Introduction:Multiple myeloma (MM) is a clinically heterogeneous malignancy in which outcomes remain difficult to predict using static baseline risk models. Increasing attention has shifted toward dynamic prognostic markers, including early disease progression and early mortality; however, their relative prognostic value-particularly the optimal definition of early progression-and their integration with patient-related factors remain insufficiently defined in real-world populations. Methods:We retrospectively analysed 207 newly diagnosed MM patients treated between 2018 and 2023. Early disease progression was defined as progression within 18 (POD18) and 24 months (POD24) from treatment initiation. Early mortality was defined as death within six months of diagnosis. Overall survival (OS) and progression-free survival (PFS) were analysed using Kaplan-Meier estimates and Cox regression models, including time-dependent analyses. Results:During a median follow-up of 60 months, POD18 occurred in 44.0% and POD24 in 51.2% of patients. POD18 was strongly associated with inferior OS (HR 9.38; 95% CI 5.98-14.70; p < 0.0001) and demonstrated superior prognostic discrimination compared with POD24 (C-index 0.742 vs. 0.719). In multivariable analysis, POD18 remained the strongest independent predictor of OS, alongside comorbidity burden and performance status. Early mortality occurred in 17.9% of patients and was independently associated with advanced disease stage. Time-dependent modelling showed that the prognostic impact of baseline staging decreased over time, supporting the dynamic nature of risk in MM. Conclusion:POD18 is a robust and clinically informative dynamic prognostic marker that outperforms POD24 in predicting survival in real-world patients with MM. Integration of early disease kinetics with baseline disease burden and comorbidity burden provides a pragmatic framework for dynamic risk stratification, particularly in settings with limited access to comprehensive molecular profiling.

Selecting eligible allogeneic haematopoietic stem cell transplantation (allo-HSCT) candidates with low-risk and intermediate-risk myelodysplastic syndrome (MDS) remains controversial. The International Working Group (IWG) for MDS prognosis identified a Revised International Prognostic Scoring System (IPSS-R) score >3.5 for benefits from early transplantation; the MDS-RIGHT group uses a broader set of poor risk features. We analysed 1145 lower risk MDS (lower risk and intermediate-risk IPSS-R) patients aged <75 years, using real-world European Myelodysplastic Syndromes registry data and identifying those meeting IWG or MDS-RIGHT criteria for allo-HSCT at baseline and 6-month follow-up. Fit patients were characterised by Karnofsky score ≥70 and Haematopoietic Cell Transplantation-specific Comorbidity Index <3. We evaluated clinical outcomes of transplant candidates, including survival, disease progression risk, new comorbidity risk and performance status decline. The IWG criterion, and not MDS-RIGHT criteria, identified patients with lower risk and intermediate-risk MDS with poorer baseline survival. Fit lower risk patients showed 2-year cumulative risks of incident comorbidity and performance status deterioration of 20% and 5% respectively. In summary, IWG and MDS-RIGHT features identify patients with lower or intermediate-risk MDS as candidates for early transplantation. Lower risk patients fit for transplantation have a cumulative incidence of adverse outcomes possibly jeopardising transplantation eligibility and should be carefully selected when planning delayed transplantation strategies.

Acquired inhibitors of coagulation factor XI (FXI) are a rare cause of bleeding disorders, typically associated with autoimmune diseases or malignancies. Although uncommon, these inhibitors can lead to severe bleeding, which can be difficult to manage. A limited number of cases have been reported where acquired FXI inhibitors are associated with malignancy. This case report presented a rare occurrence of acquired coagulation FXI inhibitors in a 60-year-old male with sigmoid colon adenocarcinoma. The patient experienced severe postpolypectomy gastrointestinal bleeding and was diagnosed with FXI inhibitors after laboratory tests revealed prolonged activated partial thromboplastin time (aPTT) and reduced activities of factors IX, XI, and XII. The patient underwent surgery, and life-threatening hemorrhagic shock developed. He was reoperated, and treatment with recombinant factor VIIa (rFVIIa), tranexamic acid, and oral corticosteroids was initiated. The therapy successfully controlled the bleeding and resolved the inhibitor. This case highlights the risk of severe bleeding in patients with acquired FXI inhibitors and emphasizes the importance of early diagnosis and personalized treatment. Regular monitoring is essential due to the risk of relapse, particularly in cases associated with malignancy.

Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expression profiles. The integration of genomic, epigenomic, and transcriptomic profiling has the potential to spotlight distinct LR-MDS categories on the basis of pathophysiological mechanisms. We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well-annotated cohort of treatment-naive patients with LR-MDS at diagnosis from the EUMDS registry (ClinicalTrials.gov.NCT00600860). Unsupervised clustering analyses identified six clusters based on genetic profiling that concentrate into four clusters on the basis of genome-wide methylation profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct clinical and genetic features and distinct methylation landscape. All clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. By contrast, one cluster gathering patients with early leukemic evolution exhibited a specific pattern of hypermethylated promoters and, distinctly from other clusters, the upregulation of AP-1 complex members FOS/FOSL2 together with the absence of hypermethylation of their binding motif at target gene enhancers, which is of relevance for leukemic initiation. Among MDS patients with lower-risk IPSS-M, this cluster displayed a significantly inferior overall survival (p < 0.0001). Our study showed that genetic and DNA methylation features of LR-MDS at early stages may refine risk stratification, therefore offering the frame for a precocious therapeutic intervention.

Introduction. Hairy cell leukemia is a rare, indolent chronic lymphoproliferative disorder characterized by circulating B cells with cytoplasmic projections, pancytopenia, and recurrent infections. This study aims to evaluate the efficacy and safety of cladribine in managing the disease among patients treated at the Clinical Centre of Vojvodina. Material and Methods. This study included 34 patients with immunohistochemically confirmed hairy cell leukemia, treated with cladribine from September 2013 to December 2023. Clinical data were reviewed and analyzed using standard statistical methods. Results. At the time of cladribine administration, the median age was 53; 50% of patients were symptomatic, 65% had pancytopenia, and 62% presented with splenomegaly. After the first cycle, 68.75% of patients achieved a complete hematologic response, and the overall response rate was 100%. The median follow-up period was 51 months. During this period, two patients were diagnosed with non-melanoma skin cancers, one with renal cell carcinoma, and one with both myelodysplastic syndrome and prostate cancer. Additionally, 88% of patients experienced at least one infection, with viral infections being the most frequent complications. Four patients died during the follow-up period, and the 5-year survival rate was 97%. Conclusion. Cladribine is an effective treatment for hairy cell leukemia, demonstrating a good safety profile and potential for long-term remission.

Key Clinical MessageParoxysmal nocturnal hemoglobinuria is a rare disease with the incidence ranging from 0.08 to 0.57 per 100,000 person‐years. Up to 25% of cases in women are detected during pregnancy. We report two cases of successful pregnancy outcomes in patients treated with eculizumab, pointing out the importance of interdisciplinary approach in these high‐risk pregnancies.

Background Rheumatoid arthritis (RA) is an independent risk factor for osteoporosis which influences bone remodeling processes via increased production of proinflammatory cytokines, especially tumor necrosis factor-α (TNF-α), or through hormone-mediated mechanisms. The presence of other classical risk factors for osteoporosis additionally raises the risk of changes in bone tissue. Some of the most commonly used biological drugs in the osteoporosis treatment are those that inhibit TNF-α action. Apart from reducing inflammation, these TNF-inhibitors suppress osteoclast activity. Objectives To determine the impact of osteoporosis risk factors on the bone turnover marker levels in RA patients treated with TNF-inhibitors. Methods This 12-month-long study included 50 patients with RA who received a drug from the TNF-inhibitor group. In order to enter the study, patients had to fulfill certain inclusion/exclusion criteria considering the RA duration, the RA treatment method, the degree of joint damage, and the presence of other diseases affecting bone tissue. Data regarding traditional risk factors for osteoporosis and fractures were collected, such as menopause length, body mass index (BMI), previous fractures due to minor trauma, family history of osteoporosis and osteoporotic fractures, reduced physical activity, cigarette smoking, and alcohol consumption. Serum levels of the bone synthesis marker procollagen type I N propeptide (P1NP), and the bone resorption marker beta C-terminal telopeptide of type I collagen (b-CTX) were assessed via ECLIA method at the baseline and upon TNF-inhibitor therapy completion. Results The mean age in this cohort was 51.6 years. A higher percentage increase in P1NP and b-CTX was recorded in patients aged below 50 years, as well as those of normal weight (BMI = 18.50−24.99 kg/m², P1NP: Wilk’s lambda =0.83, F = 9.56, p = 0.003; b-CTKS: Wilk’s lambda = 0.77, F = 14.16, p = 0.000). A greater increase in the P1NP and b-CTX levels was also observed in non-smokers (28.70% and 27.50%) relative to smokers (27.50% and 7.75%). Menopause length had a statistically significant effect on both P1NP (Wilk’s lambda = 0.84, F = 8.18, p = 0.006) and b-CTX (Wilk’s lambda = 0.77, F = 13.31, p = 0.001) concentrations, whereby the highest percentage increase in P1NP (29.85%) was related to menopause duration below 2 years. On the other hand, the greatest b-CTX increase (10.2%) was recorded in patients that had entered menopause 2−3 years ago. Physical activity had a significant effect on changes in P1NP (Wilk’s lambda = 0.84, F = 8.57, p = 0.005) as well as b-CTX (Wilk’s lambda = 0.78, F = 13.30, p = 0.001) values. Further, P1NP percentage increase was higher in patients without family history of osteoporosis, while the opposite was true for the b-CTX levels. Finally, number of previous fractures was inversely correlated with the P1NP and b-CTX percentage increase. Conclusion After 12-month TNF-inhibitor treatment, although a significant increase in both bone turnover markers was achieved, it was greater in the bone synthesis marker P1NP. Younger age, normal body weight, shorter menopause duration, greater physical activity, negative osteoporosis family history, and non-smoking emerged as the most important factors associated with the P1NP percentage increase. Reference [1]Llorente I, et al. Osteoporosis in rheumatoid arthritis: dangerous liaisons. Front Med (Lausanne) 2020;7:601618. doi: 10.3389/fmed.2020.60161 Disclosure of Interests None declared. Changes in bone biochemical markers due to the influence of osteoporosis risk factors in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors. Disclosure of Interests None Declared.

