Browsing by Author "Bogdanovic, Andrija (6603686934)"

The objective of the study was to investigate factors related to the occurrence of myelodysplatic syndromes (MDS) in the population of Belgrade (Serbia Montenegro). The case-control study was conducted during the period 2000-2003. The study group consisted of 80 newly diagnosed MDS patients and 160 sex- and age-matched hospital controls with nonmalignant and noninfectious diseases. The disease categories in the control group were circulatory (51 patients, 32%), gastrointestinal (53 patients, 33%), and ophthalmological (56 patients, 35%) disorders. Conditional univariate and multivariate logistic regression analyses were applied. Multivariate analysis showed the following factors to be significantly related to MDS: exposure to chemicals (OR=10.8, 95%CI 3.2-36.2, p=0.0001), viral upper respiratory tract infections (twice a year or more, OR=5.8, 95%CI 2.5-13.6, p=0.0001), exposure to insecticides, pesticides and herbicides (OR=5.2, 95%CI 1.8-15.1, p=0.003), coffee (OR=5.1, 95%CI 1.9-13.7, p=0.001), and alcohol consumption (OR=2.2, 95%CI 1.1-4.6, p=0.033). The findings support the hypotheses that exposure to chemical agents, pesticides, insecticides, and herbicides, certain lifestyle factors (alcohol and coffee consumption), and frequent viral infections may be involved in the etiology of MDS, but these results should be confirmed by further investigations. © Springer-Verlag 2006.

Based on the results of clinical trials, there is no global consensus on the optimal first-line therapy for patients with advanced Hodgkin lymphoma (HL) with both ABVD and BEACOPP currently being used. However, the results of clinical trials are usually better than those in daily practice. We thus describe here our experience on 314 advanced classical HL patients treated with ABVD at the Clinical Center of Serbia and associated centers between 1997 and 2008. The median follow-up for all patients was 91 months; the estimated 5-yr event-free survival was 62% and the 5-yr overall survival (OS) 76%. Multivariate Cox regression analysis revealed that patients with IPS ≥ 3 and extranodal disease involving more than one site have a poorer outcome. The data presented here show on overall improvement in outcome as compared to more previous data and illustrate the problems of treating advanced stage HL outside the setting of a clinical trial. © 2014 John Wiley & Sons A/S.

Purpose: Despite major advances in the treatment of diffuse large B cell lymphoma (DLBCL), approximately one third of the patients progress or die, suggesting the existence of additional oncogenic events. The purpose of this study was to evaluate the prognostic value of the "Hans classifier", and BCL2 and MYC protein expression and gene alterations in DLBCL patients treated with CHOP or R-CHOP chemotherapy over a 5-year period. Furthermore, we tried to correlate these parameters with the International Prognostic Index (IPI). Methods: The immunohistochemical (IHC) expression of CD10, BCL6, MUM1 and BCL2 on paraffin-embedded formalin-fixed tumor samples from 103 centroblastic DLBCLs was analyzed. IHC expression of MYC and fluorescence in situ hybridization (FISH) for MYC and BCL2 gene alterations was performed on 67 samples using the tissue microarray (TMA) method. Results: The Hans algorithm was not predictive of survival in both therapy groups. No significant difference in BCL2 and MYC alterations or MYC protein expression in relation to complete response (CR), event-free survival (EFS) and overall survival (OS) was observed in our study. High IPI correlated significantly with poor outcome and it was identified as independent prognostic factor for OS and EFS (both p=0.000). The 5-year OS was 61% in the R-CHOP compared to 38% in the CHOP group (p=0.007). Rituximab significantly improved the OS in the BCL2 positive (60 vs 29%, p=0.008), and the BCL6 negative (73 vs 25%, p=0.001) cases. Conclusion: IPI is an independent prognosticator for DLBCL patients and the addition of rituximab significantly improved survival. Furthermore, patients with BCL2+ and BCL6- DLBCL benefited from R-CHOP.

