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Myelodysplastic syndromes (MDS) are hematological malignancies characterized by ineffective hematopoiesis and increased apoptosis in the bone marrow, which cause peripheral cytopenia. Mitochondria are key regulators of apoptosis and a site of iron accumulation that favors reactive oxygen species (ROS) production with detrimental effects on cell survival. Although the energy metabolism could represent an attractive therapeutic target, it was poorly investigated in MDS. The purpose of the study was to analyze how the presence of myelodysplastic hematopoiesis, iron overload and chelation impact on mitochondrial metabolism. We compared energy balance, OxPhos activity and efficiency, lactic dehydrogenase activity and lipid peroxidation in mononuclear cells (MNCs), isolated from 38 MDS patients and 79 healthy controls. Our data show that ATP/AMP ratio is reduced during aging and even more in MDS due to a decreased OxPhos activity associated with an increment of lipid peroxidation. Moreover, the lactate fermentation enhancement was observed in MDS and elderly subjects, probably as an attempt to restore the energy balance. The biochemical alterations of MNCs from MDS patients have been partially restored by the in vitro iron chelation, while only slight effects were observed in the age-matched control samples. By contrast, the addition of iron chelators on MNCs from young healthy subjects determined a decrement in the OxPhos efficiency and an increment of lactate fermentation and lipid peroxidation. In summary, MDS-MNCs display an altered energy metabolism associated with increased oxidative stress, due to iron accumulation. This condition could be partially restored by iron chelation.

Background/Objectives: The aim of this study was to assess the unmet needs of myelodysplastic neoplasm (MDS) patients and their caregivers, focusing on how these needs impact quality of life (QoL) and daily functioning. MDS predominantly affects older adults. It is often complicated by severe red blood cell transfusion-dependent anemia and may require frequent hospital visits, conferring a substantial burden on patients and caregivers. Methods: A national survey was conducted between June 2022 and May 2023 in 46 hematology centers across Italy, involving 259 patients and 105 caregivers. The survey included validated QoL tools (QOL-E and HM-PRO) to measure the impact of disease and treatments on health-related QoL and symptoms. Results: Of the 259 patients surveyed, 42% were transfusion-dependent, with 45% reporting distress related to hospital travel, which was significantly associated with lower QoL scores (QOL-E physical score 50.0 vs. 62.5, p < 0.001). Transfusion dependency led to worse outcomes across physical, emotional, and social domains (HM-PRO Part A score 59.8 vs. 23.7, p < 0.001). Anxiety affected 66% of patients, while 56% reported feeling emotionally distressed. Forty-eight percent of patients required a caregiver, and among caregivers, 29% reported significant disruption to their work, including changing their job or reduced hours. Patients requiring frequent hospital visits showed notably worse QoL scores (HM-PRO emotional score 56.8 vs. 31.8, p < 0.001). Conclusions: This study identified substantial unmet needs for MDS patients, particularly in addressing the heavy burden of transfusions and hospital visits. Both patients and caregivers experienced significant impact on daily life and on QoL, highlighting the urgent need for treatments that reduce hospital dependency, improve patient outcomes, and alleviate the caregiver burden.

Diagnosis and prognostic stratification of myelodysplastic syndromes (MDS) have been complemented by new techniques, including flow cytometry and NGS. To analyze the relationship between molecular and cytofluorimetric data, we enrolled in this retrospective study, 145 patients, including 106 diagnosed with MDS and 39 controls. At disease onset, immunophenotypic (IF), cytogenetic tests, and cytomorphological (CM) examination on bone marrow were carried out in all patients, while NGS was performed in 58 cases. Ogata score presented a specificity of 100% and a sensitivity of 59%. The detection of at least two phenotypic aberrancies in Ogata negative patients increased the sensitivity to 83% and specificity to 87%. Correlations were identified between IF aberrancies and mutations, including positive Ogata>2 and mutations in SRSF2 (p=0.035), CD15 and U2AF1 (0.032), CD56 and DNMT3A (p=0.042), and CD38 and TP53 (p=0.026). In multivariate analysis, U2AF1 mutations, associated with del(20q) and/or abnormalities of chromosome 7 (group 4 as defined by the EuroMDS score), significantly correlated with an inferior overall survival (p=0.019). These parameters and Ogata score>2 also showed a significant correlation with inferior event-free survival (p=0.023 and p=0.041, respectively). Both CM and FC features correlated with prognosis and mutational patterns. In an integrated MDS work-up, these tools may guide indications for mutational screening for optimal risk stratification.

