Initial White Blood Cell Count Research Articles

The Effect of Hematopoietic Stem Cell Transplantation on Treatment Outcome in Children with Acute Lymphoblastic Leukemia.

Hematopoietic stem cell transplantation (HSCT) has been an important method of treatment in the advance of pediatric acute lymphoblastic leukemia (ALL). The indications for HSCT are evolving and require updated establishment. In this study, we aimed to investigate the efficacy of HSCT on the treatment outcome of pediatric ALL, considering the indications for HSCT and subgroups. A retrospective analysis was conducted on ALL patients diagnosed and treated at a single center. Risk groups were categorized based on age at diagnosis, initial white blood cell count, disease lineage (B/T), and cytogenetic study results. Data on the patients' disease status at HSCT and indications of HSCT were collected. Indications for HSCT were categorized as upfront HSCT at 1st complete remission, relapse, and refractory disease. Among the 549 screened patients, a total of 418 patients were included in the study; B-ALL (n=379) and T-ALL (n=39). HSCT was conducted on a total of 106 patients (25.4%), with a higher frequency as upfront HSCT in higher risk groups and specific cytogenetics. The overall survival (OS) was significantly better when done upfront than in relapsed or refractory state in T-ALL patients (p=0.0016). The KMT2A-rearranged ALL patients showed superior event-free survival (p=0.0023) and OS (p=0.0221) when HSCT was done as upfront treatment. HSCT had a substantial positive effect in a specific subset of pediatric ALL. In particular, frontline HSCT for T-ALL and KMT2A-rearranged ALL offered a better prognosis than when HSCT was conducted in a relapsed or refractory setting.

A propensity score–matched comparison of cytoreductive strategies in patients with acute myeloid leukemia presenting with hyperleukocytosis.

e18509 Background: Hyperleukocytosis (white blood cell (WBC) count greater than 100x109), which may lead to the clinical entity of leukostasis, is a hematologic emergency present at diagnosis in 18% of patients with acute myeloid leukemia (AML). There is controversy regarding the appropriate cytoreductive strategy, which may include cytoreductive chemotherapy, hydroxyurea, and/or leukapheresis. The American society for apheresis (ASFA) released guidelines in 2023 making leukapheresis a Category III recommendation, however significant heterogeneity and methodologic flaws exist in the evidence used to make these recommendations. Methods: Retrospective analysis of 58 patients at Massey Comprehensive Cancer Center between 2017 and 2023 who received either hydroxyurea alone (n=35) or both hydroxyurea and leukapheresis (n=23) for hyperleukocytosis at time of presentation for AML diagnosis was performed. Baseline characteristics including age, sex, Charlson Comorbidity Index (CCI), European LeukemiaNet (ELN) risk stratification, and WBC count prior to cytoreduction were collected. Comparisons of complete remission rates (CR/CRi), 30- and 60-day mortality, median overall survival (OS), and rates of therapy-induced tumor lysis syndrome (TLS) and disseminated intravascular coagulation (DIC) were analyzed using Kaplan-Meier, Fisher’s exact, Mann-Whitney tests, respectively on a propensity score matched cohort to account for differing initial WBC counts between the treatment groups. Results: PSM was used to match presenting WBC counts between the two cohorts. Other baseline characteristics including median age (65y v. 60y), median CCI (5 v. 4), ELN adverse risk rate (31.53% v. 26.1%) did not differ after PSM. No significant difference was found between the hydroxyurea group compared to the hydroxyurea and leukapheresis group, respectively, when analyzing for rate of CR/CRi (36.5% v. 43.5%), 30-day mortality (10.5% v. 17.3%), 60-day mortality (10.5% v. 34.8%), median OS (7.77 mo. v. 8.07 mo.), or rates of DIC (10.5% vs. 8.7%) and therapy induced TLS (0% v. 0%). Conclusions: Patients who received hydroxyurea alone had similar outcomes when compared to the combined treatment group with respect to median OS, CR/CRi, and mortality rates. These results are notable given that leukapheresis is not available at many medical centers and is a resource-heavy procedure, and especially so in light of new ASFA guideline changes. However, these results reflect the laboratory entity of hyperleukocytosis rather than the clinical entity of leukostasis. Further work is ongoing to assess impact of cytoreductive strategies in leukostasis in AML, and among different cytogenetic and molecular subtypes. Decisions for leukapheresis or other cytoreductive strategies should be made on a case-by-case decision at an experienced center when possible.

Pseudohyperkalemia in pediatric patients with newly diagnosed hematological malignancies

Patients with newly diagnosed hematological malignancies often present with a considerable cellular burden, leading to complications including hyperkalemia. However, pseudohyperkalemia, arising from in vitro cell lysis, can pose challenges in clinical practice. Although pseudohyperkalemia is frequently reported in adult hematological malignancies, its occurrence in pediatric patients is underreported, and its incidence in this demographic remains unclear. We retrospectively reviewed the medical records of pediatric patients who received a new diagnosis of hematological malignancies from 2011 to 2022 at Taichung Veterans General Hospital. Hyperkalemia was defined by a serum or plasma potassium level exceeding 5.5 mEq/L. Pseudohyperkalemia was defined by 1) a potassium decrease of over 1 mEq/L in within 4 h without intervention or 2) the absence of electrocardiography changes indicative of hyperkalemia. Cases with apparent red blood cell hemolysis were excluded. A total of 157 pediatric patients with a new diagnosis of hematological malignancies were included, 14 of whom exhibited hyperkalemia. Among these 14 cases, 7 cases (4.5%) were of pseudohyperkalemia. This rate increased to 21.2% in patients with initial hyperleukocytosis. Pseudohyperkalemia was associated with a higher initial white blood cell count and lower serum sodium level. All episodes of pseudohyperkalemia occurred in the pediatric emergency department, where samples were obtained as plasma, whereas all true hyperkalemia cases were observed in the ordinary ward or intensive care unit, where samples were obtained as serum. Timely recognition of pseudohyperkalemia is crucial to avoiding unnecessary potassium-lowering interventions in pediatric patients with newly diagnosed hematological malignancies.

