Adult Myelodysplastic Syndrome Patients Research Articles

Early transfusion patterns improve the Molecular International Prognostic Scoring System (IPSS-M) prediction in myelodysplastic syndromes.

The Molecular International Prognostic Scoring System (IPSS-M) is the new gold standard for diagnostic outcome prediction in patients with myelodysplastic syndromes (MDS). This study was designed to assess the additive prognostic impact of dynamic transfusion parameters during early follow-up. We retrieved complete transfusion data from 677 adult Swedish MDS patients included in the IPSS-M cohort. Time-dependent erythrocyte transfusion dependency (E-TD) was added to IPSS-M features and analyzed regarding overall survival and leukemic transformation (acute myeloid leukemia). A multistate Markov model was applied to assess the prognostic value of early changes in transfusion patterns. Specific clinical and genetic features were predicted for diagnostic and time-dependent transfusion patterns. Importantly, transfusion state both at diagnosis and within the first year strongly predicts outcomes in both lower (LR) and higher-risk (HR) MDSs. In multivariable analysis, 8-month landmark E-TD predicted shorter survival independently of IPSS-M (p<0.001). A predictive model based on IPSS-M and 8-month landmark E-TD performed significantly better than a model including only IPSS-M. Similar trends were observed in an independent validation cohort (n=218). Early transfusion patterns impacted both future transfusion requirements and outcomes in a multistate Markov model. The transfusion requirement is a robust and available clinical parameter incorporating the effects of first-line management. In MDS, it provides dynamic risk information independently of diagnostic IPSS-M and, in particular, clinical guidance to LR MDS patients eligible for potentially curative therapeutic intervention.

Red Blood Cell Transfusion Dependence Is Associated with Greater Healthcare Resource Utilization, Higher Medical Cost, and Poorer Prognosis in Patients with Lower-Risk Myelodysplastic Syndromes: A 28-Year Retrospective Observation Study Result

Myelodysplastic syndromes (MDS) encompass a heterogeneous group of myeloid neoplasms characterized by cytopenia due to inefficient hematopoiesis, with a considerable risk of progression to acute myeloid leukemia (AML) or early mortality. In lower-risk MDS (LR-MDS) patients, anemia and its associated complications have been the focus of clinical attention. A significant portion of these patients eventually develop red blood cell transfusion dependence (RBC TD), which has been linked to a poorer prognosis. Given the limited efficacy of available treatments in reducing RBC TD, most patients face increased risks of chronic anemia and various complications. Moreover, RBC TD is known to be associated with reduced overall survival (OS) and leukemia-free survival (LFS). This study aimed to assess the impact of RBC TD on the socioeconomic burden and clinical prognosis of LR-MDS patients, utilizing an electronic medical records (EMR) database spanning nearly 30 years of MDS patient data. This retrospective observational study examined adult MDS patients (≥ 18 years of age) treated at Samsung Medical Center in the Republic of Korea. Eligible patients were diagnosed with MDS between Sep 1, 1994, to Apr 1, 2022 (index period), with the observation period spanning from Sep 1, 1994, to Sep 1, 2022. Baseline assessments included estimation of revised international prognostic scoring system (IPSS-R) scores, categorizing patients with very low, low or intermediate risks as lower-risk MDS (LR-MDS). TD was defined as the occurrence of any 16-week period with RBC transfusion of ≥ 2 units per 8 weeks, without consecutive 56-day period without transfusion. Healthcare resource utilization (HCRU), medical costs, and prognosis indicators including overall survival (OS) and AML-free survival (AFS) were analyzed and compared between patients who experiencing TD and those not (non-TD). Out of 831 MDS patients, 349 (42.0%) were classified as lower-risk at baseline. Among LR-MDS patients, 29.5% (103/349) experienced TD while 23.3% (194/831) experienced TD in the entire study population. The median age at diagnosis of MDS was 63 (ranging from 18 to 89), and 65.3% (543/831) were male. In LR-MDS patients, there were no significant differences in either baseline age (61 vs 63, P=0.16) or gender (71.8% vs 61.0% males, P=0.053) between TD and non-TD groups. However, TD group exhibited significantly higher median erythropoietin (EPO) level than non-TD group (290.5U/L vs. 112U/L, P&amp;lt;0.001) among LR-MDS patients with available baseline serum EPO levels (76 TD and 178 non-TD). Among the 76 TD LR-MDS patients with baseline serum EPO levels, 51 (67.1%) exhibited &amp;gt; 200U/L, which is considered a clinical threshold for erythropoiesis-stimulating agent (ESA) treatment. As shown in Table 1, RBC TD was consistently associated with greater HCRU and higher medical costs, especially in LR-MDS patients. TD LR-MDS patients had higher rates of outpatient department and emergency room visits (15676 vs. 8303 visits and 587 vs. 328 visits per 1000 person-years [PY], respectively), and increased hospitalizations (709 vs. 456 per 1000 PY), with longer hospital stays (13343 vs. 8272 days per 1000 PY). Furthermore, TD LR-MDS patients required over four-times of packed RBC units than non-TD patients (31107 vs. 7073 units per 1000 PY). Consequently, TD LR-MDS patients incurred higher total medical cost than their non-TD counterpart (13.5 million vs. 6.1 million USD per 1000 PY). Median OS (58.4 months vs. 103.1 months) and AFS (52.7 months vs. 102.7 months) were both significantly shorter in the TD group compared to the non-TD group among LR-MDS patients, while the differences in OS and AFS did not reach the level of significance in the entire study population (Table 1 and Figure 1). Notably, median OS after the first documented RBC TD event was 33.8 months (95% confidence interval: 24.7-58.5 months) in LR-MDS patients. The findings of this study indicate that RBC TD can be a strong predictor of increased HCRU and medical costs, as well as decreased OS and AFS over a 20-year period following the initial diagnosis of LR-MDS. Given that a majority of LR-MDS patients experiencing TD may not be eligible for ESA treatment due to elevated EPO levels exceeding 200U/L, and the use of cytotoxic agents is not usually recommended for these patients, these results highlight a substantial unmet need for alternative treatment options to address RBC TD in LR-MDS patients.

