Incidence Of Acute Leukemia Research Articles

Epidemiology of childhood acute leukemias in marginalized populations of the central-south region of Mexico: results from a population-based registry.

Acute leukemias (AL) are the main types of cancer in children worldwide. In Mexico, they represent one of the main causes of death in children under 20 years of age. Most of the studies on the incidence of AL in Mexico have been developed in the urban context of Greater Mexico City and no previous studies have been conducted in the central-south of the country through a population-based study. The aim of the present work was to identify the general and specific incidence rates of pediatric AL in three states of the south-central region of Mexico considered as some of the marginalized populations of Mexico (Puebla, Tlaxcala, and Oaxaca). A population-based study was conducted. Children aged less than 20 years, resident in these states, and newly diagnosed with AL in public/private hospitals during the period 2021-2022 were identified. Crude incidence rates (cIR), standardized incidence rates (ASIRw), and incidence rates by state subregions (ASIRsr) were calculated. Rates were calculated using the direct and indirect method and reported per million children under 20 years of age. In addition, specific rates were calculated by age group, sex, leukemia subtype, and immunophenotype. A total of 388 cases with AL were registered. In the three states, the ASIRw for AL was 51.5 cases per million (0-14 years); in Puebla, it was 53.2, Tlaxcala 54.7, and Oaxaca de 47.7. In the age group between 0-19 years, the ASIRw were 44.3, 46.4, 48.2, and 49.6, in Puebla, Tlaxcala, and Oaxaca, respectively. B-cell acute lymphoblastic leukemia was the most common subtype across the three states. The incidence of childhood AL in the central-south region of Mexico is within the range of rates reported in other populations of Latin American origin. Two incidence peaks were identified for lymphoblastic and myeloid leukemias. In addition, differences in the incidence of the disease were observed among state subregions which could be attributed to social factors linked to the ethnic origin of the inhabitants. Nonetheless, this hypothesis requires further investigation.

Incidence and Outcome of Childhood Acute Leukemia in A Tertiary Care Hospital of Bangladesh Armed Forces

Background: Worldwide cancer is the second leading cause of death in children under 15 years and acute leukemia is the most prevalent cancer among children.
 Objective: The objective of the study was to analyze the incidence and overall outcome of childhood leukemia patients aged 0-12 years in Combined Military Hospital (CMH), Dhaka.
 Methods: It was a retrospective cross-sectional study. Children below 12 years of age with confirmed diagnosis of leukemia and received treatment from the paediatric oncology unit of department of paediatrics of CMH, Dhaka were taken for this study. Data has been collected from Hospital based cancer registry records from 2011 to 2021. There present status has been collected from regular OPD or by phone calls.
 Results: The commonest cancer was found Acute Leukemia (52%), among them Acute Lymphoblastic Leukemia (ALL) 83.15% and Acute Myeloid Leukemia (AML) 16.85%. Morphological (FAB classification) sub-divisions revealed ALL-L2 (31%) was the commonest group for ALL. In case of AML, AML-M3 (APML) was the commonest (27%). Immunophenotyping of cells revealed Pre-B ALL was the commonest. Cytogenetic analysis revealed ETV6-RUNX1 (21%), t(1;19) ((q23,p13) E2A/PBX1 (11%) were two most common genetic abnormalities found in ALL and t(15;17) (q22;q12) M3,M3v PML-RARA was the commonest cytogenetic abnormalities and (8;21) (q22;q22) RUNX1/RUNX1T1 for AML. In case of ALL overall survival was 54% and in case of AML 40%. About 10% of patients reported relapses.
 Conclusion: Incidence of acute leukemia was the highest among all childhood cancer. At the end of the study, overall survival was 52% of cases, and relapses were seen in 10% of cases.
 DS (Child) H J 2021; 38(1): 17-26

Environmental Risk Factors for Pediatric Acute Leukemia: Methodology and Early Findings.

