Hypocellular Myelodysplastic Syndrome Research Articles

Association Vs Causation: Epidemiologic Clues As to the Autoimmune Pathogenesis of MDS

Multiple clinical associations of MDS and autoimmunity have been described, but the pathogenesis and cause-effect relationship are likely diverse and possibly intertwining. Telomeropathies, while increasing risk of bone marrow failure, can be also associated with liver or lung fibrosis and therapies for Wegener's granulomatosis can predispose to MDS. Moreover, clonal hematopoiesis (CH) seems to be more prevalent in some autoimmune diseases 1 (AD) perpetuating a process that may ultimately lead to increased risk of MDS. Reverse scenarios are also possible and AD can be a result of MDS as a form of paraneoplastic syndrome. The recently established relationship of somatic UBA1 mutations and MDS with autoimmune manifestations exemplifies such a scenario e.g., VEXAS syndrome 2. This remarkable configuration prompted us to systematically investigate the relationships between autoimmune symptomatology and MDS including genomic features such as UBA1 mutations, pathomorphological phenotypes, and demographics. We have investigated 1,903 MDS patients for the presence and the anamnestic evidence of AD. A total of 197 patients (about 10%) had a concurrent well-defined AD (5.3%) or positive inflammatory/autoimmune markers (4.9%; fibromyalgia and chronic fatigue syndrome invoked 0.3% of MDS cases and were not counted). Of those, polymyalgia rheumatica, systemic lupus erythematosus and rheumatoid arthritis were most common accounting for 13%, 5.5% and 19% of MDS cases with autoimmunity. The remaining 60% involved the presence of serological markers such as ANA, anti-RNP and anti-SSA among others (45%, 4%, 2%, respectively) without fulfilling the criteria for specific autoimmune entities. The gender distribution of cases with MDS/autoimmune features was similar to the general MDS demographics and cases without autoimmune conditions. A similar distribution was seen among males and females in both groups, with males representing 84% of each subgroup and females accounting for 16%. When stratified by risk criteria, 58% of patients with MDS/AD were found to have low risk disease (<5% of blasts) compared to patients without AD (46%; p= .74), while intermediate to high risk (HR) categories were seen in 42% and 52% (p= .74), respectively. While trisomy 8 and complex karyotype were underrepresented in MDS with AD (15% vs 22%, 4.5% vs 10%), del(11q), del(12q) and del(20q) were more common among patients with AD (10% vs 5.8%). When we screened the genomic landscape of AD/MDS, we found more mutations in TET2 (24 vs 13%, p= .004), SF3B1 (14 vs 8%, p= .026), BCORL1 (5 vs 1.5%, p= .026), DNMT3A (13 vs 6%, p= .003), IDH1 (3 vs 0.8%, p= .01), and CEBPA (3 vs 0.8%, p= .04) compared to patients without AD ( Fig.1) With a median follow up of 19 months, female patients with AD showed better 1-year survival rate of 89% vs 65% in cases without AD, (p= .044). A similar trend was seen for transformation to AML. However, such differences were not found among males. Next, we determined the etiologic fraction of the MDS/AD clinical dyad explained by the presence of VEXAS by screening UBA1 mutation in our cohort. We found mutations in 0.5% of MDS/AD vs 0.05% of the total cohort (p=0.1). To further expand on MDS association with AD, we investigated other potential autoimmune syndromes and found 0.5% of MDS with co-associated LGL with 1/3 of them presenting with RA. Notably, in the hypocellular MDS subgroup (n=175), 9.7% had concomitant AD (p= .89). Similarly, 0.3% of evaluable patients had Sweet syndrome, of which 16% associated with autoimmune conditions. Finally, since AD appear to be frequent in MDS, we queried whether in our internal cohort of CHIP patients (n=115), their prevalence could be analogous. Indeed, AD were present in a fraction similar to that of manifest MDS (around 5%). Moreover, in all of these patients, similar to those with MDS, the autoimmune diagnosis preceded that of CHIP with the caveat that, unlike MDS, CHIP may have evolved much sooner than the original diagnosis but was not screened. Our study provides valuable insights into the intricate relationship between MDS and AD. Our findings demonstrate that MDS and autoimmunity are linked through diverse mechanisms, with potential cause-effect relationships existing in both directions. Figure 1. Frequency of mutations Graph shows frequency of mutations among patients with autoimmune diseases (AD) in MDS versus those without AD.* p<0.05, **p<0.001.

30. Chromosomal microarray analysis work-up for hypocellular MDS patients with inconclusive cytogenetics

30. Chromosomal microarray analysis work-up for hypocellular MDS patients with inconclusive cytogenetics

Retrospective Evaluation of Patients Who Underwent Allogeneic Stem Cell Transplantation for Bone Marrow Failure

