Myeloid Leukemia Research Articles

Pediatric glioma histone H3.3 K27M/G34R mutations drive abnormalities in PML nuclear bodies

BackgroundPoint mutations in histone variant H3.3 (H3.3K27M, H3.3G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in pediatric gliomas. These H3.3 point mutations affect many chromatin modifications but the exact oncogenic mechanisms are currently unclear. Histone H3.3 is known to localize to nuclear compartments known as promyelocytic leukemia (PML) nuclear bodies, which are frequently mutated and confirmed as oncogenic drivers in acute promyelocytic leukemia.ResultsWe find that the pediatric glioma-associated H3.3 point mutations disrupt the formation of PML nuclear bodies and this prevents differentiation down glial lineages. Similar to leukemias driven by PML mutations, H3.3-mutated glioma cells are sensitive to drugs that target PML bodies. We also find that point mutations in IDH1/2—which are common events in adult gliomas and myeloid leukemias—also disrupt the formation of PML bodies.ConclusionsWe identify PML as a contributor to oncogenesis in a subset of gliomas and show that targeting PML bodies is effective in treating these H3.3-mutated pediatric gliomas.

Sickle Cell Trait As a Risk Factor for Leukemia: A Nationwide Study

INTRODUCTION: Leukemia is a cancer of blood-forming cells. It can arise from cells of lymphoid or myeloid lineage. It can arise from genetic mutations in tumor suppressor genes, proto-oncogenes or both. It affects over two million people worldwide. A combination of genetic factors and extrinsic factors are believed to play a role. Sickle cell disease (SCD), an inherited disorder leading to the formation of abnormal hemoglobin (HbS) and red blood cell sickling, has been shown to increase the risk for leukemia, presumably due to an increased bone marrow turnover rate. We aimed to explore if sickle cell trait (SCT), when people inherit only one of the two sickle cell genes, is associated with an increased risk for leukemia. METHODS: In this case-control study, we evaluated an association between leukemia (and its subtypes) and SCT in a nationwide cohort of hospitalized patients included in the National Inpatient Sample (NIS) 2016-2019 database. The inclusion criteria for cases were patients who had any of the following ICD-10-CM codes for leukemia: C91 (lymphoid leukemia), C92 (myeloid leukemia), C93 (monocytic leukemia), C94 (other leukemia of specified cell type), and C95 (leukemia of unspecified cell type). The exclusion criteria were Down syndrome (Q90), Fanconi anemia (D61.09), ataxia-telangiectasia (G11.3), Bloom syndrome (Q82), myelodysplastic syndrome (D46), lymphoma (C81, 85), and solid malignancies (C00-75) as these diseases and/or their treatments are known to increase the risk for leukemia independently of SCT (ICD-10-CM D57.3). The controls included patients in the NIS database who do not have the ICD-10-CM codes for leukemia and meet the exclusion criteria applied to the cases. For each year, we used a 1:4 propensity score matching routine. Our match variables were sex, the six race categories used by NIS, and 11 age groups. Four perfect matches (controls) were identified for each case (‘any leukemia’ diagnosis). Patient characteristics were compared using Pearson chi-squared test. Odds ratios (ORs) were calculated for ‘any leukemia’ diagnosis, as well as for each subtype of leukemia. Five multivariate logistic regression models were used to examine the relationship between the leukemia subtypes and SCT while controlling for age group, sex, and race. RESULTS: We identified 181,676 cases and 726,704 controls. The mean age of subjects was 59 years. The majority of subjects (56%) were male. A greater proportion of patients with SCT were found among cases (0.12%) compared to controls (0.08%) (p < 0.0001). The OR for ‘any leukemia’ was 1.48 (95% CI 1.27-1.73, p < 0.0001). When the association between SCT and specific subtypes of leukemia was evaluated, it was statistically significant for myeloid and monocytic leukemias, OR 1.74 (95% CI 1.40 - 2.17) and 2.20 (95% CI 1.09 - 4.42) correspondingly. CONCLUSION: Our case-control study revealed statistically significantly higher odds of SCT among patients with any leukemia (and specifically myeloid and monocytic leukemias) as compared to controls which can be postulated to the common myeloid progenitor lineage of erythrocytes. Our results suggest that, similarly to SCD, SCT although a benign condition can increase the risk for leukemia. To better understand this association, future prospective studies are needed for the mapping of individual risk factors and examining the HbS% levels in SCT carriers who go on to develop leukemia.

