% CI: 1.7-4.1) for TD pts (P<0.0001). Next, in multivariable analysis, we found that TD at 8 m significantly impacted OS (HR=2.4 [95% CI: 1.9-3.1]), independently of diagnostic IPSS-M score, age, gender and type of MDS (de novo or therapy-related). Conclusion: TS at landmark 8 m, usually after outcome of first-line treatment was evaluated, appears to be a strong and independent predictor of OS in MDS. These findings are of particular importance for the LR group in which it could discriminate subsets with favorable outcomes from those with adverse prognosis. In addition to the IPSS-M calculation at diagnosis, transfusion dependency could be easily used for prognostic reassessment during follow-up. More generally, these results highlight the need of dynamic outcomes prediction tools and/or validation of current prognostic scores in dynamic settings. Finally, multistate modeling of the dataset is being completed and aims to assess how changes of transfusion patterns over time impact prognosis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Myelodysplastic Syndromes Presenting with Isolated Thrombocytopenia: A Less Aggressive Form of Presentation and with Better Prognosis

Introduction: Patients with myelodysplastic syndromes (MDS) who present with isolated thrombocytopenia (TP) represent an infrequent group. Previous studies have described clinical presentation and outcomes but none of them include the gene mutation profile. The aim of the present study was to define molecular profile and overall survival (OS) in patients with MDS-TP. Methods: We retrospectively studied 472 patients diagnosed with MDS between Sep/1988-Jun/2022. Diagnostics were established according to WHO 2017 criteria, and prognosis assessment according to IPSS-R and IPSS-M. MDS-TP patients were defined by: Hb ≥12 g/dL (female) or ≥13 g/dL (male); absolute neutrophil count ≥1.8×109/L and platelet <150x109/L. NGS sequencing data were available in 12 patients. We analyzed the full exonic regions of 25 genes associated with myeloid neoplasms (ASXL1, CALR, CBL, CSF3R, DNMT3A, ETV6, EZH2, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NRAS, PRPF8, RUNX1, SETBP1, SF3B1, SH2B3, SRSF2, STAG2, TET2, TP53, U2AF1, and ZRSR2). Statistical analysis: Categorical variables are described by frequencies and percentages and continuous variables as medians and ranges. Survival curves were constructed by the Kaplan Meier method, defining OS as the interval from date of diagnosis to last contact or death, and time to AML progression as the interval from date of diagnosis to AML progression. Survival curves were compared by log-rank test. We performed a cox regression analysis for adjusting the prognostic impact of MDS-TP by IPSS instead of IPSS-R since the latter contains thrombocytopenia as a prognostic variable. Differences were considered statistically significant when P<.05 in a 2-tailed test. Results: Of the 472 patients meeting MDS criteria, 20 (4%) had MDS-TP. Median age at diagnosis was 74 years (46-83). Median platelet was 84x109/L (23-149). Median follow-up was 83 months (8-200). Median OS was 104 months (68-206). None of the patients required treatment at diagnosis. Twelve (60%) patients died during follow-up, 4 (34%) due to infections, 2 (16%) to arrythmia, 2 (16%) solid cancers and, 1 (8%) to AML. The distribution according to WHO was: 14 (70%) MDS with multilineage dysplasia (MLD), 3 (15%) MDS with excess blasts type 1, 1 (5%) MDS with single lineage dysplasia, 1 (5%) MDS ring sideroblasts with MLD, and 1 (5%) MDS 5q deletion. Twelve (60%) had normal karyotype, 3 (15%) chromosome Y loss, 3 (15%) 20q deletion, 1 (5%) chromosome 8 gain and 1 (5%) 5q deletion. No complex karyotype was observed. IPSS-R distribution at diagnosis was: 45% very low, 45% low, and 10% intermediate. According to IPSS-M, 10/12 (83%) were very low and 2/12 (17%) low. The most common mutations were: 6 (30%) TET2, 3 (15%) SRSF2, 3 (15%) ASXL1, and 2 (10%) ZRSR2; 2/6 patients with TET2 mutation had 2 TET2 mutations. One patient did not present any mutation. Nine (45%) patients met oligomonocytic chronic myelomonocytic leukemia (OM-CMML) criteria at diagnosis, and 2 of them during follow up. Five (25%) patients evolved to CMML. Half of the patients did not present megakaryocytic dysplasia, regardless of WHO category. Interestingly, 4 patients diagnosed with MDS-MLD, which also met OM-CMML criteria, improved thrombocytopenia after short-term steroid use due to not related purposes (i.e: SARS CoV2 infection). OS was significantly longer in MDS-TP (median OS, 104 vs 48 months; p=0.036). Time to AML was also significantly longer (p=0.019). Figure 1. When adjusted by IPSS, MDS-TP did not remain as an independent good prognostic factor but showed a clear statistical trend for both OS (p=0.08) and time to AML (p=0.06). Conclusions: We found MDS-TP to be more frequently associated with MDS-MLD, normal karyotype and lower IPSS-M and IPPS-R. Most common mutations were TET2 and SRSF2, similar to OM-CMML and CMML. In this regard, almost 50% of patients met OM-CMML criteria at diagnosis or during follow up and 25% evolved to CMML. We hypothesize that isolated thrombocytopenia as the sole cytopenia at diagnosis of MDS would probably be linked to autoimmune phenomena at least in a higher proportion of patients. In this line, half of the patients did not present megakaryocytic dysplasia, some of them improved their thrombocytopenia with steroids, and the series is enriched in TET2 mutations, that have been linked to autoimmune phenomena in several articles (eg: Zhao LP et al. Leukemia 2021). Finally, this group of patients showed a significantly better OS and time to AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Myelodysplastic Syndromes with Isolated del(5q): Value of Molecular Alterations for Diagnostic and Prognostic Assessment.

