The treatment of chronic lymphocytic leukemia (CLL) consists of the continuous use of Bruton tyrosine kinase inhibitors (BTKis) such as ibrutinib, acalabrutinib, zanubrutinib and pirtobrutinib, or Bcl-2 inhibitors, such as venetoclax. Overall survival (OS) and progression-free survival (PFS) of CLL patients are significantly improved with the use of these therapies. Adverse effects (AEs) that can occur during treatment and the presence of pre-existing comorbidities in patients can influence subsequent treatment outcomes and, consequently, OS and PFS. Managing these AEs, including cardiologic toxicity and infections (including fungal infections), as well as treating cardiovascular and other comorbidities, can be challenging due to potential drug interactions with the medications used for the management of AEs and comorbidities. Therefore, this review examined the key challenges associated with the concomitant use of novel CLL therapies and medications for managing comorbidities and AEs. This review aims to enhance and facilitate the management of patients with CLL.

Introduction:Immune reconstitution (IR) after allogeneic stem cell transplantation has been highlighted as pivotal in achieving favorable long-term outcomes by influencing the rates of infection, graft versus host disease (GvHD) and relapse. However, data on the impact of different lymphocyte subsets influencing outcomes is conflicting. Furthermore, the importance of immune reconstitution parameters in patients previously not experiencing major post-transplant complications is lacking. Methods:We evaluated the clinical impact of day 90 NK cell, CD4+ T-cell, CD8+ T-cell, B-cell, and NKT cell counts on transplant outcomes by performing a landmark analysis in event-free patients. Lymphocyte subset counts were obtained from 70 patients undergoing in vivo T-cell depleted allogeneic transplantation from 2018 to 2024. Patients eligible for the study experienced no acute GvHD, poor graft function, graft failure, or relapse in the first three months after transplantation-prior to obtaining IR data. We associated lymphocyte subset counts to overall survival (OS), non-relapse mortality (NRM), cumulative incidence of relapse (RI), and secondary graft failure/poor graft function. Results:High NK cell counts on day 90 (>178/μL) were associated with improved OS (P=0.039) and lower rates of NRM (1-year cumulative incidence of 5.7% versus 31.4%, HR 0.16, 95% CI 0.04-0.69, P=0.014). A protective effect on RI was not found. We found no patient, disease or transplant-related variables to be significantly associated with day 90 NK cell counts. Conclusion:The results suggest that high NK cell counts on day 90 after T-cell depleted allogeneic transplantation independently protect from NRM and improve OS in patients without prior major post-transplant complications.

Background and Objectives: Hyperleukocytosis in acute myeloid leukemia (AML) is life-threatening, often complicated by leukostasis, tumor lysis syndrome (TLS), and disseminated intravascular coagulation (DIC), with very high early mortality. Leukapheresis (LA) can rapidly reduce circulating blast burden, but its effect on survival and prognostic relevance of disease markers remains unclear. Materials and Methods: We retrospectively analyzed 74 adult AML patients with WBC > 100 × 109/L treated at the University Clinical Center of Serbia between 2014 and 2024: 28 received LA plus cytoreduction (LA group), and 46 received cytoreduction alone (non-LA group). We evaluated 15-, 30-, and 90-day mortality and overall survival (OS), and assessed clinical, laboratory, and immunophenotypic predictors using Cox regression, with separate subgroup analyses. Results: Patients in the LA group had significantly higher baseline leukocyte counts and LDH (p = 0.18 and p = 0.024, respectively). Although LA resulted in a median 34% reduction in WBC, there was no statistically significant difference in early mortality: 15-day survival was 68% vs. 76% (HR 0.70, p = 0.423), 30-day survival 50% vs. 65% (HR 0.62, p = 0.197), and 90-day survival 39.3% vs. 41.3% (HR 0.85, p = 0.604). Median OS was similarly poor, about 1 month in the LA group compared to 2 months in the non-LA (HR 0.73). Across all patients, ECOG PS ≥2, elevated LDH, TLS, and DIC were the strongest indicators of early death. In the LA group, elevated LDH and increased peripheral blood (PB) monocyte count predicted 15-day mortality (p = 0.021 and p = 0.031, respectively), but lost significance by day 90. In non-LA patients, CD25 positivity (p = 0.034) and DIC (p = 0.045) predicted 15-day death. By day 90, CD25 expression (p = 0.048) remained prognostic, while PB blast percentage (p = 0.045) and PB monocyte count (p = 0.017) emerged as additional adverse prognostic predictors in the non-LA group. In multivariate analysis, higher PB blast percentage, CD25 positivity, and ECOG PS ≥ 2 independently predicted poorer OS. Conclusions: Although LA did not reduce early mortality in the entire cohort, the loss of prognostic significance of elevated LDH, high PB blast percentage, PB monocyte burden, and CD25 expression in the LA group may suggest that the intervention can attenuate the impact of biologically aggressive disease.