Patient Preference Studies in Hematologic Malignancies: A Systematic Review

Background: New therapies have brought about an unprecedented expansion of treatment options for patients with hematologic malignancies that require a greater understanding patient preferences, both to inform treatment decisions and direct further patient-focused drug development. We sought to synthesize existing literature evaluating the preferences of patients with hematologic malignancies to consolidate relevant knowledge and identify future directions for research. Methods: We conducted a systematic review in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (PROSPERO 2022 CRD42022364647). We searched for articles published in English from PubMed and Embase. Included articles reported primary data on the preferences of patients with hematologic malignancies or patient proxies. Review articles, articles utilizing only secondary data, and abstracts without full text were excluded. Two authors independently reviewed all abstracts and assessed studies for full-text eligibility. Conflicts were resolved by group discussion. Risk of bias (quality) and conflict of interest were assessed. Data extraction included population, method of preference elicitation, attributes included, and relative strength of preferences. Results: A total of 3,520 studies were identified, 2,960 abstracts were screened following removal of duplicates, 239 underwent full-text review, and 74 were included in data extraction. Among the 74 studies, 59 (80%) were published in the last 10 years. In total, 16,986 patients or patient proxies were represented across selected studies. Studies included patients with lymphoma (n=33, 45%), myeloma (n=25, 34%), acute myeloid (n=15, 20%) and lymphoid (n=12, 16%) leukemia, and chronic lymphoid (n=11, 15%) and myeloid leukemia (n=10, 14%). Most studies included patients from Europe (n=30), the United States (n=26), or Canada (n=10). Nearly all (n=70, 95%) included only adults. Most studies were cross-sectional (n=60, 81%), qualitative (n=13, 18%), or mixed-methods (n=13, 18%). Only 1 study was a prospective randomized trial. Preference elicitation methods included study-specific surveys (n=31, 42%), discrete choice experiments (n=28, 38%), and qualitative interviews (n=19, 26%). Most studies elicited patient preferences for treatment outcomes (n=50, 68%) followed by communication (n=14, 19%), and route of administration of therapies (n=7, 9%). Attributes included in treatment outcome studies varied but many included overall/progression free survival (n=30, 60%), side effects (n=28, 56%), route of administration (n=16, 32%), or cost (n=11, 22%). Strength of preference for outcomes was heterogeneous across studies though overall survival was frequently most important to patients. Most studies sought to inform clinical decisions (n=49, 66%), followed by policy (n=13, 18%) and regulatory decision-makers (n=6, 8%). Most studies were of high (n=44, 59%) or moderate (n=26, 35%) quality. Funding for the studies came from pharmaceutical companies (n=25, 34%), government grants (n=20, 27%), and foundations (n=18, 24%). Some studies had apparent (n=16, 22%) or likely (n=9, 12%) conflicts of interest. Only 4 studies (5%) reported implementation outcomes such as acceptability or feasibility. Conclusions: Numerous well-designed studies have been published describing the preferences of patients with hematologic malignancies. Most of these studies were cross-sectional and relied on direct elicitation or discrete choice experiments to elicit preferences. Treatment outcome preferences varied widely across studies and patient populations. This heterogeneity supports the essential role for shared decision-making and individualization of treatment recommendations for each patient. Although many studies sought to generate data to inform clinical decisions, studies evaluating how patient preference data inform individual treatment decisions are largely absent. Future work is needed to support the clinical implementation of preference measures and to standardize relevant attributes for individual diseases and populations.

