Risk Myelodysplastic Syndromes Research Articles

What is the optimal time to initiate hypomethylating agents (HMAs) in higher risk myelodysplastic syndromes (MDSs)?

Hypomethylating agents (HMAs) are the standard of care for higher risk MDS (HR-MDS) patients. The current dogma is to begin HMA therapy in all HR-MDS patients at the time of initial diagnosis. We investigated the impact of the timing of HMA initiation among HR-MDS patients presenting with adequate blood counts to discern the possible benefit of early treatment based solely on disease risk. We identified 320 HR-MDS patients with adequate hematopoiesis who were treated with HMA. The complete response rates were 21%, 26%, 23%, and 7% respectively for patients treated within 30, 31–60, 61–90, and more than 90 days from time of diagnosis (p=.046). The median OS from the date of diagnosis was 641, 550, 979, and 806 days, respectively (p=.2). A delay in initiating HMA therapy in HR-MDS patients with adequate blood counts is not associated with worsened outcomes.

Clinical Characteristics and Prognosis of Elderly Patients with Medium and High risk Myelodysplastic Syndrome

To investigate the clinical characteristics and prognosis of patients with medium and high risk myelodysplastic syndrome (MDS). 97 MDS patients above the age of 60 treated in Nanfang Hospital, Southern Medical University from February 2011 to August 2020 were enrolled. The clinical characteristics and prognosis of the MDS patients with medium risk, high risk or very high risk based on IPSS-R category were retrospectively analyzed. According to the difference of treatment regimes, the patients were divided into the transplantation group, chemotherapy group and other treatment group, and the efficacy among the patients in the 3 groups were analyzed. MDS with excess blast (MDS-EB) in the elderly patients with medium and high risk MDS were the most common, 47.4% of the patients with abnormal chromosome karyotypes, and 23.7% with complex karyotypes (≥3). 97.3% of the patients showed at least one gene mutation, and TP53 mutations were detected in nearly 20% of the patients with medium and high risk. Multivariate analysis showed that IPSS-R category and treatment regimes were the factors affecting the prognosis of elderly patients with medium and high risk MDS. The median overall survival (OS) time of the patients in the 3 groups showed significant difference (P=0.012), and the median OS of the patients in the transplantation group was significantly longer than that in the chemotherapy group and other group (P=0.003,P=0.014,respectively), while there was no significant difference in median OS between chemotherapy group and other treatment group (P=0.685). Elderly MDS patients with medium and high risk can benefit from allogeneic hematopoietic stem cell transplantation, which will prolong their OS.

IMerge: A phase 3 study to evaluate imetelstat in transfusion-dependent subjects with IPSS low or intermediate-1 risk myelodysplastic syndromes that are relapsed/refractory to erythropoiesis-stimulating agent treatment.

TPS7056 Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients (pts) with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomeres and active telomerase, characteristics observed in MDS pts across all disease stages. IMerge (MDS3001) is a Phase 2/3 global study of imetelstat for TD pts with non-del(5q) LR MDS post ESA therapy. The results from Phase 2 part indicated that imetelstat achieved durable RBC transfusion independence (RBC-TI) and the most frequently reported adverse events were manageable and reversible grade ≥3 cytopenias. Among 38 pts with median follow-up of 24 months, 8-week, 24-week and 1-year TI rates were 42%, 32% and 29%, respectively; these responses were seen across different LR MDS subtypes. Median TI duration was 20 months and the longest TI was 2.7 years. A high and durable hematologic improvement-erythroid (HI-E) rate of 68% for a median duration of 21 months were also achieved. Reduction of variant allele frequency of mutations by imetelstat treatment was observed in some pts and correlated with clinical benefits (Platzbecker et al EHA 2020; Steensma et al JCO 2020). These results support the Phase 3 part of the trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 3 part of the study is open for enrollment to adult pts with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs placebo that will enroll approximately 170 pts and will be conducted at approximately 120 centers in North America, Europe, Asia and Middle East. Imetelstat is administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of HI-E, the amount and relative change in RBC transfusions, rate of CR or PR, overall survival, progression of MDS, pharmacokinetics, and quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. The study is currently recruiting pts. Clinical trial information: NCT02598661.