INTRODUCTION:The treatment of acute myeloid leukemia (AML) is accompanied by infectious complications, particularly during induction. The surge of multi-drug resistant (MDR) bacteria represents an additional problem for the health care of patients with AML. METHODOLOGY:A retrospective analysis of infectious complications was performed in 84 patients with AML undergoing induction therapy hospitalized between October 2020 and April 2023 at the Clinic of Hematology, University Clinical Centre of Serbia. RESULTS:From 84 patients and 95 bacterial isolates, Enterococcus spp. was the most frequent Gram-positive bacterium (26%), showing a 56% resistance rate to vancomycin, and a 77.3% resistance rate to carbapenems, with a 4.3% resistance rate to linezolid and no resistance to tigecycline detected. The most common Gram-negative bacterium, Klebsiella spp. (28%), was resistant to cephalosporins, carbapenems, fluoroquinolones (88%, 84.6%, and 88.5% respectively), with a sizeable resistance rate to ceftazidime/avibactam and colistin (20% and 36.4% respectively). XDR Klebsiella spp. dominated the isolated strains, being detected in 57.7% of cultures, whereas Enterococcus spp. was identified as MDR or XDR in 40% and 28% respectively. The factors associated with developing MDR infections were ECOG PS > 2 (p = 0.024), sepsis (p = 0.0016), and the presence of two or more infectious syndromes (p = 0.016). Patients with a confirmed MDR bacterial infection had a mortality rate of 36.7%. CONCLUSIONS:Our work demonstrates that the frequency of infections in this population is high, especially with MDR and XDR strains of Klebsiella spp. and Enterococcus spp., which are accompanied by high rates of early death.

Abstract Background Patients with acute myeloid leukemia (AML) are at increased risk of venous thromboembolic events (VTE). However, thromboprophylaxis is largely underused. Objectives This study aimed to determine possible VTE development risk factors and to develop a novel predictive model. Methods We conducted a retrospective cohort study of adult patients with newly diagnosed AML. We used univariate and multivariable logistic regression to estimate binary outcomes and identify potential predictors. Based on our final model, a dynamic nomogram was constructed with the goal of facilitating VTE probability calculation. Results Out of 626 eligible patients with AML, 72 (11.5%) developed VTE during 6 months of follow-up. Six parameters were independent predictors: male sex (odds ratio [OR] 1.82, 95% confidence interval [CI]: 1.077–2.065), prior history of thrombotic events (OR 2.27, 95% CI: 1.4–4.96), international normalized ratio (OR 0.21, 95% CI: 0.05–0.95), Eastern Cooperative Oncology Group performance status (OR 0.71, 95% CI: 0.53–0.94), and intensive therapy (OR 2.05, 95% CI: 1.07–3.91). The C statistics for the model was 0.68. The model was adequately calibrated and internally validated. The decision-curve analysis suggested the use of thromboprophylaxis in patients with VTE risks between 8 and 20%. Conclusion We developed a novel and convenient tool that may assist clinicians in identifying patients whose VTE risk is high enough to warrant thromboprophylaxis.