Background: Bone marrow failure is a disease that develops due to different etiologies. Aplastic anaemia (AA) and hypocellular myelodysplastic syndrome (HMDS) are the most common bone marrow failure disorders. Treatment options include supportive therapy, immunosuppressive therapy, and allogeneic hematopoietic stem cell transplantation (allo-HCT). Allo-HCT is the only curative treatment option. This study aimed to retrospectively evaluate the demographic characteristics, treatment, and transplantation results of patients who underwent Allo-HCT for bone marrow failure.
 Material and Methods: This single-centre retrospective study enrolled 11 patients (9 with severe AA and 2 with HMDS) who underwent allo-HCT for bone marrow failure. The patients' records until 17.08.2023 were analysed. Age, gender, diagnosis, donor age and gender, type of transplantation, pre-transplant ferritin levels, time to transplantation, volume of infused product, number of CD34+ cells in the infused product, post-transplant engraftment times, discharge time, transplant-related complications, post-transplant follow-up and overall survival times were obtained.
 Results: Eleven patients underwent 12 allo-HCTs for bone marrow failure. Seven patients were male, and four were female. The median age was 40, and seven patients were ≥40 years old at the time of transplantation. Eleven transplants were performed from HLA fully matched siblings and one from a 9/10 matched sibling donor. Bone marrow was used as a stem cell source in 8 transplants and peripheral blood in 4 transplants. The conditioning regimen was fludarabine/cyclophosphamide/anti-thymocyte globulin in all patients. The median time from diagnosis to transplantation was five months. The median time for neutrophil engraftment was 23 days. The median platelet >20.000/mm3 engraftment time was 16 days. A statistically significant positive correlation was found between ferritin levels and platelet >20.000/mm3 engraftment (days) (r=0.653, p=0.040) and platelet >50.000/mm3 engraftment (days) (r=0.720, p=0.029). There was a statistically significant negative correlation between the number of infused CD34 positive cells (10⁶/kg) and platelet >50.000/mm3 engraftment (days) (r=-0.670, p=0.024). Patients were discharged in a median of 23 days. Acute graft versus host disease (GvHD) was observed in one patient, while chronic GvHD was not observed in any patient. The median overall survival time was 48 months, and the median post-transplant follow-up was 37 months. Secondary malignancy and MDS were not detected in any patient during the follow-up period. All 11 patients who underwent Allo-HCT from a matched sibling donor are alive and continue to have a complete hematological response. There was no increase in mortality and morbidity in patients aged 40 years and older.
 Conclusions: In patients with severe AA and high-risk HMDS without comorbidities between the ages of 40 and 50, allo-HCT should be considered as first-line treatment in the presence of an HLA-matched sibling donor.

The CSN5/HSF/SPI1/PU.1 Axis Regulates Cell Proliferation in Hypocellular Myelodysplastic Syndrome Patients.

This study explored the relationship between the activation of the jak/stat3 signaling pathway and the CSN5 gene transcript and protein expression levels in the hematopoietic stem cells of patients with myelodysplastic syndromes (MDSs). This study also aimed to investigate the correlation between the expression level of CSN5 and the deubiquitination of HSF1, as well as the transcript level of the spi1/pu.1 genes to explore the pathogenesis of MDS. We isolated cells from normal individuals and MDS patients, and the mRNA and protein expression levels of spi1/pu.1 in cd34+ cells (hematopoietic stem cells) were measured by PCR and western blotting, respectively. A ChIP assay was used to detect the binding of HSF1 to the spi1/pu.1 promoter in cd34+ cells. The ubiquitination of HSF1 in cd34+ cells was detected by CO-IP. The binding of HSF1 and Fbxw7α was detected in in cd34+ cells by CO-IP. The binding of HSF1 and CSN5 was evaluated. A luciferase reporter assay was used to detect the effect of STAT3 on CSN5 promoter activation in cd34+ cells. Western blotting was used to detect the phosphorylation of STAT3 in cd34+ cells of MDS patients. The binding of STAT3 and C/EBP beta in cd34+ cells was detected by CO-IP. Inhibition of SPI1/PU.1 expression was observed in MDS samples with low proliferation ability. Further experiments proved that phosphorylation of STAT3 affected CSN5 function and mediated the ubiquitination of HSF, the upstream regulator of SPI1/PU.1 transcription, which led to the inhibition of SPI1/PU.1 expression. Restoration of CSN5 rescued the inhibition of HSF1 ubiquitination, causing SPI1/PU.1 transcription to resume and increasing SPI1/PU.1 expression, promoting the recovery of cell proliferation in hypocellular MDS. Our research revealed the regulatory role of the CSN5/HSF/SPI1/PU.1 axis in hypocellular MDS, providing a probable target for clinical intervention.

Germline Variants in MDM4 Cause a Disorder of p53 Dysregulation and Insufficient Telomere Maintenance