Purpose: Despite major advances in the treatment of diffuse large B cell lymphoma (DLBCL), approximately one third of the patients progress or die, suggesting the existence of additional oncogenic events. The purpose of this study was to evaluate the prognostic value of the "Hans classifier", and BCL2 and MYC protein expression and gene alterations in DLBCL patients treated with CHOP or R-CHOP chemotherapy over a 5-year period. Furthermore, we tried to correlate these parameters with the International Prognostic Index (IPI). Methods: The immunohistochemical (IHC) expression of CD10, BCL6, MUM1 and BCL2 on paraffin-embedded formalin-fixed tumor samples from 103 centroblastic DLBCLs was analyzed. IHC expression of MYC and fluorescence in situ hybridization (FISH) for MYC and BCL2 gene alterations was performed on 67 samples using the tissue microarray (TMA) method. Results: The Hans algorithm was not predictive of survival in both therapy groups. No significant difference in BCL2 and MYC alterations or MYC protein expression in relation to complete response (CR), event-free survival (EFS) and overall survival (OS) was observed in our study. High IPI correlated significantly with poor outcome and it was identified as independent prognostic factor for OS and EFS (both p=0.000). The 5-year OS was 61% in the R-CHOP compared to 38% in the CHOP group (p=0.007). Rituximab significantly improved the OS in the BCL2 positive (60 vs 29%, p=0.008), and the BCL6 negative (73 vs 25%, p=0.001) cases. Conclusion: IPI is an independent prognosticator for DLBCL patients and the addition of rituximab significantly improved survival. Furthermore, patients with BCL2+ and BCL6- DLBCL benefited from R-CHOP.

[No abstract available]

Treatment of hairy cell leukemia (HCL) with alfa-interferon and purine analogs significantly prolongs survival in these patients. However, with life prolongation, an increased risk of secondary malignancies has been reported. Acute myeloid leukemia (AML), as a second malignancy after HCL treatment is extremely rare and has been reported in only 12 cases so far. We here report additional 2 cases of CD56+ AML developed after sustained clinical remission of HCL achieved with cladribine (2 and 6 years after, respectively). The first patient refused chemotherapy and shortly thereafter died. The second patient responded to chemotherapy and was successfully allo-transplanted. Three years later, the patient is in stable clinical remission, which is a unique case in the literature. In conclusion, it is not clear whether development of AML in HCL patients is caused by mutagenic potential of the applied chemotherapy or by immune suppression/ perturbations as a characteristic of the underlying disease. © 2019 The Author(s).

[No abstract available]

Treatment-free remission (TFR) after discontinuation of tyrosine kinase inhibitor therapy is now an emerging treatment goal for patients with chronic myeloid leukemia, who have achieved a deep and stable response to treatment. Although guidance is now available, patients’ questions regarding this progressive concept have yet to be addressed. The overall aim of this European Steering Group is a patient-centered approach that educates patients on their treatment options, including TFR, facilitates better patient–physician relationships, and meets patients’ emotional and psychological needs. The present report outlines 5 key topic areas on discontinuing tyrosine kinase therapy and the implications of TFR for patient–physician consideration: what TFR is; when TFR is appropriate; which patients might and might not be eligible for TFR; and patients’ considerations for discontinuing therapy, such as tyrosine kinase withdrawal syndrome, potential psychological implications, molecular recurrence, and repeat treatment. This Steering Group advocates that patients with chronic myeloid leukemia should have access to high-quality, frequent molecular monitoring and be treated in a specialist center with appropriate medical and psychological support. As patient concerns with attempting TFR become forefront in patient–physician discussions, a greater number of eligible patients might be willing to discontinue therapy. © 2018 The Authors

Treatment-free remission (TFR) after discontinuation of tyrosine kinase inhibitor therapy is now an emerging treatment goal for patients with chronic myeloid leukemia, who have achieved a deep and stable response to treatment. Although guidance is now available, patients’ questions regarding this progressive concept have yet to be addressed. The overall aim of this European Steering Group is a patient-centered approach that educates patients on their treatment options, including TFR, facilitates better patient–physician relationships, and meets patients’ emotional and psychological needs. The present report outlines 5 key topic areas on discontinuing tyrosine kinase therapy and the implications of TFR for patient–physician consideration: what TFR is; when TFR is appropriate; which patients might and might not be eligible for TFR; and patients’ considerations for discontinuing therapy, such as tyrosine kinase withdrawal syndrome, potential psychological implications, molecular recurrence, and repeat treatment. This Steering Group advocates that patients with chronic myeloid leukemia should have access to high-quality, frequent molecular monitoring and be treated in a specialist center with appropriate medical and psychological support. As patient concerns with attempting TFR become forefront in patient–physician discussions, a greater number of eligible patients might be willing to discontinue therapy. © 2018 The Authors