Using tissue microarray to detect inflammasome signaling components that contribute to the pathogenesis of myelodysplastic syndrome.

7044 Background: Myelodysplastic syndromes (MDS) are characterized by aberrant maturation, ineffective hematopoiesis, cytopenia, and progression to acute myeloid leukemia. MDS pathogenesis is multifactorial and potentially linked to constitutive innate immune stimulation converging upon the NLRP3 inflammasome to induce pyroptosis, a caspase-1 dependent cell death. Inflammasome assembly is initiated by both cell-extrinsic stimuli including S100A9, the TLR4 and CD33 ligand, and cell-intrinsic danger signals licensing caspase-1 which activates IL1b and beta-catenin resulting in cell death and cellular proliferation leading to maturation and differentiation blocks. Further, EYA2 has been suggested to be an inflammasome activator, whereas cPLA2 has been suggested to be an inhibitor. The purpose of this study is to determine whether immunohistochemistry (IHC) may be utilized to assess expression of inflammasome components. Methods: An IRB protocol was approved prior to initiating this study. We retrospectively identified 43 low risk MDS patients. A tissue microarray (TMA) was constructed utilizing MDS bone marrow biopsy samples (2-3 representative cores per sample). IL-1, S100A9, EYA2, cPLA2, beta-catenin, and TLR4 expression were assessed by IHC after validation of each antibody. IHC expression was scored independently by two hematopathologists by calculating scores (product of staining intensity x percent expression). IHC expression was compared using Spearman correlation estimate. Demographic and clinical data were collected and correlated with IHC expression using Kruskal-Wallis test, Spearman correlation, and Logrank test. Results: Patients were median 72 years of age, 67% men and included 47% MDS-MLD, 35% MDS-RS, 14% MDS-SLD, 2% MDS del5q and 2% MDS-U. IL-1 expression correlated with beta-catenin expression, r = 0.42, 95% CI 0.115 to 0.658 (p = 0.007). There was a trend towards significance between IL-1 and cPLA2, r = 0.30 (p = 0.067); S100A9 and cPLA2, r = 0.31 (p = 0.052); and S100A9 and EYA2, r = 0.31 (p = 0.057). Percentage EYA2 expression correlated with blast count, r = 0.425 (p = 0.008). The IHC expression of these antigens did not correlate with WHO MDS subclassification, IPSS, R-IPSS, disease progression, or survival (p > 0.05). Conclusions: IHC staining of inflammasome activators using TMA may allow better characterization of molecular pathways contributing the MDS pathogenesis. A correlation was seen between expression of antigens known to be increased downstream of NLRP3 inflammasome activation. Furthermore, increased expression of EYA2 correlated with blast count. A future study will compare expression patterns between normal, low risk MDS and high risk MDS samples and correlate these findings with clinical outcome data to further elucidate the pathogenesis of MDS and identify potential targetable markers for novel therapeutic strategies.

Activating chimeric receptor on IL-15 armored NK cells to improve in vitro and in vivo tumor response within the liver following regional delivery.

