Median White Blood Cell Count Research Articles

ORBI risk score and inflammatory response in patients with acute ST-elevation myocardial infarction

Abstract Background The ORBI risk score was developed to predict in-hospital cardiogenic shock (CS) in patients with ST-elevation myocardial infarction (STEMI) [1]. An inflammatory response is seen in STEMI and may precede CS. The association between ORBI score and systemic inflammatory response is of interest both for improving risk assessment of CS but also for identifying potential therapeutic targets. Methods Using data from one center in the Third DANish Study of Optimal Acute Treatment of Patients With ST-Segment Elevation Myocardial Infarction (DANAMI 3) trial, the inflammat ory status was detected by peak C-reactive protein level (CRP) and white blood cell count (WBC) analyzed from blood samples taken within 96 hours from percutaneous coronary intervention (PCI). Patients were stratified into two ORBI risk groups: ‘Low’ (0-7) and ‘intermediate-high’ (>=8). Patients with CS at the time of PCI were not included, nor were those with out-of-hospital cardiac arrest. Logistic- and Cox Proportional Hazards regression was used to assess the association between ORBI risk groups and 1/ an above-median inflammatory status, and 2/ one-year mortality when combining risk group with inflammatory status. Results Of 1603 patients included, at least one 0–96-hour CRP was available in 631 (39.4%), and WBC in 628 (39.2%) of patients. Mortality at 96 hours was 1.3%. Median CRP and median WBC in the ‘intermediate-high’ ORBI risk group were 61.5 mg/L (interquartile range (IQR) 16-158) and 12 x 10^9/L (IQR 8.8-15.8) vs. 14 (IQR 5-38.8) and 10 (IQR 8.3-12.8) in the ‘low-risk’ group (p<0.001). ‘Intermediate-high’ ORBI score was associated with increased odds of an above-median CRP (OR 3.34, 95% confidence interval (CI) 2.20-5.18, p<0.001), as well as increased odds of an above-median WBC (OR 2.24, 95%CI 1.50-3.38, p<0.001) in univariate analyses. In patients having CRP levels above the median compared to those below, the median age was higher (66 years vs. 60 years, p<0.001). The prevalence of chronic heart failure was greater (26% vs. 13%, p<0.001), as was the incidence of renal failure (6.1% vs. 1.2%, p=0.003). A higher number of patients were classified within Killip classes 3-4 (24% vs. 2.6%, p<0.001). For patients with WBC above the median versus those below, there was a higher prevalence of chronic heart failure (24% vs. 16%, p=0.009). Killip 3-4 was also more common (22% vs. 4.2%, p<0.001). Patients with CRP and WBC at or above the median and an ‘intermediate-high’ ORBI score faced a higher risk of one-year mortality (HR CRP: 5.23, 95%CI: 2.59-10.6, p<0.001 and HR WBC: 6.15, 95%CI 3.04-12.4, p<0.001, figure 1). Conclusions An ‘intermediate-high’ ORBI risk score in STEMI patients was associated with significantly higher odds of increased levels of systemic inflammation within 0-96 hours of admission. An intermediate-high score combined with an elevated inflammatory response was associated with a five to six-fold increased risk of one-year mortality.Fig. 1:KM-plot, 1 year (scale is 1-0.9)

Clinical features of Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuritis associated with SLE

ObjectiveWe report on the clinical characteristics, treatments and outcomes of Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuritis (CIDP) associated with SLE.MethodsPatients treated at Peking Union Medical College Hospital between...

Risks and outcomes among coronavirus disease 2019 patients admitted to Assiut University Hospital

Introduction The clinical characteristics present with coronavirus disease 2019 (COVID-19) encompasses asymptomatic to severe disease and mortality. Clinicians need to detect patients whose risk of illness progression and unfavorable outcomes is high. Aim To evaluate potential risk factors affecting the severity and outcome of coronavirus infection in patients admitted to Assiut University. Patients and methods From October 2021 to October 2022, Assiut University Hospital served as the site of this observational analytical cross-sectional single-centered study. A full medical history, examination, radiographic, and laboratory investigations were performed on patients. Results The primary risk variables for mortality of COVID-19 patients include a greater mean age (73.61 ± 10.51) (P value<0.001). Individuals with chronic kidney disease (P value=0.005), and liver cirrhosis (P value<0.001). Those unvaccinated against COVID-19 the (P value = 0.004). Laboratory findings can be used as a predictor of infection severity as higher median white blood cell count (P value=0.044), lower median lymphocytic count (P value=0.028), higher serum ferritin (P value=0.02). Radiologically, a significant higher mean computed tomography severity score percentage is noticed among died patients (16.61 ± 4.55%) (P value<0.001). Conclusion Advanced age, patients with renal or hepatic impairment, patients with lower lymphocytic counts or with higher computed tomography severity score are linked to a worse clinical course and outcome among COVID-19 patients who were admitted to Assiut University Hospital. Trial registration ClinicalTrials.gov. NCT04860232.

Sandfly Virus Infection in Adana, Türkiye.

We described the clinical and laboratory characteristics of the patients infected by sandfly viruses between August and September 2008 in Adana, Türkiye. The immunofluorescence antibody test (EUROIMMUN Medizinische Labordiagnostika AG, Lübeck, Germany) was used for diagnosis. Antibodies of immunoglobulin M (IgM) type against Cyprus and Sicily species of phleboviruses were detected in 15 patients. In one patient, IgM antibodies against Naples and Tuscany species were found to be positive. The mean age of the patients was 28, and 47% was female. The most common symptoms were myalgia, fatigue, fever, and arthralgia. The mean duration of fever was four days, and the mean duration of the symptoms was 7-10 days. The median platelet count was 137,000/mL, the median white blood cell count was 3040/mL, the median aspartate transaminase (AST) was 57 (22-1251) IU/L, the median alanine transaminase (ALT) was 71 (17-1137) IU/L, the median creatinine kinase was 314 (33-4638) IU/L, and the median lactate dehydrogenase (LDH) was 193 (111-490) IU/L. The sandfly virus infections should be differentiated from similar viral infectious diseases such as Crimean-Congo hemorrhagic fever.