Acute leukemia is the most common type of malignancy in children, and no major environmental risk factors have been identified relating to its pathogenesis. This study has been conducted with the aim for identifying risk factors associated with this disease. This study was conducted in 2016-2020 among children aged <15 years residing in Isfahan Province, Iran. Children with newly diagnosed Acute lymphoblastic leukemia, including Acute myeloid leukemia (ALL and AML) were considered a case group. The control group was selected among children hospitalized in orthopedic and surgery wards in the same region. Demographic data, parental occupational exposures and educational level, maternal obstetric history, type of feeding during infancy and parental smoking habits, exposure to pesticides, and hydrocarbons besides dietary habits (using a food frequency questionnaire) were evaluated. Overall, 497 children (195 cases and 302 controls) completed the survey. In the initial analysis, there was no significant difference between case and control groups about type of milk feeding (P = 0.34) or parental age (P = 0.56); however, an association between mothers' education and increased risk for ALL was observed (P = 0.02). The results of this study can be helpful in better understanding the environmental risk factors involved in the incidence of acute leukemia. Future publications based on the analysis of the database created in the present study can lead to recognizing these factors. In addition, evaluating the effect of these factors on treatment outcomes is an important step in reducing the burden of the disease.

Epidemiology of Acute Leukemia among Children with Down Syndrome in Korea.

PurposeChildren with Down syndrome (DS) show a higher risk of acute leukemia than those without DS. In this study, we investigated the nationwide incidence of acute leukemia among children with DS and compared their epidemiologic characteristics with those of children with acute leukemia but without DS.Materials and MethodsUsing the National Health Insurance Service database, we selected patients with acute leukemia aged 0–19 years at diagnosis between 2007 and 2016.ResultsAmong the 4,697 children with acute leukemia, 54 (1.1%) had DS. The median incidence rate of leukemia with DS by year was 1.3% (range, 0.2% to 2.0%). Sixteen patients with acute lymphoblastic leukemia (ALL; 29.6%) and 36 with acute myeloid leukemia (AML; 66.7%) had DS. The DS group showed younger age at diagnosis than the non-DS group, and diagnosis of AML was more frequent in the DS group than in the non-DS group (3 years vs. 9 years, p < 0.001; 66.7% vs. 32.4%, p < 0.001, respectively). The 5-year overall survival was comparable between the DS and non-DS groups (88.0% vs. 81.9%, p=0.375). Among all the Koreans born between 2007 and 2008, the incidences of acute leukemia, ALL, and AML were 49.25, 20.75, and 163.38 times higher, respectively, in the DS group than in the non-DS group.ConclusionOur findings support the fact that the incidence of acute leukemia is higher among patients with DS than among those without DS in Korea. However, the DS and non-DS groups in this study had a comparable overall survival rate.

Acute Leukemia

The acute leukemias are malignant clonal disorders characterized by aberrant differentiation and proliferation of transformed hematopoietic progenitor cells. These cells accumulate within the bone marrow and lead to suppression of the production of normal blood cells, with resulting symptoms from varying degrees of anemia, neutropenia, and thrombocytopenia or from infiltration into tissues. They are currently classified by their presumed cell of origin, although the field is moving rapidly to genetic subclassification. This review covers epidemiology; etiology; classification of leukemia by morphology, immunophenotyping, and cytogenetic/molecular abnormalities; cytogenetics of acute leukemia; general principles of therapy; acute myeloid leukemia; acute lymphoblastic leukemia; and future possibilities. The figure shows the incidence of acute leukemias in the United States. Tables list World Health Organization (WHO) classification of acute myeloid leukemia and related neoplasms, expression of cell surface and cytoplasmic markers for the diagnosis of acute myeloid leukemia and mixed-phenotype acute leukemia, WHO classification of acute lymphoblastic leukemia, WHO classification of acute leukemias of ambiguous lineage, WHO classification of myelodysplastic syndromes, European LeukemiaNet cytogenetic and molecular genetic subsets in acute myeloid leukemia with prognostic importance, cytogenetic and molecular subtypes of acute lymphoblastic leukemia, terminology used in leukemia treatment, and treatment outcome for adults with acute leukemia. This review contains 2 figures, 15 tables, and 119 references. Keywords: Acute leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, cancer, cytogenetics, chromosomal abnormality