Introduction: Telomere biology disorders (TBD) comprise a group of hereditary disorders characterized by a genetically determined insufficiency of telomere maintenance leading to fibrosis and malfunction, especially of bone marrow (BM), liver, and lungs. TBD can present with highly variable phenotype as so-called "cryptic" forms with only mild clinical manifestations. Known genetic causes include defects in genes encoding mainly for proteins directly involved in telomere biology. However, today, still a relevant subgroup of patients with the clinical picture of TBD remain without a molecular diagnosis. Recently, members of yet a single family carrying a dominantly inherited missense variant in MDM4 (NM_002393.5:c.1361C>T, p.(Thr454Met)) with premature telomere length (TL) shortening were reported (Toufektchan et al., 2020) presenting with a phenotype similar to the classical TBD, Dyskeratosis congenita. The MDM4-gene encodes a 490-amino acid protein that interacts with and negatively regulates p53. In vitro and murine studies suggested a loss of p53 regulation by the defective MDM4 protein leading to augmented p53 activity and insufficient telomere maintenance. In line with this finding, mice with an overactive TRP53 developed BM failure and lung fibrosis resembling the phenotype of TBD. Here, we report three patients from different families carrying germline variants in MDM4 presenting with a TBD phenotype of varying severity. Methods: All patients were included in the Aachen Telomere Registry (ATR). Informed consent for genetic analyses was obtained from all participants. All patients received analysis of TL via flow-FISH and genetic work-up using whole exome sequencing (WES). Results: Patient 1 is a newborn boy with uncomplicated delivery. At 4 weeks of age, the patient presented jaundice and a routine blood sample was taken. Clinical examination showed no abnormalities. Blood counts showed neutropenia with 500/µl and normal hemoglobin and platelet counts. WES revealed the identification of the same heterozygous MDM4-variant ( NM_002393.5:c.1361C>T, p.(Thr454Met)) previously reported by Toufektchan et al.. Subsequent analyses of the parents showed maternal inheritance. Additional TL measurement showed no significant shortening of TL for all family members. Physical examination and medical history of the mother revealed no relevant abnormalities. Patient 2 is a male patient who, at the age of six years, first showed thrombocytopenia and leukopenia. During follow-up, he developed liver dysfunction with persisting elevated transaminases at the age of eleven years and portal hypertension and esophageal varicosis at the age of 13. During follow-up, the patient developed progressive cytopenia at the age of 16 and BM hypocellularity with reduced and partially dysplastic megakaryopoiesis and granulopoiesis. Flow-FISH analyses revealed a TL below the 1% percentile in lymphocytes. Genetic work-up using trio-based WES of the parents and the patient showed a de-novo stopgain variant in MDM4 (NM_002393.5:c.1333C>T, p.(Arg445*)). Patient 3 is an adult 53-year-old male patient presenting with BM failure. Initial diagnostic work-up including BM biopsy showed hypocellular BM. FISH analysis of the BM sample revealed a deletion of 7q and the diagnosis of hypocellular myelodysplastic syndrome was established. TL measurement showed TL below the 1% percentile in lymphocytes. Clinical examination showed no TBD typical stigmata or abnormalities. However, hepatic steatosis was reported. Additional WES revealed a rare missense variant in MDM4 (NM_002393.5:c.1334G>A, p.(Arg445Gln)). Conclusions: Here, we provide strong evidence from three unrelated patients that genomic germline variants in MDM4 cause a disorder of insufficient telomere maintenance resulting in a phenotype resembling features of TBD. Similar to TBD, the age at disease onset of our reported patients varied from early infant age to adulthood. So far, a single family with a proposed pathogenic MDM4 variant had been reported, which left a degree of uncertainty concerning the pathogenicity of MDM4 variants in general. In summary, our data confirm that there is an MDM4-associated TBD disorder with a broad phenotypic clinical spectrum.

Sternal bone marrow cell morphology evaluation utility for diagnostic categorization in patients with acquired hypocellular bone marrow failure syndromes

Objective: Diagnostic value assessment of sternal bone marrow cell morphology in patients with acquired hypocellular bone marrow failure syndromes (BMFS) characterized by normal cytogenetics. Methods: A total of 194 eligible patients with an acquired hypocellular BMFS pre-sternum diagnosis in Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College from June 2014 to January 2019 were reviewed. Sternal bone marrow evaluation was performed, and a post-sternum diagnosis was made. Clinical characteristics and overall survival (OS) were then compared among patients with different post-sternum diagnosis. Binary logistic regression was used to develop a predictive scoring system. Results: In 152 patients with pre-sternum AA diagnosis, 29 patients with a pre-sternum idiopathic cytopenia of undetermined significance (ICUS) diagnosis, and 13 patients with a pre-sternum clonal cytopenia of undetermined significance (CCUS) diagnosis, sternal bone marrow evaluation resulted in a change of diagnosis to hypocellular myelodysplastic syndrome (hypo-MDS) in 42.8% (65/152) , 24.1% (7/29) , and 30.8% (4/13) , respectively. Patients with a post-sternum hypo-MDS diagnosis showed a significant difference in OS compared with patients with a post-sternum AA diagnosis (P=0.005) . Patients with ICUS/CCUS showed no difference in OS compared with AA and hypo-MDS (P=0.095 and P=0.480, respectively) . A 4-item predictive scoring system to identify hypocellular BMFS patients that need sternal bone marrow evaluation was developed, including age > 60 years old (OR=6.647, 95% CI 1.954-22.611, P=0.002, 2 points) , neutrophil alkaline phosphatase score ≤ 160 (OR=2.654, 95% CI 1.214-5.804, P=0.014, 1 point) , abnormal erythroid markers evaluated by flow cytometry on iliac bone marrow (OR=6.200, 95% CI 1.165-32.988, P=0.032, 2 points) , and DAT (DNMT3A, ASXL1, TET2) genes mutation (OR=4.809, 95% CI 1.587-14.572, P=0.005, 1 point) . The Akaike information criterin (AIC) was 186.1. Conclusion: Patients with a pre-sternum acquired hypocellular BMFS diagnosis characterized by normal cytogenetics may not reach accurate diagnostic categorization without sternal bone marrow cell morphology evaluation, which could be considered a diagnostic tool for this patient population. A predictive scoring system was developed, and when the total score is ≥ 2 points, sternal bone marrow evaluation should be performed for accurate diagnostic categorization that is critical to optimal patient care.