Growth and differentiation factor-15 (GDF-15) correlates with worse outcome of many tumours and any cause mortality. Data about its role in lymphoproliferative neoplasms (LPN) are scarce. Our research aimed to reveal the correlation between GDF-15 and standard laboratory parameters of LPN activity, and to get insight into the possible value of this cytokine assessment in lymphoma patients. Prospective research included 40 patients treated for aggressive or indolent LPN, and 31 with indolent LPN on “watch and wait” regimen. Analyses were performed before and after treatment in treated patients and on two separate occasions in the “watch and wait” group. ELISA technique with R&D assays according to the manufacturer manual, from stored sera at − 70 °C was used for GDF-15 level measurement. Statistical analyses were performed by IBM SPSS Statistics 22 using descriptive and inferential statistics. As appropriate, differences between groups were assessed by two tailed t -test, Mann–Whitney or x 2 test. Spearman Rank Order Correlation was done to correlate GDF-15 with standard laboratory markers of disease activity. All tests are two-tailed with significance level p < 0. 05. GDF-15 ( p = 0.028) and fibrinogen ( p = 0.001) concentrations increased after treatment in indolent lymphoma patients while β2 microglobulin decreased ( p < 0.001). GDF-15 positively correlated with β2microglobulin before ( p < 0.001) and after ( p = 0.031) therapy. There were no differences in any of the aforementioned parameters in the “watch and wait” group during observation. A positive correlation between GDF-15 and β2 microglobulin in patients with indolent LPN who need treatment suggests potential value in risk assessment.