Myelodysplastic syndromes (MDS) are a group of clonal hematological neoplasms characterized by ineffective hematopoiesis in one or more bone marrow cell lineages. Consequently, patients present with variable degrees of cytopenia and dysplasia. These characteristics constitute the basis for the World Health Organization (WHO) classification criteria of MDS, among other parameters, for the current prognostic scoring system. Although nearly half of newly diagnosed patients present a cytogenetic alteration, and almost 90% of them harbor at least one somatic mutation, MDS with isolated del(5q) constitutes the only subtype clearly defined by a cytogenetic alteration. The results of several clinical studies and the advances of new technologies have allowed a better understanding of the biological basis of this disease. Therefore, since the first report of the "5q- syndrome" in 1974, changes and refinements have been made in the definition and the characteristics of the patients with MDS and del(5q). Moreover, specific genetic alterations have been found to be associated with the prognosis and response to treatments. The aim of this review is to summarize the current knowledge of the molecular background of MDS with isolated del(5q), focusing on the clinical and prognostic relevance of cytogenetic alterations and somatic mutations.

Progress in diagnostic staging of myelodysplastic syndrome

Myelodysplastic syndromes (MDS) are a group of acquired heterogeneous clonal disorders that originate from hematopoietic stem cells. It is characterized by a reduction in one or more blood lines in the myeloid system with abnormal development, pathological hematopoiesis and a high risk of transformation to acute myeloid leukemia (AML). In 2016, the World Health Organization (WHO) revised the diagnostic staging criteria for MDS, but with the development of next-generation sequencing (NGS) technology, the diagnostic staging of MDS has opened a new era of accurate diagnosis and individualized treatment. In this paper, we review the diagnostic typing of MDS.

Better Therapeutic Approach after Comprehensive Geriatric Evaluation in Older Patients with ACUTE Myeloid Leukemia and Myelodysplasic Syndromes

Better Therapeutic Approach after Comprehensive Geriatric Evaluation in Older Patients with ACUTE Myeloid Leukemia and Myelodysplasic Syndromes

A Phase I/II Study of Venetoclax in Combination with 5-Azacytidine in Treatment-Naïve and Relapsed/Refractory High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

A Phase I/II Study of Venetoclax in Combination with 5-Azacytidine in Treatment-Naïve and Relapsed/Refractory High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

Evaluation of International Working Group 2006 Response Criteria in Patients with Higher-Risk Myelodysplastic Syndromes (HR-MDS) Treated with Hypomethylating Agent Monotherapy in the Frontline Setting

Evaluation of International Working Group 2006 Response Criteria in Patients with Higher-Risk Myelodysplastic Syndromes (HR-MDS) Treated with Hypomethylating Agent Monotherapy in the Frontline Setting