MDS-406 Prognostic Implication of the Molecular Profiles of Patients With Hypocellular Myelodysplastic Syndrome

Hypocellular myelodysplastic syndrome (hMDS) is a subset of MDS that has not been fully characterized. This study aimed to better identify the clinical characteristics and molecular profile of hMDS and study the prognostic impact of mutations in hMDS. We conducted a retrospective review of patients with newly diagnosed MDS in a single tertiary cancer center registry from 2010 to 2021. Of 1,899 patients with MDS, 176 (10%) patients had hMDS. The median follow-up period was 19.5 months. hMDS patients were more likely to be younger and have therapy-related disease and more thrombocytopenic and neutropenic than normo/hypercellular MDS (non-hMDS). All other clinical characteristics were comparable. The distributions of IPSS-R cytogenetic scores (≥3, or <3) were comparable. hMDS patients had similar overall survival (OS) to non-hMDS (median 28.3 vs. 29.0 months) or AML transformation rates (23% vs. 19%). These findings were maintained after multivariate adjustment. Hypocellularity did not affect survival in either de novo or t-MDS. We further analyzed 1,352 (71%) pts with mutation data available. Patients with hMDS had less frequent ASXL1, RUNX1, TET2, or IDH1 mutations, whereas the frequency of TP53 and RAS pathway mutations were comparable. In de novo MDS, hMDS patients had less frequent RUNX1, SRSF2, or TET2 mutations. In t-MDS, hMDS pts had less frequent TP53 or U2AF1 mutations. The survival of hMDS can be stratified by IPSS-R with some overlaps. In hMDS, mutations in the RAS pathway or TP53 were associated with inferior OS, whereas TET2 mutations correlated with superior OS. Based on the mutation data, patients were stratified into 3 groups: (1) with TET2 mutations, (2) with TP53 or RAS pathway mutations without TET2 mutations, and (3) without TET2/TP53/RAS mutations. The TET2 mutant group showed marginally better mOS (HR 0.50, P=0.081), and the TP53/RAS pathway group showed inferior mOS (HR 2.74, P=.005) compared with the group without TET2/TP53/RAS pathway mutation. Patients with hMDS had similar outcomes to patients with non-hMDS but exhibit distinct molecular profiles; hMDS had less frequent driver mutations commonly seen in non-hMDS. The integration of molecular profiles into risk stratification in hMDS could be a study of interest.

Apoptosis in myelodysplasia: Association with patient age, bone marrow cellularity and karyotypes

Background: Myelodysplastic syndrome (MDS) comprises a heterogeneous group of clonal hematopoietic stem cell diseases, characterized by dysplasias and apoptosis in bone marrow (BM) and cytopenias in peripheral blood. In this study, we analyzed apoptosis in MDS to verify associations with patient age, bone marrow cellularity and karyotypes and to investigate the role of apoptosis in MDS pathogenesis. Methods: Bone marrow cells were collected from 81 patients with primary MDS, of which 60 were adults and 21 children. BM cells were also collected from 10 healthy donors for bone marrow transplants, 5 adults and 5 children, as controls. The patients and controls came from public onco-hematology institutions in Rio de Janeiro. The percentage of apoptotic BM cells was assessed by flow cytometry using two combinations: annexin V-FITC/CD34PE/CD45PerCP and annexin V-FITC/CD14PE/CD45PerCP in BM cells. Cytogenetic analysis was performed by G-banding. Results: The comparison between adult and pediatric patients showed that these patients show a similar behavior with regard to apoptotic cells percentages in BM samples. Apoptosis occurs independently of BM cellularity, being more prominent in patients with hyper/normocellular BM. Patients with normal karyotypes, del(5q), del(17p) had higher apoptosis rates than patients with del(11q) and complex karyotypes. Cells committed to a differentiation program were associated with high rates of apoptosis, suggesting that apoptosis may be a consequence of inefficient hematopoiesis, such that the hematopoietic system may eliminate dysplastic cells at the beginning of the disease. Conclusions: Our results suggest that apoptosis is an important characteristic of BM cells from adult and pediatric MDS patients and may be a consequence of inefficient hematopoiesis. In addition, we suggest that apoptosis is not the main mechanism associated with hypocellular MDS, and it occurs preferentially in MDS cases of hyper/normocellular BM and is associated with a good prognosis. Keywords: Myelodysplastic Syndrome; Apoptosis; Patient age; Bone marrow cellularity; Karyotypes.

Hypocellular myelodysplastic syndromes (h-MDS): from clinical description to immunological characterization in the Italian multi-center experience

Hypocellular myelodysplastic syndromes (h-MDS): from clinical description to immunological characterization in the Italian multi-center experience

Plasma lipidome acts as diagnostic marker and predictor for cyclosporin response in patients with aplastic anemia.