BackgroundThe aging process is a normal physiological phenomenon and has an impact on the body composition and physical fitness of the elderly. It is characterized by a progressive increase in total body fat mass, a decrease in muscle mass and changes in distribution in terms of an increase in abdominal fat tissue. These changes in the elderly have a great impact on health, functional capacity, and quality of life. The variability of body composition components contributes to the origin and progression of pathology and disability. Today osteodensitometric examination is considered one of the most versatile imaging techniques for assessing osteoporosis, sarcopenia, and obesity, and is currently the only technique capable of identifying all of these conditions at the same time. Osteoporosis is characterized by low bone mass and microarchitectural bone loss, leading to an increased risk of fracture caused by a minor trauma.ObjectivesTo determine the presence of normal values of T score, osteopenia and osteoporosis, to determine the distribution of BMI and values of lean muscle mass, adipose tissue and visceral adipose tissue of the examined population.MethodsIn this retrospective study conducted from March to April 2019 at the University Clinical Center of Vojvodina, 699 respondents of both sexes over 65 participated. Exclusion criteria were established osteoporosis and treatment. The research consisted of collecting general information of the respondents (gender, age, smoking status, level of education, marital status). Body composition (BMD, FM, VAT, LM) was measured by osteodensitometric examination. Also, all subjects body weight, and height were measured and their body mass index (BMI) was determined.ResultsThe average age of respondents was 71.92 ± 5.14, most respondents 50.6% have secondary education, 52.2% are married, 9.5% are smokers. The classification of the total T score shows a normal finding in 26.8%, with osteopenia 58.4% and with osteoporosis 14.8% of subjects. According to (BMI) with a normal finding is 16.5%, overweight is 38.5% and obese 45% of respondents. The average BMI of men is 28.79 ± 4.01, and for women the average BMI is 29.92 ± 4.91. The average value of VAT is 1,537 ± 0,820, FM 31,105 ± 9,152 and LM 43,735 ± 8,279. Men have higher average VAT values (2.06 ± 0.90) compared to women (1.32 ± 0.67). The average FM is higher in women (32.49 ± 8.88) than in men (27.60 ± 8.89). The average LM is higher in men (53.38 ± 7.05) than in women (39.92 ± 4.97). Subjects with normal findings were 61.5% obese, with osteopenia 40.2%, and with osteoporosis 28% obese. The measured value of LM in persons with normal findings is 47,921 ± 8,738, with osteopenia 42,342 ± 7,378, with osteoporosis 40,443 ± 6,949. The measured value of FM in persons with normal findings is 34.37 ± 9.51, with osteopenia 30.20 ± 8.75, and with osteoporosis 27.60 ± 7.14. The measured value of VAT in persons with normal findings is 34.37 ± 9.51, with osteopenia 34.37 ± 9.51, with osteoporosis 27.60 ± 7.14.ConclusionHigher values of BMI, LM, FM, and VAT have a positive effect on the hip and spine T score, and a protective role against osteoporosis.References[1]Salvio G, Petrelli M, Paolini S, Baldini V, Sbaffi C, Basili S, Giordano A, Balercia G, Cinti S. Gender-specific effects of capsiate supplementation on body weight and bone mineral density: a randomized, double-blind, placebo-controlled study in slightly overweight women. J Endocrinol Invest. 2023 Jan 6. doi: 10.1007/s40618-022-01999-w [2]Pana TA, Kioh SH, Neal SR, Tan MP, Mat S, Moayyeri A, Luben RN, Wareham NJ, Khaw KT, Myint PK. Body Fat Percentage and the Long-term Risk of Fractures. The EPIC-Norfolk Prospective Population Cohort Study. Maturitas. 2023 Feb;168:71-77. doi: 10.1016/j.maturitas.2022.11.005. [3]Chen YC, Wang YW, Ko CH, Chen JF, Hsu CY, Yu SF, Cheng TT. Hip BMD is associated with visceral fat change: a registry study of osteoporosis and sarcopenia. Ther Adv Chronic Dis. 2022 Nov 17;13:20406223221134051. doi: 10.1177/20406223221134051.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Myelodysplastic syndromes (MDS) are a group of heterogeneous disorders caused by the accumulation of somatic mutations in the hematopoietic stem and progenitor compartment. Besides del(5q), SF3B1 or TP53 mutations, referred to as defining genetic abnormalities, mutation patterning hardly structured the classification of MDS. Mutations in epigenetic factors occur early in the development of clonal hematopoiesis leading to precocious alterations of DNA methylation implicated in oncogenesis. Convergent DNA methylation patterns related to both mutations and microenvironment imprinting may induce specific gene expression profiles and contribute to phenotypic variations. To refine a pathophysiological classification of lower-risk MDS, we combined genetic profiling to DNA methylation and transcriptome data. Methods: We enrolled 543 lower-risk treatment-naïve MDS patients at diagnosis and performed DNA-sequencing of 24 genes. DNA methylation and RNA-sequencing data were generated in a representative subset of 175 cases with available material (75 MDS-SLD/MLD, 40 MDS-EB1, 53 MDS-RS-SLD/MLD, 5 MDS del(5q), 2 MDS-U) and 7 age-matched healthy controls. IPSS-R was very low, low or intermediate in 87.4%. During a median follow-up of 2 years, 16% of MDS cases progressed to AML (MDSp). Infinium EPIC 850K array allowed after filtering the examination of methylation of 723,612 CpG sites with enrichment at enhancers and promoters. Differentially methylated regions with differentially methylated CpG sites (DMR-CpG) between cases and controls were defined with a minimum of 2 probes, a Benjamini-Hochberg-adjusted P-value cut-off of 0.05, a false discovery rate of 0.001 and a mean Δβ-value >20% at CpG sites. Consensus motifs for transcription factors were identified using Homer. Results: Unsupervised clustering on genetic profiling of 543 patients identified distinct subsets of lower-risk MDS with different clinical features: one cluster (group A) was enriched in del(5q), three clusters were characterized by SF3B1 mutations, either isolated (group B) or associated with DNMT3A (group E) or TET2 (group F), while the two remaining clusters were enriched in either complex pattern of mutations (group C) or SRSF2 mutations (group D). Genetic clusters showed significantly different clinical outcomes, clusters C, D and E having lower overall survival and higher risk of progression to high risk MDS or AML compared to other clusters. In the subset of 175 cases, a total of 2,953 unique DMR-CpGs allowed a robust repartition of patient samples in 4 groups using the k-means method. The 4 methylation groups were clinically distinct in terms of age, hemoglobin, neutrophils, monocytes, platelets, BM blasts, WHO classification, IPSS-R, and mutation pattern. A significant correlation was found between genetic and methylation groups ( P<0.001). Hypomethylated CpGs defined group 4 which was enriched in MDS-RSwith low blast count and few co-mutations, while groups 1 and 3 demonstrated hypermethylated profiles driven by TET2/ IDH1-2 mutations and TET2/ SRSF2 mutations, respectively. TET2-mutated cases exhibited an increased proportion of hypermethylated DMR-CpGs at enhancers (DME) significantly enriched in C/EBP and ETS family transcription factor motifs. In MDS without evidence of progression, we identified 1,418 DME and their gene targets of which those significantly deregulated in RNA-seq were involved in the control of translation and response to TGF-β. By contrast, in MDS with rapid progression to AML, DMR-CpGs were significantly enriched at CpG islands and promoters ( P<0.0001) and a set of 10-20 genes downstream of these promoters were specifically deregulated. Conclusion: Somatic mutations and DNA methylation at enhancers and promoters identify distinct subsets of lower-risk MDS with different clinical behavior. Hypermethylation at enhancers with C/EBP or ETS family motifs is a hallmark of MDS and may account for changes in transcription factor recruitment and cell fate. Hypermethylation of promoters with downstream effects on gene expression may indicate a propensity to rapid evolution to AML.