Iron chelation therapy can improve hematopoiesis in myelodysplastic syndromes. Only few studies showed hematologic improvement with deferoxamine, and the erythroid responses were correlated with good compliance to long-term treatment. Indeed, single-case reports and data from clinical trials testing the efficacy of deferasirox reported hematologic improvements with varying rates of response in different lineages. Overall, about 760 myelodysplastic syndrome (MDS) patients with iron overload receiving deferasirox were included in six different studies, and an increase in hemoglobin level was reported to range from 6 to 44.5 %, an increase in platelet count from 13 to 61 %, and in neutrophil count from 3 to 76 %. In all the published studies, hematologic improvements were not related to serum ferritin or to non-total binding iron changes; indeed, other pathways were indicated as possible pathogenetic mechanisms, such as decreased NF-kB activity, modulation of mTOR signalling, and reduced reactive oxygen species. The aims of this review are to provide all available information relating clinical and hematologic changes after chelation therapy and to discuss potential mechanisms involved in such responses.

Aims: To define the peculiar features of patients with the deletion of the chromosome 20 long arm (del20q), data from 69 patients with myelodysplastic syndromes (MDSs) and isolated del20q, followed by the Gruppo Romano-Laziale Sindromi Mielodisplastiche (GROM-L) and Ospedale Torrette of Ancona, were collected and compared with those of 502 MDS patients with normal karyotype (NK-MDS). Results: Compared to the NK-MDS group, patients with del20q at diagnosis were older (p = 0.020) and mainly male (p = 0.006). They also had a higher rate of bone marrow blast < 5% (p = 0.004), a higher proportion of low and int-1 risk according to IPSS score (p = 0.023), and lower median platelet (PLT) count (p < 0.001). To date, in the del20q cohort, 21 patients (30.4%) received no treatment, 42 (61.0%) were treated with erythropoiesis-stimulating agents (ESA), 3 (4.3%) with hypomethylating agents, and 3 (4.3%) with other treatments. Among 34 patients evaluable for response to ESA, 21 (61.7%) achieved stable erythroid response according to IWG 2006 criteria and 13 (38.2%) were resistant. Nine patients (13.0%) progressed to acute myeloid leukaemia (AML) after a median time from diagnosis of 28 months (IR 4.1–51.7). The median overall survival (OS) of the entire cohort was 60.6 months (95% CI 54.7–66.4). the 5-year cumulative OS was 55.9% (95% CI 40.6–71.2). Conclusion: According to our results, we hypothesize that MDSs with isolated del 20q may represent a distinct biological entity, with peculiar clinical and prognostic features. The physio-pathological mechanisms underlying the deletion of the chromosome 20 long arm are still unclear and warrant future molecular analysis.

The Gruppo Romano Mielodisplasie (GROM) conducted a retrospective study in 543 patients with myelodysplastic syndromes (MDS) to evaluate the safety and efficacy of erythropoiesis-stimulating agents (ESAs) in “real-life” clinical practice. The 40.000-UI/week erythropoietin (EPO)-alpha and 30.000-UI/week EPO-beta starting dose were defined “standard,” and 80,000 UI/week EPO-alpha and 60.000 UI/week EPO-beta were defined “high.” Response was defined according to International Working Group (IWG) 2006 criteria. At ESA’s start, median age was 74.2 years (interquartile range (IR) 67.8–79.5) and median hemoglobin was 8.9 g/dl (IR 8.2–9.6). Median time from diagnosis to ESAs start was 3.8 months (IR 0.8–13.2). ESA starting dose was “standard” in 361 patients (66.5 %) and “high” in 182 patients (33.5 %). Erythroid response was observed in 82/185 (44.3 %) transfusion dependent (TD) patients as compared with 226/329 (68.6 %) transfusion independent (TI) ones ( p  < 0.001). At multivariate analysis, in TD patients, only endogenous EPO levels <50 mU/l were significant ( p  = 0.046), whereas in TI patients, high-dose ESAs ( p  < 0.001), abnormal creatinine levels (0.009), and endogenous EPO levels <50 mU/l ( p  = 0.014) were predictors of response. Responders showed a higher 5-year overall survival (OS) (57.8 vs. 32.2 %, p  < 0.001) and leukemia-free survival (76.0 vs. 49.8 %, p  < 0.001). At multivariable analysis for OS, response to ESA, low International Prognostic Scoring System (IPSS), no transfusion need, and female sex showed an independent favorable prognostic role. Our results confirm that treatment with ESAs is effective in a real-life MDS setting, particularly at high dose and in TI patients. Prospective studies are needed to define the optimal starting dose.