The lipid metabolomic profile has been well defined in the pathogenesis and differential diagnosis in patients with different myeloid diseases. We assumed that the serum lipid metabolites could also help the diagnosis and prognostic prediction of aplastic anemia (AA). In this study, serum lipid profiles were explored in AA patients before and after cyclosporin (CsA) treatment. Meanwhile, hypocellular myelodysplastic syndrome (h-MDS) patients and the healthy volunteers were compared as controls. 15 AA patients, 11h-MDS patients and 20 age and sex matched health controls were enrolled. All the AA patients were diagnosed to be non-severe aplastic anemia with transfusion dependency and were treated by CsA 3-5mg/kg/d for at least 6months. AA patients had decreased arachidonic acid pathway metabolites and retinol metabolism-related metabolites as compared with h-MDS and the health (P < 0.05), whereas h-MDS patients had increased metabolism of proline and threonine and abnormal sphingolipid metabolism compared with AA patients and the normal controls. After 6month of CsA treatment, serum arachidonic acid, PGE2, PGJ2, 15(S)-HETE, leukotriene B4 and Protectin D1 decreased significantly. Patients who had response to CsA had higher levels of baseline protectin D1 (P = 0.011), leukotriene B4 (P = 0.011), 15(S)-HETE (P = 0.004) and all-trans-retinal (P = 0.000) than those who had no response.

New Approaches to Myelodysplastic Syndrome Treatment.

The treatment of myelodysplastic syndromes (MDS) begins with risk stratification using a validated tool such as the International Prognostic Scoring System (IPSS) or its revised version (IPSS-R). This divides patients into lower- and higher- risk categories. Although treatment objectives in lower-risk MDS (LR-MDS) have traditionally been directed at improving cytopenias (usually anemia) as well as quality of life, recent data supports a potential role for early intervention in delaying transfusion dependency. In addition, careful individualized risk stratification incorporating clinical, cytogenetic, and mutational data might help identify patients at higher-than-expected risk for progression. Given the need for supportive care with red blood cell (RBC) transfusions leading to iron overload, iron chelation should be considered for patients with heavy transfusion requirements at risk for end-organ complications. For patients with LR-MDS and isolated anemia, no high-risk features, and endogenous erythropoietin (EPO) levels below 500 U/L, erythropoiesis-stimulating agents (ESAs) can be attempted to improve anemia. Some LR-MDS patient subgroups may also benefit from specific therapies including luspatercept (MDS with ring sideroblasts), lenalidomide (MDS with deletion 5q), or immunosuppressive therapy (hypocellular MDS). LR-MDS patients failing the above options, or those with multiple cytopenias and/or higher-risk features, can be considered for oral low-dose hypomethylating agent (HMA) therapy. Alternatively, these patients may be enrolled on a clinical trial with promising agents targeting the transforming-growth factor beta (TGF-β) pathway, the hypoxia-inducible factor (HIF) pathway, telomerase activity, inflammatory signaling, or the splicing machinery. In higher-risk MDS (HR-MDS), therapy seeks to modify the natural history of the disease and prolong survival. Eligible patients should be considered for curative allogeneic hematopoietic stem cell transplantation (aHSCT). Despite promising novel combinations, the HMAs azacitidine (AZA) or decitabine (DAC) are still the standard of care for these patients, with intensive chemotherapy-based approaches being a potential option in a small subset of patients. Individuals who fail to respond or progress after HMA experience dismal outcomes and represent a major unmet clinical need. Such patients should be treated as part of a clinical trial if possible. Experimental agents to consider include venetoclax, myeloid cell leukemia 1 (MCL-1) inhibitors, eprenetapopt, CPX-351, immunotherapies (directed towards CD47, TIM3, or CD70), interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, pevonedistat, seclidemstat, and eltanexor. In this review, we extensively discuss the current landscape of experimental therapies for both LR- and HR-MDS.

Circulating HMGB1 is increased in myelodysplastic syndrome but not in other bone marrow failure syndromes: proof-of-concept cross-sectional study.

Background:Myelodysplastic syndrome (MDS) is associated with persistent immune activation. High mobility group box-1 (HMGB1) is a ubiquitous, functionally diverse, non-histone intranuclear protein. During acute and chronic inflammatory states, HMGB1 is actively released by inflammatory cells, further amplifying the inflammatory response. A role in MDS and other hypoplastic bone marrow (BM) disorders is incompletely understood.Objectives:The objective of the study is to evaluate whether circulating HMGB1 is elevated in patients with MDS and other BM failure syndromes [namely, aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH)].Design:This is a observational, cross-sectional, single-center, exploratory study.Methods:We evaluated circulating concentrations of HMGB1, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in patients with MDS and age-matched hematologically healthy controls as well as patients with AA and PNH.Results:We included 66 patients with MDS and 65 age-matched controls as well as 44 patients with other BM failures (AA = 27, PNH = 17). Circulating levels of HMGB1 were higher in patients with MDS [median, 4.9 ng/ml; interquartile range (IQR): 2.3–8.1] than in AA (median, 2.6 ng/ml; IQR: 1.7–3.7), PNH (median, 1.7 ng/ml; IQR: 0.9–2.5), and age-matched healthy individuals (median, 1.9 ng/ml; IQR: 0.9–2.5) (p = 0.0001). We observed higher concentrations of HMGB1 in the very low/low-risk MDS patients than in the intermediate/high/very high-risk ones (p = 0.046). Finally, in comparison with patients with AA, those with hypocellular MDS (h-MDS) had significantly higher levels of circulating HMGB1 (n = 14; median concentration, 5.6 ng/ml, IQR: 2.8–7.3; p = 0.006). We determined a circulating HMGB1 value of 4.095 ng/ml as a diagnostic cutoff differentiator between h-MDS and AA.Conclusion:These observations indicate that circulating HMGB1 is increased in patients with MDS. HMGB1 (but not IL-1β or TNF-α) differentiated between MDS and other BM failures, suggesting that HMGB1 may be mechanistically involved in MDS and a druggable target to decrease inflammation in MDS.