Acute Leukemia

The acute leukemias are malignant clonal disorders characterized by aberrant differentiation and proliferation of transformed hematopoietic progenitor cells. These cells accumulate within the bone marrow and lead to suppression of the production of normal blood cells, with resulting symptoms from varying degrees of anemia, neutropenia, and thrombocytopenia or from infiltration into tissues. They are currently classified by their presumed cell of origin, although the field is moving rapidly to genetic subclassification. This review covers epidemiology; etiology; classification of leukemia by morphology, immunophenotyping, and cytogenetic/molecular abnormalities; cytogenetics of acute leukemia; general principles of therapy; acute myeloid leukemia; acute lymphoblastic leukemia; and future possibilities. The figure shows the incidence of acute leukemias in the United States. Tables list World Health Organization (WHO) classification of acute myeloid leukemia and related neoplasms, expression of cell surface and cytoplasmic markers for the diagnosis of acute myeloid leukemia and mixed-phenotype acute leukemia, WHO classification of acute lymphoblastic leukemia, WHO classification of acute leukemias of ambiguous lineage, WHO classification of myelodysplastic syndromes, European LeukemiaNet cytogenetic and molecular genetic subsets in acute myeloid leukemia with prognostic importance, cytogenetic and molecular subtypes of acute lymphoblastic leukemia, terminology used in leukemia treatment, and treatment outcome for adults with acute leukemia. This review contains 2 figures, 15 tables, and 119 references. Keywords: Acute leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, cancer, cytogenetics, chromosomal abnormality

Acute Leukemia

The acute leukemias are malignant clonal disorders characterized by aberrant differentiation and proliferation of transformed hematopoietic progenitor cells. These cells accumulate within the bone marrow and lead to suppression of the production of normal blood cells, with resulting symptoms from varying degrees of anemia, neutropenia, and thrombocytopenia or from infiltration into tissues. They are currently classified by their presumed cell of origin, although the field is moving rapidly to genetic subclassification. This review covers epidemiology; etiology; classification of leukemia by morphology, immunophenotyping, and cytogenetic/molecular abnormalities; cytogenetics of acute leukemia; general principles of therapy; acute myeloid leukemia; acute lymphoblastic leukemia; and future possibilities. The figure shows the incidence of acute leukemias in the United States. Tables list World Health Organization (WHO) classification of acute myeloid leukemia and related neoplasms, expression of cell surface and cytoplasmic markers for the diagnosis of acute myeloid leukemia and mixed-phenotype acute leukemia, WHO classification of acute lymphoblastic leukemia, WHO classification of acute leukemias of ambiguous lineage, WHO classification of myelodysplastic syndromes, European LeukemiaNet cytogenetic and molecular genetic subsets in acute myeloid leukemia with prognostic importance, cytogenetic and molecular subtypes of acute lymphoblastic leukemia, terminology used in leukemia treatment, and treatment outcome for adults with acute leukemia. This review contains 2 figures, 15 tables, and 119 references. Keywords: Acute leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, cancer, cytogenetics, chromosomal abnormality

Opportunities and Challenges for Gut Microbiota in Acute Leukemia.

Acute leukemia (AL) is a highly heterogeneous hematologic malignancy, and although great progress has been made in the treatment of AL with allogeneic hematopoietic stem cell transplantation (Allo-HSCT) and new targeted drugs, problems such as infection and GVHD in AL treatment are still serious. How to reduce the incidence of AL, improve its prognosis and reduce the side effects of treatment is a crucial issue. The gut microbiota plays an important role in regulating disease progression, pathogen colonization, and immune responses. This article reviews recent advances in the gut microbiota and AL pathogenesis, infection, treatment and its role in allo-HSCT.

PIM2 and NF-\u03ba\u03b2 gene expression in a sample of AML and ALL Egyptian patients and its relevance to response to treatment

BackgroundThe relation between PIM2 and the transcriptional factor NF κβ have been controversial in literature. The significance of PIM2 and NF-κβ genes expression on the incidence of acute leukemia (AML and ALL) and its relevance to the response rate was evaluated. Sixty de novo acute leukemia patients were stratified in 2 groups: 30 acute myeloid leukemia (AML) and 30 acute lymphoblastic leukemia (ALL) patients and compared to 30 sex- and age-matched controls. The expression level of PIM2 and NF κβ genes was measured using quantitative real-time polymerase chain reaction (QRT-PCR). The patients were followed with clinical examination and complete blood counts.ResultsThe expression level of PIM2 gene was significantly higher in AML patients (P<0.001) compared to the control group. The mean expression level of NF κβ gene was significantly high in AML and ALL patients compared to the healthy control group (P=0.037 and P<0.001; respectively). The overall survival in AML patients was higher in NF κβ gene low expressers compared to high expressers (P=0.047). The number of AML patients who achieved complete remission was significantly higher in PIM2 gene low expressers in comparison to PIM2 gene high expressers (P=0.042).ConclusionPIM2 and NF κβ genes might have a role in the pathogenesis of acute leukemia, poor overall survival, and failure of response to induction therapy.