Recent Trends in the Prevalence of Antibiotic-Resistant Organism Infections (AROI) in Acute Leukemia Patients

Introduction:Infections and related complications are a major cause of morbidity and mortality in acute leukemia patients. There is a growing concern for increased antibiotic-resistant organism infections (AROI), including methicillin resistant Staphylococcus aureus pneumonia (MRSA) with the widespread use of antibiotics. Risk factors include older age, prior use of antibiotics, duration of use and type of antibiotics. The role of race, gender, income and insurance status has not been studied. We aimed to study the trends in the prevalence of AROI from 2016 to 2020. Methods: The National Inpatient Sample (NIS) database was queried to identify adult patients admitted with a principal diagnosis of acute lymphoblastic or myeloid leukemia using the International Classification of Disease (ICD-10) codes. Total leukemia admissions were then analyzed using secondary diagnoses codes for resistance to antimicrobial agents and MRSA pneumonia to assess trends for AROI prevalence and demographic characteristics. Statistics were performed using STATA, and multivariate linear and logistic regression analysis was used to adjust for confounders. Results:There were a total of 144,385 admissions for acute leukemia in the study period. The leukemia admission rate increased steadily from 2016 to 2020 (p=0.003). A higher proportion of patients belonged to the elderly group (>65 years, 45.2%) compared to middle-aged (45-65 years, 31.9%) and young adults (18-45 years, 22.8%), [p=0.018]. Most of the study population was White (60.9%), followed by Hispanics (15.7%) and African Americans (9.4%). The study population's predominant types of insurance were Medicare (37.5%) and private insurance (38.9%) followed by Medicaid (20.5%). Admissions related to AROI constituted only a small percentage of total leukemia admissions but the proportion of AROI increased from 1.16% in 2016 to 1.90% in 2020 [Adjusted Odds ratio (AOR): 1.12, 95% Confidence Interval (CI)-1.02-1.24; p=0.021]. Woman had a higher prevalence of AROI than men (AOR: 1.39, 95% CI-1.11-1.76; p=0.004). Elderly patients (> 65 years) have nearly similar odds of getting AROI (AOR 1.01) as younger patients (< = 65 years). Compared to Whites, the prevalence trend of AROI is higher in African Americans (AOR: 1.87, 95% CI-1.32-2.66; p<0.01) and Hispanic populations (AOR: 1.99, 95% CI-1.46-2.74; p<0.01). Higher-income population had increased odds of antibiotic resistance infections than the lower-income population (AOR: 1.36, 95% CI-1.01-1.85; p=0.046). Compared to patients with Medicare, those with Medicaid (AOR: 1.63, 95% CI-1.05-2.52; p=0.027) and Private insurance (AOR: 1.85, 95% CI-1.33-2.57; p=<0.01) had higher AROI, and there was no statistically significant difference with uninsured population. Over the study years, those admitted to larger hospitals (AOR: 1.82; p=0.007) and teaching hospitals (AOR: 2.07; p=0.006) had higher AROI trends than smaller hospitals and non-teaching hospitals respectively. When stratified by Charlson comorbidity index, there was statistically significant trend with increased rates of AROI in patients with lower index points (< = 4) but not in those with higher index points (> 4). Conclusion:There was a statistically significant rise in the prevalence of AROI across the study years. Racial and economic disparities exist in the prevalence of these resistant infections. Further studies are needed to assess the underlying reasons and steps to address these.

Determination of the Presence, Concentration, and effects of Formalin on Raw milk around Nyeri Municipality

Milk adulteration is done to increase the milk quantity or its shelf life. This research focused on the latter, accomplished by adding chemicals such as formalin. This is a great global concern and it causes detrimental effects such as cancer, myeloid leukemia. The chemical effects of formalin on milk include reducing its pH, protein, and fat percentage. Five samples were collected from several milk vendors around Nyeri Municipality and a sample directly from the cow. The pure milk had the fastest reduction time (18.3±1.53minutes) in Methylene Blue Reduction Test. The milk samples had an average of 3.3929±2.0579ppm formalin. In UV-Vis, the LOD and LOQ, R2 were 0.001M and 0.004M, 0.9868 respectively. Both the butter fat, and pH values decreased with formalin concentration increase. Their mean was 3.1±0.4% and 5.47 ± 0.806 respectively. Out of the six samples, 83.33% of them were adultered with formalin.