Risk factors and remaining challenges in the treatment of acute promyelocytic leukemia.

The treatment of acute promyelocytic leukemia (APL) has evolved with the introduction of all-trans retinoic acid (ATRA) and subsequent arsenic trioxide (ATO), particularly in standard-risk APL with an initial white blood cell count (WBC) < 10,000/μL, where a high cure rate can now be achieved. However, for some patients with risk factors, early death or relapse remains a concern. Insights from the analysis of patients treated with ATRA and chemotherapy have identified risk factors such as WBC, surface antigens, complex karyotypes, FLT3 and other genetic mutations, p73 isoforms, variant rearrangements, and drug resistance mutations. However, in the ATRA + ATO era, the significance of these risk factors is changing. This article provides a comprehensive review of APL risk factors, taking into account the treatment approach, and explores the challenges associated with APL treatments.

MAJOR REASONS FOR HOSPITALIZATION TO ICU OF CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA: A LITERATURE REVIEW

Relevance: Acute lymphoblastic leukemia (ALL) is a common malignancy in children. Approximately 85% of ALLs have B-cell origin, and 15% are T-cell ALLs. Many patients diagnosed with hematologic cancer will require hospitalization in the intensive care unit (ICU) at some point in their treatment.&#x0D; The aim was to study the available literature on clinical deterioration in patients with АLL admitted to the ICU, the clinical significance and prognostic value of causes of clinical deterioration, and adverse outcomes in patients with АLL staying in the ICU.&#x0D; Methods: A descriptive cross-sectional study approach was used. We reviewed published sources from 2016 to 2023 to collect data on major reasons for ALL patients’ hospitalization to ICU.&#x0D; Results: First, the patient’s age at the time of initial diagnosis of ALL is crucial. Cure rates for B-cell ALL are higher between 1 and 9 years of age than in other age groups. Second, the initial white blood cell count during diagnosis is a prognostic indicator. Third, the specific subtype of ALL also affects prognosis. The risk factors emphasize the importance of comorbidities and infectious diseases, as well as monitoring and managing pulmonary and cardiovascular function in patients to avoid hospitalization in the ICU. The main causes of hospitalization in the ICU are complications related to chemotherapy, infection, and unplanned hospitalizations. Compared to normal-risk patients, high-risk patients had a higher rate of OIT hospitalization in the ICU. It is important to control chemotherapy and infections to reduce the number of admissions to the ICU in this group.&#x0D; Conclusion: Chemotherapy, concomitant and infectious diseases, hypoxia, and hemodynamic instability are reasons for hospitalization of these patients to ICU. The condition of various organs and systems shall be monitored.

MAJOR REASONS FOR HOSPITALIZATION TO ICU OF CHILDREN&#x0D; WITH ACUTE LYMPHOBLASTIC LEUKEMIA:&#x0D; A LITERATURE REVIEW

Relevance: Acute lymphoblastic leukemia (ALL) is a common malignancy in children. Approximately 85% of ALLs have B-cell origin, and 15% are&#x0D; T-cell ALLs. Many patients diagnosed with hematologic cancer will require hospitalization in the intensive care unit (ICU) at some point in their treatment.&#x0D; The aim was to study the available literature on clinical deterioration in patients with АLL admitted to the ICU, the clinical significance&#x0D; and prognostic value of causes of clinical deterioration, and adverse outcomes in patients with АLL staying in the ICU.&#x0D; Methods: A descriptive cross-sectional study approach was used. We reviewed published sources from 2016 to 2023 to collect data on major&#x0D; reasons for ALL patients’ hospitalization to ICU.&#x0D; Results: First, the patient’s age at the time of initial diagnosis of ALL is crucial. Cure rates for B-cell ALL are higher between 1 and 9 years of&#x0D; age than in other age groups. Second, the initial white blood cell count during diagnosis is a prognostic indicator. Third, the specific subtype of ALL&#x0D; also affects prognosis. The risk factors emphasize the importance of comorbidities and infectious diseases, as well as monitoring and managing&#x0D; pulmonary and cardiovascular function in patients to avoid hospitalization in the ICU. The main causes of hospitalization in the ICU are complications related to chemotherapy, infection, and unplanned hospitalizations. Compared to normal-risk patients, high-risk patients had a higher rate of&#x0D; OIT hospitalization in the ICU. It is important to control chemotherapy and infections to reduce the number of admissions to the ICU in this group.&#x0D; Conclusion: Chemotherapy, concomitant and infectious diseases, hypoxia, and hemodynamic instability are reasons for hospitalization of&#x0D; these patients to ICU. The condition of various organs and systems shall be monitored.

Neutrophil-to-lymphocyte ratio at admission for early diagnosis, severity assessment, and prognosis of acute traumatic spinal cord injury.

A retrospective study. This study examined the value of neutrophil-to-lymphocyte ratio at admission for early diagnosis, severity assessment, and prognosis of acute traumatic SCI. The First People's Hospital of Neijiang, China. This was a single-center, retrospective, cohort study of patients treated within 12 h of acute SCI between January 2018 and October 2022. Ninety-four SCI patients were selected as the Observation group, including 26 with complete injury (AIS grade A) and 68 with incomplete injury (AIS grade B-D), while 94 patients with simple spinal fracture were randomly selected as the Control group. Eighty-one observation group patients underwent surgical treatment, of which 33 had a higher AIS grade (Good prognosis subgroup) and 48 a lower or equal grade post-surgery (Poor prognosis subgroup). Univariate and multivariate analyses were performed to assess predictors of early diagnosis, severity, and 6-month outcome. Initial white blood cell count, neutrophil count, monocyte count, and NLR were higher in the Observation group than the Control group, while lymphocyte count was lower in the Observation group. Multivariate logistic regression analysis identified NLR as an independent predictor of early diagnosis. Spinal canal encroachment ≥50%, neutrophil count, and NLR were higher in the complete injury subgroup, and spinal canal encroachment ≥50% was an independent predictor of complete injury, while NLR was not. The NLR was higher in the poor prognosis subgroup and was an independent risk factor. Peripheral blood NLR is useful for early diagnosis of acute SCI and is predictive of clinical outcome.