The impact of clonal hematopoiesis on outcomes in patients with aplastic anemia

Over the years, not only have the T-cell mediated immune mechanisms of aplastic anemia (AA) involved in AA development started to become better understood, but there is now also a better understanding of the roles played by somatic mutations, cytogenetic abnormalities and defective telomerase functions and other genetically-related factors. Somatic gene mutations suggestive of clonal hematopoiesis are detected in approximately one third of patients with AA. Recent studies have suggested that some of these may predict a better response to immunosuppressive therapy, whereas others indicate poorer outcomes with higher risks of clonal evolution to myelodysplastic syndrome or acute myeloid leukemia, and that therefore better results may be obtained based on allogeneic stem cell transplantation. Furthermore, recent advances in molecular techniques may be useful in differentiating aplastic anemia from hypocellular myelodysplastic syndrome and other clonal hematopoiesises of indeterminate potential. All of these are summarized in this review which includes further insights into treatment personalization based on the molecular pathogenesis of AA.

Clinical and Pathological Characteristics of Hypocellular Myelodysplastic Syndrome : A Single-Center Retrospective Study

Background : Hypocellular myelodysplastic syndrome(MDS) is a distinct subset of MDS. It is defined as cellularity less than 30% in patients' age ≤70, or less than 20% in patients' age>70. More studies suggest that hypocellular MDS has distinct biology and clinical characteristics. Here we investigated clinical, pathological characteristics of patients with hypocellular MDS and their outcome.Methods : Patients with newly diagnosed MDS from January 2010 to June 2021 at the University of Texas MD Anderson Cancer Center were retrospectively reviewed. Patient and disease characteristics were collected to compare between hypocellular MDS and normo-/hypercellular MDS groups. Further detailed analysis focusing on patients who were investigated 28-gene or 81-gene mutation panels were conducted including de novo MDS and therapy-related MDS(t-MDS). Survival data for detailed analysis was updated in July 2021, and multivariate analyses were conducted with step-wise selection(p-value cutoff 0.10). IPSS-R was used to confirm risk stratification in hypocellular MDS patients.Results : Out of 1,789 newly diagnosed MDS patients, 179 patients were identified as hypocellular MDS. Hypocellular MDS patients present with lower CBC counts(p<.0001). More t-MDS were identified in hypocellular MDS group (n=83, 46%) compared to normo/hypercellular MDS group (n=513, 32%), (p< .001). Other baseline characteristics were comparable between hypocellular MDS patients and normo/hypercellular MDS patients (Table 1). There was no difference in overall survival (OS)(median 25.3 months vs 22.5 months, respectively, Figure 1a) or transformation-free survival(TFS)(Figure 1b) between hypocellular MDS group and normo/hypercellular MDS group (HR in OS for hypocellular MDS patients : 1.05, 95% CI 0.86-1.29, p=.645). Hypocellularity did not affect survival outcome in t-MDS (p=.420) or de novo MDS (p=.745).A total number of 153 hypocellular MDS patients were available for 28- or 81-gene panels. 78 patients (51%) had t-MDS. They presented with lower Hb (p= 0.045) and platelets (p=.016) than de novo MDS patients at diagnosis. Treatment history was similar; 54% of t-MDS patients were treated with HMA compared to 56% patients of de novo MDS with HMA treatment(p=.870). t-MDS patients had frequent TP53 (33% vs 15%, p=.008) and RUNX1 mutation(10% vs 0%, p=.007)(Figure 2). AML transformation rates of t-MDS(29%) were similar to that of de novo MDS (20%, p=.313). t-MDS has shorter median survival at 24.8 months compared with de novo MDS at 60.1 months (p= .018) (HR 1.75 in OS for t-MDS, 95% CI 1.09-2.81, p=.020). 17 patients were diploid without mutation, which includes 5% of t-MDS patients and 17% of de novo MDS patients. Median survival was longer at 60.1 months in those patients without significance(p=.479). Multivariate models for OS selected t-MDS, TP53, TET2 and Age 70. IPSS-R risk group of very low and low, intermediate and high were not well separated(Figure 3a), especially in t-MDS patients(Figure 3b). However, simplified mode of IPSS-R into very low, low vs. intermediate, high vs. very high has good prediction of survival including t-MDS and de novo MDS(Figure 3c). Patients with TP53 mutation had worse survival and TET2 mutation had better survival distinctively, compared to patients without those mutations(Figure 3d).Conclusion : Hypocellular MDS patients did not have survival difference compared to rest of MDS patients. These patients present with lower blood counts, and more frequently having t-MDS. t-MDS patients with hypocellularity tend to have high risk mutations of TP53 and RUNX1. IPSS-R does not stratify well to either hypocellular or t-MDS with hypocellularity patients. Risk stratification model with integration of molecular characteristics will be a study of interest. [Display omitted] DisclosuresKadia: Astellas: Other; AstraZeneca: Other; Genfleet: Other; Ascentage: Other; Cellonkos: Other; Sanofi-Aventis: Consultancy; Pulmotech: Other; Pfizer: Consultancy, Other; Novartis: Consultancy; Liberum: Consultancy; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Alvarado: FibroGen: Research Funding; Sun Pharma: Consultancy, Research Funding; Jazz Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; CytomX Therapeutics: Consultancy; BerGenBio: Research Funding; Astex Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Kantarjian: Novartis: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; Ascentage: Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Astellas Health: Honoraria; KAHR Medical Ltd: Honoraria; Amgen: Honoraria, Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria; Astra Zeneca: Honoraria; NOVA Research: Honoraria; Taiho Pharmaceutical Canada: Honoraria; Daiichi-Sankyo: Research Funding.