Residential exposure to natural background radiation at birth and risk of childhood acute leukemia in France, 1990–2009

BackgroundThe role of natural background radiation (NBR) in childhood acute leukemia (AL) remains unclear. Several large record based studies have recently reported heterogeneous results. Differences in exposure assessment timing may explain this heterogeneity. ObjectivesIn a previous ecological study we did not observe any association between childhood AL incidence in France and NBR exposure at the time of diagnosis. With the same methodology, the present study focused on NBR exposure at the time of birth. Based on data from the French national registry of childhood cancer, we analyzed all AL together, and lymphoblastic and myeloid AL, separately. MethodsWe included 6,059 childhood AL cases born and diagnosed in mainland France between 1990 and 2009. NBR levels in municipalities of residence at birth were estimated by cokriging models, using NBR measurements and precise geological data. The incidence rate ratio (IRR) per unit variation of exposure was estimated with Poisson regression models, with adjustment for socio-demographic indicators and ultraviolet radiation levels. NBR exposures were considered at the time of birth, and cumulatively from birth to diagnosis. We also estimated a total NBR dose to red-bone marrow (RBM). ResultsThere was no evidence for an association between NBR exposure at birth and childhood AL incidence, neither overall (gamma radiation: IRR = 0.99 (0.94,1.05) per 50 nSv/h; radon: IRR = 0.97 (0.91,1.03) per 100 Bq/m3) nor for the main AL types. The conclusions were similar with the cumulative exposures, and the total RBM dose. ConclusionsThe study was based on high quality incidence data, large numbers of AL cases, and validated models of NBR exposure assessment. In all, the results further support the hypothesis that NBR are not associated to childhood AL in France.

SOLUBLE CD14 AS A BIOMARKER OF SEPSIS AND ITS RELATION TO BLOOD CULTURES IN FEBRILE NEUTROPENIC ACUTE MYELOID LEUKEMIA PATIENTS RECEIVING CHEMOTHERAPY

• The incidence of acute leukemia in Egypt according to the National Population-Based Cancer Registry Program is about 3 cases per 100 000 population.• Acute leukemia is classified according to WHO classification which incorporates clinical, prognostic, morphologic, immunophenotypic, and genetic data.• Manifestations of acute leukemia can result from constitutional symptoms, bone marrow failure , infilteration of other organs and of leukocytosis.• Acute leukemia patients are more prone to infections due to several factors including neutropenia, disruption of mucosal barriers and administration of immune suppressive drugs. • The most popular tool used to predict the risk of complications associated with a febrile neutropenia is the Multinational Association of Supportive Care in Cancer (MASCC) score.• The use of standard culture techniques for the detection and isolation of pathogenic organisms from a sterile body fluid specimen is still considered the “gold standard” for the diagnosis of infection and sepsis.• Bacterial infections are commonly caused by six main etiologies: three Gram-negative (E. coli, Klebsiella sp and Pseudomonas aeruginosa) and three Gram-positive (S. aureus, S. epidermidis and S. Viridans). • Presepsin is a new sepsis marker that show a potential as an early marker of sepsis recognition, for antimi‌crobial therapy monitoring and as a prognostic marker. • Presepsin (sCD14-ST) is a peptide sized 13 kDa that is generated by proteolytic cleav‌age of soluble forms of CD14 cluster (sCD14). • The major CRP drawback in sepsis lies in its lack of specificity.

Evaluation of seasonal changes in the diagnosis of acute leukemia in Turkey

Objective: The etiology of acute leukemia (AL) has been under investigation for decades but the exact cause is still unknown. There are studies suggesting that infection plays a critical role in the development of AL in conjunction with other risk factors. In some studies, it has been shown that the incidence of AL increases after influenza endemics. This shows that viruses may play a role in the etiology. The theory that viruses might have a role in the etiopathogenesis created the idea that AL frequency may peak during some specific months; therefore, in this study, we aimed to research the relationship between AL diagnosis frequency and seasons in Turkey. &#x0D; Method: 186 patients who were diagnosed with de novo acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) diagnosis at our center were included in the study.&#x0D; Results: The frequency of ALL diagnoses were as follows: 25 (34.3%) in winter, 19 (26%) in spring, 15 (20.5%) in autumn, and 14 (19.2%) in summer. The frequency of AML diagnose was as follows: 24 (21.2%) in winter, 30 (26.6%) in spring, 27 (23.8%) in autumn and 32 (28.4%) in summer. In our study, we did not find a statistically significant relationship between AL diagnosis frequency and seasons.&#x0D; Conclusion: According to our literature review, there are two studies including our study, searching for a relationship between AL diagnosis frequency and seasons in Turkey. Neither of the studies found a relationship between AL and seasons. According to our analysis the numbers of the patient in studies are limited; therefore the studies with high number of patients are needed to find out a relation between seasons and diagnosis time of AL.