Incidence of cardiac events in patients with MDS or AML receiving azacitidine or decitabine within a large community health system.

e19074 Background: Hypomethylating agents (HMA) such as decitabine and azacitidine are frontline therapies for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Limited data exist on subsequent cardiovascular (CV) events. Johnson et al. reported 170 patients receiving HMA + venetoclax with a CV event rate of 20%. Aims: To investigate the incidence of CV events in patients receiving HMA. Methods: We analyzed adult AML and MDS patients with &gt; 1 dose of azacitidine or decitabine from 1/2018-12/2020. New CV events were defined as new atrial fibrillation, acute coronary syndrome, cardiomyopathy, congestive heart failure, myocarditis, or pericarditis. Competing risks regression identified baseline predictors associated with time to first CV event while accounting for the competing event of death. Results: 94 patients with no CV history were evaluated which consisted of a mean age 69 +/- 12 years and 50% male. 56% had MDS and 44% AML. Patients with BMI ≥ 30 accounted for 38.3% of the sample. 44 (47%) patients had baseline echocardiogram assessments prior to initiation of HMA with EF of 61+/- 8%; 57 (61%) had a documented prescription of beta-blocker, ACE-I, or ARB at time of HMA initiation. In the 94 patients, 16 new cardiac events occurred. Median survival after therapy initiation was 14.8 months. In a competing risks univariate analysis, lower prior EF (after adjusting for no EF performed) and absence of pre-chemotherapy beta-blocker, ACE-I, or ARB were significantly associated with having a new cardiac event post chemotherapy start (hazard ratio per 5-unit decrease = 1.62 (1.33-1.99), p&lt;0.01 and HR=2.89 (1.08-7.77), p=0.03, respectively). Baseline BMI did not affect risk of a new CV event on HMA therapy (HR per 5 units=1.08 (0.78-1.50), p=0.63). Total HMA dose did not show significance as a predictor for CV events (HR=0.99 (0.987-1.009), p=0.72). Conclusions: We observed a CV event incidence of 19% at 3 years after the start of HMAs. Among patients receiving HMA chemotherapy, those with a lower baseline EF and those not on beta-blocker, ACE-I or ARB therapy prior to initiation of HMA had a higher incidence of cardiotoxicity. Neither pre-HMA BMI nor total HMA dose received appeared to predict risk for CV events. Further research is warranted evaluating the association between HMAs and cardiotoxicity. [Table: see text]

Is Klotho Gene a Biomarker to Pathogenesis of Myelodysplastic Syndrome in Elderly Patient? A New Hypothesis

An important new biomarker for cancer is the Klotho, an anti-aging target, associated to proliferation and apoptosis of tumor cells. In this study, we hypothesized that the Myelodysplastic syndrome (MDS) pathogenesis, an elderly hematopoietic disease, can be affect by block of the Klotho expression, increasing ROS production in the medullary microenvironment, attenuating the DNA damage in HSCs, and leading to reduced count of blood cell precursors, characterizing the cytopenic profile of MDS patient. The absence or negative regulation of Klotho may be a poor prognostic marker of MDS, especially when patients are stratified by age. We believed that younger adult MDS patients show a higher Klotho expression while compared to old adults MDS patients, demonstrating that its expression is decreased with increasing age, representing a more aggressive disease. To confirm this hypothesis, an extensive clinical case-control study can be performed on bone marrow cell samples of MDS patients to show differential expression of Klotho gene and protein, and as this target can be modulate in this disease (based on promoter region methylation analysis). These approaches may define the Klotho as a new pathologic marker to MDS in elderly and improve future potential therapies.

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.

MDS-Associated Splicing Factor Mutations Promote Alternative Splicing of a Differentiation-Impaired CSF3R Isoform

▪Background. Myelodysplastic syndromes (MDS) constitute the most common group of bone marrow failure disorders, characterized by ineffective hematopoiesis and a significant risk of transformation to AML. Efforts to understand the molecular basis of MDS led to the identification of acquired somatic mutations in the RNA splicing factors SF3B1, U2AF1, SRSF2, ZRSR2, and LUC7L2 in 45-85% of adult MDS patients. How they perturb hematopoiesis and promote expansion of abnormal clones remain unknown. Elevated levels of alternate isoforms of granulocyte colony stimulating factor receptor (CSF3R) patients with MDS and other myeloid neoplasias have been reported with a strong correlation reported with loss of chromosome 7. Constitutive splicing produces the canonical Class I CSF3R isoform that supports proliferation and differentiation. Alternative splicing promoting intron excision in CSF3R exon 17 results in a differentiation-defective Class IV CSF3R isoform. We hypothesized that aberrant splicing activity of MDS-associated splicing factor mutations promote Class IV CSF3R expression, resulting in dysgranulopoiesis. Methods. We constructed a CSF3R minigene that was transiently expressed in K562 cells along with eukaryotic expression vectors containing cDNAs for wild-type or mutant forms of SF3B1, U2AF1, or SRSF2. To determine role of LUC7L2, a splicing factor residing on chromosome 7, the CSF3R minigene was transiently expressed in K562 cells with knockout LUC7L2. Class IV or Class I was measure by qPCR using specific primers. Putative exonic splicing enhancer motifs (ESEs) within exon 17 were deleted in the minigene and transfected into K562 cells expressing either wildtype or mutant SRSF2. To determine impact of mutant SRSF2 on granulopoiesis, wildtype or mutant SRSF2 were overexpressed in GCSF-treated CD34+ cells and morphology was assessed on day 14. To determine impact of Class IV isoform on granulopoiesis, Lin-, Sca-1+, and c-Kit+ (LSK) cells from Csf3r null mice were transduced with Class I or Class IV and colony forming unit (CFU) assay for granulopoiesis was performed with Methocult 3534. Colony scores and cell morphology were assessed on day 8.Results. K562 cells with transient expression of mutant SRSF2 P95H and LUC7L2 knockout resulted in statistically significant increase in Class IV:I CSF3R mRNA ratios normalized to a minigene-only control. Interestingly, expression of mutant U2AF1 S34F significantly decreased Class IV:I while U2AF1 Q157P increased Class IV:I ratios. K562 cells expressing mutant SF3B1 K700E did not show significant differences in Class IV splicing. To further investigate how SRSF2 regulates CSF3R splicing, we deleted two putative SRSF2-binding ESE motifs (ESE1 and ESE2) within exon 17 of the CSF3R minigene and transfected them into K562 cells stably expressing either wildtype SRSF2 or mutant P95H, P95L, or P95R. Deletion of either ESE1 or ESE2 resulted in decreased Class IV:I in all SRSF2 P95 mutant cells compared to minigene-only and wildtype controls. Next, we assessed the effect of SRSF2 P95 mutations on neutrophil differentiation in CD34+ cells. Overexpression of SRSF2 P95H, P95L, or P95R led to increased neutrophilic precursors compared to untransduced CD34+ cells. To determine the effect of a single CSF3R isoform on granulopoiesis, we cultured LSK cells from Csf3r null mice transduced with either Class I or Class IV on MethoCult 3534 with addition of GCSF. On day 8, cells expressing Class I had more total colony numbers with significantly higher CFU-GM colonies than cells expressing Class IV compared to empty vector control.Conclusions. We demonstrated that mutated SRSF2, U2AF1, and LUC7L2 deficiency alters CSF3R splicing in its terminal exon. Interestingly, mutations on different residues of the same gene (U2AF1) had opposing effects on CSF3R splicing. Mutant SRSF2 resulted in increased intron excision to promote increased levels of Class IV isoform. Mutation of two putative SRSF2 binding sites within CSF3R exon 17 reversed the increased splicing promoted by mutant SRSF2, further support our observation that CSF3R is a target for mutant SRSF2. Our observation with overexpression of mutant SRSF2 P95 in CD34+ cells suggests that defective neutrophil differentiation is related to increased Class IV. Our findings shed insights into how aberrant splicing of CSF3R drives MDS progression and provides a new model of dysgranulopoiesis. DisclosuresNo relevant conflicts of interest to declare.