Evaluation of Neddylation and Apoptosis-Related Gene Expression in Patients with Acute Myeloid Leukemia

Introduction Regulated cell death (RCD) is a process commonly dysregulated in patients (pts) with acute myeloid leukemia (AML), resulting in the survival of genetically unstable cells. Apoptosis, as the best-known form of RCD, interacts with neddylation, a process that contributes to tumorigenesis and apoptosis resistance. Aims This study was conducted to determine the expression of the selected genes involved in the neddylation pathway and to assess their clinical importance along with selected interacting proapoptotic genes. In addition, we correlated the expression levels of these genes with known prognostic factors in AML and determined their impact on the survival of AML pts. Methods The expression of selected proapoptotic genes BIK, BAX, BAK, BCL2L11, BBC3 , PMAIP1 CASP3, CASP7, and neddylation-related genes: CUL1, CUL2 , CUL4A, CUL5, CUL7, CUL9, NEDD8 was determined in duplicates in bone marrow samples of newly diagnosed AML pts. Real-Time PCR was carried out using the TaqMan chemistry and the QuantStudio7 thermal cycler (Applied Biosystems-Thermo Fisher Scientific). Gene expression was normalized using reference genes selected by the Normirazor tool. The normalization was performed by ∆Ct = Ct (reference) - Ct (mRNA of interest). This approach results in higher values for higher mRNA expression. Differential expression analysis was performed using a Welch t-test. Kaplan-Meier method with the log-rank test was used to assess overall survival (OS). Results In a prospective study, we included 40 newly diagnosed AML pts (mean age 62; range 26-87) with a median (m) follow-up of 6.7 months (95% CI: 4.5-9.1). High-risk AML was present in 52.5%, intermediate-risk in 32.5%, and low-risk in 15% of pts, according to European LeukemiaNet (ELN) 2022 risk stratification. NPM1 mutation was present in 23%, whereas FLT3 ITD or TKD mutation in 25% of pts. Intensive treatment was introduced in 43% of pts, while 25% were treated with azacitidine+venetoclax. Non-intensive treatment with azacitidine in monotherapy was administered to the remaining pts. BAK expression was detected in 70%, BIK in 98%, while expression of the other genes was found in all pts. In the high-risk group, we detected lower expression of both proapoptotic BAX (fold change - FC=0.7, p=0.01) and BIK gene (FC=0.4, p=0.01), as well as lower expression of CUL9 (FC=0.7, p=0.03). Accordingly, in pts with NPM1 mutation we revealed upregulation of BIK (FC=6.1, p=0.001), and CUL9 (FC=1.6, p=0.01). Whereas pts with FLT3 mutation had lower expression of proapoptotic BBC3 (FC=0.5, p=0.01), and neddylation-related CUL1 (FC=0.6, p=0.01). In cases of initial bone marrow blasts infiltration above median value (&amp;gt;49%) BCL2L11 CUL5 , NEDD8 and PMAIP1were downregulated ( p=0.001-0.02), while CUL7 ( p=0.00) and CASP3 ( p=0.04) were upregulated. Patients with initial white blood cell count &amp;gt;20 G/l had lower expression of BCL2L11 ( p=0.005), and CUL4A ( p=0.02), while higher expression of CASP7 ( p=0.04). The mOS in the study cohort was not reached. OS was longer in pts with higher (&amp;gt; -2.061, cutoff was determined with CutOff Finder) BAX expression (log-rank: p=0.03) [Figure 1]. The mOS was not reached in this group, whereas the mOS in pts with lower BAX expression was 1.3 months (95% CI: 0.6-1.3). In univariate Cox regression analysis, higher BAX expression (HR 0.31, 95%CI: 0.11-0.84, p=0.022), higher albumin level (HR 0.13, 95%CI: 0.04-0.41, p=0.0004), and intensive treatment (HR 0.18, 95%CI: 0.04-0.69, p=0.012) were factors influencing the outcome. In the multivariate model for OS, higher expression of BAX (HR 0.03, 95%CI: 0.003-0.33, p=0.004) retained its significant protective effect in the context of established prognostic factors [Table 1]. Conclusions To our knowledge, we were the first to evaluate such a complex spectrum of neddylation and apoptosis-related genes in AML. We revealed dysregulation of these genes in AML. Our data indicate that upregulation of BAX at the diagnosis is associated with longer OS. Moreover, we reported significantly lower BAX expression in ELN high-risk group. Thus, indicating BAX may be a potential prognostic factor in AML. Our preliminary results did not prove significant differences in the effect of neddylation gene expression levels on the prognosis of AML patients. As studies are emerging on the potential of neddylation-targeted therapies, we are conducting further research to verify the effect of neddylation on AML.

Long-Term Outcomes of T-Cell Acute Lymphoblastic Leukemia and Risk Factors for Survival in a Multicenter Registry Study from Brazil