Improved T- and B-Cell Neogenesis in Children with Acute Leukemia Given an Alpha-Beta T-Cell Depleted Haplo-HSCT Combined with the Infusion of Donor T-Cells Genetically Modified with Inducible Caspase 9 Suicide Gene (Rivo-cel)

Background αβ T- and B-cell depleted HLA-haploidentical HSCT (αβhaplo-HSCT) is a suitable transplant option promptly available and virtually applicable to any children in need of an allograft. However, the suboptimal recovery of adaptive immunity still represents a limitation of the approach. In order to better deconvolute the reconstitution of adaptive immunity, in this study we measured T-cell receptor and kappa chain-deleting recombination excision circles (TREC and KREC), which represent reliable surrogates of T and B-cell neogenesis, respectively. We also analyzed a cohort of patients who received after the allograft infusion of a titrated number of donor T-cells genetically modified with inducible caspase 9 (iC9) suicide gene (Rivo-cel) as part of a prospective clinical trial (NCT02065869) with the goal of accelerating the recovery of thymus-independent adaptive immunity. Patients and study design We retrospectively analyzed 134 patients (≤ 25 years) with acute lymphoblastic (ALL) or myeloid leukemia (AML) who received a αβ haplo-HSCT between 2014 and 2021; 65 of them received post-transplant infusion of Rivo-cel, at the dose of 1x10 6 cells/kg, after a median time of 26 days (range: 11-87) post-transplant. No patient received post-transplantation pharmacological GVHD prophylaxis (Locatelli et al. Blood 2017). Details on patient and donor characteristics, as well as on graft composition are reported in Table 1. T-cell neogenesis was investigated by quantifying signal joint- (sj-) and beta (b-) TREC while B-cell neogenesis was analyzed by measuring coding-joint (cj-) and sj- KREC. We performed real-time quantitative PCR, as previously described (Arruda et al. 2018), on genomic DNA extracted from PBMC collected at 6 different time points (before and 1, 3, 6, 12 and 18 months after the allograft). At the same time-points peripheral blood of patients was also evaluated by flow-cytometry to phenotypically characterize the pool of leukocytes. Results With a median follow-up of 6 years (range 1-9) the overall (OS) and disease-free survival (DFS) probabilities of the entire cohort were 88,1% and 82%, respectively. The cumulative incidence (CI) of relapse was 15%. CI of grade II-IV acute Graft-versus-Host Didease (GvHD) was 19%, while that of chronic GvHD (cGvHD) was 7%. In the Rivo-cel cohort, sjTREC and bTREC were consistently detectable as early as one month post-HSCT, while started to recover by 3 months after αβhaplo-HSCT alone, and were significantly higher at +3 ( p=0,0006 and p=0,02, respectively) and +6 ( p=0,0003 and p= 0,001) months post-HSCT as compared with αβhaplo-HSCT. sjTREC and bTREC reached pre-transplant values at 6 and 12 months in Rivo-cel and αβhaplo-HSCT cohort, respectively. B-cell neogenesis, assessed by sj and cjKRECs, showed a superimposable recovery kinetics. A higher number of sjKRECs was observed in Rivo-cel cohort at + 1, +3 and +6 months after transplantation as compared with αβhaplo-HSCT ( p=0,007 , p=0,02 and p=0,04for sjKRECs ; p=0,005 , p=0,092 p=0,035forcjKRECs, respectively) . Furthermore, in the Rivo-cel cohort, patients with detectable sj and bTREC values at +3 months after transplant showed a significantly higher overall survival ( p=0,01 p=0,02, respectively). Also in this cohort, aGvHD was confirmed to play a detrimental effect on T-cell neogenesis, at 3 and 6 months after transplant. The same negative effect was documented for chronic GvHD at +6, +12 and +18 months, also affecting B-cell neogenesis at +6 months after transplant. Type of leukemia did not affect T and B-cell neogenesis. Conclusions In patients given αβhaplo-HSCT, T-cell and B-cell neogenesis were shown to be significantly accelerated by the post-transplant infusion of a titrated number of donor T-cells genetically modified with the iC9 suicide gene. Further studies are needed to elucidate the biologic mechanisms responsible for this favorable effect on recovery of adaptive immunity. Our data confirm the detrimental effect of both acute and chronic GvHD in recovery of thymic function and B-cell neogenesis. In this perspective, the possibility to successfully control/abrogate GvHD through the apoptosis of Rivo-cel triggered by the infusion of the dimerizing agent (AP1903) offers also the advantage of, at least partly, preventing the detrimental effect played by this complication on immune recovery.