Acute Leukemia Presenting with Musculoskeletal Manifestations: A Case Series

Abstract Introduction: Leukemia is the most common childhood malignancy accounting for 30%–40% of cases. Acute lymphoblastic leukemia is the most common leukemia in children with peak incidence in 2–6 years of age. The present study aims to assess the incidence of acute leukemia in patients presenting with musculoskeletal manifestations. Materials and Methods: This is a retrospective study conducted in a tertiary center from January 2014 to December 2018. A total of 63 children presented with musculoskeletal manifestations and underwent bone marrow examination. Based on final marrow diagnosis, the study group was divided into leukemic and nonleukemic groups. Results: Fever was the most common presenting complaint and was present in all the patients of both the groups. The occurrence of hepatosplenomegaly was comparatively higher in the leukemic group than in patients with juvenile idiopathic arthritis (JIA). The predominant type of arthritis was oligoarticular (68.15%) in the leukemic group and polyarticular (77.27%) in the nonleukemic group. Rheumatoid rash was noted in 20% of JIA patients, and none of the patients in the leukemic group had rash. The percentages of anemia, leukopenia, and thrombocytopenia were statistically higher in leukemia patients than in JIA patients. Conclusion: Bone marrow studies are a prerequisite in diagnosing leukemias. However, based on the presence of few atypical clinical and laboratory features, leukemia can be excluded in JIA patients.

PB1682 ADULT ACUTE LEUKEMIA AND SEASONALITY: A SINGLE CENTER EXPERIENCE

Background: Etiology of acute leukemias have been investigated for a long time. Although the exact causes are not known, both genetic and environmental factors are thought to play an important role. Some infectious agents underlie etiology of many haematological malignancies. Evidence suggests antigenic stimulation consequent to community – acquired infections may stimulate oncogens or may disrupt tumor supressor genes. Therefore seasonal changes in incidence of acute leukemia have been studied over the last 2 decades with mixed results. Aims: The aim of this study was to investigate seasonal changes in the incidence of acute leukemia in adults. Methods: Data from Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Stem Cell Transplantation Unit database were retrospectively analyzed. Results: A total of 252 patients with acute leukemia had received allogeneic bone marrow transplantation at our center between March 2009 and December 2018. Their data were retrospectively analyzed. 152 patients had acute myeloid leukemia (AML, n = 152) and 100 patients had acute lymphoblastic leukemia (ALL, n = 100). No relation was found between season of first diagnose date and incidence of AML and ALL(p = 0.900, p = 0.206,respectively) Summary/Conclusion: Environmental factors including infections have long been suspected as a probable factor in the etiology of leukemias. If there is a seasonal variation in the onset of leukemia, this may be interpreted as supportive evidence of infectious etiology but in our study, we found no seasonal effect related to date of diagnosis.

Obstetrical and newborn outcomes among women with acute leukemias in pregnancy: a population-based study

Purpose: Acute leukemias (ALs) are rare but aggressive malignancies. The goal of our study was to determine the incidence, obstetrical, and newborn outcomes of ALs in pregnancy.Materials and methods: We performed a retrospective population-based cohort study on all births reported in the Health-Care Cost and Utilization Project-Nationwide Inpatient Sample between 1999 and 2014. We calculated the incidence of ALs in pregnancy and conducted multivariate logistic regression to obtain adjusted odds ratios for various maternal and newborn outcomes among this population compared to a nonaffected one.Results: We identified 291 maternal cases of ALs among 14,513,587 births, yielding an incidence of 2.01 per 100,000 births over the 15-year study period. There were approximately twice as many diagnoses of acute myeloid leukemia (AML) as compared to acute lymphoid leukemia (ALL). After adjusting for differing baseline characteristics and maternal and fetal deaths, we found that pregnant women with ALs were more likely to experience post-partum hemorrhage, to suffer from disseminated intravascular coagulation (DIC), to require transfusions, to have wound complications, and to experience venous thromboembolism (VTEs). Maternal death, preterm delivery, and intrauterine fetal death (IUFD) were more common in pregnant women with ALs.Conclusion: The incidence of ALs in pregnancy appears to be greater than what was previously believed. As it is associated with several adverse maternal and fetal outcomes, affected patients should be cared for in tertiary care institutions with access to high-risk obstetrical specialists, hematologists, and neonatologists.