Introduction T-cell acute lymphoblastic leukemia (T-ALL) constitutes around 25% of all newly diagnosed cases of acute lymphoblastic leukemia (ALL) in adults. While most pediatric treatment protocols categorize patients (pts) based on their phenotype, this approach is seldom applied to adults. Nevertheless, there is a scarcity of reported cohorts specifically focusing on adult T-ALL. Often, these cases are studied alongside B-cell cases, despite their notable biological differences, or grouped with T-cell lymphoblastic lymphoma, which exhibits a more favorable prognosis compared to T-ALL. The objective of this study is to present outcomes and identify prognostic factors for survival of adults newly diagnosed with T-ALL, utilizing data from a real-world multicenter registry study conducted in Latin America. Methods This registry encompassed four different academic centers in Brazil. The study included pts aged 15 years and above newly diagnosed with T-ALL between January 2009 and June 2022. Clinical data were collected from medical records after ethical approval. Overall (OS) and event-free (EFS) survivals were calculated by Kaplan-Meier method, with Cox regression multivariate analysis (MVA) for finding risk factors and competing risk analysis for relapse. Results A total of 97 pts were included, with a median age of 27 years (range, 15 - 82). Thymic T-ALL accounted for 51% of the cases. Mediastinal bulky was found in 48% and positivity of initial cerebrospinal fluid (CSF) evaluation was 12.5% (by morphology or flow cytometry). Baseline features of this cohort are summarized in table 1. Most pts (88%) were treated with pediatric-inspired regimens (asparaginase [ASP]-based), mostly adapted GMALL (43%) and adapted BFM (22%). Native E. coli ASP was used in 76% and pegylated ASP (PEG-ASP) was used in remaining cases. During presentation or treatment, 15% of the subjects experienced thrombosis of any site, with most cases being associated with the use of ASP (64%) and diagnosed during induction (64%). Following the frontline regimen, 77.3% of pts achieved complete response (CR). Overall, 11.3% of pts died during the induction phase, while 8% were primary refractory. Univariate analysis for CR showed correlation with age (p=0.002), bulky size (p=0.016), and use of ASP (p=0.009). Median follow-up period was 6 years. Overall, allogeneic stem cell transplant (alloHSCT) was performed in 18 pts, being 11/18 in first CR. Five-year OS and 5y EFS were 43.7% (95% confidence interval [CI]: 34.4-55.5) and 36.4% (95% CI 27.9-47.5), respectively. Over the follow-up, 5-year relapse rate and non-relapse mortality (NRM) were 35.6% and 27.9%, respectively. Among pts who underwent alloHSCT, 5y OS was 64%. In the univariate analysis, older age (HR 1.02 [1.01-1.04], p&amp;lt;0.01) was associated with lower OS. Conversely, thymic T-ALL (HR 0.54 [0.3-0.96], p=0.03) and use of ASP (HR 0.35 [0.17-0.716], p&amp;lt;0.01) were associated with higher OS. Initial white blood cell count was not statistically associated with OS. Subsequently, we performed a subgroup analysis focusing on the adult and young adult population (AYA, age between 15-45 years). In this subgroup (n=85), 89% were treated with pediatric-inspired regimens and 5y OS was 46.5%. In the univariate analysis, thrombosis (HR 2.21 [1.09-4.48], p=0.02) was associated with lower OS, while thymic T-ALL (HR 0.48 [0.24-0.93], p=0.03) and the use of ASP (HR 0.317 [0.13-0.75], p&amp;lt;0.01) were associated with higher OS. In the MVA for AYA, thymic T-ALL (HR 0.50 [0.25-0.98], p=0.04) and thrombosis (HR 2.23 [0.97-5.13], p=0.054) remained associated with OS, while older age was not (HR 1.004 [0.96 - 1.04], p=0.81) (Figure 1). Conclusions Reported outcomes of T-ALL in this registry from Latin America are comparable to older reports from large groups worldwide. Currently, European groups have reported OS rates surpassing 70% for adults with T-ALL.However, in our setting, even in the AYA population, OS was disappointing. This could be attributed to increased NRM due to treatment toxicity and limited access to HSCT, which may have contributed to these findings. As previously reported, thymic T-ALL remains a lower-risk subtype. Additionally, thrombosis has emerged as an independent risk factor for OS in the AYA population, which is a novel finding that warrants further research. To the best of our knowledge, this is the first study specifically focusing on adult T-ALL from Latin America.

Association of Age with Acuity and Severity of Illness at Initial Presentation in Children, Adolescents, and Young Adults with Leukemia

Background: Adolescent and Young Adult (AYA) patients, historically defined by the National Cancer Institute as patients between 15-39 years, diagnosed with cancer are at risk for increased mortality compared with younger patients. Age 10 has been an alternate threshold for higher risk of treatment failure in leukemia. Acuity of illness - as defined by intensive care unit (ICU) level resource use at admission - in children with acute myeloid leukemia (AML) was shown in prior data from the Pediatric Health Information System to mediate excess mortality in Black patients (Winestone et al, Am J Hematol., 2017). This study aims to evaluate the acuity and severity of illness in patients presenting with new diagnoses of leukemia and evaluate whether AYAs have a higher acuity and severity of illness compared to younger patients. Methods: We performed a retrospective analysis of 771 patients aged 1-21 years with initial presentation of newly diagnosed leukemia at Children's Healthcare of Atlanta (CHOA) between 2010-2018. Exclusion criteria included those who received any treatment at another facility or those for whom information about the first 72 hours following presentation to the hospital was not available. High acuity of illness was defined (yes/no) as any ICU admission or ICU-level resource use - regardless of physical location in the hospital - by organ system (cardiovascular, respiratory, renal, hematologic, and neurologic) on manual chart review. High severity of illness was defined as initial white blood cell (WBC) count ≥ 50,000 cells/microliter or central nervous system (CNS) disease. Both acuity and severity were assessed during the first 72 hours following the point of diagnosis. Multivariable logistic regression was used to examine the association of age at diagnosis with acuity or severity of illness, controlling for sex, race/ethnicity, insurance status, and type of leukemia. Results: Among 536 patients with complete data to date, the median age was 6 years (interquartile range 3-12 years, 65.5% aged 1-9 years, 34.5% aged 10-21 years), 53.4% were male, 45.7% were Non-Hispanic White, and 65.7% had private insurance. Diagnoses included B-cell acute lymphoblastic leukemia (ALL) (70.5%), AML (16.4%), T-cell ALL (9.3%), and other leukemias (3.7%) (juvenile myelomonocytic, chronic myeloid, and Burkitt's). High acuity of illness was seen in 24.2% of patients and was more likely in older patients (10-21 years, 33.5% versus 1-9 years, 19.4%, p &amp;lt;0.01). Figure 1 illustrates involved organ systems by age group. High severity of illness was seen in 31.3% of cases, and although not significant, was also more likely in older patients (10-21 years, 32.5% versus 1-9 years, 27.9%, p=0.06). In multivariable analysis, compared to patients aged 1-9 years, patients aged 10-21 years had an increased odds of high acuity of illness [odds ratio (OR) 1.69, 95% confidence interval (CI 1.09-2.63)]. Patients with T-ALL also had an increased odds of high acuity of illness [OR 3.40 (CI 1.76-6.54); referent B-ALL]. The odds of high severity of illness did not differ by age [10-21 years OR 1.23 (CI 0.81-1.86)], but was significantly higher by Non-Hispanic Black race [OR 1.83 (CI 1.14-2.94); referent Non-Hispanic White] and type of leukemia [T-ALL OR 3.90 (CI 2.03-7.48); other leukemia OR 3.26 (CI 1.28-8.32); referent B-ALL] (Table 1). Discussion and Conclusions: AYA patients had an increased likelihood of high acuity of illness requiring ICU-level care at presentation, indicating a risk for disparities of outcomes from the point of initial presentation. Future directions will examine the association of acuity of illness with mortality in this cohort, as well as the role of race/ethnicity on severity of illness and mortality. This research will ultimately help inform strategies toward narrowing age disparities in outcomes of AYA leukemia.