CD123-Directed Bispecific Antibodies for Targeting MDS Clones and Immunosuppressive Myeloid-Derived Suppressor Cells (MDSC) in High-Risk Adult MDS Patients.

There is an urgent need to identify effective strategies to prevent leukemic transformation and induce sustained deep remissions in adult high-risk myelodysplastic syndrome (MDS) patients. This article discusses the clinical impact potential of bispecific antibodies (BiAB) capable of redirecting host T-cell cytotoxicity in an MHC-independent manner to malignant clones as well as immunosuppressive myeloid-derived suppressor cells (MDSC) as a new class of anti-MDS drug candidates. T-cell engaging BiAB targeting the CD123 antigen may help delay disease progression in high-risk adult MDS and potentially reduce the risk of transformation to secondary AML.

Fludarabine/busulfan versus busulfan/cyclophosphamide as myeloablative conditioning for myelodysplastic syndrome: a propensity score-matched analysis.

Myeloablative conditioning with fludarabine/busulfan (Flu/Bu4) prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) is effective for acute myeloid leukemia. However, the effectiveness of Flu/Bu4 for myelodysplastic syndrome (MDS) remains poorly understood. Therefore, we retrospectively analyzed nationwide registry data in Japan from 2006 to 2018 and compared transplant outcomes of adult MDS patients receiving Flu/Bu4 and busulfan/cyclophosphamide (Bu4/Cy) using propensity score (PS) matching. The primary endpoint was overall survival (OS). Among 2,482 MDS patients, 153 patients were assigned each to the Flu/Bu4 and Bu4/Cy groups. The 3-year OS rates were 52.7% (95% confidence interval [CI], 43.8-60.8%) and 49.5% (95% CI, 40.8-57.6%) in the Flu/Bu4 and Bu4/Cy group, respectively (P = 0.548). The 3-year progression-free survival (P = 0.858), the cumulative incidence of relapse (P = 0.536), and cumulative incidence of non-relapse mortality (P = 0.684) were not significantly different between the two groups. According to the findings of subgroup analyses, no patient had a favorable OS when using either of the two regimens. In conclusion, although our PS-matched cohort mainly comprised older patients who had a low hematopoietic cell transplantation-comorbidity index and low-risk disease status, Flu/Bu4 could be an alternative to Bu4/Cy for MDS patients prior to allo-HSCT.

Red Cell Alloimmunisation Is Associated with Development of Autoantibodies and Increased Red Cell Transfusion Requirements in Myelodysplastic Syndromes (MDS)