729: Incidence and maternal and fetal outcomes of acute leukemias in pregnancy: a population-based study

Acute leukemias (ALs) are rare but aggressive malignancies. The goal of our study was to determine the incidence and maternal and fetal outcomes of pregnancies afflicted by ALs. We performed a retrospective population-based cohort study on all births reported in the Health- care Cost and Utilization Project-Nationwide Inpatient Sample between 1999 and 2014. Using ICD9 codes, we established a cohort of births to women affected by ALs during pregnancy and compared it to a control group of unaffected deliveries. We calculated the incidence of ALs in pregnancy and conducted multivariate logistic regression to obtain adjusted odds ratios for several maternal and fetal outcomes among this population compared to a non-affected one. We identified 291 maternal cases of ALs among 14 513 587 births, yielding an incidence of 2.01 per 100,000 births over the 16-year study period. There were approximately twice as many diagnoses of acute myeloid leukemia as compared to acute lymphoblastic leukemia. Pregnant women with ALs were more likely to be Caucasian, to deliver at an urban teaching hospital, and to have medicare. After adjusting for differing baseline characteristics and maternal and fetal deaths, we found that pregnant women with ALs were more likely to experience post- partum hemorrhage (OR 2.42, 95% CI 1.55-3.79), to suffer from disseminated intravascular coagulation (OR 24.85, 95% CI 14.48-42.62), to require transfusions (OR 54.43, 95% CI 41.98-70.58), to have wound complications (OR 4.73, 95% CI 2.23-10.03), and to experience venous thromboembolisms (OR 10.09, 95% CI 5.87-17.33). Maternal death (OR 284.63, 95% CI 157.81-513.39), preterm delivery (OR 2.42, 95% CI 1.74-3.36), and intrauterine fetal death (OR 3.72, 95% CI 1.65-8.39) were also more common in pregnant patients with ALs. The incidence of ALs in pregnancy appears to be greater than what was previously believed. As it is associated with several adverse maternal and fetal outcomes, affected patients should be cared for in tertiary care institutions with access to high risk obstetrical specialists, hematologists, and neonatologists. Measures should be established to be adequately prepared for and try to mitigate the potential obstetrical emergencies and complications that may arise in this population.

A case of pediatric leukemia with multi drug resistant bacterial infections

Infections still remain a major cause of therapy-associated morbidity and mortality in pediatric cases with acute myeloid leukemia (AML). Down syndrome (DS) children have an approximately 10-20 fold higher incidence of acute leukemia and approximately 150 fold increased risk of developing myeloid leukemia of DS (ML-DS). Multi-drug resistant (MDR-GNB) Gram-negative bacterial septicaemia is an emerging global challenge. Authors are reporting a 4 and half year old boy with diagnosis Acute Megakaryocytic Leukemia (AMKL) who developed septicaemia and diaper rash. MDR E. coli was isolated and he was treated with fosfomycin followed by colistin. The boy developed cardiac arrest with chest compression and expired.

The Persistent Survival of MPN Cells to JAK2 Inhibition Is Dependent on SHP2 Activity, Which May Provide a Therapeutic Target to Enhance Current Anti-MPN Therapies

Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis, are hematopoietic stem cell disorders that affect about 300,000 people in the U.S. PV and ET can progress to myelofibrosis where patients are susceptible to bone marrow failure, increased incidence of acute leukemia, and poor survival. MPNs are driven by aberrant JAK2 activity that is a consequence of mutations in JAK2, Mpl, or CalR. The JAK1/2 inhibitor ruxolitinib, which is FDA-approved for a subset of MPN patients, is effective in reducing patient symptomology but fails to induce remission, as it has little effect on the neoplastic cell burden. However, a modest increase in survival and decrease of allele burden has been suggested following long-term ruxolitinib treatment. The quality of life benefit afforded by ruxolitinib suggests it will likely remain a mainstay of future MPN therapies. Identifying the mechanism(s) by which cells persistently survive in the presence of ruxolitinib could prove pivotal to improving JAK2 inhibitor therapies in MPN patients.In order to identify mechanisms by which JAK2-driven MPN cells survive ruxolitinib treatment, we utilized global phospho-tyrosine proteomics to compare ruxolitinib-sensitive and persistent cells, the latter of which are drug persistent by nature due to their reacquisition of JAK2 inhibitor sensitivity upon removal of ruxolitinib. We utilized the JAK2-V617F-driven MPN model cell lines UKE1 and SET2 for this analysis. Pathway analysis from the datasets obtained indicated changes in phosphorylation of proteins involved in growth factor and cytokine signaling. Notably, we identified changes in phosphorylation of several tyrosine phosphatases, including SHP1 and SHP2. The SH2 domain-containing tyrosine phosphatase SHP2 (encoded by PTPN11) plays important roles in relaying signals from cell surface receptors, notably mediating activation of ERKs, and was the first phosphatase identified as leukemogenic. SHP2 regulates JAK2 signaling and is found mutated in ~8% of post-MPN leukemia, suggesting it may play a role in the biology of MPNs. In addition, SHP2 has been identified as a potential mediator of targeted therapy resistance in cancer. Therefore, we hypothesized that SHP2 activity may contribute to the persistent survival of MPN cells in ruxolitinib and provide a therapeutic target in MPNs. To test our hypothesis, we treated ruxolitinib-sensitive (drug naïve) and persistent cells with a specific allosteric inhibitor of SHP2, SHP099. Ruxolitinib-persistent cell growth was more sensitive to SHP2 inhibition, and SHP099 enhanced the growth inhibitory effects of ruxolitinib on ruxolitinib-sensitive cells. Treatment of UKE1 cells with a high concentration (~10X GI50) of ruxolitinib leads to the persistent survival of a small population of cells and this was prevented by SHP099. SHP2 inhibition was also deleterious to the maintenance of an existing drug persistent state in a high concentration of ruxolitinib. Interestingly, signaling pathways in cells persistently growing in ruxolitinib differentially respond to SHP2 inhibition. In both ruxolitinib-sensitive and persistent cells activation of ERK was inhibited by SHP099. However, in ruxolitinib-persistent UKE1 cells, this inhibition was more rapid, suggesting the kinetic regulation of ERK activation by SHP2 is altered in these cells. Also, SHP099 led to an increase in pSTAT3 in both ruxolitinib-sensitive and persistent cells. However, SHP099 led to an increase in pSTAT5 in ruxolitinib sensitive UKE1 cells, but not in cells persistently growing in ruxolitinib. Re-activation of signaling pathways following ruxolitinib treatment likely contributes to cell survival. We observed that ERK becomes re-activated shortly after ruxolitinib treatment, and this re-activation depends on SHP2 activity. Finally, we observed dose-dependent inhibition of the neoplastic growth of primary MPN patient cells by SHP099 and synergistic inhibition with ruxolitinib, suggesting co-targeting SHP2 may improve JAK2-targeted MPN therapies.In conclusion, our data suggest that re-wiring of signaling in cells challenged with ruxolitinib may create greater dependence on SHP2 activity that contributes to cell survival to JAK2 inhibition. Thus, targeting SHP2 may improve the efficacy of ruxolitinib as an anti-MPN therapy. DisclosuresHaura:Incyte Corporation: Research Funding. Reuther:Incyte Corporation: Research Funding.

Abstract 17207: Cardiovascular Risks in Acute Leukemia Patients Treated With Anthracyclines