Background: Allogeneic hematopoietic stem cell transplantation is the only curative treatment for myelodysplastic syndrome (MDS). How to select lower-risk (LR) patients (pts) for transplantation is a matter of debate. The International Working Group for Prognosis in MDS (IWG) defined intermediate IPSS-R risk pts as a higher-risk if IPSS-R score is above 3.5. MDS-RIGHT criteria recommend transplantation in LR-MDS if: very/poor risk cytogenetics, >50% blasts increase from baseline or >15% BM blasts, neutrophils <0.3x109/l, platelets <30x109/l, high transfusion intensity ≥2 units/month for 6 months, progression to higher risk IPSS-R group or drop of platelets >25% in 6 months (MDS Europe. https://www.mds-europe.org). Aims: The primary aim of the study was to compare the survival of LR-MDS pts candidate for transplant by IWG and MDS-RIGHT criteria with non-candidate pts using registry data. The secondary aim was to compare the survival of IWG and MDS-RIGHT registry based cohorts with survival in published transplant cohort. Methods: 2284 pts from the EUMDS registry with LR-MDS (very/low and intermediate risk IPSS-R) were included in the registry based cohort. Survival analysis of pts meeting IWG and MDS-RIGHT criteria at baseline, 6 and 12 months was done in all candidates and those fit for transplantation, defined by Karnofsky ≥70, HCT-CI <3 according to MDS-RIGHT. Systematic review of transplantation studies in MDS was conducted. Published survival from transplant cohort were compared to the registry based cohorts. Results: Number of all and fit [Nall (Nfit, %)] candidates for transplant at baseline, 6 and 12 months was: IWG: 280 (146, 52%), 15 (5, 33%) and 22 (0, 0%); MDS-RIGHT: 182 (97, 53%), 428 (112, 26%) and 125 (39, 31%), respectively. Median OS, PFS and LFS survival in candidate and non-candidate patients at baseline were significantly different (p<0.01). Median OS was: IWG: 2.5 vs 4.6 years; MDS-RIGHT: 3.3 vs 4.6 years (Fig.1A and B). MDS-RIGHT pts with IPSS-R >3.5 (28% of IWG group) shown unfavorable median OS comparing with other pts (1.5 vs 4.8 years, p <0.001, Fig.1C). Published OS of transplanted intermediate IPSS-R risk pts (Scheid et al., BMT 2017) at 12, 24 and 36 months was: 59%, 48%, and 43%. Survival in IWG and MDS-RIGHT pts was better at all time points. MDS-RIGHT pts with IPSS-R >3.5 had higher survival at 1 year (68%) but worse survival at 2 and 3 years (42% and 33%) (p=0.07, Fig.1D). Summary/Conclusion: Both transplant selection criteria identify LR-MDS patients with unfavorable survival. MDS-RIGHT pts with IPSS-R above 3.5 have particularly unfavorable prognosis. There is no clear evidence for upfront transplantation in any of prognostic group.Keywords: Myelodysplastic syndrome, Prognosis, Allogeneic hematopoietic stem cell transplant