Introduction: Chemotherapy-induced neutropenia is often complicated by the development of febrile neutropenia (FN) which is associated with infections, dose reductions/delay of chemotherapy, quality of life deterioration, and increased treatment costs. Study aim: The study aims to research the association between risk factors for FN and the significance of applying G-CSF in patients with hematological malignancies. Materials and methods: We evaluated 90 patients with lymphoma, multiple myeloma (MM), and myelodysplastic syndrome (MDS) treated at the Day-care Unit of the University Clinical Center of Serbia (UCCS) Clinic for Hematology, between January and June 2024. Results: The study included 90 patients with the following diagnoses: 70 (77.8%) patients with lymphomas, 12 (13.3%) patients with MM, and 8 (8.9%) patients with MDS, of whom 42.2% (38/90) male and 57.8% (52/90) female. FN was observed in 22 (24.4%) patients, while 68 (75.6%) patients did not develop FN. The distribution of FN by lymphoma type was as follows: 57.9% in aggressive lymphomas, 31.6% in indolent lymphomas, and 10.5% in Hodgkin's lymphoma. FN was associated with a higher incidence of advanced clinical stages of disease, with 70% in stages III and IV. Patients with FN had significantly higher rates of bulky tumor mass (54.5% vs. 25%; p = 0.010), more lines of chemotherapy (p = 0.020), more cycles of chemotherapy (p = 0.027), more immunotherapy cycles (p = 0.025), as well as more infections (59.1% vs. 27.9%; p = 0.008), antibiotic use (95.5% vs. 33.8%; p = 0.004), and G-CSF administration (54.5% vs. 11.8%; p < 0.001), with more G-CSF ampoules used (5.0 vs. 1.0; p < 0.001). Higher CRP levels were also significantly associated with FN (7.2% vs. 3.3%; p = 0.012). Conclusion: Our study has shown that the number of lines of therapy, the number of immunochemotherapy cycles, the clinical stage, the presence of bulky tumor mass, and the aggressiveness of the lymphoma affected FN development.

Introduction: Acute myeloblastic leukemia (AML) is an umbrella term for a heterogeneous group of clonal neoplastic diseases of hematopoietic cells. Detecting residual leukemic cells (measurable residual disease - MRD) is the most important prognostic and predictive factor in AML. The aim: The study aims to analyze the effect of administered chemotherapy based on the results of MRD testing in patients with AML treated at the University Clinical Center of Serbia (UCCS) Clinic for Hematology. Materials and methods: Our study included the analysis of 111 AML patients, treated between January 2020 and January 2024. All diagnostic procedures performed were based on the most recent recommendations of European LeukemiaNet (ELN). Results: MRD+ patients who continued treatment with intensive chemotherapy (CHT), using full doses of 3+7 CHT as reinduction therapy, had a significantly longer remission (complete remission - CR) and a longer overall survival (OS). The duration of CR (p = 0.004) and OS (p = 0.019) were statistically significantly longer in patients who maintained a negative MRD status at the end of treatment. In transplanted patients, overall survival (OS; p = 0.006) and duration of remission (CR; p = 0.002) were significantly longer (median: OS 20 months; CR 21 months), as compared to the group of non-transplanted patients (median: OS 13 months; CR 8 months). Discussion: Measurable residual disease (MRD) can be both prognostic and predictive. However, the absolute measurable level of the disease is not the only determinant of the patient's outcome, since the biology of AML, as well as other clinical patient-related factors (age, comorbidities, various complications of applied chemotherapy, especially infections), modify the risk associated with MRD test results. Conclusion: The study has demonstrated the great importance of timely detection of MRD, as well as the appropriateness of applying more intensive CHT in MRD-positive patients, along with continued treatment with allogeneic hematopoietic stem cell transplantation.

Background: Cytarabine-anthracycline-based induction chemotherapy remains the standard of care for remission induction among patients with newly diagnosed acute myeloid leukaemia (AML). There are remarkable differences in therapy response among AML patients. This fact could be partly explained by the patients' genetic variability related to the metabolic paths of cytarabine and anthracyclines. This study aims to evaluate the effect of variants in pharmacogenes SLC29A1, DCK, ABCB1, GSTM1, and GSTT1 , as well as laboratory and AML -related parameters on clinical outcomes in adult AML patients. Methods: A total of 100 AML patients were included in the study. Pharmacogenetic variants SLC29A1 rs9394992, DCK rs12648166, ABCB1 rs2032582, and GSTM1 and GSTT1 gene deletions were detected by methodology based on PCR, fragment analysis and direct sequencing. The methods of descriptive and analytic statistics were used. Survival analysis was done using the Kaplan -Meier method using the Log -Rank test. Results: This is the first study of adult AML pharmacogenetics in the Serbian population. Clinical outcomes in our cohort of AML patients were not impacted by analysed variants in SLC29A1 , DCK , ABCB1 and GST T1, and GSTM1 genes , independently or in combinations. Achievement of complete remission was identified as an independent prognostic indicator of clinical outcome. Conclusions: The population -specific genomic profile has to be considered in pharmacogenetics. Since the data on AML pharmacogenetics in European populations is limited, our results contribute to knowledge in this field and strongly indicate that a high -throughput approach must be applied to find particular pharmacogenetic markers of AML in the European population.