Plasma Lipidome Acts As Diagnostic Marker and Predictor for Cyclosporin Response in Patients with Aplastic Anemia

Background：The lipid metabolomic profile has been well defined in the pathogenesis and differential diagnosis in patients with different myeloid diseases. However, the role of plasma lipidome was rarely explored, especially in aplastic anemia (AA), a disease which has close connection with lipid metabolism.Methods: Peripheral fasting serum levels of patients newly diagnosed with AA from March 2019 to December 2019 were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the serum lipid profiles. Meanwhile, the lipidomes for patients with hypocellular myelodysplastic syndrome (h-MDS) and age and sex matched healthy volunteers were taken as controls. The lipid profiles were tested again 6 months after standard cyclosporin A（CsA）treatment in patients with AA. For all the patients, those with a history of hyperlipidemia, diabetes, obesity (body mass index > 28 kg/m 2) or complications with other malignant diseases at diagnosis were excluded.Results: The study enrolled 15 patients with AA, 11 patients with h-MDS and 20 healthy controls. All the enrolled AA patients were non-severe and transfusion dependent, and were treated with CsA 3-5mg/kg/d for at least 6 months. For h-MDS patients, five were MDS with single lineage dysplasia, three were MDS with multilineage dysplasia, and three were MDS-Excess Blasts 1 (MDS-RAEB1). Metabolites in arachidonic acid pathway and retinol metabolism were significantly decreased in the AA patients compared with the healthy controls (P<0.05). AA patients had decreased arachidonic acid pathway metabolites and retinol metabolism-related metabolites as compared with h-MDS（P<0.05), whereas h-MDS patients had increased metabolism of proline and threonine and abnormal sphingolipid metabolism compared with AA patients and the normal controls. After 6-month of CsA treatment, leukotriene B4, 15(S)-HETE, all-trans-retinal and protectin D1 decreased significantly. Patients who had response to CsA had higher levels of baseline protectin D1 (p=0.011), leukotriene B4 (p=0.011), 15(S)-HETE (p=0.004) and all-trans-retinal (p=0.000) than those who had no response.Conclusion: The lipid profiles showed significant difference not only between patients with AA and healthy controls, but also between AA and h-MDS. Meanwhile, some of baseline value and the change in lipid molecules may predict the CsA response at 6 months. DisclosuresNo relevant conflicts of interest to declare.

Anti Thymocyte Globulin-Based Treatment for Acquired Bone Marrow Failure in Adults.

Idiopathic acquired aplastic anemia can be successfully treated with Anti Thymocyte Globulin (ATG)-based immune suppressive therapy and is therefore considered a T cell-mediated auto immune disease. Based on this finding, several other forms of idiopathic acquired bone marrow failure are treated with ATG as well. For this review, we extensively searched the present literature for evidence that ATG can lead to enduring remissions in different forms of acquired multi- or single-lineage bone marrow failure. We conclude that ATG-based therapy can lead to an enduring hematopoietic response and increased overall survival (OS) in patients with acquired aplastic aplasia. In patients with hypocellular myelodysplastic syndrome, ATG can lead to a hematological improvement without changing the OS. ATG seems less effective in acquired single-lineage failure diseases like Pure Red Cell Aplasia, Amegakaryocytic Thrombocytopenia and Pure White Cell Aplasia, suggesting a different pathogenesis in these bone marrow failure states compared to aplastic anemia. T cell depletion is hypothesized to play an important role in the beneficial effect of ATG but, as ATG is a mixture of polyclonal antibodies binding to different antigens, other anti-inflammatory or immunomodulatory effects could play a role as well.

O19 - Topic: AS04-MDS Biology and Pathogenesis/AS04h-Immune deregulation: A MULTI-CENTER EXPERIENCE OF HYPOCELLULAR MYELODYSPLASTIC SYNDROMES (H-MDS): FROM CLINICAL DESCRIPTION TO IMMUNOLOGICAL CHARACTERIZATION

O19 - Topic: AS04-MDS Biology and Pathogenesis/AS04h-Immune deregulation: A MULTI-CENTER EXPERIENCE OF HYPOCELLULAR MYELODYSPLASTIC SYNDROMES (H-MDS): FROM CLINICAL DESCRIPTION TO IMMUNOLOGICAL CHARACTERIZATION

Immunoexpression of CD34, CD117, and p53 in Hypocellular Bone Marrow Disorders.