The widely used current International Prognostic Scoring System (IPSS) for primary myelofibrosis (PMF) is based on clinical parameters. The objective of this study was to identify additional prognostic factors at the time of diagnosis, which could have an impact on the future treatment of patients with PMF. We conducted a study of 131 consecutive PMF patients with median follow-up of 44 months. Data on baseline demographics, clinical and laboratory parameters, IPSS, grade of bone marrow fibrosis (MF), as well as influence of concomitant comorbidities were analyzed in terms of survival. Comorbidity was assessed using the Adult Comorbidity Evaluation-27 (ACE-27) score and the hematopoietic cell transplantation comorbidity index. An improved prognostic model of survival was obtained by deploying the MF and ACE-27 to the IPSS. A multivariable regression analyses confirmed the statistical significance of IPSS (P < 0.001, HR 3.754, 95 % CI 2.130-6.615), MF > 1 (P = 0.001, HR 2.694, 95 % CI 1.466-4.951) and ACE-27 (P < 0.001, HR 4.141, 95 % CI 2.322-7.386) in predicting the survival of patients with PMF. When the IPSS was modified with MF and ACE-27, the final prognostic model for overall survival was stratified as low (score 0-1), intermediate (score 2-3) and high risk (score 4-6) with median survival of not reached, 115 and 22 months, respectively (P < 0.001). Our findings indicate that the combination of histological changes, comorbidity assessment and clinical parameters at the time of diagnosis allows better discrimination of patients in survival prognostic groups and helps to identify high-risk patients for a poor outcome. © 2014 Springer Science+Business Media New York.

The widely used current International Prognostic Scoring System (IPSS) for primary myelofibrosis (PMF) is based on clinical parameters. The objective of this study was to identify additional prognostic factors at the time of diagnosis, which could have an impact on the future treatment of patients with PMF. We conducted a study of 131 consecutive PMF patients with median follow-up of 44 months. Data on baseline demographics, clinical and laboratory parameters, IPSS, grade of bone marrow fibrosis (MF), as well as influence of concomitant comorbidities were analyzed in terms of survival. Comorbidity was assessed using the Adult Comorbidity Evaluation-27 (ACE-27) score and the hematopoietic cell transplantation comorbidity index. An improved prognostic model of survival was obtained by deploying the MF and ACE-27 to the IPSS. A multivariable regression analyses confirmed the statistical significance of IPSS (P < 0.001, HR 3.754, 95 % CI 2.130-6.615), MF > 1 (P = 0.001, HR 2.694, 95 % CI 1.466-4.951) and ACE-27 (P < 0.001, HR 4.141, 95 % CI 2.322-7.386) in predicting the survival of patients with PMF. When the IPSS was modified with MF and ACE-27, the final prognostic model for overall survival was stratified as low (score 0-1), intermediate (score 2-3) and high risk (score 4-6) with median survival of not reached, 115 and 22 months, respectively (P < 0.001). Our findings indicate that the combination of histological changes, comorbidity assessment and clinical parameters at the time of diagnosis allows better discrimination of patients in survival prognostic groups and helps to identify high-risk patients for a poor outcome. © 2014 Springer Science+Business Media New York.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired clonal haematological disease characterized by complement-mediated haemolysis, bone marrow failure and venous thrombosis. Anticomplement therapy eculizumab improves survival and reduces complications. Severe acute respiratory distress syndrome corona virus 2 (SARS-CoV-2) disease 2019 (COVID-19) is associated with high incidence of both venous and arterial thrombosis in hospitalized patients with pneumonia. Deep venous thrombosis (DVT) as the presenting symptom of COVID-19 is a rare event. We describe a well-controlled PNH patient on eculizumab for more than 5 years who presented with DVT, while on warfarin, as the first sign of COVID-19. To our knowledge, this is the first described case of DVT in a PNH patient with COVID-19. © 2021 Georg Thieme Verlag. All rights reserved.