Background: Acute promyelocytic leukemia (APL) is frequently associated with disseminated intravascular coagulation (DIC), leading to potentially life-threatening bleeding. Compared to bleeding, thromboses are a less commonly encountered problem. Objective: The objective of our study was to identify the incidence and predictive value of demographic data, clinical-laboratory parameters, and thrombosis risk assessment models (RAMs) for venous thromboembolism (VTE) in patients with APL. Methods: This study was a retrospective study conducted on adult patients with APL who were treated between 2006 and 2024 at the Clinic of Hematology UCCS with all-trans retinoic acid (ATRA) and anthracycline. The demographic and clinical-laboratory data related to VTE were collected and analyzed alongside the predictive value of two RAMs proposed by Al-Ani and Paterno and colleagues. Results: Among the one-hundred-fifty-five adult patients with APL, VTE was diagnosed in twenty-eight cases (18.1%). The most common location for thrombosis was in the central venous catheter (CVC), which affected twelve (42.8%) patients. A total of six (21.4%) patients had deep vein thrombosis (DVT), one patient (3.6%) showed a pulmonary embolism (PE), and thrombosis at unusual sites was present in nine (32.1%) patients. Our analyses showed that neither Al-Ani's RAM nor the RAM proposed by Paterno and colleagues were predictive for VTE in patients with APL. The C statistics value for the Al-Ani model was ROC = 0.514, and, for Paterno's RAM, it was ROC = 0.521. The independent risk factors for VTE, identified via multivariate analysis, were CD114 expression (p = 0.005, OR = 6.4 IC 95%: [1.8-23.2]) and the absence of bleeding at presentation (p = 0.013, OR = 0.086 IC 95%: [0.01-0.59]). Conclusions: To the best of our knowledge, this is the first study showing that a higher expression of CD114 increases the risk of VTE. The absence of bleeding at presentation in patients with APL correlates with thrombosis. Further analyses are needed to confirm these findings and help to develop therapeutic strategies to prevent VTE complications. So far, no risk assessment model has been sufficient to stratify patients with APL according to their risk of VTE.

Examination of central nervous system (CNS) involvement is not routine diagnostic practice in adult patients with acute myeloid leukemia (AML). Therefore, many asymptomatic patients with CNS involvement might go undetected. The effect of CNS involvement on the AML disease course is not well defined, with conflicting results regarding clinical outcome. This study aimed to determine the incidence of asymptomatic CNS involvement in AML estimated by multiparametric flow cytometry of cerebrospinal fluid (MFC-CSF) at diagnosis, the related potential risk factors, and prognosis. In total, 645 patients with de novo AML were screened; 183 (28.4%) of them fulfilled institutional practice for MFC-CSF analysis based on presence of CNS symptoms and/or clinical features. CNS symptoms and signs were observed in 8/183 (4.4%) patients, but most patients (175/183, 95.6%) were asymptomatic. In the asymptomatic group, 73/175 (41.7%) patients had positive or suspicious cerebrospinal fluid (CSF) findings categorized as CNS positive (CNSpos) and 102/175 (58.3%) had normal CNS findings categorized as CNS negative (CNSneg). The presence of leukemic blasts was confirmed in 81/183 (44.3%) patients; the total incidence of CNS involvement in the whole AML group was 12.6% (81/645). Compared with asymptomatic patients with CNSneg, those with CNSpos had a significantly higher frequency of lymphadenopathy, white blood cell count >= 30 x 109/L, presence of the monocytic phenotype, and a high percentage of bone marrow (BM) blasts. The multivariate logistic regression model identified monocytic phenotype (p = 0.047) and high percentage of BM blasts (p = 0.042) as predictors for CNSpos. CNSpos did not affect overall survival in patients with AML. There was a higher incidence of CNS involvement in asymptomatic adult patients with de novo AML, emphasizing possible undervalued rates of CNS disease at diagnosis. Prospective studies should determine whether diagnostic lumbar puncture for MFC-CSF analysis and CNS prophylaxis could contribute to better selection and prognosis in this patient population.

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.