e14517 Background: Colorectal cancer liver metastases (CRCLM) are a major source of morbidity and mortality. Historically, curative therapy has been limited to surgical resection, but only a small fraction of patients are eligible. Cellular immunotherapy has shown promise in hematologic cancers, but challenges to solid tumor therapy remain, including lymphocyte trafficking, elevated interstitial fluid pressures, and immunosuppression. Regional intravascular infusion is a non-surgical, minimally invasive procedure commonly used in liver cancer to deliver therapeutics, which can be augmented by Pressure Enabled Drug Delivery (PEDD). We hypothesized that utilizing established regional delivery strategies to administer natural killer (NK) cells engineered to express a natural killer group 2, member D (NKG2D) activating chimeric receptor and membrane bound IL-15 (CAR NKG2D cells) could increase anti-tumor activity against liver cancer. Methods: In vitro cytotoxicity of CAR NKG2D NK cells was determined in co-culture systems. CRCLM-bearing NSG mice were treated with either CAR NKG2D, non-transduced NK cells (NT-NK), or vehicle via portal vein (PV) for regional PEDD or tail vein (TV) for systemic delivery (SD). Tumor burden was measured via tumor bioluminescence. Mann-Whitney tests were performed for statistical comparisons. Correlation of NKG2D ligand expression in tissue and serum was measured by CODEX and Luminex. Results: Multiple NKG2D ligands are highly expressed in hepatocellular and colorectal carcinoma cell lines (HCC and CRC respectively). As such, these cells lines are highly susceptible to NKG2D-mediated cytotoxicity. CAR NKG2D NK cells were 3- to 4-fold more potent in vitro than NT-NK cells against multiple HCC and CRC cell lines, including those bearing Ras pathway mutations. Using a mouse model of locoregional delivery under high pressure (10 mL/minute), we show that significant tumor reduction (p < 0.05) is only achieved when CAR NKG2D NK cells, but not vehicle or NT-NK cells, were delivered via PV and not via TV. Recovery of CAR NKG2D NK cells in hepatic tissues was on average 2-fold higher after administration via PV than that observed after TV delivery (p = 0.0001). PV delivery of NT-NK cells did not result in appreciable liver engraftment or tumor growth inhibition. Conclusions: CAR NKG2D NK cells demonstrate enhanced in vitro and in vivo cytotoxicity against CRC and HCC cell lines. Significant tumor control using regional delivery in initial studies support continued clinical development. NKX101 is an investigational agent comprised of CAR NKG2D NK cells being evaluated in a phase 1 clinical study for treatment of relapsed/refractory acute myeloid leukemia or higher risk myelodysplastic syndrome. Studies are ongoing to understand NKX101 kinetics, role of delivery pressure, and activity in combination in preclinical models of CRCLM.

TERT Genotype Polymorphism: A Glance of Change Egyptian MDS Outcomes.

Background:Myelodysplastic Syndromes (MDS)are clonal hematologic disorders characterized by genetic instability and ineffective hematopoiesis associated with telomere dysfunction. We aimed at investigating the association between the rs2242652 single nucleotide variant of the TERT gene and susceptibility for MDS, as well as its prognostic impact and relation to disease phenotype. Methods:Genotyping analysis was carried on 100 MDS patients recruited at Mansoura Oncology center, in addition to 100 healthy subjects for detection of rs2242652 variant of TERT gene on chromosome 5 by real time PCR following the protocol of Custom TaqMan® SNP Genotyping. Results:The rs2242652 TERT genetic polymorphism was associated with an increased risk of MDS (odds ratios 2.6 for genotype GA, 6.4 for genotype AA). The majority of AA homozygous mutant variant were associated pancytopenia (88%), poor risk cytogenetics (92%) and High/very high IPSS-R score (88%). At the end of follow-up (median 30 months), 14% of the cases transformed to secondary AML. The rate of leukemic transformation was significantly associated with the mutant AA genotype (93% of transformed cases, 52% of AA genotype cases; P< 0.0001). Survival outcome was inferior in AA mutant genotype (median 14 months, 95% CI: 12-16 months) to the GA genotype (median 30 months, 95% CI: 26-33 months) and those of the GG genotype (median not reached), P<0.001. Conclusion:Our study shows an intriguing and previously unrecognized association between rs2242652 TERT mutation and MDS risk. The presence of rs2242652 mutation defines a subgroup of patients with aggressive disease phenotype and dismal outcome. Further research is recommended to elucidate underlying pathologic mechanisms and to define an efficient therapeutic target.