Discharge C-reactive protein predicts 90-day readmission after pancreatoduodenectomy: a conditional inference tree analysis

BackgroundThe aim of this study was to assess the predictive value of discharge C-reactive protein (CRP) and white blood cell (WBC) levels for 90-day readmission after pancreatoduodenectomy (PD) and to determine cutoff values for detecting complications at discharge. MethodsA two-centre, retrospective study was performed between 2008 and 2022. Receiver operating characteristic (ROC) curve analysis was used to determine the predictive value of CRP level and WBC count at discharge. A conditional inference tree (CTREE) was constructed to identify combined risks within subgroups using variables associated with readmission. ResultsA total of 438 patients were included in the analysis. Of these, 54 (12%) were readmitted. The median WBC count at discharge was comparable between the readmitted and not readmitted groups (9.1 vs. 8.5 G/l). The CRP levels at discharge were predictive of 90-day readmission, with an area under the ROC curve (AUC) of 0.63 (95% CI: 0.55−0.63). A CRP concentration below 105 mg/l ruled out 90-day readmission, with a negative predictive value (NPV) of 90% (95% CI: 81%–95%). CTREE confirmed the diagnostic value of CRP at discharge (AUC = 0.68, 95% CI 0.60–0.68). CTREE additionally identified previous wound infection as a second risk factor for readmission in patients with CRP levels less than 101 mg/l (P = 0.003). The sensitivity, specificity, and NPV of CTREE were 52%, 90% and 97%, respectively. DiscussionCRP levels below 105 mg/l at discharge allow for a safe discharge with a low 90-day readmission rate. Furthermore, wound infection, but not WBC count, was a positive predictor of 90-day readmission with moderate accuracy, suggesting the need for predischarge imaging for undetected complications in this patient cohort. Trial registrationOur retrospective analysis did not require registration with a publicly accessible registry.

Clinical Characteristics and Outcomes of CML in Adolescents and Young Adults

BackgroundWhile Chronic Myeloid Leukemia (CML) is a disease of older adults, there is a growing population of adolescent and young adults (AYAs) with CML. This study evaluated the clinical characteristics and outcomes of CML in AYAs. Patients and methodsData from medical records of adults with chronic phase CML diagnosed and treated at our center from 2011until 2021were retrospectively analyzed. Age between 18 and 29 years was used to define AYAs. Response to tyrosine kinase inhibitors (TKIs), progression to accelerated phase (AP) or blast crisis (BC), event-free survival (EFS) and overall survival (OS) were compared between AYAs and older adults. ResultsAmong 163 patients included, 41 (25.1%) were AYAs. AYAs were more likely to be males (P = .02), to present with symptoms (P = .004), had a higher median white blood cell count (P = .007), neutrophil count (P = .029), eosinophil count (P = 0.01), low-risk Sokal (P = .033) and Hasford (P = .005) groups. TKI-sensitivity as well as median times for achievement of complete cytogenetic and major molecular response were comparable between both groups. After a median follow-up of 76 (range: 11-235) months, there was no difference in OS (P = .528), or cumulative incidence of transformation to accelerated phase or blast crisis (P = .11). On the other hand, AYA had an inferior EFS (P = .034). ConclusionA quarter of the patients diagnosed with CML in our population were AYAs. Despite being characterized as “lower-risk,” they presented with a greater disease burden, had a shorter EFS but comparable OS. Further studies are needed to better understand the disease biology of this group.

Evaluating the efficacy and safety of letermovir compared to valganciclovir for the prevention of human cytomegalovirus disease in adult lung transplant recipients.

Lung transplant recipients are at high risk for severe cytomegalovirus (CMV) disease. Off-label use of letermovir (LET) may avert myelotoxicity associated with valganciclovir (VGCV), but data in lung transplantation are limited. This study aims to evaluate the outcomes of LET prophylaxis among lung transplant recipients. This retrospective, matched cohort study included lung transplant recipients who received LET for primary CMV prophylaxis following VGCV intolerance. Patients were matched 1:1 to historical VGCV controls based on age, serostatus group, and time from transplant. The primary outcome was CMV breakthrough within 1 year post-LET initiation; secondary outcomes included hematologic changes. A total of 124 lung transplant recipients were included per group (32% CMV mismatch, D+R-), with LET initiated a median of 9.6 months post-transplantation. One CMV breakthrough event (0.8%) was observed in the LET group versus four (3.2%) in the VGCV group (p=.370). The median (interquartile range) white blood cell (WBC) count was3.1 (2.1-5.6)at LET initiation which increased to5.1 (3.9-7.2)at the end of follow-up (p <.001). For VGCV controls, WBC was4.8 (3.4-7.2)at baseline and5.4 (3.6-7.2)at the end of follow-up; this difference was not statistically significant (p=.395). Additionally, 98.4% of LET patients experienced ≥1 leukopenia episode in the year prior to LET compared to 71.8% the year after initiation (p <.001). Similar results were observed for neutropenia (48.4% and 17.7%, p <.001). LET prophylaxis was associated with a low rate of CMV reactivation and leukopenia recovery. LET may represent a reasonable prophylaxis option for lung transplant recipients unable to tolerate VGCV.

Eltrombopag can promote platelet implantation after allogeneic hematopoietic stem cell transplantation as safely and similarly to thrombopoietin.