Objectives Hypocellular bone marrow (BM) disorders comprise heterogeneous entities associated with peripheral cytopenias and decreased production of hematopoietic cells in BM. This study was undertaken to analyze immunohistochemical expression of CD34, CD117, and p53 in morphologically diagnosed patients of hypocellular BM (aplastic anemia [AA], hypocellular myelodysplastic syndrome [h-MDS], and hypocellular acute myeloid leukemia [h-AML]). Materials and Methods BM specimens were obtained from patients presenting with pancytopenia/bicytopenia. On 30 patients diagnosed as hypocellular BM, immunohistochemistry (IHC) for CD34, CD117, and p53 was performed. Results BM cellularity was < 30% in all (100%) patients. Blast count was increased in h-MDS and h-AML. Features of dysplasia were noted in six (20%) patients. Out of these, three patients were diagnosed as h-MDS having bilineage/trilineage dysplasia, and the other three patients were of AA (11.5% patients) displaying only dyserythropoiesis. On IHC, percentage of BM CD34+ cells was increased in h-MDS+ h-AML (3.87 ± 0.86) as compared with AA (0.19 ± 0.15) and controls (0.81 ± 0.21), p = 0.01. Percentage of BM p53+ cells was also increased in h-MDS+ h-AML (2.9 ± 2.07) as compared with AA and controls, which did not show any p53+ cells, p = 0.0. No statistically significant difference was observed in the expression of CD117 in h-MDS+ h-AML (4.95 ± 3.40) compared with AA (4.49 ± 1.07), p = 0.99. Conclusion The study demonstrates the usefulness of CD34 and p53 immunoexpression as an important ancillary method in distinguishing various hypocellular BM disorders, especially h-MDS and AA. However, the role of CD117 remains unclear and needs to be evaluated further by larger studies.

Prognostic Factors and Response to the Hypomethylating Agents in Hypocellular Myelodysplastic Syndromes: A Retrospective Study from the Korean Society of Hematology AML/MDS Working Party

Introduction: Hypocellular myelodysplastic syndrome (h-MDS) comprised approximately 10-20% of total MDS cases. The difference in clinical features and prognosis between h-MDS and normo/hypercellular MDS (NH-MDS) remains uncertain and the treatment strategy of h-MDS patients has not been well-defined in epigenetic therapy era. Therefore, we conducted this study to define the prognostic factors and response to the hypomethylating agents (HMA) for Korean h-MDS patients.Methods: We collected clinical and laboratory data from web-based Korean MDS registry (www.mdsregistry.or.kr). A total of 1976 evaluable MDS patients, who were diagnosed between the years 1993 and 2014, form 23 Korean hospitals were registered in Korean MDS Registry. Hypocellularity was defined as less than 30% of cellularity in patients <70 years, and <20% in patients 70 years or older in the bone marrow biopsy specimens.Results: We identified 358 (18.1%) h-MDS patients among 1976 evaluable MDS patients. Gender, performance status, Hemoglobin, platelet counts, prior transfusion and bone marrow blast percentage did not differ between h-MDS and NH-MDS patients. However, h-MDS patients were younger (median 59.8 years vs 63.4 years, p=0.002), more neutropenic (median ANC 0.9x109/L vs. 1.14x109/L, p=0.000), with lower level of LDH (median 357 unit/L vs. 386 unit/L, p=0.041).There was no difference in overall survival (OS) between the h-MDS and the NH-MDS patients (110.9 months vs. 71.8 months, P=0.174) and 9% of h-MDS patients and 15.1% NH-MDS patients transformed to acute leukemia (p=0.075).The IPSS and IPSS-R were able to identify different risk groups within each group and were not significantly different between the groups. Based on IPSS-R, the overall survival for h-MDS patients were very low, low, intermediate, high and very high in 115.4, 110.9, Not reached, 30.5 and 29.8 months, respectively. The IPSS-R was a lesser ability to predict OS for h-MDS patients. Of the 358 h-MDS patients, 141 h-MDS patients were treated with HMA (60.3% azacitidine and 39.7% decitabine). The median OS after the treatment of HMA was 31.4 months and 32 months for h-MDS and NH-MDS patients (p=0.909) and leukemic transformation rate at 3 years was 24.1% and 27.6%, respectively (p=0.224).At univariate analysis to define prognostic factors in h-MDS, the factors associated with a poor overall survival were age (≥70), poor performance status, low albumin (<4.0g/dL), anemia (<10g/dL), neutropenia (<0.8x109/L), prior transfusion and high LDH (≥600IU/L). Using the Cox proportional hazard regression model, older age, neutropenia, low albumin and prior transfusion were independent prognostic indicators. Based on those independent factors, h-MDS patients were divided into 3 risk groups and it discriminated 3 discreet groups with distinct survival rates (median OS, 150.2 vs. 46.9 vs.21.5 months, p<0.0001).Conclusions: h-MDS had similar clinical features and survival compared to NH-MDS and response to HMA treatment was not different. However, IPSS-R was less powerful in detecting difference for h-MDS and h-MDS patients had a different pattern from those of NH-MDS regarding prognostic factors. Further study and validation are warranted to stratify the risk of h-MDS patients. DisclosuresNo relevant conflicts of interest to declare.

British Society for Haematology guidelines for the diagnosis and evaluation of prognosis of Adult Myelodysplastic Syndromes.

British Society for Haematology guidelines for the diagnosis and evaluation of prognosis of Adult Myelodysplastic Syndromes.