Severe allo-immune antibody-associated peripheral and central nervous system diseases after allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a curative treatment for hematologic malignancies. Acute and chronic graft-versus-host disease (GvHD) are the major immune-mediated complications after alloHSCT. However, there is controversy whether neurologic complications after alloHSCT might represent manifestations of GvHD. We report three patients who acquired distinct, severe immune-mediated peripheral or central nervous system diseases after alloHSCT without other, concomitant GvHD manifestations. One patient had been diagnosed with B-cell chronic lymphocytic leukemia and two patients with high risk myelodysplastic syndrome. Patient #1 presented as LGI1- and GAD-IgG positive immune-mediated encephalitis, patient #2 was diagnosed with MOG-IgG positive encephalomyelitis, and patient #3 had chronic inflammatory polyneuropathy associated with SSA(Ro)-IgG positive Sjögren’s syndrome. 100% donor chimerism was detectable in the peripheral blood in all three. The specific antibodies were undetectable in donors’ and patients’ blood before alloHSCT suggesting that the antibodies had arisen from the transplanted donor immune system. Early intensive immunotherapy led to improvement of clinical symptoms and stability of the neurological disease, however, at the cost of losing the graft-versus-malignancy effect in one patient. In conclusion, we provide evidence of isolated, severe allo-immune diseases of the peripheral and central nervous system as complications of alloHSCT (“neuro-GvHD”). Interdisciplinary surveillance and thorough diagnostic work-up are needed for early diagnosis and treatment of neuro-immunologic complications after alloHSCT to improve the otherwise poor outcome.

Stem cell concepts in myelodysplastic syndromes: lessons and challenges.

According to the cancer stem cell (CSC) hypothesis, CSCs are the only cancer cells that can give rise to and sustain all cells that constitute a cancer as they possess inherent or acquired self-renewal potential, and their elimination is required and potentially sufficient to achieve a cure. Whilst establishing CSC identity remains challenging in most cancers, studies of low-intermediate risk myelodysplastic syndromes (MDS), other chronic myeloid malignancies and clonal haematopoiesis of indeterminant potential (CHIP) strongly support that the primary target cell usually resides in the rare haematopoietic stem cell (HSC) compartment. This probably reflects the unique self-renewal potential of HSCs in normal human haematopoiesis, combined with the somatic initiating genomic driver lesion not conferring extensive self-renewal potential to downstream progenitor cells. Mutational 'fate mapping' further supports that HSCs are the only disease-propagating cells in low-intermediate risk MDS, but that MDS-propagating potential might be extended to progenitors upon disease progression. The clinical importance of MDS stem cells has been highlighted through the demonstration of selective persistence of MDS stem cells in patients at complete remission in response to therapy. This implies that MDS stem cells might possess unique resistance mechanisms responsible for relapses following otherwise efficient treatments. Specific surveillance of MDS stem cells should be considered to assess the efficiency of therapies and as an early indicator of emerging relapses in patients in clinical remission. Moreover, further molecular characterization of purified MDS stem cells should facilitate identification and validation of improved and more stem cell-specific therapies for MDS.

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The cover image depicts Anti-Hif-1a immunohistochemistry of BM biopsy sectionsfrom a 5-AZA-R patient, with high frequency of Hif-1α (+) cells, and is based on the Original Article Upregulated Hif-1α signaling pathway in high risk myelodysplastic syndrome and acute myeloid leukemia patients is associated with better response to 5-azacytidine - Data from the Hellenic MDS study group by Vassiliki Pappa et al., https://doi.org/10.1002/hon.2834.