Introduction: Up to 90% of MDS patients require red blood cell (RBC) transfusions and 30-45% become RBC transfusion dependent (RBC-TD). However, literature addressing RBC alloimmunisation in MDS is limited. This study evaluates the incidence and clinical impact of RBC alloimmunisation in 817 adult MDS (or related disorders) patients enrolled in the South Australian-MDS registry.Methods: Demographic, clinical, laboratory and treatment (including transfusions) details of patients with at least 6-month follow up were analysed. RBC-TD was defined as >1unit of RBC transfusion every 8 weeks over a period of 4 months. Azacitidine, intensive chemotherapy or allogeneic stem cell transplantation were denoted as disease modifying therapies (DMT).Results: Median age at diagnosis was 73 years and 66% were male. During the study, 695 (85%) patients received >1 RBC unit, and 98 developed 175 alloantibodies. Of these, 11 patients developed alloantibodies following MDS-unrelated RBC transfusion well before the MDS diagnosis, and seven developed antibodies before their first documented RBC transfusion. Remaining 80 patients developed alloantibodies following MDS-related RBC transfusion. The cumulative incidence of RBC alloimmunisation with death as competing risk was 11% at 50 months following the first MDS-related RBC transfusion (Fig. 1A). Importantly, 73% and 50% of allo-immunised patients developed alloantibodies during first 20 RBC transfusions and within 6 months of commencement of RBC transfusion, respectively. Of the 98 allo-immunised patients, 50 (51%) developed one alloantibody, while 48 (49%) developed multiple alloantibodies. Rh (93/175; 54%) and Kell (41; 24%) alloantibodies were most frequent followed by Kidd (13, 7.5%) and Lutheran (10, 5.7%). Within Rh system anti-E, anti-C and anti-D were the most frequent.Autoantibodies were detected in significantly more alloimmunised than in non-alloimmunised patients (65% vs. 18%, p<0.0001; Fig 1B) and >85% autoantibodies occurred within 5 months of alloimmunisation. Though 73% of alloimmunised patients developed alloantibody during their first 20 RBC units, total RBC units transfused were significantly higher in alloimmunised compared to non-alloimmunised patients (90±100 vs. 30±52; p<0.0001) (Fig. 1C). In alloimmunised patients, total RBC transfused after alloimmunisation were significantly higher than before alloimmunisation (p<0.0001, Fig. 1D). In MDS patients, multiple other factors such as disease progression, infection, bleeding and treatment can influence RBC-transfusion intensity. Hence, we evaluated RBC-transfusion intensity in 33 patients meeting strict inclusion criteria (Fig. 2A). In these patients, RBC-transfusion intensity substantially increased after alloimmunisation (p=0.002; Fig. 2B-C).We then evaluated risk factors for alloimmunisation using RSF and R-PART analysis. RBC units transfused before alloantibody formation was the most important predictor of alloimmunisation, followed by RBC-TD status, treatment type and age. A classification tree using RPART suggested that 46% patients who were RBC-TD developed an alloantibody within first 20 units of RBC transfused. Landmark analyses using CRR model both at baseline (using age, sex, WHO subtype, IPSS-R risk groups and type of treatment) and at six months (baseline factors plus number of RBCs transfused within 6 months and RBC-TD status at 6 months) following the start of RBC transfusions were performed. At both time-points, alloimmunisation risk was significantly lower in DMT treated patients (HR -3.04; p=0.0023) and appears unrelated to number of RBC transfusions as patients managed with DMT received significantly more RBC units than patients treated with supportive care (p<0.0001).Conclusion: This study characterises alloimmunisation in a large statewide cohort of MDS patients and demonstrates a significant increase in RBC transfusion requirements following alloimmunisation, most probably due to development of additional alloantibodies and autoantibodies, resulting in subclinical/clinical haemolysis. Use of DMT is associated with lower alloimmunisation risk. Strategies mitigating alloimmunisation risk are critical for optimising RBC-transfusion management. [Display omitted] 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.

Evaluation of Reduced-Dose Decitabine and Azacitidine for Treating Myelodysplastic Syndromes: A Retrospective Study

BackgroundHypomethylating agents (HMA) are considered the first-line therapy for high-risk myelodysplastic syndromes (MDS). However, as the efficacy and safety of rational dosing regimens are lacking, we evaluated the effectiveness and safety of reduced-dose azacitidine (AZA) vs. decitabine (DAC) in adult MDS patients.Material/MethodsThis retrospective study was conducted at the Institute of Hematology & Blood Diseases Hospital, for hospitalized MDS patients diagnosed (WHO 2008 classification criteria) from May 2006 to February 2020. These AZA- and DCA-naive patients treated with AZA 100 mg/(m2·day) for 5 days to 7 days or DAC 20 mg/(m2·day) for 3 days to 4 days, or 20 mg/(m2·day) 1 day/week for 3 weeks/month were assessed for treatment responses and adverse events.ResultsOf the 158 enrolled MDS patients, 120 and 38 patients were administered reduced-dose DAC and AZA, respectively. All the patients received a median of 2 treatment cycles. The overall response rates (ORR) were 50.0% and 73.3% in the AZA and DAC groups, respectively (P=0.007). The percentage of platelet transfusion dependence in the AZA group was lower than the DAC group (P=0.026). The multivariate analysis demonstrated that the DAC treatment was a significant factor for improved responses (OR 2.928; 95% CI 1.267–6.896; P=0.012), and the absolute neutrophil count (ANC) was a predictor of the ORR (OR 0.725; 95% CI 0.558–0.898; P=0.008). Neutropenia (P=0.016) and infection (P=0.032) incidences were higher in the DAC group.ConclusionsThe reduced-dose DAC group demonstrated a better response than the AZA group in MDS patients with different prognostic risks. The patients’ pre-treatment ANC was a significant factor associated with the ORR.

Reduced-Intensity Versus Myeloablative Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients with Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis of Randomized Clinical Trials & Cohort Studies

Background: Conditioning regimen given before allogeneic hematopoietic stem cell transplantation (allo-HSCT) contributes significantly to the outcomes following transplant for myelodysplastic syndrome (MDS). Myeloablative conditioning (MAC) regimens are often associated with a lower risk of relapse; however, their use is often limited by toxicity and a higher risk of non-relapse mortality (NRM). Reduced-intensity conditioning (RIC) regimens are associated with a higher risk of relapse, a lower NRM, a lower incidence of graft versus host disease (GVHD), and hence is feasible in patients with advanced age or comorbidities. This study highlights the importance of the difference between the two interventions used in allo-HSCT for myelodysplastic syndrome (MDS). Methods: We conducted a comprehensive literature search using PubMed, Clinicaltrial.gov, Embase, Cochrane, and Web of Science on 5th May 2020 with no restriction of language or period. Initial research revealed 1698 articles. After excluding review articles, duplicates, and non-relevant articles, we included two randomized clinical trials and three cohort studies, which reported overall survival (OS), relapse-free survival (RFS), relapse incidence (RI), and incidence of acute and chronic (GVHD). Based on inclusion criteria, two randomized clinical trials (BMT CTN 0901 Trial Scott et al. 2017 &amp; EBMT RICMAC Trial Kroger et al. 2017) and three cohort studies (BBMT 55226 Park et al. 2018, BBMT Orozco et al. 2019, BMT Alatrash et al. 2019) were included. Results: Among combined MDS and acute myeloid leukemia (AML) patients (n=1188) enrolled in 5 studies, 651 patients had MDS. Patients underwent MAC (n=484) or RIC (n=692) followed by either a matched related donor (MRD), n=236, or matched unrelated donor (MUD), n=236, allo-HCT. The median age range at the time of transplant was 50-54 years The use of RIC causes statistically non-significant trend of improved overall survival (OS) (OR 1.11: 95% CI: 0.74-1.67, p-value= 0.61) along with more risk of relapse incidence (RI) (R 1.34: 95% CI: 0.56-3.18, p value= 0.51), and reduced relapse free survival (RFS) (OR 0.88, 95% CI: 0.55-1.44: p value= 0.59). Differences were found in terms of safety of both conditioning regimens. MAC allo-HCT have more acute GVHD, grade 3 and 4 (OR 0.66: 95% CI: 0.29-1.52, p value= 0.33) and chronic GVHD, grade 3 and 4 (OR 0.72: 95% CI: 0.41-1.27: p value= 0.26) and treatment-related mortality (TRM) (OR 0.83, 95% CI: 0.37-1.86, p value= 0.65). The meta-analysis results are shown in figure-1. Conclusion: In adult MDS patients undergoing allo-HSCT, RIC is associated with improved overall survival, but at the cost of reduced RFS, and a higher risk of relapse. MAC, on the other hand, is associated with more treatment-related mortality and GVHD. Results of our analysis point out these trends but these are not statistically significant Figure 1 Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Guideline-based indicators for adult patients with myelodysplastic syndromes