Introduction. We present the recommendations for treatment of the lower-risk myelodysplastic syndromes on behalf of the Serbian myelodysplastic syndromes group. Material and Methods. A literature review was conducted using the following bibliographic databases: Google Scholar, MEDLINE and Kobson. The recommendations for treatment of lower-risk myelodysplastic syndromes are based on expert opinion based on review of the literature and contemporary recommendations for treatment of lower risk myelodysplastic syndromes. Recommendations. Anemia is the most relevant cytopenia in terms of frequency and symptoms in lower-risk myelodysplastic syndromes, and may be treated successfully with erythropoietic stimulating agents, with or without granulocyte growth factor, provided a careful selection is performed on the basis of Revised International Prognostic Scoring System, endogenous erythropoietin levels, and transfusion independence. In case a patient fails erythropoietic stimulating agents treatment, the available options may include lenalidomide, hypomethylating agents, and a rather large number of experimental agents. Chelation therapy is recommended in patients who have received or are anticipated to receive > 20 red blood cell transfusions and those with serum ferritin levels > 2500 ng/mL. Specific therapy for thrombocytopenia has been proposed in experimental clinical trials with thrombomimetic agents that have shown good efficacy, but raised some safety concern. Severe neutropenia is targeted symptomatically with growth factor supportive care. The immunosuppressive treatments are indicated mainly for pancytopenia, hypoplastic lowerrisk myelodysplastic syndromes. Finally, hematopoietic stem cell transplantation is the curative option for younger, good performance (fit) lower-risk patient with poor risk features, according to European Blood and Marrow Transplantation/European Leukemia Net International expert panel and myelodysplastic syndrome-RIGHT group. Conclusion. Treatment of myelodysplastic syndromes is mainly based on resolution of symptoms due to particular cytopenia(s).

Introduction. Myelodysplastic syndromes represent clonal neoplastic disorders characterized by hematological dysplasia, ineffective hematopoiesis, cytopenia, and increased risk of transformation to acute myeloid leukemia. Material and Methods. A literature review was conducted using the following bibliographic databases: Google Scholar, MEDLINE, and Kobson. The recommendations for diagnosis, classification, and prognosis are based on expert opinions grounded on a review of the literature and contemporary recommendations for diagnosis and prognosis in myelodysplastic syndrome. Diagnosis and classification. Diagnosis of myelodysplastic syndrome should be based on detailed patient and family history, physical examination, and comprehensive blood examinations in to exclude all other causes of cytopenia and dysplasia. Mandatory for myelodysplastic syndrome diagnosis is cytology of blood and bone marrow, bone marrow biopsy with immunohistology and cytogenetics. 2016 World Health Organization classification should be used for myelodysplastic syndrome diagnosis. SF1B3 genetic analysis is recommended in patients with suspected myelodysplastic syndrome with ringed sideroblasts and p53 mutation status. Prognosis. Revised International Prognostic Scoring System for myelodysplastic syndrome (IPSS-R) risk score should be defined for every patient in order to determine prognosis. The next-generation sequencing could provide additional diagnostic and prognostic information, particularly in young transplant candidates. Conclusion. Myelodysplastic syndrome diagnosis is based on the 2016 World Health Organization classification. The prognosis should be based on the Revised International Prognostic Scoring System with the possible addition of genetic analysis.

Introduction. The myelodysplastic syndromes are a group of clonal haematopoietic stem cell disorders characterized by cytopenia, dysplasia, ineffective hematopiesis, recurrent genetic abnormalities, and increased risk of developing acute myeloid leukemia. In this paper, we present the review and recommendations for treatment of high risk myelodysplastic syndromes on behalf of the Serbian myelodysplastic syndromes group. Material and Methods. A literature review was conducted using the following bibliographic databases: Google Scholar, MEDLINE and Kobson. The recommendations treatment of high risk myelodysplastic syndromes are based on expert opinion based on review of literature and contemporary recommendations for treatment of high risk for myelodysplastic syndromes. Recommendations. Higher-risk myelodysplastic syndromes should be defined in patients risk group with > 3.5 IPSS-R score. Allo- HSCT is recommended in fit higher-risk patients with IPSS-R > 3.5 as well as in fit lower-risk patients with poor risk features according to EBMT/ELN International expert panel and myelodysplastic syndromes right group. Acute myeloid leukemia like or hypomethylation treatment before Allo-HSCT is indicated in patients with myelodysplastic syndromes with ? 10% of blasts. Azacitidine is recommended in intermediate-2 and high risk IPSS patients who are not eligible for transplantation with minimal number of six cycles to define response. Acute myeloid leukemia like treatment is recommended in fit higher-risk for patients with myelodysplastic syndromes with excess of blasts, good performance status, without substantial comorbidities, and with no poor/very poor cytogenetics/genetics. Conclusion. The treatment of fit higher-risk patients should be based on allo-SCT. In patients who are not candidates for transplant hypomethylation treatment is indicated as well as acute myeloid leukemia like treatment in selected patients.