Progression to Myelofibrosis in Patients with Essential Thrombocythemia: A Real-World Analysis from the Prospective MOST Study

Background: Essential thrombocythemia (ET) is a myeloproliferative neoplasm (MPN) characterized by clonal blood cell proliferation, excessive platelet production, constitutional symptoms, and increased risk of vascular complications, as well as a risk of progression to myelofibrosis (MF). Previous prognostic studies of patients with ET have largely been based on retrospective analyses, and limited prospective data exist regarding disease progression. The prospective Myelofibrosis and Essential Thrombocythemia Observational Study (MOST) collected real-world data from patients with ET. This analysis evaluates disease progression in patients with ET enrolled in MOST. Methods: MOST (NCT02953704) enrolled patients with ET aged ≥60 years, or with a history of thromboembolic events, or who were receiving ET-directed therapy (excluding aspirin only). Baseline clinical characteristics data were collected as previously described (Yacoub A. CLML. 2021). For this analysis, progression from ET to MF was defined as meeting 1 or more of the following criteria during the study period: 1) Bone marrow biopsy with fibrosis grade ≥2 or pathologic diagnosis of MF; 2) death owing to MF/myelodysplastic syndrome/acute myeloid leukemia; 3) circulating blasts >1% and new/worsening splenomegaly (SPM); 4)new/worsening SPM and ≥2 of white blood cell (WBC) count >11×10 9/L, hemoglobin (Hb) <10 g/dL, and platelet count <100×10 9/L. Median (range) follow-up was 57.3 months (42-70). Results: Of the 1237 patients with ET enrolled in MOST; 53 (4.3%) met criteria for progression to MF. Among patients with progression, most had progressed due to fibrosis (criteria 1, 56.6%); 15.1%, 11.3%, and 28.3% of patients progressed due to criteria 2, 3, and 4, respectively. Notably, only 176 patients (14.2%) enrolled in the study had bone marrow data available. Comparison of the enrollment characteristics of patients with and without progression identified no differences in age at enrollment or diagnosis (Table 1). However, time from diagnosis to enrollment and from diagnosis to end of study were significantly longer in patients with progression than those without (median 7.9 vs 4.2 years, median 12.7 vs 9.0 years, respectively; both P=0.001). Of all enrolled patients with vs without progression tested for known driver mutations, a higher percentage with progression were JAK2-positive vs those without progression (80.6% [29/36] vs 69.7% [598/858]). At enrollment, the percentages of patients with vs without progression receiving ET-directed therapies were similar (94.3% vs 94.8%). Among patients with vs without progression, mean baseline Hb was significantly lower (12.5 g/dL vs 13.1 g/dL; P=0.026), mean WBC counts were significantly higher (10.4×10 9/L vs 7.4×10 9/L; P<0.001), and mean platelet counts were comparable (418.6×10 9/L vs 455.0×10 9/L; P=0.466). MPN-SAF TSS was similar for patients with vs without progression at baseline. Fewer patients with vs without progression had ≥1 thrombotic events (1.9% [1/53] vs 3.7% [44/1184]) during the study, whereas a higher percentage of patients had ≥1 hemorrhagic events (7.5% [4/53] vs 1.3% [15/1184]). Conclusions: This real-world analysis of data from MOST showed that 4.3% of patients with ET progressed to MF during the study period. Compared with patients without progression, patients with ET to MF progression had longer duration of disease, higher WBC count, and lower Hb at enrollment; symptom burden at enrollment was similar between the 2 groups. One limitation of this study is the lack of bone marrow data for the majority of patients, suggesting a possible underestimation of progression to MF. These findings and further analysis of MOST data will add insight into disease progression in patients with ET and facilitate clinical management of this patient population.