Myelodysplastic syndromes (MDSs) represent a heterogeneous group of hematological stem cell disorders with an increasing burden on health care systems. Evidence-based MDS guidelines and recommendations (G/Rs) are published but do not necessarily translate into better quality of care if adherence is not maintained in daily clinical practice. Guideline-based indicators (GBIs) are measurable elements for the standardized assessment of quality of care and, thus far, have not been developed for adult MDS patients. To this end, we screened relevant G/Rs published between 1999 and 2018 and aggregated all available information as candidate GBIs into a formalized handbook as the basis for the subsequent consensus rating procedure. An international multidisciplinary expert panel group (EPG) of acknowledged MDS experts (n = 17), health professionals (n = 7), and patient advocates (n = 5) was appointed. The EPG feedback rates for the first and second round were 82% (23 of 28) and 96% (26 of 27), respectively. A final set of 29 GBIs for the 3 domains of diagnosis (n = 14), therapy (n = 8), and provider/infrastructural characteristics (n = 7) achieved the predefined agreement score for selection (>70%). We identified shortcomings in standardization of patient-reported outcomes, toxicity, and geriatric assessments that need to be optimized in the future. Our GBIs represent the first comprehensive consensus on measurable elements addressing best practice performance, outcomes, and structural resources. They can be used as a standardized instrument with the goal of assessing, comparing, and fostering good quality of care within clinical development cycles in the daily care of adult MDS patients.

I-Care for MDS: Development of Guidelines-Based Indicators for Appropriate Care in Adult Patients with Myelodysplastic Syndromes

I-Care for MDS: Development of Guidelines-Based Indicators for Appropriate Care in Adult Patients with Myelodysplastic Syndromes

PF550 AZACITIDINE (VIDAZA®) IN PEDIATRIC PATIENTS WITH RELAPSED ADVANCED MDS: RESULTS OF A PHASE I/II STUDY BY THE ITCC CONSORTIUM AND THE EWOG‐MDS GROUP: STUDY ITCC‐015

Background:Pediatric myelodysplastic syndromes (MDS) are a rare heterogenous group of clonal malignant diseases, characterized by ineffective hematopoiesis and subsequent development of AML. So far, stem cell transplantation (SCT) is the only curative treatment option which results in approximately 60% survival (Strahm et al, 2011). The demethylating agent azacitidine improves survival in adult MDS patients not fit for SCT and is approved for this indication. The safety and efficacy of azacitidine in pediatric MDS has not yet been established.Aims:To establish a recommended dose and preliminary efficacy of azacitidine in children with advanced primary relapsed MDS or juvenile myelomonocytic leukemia (JMML) in a pre‐transplantation window.Methods:An international, collaborative, prospective phase I/II trial (Dutch Trial registry 2578) was initiated and sponsored by Erasmus MC, Rotterdam, the Netherlands. Azacitidine was provided by Celgene. Key inclusion criteria were: age 1 month to 18 yrs; advanced primary relapsed MDS or JMML; life expectancy 3 months; and resolved toxicities from prior therapy. Both Azacitidine intravenous (iv) and subcutaneous (sc) were allowed, with a starting dose level (DL1) of 75 mg/m2 x 7 days in cycles of 28 days. It was aimed to prescribe at least 3 cycles prior to HSCT. Tumor response was evaluated after the 1st and subsequent courses with bilateral bone marrow aspirates and trephines, using central morphology review. The overall morphologic response rate (ORR) was defined as the number of patients with either complete response (CR) or partial response (PR). Adverse events were graded using CTCAE version 4.0. DLTs were limited to the 1st course. The two independent study‐arms followed a 2‐stage design taking treatment tolerability and response data into account. For the MDS arm the dose would be increased only if &lt;2/6 evaluable patients achieved a response (CR or PR), and/or there were £ 2 dose‐limiting toxicities (DLTs). Pharmacokinetic (PK) parameters of the 1st course were calculated from plasma concentration‐time profiles using non‐compartmental methods. The enrollment in the MDS arm of the study was closed on 28‐nov‐2018, the enrollment in the JMML arm is ongoing.Results:From 2013 to 2018, 9 pediatric patients were recruited: 6 MDS and 3 JMML. Three boys and 3 girls with MDS were recruited with a median age of 14.3 yrs. In total 17 cycles were administered, 14 iv and 3 sc. Median duration of treatment was three cycles (range 2–4). One patient experienced several DLTs: pulmonary hemosiderosis, splenomegaly, erytrocytosis and erythema nodosum, reported as SUSARs. Other grade 3 and 4 events consisted of febrile neutropenia, anemia, thrombocytopenia, elevation of ALT or bilirubin, anorexia and headache. After a median follow‐up of 14.2 months, the ORR was 0/6 patients: 4 stable disease and 2 progression. No patients were dose‐escalated to DL2. In 2 of 4 patients who received SCT graft‐versus‐host disease was reported. The 3‐year overall survival of transplanted patients was 75% (95% CI 42,6 – 100). Both non‐transplanted patients deceased. PK analyses (n = 9) showed drug exposure in line with results in adults. Median AUC0‐inf was 631 h∗ng/mL and Cmax was 2285 ng/mL (n = 6) after iv administration and 913 h∗ng/mL and 1430 ng/mL (n = 3) after s.c. administration. High interindividual variability was observed mainly caused by a single outlier.Summary/Conclusion:Despite the fact that azacitidine was in general well tolerated, the ORR in the MDS patients was not satisfactory. Recruitment in JMML is ongoing. The PK behavior of azacitidine was similar to adult PK.