Feasibility and Outcome of Post-Induction Therapy Incorporating Dasatinib for Patients with Newly Diagnosed ABL-Class Fusion B-Lymphoblastic Leukemia (ABL-class Fusion B-ALL): Children's Oncology Group AALL1131

Background: Approximately 2-3% of B-ALL patients have Philadelphia chromosome like (Ph-like) B-ALL with an ABL-class fusion ( ABL1, ABL2, PDGFRB, or CSF1R fusions), but lacking BCR::ABL1. These patients are predicted to be sensitive to ABL-class tyrosine kinase inhibitors, such as imatinib or dasatinib. Ph-like B-ALL is associated with male sex, older age, higher initial white blood cell (WBC) count, elevated end of induction (EOI) minimal residual disease (MRD), and poor outcome. The AALL1131 Dasatinib arm was designed to evaluate response to therapy following induction of patients with ABL-class fusion B-ALL, when given dasatinib continuously on a modified Berlin-Frankfurt-Münster (MBFM) backbone. Methods: Between February 2012 and March 2019, AALL1131 enrolled patients 1-30 years with newly diagnosed high risk (HR) B-ALL. AALL1131 was amended in August 2016, to include the Dasatinib arm for patients with ABL-class fusions involving ABL1, ABL2, PDGFRB, and CSF1R. Patients with Down Syndrome were not eligible for the Dasatinib arm. ABL-class fusion B-ALL patients with a predicted TKI-sensitive mutation were screened by low density array (LDA) PCR and confirmed by additional molecular testing. Following 4-drug induction, patients with HR B-ALL and ABL-class fusions received MBFM with dasatinib (60 mg/m 2, maximum 140 mg) daily from start of consolidation through end of maintenance. Dasatinib was held only for toxicity. Results: Twenty-two evaluable patients with HR B-ALL were non-randomly assigned to the Dasatinib arm. ABL-class 3' partners included ABL1 (n=4), ABL2 (n=4), PDGFRB (n=12), and CSF1R (n=2). Compared to all patients on AALL1131, patients treated on the Dasatinib arm were older (median age at diagnosis 14 versus 10 years, p=0.008), more often male (77% versus 56%, p=0.046), and had a trend towards an increased initial WBC (median WBC at diagnosis 44,000/µL versus 19,000/µL, p=0.086). Patients with ABL-class fusions had EOI MRD &amp;gt; 0.01% in 20 of 22 patients and available end of consolidation MRD &amp;gt;0.01% in 6 of 10 patients. Only 5 of 22 (22.7%) patients completed prescribed protocol therapy. Reasons for therapy discontinuation included induction failure (n=2), relapse (n=1), alternate therapy (n=1), determined to be in the patient's best interest (n=10), death (n=1), unknown (n=2). Compared to all patients on AALL1131, four-year disease-free survival was 52.5+18.1% versus 86.8+0.7% (p&amp;lt;0.0001) and overall survival 79.4+13.6% versus 89.2+0.4% (p&amp;lt;0.0001). Dasatinib was well tolerated with no unexpected treatment related toxicities. Conclusion: Patients with ABL-class fusions were more likely male, EOI MRD+, and had poorer outcomes. Seventy-seven percent of patients enrolled on the Dasatinib arm did not complete prescribed therapy. While dasatinib was well tolerated, treatment failures occurred early, indicating alternate strategies are needed.

Survival outcomes of myeloid leukemia associated with Down syndrome and de novo acute myeloid leukemia in children: Experience from a single tertiary center in Thailand

Few studies have reported the survival outcomes of myeloid leukemia associated with Down syndrome (DS) in resource-limited countries. This study aimed to compare characteristics and survival outcomes of children with acute myeloid leukemia (AML) between those with and without DS in Thailand. The medical records of AML patients aged 0-15 years treated in a major tertiary center in Southern Thailand between October 1978 and December 2019 were reviewed retrospectively. The overall (OS) and event-free survivals (EFS) rates were calculated using the Kaplan-Meier method. A total of 362 AML patients were included, of which 41 (11.3%) had DS. The mean age at diagnosis of the DS patients was 2.5 ± 1.9 years and most of them (90.2%) were under the age of five. The DS patients had lower initial white blood cell counts and peripheral blasts compared to the non-DS patients. The AML-M7 subtype was more common in the DS than in the non-DS patients (80.5% vs. 9.1%, p < 0.01, respectively). The 5-year OS and EFS rates of the DS patients were lower compared to the non-DS patients (12.9% vs. 20.5%, p = 0.05 and 13.7% vs. 18.4%, p = 0.03, respectively). DS patients had a significantly higher rate of early and treatment-related deaths compared to non-DS patients (30.3% vs. 13.5%, p < 0.01 and 39.4% vs. 19.5%, p = 0.02, respectively). Over the study period, there were a decrease in early death rate and an increase in survival rates of DS patients, which suggests that chemotherapy regimens and supportive care have improved over time.

Poor outcome of pediatric B-cell acute lymphoblastic leukemia associated with high level of CRLF2 gene expression in distinct molecular subtypes.