Eltrombopag has demonstrated efficacy in treating low platelet (PLT) levels, but it remains unclear whether eltrombopag can promote PLT engraftment after hematopoietic stem cell transplantation (HSCT). Forty-one HSCT patients received eltrombopag 50 mg/d from +1 day until PLT >50 × 109/L or 1 month after HSCT. Fifty-one patients in the same period received thrombopoietin (TPO) to promote PLT graft after HSCT and served as a control group. A total of 51 patients who applied TPO during the same period were treated as a control. In the eltrombopag group, the median time to white blood cells (WBC) graft was 12 days (range, 10-17 days) and the PLT graft was 15 days (range, 10-30 days), whereas for the patients in the TPO group, the median time to WBC and PLT graft was 12 days (range, 9-23 days) and 15.5 days (range, 9-41 days), respectively. In the first month after HSCT, the median WBC count in the eltrombopag group was 4.41 × 109/L (range, 0.87-40.01 × 109/L) and the median PLT was 89x109/L (range, 30-401 × 109/L); the median WBC and PLT \counts in the TPO group were 4.65 × 109/L (range, 0.99-23.63 × 109/L) and 86 × 109/L (range, 5-512 × 109/L), respectively. Patients in the TPO or eltrombopag group did not experience serious side effects after drug administration, and the difference in side effects on liver and kidney function between the two groups was not statistically significant. Eltrombopag is safe and similarly promotes platelet engraftment to thrombopoietin after allogeneic HSCT.

Joint Fluid Cell Count in Acute Bacterial Arthritis Patients Proven Positive Culture in Children.

Acute bacterial arthritis (ABA) is a serious, pediatric infection that can result in motor comorbidities. Normally, a joint fluid white blood cell (WBC) count of 50,000 or more cells/mm 3 is used to make a presumptive diagnosis of ABA. This study evaluated the utility of the joint fluid WBC count for diagnosing pediatric ABA confirmed by a positive culture result. Patients with ABA between March 2010 and March 2023 at Tokyo Metropolitan Children's Medical Center were included. ABA was confirmed by positive joint fluid culture results for a pathogenic organism. Patients with negative results and those without a joint fluid WBC count were excluded. Electronic medical records were retrospectively reviewed for demographic data, timing of arthrocentesis, culture results and the joint fluid WBC count. Ninety-five patients with ABA were identified; of these, 22 were included. The median age was 5 years [interquartile range (IQR): 2-10 years]. Males comprised 55% of the population. The median joint fluid WBC count was 19,575 (IQR: 6806-47,388) cells/mm 3 , and 23% of the patients had 50,000 cells/mm 3 or more. The median time from symptom onset to arthrocentesis was 3 days (IQR: 2-5 days). The isolated organisms were methicillin-susceptible Staphylococcus aureus (50%), methicillin-resistant S. aureus (9%), Streptococcus pyogenes (27%), Streptococcus pneumoniae (5%), Klebsiella pneumoniae (5%) and Salmonella spp. (5%). Most of the patients with ABA confirmed by positive results of a joint fluid culture had a joint fluid WBC count of less than 50,000 cells/mm 3 .

Analysis of Vaginal Microbiota Variations in the Third Trimester of Pregnancy and Their Correlation with Preterm Birth: A Case-Control Study.

This study conducted a detailed analysis of the vaginal microbiota in pregnant women to explore its correlation with preterm birth (PTB) outcomes. The primary objective was to identify microbial variations associated with increased PTB risk. Secondary objectives included investigating how changes in microbial composition relate to the local immune environment and PTB. Utilizing a retrospective case-control design, the study involved pregnant women with liveborn infants between 2019 and 2023. In total, 89 women who delivered preterm and 106 term deliveries were included. Data collection focused on third-trimester vaginal cultures. Statistically significant differences were observed between the preterm and full-term groups in several areas. The median white blood cell count (10.2 × 103/mm3 vs. 7.6 × 103/mm3, p = 0.009) and neutrophil count (7.2 × 103/mm3 vs. 5.1 × 103/mm3, p < 0.001) were higher in the preterm group. Vaginal pH was also elevated in preterm births (5.6 vs. 4.4, p < 0.001), with a higher prevalence of bacterial vaginosis (29.2% vs. 12.3%, p = 0.001) as indicated by the Nugent Score. The study noted a significant association of PTB with the presence of Candida spp. (OR = 1.84, p = 0.018), Gardnerella vaginalis (OR = 2.29, p = 0.003), Mycoplasma hominis (OR = 1.97, p = 0.007), and Ureaplasma urealyticum (OR = 2.43, p = 0.001). Conversely, a reduction in Lactobacillus spp. correlated with a decreased PTB risk (OR = 0.46, p = 0.001). The study provides compelling evidence that specific vaginal microbiota components, particularly certain pathogenic bacteria and an altered Lactobacillus profile, are significantly associated with PTB risk. These findings highlight the potential of targeting microbial factors in strategies aimed at reducing PTB rates. Further research is necessary to fully understand the complex interplay between microbial dynamics, host immunity, and PTB outcomes.

Role of granulocyte colony stimulating factor (G-CSF) in dengue patients with severe thrombocytopenia.

To determine the effects of granulocyte colony-stimulating factor in improving platelet count in patients with dengue fever. The retrospective, cross-sectional study was conducted at Northwest General Hospital and Research Centre, Peshawar, Pakistan, between January 2021 and October 2022, and comprised dengue fever inpatients regardless of age and gender who received granulocyte colony-stimulating factor subcutaneously. The impact of colony-stimulating factor on platelet and white blood cell counts as well as any unfavourable consequences was assessed. Convenient sampling was used and a structured format was used for data collection. Data was analysed using SPSS 21. Of the 100 patients, 67(67%) were males and 33(33%) were females. The largest age group was that of >55 years 31(31%), fever was present in all the 100(100%) cases, bleeding in 18(18%) and platelet count <30,000 in 83(83%) cases. Dengue fever was confirmed by rapid dengue nonstructural protein 1 antigen in 76(76%) cases, dengue immunoglobulin G antibody test 28(28%), and immunoglobulin M antibody test in 31(31%) cases. Overall, 72(72%) patients received only one dose of granulocyte colony-stimulating factor. Post-administration, a substantial rise in the median platelet and white blood cell counts was seen compared to the baseline (p<0.05) on day 2. Granulocyte colony-stimulating factor helped increase platelet and white blood cell counts quickly in dengue fever patients.

Comparative Analysis of Microbial Species and Multidrug Resistance Patterns Associated with Lower Urinary Tract Infections in Preterm and Full-Term Births.