Background/Aim. The treatment of chronic myeloid leukemia (CML) has changed dramatically with the advent of targeted therapies. This study aimed to assess the efficacy of generic imatinib in CML patients treated in our center. Methods. The study was retrospective. It included 101 patients diagnosed with CML ? chronic phase (CP). The patients were divided into two groups. Group 1 included 55 patients initially treated with branded imatinib and then switched to generic imatinib. Group 2 consisted of 46 newly diagnosed patients who received only generic imatinib from the beginning of therapy. Results. The patients were treated with branded imatinib for the mean of 42 months (range 6?132 months) before switching to generic imatinib. Treatment with generic imatinib lasted for 25 months on average (range 3?66 months). A quarter of the patients from the group 1 lost their cytogenetic reponse after being switched to generic imatinib, but with-out signs of transformation to acute leukemia. The patients treated with branded imatinib had a significantly longer event-free survival (EFS) and failure-free survival (FFS) (log-rank p = 0.01 and p = 0.03, respectively). These results could have been influenced by frequent changes of the brand and dosage formulation of generic imatinib. Conclusions. Our study showed a significantly longer EFS and FFS in the patients who were initially treated with branded imatinib, compared to those treated with generic imatinib only. These results provide useful information, but have to be interpreted within the context of the crossover study.

Introduction. The development of inflammatory bowel disease during the treatment with tumor necrosis factor-? inhibitors is seen in patients with ankylosing spondylitis. Crohn?s disease is the mainly developing form, and etanercept is the most frequently associated agent. Although thrombocytosis in patients with ankylosing spondylitis and inflammatory bowel diseases is often seen due to chronic inflammation, iron deficiency anemia or drug administration, presence of essential thrombocythemia is not common. To our knowledge, there is no published data of coexistence of these three diseases in one patient. Case report. We reported a 35-year-patient with simultaneous presentation of ankylosing spondylitis and essential thrombocythemia. Due to hepatotoxicity of initial treatment with sulfasalazine and metotrexate, tumor necrosis factor-? inhibitor (etanercept) was introduced. Both diseases were well controlled until Crohn?s disease emerged. Two years after switching from etanercept to adalimumab all three coexisting diseases were in remission. Conclusion. Treatment with tumor necrosis factor-? inhibitors significantly improved clinical outcome of patients with chronic inflammatory diseases. However, the appearance of adverse effects may cause a discontinuation or change of a drug. The existence of comorbidities additionally complicates the treatment of such patients.

Introduction. Bacterial blood infections during febrile neutropenia episodes are urgent medical conditions which were and still are the main cause of morbidity and mortality among patients with hematologic malignancies. The aim of this study was to determine the incidence and clinical characteristics of bacteremia, infectious agents, presence and incidence of antibiotic resistance, as well as the treatment outcome of bloodstream infections in patients with hematologic malignancies. Material and Methods. A three-year retrospective study included 107 patients with hematologic malignancies and positive blood culture results during febrile neutropenia. Results. The most common isolates were Gram-negative bacteria (58.5%), with Escherichia coli being the most frequent pathogen. The Gram-negative microorganisms were mostly sensitive to carbapenems in 70.7%, whereas sensitivity to other antibiotics was as follows: piperacillin/ tazobactam 62%, amikacin 58.5%, and third-generation cephalosporins 50.5%. Acinetobacter spp. was sensitive only to colistin (94.1%). The antibiotic sensitivity among Gram-positive bacteria was highest to linezolid (97.1%), followed by teicoplanin (81.4%) and vancomycin (81.4%). In our patients, the mortality rate during the first 28 days from the moment of positive isolates was high (37.4%). Most patients died within the first seven days. Bacterial blood infections caused by Gram-negative bacteria were associated with significantly higher mortality (?2 = 4.92, p = 0.026). Acinetobacter spp. was isolated in almost half of the patients with fatal outcome, of whom 62.5% died in the first 24 hours. Conclusion. Bacterial bloodstream infections are severe complications with a high rate of mortality in febrile neutropenic hematological patients. Gram-negative bacteria were the most common isolates in our Clinic, with high mortality. It is of utmost importance to constantly monitor the resistance of bacteria to antibiotics, as well as to prevent and control the spread of resistant strains. Antibiotics resistance patterns should regularly be followed.