Overexpression of the cytokine receptor-like factor 2 (CRLF2) gene is the most common feature in the Philadelphia chromosome (Ph)-like subtype of B-cell acute lymphoblastic leukemia (B-ALL). However, the predictive value of CRLF2 overexpression for the prognosis of pediatric B-ALL patients remain controversial. The molecular mechanisms that upregulate CRLF2 expression level in patients has not been fully elucidated. In this study, the prognostic impact of CRLF2 expression level on molecular types of B-ALL in pediatric patients from Zhujiang Hospital (n = 111) was retrospectively analyzed. Youden index analysis was used to categorize CRLF2 expression into 3 groups, and these categories more precisely described the differences in the prognosis of patients with varying expression levels of CRLF2 in both the Zhujiang Hospital cohort and the TARGET cohort. We used the Zhujiang Hospital cohort as a discovery cohort to determine the cutoff value of CRLF2 expression. CRLF2-high patients accounted for approximately 6%. In addition, the percentage of bone marrow blast cells and initial white blood cell count in CRLF2-high patients were higher than those in CRLF2-low patients, and MRD turned negative slower. The results were validated in the TARGET cohort and indicated that CRLF2 overexpression could be subdivided by CRLF2 expression levels into 2 categories: CRLF2-high with a poor survival and CRLF2-medium with a good OS and EFS. Such heterogeneity was attributed to the different molecular mechanisms leading to CLRF2 upregulation, where the CRLF2 overexpression level was high in Ph-like B-ALL and medium in high hyperdiploid B-ALL. This study highlights the importance of the molecular mechanisms of the upregulation of CRLF2 expression in predicting the prognosis of pediatric B-ALL patients.

Real-World Performance of 2022 Revised World Health Organization (WHO) Criteria for Mixed Phenotype Acute Leukemia (MPAL) B/Myeloid Defined Only By Isolated MPO Expression (isoMPO)

Mixed phenotype acute leukemia (MPAL) is biologically and immunophenotypically heterogeneous, and optimal diagnostic criteria remain unclear. The two current pathologic classifications [2022 World Health Organization (WHO) 5 th Ed. and International Consensus Classification (ICC)] group MPAL by cell lineages and, when present, cytogenetic drivers. In both, myeloperoxidase (MPO) is a key determinant of myeloid lineage. However, the diagnosis of MPAL has been inconsistently applied to cases of acute leukemia expressing MPO alone to define myeloid lineage. To address this, the 2022 WHO revised prior cell lineage definitions to emphasize antigen intensity (≥50%) relative to a positive control population, attempting to standardize lineage assignment across flow cytometer settings and pathologist interpreters. Distinction between pediatric B-lymphoblastic leukemia (B-ALL) and MPAL B/Myeloid with isolated MPO is crucial for therapeutic decision-making. For example, on Children's Oncology Group (COG) regimens, patients with MPAL B/Myeloid receive an anthracycline during induction and intensified chemotherapy post-induction, whereas standard-risk B-ALL patients do not. We hypothesized that the 2022 WHO criteria applied to MPO expression in children with acute leukemia would identify leukemic subtypes (B-ALL vs. MPAL B/Myeloid with isolated MPO) with differences in clinical characteristics and/or outcome. We applied 2022 WHO criteria to flow cytometry data from a multicenter pediatric cohort of leukemias originally classified as MPAL B/Myeloid or B-ALL (Oberley AJCP 2017; Raikar Blood 2018; Oberley Leukemia 2020). Maximal antigen intensity on the leukemic population was measured in 0.5 log increments and normalized to maximal intensity of a control (neutrophil) population. MPO expression was scored as none, low (&amp;lt;50% intensity of mature neutrophils, the typical level in B-ALL with isolated MPO expression) or high (≥50% intensity of neutrophils, meeting 2022 WHO criteria for myeloid lineage assignment). Since the current study focused on MPAL B/Myeloid cases with isolated MPO expression, cases of MPAL T/Myeloid and of MPAL B/Myeloid with myeloid lineage assignment based on monocytic markers were excluded. Clinicopathologic data were compared with MPO expression scores by univariate and multivariate analyses. Primary endpoint was categorical difference in presenting features. Secondary endpoints were end of induction minimal residual disease (EOI MRD) ≥0.01%, event-free survival (EFS) and overall survival (OS). All analyses were two-sided; p&amp;lt;0.05 was the threshold for statistical significance. Among all patients at diagnosis (n=176), median age was 6.14 years (range 0.3-21), 68% were &amp;lt;10 years old, 59% were male, 63% were Hispanic, 76% had initial white blood cell (WBC) count &amp;lt;50K/µL, and 81% were CNS1. MPO was absent, low (&amp;lt;50%) or high (≥50%) in 48%, 29% and 23% of the cohort, respectively. Prevalence of favorable cytogenetics ( ETV6:: RUNX1 or double trisomy) was inversely proportional to MPO intensity [no MPO (50%), low MPO (27%), high MPO (17%); p&amp;lt;0.001). MPO expression (low or high) was more prevalent in patients &amp;gt;10 years of age (p&amp;lt;0.001). There was no difference in MPO by presenting WBC count (p=0.40). Among patients treated with ALL induction with known EOI MRD results (n=166), MPO intensity was not significantly associated with EOI MRD positivity, EFS or OS (multivariate p&amp;gt;0.40 for all three endpoints after accounting for presenting features and initial therapy). Our study demonstrates that 2022 WHO criteria for interpreting MPO intensity can be consistently applied to flow cytometry data from a variety of laboratories. Based on our analysis, only 44% of previous MPAL B/Myeloid cases with isolated MPO were now classified as MPAL. However, the clinical significance of this distinction remains unclear. After accounting for differences in presenting features, MPO expression was not additionally predictive of MRD positivity, EFS or OS. Further investigation is required to support the proposed threshold of 50% MPO intensity of a neutrophil control population as clinically relevant to assign myeloid lineage. Prospective standardized application of 2022 WHO cell lineage assignment criteria across centers will facilitate detailed understanding of the biological underpinnings and optimal therapeutic strategies for this heterogeneous disease.

Factors influencing the surveillance of re-emerging intracranial infections in elective neurosurgical patients: A single-center retrospective study.