Venetoclax and Azacitidine in Relapsed/Refractory Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome: Bursa Uludag University Experience

The management of acute myeloid leukemia (AML) gradually turns into an individualized approach with the application of targeted therapies. Venetoclax is a BCL-2 inhibitor that is synergistic with azacitidine. In this case series, 14 patients diagnosed with relapsed / refractory AML and 1 MDS RAEB-1 were followed up with venetoclax + azacitidine in the Hematology Department Bursa Uludag University Faculty of Medicine were evaluated. The best responses obtained with venetoclax + azacitidine were complete remission (CR) in one patient, complete remission with incomplete hematologic recovery (CRi) in one patient, morphological leukemia-free state (MLFS) in 4 patients, and partial response (PR) in one patient. The median time to first response with treatment was one month (0.5-5). The time to enter early remission is critical. For this reason, deaths due to infection should be prevented. Although the toxicities of this combination therapy can be managed, close follow-up of the patients is mandatory. In conclusion, this combination therapy is promising as it is relatively well-tolerated, improves the quality of life, and prolongs survival.

A systematic review of higher-risk myelodysplastic syndromes clinical trials to determine the benchmark of azacitidine and explore alternative endpoints for overall survival

The hypomethylating agent azacitidine can prolong overall survival (OS) in patients with higher risk-myelodysplastic syndromes (HR-MDS) compared to conventional regimens. However, outcomes differ largely between studies, making it challenging to determine the contribution of novel therapies added to azacitidine. Further, a discrepancy is seen between complete (CR) or partial (PR) response rates and OS improvement with azacitidine, making it challenging to rely on earlier endpoints than OS.We conducted a systematic literature search and study-level systematic review of 237 clinical studies to better understand outcomes for HR-MDS patients treated with azacitidine. Pooled marrow CR was 9% (N = 2654; 95% CI: 6–13 %), CR rate was 17 % (N = 6943; 95% CI: 15–20 %), and median OS (mOS) was 18.6 months (N = 2820; 95% CI: 15.3–21.9). A weak correlation to mOS was detected with CR rate (207 patient cohorts, Pearson’s r = 0.315; P < 0.0005), and a much stronger correlation with median progression-free survival (mPFS) (r=0.88, P = 3 × 10−14). Six-months progression-free survival rates correlated with 1-year OS rates but were only infrequently reported (N = 41 patient cohorts) therefore not allowing a robust recommendation for a surrogate to the established OS endpoint. Larger patient numbers and patient-level data appear necessary, especially for designing future clinical trials using azacitidine combinations.

Reduced frequencies and functional impairment of dendritic cell subsets and non-classical monocytes in myelodysplastic syndromes.

In myelodysplastic syndromes (MDS) the immune system is involved in pathogenesis as well as in disease progression. Dendritic cells (DC) are key players of the immune system by serving as regulators of immune responses. Their function has been scarcely studied in MDS and most of the reported studies didn’t investigate naturally occurring DC subsets. Therefore, we here examined the frequency and function of DC subsets and slan+ non-classical monocytes in various MDS risk groups. Frequencies of DC as well as of slan+ monocytes were decreased in MDS bone marrow compared to normal bone marrow samples. Transcriptional profiling revealed down-regulation of transcripts related to pro-inflammatory pathways in MDS-derived cells as compared to normal bone marrow. Additionally, their capacity to induce T-cell proliferation was impaired. Multidimensional mass cytometry showed that whereas healthy donor-derived slan+ monocytes supported Th1/Th17/Treg differentiation/expansion their MDS-derived counterparts also mediated substantial Th2 expansion. Our findings point to a role for an impaired ability of DC subsets to adequately respond to cellular stress and DNA damage in the immune escape and progression of MDS. As such, it paves the way toward potential novel immunotherapeutic interventions.

Nicotinamide (vitamin B3) treatment improves response to G‐CSF in severe congenital neutropenia patients

Nicotinamide (vitamin B3) treatment improves response to G‐CSF in severe congenital neutropenia patients

Integration Analysis of JAK2 or RUNX1 Mutation With Bone Marrow Blast Can Improve Risk Stratification in the Patients With Lower Risk Myelodysplastic Syndrome.