Introduction/Aim: Acute myeloid leukemia (AML) is a heterogeneous disease, in terms of its biological characteristics and response to therapy. Numerous prognostic factors at diagnosis related to the disease itself, the treatment, and the response to treatment influence the outcome of AML. Despite the high rate of complete remission, overall survival (OS) is still poor. This study aims to determine the clinical and biological profile of patients with AML and its prognostic impact on the OS rate and disease-free survival (DFS). Materials and methods: The retrospective analysis included 271 patients diagnosed with acute myeloid leukemia at the University Clinical Center of Serbia (UCCS) Hematology Clinic, between January 2018 and January 2023. Demographic parameters, the Eastern Cooperative Oncology Group performance status (ECOG PS), comorbidities, and the parameters of laboratory analysis and hematological diagnosis of AML were analyzed as potential risk factors for OS and DFS, using the univariate Cox regression model. Results: Out of a total of 271 patients, 206 (76%) were treated with intensive chemotherapy, of whom 108 were men and 98 were women. The average age of these respondents was 50.3 years. According to the European Leukemia Network (ELN) risk classification, the patients were mostly in the group with intermediate risk, i.e. 128 (62.1%) patients. The most common subtype of AML was AML NOS (AML not otherwise specified), present in 123 (59.7%) patients. Univariate analysis showed that age ≥ 60 years (p = 0.009) and WBC ≥ 30 x 109 /l (p = 0.031) were unfavorable prognostic parameters for OS. AML subtype, MRC (myelodysplasia-related changes) was the most significant risk factor for shorter disease-free survival (p = 0.027). Conclusion: In the analyzed group of AML patients treated with intensive therapy, we demonstrated a low OS rate and showed that age and the MRC subtype of AML represent unfavorable risk factors for shorter OS and DFS, respectively.

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: Deregulation of the apoptotic process underlies the pathogenesis of many cancers, including leukemia, but is also important for the success rate of chemotherapy. Therefore, the gene expression profile of main apoptotic factors, such as anti-apoptotic BCL2 (B-cell lymphoma protein 2) and pro-apoptotic BAX (BCL2-associated X), as well as genes involved in the multi-drug resistance (MDR1), could have significant impact on the prognosis of acute myeloid leukemia (AML). Aims: The influence of BCL2, BAX, and MDR1 expression on prognosis in AML patients with normal karyotype (AML-NK). Methods: We analyzed the expression of BCL2, BAX, and MDR1 in bone-marrow samples collected at diagnosis from 51 adult patients (age 18-65 years), male/female (26/25) with de novo AML-NK using real-time polymerase chain reaction method (PCR), and examined their prognostic potential. Baseline detection of FLT3-ITD and NPM1 mutations were analyzed also by PCR. All patients received induction chemotherapy with daunorubicin and cytarabine (3 + 7) followed by three consolidation cycles of high/intermediate doses of cytarabine. Median gene expression values were as follows: BCL2 1.22 (range 0.13-8.97), BAX 0.92 (range 0.27-2.64), BAX/BCL2 ratio 0.62 (range: 0.11-7.77), MDR1 0.16 (range 0.00-13.74). Based on the median expression values, patients were divided into: higher than median (BCL2+, BAX+, BAX/BCL2high and MDR1+) and lower than median (BCL2-, BAX-, BAX/BCL2low and MDR1-) expression groups. Overall and disease-free survival (OS and DFS) were calculated, while patients undergoing hematopoietic stem cell transplantation were censored at the time of transplantation (15 patients). Standard statistical methods were performed. Results: Increased expression of BCL2 (BCL2+) was associated with chemoresistance (p=0.018), while patients with low BAX expression (BAX-) were more prone to relapse (p=0.034). Analysis of the combined effect of BCL2 and BAX expression showed that 87% of patients with BAX/BCL2low ratio were refractory to chemotherapy (p=0.024). High expression of MDR1 (MDR1+) was associated with BCL2+ status (p<0.001), and with absence of NPM1 and FLT3-ITD mutations (p=0.048 and p=0.010, respectively). None of the analyzed genes influenced OS and DFS. Summary/Conclusion: Our analysis of BCL2, BAX and MDR1 gene expression profiles is the first study focusing exclusively on AML-NK patients. Preliminary results showed that patients with high BCL2 expression are likely to be chemo resistant, and possibly may benefit from specific anti-BCL2 treatment. Further investigations conducted on a larger number of patients could elucidate actual prognostic significance of these genes in AML-NK patients. Keywords: AML, ABC transporter, BCL2, Bax