Diagnostic Utility of Proteogenomic Analysis for Inherited Bone Marrow Failure Syndrome

Background: Inherited bone marrow failure syndrome (IBMFS)-a heterogeneous group of disorders characterized by marked cytopenia in one hematopoietic cell lineage-may progress to pancytopenia and make the patient susceptible to hematological malignancies or solid tumors. No clinically useful screening tests have been established for IBMFS, with a few exceptions, including the chromosome fragility test in Fanconi anemia (FA) and telomere length measurement in dyskeratosis congenita (DC). Therefore, high-throughput sequencing is widely used for not only clinical diagnosis of IBMFS but also screening applications; however, a significant number of patients remain genetically undiagnosed. Recent technological advances in in-depth data-independent acquisition proteomic analysis have enabled comprehensive quantitative analysis of >9000 proteins, including very low-abundant proteins. Integration of proteomic analysis with genomic information has been performed in brain tumors and acute leukemia, showing the potential to bridge the gap between genetic information and clinical validation; however, to our knowledge, proteogenomics in IBMFS has not been fully evaluated thus far. Herein, an omics analysis of patients with various IBMFS was performed to assess the diagnostic utility of in-depth proteomic techniques. Methods: We performed an omics analysis of the discovery cohort of 60 patients with IBMFS for in-depth proteomic analysis, targeted capture DNA sequencing, and RNA sequencing. For non-targeted proteomic analysis, digested peptides from the peripheral blood mononuclear cell samples were processed using a Q Exactive HF-X (Thermo Fisher Scientific, Waltham, MA, USA) data-independent acquisition mass spectrometer. Furthermore, diagnostic proteomic analyses targeting several IBMFS-related proteins were performed on a developmental cohort (417 samples; IBMFS [n = 229], aplastic anemia [n = 75], myelodysplastic syndrome/acute myeloid leukemia [n = 113], and healthy controls [n = 27]) using an Orbitrap Exploris 480 mass spectrometer (ThermoFisher Scientific) equipped with an EVOSEP ONE system (EVOSEP, Odense, Denmark). This study was approved by the ethics committee of the Nagoya University Graduate School of Medicine. Results: Non-targeted proteomic analysis was performed on 74 samples obtained from 60 patients with IBMFS and 14 healthy controls. Unsupervised clustering identified eight independent proteomic clusters (C1-C8), with ribosomal pathway-associated protein expression specifically downregulated in C1 and C2. Patients with Diamond-Blackfan anemia, Shwachman-Diamond syndrome (SDS), FA, ADH5/ALDH2 deficiency, and DC were enriched in C1, C2/C8, C3/C4, C6, and C7 clusters, respectively. In particular, among the 74 samples, four patients with ADH5/ALDH2 deficiency showed significantly reduced ADH5 protein expression, whereas the remaining patients showed normal expression, with 100% diagnostic concordance. In addition, 6 of 74 samples had significantly decreased SBDS protein expression, including two patients with monoallelic pathogenic variants in the SBDS gene. This suggested that proteomic analysis may play a complementary role to genetic analysis. To provide a large-scale rapid screening system for IBMFS in a practical clinical setting, targeted proteomic analysis was performed using a small panel of ADH5, SBDS, and GAPDH proteins in a developmental cohort of 417 patients. We demonstrated the significantly decreased SBDS protein expression levels in patients with SDS ( P = 4.98 × 10 -9). ADH5 protein expression levels were also significantly reduced in ADH5/ALDH2 deficiency ( P = 1.66 × 10 -6). Regarding the diagnostic tests, the sensitivity and specificity values were 85.7% and 93.4% for SDS, and 100.0% and 97.5% for ADH5/ALDH2 deficiency, respectively, indicating the sufficient performance to identify patients who required early diagnosis and therapeutic intervention. Conclusion: We performed the first proteogenomic analysis of patients with IBMFS and identified eight independent proteomic clusters associated with IBMFS subtypes and characteristic pathways. Furthermore, the clinical application of targeted proteomic assays constructed from these results may help diagnose and screen IBMFS, including SDS and ADH5/ALDH2 deficiency, for which appropriate clinical screening tests are lacking.