Despite the improvements in prognostication of the revised International Prognostic Scoring System (IPSS-R) in myelodysplastic syndrome (MDS), there remain a portion of patients with lower risk (low/intermediate risk, LR) but poor prognostics. This study aimed to evaluate the relative contribution of mutational status when added to the IPSS-R, for estimating overall survival (OS) and progression-free survival (PFS) in patients with LR-MDS. We retrospectively analyzed clinical and laboratory variables of 328 patients diagnosed with MDS according to the FAB criteria. Twenty-nine-gene NGS assay was applied to bone marrow samples obtained at diagnosis. 233 (71.04%) patients were classified as LR-MDS. Univariate analysis showed association between inferior outcome (OS and PFS) and presence of JAK2 (p = 0.0177, p = 0.0002), RUNX1 (p = 0.0250, p = 0.0387), and U2AF1 (p = 0.0227, p = 0.7995) mutations. Multivariable survival analysis revealed JAK2 (p < 0.0001) and RUNX1 (p = 0.0215) mutations were independently prognostic for PFS in LR-MDS. Interestingly, bone marrow blast >1.5% could further predict disease progression of patients with LR-MDS (HR 8.06, 95%CI 2.95–22.04, p < 0.0001). Incorporation of JAK2, RUNX1 mutation and bone marrow blast in the IPSS-R can improve risk stratification in patients with LR-MDS. In summary, our result provided new risk factors for LR-MDS prognostics to identify candidates for early therapeutic intervention.

Treatment patterns and outcomes in patients with myelodysplastic syndromes treated with hypomethylating agents: a SEER-Medicare analysis

To describe real-world treatment patterns and outcomes among adult patients with myelodysplastic syndromes (MDS) treated with hypomethylating agents (HMA), patients were identified in the SEER-Medicare database (01/2006–12/2016); 3,046 patients with MDS treated with HMA were included. An algorithm was developed to categorize patients into MDS risk groups: the majority of patients were classified as Higher-risk (70.9%), 8.0% as Intermediate-risk, and 21.1% as Unknown-risk. Overall, 77.4% of patients initiated azacitidine and 22.6% decitabine; they received an average of 5.1 index-HMA cycles, of which 90.9% were complete with a median cycle duration of 28 days. Median survival was 11.6, 18.4, and 19.1 months for the Higher-risk, Intermediate-risk, and Unknown-risk groups, respectively. Median time-to-AML transformation was 19.3 months for the Higher-risk group and 50.4 months for the Intermediate-risk group (not reached for Unknown-risk). Data highlight the unmet medical needs of patients with MDS treated with HMA, particularly for the Higher-risk MDS group.

Risk factors for de novo and therapy-related myelodysplastic syndromes (MDS).

Myelodysplastic syndromes (MDS) are classified as de novo and therapy-related (tMDS). We evaluated associations between MDS risk factors separately for de novo and tMDS. The study population included 346 de novo MDS cases, 37 tMDS cases and 682 population controls frequency matched by age and sex. Polytomous logistic regression was performed to calculate odds ratios (OR) and 95% confidence intervals (CI). After adjustment, former smoking status (OR = 1.45, 95% CI: 1.10-1.93), personal history of autoimmune disease (OR = 1.34, 95% CI: 0.99-1.82) and exposure to benzene (OR = 1.48, 95% CI: 1.00-2.19) were associated with de novo MDS. Risk estimates for the associations between smoking, autoimmune disease, and benzene exposure were similar in magnitude but non-significant in tMDS cases. Among individuals with a previous diagnosis of cancer, de novo MDS cases and controls were more likely to have had a previous solid tumor, while tMDS cases more commonly had a previous hematologic malignancy. We observed similar associations between smoking, history of autoimmune disease and benzene exposure in de novo and tMDS although estimates for tMDS were imprecise due to small sample sizes. Future analyses with larger sample sizes will be required to confirm whether environmental factors influence risk of tMDS.