Background: Patients with hematological malignancies have an increased risk of arterial thrombotic events (ATEs) after diagnosis, compared to matched controls without cancer. However, data about incidence and risk factors for ATE development in patients with acute myeloid leukemia (AML) are missing. Aim: The objectives of this study were to determine the incidence of ATE in non-promyelocytic-AML patients and to define the potential risk factors for ATE development. Methods: We conducted a retrospective cohort study of adult patients with newly diagnosed AML. The primary outcome was the occurrence of confirmed ATE, defined as myocardial infarction, stroke or critical limb ischemia. Results: Out of 626 eligible AML patients, 18 (2.9%) patients developed ATE in the median time of 3 (range: 0.23-6) months. Half of these patients died due to ATE complications. Five parameters were predictors of ATE: BMI > 30 (p = 0.000, odds ratio [OR] 20.488, 95% CI: 6.581-63.780), prior history of TE (p = 0.041, OR 4.233, 95% CI: 1.329-13.486), presence of comorbidities (p = 0.027, OR 5.318, 95% CI: 1.212-23.342), presence of cardiovascular comorbidities (p < 0.0001, OR 8.0168, 95% CI: 2.948-21.800) and cytogenetic risk score (p = 0.002, OR 2.113, 95% CI: 1.092-5.007). Conclusions: Our study showed that patients with AML are at increased risk of ATE. The risk was increased in patients with cardiovascular comorbidities, previous thrombosis, adverse cytogenetic risk as well as BMI > 30.

Introduction Hemorrhagic early death (HED) remains a major cause of treatment failure among patients with acute promyelocytic leukemia (APL). We aimed to investigate the prognostic potential of rotational thromboelastometry (ROTEM) for bleeding in patients with APL. Materials and Methods 31 newly-diagnosed APL patients (median age of 40 years; 14 female/17 male) that underwent treatment at the Clinic of Hematology UCCS from 2016-2020 with all-trans retinoic acid and anthracyclines were recruited. CBCs (complete blood count), conventional coagulation tests (CCTs), and ROTEM parameters obtained before treatment initiation were evaluated. Results All patients demonstrated at least one ROTEM parameter out of the reference range. ROTEM parameters associated with significant hemorrhage were EXTEM clotting time (CT) (P = 0.041) and INTEM amplitude 10 (A10) (P = 0.039), however, only EXTEM CT (P = 0.036) was associated with HED. Among CBCs and CCTs, only platelets were associated with significant bleeding (P = 0.015), while D-dimer was associated with both bleeding and HED (P = 0.001 and P = 0.002, respectively). Conclusion Our results indicate that ROTEM parameters may reveal hypocoagulability in APL patients and have the potential to improve current hemorrhage prognostic methods. Additionally, these results suggest the combination of ROTEM and CCTs might be useful in identifying patients at risk for HED.