The rise of multidrug-resistant organisms has significantly complicated the clinical management of urinary tract infections (UTIs), particularly in the context of pregnancy. This study aimed to identify and analyze the significant differences in microbial species and multidrug resistance patterns associated with UTIs in preterm versus full-term births, determine the bacterial species significantly associated with preterm birth, and describe the antibiotic resistance patterns affecting pregnant women with UTIs. This case-control study was conducted in western Romania and focused on pregnant women with UTIs admitted from 2019 to 2023. Data were retrospectively collected from 308 patients with positive cultures. Statistical analyses, including the Chi-square test, Fisher's exact test, and logistic regression models, were employed to compare the proportions of microbial species and resistance patterns between preterm (n = 126) and full-term (n = 182) birth groups and identify factors independently associated with preterm birth. The study found no significant differences in demographic or lifestyle factors between the groups. However, significant differences were observed in several infection and inflammation markers. The median white blood cell count was higher in the preterm group (12.3 vs. 9.1, p = 0.032), and the median C-reactive protein level was significantly higher in the preterm group (18 vs. 7, p < 0.001). The preterm group exhibited a higher incidence of multidrug-resistant organisms, notably ESBL-producing organisms (19.8% vs. 4.4%, p < 0.001) and carbapenem-resistant Enterobacteriaceae (4.8% with p = 0.003). Notably, the resistance to amoxicillin was significantly higher in the preterm group (20.6% vs. 6.6%, p < 0.001). Significant bacterial associations with preterm births included Group B Streptococcus (OR 2.5, p = 0.001) and Enterobacter spp. (OR 1.8, p = 0.022). The study confirmed significant differences in microbial species and multidrug resistance patterns between UTIs associated with preterm and full-term births. The higher prevalence of certain bacteria and increased resistance to commonly used antibiotics in the preterm group underscore the need for tailored antimicrobial therapies and robust microbial identification in managing UTIs during pregnancy.

Tyrosine Kinase Inhibitors in pediatric chronic myeloid leukemia: a focused review of clinical trials.

Tyrosine Kinase Inhibitors (TKIs) is revolutionizing the management of pediatric Chronic Myeloid Leukemia (CML), offering alternatives to Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT). We conducted a comprehensive review of 16 Randomized Controlled Trials (RCTs) encompassing 887 pediatric CML patients treated with TKIs including Imatinib, Dasatinib, and Nilotinib. The median patient age ranged from 6.5 to 14 years, with a median white blood cell count of 234 x 10^9/uL, median hemoglobin level of 9.05 g/dL, and median platelet count of 431.5 x 10^9/µL. Imatinib seems to be predominant first line TKI, with the most extensive safety and efficacy data. BCR::ABL response rates below 10% ranged from 60% to 78%, CCyR at 24 months ranged from 62% to 94%, and PFS showed variability from 56.8% to 100%, albeit with differing analysis timepoints. The Safety profile of TKIs was consistent with the known safety profile in adults. With the availability of three TKIs as first line options, multiple factors should be considered when selecting first line TKI, including drug formulation, administration, comorbidities, and financial issues. Careful monitoring of adverse events, especially in growing children, should be considered in long term follow-up clinical trials.

Admission Total Leukocyte Count as a Predictor of Mortality in Cardiac Intensive Care Unit Patients

BackgroundInflammation is a sequela of cardiovascular critical illness and a risk factor for mortality. ObjectivesThis study aimed to evaluate the association between white blood cell count (WBC) and mortality in a broad population of patients admitted to the cardiac intensive care unit (CICU). MethodsThis retrospective cohort study included patients admitted to the Mayo Clinic CICU between 2007 and 2018. We analyzed WBC as a continuous variable and then categorized WBC as low (<4.0 × 103/mL), normal (≥4.0 to <11.0 × 103/mL), high (≥11.0 to <22.0 × 103/mL), or very high (≥22.0 × 103/mL). The association between WBC and in-hospital mortality was evaluated using multivariable logistic regression and random forest models. ResultsWe included 11,699 patients with a median age of 69.3 years (37.6% females). Median WBC was 9.6 (IQR: 7.4-12.7). Mortality was higher in the low (10.5%), high (12.0%), and very high (33.3%) WBC groups relative to the normal WBC group (5.3%). A rising WBC was incrementally associated with higher in-hospital mortality after adjustment (AICc adjusted OR: 1.03 [95% CI: 1.02-1.04] per 1 × 103 increase in WBC). After adjustment, only the high (AICc adjusted OR: 1.37 [95% CI: 1.15-1.64]) and very high (AICc adjusted OR: 1.99 [1.47-2.71]) WBC groups remained associated with increased risk of in-hospital mortality. ConclusionsLeukocytosis is associated with an increased mortality risk in a diverse cohort of CICU patients. This readily available marker of systemic inflammation may be useful for risk stratification within the increasingly complex CICU patient population.

Changes in White Blood Cell Counts Early during Treatment of Acute Leukemia Using Differentiating Chemotherapies