Introduction: The incidence of acute leukemia has been increasing by about 1.6% per year in the last decade. Anthracyclines remain a standard of care for patients with acute leukemia; survival is increasing at about 1.0% per year. However, little is known about the incidence and risk of major adverse cardiovascular events (MACE) in patients with acute leukemia. Hypothesis: To investigate the incidence of MACE and the risk factors for MACE in patients with acute leukemia treated with anthracyclines. Methods: All adult patients with acute leukemia treated with anthracyclines between January 2005 and April 2018 at the hospital of University of Pennsylvania were studied. MACE were defined as cardiovascular death, symptomatic heart failure, non-fatal acute coronary syndrome, non-fatal ventricular arrhythmia and non-fatal ischemic stroke. Differences between patients with or without MACE were compared by Student’s t test or the Wilcoxon rank comparison. Cox proportional hazard analysis was used to determine significant clinical and echocardiographic parameters associated with MACE. Results: Six hundred and seventy-four patients (234 acute lymphoblastic leukemia (ALL), 440 acute myeloid leukemia (AML), age range: 22 to 93 years) were studied. Seventy-one patients (10.5%) experienced MACEs during a median follow-up period of 16 months (4 to 146 months) after the initiation of chemotherapy. The median time to MACE was 13 months (5 to 107 months). In the patients with MACE,59 (8.8%) developed symptomatic heart failure, 7 (1.0%) died of cardiovascular causes, 3 (0.4%) experienced non-fatal acute myocardial syndrome and 2 (0.3%) had an ischemic stroke. The Table summarizes the characteristics of patients with and without MACE. In a multivariable analysis, a previous history of heart failure (HR: 4.632, P=0.000, 95% CI: 2.572-8.341), leukemia type (HR: 3.155, P=0.002, 95% CI: 1.544-6.446) and baseline LVEF (HR: 0.973, P=0.000, 95% CI: 0.955-0.991) remained associated with MACE. Conclusion: Patients with acute leukemia treated with anthracyclines have a high rate of MACE after chemotherapy. A previous history of heart failure, baseline LVEF and type of leukemia may help to stratify acute leukemia patients at highest risk for MACEs after anthracycline therapy.

Abstract 1199: Adult Hispanic males experience a higher incidence of acute lymphoblastic leukemia compared to non-Hispanic Whites

Abstract Introduction: Acute leukemia is an important cause of morbidity and mortality with differences in incidence and outcomes between patients of different ethnic backgrounds. We conducted this study to examine the ethnic disparities in incidence of ALL as well as other types of acute leukemia in the Latino population in South Texas. Methods: Data were obtained from the U.S. Surveillance, Epidemiology and End Results 18 (SEER) Program and the Texas Cancer Registry (TCR) under Limited-Use Data Agreements between sources and authors. Adult patients (15 years or older) were identified in both SEER and TCR databases from 2000 to 2014 and ICD-O-3 codes were used to select specific malignancies: ALL (9727-9729, 9835-9837), acute promyelocytic leukemia (APL) (9866) and non-APL acute myeloid leukemia (AML) (9840, 9861, 9867, 9870-9874, 9891, 9895-9897, 9910, 9920, 9930, 9931). Ethnicity was classified as Hispanic (H) and non-Hispanic White (NHW) per the North American Association of Central Cancer Registry (NAACR) Hispanic Identification Algorithm. Cases were obtained from SEER 18 and TCR, including Texas and the 38 counties of South Texas. Comparisons used the SEER population of NHW as reference. We used SEER*Stat software v 8.3.4 (SEER*Stat, NIH), to generate 2000-2014 average annual age-specific and age-adjusted acute leukemia incidence rates (per 1000000), rate ratios (RR) and 95% confidence interval (CI) for Hispanic and NHW populations in SEER, Texas, and South Texas. Results: Table 1 shows Hispanic males in South Texas had significantly higher RR for development of ALL (p&amp;lt;0.05), and lower for non-APL AML; there was no statistical difference for APL RR compared to NHW. Males (15-39 and 70-79 years) had higher rates of ALL. Conclusion: Latinos in South Texas experience a higher incidence of ALL and a lower incidence of non-APL AML compared to NHW. Future studies are needed to identify specific risk factors associated with this higher burden in Hispanic population. Table 1SEERTCRTexasSouth TexasHNHWRR (95%CI)HNHWRR (95%CI)HNHWRR (95%CI)ALL213744421.50 (1.42-1.59)9789851.43 (1.33-1.53)3771071.63 (1.46-1.81)Non-APL AML3398047190.77 (0.75-0.80)216375930.41 (0.40-0.43)8488980.48 (0.45-0.51)APL77022241.22 (1.11-1.33)3094720.90 (0.80- 1.02)109510.94 (0.77- 1.14) Citation Format: Manuel R. Espinoza-Gutarra, Edgar Munoz, Dimpy P. Shah, Anand Karnad, Ruben A. Mesa, Amelie G. Ramirez. Adult Hispanic males experience a higher incidence of acute lymphoblastic leukemia compared to non-Hispanic Whites [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1199.