Topic: 30. Infections in hematology (incl. supportive care/therapy) Background: Intensive chemotherapy/radiotherapy in patients with acute leukemias causes cellular injury and suppression of inflammatory responses, which increase the risk of neutropenia and febrile episodes. FN remains a common complication in chemotherapy causing serious clinical results, including death. Wide application of broad-spectrum antibiotics has effectively decreased the mortality of FN patients. Neutropenic patients who remain febrile despite 4-7 days of broad spectrum antibacterial therapy are at a high risk of invasive fungal infection. Empirical antifungal therapy with liposomal Amphotericin B or Caspofungin in high risk patients has shown to reduce the risk of invasive fungal infection by 50-80% and the risk of fungal infection related mortality by 23¬ 45%. Aims: The aim of study was to analyze frequency, causes, treatment and outcome of infectious complications in patients with acute leukemia. Methods: Sixty patients (pts) with acute leukemia treated between January 1, 2021 and March 2022 at the Clinic of Hematology, University Clinical Center of Serbia were examined. Median age was 60yrs (range 21-76yrs, F/M: 35/25pts). The diagnosis of acute leukemia was made based on WHO 2016 criteria and ELN 2022 recommendations. The principles of diagnosis and treatment of infectious complications according to ESMO 2016, NCCN 2019, ECIL-6, 2017 were applied. Patients are treated with the use of broad-spectrum antibiotics according to the de-escalation principle, and if a diagnosis of possible/probable IA is made, with the use of Voriconazole or the lipid formulation of Amphotericin. Statistical analysis was performed using the IBM SPSS 21 (Chicago, IL, USA, 2012) package. Results: AML was diagnosed in 48pts, APL in 4pts; ALL 6pts, MPAL 2 patients. 17/60 patients had a favorable cytogenetic/molecular form of the disease; 26/60pts intermediate and 17/60ptsadvers e risk group. In relation to the treatment phase: 33/60pts received induction therapy; 28/60pts consolidation; reinduction in 7/60pts; salvage protocol in 10/60pts, while 10/60pts were treated only with supportive therapy. Febrile neutropenia occurred in 50/60pts (83.3%); with a median duration of aplasia of 12 days (5-27). Blood cultures were positive in 19% of analyzed samples (183/963). The most common isolates were: Klebsiella 46.4%; E Coli 8.7%; Enterococcus 8.7%; Pseudomonads aeruginosa 9.8%; Coagulase-negative Staphylococcus 15.8%; Acinetobacet 0.5%; Staphylococcus aureus 0.5%, remaining 9.3%. In relation to the diagnosis of IA, non-culture techniques showed positive beta2 glucan in 13/60pts, and elevated values of antiAspergillus IgM and antiAspergillus IgG antibodies in 33/60pts. Chest HRCT showed the following results; normal findings in 35/60pts, GGO in 11/60pts; nodular changes in 11/60pts and consolidation in 3/60pts. 15/60pts had possible IA, and 10/6 - probable IA. Outcome: at the time of examination, 32/60pts were alive (53.3%). Median survival was 206 days (range 5-1801 days). Summary/Conclusion: Bearing in mind that serious infections in patients with hematological malignancies are the main cause of morbidity and mortality, it is necessary to further develop a strategy for the prevention and treatment of febrile neutropenia. Prompt application of empiric/preeptive antibiotic and antifungal therapy is crucial for the outcome of the treatment of these high-risk hematological patients. The teamwork of hematologists, microbiologists, infectious disease specialists, epidemiologists, and radiologists is extremely important. Keywords: Acute leukemia

TPS7074 Background: Patients with relapse/refractory (r/r) AML have poor outcomes. Allogeneic stem cell transplantation (allo-SCT) can potentially cure some patients with r/r AML who achieve second CR (CR2). However, barriers to transplantation such as advanced age, poor functional status/comorbidities or lack of donor exist and not all patients are able to proceed to allo-SCT. Therefore, novel strategies to decrease relapse risk in these patients are urgently needed. A National Cancer Institute consensus study on prioritization of cancer antigens ranked the Wilms tumor 1 (WT1) protein as the top immunotherapy target in cancer. WT1 has emerged as an encouraging vaccine target in AML due to its overexpression in leukemic blasts. Maintenance therapy with Galinpepimut-S (GPS), a multivalent heteroclitic WT1 peptide vaccine, has shown promising activity in patients with AML by inducing a strong innate immune response (CD4+/CD8+) against the WT1 antigen and across a broad range of HLA types. Methods: This is an open-label, multicenter, randomized, phase III study of GPS vs. BAT in patients with AML in CR2/CRp2 (CR2 with incomplete platelet recovery). BAT may include observation, low dose cytarabine and hypomethylating agents +/- venetoclax. The primary endpoint of the study is overall survival (OS). Secondary endpoints include safety and tolerability of GPS and leukemia-free survival. Exploratory endpoints include WT1-specific immune response dynamics in blood and bone marrow. Approximately 125 - 140 patients will enroll, in a 1:1 ratio, to provide at least 90% power under an assumed hazard ratio of 0.52, based on median OS of 8.0 m (BAT) and 15.4m (GPS). Randomization will be stratified by duration of CR1 ( < 12m vs. ≥12m), Cytogenetics (poor-risk vs. all other), CR2 vs. CRp2 and measurable residual disease (MRD) after CR2 (MRD- vs. MRD+). Inclusion criteria consists of willing subjects ≥18y with AML within 6m of achieving CR2/CRp2, ineligible for allo-SCT due to any reason, with ≥300 lymphocytes/ul and with adequate renal and hepatic function. Subjects with central nervous involvement, having received a live vaccine 30d prior to first dose of study drug, having a diagnosis of immunodeficiency, receiving ≥10mg daily of prednisone equivalent (or any other systemic immunosuppressant) for any indication 7d prior to first dose of study drug, hypersensitivity to study agent and with a history of solid organ transplant would be excluded. The clinical trial is actively enrolling, and the registry number is NCT04229979 . Clinical trial information: NCT04229979 .