De novo AMLs with typical nonrandom chromosomal abnormalities are often associated with specific morphology subtypes. The t(8;21) is one of the most prominent recurrent cytogenetic aberrations (RCA) in AML, frequently associated with AML with maturation, and is characterized as a good prognostic marker. On the contrary, BCR::ABL1 rearrangement is rarely observed in AMLs, without specific morphology, carrying poor prognosis. Its distinction from blastic transformation of chronic myeloid leukemia has been a matter of long debate. The revised WHO classification (2016) recognized AML with BCR::ABL1+ as a provisional entity. The occurrence of additional cytogenetic aberrations in AML RCA within the same leukemic clone has been detected, albeit rare cases of BCR::ABL1+ were reported, mainly as subclones. Those additional cytogenetic and molecular findings seem to significantly affect patient prognosis. Conventional cytogenetic analysis, fluorescent in situ hybridization (FISH), and polymerase chain reaction (PCR) were applied at presentation and during the follow-up of the patient. We present a 34-year-old male patient with de novo AML harboring concomitant t(8;21) and t(9;22) in a single clone. The presence of both t(8;21) and Philadelphia chromosome (Ph+) in the same metaphases but in less than 100% of the analyzed cells, the p190 BCR::ABL transcript type, and absence of splenomegaly support that additional BCR::ABL1+ is a part of the main leukemic clone. These findings, accompanied with an encouraging outcome of continuous cytogenetic and molecular remission after induction therapy, support BCR::ABL1 being a secondary genetic event in AML with t(8;21). © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Background: The occurrence of myeloproliferative neoplasms (MPNs) that evolve into each other is well-described, as is this occurrence of lymphoproliferative neoplasms (LPNs). However, less is known about rare MPN/LPN coexistence, and the aim of our study was to analyze charachteristics of these patients after long term follow-up. Methods: Fourteen patients with MPN/LPN coexistence were diagnosed and treated according to guidelines at a single university center across two decades. Results: The overall median age was 53 years (22–69). MPNs patients with subsequent LPNs had a shorter period of second malignancy development and a more aggressive course of LPN, which can cause fatal outcomes. Polycythemia vera and chronic lymphocytic leukemia were most commonly associated (36%). The JAK2V617F mutation had 2/3 and cytogenetic abnormalities occurred in 1/3 of patients. MPN/LPN coexistence cases had significantly higher thrombotic potential (42.8%) and a higher third malignancy accruement frequency (21.4%) versus those without such malignancies. Conclusions: Considering the younger ages at MPN diagnosis, it is recommended to check regularly for blood lymphocytosis or lymphadenopathy occurrences and organomegaly progression faster than expected for MPN, with the aim of timely LPN diagnoses. The presence of molecular-cytogenetic abnormalities in a majority of patients indicate possible genetic instability and increased risk of development of multiple neoplasms, thus elevating thrombotic risk. © 2024 by the authors.

Background and Objectives: With the advent of novel therapies for nucleophosmin gene (NPM1)-mutated acute myeloid leukemia (AML), there is a growing need for the reliable prediction of NPM1 mutations. This study explored the role of cytomorphological features in the early prediction of NPM1-mutated AML. Materials and Methods: Altogether, 212 de novo AML cases with normal karyotypes, diagnosed and treated at a single institution within 5 years (2018–2023), were retrospectively evaluated. A final diagnosis of NPM1-mutated AML, based on the World Health Organization (WHO) integrated criteria, including real-time based identification of NPM1 mutation and normal karyotype, was established in 83/212 (39.15%) cases. Results: Cup-like blasts (CLBs), a cytomorphological feature suggestive of NPM1-mutated AML, were detected in 56/83 (67%) patients. Most cases (44/56, 78.6%) had CLB ≥ 10%. In total, 27 of 83 AML NPM1-mutated patients had no CLB morphology (missed call). Additionally, two of 212 had CLB morphology without confirmed NPM1 mutation (wrong call). The positive/negative predictive values of cytomorphological evaluation for CLB ≥ 10% were 95.7%/75.6%, with sensitivity/specificity of 53%/98.5%, while the accuracy was 80.7%. We noted an increased percentage of CLBs (≥15%) in 77.8% and 50% of patients with AML without and with granulocytic maturation, respectively (the specificity for NPM1 mutation prediction was 100%). CLB was associated with fms-like tyrosine kinase 3 (FLT3) mutation (p = 0.03), but, without statistical significance for CLB ≥ 10% and CLB ≥ 15%. Conclusions: Our investigation confirmed that the morphological identification of CLB at diagnosis represents a reliable and easily reproducible tool for the early prediction of NPM1 mutations, enabling a streamlined genetic work-up for its confirmation. This may facilitate considering the early administration of individualized therapies by clinicians for specific patients. © 2024 by the authors.

Essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (prePMF) initially have a similar phenotypic presentation with thrombocytosis. The aim of our study was to determine significant clinical-laboratory parameters at presentation to differentiate prePMF from ET as well as to develop and validate a predictive diagnostic prePMF model. This retrospective study included 464 patients divided into ET (289 pts) and prePMF (175 pts) groups. The model was built using data from a development cohort (229 pts; 143 ET, 86 prePMF), which was then tested in an internal validation cohort (235 pts; 146 ET, 89 prePMF). The most important prePMF predictors in the multivariate logistic model were age ≥ 60 years (RR = 2.2), splenomegaly (RR = 13.2), and increased lactat-dehidrogenase (RR = 2.8). Risk scores were assigned according to derived relative risk (RR) for age ≥ 60 years (1 point), splenomegaly (2 points), and increased lactat-dehidrogenase (1 point). Positive predictive value (PPV) for pre-PMF diagnosis with a score of ≥points was 69.8%, while for a score of ≥3 it was 88.2%. Diagnostic performance had similar values in the validation cohort. In MPN patients with thrombocytosis at presentation, the application of the new model enables differentiation of pre-PMF from ET, which is clinically relevant considering that these diseases have different prognoses and treatments. © 2023 by the authors.

Essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (prePMF) initially have a similar phenotypic presentation with thrombocytosis. The aim of our study was to determine significant clinical-laboratory parameters at presentation to differentiate prePMF from ET as well as to develop and validate a predictive diagnostic prePMF model. This retrospective study included 464 patients divided into ET (289 pts) and prePMF (175 pts) groups. The model was built using data from a development cohort (229 pts; 143 ET, 86 prePMF), which was then tested in an internal validation cohort (235 pts; 146 ET, 89 prePMF). The most important prePMF predictors in the multivariate logistic model were age ≥ 60 years (RR = 2.2), splenomegaly (RR = 13.2), and increased lactat-dehidrogenase (RR = 2.8). Risk scores were assigned according to derived relative risk (RR) for age ≥ 60 years (1 point), splenomegaly (2 points), and increased lactat-dehidrogenase (1 point). Positive predictive value (PPV) for pre-PMF diagnosis with a score of ≥points was 69.8%, while for a score of ≥3 it was 88.2%. Diagnostic performance had similar values in the validation cohort. In MPN patients with thrombocytosis at presentation, the application of the new model enables differentiation of pre-PMF from ET, which is clinically relevant considering that these diseases have different prognoses and treatments. © 2023 by the authors.

[No abstract available]

[No abstract available]

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder characterized by complement-mediated hemolysis. C5 inhibitors (eculizumab/ravulizumab) control intravascular hemolysis but do not prevent residual extravascular hemolysis. The newly approved complement inhibitor, pegcetacoplan, inhibits C3, upstream of C5, and has the potential to improve control of complement-mediated hemolysis. The PADDOCK and PALOMINO clinical trials assessed the safety and efficacy of pegcetacoplan in complement inhibitor-naïve adults (≥ 18 years) diagnosed with PNH. Patients in PADDOCK (phase 1b open-label, pilot trial) received daily subcutaneous pegcetacoplan (cohort 1: 180 mg up to day 28 [n = 3]; cohort 2: 270–360 mg up to day 365 [n = 20]). PALOMINO (phase 2a, open-label trial) used the same dosing protocol as PADDOCK cohort 2 (n = 4). Primary endpoints in both trials were mean change from baseline in hemoglobin, lactate dehydrogenase, haptoglobin, and the number and severity of treatment-emergent adverse events. Mean baseline hemoglobin levels were below the lower limit of normal in both trials (PADDOCK: 8.38 g/dL; PALOMINO: 7.73 g/dL; normal range: 11.90–18.00 g/dL), increased to within normal range by day 85, and were sustained through day 365 (PADDOCK: 12.14 g/dL; PALOMINO: 13.00 g/dL). In PADDOCK, 3 serious adverse events (SAE) led to study drug discontinuation, 1 of which was deemed likely related to pegcetacoplan and 1 SAE, not deemed related to study drug, led to death. No SAE led to discontinuation/death in PALOMINO. Pegcetacoplan was generally well tolerated and improved hematological parameters by controlling hemolysis, while also improving other clinical PNH indicators in both trials. These trials were registered at www.clinicaltrials.gov (NCT02588833 and NCT03593200). © 2022, The Author(s).