Background: Differentiation syndrome (DS) is a life-threatening complication that can occur with a number of therapies used for the treatment of acute myeloid leukemia (AML). It is best characterized in patients treated with All-trans retinoic acid (ATRA) and Arsenic for acute promyelocytic leukemia (APL), or for patients receiving an IDH inhibitor for IDH1/2 mutant AML, but can also be seen with other therapies such as with FLT3 inhibitors, and in novel therapies under development such as menin inhibitors. It is critical to identify DS early, as corticosteroids can mitigate complications. The diagnosis of DS is made by recognizing a constellation of symptoms, typically including a rising white blood cell count, peripheral edema, rash, shortness of breath, pulmonary edema, and fevers. We evaluated white blood cell (WBC) count changes during treatment according to whether patients DS or not on chemotherapy. Methods: We identified adult patients who received ATRA+Arsenic for newly diagnosed APL, as well as patients with AML harboring a mutation in IDH1 or IDH2 who were treated with monotherapy IDH inhibitors (enasidenib or ivosidenib) at any point during their treatment for active AML and treated at MGH. Patients were treated at MGH between 2015 and 2023. Patients were 18 or older and had a confirmed pathological diagnosis. We interrogated the medical record to identify patients with clinical documentation of DS during treatment, as well as the treatments used for management and clinical complications. Descriptive statistics were used to identify differences in median WBC counts between patients with DS and those without DS, and comparisons were made using Wilcoxon or chi square testing as appropriate. Results: We identified 33 patients with APL who received ATRA+Arsenic, and 35 patients with AML harboring an IDH1/2 mutation treated with monotherapy IDH inhibition. Our analysis revealed that 26% (18/68) of patients had clinical documentation of differentiation syndrome, including 21% (14/33) of patients treated with ATRA+Arsenic and 11% (4/35) of patients on IDH inhibitors. In APL, the median day of a recorded diagnosis of DS was 4 days after treatment start (range 1-14 days). Patients with APL who developed DS had a higher initial WBC at treatment start compared to those who did not develop DS (6.7 vs 1.05 K/uL, p=0.03). There was no difference in hemoglobin, platelets, ANC, and percentage of peripheral blood blasts (Table 1). The WBC in DS patients started rising during the first week of treatment and peaked on Day 15 (Figure 1). Regarding treatment approaches for DS, the majority of patients were treated with steroids, (78%, 11/14) while 43% (6/14) received cytoreduction, most commonly with gemtuzumab. In IDH-mutant AML, the median day of a recorded diagnosis of DS was 35 days after treatment start (range 16-69 days). Patients with IDH-mutated AML on IDH Inhibitor monotherapy who experienced DS had a similar finding of an early temporal rise in WBC to those with APL on ATRA+Arsenic, although this rise started on day 12 and peaked on day 16 of monotherapy. Of note, these peaks occurred prior to the documentation of a clinical DS diagnosis. In contrast to APL, patients with IDH-mutant AML who developed DS had a lower baseline ANC (p=0.03) and higher percentage of peripheral blasts circulating than those without DS (p=0.03). All patients with IDH inhibitor associated DS received dexamethasone. Discussion: Patients with DS during treatment for APL on ATRA+Arsenic, as well as patients with DS with IDHmut AML on IDH inhibitors, had similar early peaks in the WBC count, occurring around 2 weeks from the start of treatment. In this small group, the IDHmut AML showed a rise in WBC that preceded the actual DS diagnosis. Understanding the timing of and risk factors for DS may help to identify at risk patients early for mitigation strategies.

Hyperleukocytosis Increases the Risk of Early Relapses Independently of Genetics in AML

Background. Higher white blood cell (WBC) count at diagnosis is associated with specific gene lesions and higher early death rates in AML patients (pts) treated intensively. Whether higher WBC count at diagnosis affects outcome beyond remission independently of genetics is unknown. Methods. 1,371 AML pts treated intensively in 3 ALFA trials (0702 18-60y, 0701 50-70y, 1200 60y+) with centralized genetics were studied. Genetic alterations found in &amp;gt;5% of pts (n=22) were analyzed. Hyperleukocytosis (HL) was defined as WBC &amp;gt; 50 x10 9/L. NPM1 MRD was stratified as published (Balsat, J Clin Oncol 2017). All prognostic analyses were stratified on trial. Time-dependent effects were introduced in multivariable Cox models when the proportional hazard (PH) assumption was violated. Results. The median WBC count at diagnosis was 7.1 x10 9/L (range 0.3-546.6), and 235 pts (17.1%) had HL. HL pts had poorer performance status (p&amp;lt;0.001), lower platelet counts (p=0.003), higher frequency of de novo AML (p=0.006) and more favorable genetic risk (ELN 2022 criteria, p&amp;lt;0.001). In a multivariable model, HL was independently associated with more frequent NPM1, FLT3-ITD and -TKD mutations, and less frequent STAG2 and -17/17p- alterations (all p&amp;lt;0.05, Figure 1A). Complete remission (CR [including CR with incomplete platelet recovery, CRp]) and early death (ED) rates were 77.4 vs 80.0% (p=0.38) and 8.9 vs 5.0% (p=0.03) in pts with and without HL, respectively (resp). In a multivariable model accounting for ELN22 risk and age, HL was independently associated with more frequent ED (OR =2.20, 95%CI 1.26-3.75, p=0.004), and a trend to more frequent primary induction failure (OR=1.40, 95%CI 0.95-2.05, p=0.08). In the 1,091 pts achieving CR/CRp (182 and 909 with and without HL resp), 1-y and 2-y cumulative incidence of relapse were 39.0% vs 26.1% and 44.0% vs 40.2% resp, suggestive of a time-dependent effect of HL on post-remission outcome ( Figure 1B). Considering relapse and death as competing events, a multivariable model revealed a significant impact of HL on relapse (subdistribution hazard ratio, sHR=1.59, p=0.0003), independent of ELN22 risk and age, but not on non-relapse mortality (sHR=0.69, p=0.23). HL violated the PH assumption in a univariable Cox model for DFS (p=0.0003). We thus performed multivariable Cox models for DFS separating early (&amp;lt; 1 year from CR) and late (≥1 year) effects for HL. In a multivariable time-dependent model, HL significantly impaired early (HR=1.89, p&amp;lt;10 -4), but not late (HR=0.79, p=0.29) DFS, independently of ELN risk and age. These results were confirmed considering WBC count as a (log-transformed) continuous variable, accounting for all differentially represented genetic lesions instead of ELN22 risk or censoring at allogeneic HCT. In a validation cohort of 1,089 pts &amp;lt;60y reaching CR after intensive chemotherapy in the BIG-1 trial (NCT02416388) where median WBC was 7.7 x10 9/L and 16.1% of pts were HL, the adverse risk of HL on CIR (sHR=1.39, p=0.007) but not NRM (sHR=1.02, p=0.95) and on early (HR=1.42, p=0.01), but not late (HR=1.24, p=0.23) DFS independent of ELN22 risk and age was validated. Finally, to explore the mechanism underlying the higher early relapse rate of HL pts, we analyzed NPM1 MRD (n=152) and LSC17 (n=504) data from the 0702 trial. A higher WBC count was predictive of suboptimal MRD (OR=1.97, p=0.05) independently of FLT3-ITD status. A higher WBC count was significantly correlated to lower LSC17 score (Spearman rho=0.23, p&amp;lt;10-5). Conclusion. A high WBC count at diagnosis predicts higher rates of early, but not late relapse, independent of genetic risk. Our results strengthen the hypothesis that distinct biological mechanisms underpin early vs late chemoresistance in AML.