Opposing Pathogenesis of Germline SAMD9/SAMD9L Variants in Adult Myelodysplastic Syndrome (MDS)

Familial myelodysplastic syndromes (MDS), leukemias, and bone marrow failure (BMF) syndromes, typically present in children and young adults. Such cases associate with germ line (GL) mutations in DDX41, RUNX1,ETV6, GATA2 and ANKRD26 and were recently designated by WHO to constitute a separate disease. Gain-of-function (GOF) GL mutations in SAMD9 and SAMD9L associate with familial pediatric myelodysplastic syndrome (MDS) cases that often have early onsets and -7/del(7q). It was not known if this was the case in sporadic adult MDS. With this question in mind, we compiled sequencing results on 799 adults with presumably acquired MDS and BMFs, and further enhanced these results through public WES data on 349 myeloid neoplasms. We also performed cell growth assays of exemplary SAMD9 and SAMD9L GL variants identified in adult MDS.We used Broad Institute's Genome Aggregation Database (gnomAD) as healthy controls (n = 138,632). After comparing ethnicities between gnomAD and our cohort, we matched healthy controls to patients by ethnicities. Defining rare variants as those present in <0.1% of ethnically-matched healthy controls, we found 26 rare SAMD9/SAMD9L GL variants in 3% (24/799) patients. Most were missense; 3 were truncating (nonsense or frameshift All variants were heterozygous except two patients with two variants. We further validated these data were validated in public WES databases. We identified 2% (7/349) of adult MDS patients in public database with GL SAMD9/SAMD9L variants. SAMD9/SAMD9L GL variants were located in the N-terminal significantly more in adult MDS than reported for pediatric MDS [SAMD9; 62% (8/13) vs. 17% (5/30), p=.044, SAMD9L; 62% (7/13) vs. 0% (0/30), p=.0026]. Compared to reported pediatric MDS patients, adult MDS patients had significantly less deletions of chromosome7/del(7q) [8% (2/24) vs. 69% (22/32), p=.0037] and more 5q deletions [33% (8/24) vs. 4% (1/24), p=.022].Conservative predictions for specific SAMD9 missense variants were made by using SAMD9 GL variants reported in previous papers or public databases of registered healthy donors, and comparing Area Under the Curve of 8 different prediction algorithms. It defined 11 missense variants as “pathogenic”. 57% (4/7) of the variants identified in public WES database were also likely pathogenic by our criteria. We evaluated the growth activity of these 11 unique pathogenic missense variants and 1 frameshift variant identified in a patient with -7. Compared to WT-SAMD9, Thr205Pro-SAMD9, Ile247Thr-SAMD9, and Leu574Pro-SAMD9 showed more proliferative cell growth, whereas, I268T-SAMD9 and D550V-SAMD9L had no significant differences compared to the WT. Compared to WT-SAMD9L, 6 variants (Glu220Gly, Leu1323fs, Cys228Tyr, Trp517Arg, Gly235Ser, and Trp333Cys), fused SAMD9L separately, also had higher proliferation rates than WT-SAMD9L. In total, 9 out of 13 variants (69%) cell growth was not suppressed compared to wild-type cells. Pediatric MDS variants showing less cell growth than the wild type cells suggests that they enhance the normal function of SAMD9/SAMD9L, which is to slow cell cycle progression. In this sense they are gain of function mutations (GOF). In contrast, the majority of variants identified in adult MDS were loss-of-function (LOF) mutations.Thus, given the different distribution of variants, lack of genetic reversion, and opposing functional results, we conclude that GL SAMD9/SAMD9L variants might have different consequences in familial childhood vs. adult disease. Sporadic adult MDS patients lacked early onset and genetic reversions following acquisition of -7/del(7q) or another mutations in cis characterized in pediatric MDS patients. SAMD9/SAMD9L variants could have two conflicting consequences; i) GOF mutations in pediatric patients that result in genetic reversion or MDS associated with aberrations of chromosome 7 with an early onset, or ii) LOF variants resulting in a late development of MDS due to haplo-insufficiency of SAMD9/SAMD9L. Our findings suggest that GL SAMD9/SAMD9L variants may be linked to the pathogenesis of a subset of adult sporadic MDS patients. DisclosuresSekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Ra Pharmaceuticals, Inc: Consultancy.

A Leukemic Stem Cell Signature-Based Scoring System for Predicting Prognosis in Myelodysplastic Syndrome Patients