At present, many studies have reported the risk factors for postoperative intracranial reinfection, including age, sex, time to surgery, duration of postoperative catheterization, emergency procedures, type of disease and cerebrospinal fluid leakage, but the academic community has not reached a unified conclusion. To find factors influencing the surveillance of re-emerging intracranial infections in elective neurosurgical patients. Ninety-four patients who underwent elective craniotomy from January 1, 2015 to December 31, 2022 in the Department of Neurosurgery, First Hospital of Jilin University, were included in this study. Of those, 45 patients were enrolled in the infection group, and 49 were enrolled in the control group. The clinical data of the patients were collected and divided into three categories, including preoperative baseline conditions, intraoperative characteristics and postoperative infection prevention. The data were analyzed using SPSS 26.0 software. There were 23 males and 22 females in the infection group with a mean age of 52.8 ± 15.1 years and 17 males and 32 females in the control group with a mean age of 48.9 ± 15.2 years. The univariate analysis showed that the infection group had higher systolic blood pressures and postoperative temperatures, fewer patients who underwent a supratentorial craniotomy, more patients with a history of hypertension and higher initial postoperative white blood cell counts than the control group, with statistically significant differences (P < 0.05). The multifactorial logistic regression analysis showed that a history of hypertension and a high postoperative body temperature were independent risk factors for postoperative infection in neurosurgical patients. The results obtained in this study indicated that a history of hypertension and a high postoperative body temperature were independent risk factors for postoperative neurological symptoms.

Prognostic value of hemoglobin-to-red cell distribution width ratio in patients with cardiopulmonary resuscitation after out-of-hospital cardiac arrest

To investigate the prognostic value of hemoglobin-to-red cell distribution width ratio (HRR) in patients with cardiopulmonary resuscitation (CPR) after out-of-hospital cardiac arrest (OHCA). A retrospective study was conducted. Patients aged ≥ 18 years with OHCA who were transferred to intensive care unit (ICU) after successful CPR from the emergency room of the First Affiliated Hospital of Zhengzhou University from August 2016 to February 2022 were enrolled. General clinical data, initial vital signs, acute physiology and chronic health evaluation II (APACHE II), Glasgow coma scale (GCS), first laboratory indicators after admission to ICU [including white blood cell count (WBC), red blood cell count (RBC), hemoglobin (Hb), pH value, lactic acid (Lac), 6-hour lactic acid clearance (LCR), red cell distribution width (RDW), HRR], length of ICU stay were collected. According to whether the patients died in hospital, the patients were divided into survival group and death group. Binary Logistic regression was used to analyze the independent factors influencing the prognosis of patients after CPR. Receiver operator characteristic curve (ROC curve) was drawn to analyze the predictive value of independent influencing factors for the prognosis of patients after CPR. A total of 122 patients were enrolled after OHCA CPR, of which 88 died in hospital, the in-hospital mortality was 72.13%. There were no significant differences in age, past medical history, initial vital signs and WBC in ICU between the two groups. Compared with the death group, the survival group had higher GCS score, RBC, Hb, pH value, 6-hour LCR, HRR, lower APACHE II score, Lac, RDW level, and longer length of ICU stay. Multivariate Logistic regression analysis showed that APACHE II score, GCS score, 6-hour LCR, HRR, length of ICU stay were independent factors influencing the prognosis of patients after CPR [APACHE II score: odds ratio (OR) = 0.784, 95% confidence interval (95%CI) was 0.683-0.901, P = 0.001; GCS score: OR = 1.390, 95%CI was 1.059-1.823, P = 0.018; 6-hour LCR: OR = 1.039, 95%CI was 1.015-1.064, P = 0.001; HRR: OR = 2.047, 95%CI was 1.383-3.029, P < 0.001; length of ICU stay: OR = 1.128, 95%CI was 1.046-1.216, P = 0.002]. ROC curve analysis showed that HRR, 6-hour LCR and APACHE II score could predict the prognosis of patients after CPR. The sensitivity was 85.3% and the specificity was 54.5% when the area under the ROC curve (AUC) of HRR was 0.731, and the cut-off value was 8.555. The sensitivity was 88.2% and the specificity was 46.6%, when the AUC of 6-hour LCR was 0.701, and the cut-off value was 28.947%. The sensitivity was 73.9% and the specificity was 79.4% when the AUC of APACHE II score was 0.848, the cut-off value was 22.000. The predictive value of the combination of HRR and 6-hour LCR was higher than that of a single index. The sensitivity was 79.3% and the specificity was 76.1%, when the AUC was 0.796, the cut-off value was 0.296. HRR, 6-hour LCR and APACHE II score have high prognostic value in patients with OHCA after CPR. HRR < 8.555, 6-hour LCR < 28.947% and APACHE II score > 22.000 indicated poor prognosis.

Classification and genetics of pediatric B-other acute lymphoblastic leukemia by targeted RNA sequencing.

Acute lymphoblastic leukemia (ALL) can be classified into different subgroups based on recurrent genetic alterations. Here, targeted RNA sequencing was used to identify the novel subgroups of ALL in 144 B-other and 40 "classical" ALL samples. The classical TCF3-PBX1, ETV6-RUNX1, KMT2A-rearranged, and BCR-ABL1, and novel P2RY8-CRLF2, ABL-, JAK2-, ZNF384-, MEF2D-, and NUTM1-fusions were easily identified by fusion transcript analysis. IGH-CRLF2 and IGH-EPOR were found by abnormally high levels of expression of CRLF2 or EPOR. DUX4-rearranged was identified by the unusual expression of DUX4 genes and an alternative exon of ERG, or by clustering analysis of gene expression. PAX5-driven ALL, including fusions, intragenic amplifications, and mutations were identified by single-nucleotide variant analysis and manual inspection using the IGV software. Exon junction analysis allowed detection of some intragenic ERG and IKZF1 deletions. CRLF2-high associated with initial white blood cell (WBC) counts of ≥50× 103/μL and GATA3 risk alleles (rs3781093 and rs3824662), whereas ABL/JAK2/EPOR-fusions associated with high WBC counts, National Cancer Institute's high-risk classification, and IKZF1del. ZNF384-fusions associated with CALLA-negativity and NUTM1-fusions in infants. In conclusion, targeted RNA sequencing further classified 66.7% (96 of 144) B-other ALL cases. All BCP-ALL subgroups, except for iAMP21, hyperdiploid and hypodiploid cases, were identified. Curiously, we observed higher frequencies of females within B-rest ALLs and males in PAX5-driven cases.