Predictors and Timing of Venous Thromboembolism in Lung Cancer

Introduction Venous thromboembolism (VTE) is a common complication in lung cancer, but its risk factors and incidence have not been fully characterized. While prophylactic anticoagulation is recommended for some patient with cancer to prevent VTE, the thrombosis-risk prediction Khorana score considers lung cancer intermediate risk for development of VTE and combines all subtypes of lung cancer into a single entity. There are also limited data on the impact of therapy-type on VTE risk in patients with lung cancer. This study aimed to identify the incidence of VTE and its associated risk factors in patients with lung cancer at our university cancer center. Methods Using data from our tumor registry, we identified patients diagnosed with lung cancer between 2018 and 2022 who received first therapy beyond surgery alone after date of first contact. Using automated text search from our electronic medical record (EPIC®) combined with natural language processing review, VTE events were identified from 90-days before and up to one year(y) after initiation of systemic therapy. VTE events, including lower extremity deep vein thrombosis (DVT) or pulmonary embolism (PE), were captured by physician investigators, with final, secondary adjudication by one of us (GAS). We report time to event analysis and survival analysis using Kaplan-Meier curve. The study was censored at one year. Univariate and multivariate analyses were performed using COX-regression model. We evaluated the effect of lung cancer subtype, stage, age, sex, race, ethnicity, white blood cell count, hemoglobin, and platelet count. Results A total of 635 lung cancer patients were included in the study with a median age of 65 years. The median white blood cell count (WBC) was 8.8 × 109/L, median hemoglobin (Hgb) was 12.7 g/dL, and platelets (Plt) was 284 × 109/L. Other patient characteristics can be seen in Table 1. The overall 12-month incidence of VTE (lower extremity DVT and/or PE) was 10.1% (n=64). Of the 64 VTE events, 20 were identified before the start of therapy. Univariate analysis revealed that age &amp;lt;60 and WBC &amp;gt;= 11 were associated with a higher risk of VTE (p&amp;lt;0.05), which remained significant after multivariate analysis including age, stage, WBC, and surgery. There was a trend towards a higher risk of VTE in patients receiving chemoimmunotherapy, compared with chemotherapy alone, (HR 1.22), although this trend did not reach significance. Targeted therapy was associated with a lower trend (HR = 0.89), but that also was not significant. The median overall survival was 18 months. Univariate analysis showed that VTE was associated with an increased risk of death (HR 2.05, p&amp;lt;0.001). Other parameters associated with reduced Overall Survival (OS) were age &amp;gt;=60, male sex, stage III-IV, WBC, Hgb, and Plt. After multivariate analysis considering age, sex, stage, lung cancer histology, Hgb, Plt, WBC, surgery, therapy type, and VTE, age &amp;gt;=60, stage III-IV, WBC &amp;gt;=11, Hgb &amp;lt;10, and VTE remained significant predictors of death. Discussion In a retrospective study of more than 600 patients with lung cancer, there was a significant risk of VTE. Every subgroup of patients analyzed in this study retained a high risk of VTE after multivariate analysis. The only hematologic parameter from the Khorana score significantly associated with VTE after multivariate analysis was WBC. WBC and Hgb were associated with increased risk of death. Age &amp;lt;= 60 was associated with increased risk of VTE, while age &amp;gt;60 was associated with increased mortality. There was a trend towards a higher risk of VTE in patients receiving chemoimmunotherapy compared with chemotherapy alone. There were too few immunotherapy-only patients to allow for any interpretation. The development of thrombosis was associated with a significantly decreased overall survival, although we do not have data on the potential contribution of VTE to death. These findings were derived from a single-center data set, and further validation using independent data sets is warranted. If confirmed, a prospective study re-evaluating the risk of VTE and benefits of prophylactic anticoagulation specifically in contemporary patients with lung cancer receiving systemic therapy regardless of histology, treatment, or other factors described here may be indicated. Our findings do not support limiting any such study to any specific sub-group of patients with lung cancer.

The Signaling Pathways Enriched in High-Risk AML Patients Revealed By the Integrative miRNA-mRNA Analysis - Pilot Study