Leukemic stem cells (LSCs) possess biological properties shared with normal hematopoietic stem cells. They are responsible for chemoresistance and relapse in acute myeloid leukemia (AML). Although myelodysplastic syndrome (MDS) has traditionally been regarded as a “hematopoietic stem cell disorder”, the clinical and biological impact of LSCs on MDS patients are not well defined. To address this question, we used the Affymetrix HTA 2.0 microarray platform to profile 16 out of the 17 recently reported stemness genes (one of them, the ARHGAP22 gene was not included in our array) in our 160 adult primary MDS patients. The diagnoses were based on the 2016 World Health Organization (WHO) classification. Patients with antecedent chemotherapy or hematologic malignancies were excluded. Forty-one (25.6%) patients had MDS with single lineage dysplasia (MDS-SLD), 20 (12.5%) had MDS with ring sideroblasts (MDS-RS), 31 (19.4%) had MDS with multilineage dysplasia (MDS-MLD), 32 (20%) had MDS with excess blasts-1 (MDS-EB1) and 36 (22.5%), MDS-EB2. The risk distribution of the cohort was very-high risk, 15.3%; high risk, 21.3%; intermediate risk, 24.7%; low risk 34.7%; and very-low risk 4% according to the revised international prognosis scoring system (IPSS-R). We identified 4 genes (LAPTM4B, NGFRAP1, NYNRIN, and EMP1) whose expression levels were significantly correlated with overall survival (OS). An LSC4 score (0.731 x LAPTM4B - 1.259 x NGFRAP1 + 0.304 x NYNRIN + 0.231 x EMP1) was constructed based on the weighted sums derived from Cox regression analysis. Higher LSC4 scores were associated with higher IPSS-R scores, complex cytogenetics, and higher incidences of mutations of RUNX1, ASXL1, TP53, SRSF2 and ZRSR2. High-score patients had significantly higher 3-year AML transformation rate (36.3% vs 11.3%, P<0.001), shorter leukemia-free survival (LFS, median, 33.6 months vs not reached, P< 0.001, Figure 1A), and shorter OS (median, 15.9 months vs 77.3 months, P<0.001, Figure 1B). In subgroup analysis, LSC4 score could also well stratify MDS patients with normal karyotype into different risk groups (p<0.001). The prognostic significance of LSC4 scores for LFS, AML transformation rate, and OS still remained valid in both IPSS-R lower-risk (very low, low, and intermediate risk) subgroup (Figures 2A and 2B) and higher-risk subgroup (high and very high risk). In multivariate analysis, higher LSC4 score was an independent adverse risk factor for OS, irrespective of age, IPSS-R, and mutation status of ASXL1, TP53, EZH2, SRSF2, and ZRSR2 (Table). We also well validated the prognostic significance of the LSC4 scores in an independent cohort of 30 MDS patients (Figures 3A and 3B). Interestingly, patients with higher LSC4 scores had a better OS if they received allogeneic transplantation than those who did not. It implied that transplantation might ameliorate the poor survival impact of high LSC4 scores. In conclusion, through comprehensive analysis, we have created a simple and powerful LSC4 scoring system, which serves as an independent prognostic factor for OS and LFS in MDS patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pretreatment Health-Related Quality of Life Profile According to the EORTC QLQ-C30 in Patients with Myelodysplastic Syndromes (MDS): Analysis on 443 Lower-Risk MDS Patients

Background:Understanding health-related quality of life (HRQOL) profile, including functional aspects and symptom burden, of yet untreated patients with myelodysplastic syndromes (MDS) is important to help clinicians to better identify subgroup of patients in need of special attention from the very beginning of therapy.Aims:The primary objective of this study was to investigate baseline (i.e., pretreatment) HRQOL profile of untreated patients with lower-risk MDS, examining differences by age, gender, risk score category and comorbidity. A secondary objective was to provide age and sex baseline reference HRQOL values, according to the EORTC QLQ-C30 questionnaire, to be used as benchmark comparisons in future MDS studies.Methods:This analysis is based on 443 newly diagnosed adult MDS patients with International Prognostic Scoring System (IPSS) risk score of low (46 %) or intermediate-1 (54%), enrolled in an international prospective cohort observational study. Median age was 75 years (range 32-94), with 261 men (59%) and 182 (41%) women. HRQOL was assessed by the EORTC QLQ-C30 questionnaire at study entry, before any treatment (except for transfusions). This well validated questionnaire consists of five functioning scales: physical, role, emotional, cognitive and social; three symptom scales: fatigue, nausea/ vomiting and pain; six single item scales: dyspnoea, sleep disturbance, appetite loss, constipation, diarrhea and financial impact; and the global health status/HRQOL scale. The items were scaled and scored using the recommended EORTC procedures. At the time of baseline HRQOL assessment, 111 (25%) patients had received at least one red blood cell transfusion. We used Wilcoxon-Mann-Whitney and Kruskal-Wallis tests for all comparisons. We used the false discovery rate approach to account for multiple testing, with a nominal α-level=0.05. In addition to statistical significance, clinically relevant HRQOL differences were also evaluated based on previously published criteria (Cocks K, et al, J Clin Oncol 29:89-96, 2011).Results:There were not statistically significant differences in any of the HRQOL scales measured by the EORTC QLQ-C30, by the specific IPSS risk category (i.e., low risk vs intermediate-1 risk score). Overall, women reported worse HRQOL scores than men, with clinically relevant differences for physical (Δ=-7.1, P=0.002), role (Δ=-9.9, P=0.002) and emotional functioning, (Δ=-10, P<0.001), nausea/vomiting (Δ=3.7, P<0.001), insomnia (Δ=7.6, P=0.011) and appetite loss (Δ=5.6, P=0.019). Younger patients also reported better outcomes than older patients and this was more evident in the Physical Functioning domain. Also, HRQOL profile varied substantially by number of comorbidities (zero, one, two or more). In general, there was a worsening HRQOL trend with the increase of comorbidities. However, HRQOL impairments were markedly larger in patients with at least two comorbidities, who showed both small and medium clinically relevant differences, when compared to patients with no comorbidities. The largest differences between patients with no comorbidity and those with two or more were found in the following HRQOL domains: Physical Functioning (Δ=-15.3, P<0.001), Fatigue (Δ=-11.9, P<0.001) and Global health status/QOL (Δ=10.0, P<0.001). Full baseline reference values by specific age group categories and sex, according to the EORTC QLQ-C30, are reported in Table 1.Conclusion:Pretreatment HRQOL profile in lower-risk MDS patients vary substantially by age group categories, sex and number of comorbidities, and these differences should be highly considered at the time of treatment start. As in MDS research, the EORTC QLQ-C30 is currently one of the most frequently used HRQOL measure, our baseline reference values provide benchmark data against which other MDS studies using this questionnaire may be compared. [Display omitted] DisclosuresEfficace:Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy; Orsenix: Consultancy; Incyte: Consultancy; TEVA: Research Funding; TEVA: Consultancy; Lundbeck: Research Funding; Amgen: Consultancy; AMGEN: Research Funding. Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Platzbecker:Celgene: Research Funding. Stauder:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Breccia:Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Voso:Celgene: Research Funding, Speakers Bureau. Santini:AbbVie: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy; Novartis: Honoraria. Lubbert:Teva: Other: Study drug; Celgene: Other: Travel Grant; Janssen: Honoraria, Research Funding. Cuneo:Gilead: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; Roche: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau.