Association between TNF-α gene polymorphisms and susceptibility of myelodysplastic syndromes: a meta-analysis

ABSTRACT Objective Myelodysplastic syndromes (MDS) constitute a heterogeneous group of clonal hematological diseases. Previous investigations reported that tumor necrosis factor-alpha (TNF-α) gene polymorphisms were associated with MDS susceptibility, but the results remained controversial. Thus, we conducted a meta-analysis to higher elucidate the correlation between TNF-α gene polymorphisms and MDS susceptibility. Methods The PubMed, Cochrane Library, Embase, Chinese National Knowledge Infrastructure (CNKI), and Wan Fang databases were searched for eligible literatures published up to July 2021. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the strength of association. Results Eight studies involving 1180 MDS patients and 1387 controls were included in this meta-analysis. For the TNF-α G308A polymorphism, we confirmed that the G allele (G versus A: P = 0.001), GG genotypes (GG versus GA: P = 0.005; GG versus GA + AA: P = 0.002), and GG + AA genotypes (GG + AA versus GA: P = 0.008) was significantly associated with decreased MDS susceptibility according to different genetic models. Furthermore, the G308A polymorphism was significantly correlated with decreased occurrence risk of MDS in the Caucasian population as compared with Asians in the above four genetic models (P < 0.05). However, no significant association was observed between the TNF-α G238A polymorphism and MDS risk. Conclusion This research showed that TNF-α G308A polymorphism might be a potential biomarker in early clinical screening of MDS, which would contribute to improving the individualized prevention of MDS patients in clinic.

Upregulated hypoxia inducible factor 1α signaling pathway in high risk myelodysplastic syndrome and acute myeloid leukemia patients is associated with better response to 5-azacytidine-data from the Hellenic myelodysplastic syndrome study group.

5-azacytidine (5-AZA) is considered the standard of care for patients with high-risk myelodysplastic syndromes (MDS) and patients with acute myeloid leukemia (AML) not candidate for intensive chemotherapy. However, even after an initial favorable response, almost all patients relapse, with the exact mechanisms underlying primary or secondary 5-AZA resistance remaining largely unknown. Several reports have previously demonstrated the significance of hypoxia in the regulation of both physiological and malignant hematopoiesis. In MDS, high hypoxia inducible factor 1α (Hif-1α) expression has been correlated with poor overall survival and disease progression, while its involvement in the disease's pathogenesis was recently reported. We herein investigated the possible association of the Hif-1α signaling pathway with response to 5-AZA therapy in MDS/AML patients. Our data demonstrated that 5-AZA-responders present with higher Hif-1α mRNA and protein expression compared to 5-AZA-non-responders/stable disease patients, before the initiation of therapy, while, interestingly, no significant differences in Hif-1α mRNA expression at the 6-month follow-up were observed. Moreover, we found that 5-AZA-responders exhibited elevated mRNA levels of the Hif-1α downstream targets lactate dehydrogenase a (LDHa) and BCL2 interacting protein 3 like (BNIP3L), a further indication of an overactivated Hif-1a signaling pathway in these patients. Kaplan-Meier survival analysis revealed a significant correlation between high Hif-1α mRNA expression and better survival rates, while logistic regression analysis showed that Hif-1α mRNA expression is an independent predictor of response to 5-AZA therapy. From the clinical point of view, apart from proposing Hif-1α mRNA expression as a significant predictive factor for response to 5-AZA, our data offer new perspectives on MDS combinational therapies, suggesting a potential synergistic activity of 5-AZA and Hif-1α inducers, such as propyl hydroxylases inhibitors (PHDi).