Available evidence suggests that in most patients with LR-MDS the risk of death is not related to disease progression but is mainly attributable to non-leukemic death. 2,17 In addition, a proportion of these patients have prolonged survival that precludes the design of clinical trials adopting OS as a primary endpoint. These challenges have resulted in potentially biased assessment of the effectiveness and appropriate use of the available interventions in this patient population. The EUMDS Registry has identified novel meaningful outcome indicators and clinical endpoints, and reliable measures of response to HCI (Figure 4). The results of our analysis indicate that RBCT density is strongly associated with a decreased OS, even at relatively low dose densities. In addition, we observed that an early decrease in platelet count is an independent adverse prognostic indicator in LR-MDS, and combining relative platelet drop and transfusion dependency allows early identification of patients at risk of rapid progression, and may guide early therapeutic interventions, including allogeneic hematopoietic stem cell transplantation or experimental interventions. Taken together, these results indicate that regular RBCT requirement, early platelet count kinetics, and restriction in HRQoL are early independent and meaningful outcome indicators, and reliable measures of effectiveness of therapeutic interventions, evaluated in this set of studies. These findings support the integration of RBCT requirement and HRQoL in the general core outcome sets and in response criteria in patients with LR-MDS, and have important implications for clinical practice and the design of clinical endpoints. Our results strongly support the adoption of freedom from transfusion as a meaningful clinical endpoint in patients with LR-MDS. Anemia is the main determinant of therapeutic intervention in patients with LR-MDS, and ESA are recommended as first-line treatment for patients with symptomatic anemia. 10 The observational studies within the EUMDS Registry showed that the response rate, as well as the capacity of these agents to delay the onset of a regular RBCT need, is most pronounced in RBCT-naive patients. These results identified early initiation of treatment with ESA as a major treatment response indicator, and indicate that ESA should be recommended in LR-MDS patients with symptomatic anemia before starting regular RBCT. After the onset of RBCT dependency, patients with LR-MDS are prone to long-term accumulation of iron. 1,43 The EUMDS Registry studies provided evidence that elevated LPI levels are associated with reduced survival in RBCT dependent patients, whereas iron chelation therapy normalizes LPI levels. These findings suggest that NTBI and LPI may serve as early indicators of iron toxicity and a means to measure the effectiveness of iron chelation therapy in patients with LR-MDS. However, qualified NTBI and LPI are only currently available in specialized laboratories. 44 Large observational cohorts with detailed clinical and laboratory data, like the EUMDS cohort, are the ideal framework in which to identify well defined MDS subtypes that may benefit from novel targeted treatments. An example of such a subtype is MDS with loss of parts of chromosome 5, namely del5q; these patients have a relatively favorable outcome on lenalidomide treatment. In order to identify homogeneous subsets of patients within MDS, preliminary evidence has suggested that recently identified mutations in splicing factors may recognize distinct disease entities within myeloid neoplasms. 45 Splicing modulators are now in pre-clinical testing, and are very likely to lead to the introduction of effective drugs for specific groups of MDS patients. Luspatercept, a specific inhibitor of growth and differentiation factor-11, a member of the transforming growth factor β superfamily, induced substantial improvement of anemia, especially in patients with ring sideroblasts. 46 Characterization of individual cases by new genetic markers (one of the main objectives of the MDS-RIGHT project) will allow refined classification of patients into biological subgroups that are expected to respond differently to therapeutic interventions to guide discontinuation of those interventions that are less effective or less cost-effective. The main question is whether RCT data and retrospective cohort data in selected tertiary care centers are representative of the 'real world' data of the older patients with LR-MDS in the general population. A careful comparison of the 'real world' data and the RCT data will be needed in order to provide a clear answer to these questions. Meanwhile, the current analyses of data collected over 10 years in the EUMDS Registry provides relevant and important information which could help assess prognosis and response to standard interventions in this older patient group.

Introduction: Evidence on long-term effectiveness and cost effectiveness of treatment sequences for multiple myeloma (MM) is sparse. We used published data and country-specific data to assess the cost effectiveness of four-line treatment sequences for elderly transplant-ineligible patients with MM in Serbia. Method: We developed a Markov cohort model to compare long-term effectiveness and cost effectiveness of five sequential MM treatment alternatives from the perspective of the national healthcare provider. Effectiveness parameters on progression, mortality and adverse events were extracted from published clinical trials. Costs were based on price lists of the National Health Insurance Fund. We compared life expectancy, costs, and incremental cost-effectiveness ratios among alternative courses of action. The model was analyzed over a lifelong time horizon applying a 3% annual discount rate for effectiveness outcomes and costs. Robustness of the model was tested in multiple deterministic sensitivity analyses. Results: The sequences were defined by the frontline treatment: MPT (melphalan-prednisone-thalidomide), MPV (melphalan-prednisone-bortezomib), CTD (cyclophosphamide-thalidomide-dexamethasone), VCD (bortezomib-cyclophosphamidedexamethasone) and BP (bendamustine-prednisone). MPV sequence resulted in the highest remaining life expectancy (4.76 life years). Cost-effectiveness analysis resulted in three non-dominated strategies: MPT, VCD, and MPV sequences, with an incremental cost-effectiveness ratio of EUR 35,300 per life-year gained (LYG) for VCD and EUR 47,200/LYG for MPV relative to MPT. Conclusion: MPV sequence was the most effective in terms of life expectancy for elderly transplant-ineligible MM patients in Serbia. Bortezomib-based strategies would be recommended for the frontline treatment of patients with MM in Serbia if the willingness-to-pay threshold is around EUR 35,000-60,000/LYG.