Patient-reported distress in myelodysplastic syndromes and its relationship with clinical outcomes.

e21564 Background: The National Comprehensive Cancer Network (NCCN) defines distress as an unpleasant emotional experience associated with the psychosocial complications of cancer. Patients with myelodysplastic syndromes (MDS) are at risk for distress given the largely incurable nature of this hematopoietic malignancy and its symptom burden, yet associations with clinical outcomes are unknown. Methods: We retrospectively reviewed patient-reported distress from ambulatory adult MDS patients visiting a single tertiary care medical center from July 2013-Sept 2015. Demographic, diagnostic, treatment, and comorbidity information were abstracted from records along with the NCCN Distress Thermometer (DT) and Problem List (PL). Survival was analyzed using the Kaplan-Meier method and Cox proportional hazards regression, controlling for age and risk stratification at diagnosis (Low or Intermediate/High Risk by IPSS, IPSS-R, or WPSS), ever use of therapy (hypomethylating agents/lenalidomide/growth factors/transfusions/chelation), Charlson comorbidity score, ever-report of fatigue, and frequency of fatigue. Results: We abstracted 376 DT (median = 1, range = 0-10) from 606 visits and 110 patients (median = 2 DT/patient, range = 1-16). NCCN guidelines suggest DT &gt; = 4 should be evaluated for referral to specialty services to address unmet needs. Fifty-four patients (49%) had at least 1 DT &gt; = 4 and 20 (18%) had 2 or more DT &gt; = 4. Ninety-eight patients (89.1%) reported 1,379 problems during 23,613 person-days of follow-up (median = 4 problems/patient/visit, range = 1-23). The 5 most frequent were fatigue (181 times; 78 patients), pain (95 times; 46 patients), worry (80 times; 45 patients), sleep (78 times; 41 patients), and tingling hands/feet (68 times; 33 patients). After adjustment for risk stratification, a single-point increase on the DT was associated with an increased risk of death (HR = 1.18, 95% confidence interval: 1.01, 1.36). Conclusions: The distress burden is high inMDS, and patient-reported distress scores are associated with clinical outcomes after controlling for typical prognostic variables. Distress should be further studied as a marker of prognosis and of unmet needs in this population.

P53 Protein Expression Correlates with Adverse Outcome in Low-Risk Myelodysplastic Syndromes

BackgroundThe presence of diverse spectrum of mutations in myelodysplastic syndromes (MDS) has largely revolutionized the understanding of the disease. Although certain mutations have doubtful prognostic significance, the adverse impact of TP53 mutation is irrefutable in all publications. We and others have shown the strong correlation between presence of TP53 mutation and overexpression of p53 by immunohistochemistry (IHC). This evidence provides the rationale for the evaluation of p53 overexpression which is available in routine diagnostic workup, as a surrogate marker to predict TP53 mutations. Additionally, we predicted that the overexpression of p53 might be an independent prognosticator, even in the absence of TP53 mutations or RPS14 haploinsufficiency, in low risk MDS.In our study,we analyzed the p53 protein expression in a cohort of 277 'lower risk' MDS patients and compared the clinico-pathological features, overall survival and risk of progression and evolution to AML with respect to p53 IHC status.MethodsThis study enrolled 277 adult low risk MDS patients seen at King’s College Hospital between March 2009 and February 2016. All marrow samples were assessed for p53 expression (intensity and proportion of cells) and scored using a Modified Quick Score (MQS). MQS ≥2 was chosen to define p53-positive staining. The median follow-up was 18.7 months [95% confidence interval (CI), 16.5-21.0 months].ResultsAccording to WHO categories, the predominant group was RCMD (78%). Patients were either IPSS low (n=134, 48%) or int-1 (n=91, 33%). We included 52 (19%) pts for whom the IPSS category was not available, due to the lack or failed cytogenetic data, but these were low-risk WHO categories with no excess of blasts. IPSS-R categories were very low 103 (37%), low 77 (28%), intermediate 38 (14%) and high risk 7 (3%). Overall, 19 (7%) patients progressed to AML and 41 (15%) patients died of which 25 (61%) were disease-related deaths.Of the 277 patients, 148 (53%) showed p53 protein expression with MQS ≥ 2 and were considered "p53-positive" patients (p53+). The p53 stain intensity was negative in 125 (45%), weak in 84 (30%), moderate in 40 (14%) and strong in 28 (11%). Seventy six (28%) patients had >5% p53 staining cells.p53 expression correlated with a higher age at diagnosis (median age 64 vs. 60 years, p=0.01). lower haemoglobin levels (9.8 vs 11 g/dL, p=0.002), but a higher platelets count (139 vs 99 x109/L, p =.003) (Table 1). This significance persisted even on exclusion of patients with 5q- and MDS/MPN. P53+ did not correlate with any cytogenetic risk group or degree of fibrosis.Sequencing data was available in 121 patients with 63 harbouring somatic mutations. Among these patients, only 3 showed the TP53 gene mutation; all of them were classified as positive when assessed for p53 stain (MQS≥2), showing that the nuclear staining reflects underlying TP53 mutations in such cases. Additionally, presence of SF3B1 mutation correlated strongly with p53+ (p=0.02).Patients with p53+ had a significantly shorter OS compared with those with p53- (figure 1a) with 2yr and 4yr survival probability of 87% &68% vs 95% & 90% , respectively (p=0.03 ).Analysis of progression-free survival (progression to AML, cytogenetic evolution, increase of blasts or fibrosis) showed that patients with p53 expression had a significantly shorter PFS compared to patients without p53 expression (Figure 1b): 2yr & 4yr PFS 70% & 54% vs 85% &75% respectively, p=0.01). Multivariate analysis confirmed the independent prognostic value of p53 expression for PFS (p=0.013, HR 2.6, 95% CI 1.2-5.2).ConclusionIn conclusion, our study showed that p53 overexpression by IHC, represented as MQS cutoff ≥ 2, correlates with features of poor prognosis, such as more advanced age at diagnosis, lower haemoglobin levels and shorter overall survival, adversely impacting progression-free survival.p53 IHC in MDS patients may represent an important, easily available, cheap and applicable prognostic tool and it should be considered for auxiliary analysis when determining the therapeutic options for a patient. The p53+ predicts poor outcome, especially disease progression, independent of the TP53 mutation status, indicating an alternate yet undefined pathway for p53 overexpression. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.