The primary objective of this study was to evaluate the health-related quality of life (HRQOL) in lower-risk, transfusion-dependent patients with myelodysplastic syndromes (MDS) treated with deferasirox. A secondary objective was to investigate the relationship between HRQOL, serum ferritin levels and transfusion dependency. This was a prospective multicentre study enrolling 159 patients, of whom 152 received at least one dose of deferasirox. HRQOL was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) at baseline and then at 3, 6, 9 and 12 months. Primary analysis was performed estimating mean HRQOL scores over time by a linear mixed model on selected scales. The median age of treated patients was 72 years (range 24-87 years). No statistically significant changes over time were found in mean scores for global health status/quality of life (p=0.564), physical functioning (p=0.409) and fatigue (p=0.471) scales. Also, no significant changes were found for constipation (p=0.292), diarrhoea (p=0.815) and nausea and vomiting (p=0.643). Serum ferritin levels were not associated with HRQOL outcomes. A higher patient-reported baseline pain severity was an independent predictive factor of an earlier achievement of transfusion independence with a HR of 1.032 (99% CI 1.004 to 1.060; p=0.003). HRQOL of transfusion-dependent patients with MDS receiving deferasirox therapy remains stable over time. HRQOL assessment might also provide important predictive information on treatment outcomes. NCT00469560.

Myelodysplastic syndromes (MDS) are common in elderly patients. Recombinant human erythro-poietin (rHuEPO) has been widely used to treat anemia in lower risk MDS patients, but few data are known about rHuEPO treatment in the very elderly patient group. In order to investigate the role of rHuEPO treatment in terms of response, overall survival (OS), and toxicity in a very elderly MDS patient group, 93 MDS patients treated with rHuEPO when aged ≥80 years were selected among MDS cases enrolled in a retrospective multicenter study by the cooperative group Gruppo Romano Mielodisplasie (GROM) from Jan 2002 to Dec 2010. At baseline, median age was 82.7 (range 80–99.1) with a median hemoglobin (Hb) level of 9 g/dl (range 6–10.8). The initial dose of rHuEPO was standard (epoetin alpha 40,000 IU/week or epoetin beta 30,000 IU/week) in 59 (63.4 %) pa-tients or high in 34 (36.6 %) (epoetin alpha 80,000 IU/week) patients. We observed an erythroid response (ER) in 59 (63.4 %) patients. No thrombotic event was reported. Independent predictive factors for ER were low transfusion requirement before treatment ( p  = 0.004), ferritin <200 ng/ml ( p  = 0.017), Hb >8 g/dl ( p  = 0.034), and a high-dose rHuEPO treatment ( p  = 0.032). Median OS from rHuEPO start was 49.3 months (95 % CI 27.5–68.4) in responders versus 30.6 months (95 % CI 7.3–53.8) in resistant patients ( p  = 0.185). In conclusion, rHuEPO treatment is safe and effective also in the very elderly MDS patients. However, further larger studies are warranted to evaluate if EPO treatment could be worthwhile in terms of quality of life and cost-efficacy in very old patients.

The authors describe an outbreak of Cryptosporidium diarrhea that occurred in the bone marrow transplantation (BMT) unit of the Department of Hematology at the University of Rome.