Introduction Acute myeloid leukemia (AML) is highly heterogeneous disease with broad spectrum of mechanisms involved in pathogenesis. The unique microenvironment of hematopoietic niche (HN) consists of several proteins with corresponding receptors on normal and leukemic cells. The interactions within HN include ligand-receptor pairs as SDF-1/CXCR4; OPN/CD44; Jagged-1/Notch-1; ANG-1/Tie-2 and Slit2/Robo4. MicroRNAs (miRNAs) are small noncoding RNA molecules that post-transcriptionally modulate gene expression by binding to targeted mRNAs. The dysregulation of ligand-receptor interactions by miRNAs could disrupt the niche's equilibrium and may contribute to the establishment of a leukemic burden and progression of AML. In our study we aimed to explore the clinical impact of miRNAs profile in the context of the mRNA genes expression involved in ligand-receptors interactions in the bone marrow of newly diagnosed AML patients (pts). Methods The expression of 12 mature miRNAs: miR-15a-5p, miR-34a-5p, miR-125b-5p, miR-139-5p, miR-146-5p, miR-181a-5p, miR-199b-5p, miR-204-5p, miR-218-5p, miR-299-5p, miR-424-3p, miR-452-5p was determined in duplicates in bone marrow samples of de novo AML pts using real-time PCR. The miRNAs expression was normalized using the mean expression of all miRNAs in a given sample. The expression assessment of 10 following genes: CXLC12 (coding SDF-1 ), CXCR4, NOTCH1, JAG1 (coding Jagged-1), SPP1 (coding osteopontin) , CD44, SLIT2, ROBO4, ANGPT1 (coding angiopoietin-1) , TEK (coding Tie-2 receptor) was performed in the bone marrow at the time of AML diagnosis. The gene expression was determined in duplicates by real-time PCR using the QuantStudio 7 (Applied Biosystems-ThermoFisher Scientific). Gene expression was normalized using selected reference genes ( MRPL19 and PPIA). Differential expression analysis was conducted using a heteroscedastic t-test, volcano plots were used to visualize results. Using significantly deregulated miRNAs and genes in high-risk AML, OmicsNet (https://www.omicsnet.ca) was used to create miRNA-mRNA biological network. For network creation, protein-protein interactions (STRING) and miRNA-mRNA (TarBase) databases were used. Further, a pathway enrichment analysis was performed using Reactome database. Results The study group consisted of 28 (16 women and 12 men) newly diagnosed AML adults with the mean age 57.7 ± 12.8 years. Among them, 14.3% pts had a low-risk, 39.3.% intermediate-risk and 39.3% high-risk AML according to European LeukemiaNet ( ELN) 2022 risk stratification. In 2 pts molecular data was not available. The most common subtype was AML not otherwise specified (11 pts, 39.3%), followed by AML with myelodysplasia-related cytogenetic abnormality (6 pts, 21.4%), AML with myelodysplasia-related gene mutation (5 pts, 17.9%), and AML with recurrent genetic abnormality (4 pts, 14.3%). At diagnosis the median white blood cell count was 26.7 × 10 9/L (interquartile range, IQR: 3.0 - 73.1 × 10 9/L), the median bone marrow blasts was 63.0% (IQR: 41.0- 88.3) and the median lactate dehydrogenase (LDH) level was 532.5 U/L (IQR: 284.0-986.5). The majority of pts (86%) received intensive chemotherapy according to Polish Adult Leukemia Group (PALG) protocols. In FLT3 mutated pts standard induction/consolidation therapy was enriched with midostaurin. Low intensity treatment consisted of azacitidine (1 pts), low dose Ara-C (LDAra-C, 2 pts) and LDAra-C + cladribine (1 pts). Patients with high-risk AML had higher expression of miR-125b-5p (fold change- FC=2.3, p=0.017) and lower expression of miR-15a-5p (FC=0.6, p=0.043) as compared to low- and intermediate-risk pts. Similarly, two genes were significantly upregulated in ELN high-risk group - TEK (FC=4.1, p=0.017) and SPP1 (FC=6.7, p=0.041). OmicsNet was used to construct miRNA-gene interaction networks between miR-125b-5p, miR-15a-5p, TEK, SPP1 and other miRNAs target genes. In final multi-omic network, 6 miRNAs and 50 mRNA/proteins were included (Figure 1). We found that the pathways of PDGF, NGF, FGFR, PI3K, IGF1R and EGFR signaling are significantly enriched in high-risk AML patients. Conclusions Our preliminary results indicate the signaling pathways disturbed in high-risk AML patients. The miR-125b-5p, miR-15a-5p as well as the TEK and SPP1 gene expression may possibly act as biomarkers in patients with de novo AML.

The Impact of Adding Rituximab to the Standard Chemotherapy + TKI Regimen in Adults with Philadelphia-Positive B Acute Lymphoblastic Leukemia: A Multicenter Retrospective Study

Introduction: The addition of rituximab to the treatment of CD20-positive (CD20+) Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) patients has demonstrated considerable benefits in terms of event-free survival in a large randomized clinical trial, as well as overall survival (OS) in retrospective analyses. Consequently, it is now an integral part of the standard care chemotherapy regimen for these patients. Conversely, Ph-positive (Ph+) B-ALL patients have been excluded from these trials and are typically managed with tyrosine-kinase inhibitors (TKI) in combination with chemotherapy, steroids, or novel agents such as blinatumomab. However, the potential benefits and concerns of adding rituximab to CD20+ Ph+ B-ALL patients remain uncertain, as there are worries about prolonged immunosuppression and potential infectious complications. Methods: We conducted a multicenter retrospective study involving five tertiary care centers in Mexico. The study included patients older than 16 years with newly diagnosed Ph-positive B ALL between January 2009 and June 2022, according to the WHO criteria. CD20+ was defined as CD20 expression ≥20% by flow cytometry. The decision to administer rituximab was based on the physician's discretion. The primary objective was to compare the 3-year OS between CD20-negative patients and CD20-positive patients who received or did not receive rituximab, and as secondary objectives to evaluate infection rates and mortality during induction with the addition of rituximab. Results: The study comprised 119 patients who met the inclusion criteria. The median age at diagnosis was 38 years (16 - 73), with 52.1% being male. The median white blood cell count (WBC) count was 114 x 10 9/L (0.5 - 466). Of these, 45 patients (37.8%) had CD20+ B-ALL, and 24 of them (53.3%) received rituximab. A total of 111 patients (93.2%) received TKI treatment, with imatinib being the most common (79%), followed by dasatinib (13.4%) and ponatinib (0.8%). The majority of the patients received either Hyper-CVAD (41.2%) or a local adult regimen (31.9%). There were no significant differences in age, WBC count, or treatment/TKI between patients who received rituximab and those who did not. Table 1 presents the characteristics of the population based on CD20 expression and treatment. Early mortality was 5.8%, with no significant difference observed between patients who received rituximab and those who did not (0% vs. 7.4%; OR 0.78, 95% CI 0.71 - 0.86, p=0.342). The rate of neutropenic fever during induction was 72.3%, and it was lower in patients who received rituximab (50.0% vs. 77.9%; OR 0.28, 95% CI 0.11 - 0.72, p=0.010). The intensive care unit (ICU) admission rate during induction was 11.8%, with no significant difference observed between patients with or without rituximab (8.3% vs. 12.6%; OR 0.62, 95% CI 0.13 - 3.01, p=0.733). Molecular response at 3 months was measured in 72 patients and the use of rituximab was associated with a non-significant higher rate: 83.3% vs 57.4% with an OR of 3.71 (95% CI, 0.96-14.33, p=0.056).The median OS for the entire cohort was 20 months (95% CI, 13.34 - 26.65), with a 3-year OS of 35.7%. The leading cause of death was disease progression (77.3%), while 10.7% died in remission: 7.7% of CD20- patients, 21.4% of CD20+ patients without rituximab, and 11.1% of CD20+ patients receiving rituximab (p=0.436). There was a trend towards a better OS in CD20+ patients who received rituximab: median OS not reached vs. 21 months (95% CI 13.27 - 28.72) in CD20- patients, and 13 months (95% CI 9.7 - 16.29) in CD20+ patients without rituximab. The 3-year OS rates for these groups were 52.7%, 34%, and 24.6%, respectively (p=0.222; Figure 1). Conclusions: In real-world practice, rituximab is added to the chemotherapy regimen and TKI in 53.3% of CD20+ Ph+ B-ALL cases. Rituximab is not associated with a higher incidence of infections, ICU admission, early mortality, or deaths in remission. Although there is no significant benefit observed, there is a trend towards better OS with the addition of rituximab to the standard treatment of CD20+ Ph+ ALL. There is an unmet need to explore the concomitant use of rituximab and TKI in prospective studies.