Background: Examination of central nervous system (CNS) involvement is not routine diagnostic in adult patients with acute myeloid leukemia (AML). Therefore, its impact on the disease course is not well defined. There are studies showing that CNS involvement in AML is associated with a worse outcome, whereas others did not confirm such impact on long-term survival. Aims: To determine the incidence of CNS involvement, its impact on the disease free and overall survival, and to define risk factors for CNS involvement. Methods: This single center, retrospective study involved 645 adult patients with nonpromyelocytic AML, diagnosed in period of 2013. and 2021. In patients with the presence of CNS symptoms, with increased leukocyte count (≥30x109/L), FLT3 mutation, monocyte phenotype, CD56 positivity, a lumbar puncture was performed. All cerebrospinal fluid (CSF) samples were examined by flow cytometry (FCM). Treatment of CNS+ include intrathecal CT: cytarabine 100 mg. Assessment of remission of CNS+ was performed after 8 i.t. CT. The following parameters were estimated as risk factors for CNS+ at diagnosis of AML: age, WBC (<30x109/L vs. ≥30x109/L), ECOG PS, HCT CI score, elevated lactate dehydrogenase (LDH), leukemia-related parameters (cytogenetics (including ELN risk stratification), flow cytometry). The methods of descriptive and analytical statistics were used. Univariate and multivariate Cox Proportional Hazards models were used to identify risk factors. Results: CNS involvement examination was performed in 272 patietns. A total of 55/272 (20.2%) patients had proven CNS involvement, while 217/272 (79.8%) were without neuroleukemia. Complete remission was achieved by 168/272 (61.7%) of patients, but there was no statistically significant difference between CNS positive and CNS negative patients (p=0.619). Patients with CNS involvement at diagnosis had a significantly higher frequency of hyperleukocytosis (≥30x109/L), age ≤50 years, French–American–British M5 subtype, expression of CD56 and CD15 antigen. Multivariate analysis identified CD56+ as the most important risk factor for CNS+ at diagnosis in AML patients: p=0.003, HR 2.271; 95% confidental interval (CI)= 1.320-3.908. There were no statistically significant differences in 5-year overall survival and disease free survival between CNS positive and CNS negative patients. Summary/Conclusion: Our study showed a high incidence of CNS involvement in AML patients, compared to studies in which the incidence was significantly less (3.3%). Our study confirmed the accuracy of the factor we used to assess CNS involvement. There was no difference in the outcome between patients with CNS involvement and those without.

Intensive chemotherapy/radiotherapy in cancer, especially with hematologic malignancies, causes cellular injury and suppression of inflammatory responses, which increase the risks of neutropenia and febrile episodes. Absolute neutrophil count < 1 ? 109/L is considered neutropenia, with absolute neutrophil count < 0.5 ? 109/L or < 1 ? 109/L that is expected to decrease to < 0.5 ? 109/L in the next 48 hours considered severe neutropenia, while absolute neutrophil count < 0.1 ? 109 is referred as profound neutropenia. Febrile episodes are usually defined as oral temperature > 38.3?C or two consecutive readings > 38.0?C lasting more than 1 hour. Although there is the possibility of non-infection-caused febrile neutropenia, most episodes are caused by infections. Febrile neutropenia is a clinical emergency that requires prompt management. Despite advances in therapy in recent years, febrile neutropenia remains a common complication in chemotherapy causing serious clinical results, including death. The administration of empirical antibacterial therapy has been successful in the management of febrile neutropenia since its launching 50 years ago. The wide application of broad-spectrum antibiotics has effectively decreased the mortality of febrile neutropenia patients. Neutropenic patients who remain febrile despite 4-7 days of broad-spectrum antibacterial therapy are at a high risk of invasive fungal infection. Empirical antifungal therapy with Amphotericin B or Caspofungin in persistently febrile neutropenic patients and other high-risk patients has shown to reduce the risk of invasive fungal infection by 50 - 80% and the risk of fungal infection-related mortality by 23- 45%. Lipid formulations which improve the therapeutic ratio of the traditional formulation are available