Impact of obesity on survival of patients with myelodysplastic syndromes

ABSTRACT Background: Obesity has been associated with increased incidence of myelodysplastic syndromes (MDS). Recently intriguing data in mouse models suggested that obesity increases survival in animals with MDS. Methods: This was a retrospective analysis using the Moffitt MDS database. Obesity was defined by using body mass index (BMI), whereby a BMI ≥ 30 was regarded as obese. Results: Among 3089 MDS patients with known BMI, 963 patients (31%) were categorized as obese. There were no differences in baseline characteristics between patients with BMI ≥ 30 and those with <30. The median OS for patients with BMI ≥ 30 was 34 months compared to 37 months for those with BMI < 30 (p 0.04). For patients with lower-risk MDS median OS was 52 months versus 57 months, respectively, (p 0.08) while for higher-risk patients median OS was 17 months for both groups. The rate of AML transformation was 36% for patients with BMI ≥ 30 compared to 32% for those with BMI < 30 (p 0.009). There was no difference in response to azacitidine. In multivariable analysis, BMI was associated with inferior OS. For patients < 45 years old, the median OS was 25 months for patients with BMI ≥ 30 compared to 116 months for those with BMI < 30 (p 0.034). Conclusions: Obesity is associated with inferior overall survival (OS) in MDS patients in less than 65 years old and lower MDS risk. Impact of obesity on the outcome of MDS is being explored in both mice and human. Here we reported the impact of obesity on OS in MDS patients. Obesity is associated with inferior OS in MDS patients particularly younger age groups and lower MDS risk.

Clinical Response to the CD95-Ligand Inhibitor Asunercept Is Defined by a Pro-Inflammatory Serum Cytokine Profile.

Simple SummaryAsunercept showed promising clinical efficacy in anemic, transfusion-dependent patients with low and intermediate risk myelodysplastic syndrome. In this retrospective post hoc analysis, serum levels of biomarkers were measured in study patients focusing on cytokines associated with erythropoiesis, inflammation, apoptosis, bone marrow fibrosis, and inflammasome activity. Baseline serum biomarkers were correlated with treatment response in order to propose a hypothetical responder serum profile. Response to asunercept was associated with improved overall survival. Higher baseline values of interleukin-18 (IL-18), S100 calcium-binding protein A9 (S100A9) and soluble p53 were predictive of non-response to asunercept. Non-responding patients showed a distinct, pro-inflammatory serum cytokine profile which was persistent throughout the first half of the treatment phase and appeared unaffected by asunercept. Our post hoc analysis suggests that serum cytokine profiling based on IL-18, S100A9 and soluble p53 may represent an approach to identify and select low-risk myelodysplastic syndrome patients most likely to benefit from asunercept treatment.Asunercept (APG101) is a well-tolerated CD95-ligand inhibitor that showed promising efficacy in a prospective, single-arm phase I study in anemic, transfusion-dependent patients with low and intermediate risk myelodysplastic syndrome (MDS). In this retrospective post hoc analysis, serum levels of biomarkers were measured in study patients focusing on cytokines associated with erythropoiesis, inflammation, apoptosis, bone marrow fibrosis, and inflammasome activity. Baseline serum biomarkers were correlated with treatment response, in order to propose a hypothetical responder serum profile. After an updated median follow-up of 54 months (range 7–65), response to asunercept was associated with improved overall survival (at 3-years: 67% [95%CI 36–97] versus 13% [95%CI 0–36] in responders versus non-responders, respectively). Higher baseline values of interleukin-18 (IL-18), S100 calcium-binding protein A9 (S100A9) and soluble p53 were predictive of non-response to asunercept (area under the receiver operating characteristic curve 0.79–0.82). Furthermore, non-responding patients showed a distinct, pro-inflammatory serum cytokine profile which was persistent throughout the first half of the treatment phase and appeared unaffected by asunercept. Although prospective validation is required, our post hoc analysis suggests that serum cytokine profiling based on IL-18, S100A9 and soluble p53 may represent an approach to identify and select low-risk MDS patients most likely to benefit from asunercept treatment.