Achievement of Undetectable BCR::ABL1 (uBCR::ABL1) Is Predictive of Improved Survival in Philadelphia Chromosome Positive (Ph+ve) Acute Lymphoblastic Leukemia (ALL) Patients Not Receiving Allogeneic Stem Cell Transplantation

Background With the advent of tyrosine kinase inhibitor (TKI)-based therapy the outcome of Philadelphia chromosome-positive (Ph +) acute lymphoblastic leukemia (ALL) has significantly improved. Moreover, patients (pts) who achieved undetectable (u) BCR::ABL1 at 3 months (mo) from the time of initiating therapy, tend to have improved outcomes (Short et al. Blood 2016; 128 [4];504-507). We conducted a retrospective multicenter study to analyze the predictors of achieving uBCR::ABL1 in adult (&amp;gt; 18 years) Ph + ALL pts. Methods A total of 458 adult Ph + ALL pts from 10 US academic institutions, who were diagnosed between May 2003 and April 2023, were evaluated to assess the rates of uBCR::ABL1 at 3 mo after initiating therapy and factors that predict the achievement of molecular response. Continuous variables were summarized as median (range), while categorical variables were reported as frequency (percentage). Unadjusted comparisons of patient/ treatment related characteristics and molecular response were made using a non-parametric test (continuous variables) or Fisher's exact test (categorical variables). Survival curves were estimated using the Kaplan-Meier method and compared between molecular responses via the log-rank test. Results Baseline characteristics The median age of the pts was 53 years (range [R] 19-85), median white blood cell count (WBC) was 17.6 (10 9/L) (R, 1.2-571), 249 (55%) pts had additional cytogenetic (CG) abnormalities, 98 (22%) pts had p210 fusion protein, and 35 (8%) pts had CNS disease at diagnosis. A higher proportion of pts received TKI in combination with intensive chemotherapy (IC) (69%), than TKI + steroids (15%), TKI + low intensity chemotherapy (LC; combination of vincristine, steroids +/- rituximab) (9%), TKI + blinatumomab (3%) and IC without TKI (4%) during induction. During induction, the highest proportion of pts received 2 nd generation TKI combinations (67%; majority dasatinib 98%), compared to imatinib (19%) or ponatinib (10%): 4% of pts did not receive TKI with induction. The complete remission (CR) rate was 94%; measurable residual disease (MRD) negative by flow cytometry 51% (181/352 evaluable pts) and 58.5% (209/354 evaluable pts) of pts had uBCR::ABL1 by PCR at 3 mo from induction. A total of 212 (46%) pts received allogeneic stem cell transplantation (allo-HCT) in CR1, among them 61% of pts received TKI maintenance post allo-HCT. Predictors of uBCR::ABL1 at 3 months Predictors for uBCR::ABL1 at 3 mo are summarized in Table 1. The proportion of pts with WBC &amp;gt; 100 (45% vs 60%, p= 0.04), p210 fusion protein (35% vs 85%, p= &amp;lt;0.001), additional CG abnormality with monosomy 7 (40% vs 61%, p= 0.03), additional somatic myeloid co-mutation (39% vs 61%, p= 0.09; 94 pts evaluable), received induction with steroid plus TKI (41% vs 63%, p= 0.002) or received imatinib based induction (47% vs 61%,p= 0.07) had inferior uBCR::ABL1 rates at 3 mo. Conversely pts who received ponatinib based induction had significantly better uBCR::ABL1 rates (79% vs 57%, p= 0.009). Survival The median relapse free survival (RFS) was 72.3 mo (95% CI; 50.1-94.4), RFS was numerically higher among pts who achieved uBCR::ABL1 at 3 mo but not statistically significant (84.2 mo vs 62.9 mo, p= 0.20). The median overall survival (OS) was 129.2 mo (95% CI; 81.2-177.2), OS was not significantly different among pts who achieved uBCR::ABL1 at 3 mo (129.2) versus no uBCR::ABL1 (not reached; 50% alive at 94 mo), p= 0.47. In sub-set analysis, among non-transplanted pts, RFS was not statistically significant between those who achieved uBCR::ABL1 vs those who did not (38.9 vs 22.0 mo, respectively p= 0.24). However, the median OS was significantly higher in pts who achieved uBCR::ABL1 at 3 mo compared to pts who did not achieve uBCR::ABL1 at 3 mo: 149.3 vs 77.5 mo, p= 0.04 ( Figure 1). Conclusion In this large multicenter study, we observed significantly inferior uBCR::ABL1 rates among pts with WBC &amp;gt; 100, p210 fusion protein, monosomy 7 CG abnormality, pts receiving induction with steroid plus TKI or imatinib based induction. Conversely, uBCR::ABL1 rates were significantly better in pts receiving ponatinib based induction therapy. Overall, we did not see significant impact of uBCR::ABL1 at 3 mo, on RFS or OS. It is likely subsequent therapies and allo-HCT abrogates the negative impact of not achieving uBCR::ABL1 at 3 mo. However, among non-transplanted pts achievement of uBCR::ABL1 at 3 mo showed a significantly improved OS.