Application of G-CSF in high-leukocyte acute myeloid leukemia is a poor prognostic factor

ABSTRACTObjectiveTo analyze the effect of granulocyte colony-stimulating factor (G-CSF) on outcomes in patients with acute myeloid leukemia (AML).MethodsA total of 526 patients with AML in the Haematology Department were enrolled. They were divided into a G-CSF treatment group and a no G-CSF group according to whether G-CSF was administered in the induction chemotherapy period, with 355 cases in the G-CSF group and 171 cases in the no G-CSF group. Cox regression analysis and Kaplan-Meier curve analysis were used to analyze the effect of G-CSF on the first complete remission (CR1) phase and overall survival (OS). In addition, further analysis was performed based on an initial white blood cell count of 50 * 10^9/L.ResultsThe application of G-CSF significantly shortened the CR1 phase and OS in patients with high leukocytes.ConclusionsG/GM-CSF should be used with caution in patients with AML, especially those with high leukocytes.

Hyperleukocytosis in Childhood Acute Leukemia: Early Complications and Survival Outcomes

Hyperleukocytosis and extreme hyperleukocytosis, defined as initial white blood cell counts greater than 100 × 109/L and 200 × 109/L, respectively, have been associated with unfavorable outcomes. This study aimed to determine the early complications and survival outcomes of childhood leukemia patients with hyperleukocytosis. The medical records of 690 children newly diagnosed with acute leukemia between January 1998 and December 2017 were retrospectively reviewed. The Kaplan–Meier method and log-rank test were used to assess and compare the survival outcomes. Multivariate Cox proportional hazards regression was used to determine associated risk factors for overall survival. We found that 16.6% of 483 childhood acute lymphoblastic leukemia (ALL) patients and 20.3% of 207 childhood acute myeloid leukemia (AML) patients had hyperleukocytosis at diagnosis. ALL patients with hyperleukocytosis had more early complications than those without hyperleukocytosis (p &lt; 0.05). Among the ALL group, the 5-year overall survival rate for those with hyperleukocytosis was significantly lower than for those without hyperleukocytosis (37.2% vs. 67.8%, p &lt; 0.0001), while the difference was not statistically significant in the AML group (19.0% vs. 30.2%, respectively, p = 0.26). Hyperleukocytosis (hazard ratio [HR]: 2.04), extreme hyperleukocytosis (HR: 2.71), age less than 1 year (HR: 3.05), age greater than 10 years (HR: 1.64), and male sex (HR: 1.37) were independently associated with poorer overall survival in childhood ALL patients. Extreme hyperleukocytosis (HR: 2.63) and age less than 1 year (HR: 1.82) were independently associated with poorer overall survival in AML patients. Hyperleukocytosis was associated with adverse survival outcomes in childhood leukemia.

Assessing inpatient antibiotic use during COVID-19 surges with or without infectious diseases consultation

Background: Throughout the COVID-19 pandemic, increased inappropriate antibiotic use (AU) drove concern for antimicrobial resistance. Antimicrobial stewardship efforts are critical for combatting antimicrobial resistance. Our objective was to compare AU between SARS-CoV-2 delta and omicron variant surge periods in COVID-19 patients hospitalized at Tufts Medical Center (TMC) in Boston. Infectious diseases consultation (IDC) was mandatory for patients diagnosed with COVID-19 throughout the SARS-CoV-2 delta variant surge. During the SARS-CoV-2 omicron variant surge, IDC was optional for certain patient populations. Instead, the antibiotic stewardship program (ASP) reviewed these patients for appropriate medical management. We hypothesized that AU would increase during the SARS-CoV-2 omicron variant surge compared to the delta variant surge due to optional IDC because IDC would reduce inappropriate AU for suspected viral pneumonia. Methods: Retrospective medical record review of patients hospitalized with COVID-19 during the SARS-CoV-2 delta and omicron variant surges was conducted. We collected data regarding vital signs, white blood cell count (WBC), length of stay (LOS), steroid use, IDC, and AU (defined as percentage of patients receiving at least 1 antibiotic dose), with a separate category for antibiotics commonly used for bacterial pneumonia (ampicillin-sulbactam, azithromycin, cefepime, cefpodoxime, ceftazidime, ceftriaxone, doxycycline, piperacillin-tazobactam, vancomycin). We determined that 71 patients from each group were needed to detect an absolute difference of 20% in AU between surges with 75% power, based on the CDC estimate that 80% of patients hospitalized with COVID-19 receive an antibiotic. Unpaired t tests and χ2 analyses were conducted on demographic data. Inferential statistics assessed for differences between the 2 SARS-CoV-2 variant surges in AU and days of therapy (DOT), supplemental oxygen (SaO2), steroid use, and IDC utilizing a Wilcoxon rank-sum test and logistic regression analyses. Results: Results showed no significant differences in AU between surges (38.0% during the SARS-CoV-2 delta variant surge vs 42.3% during the SARS-CoV-2 omicron variant surge; P = .131). Disease severity was not different between surges as measured by steroid use, initial WBC, and SaO2. WBC was a predictor for AU in both surges (delta surge, P = 0.007; omicron surge, P = .002). Average LOS was higher throughout the SARS-CoV-2 delta variant surge for all patients (11.58 days during the delta surge, vs 5.97 days during the omicron variant surge; P = .047) and those who received antibiotics (18.44 days during the delta variant surge vs 6.70 days dring the omicron variant surge; P = .210). Total DOT was significantly longer during the SARS-CoV-2 delta variant surge for all antibiotics (463 DOT during the delta variant surge vs 277 DOT during the omicron variant surge; P = .047) and antibiotics commonly used for bacterial pneumonia (315 DOT during the delta variant surge vs 202 DOT during the omicron variant surge; P = .021). Conclusions: Making IDC optional for certain patient populations diagnosed with COVID-19 did not affect AU in a large, urban academic medical center with a comprehensive ASP.Disclosures: None