A split-type electrochemical biosensor using enzyme-linked DNA magnetic beads realizes the detection of BCR/ABLp210 fusion gene in clinical samples: Duplex ligation chain reaction coupled with OR logic gate design

Detection of BCR/ABLp210 transcript levels, allowing for the early diagnosis of chronic myelocytic leukemia (CML) and its minimal residual disease (MRD) monitoring, plays a decisive role in the cure of CML. Herein, to realize the sensitive detection of BCR/ABLp210 transcript by electrchemical DNA (E-DNA) sensors in clinical samples, a split-type strategy using enzyme-linked DNA magnetic beads (MBs) was intelligently provided. Specifically, the utilization of magnetic separation makes the target recognition event separate from electrochemical measurements, avoiding the interference of complex matrices on the sensing interface. Besides, the MBs adopted as dispersible electrodes could improve mass transfer of target compared to that of a planarelectrode. Consequently, the proposed E-DNA sensor combined with the ligation chain reaction (LCR) could achieve an exceptional performance with a low detection limit of 1 aM, a broad linear concentration range, and a remarkable specificity with a single-base resolution. Also, K562 cells in up to a 1000-fold excess of NB4 cells could be successfully detected by this E-DNA sensor. Finally, the integration of duplex LCR and OR logic gate into the E-DNA sensor has enabled the detection of e13a2/e14a2/both isoforms of BCR/ABLp210 transcript in a single assay in both newly diagnosed CML patients and those undergoing or having undergone treatment by tyrosine kinase inhibitors. Therefore, this method offers an alternative for the early diagnosis of CML and its MRD monitoring, and holds a huge potential of clinical translation due to its advantage of low cost, ease of miniaturization and generalizability.

Unexpected Noremestrin with a Sulfur-Bearing 15-Membered Macrocyclic Lactone from Emericella sp. 1454.

Two previous unreported epipolythiodioxopiperazines of the emestrin family, namely, noremestrin A (1) and secoemestrin E (2), were successfully isolated from the fungal source Emericella sp. 1454. Employing comprehensive spectroscopic techniques, such as high-resolution electrospray ionization mass spectrometry, infrared, and nuclear magnetic resonance (NMR), along with NMR and electronic circular dichroism calculations, the chemical structures of compounds 1 and 2 were elucidated. Particularly noteworthy is the distinctive nature of noremestrin A, representing the inaugural instance of a noremestrin variant incorporating a sulfur-bearing 15-membered macrocyclic lactone moiety. Compounds 1 and 2 exhibited weak cytotoxic activities against the human chronic myelocytic leukemia cell lines MEG-01 and K562.

Therapeutic Leukocytapheresis to relieve priapism due to leukostasis in CML patients: Our experience in a tertiary care centre

Hyperleukocytosis in leukemic patients may cause tumour lysis syndrome, disseminated intravascular coagulopathy, and leukostasis, resulting in decreased tissue perfusion and increasing the risk of mortality. Since the myeloid blasts are larger than lymphoid blasts and are less deformable, complications of leukostasis are seen more frequently in myeloid leukemia. Priapism is a less common complication associated with leukostasis in leukaemia patients that should be treated as soon as possible to avoid ischemic injuries. Although chemotherapeutic drugs such as hydroxyurea and imatinib are used to treat hyperleukocytosis in CML patients, leukocytapheresis (LCP) can achieve rapid cytoreduction. Prophylactic LCP could not offer any advantage over aggressive chemotherapy, but therapeutic leukocyte depletion has a proven role in patients having symptomatic leukostasis due to high tumour burden. Three patients with ischaemic priapism were reported at our institute's emergency department, where detumescence could not be achieved by distal shunting or aspiration with phenylephrine instillation. The procedure of therapeutic LCP was performed in all three patients on an emergency basis, which resolved painful priapism by rapid cytoreduction.

Abstract 12582: Predicting a Relationship Between Cancer and Cardiovascular Comorbidities by a Machine Learning Model

Introduction: Cardiovascular disease and cancer have previously been linked to share similar pathophysiological pathways, although these two entities are rarely studied in congruence. Method: We analyzed the 2019 National Readmission Database (NRD) and used unsupervised learning and K-means clustering for data analysis. We employed the Shapley Additive Explanation (SHAP) model to explain which features contribute the most to clustering. The final cohort was divided into four clusters guided by the Elbow method. Continuous variables were analyzed with Kruskal-Wallis test and reported as medians and interquartile ranges (IQR) after checking for normality test. We also performed sensitivity analysis on patients with cancer without applying a Boruta algorithm. Results: The final cohort includes 297,597 patients, and we randomly sampled 100,000 patients within divided into 4 clusters. The most prevalent types of cancer in clusters 1 were brain cancer (15%), prostate cancer (9.4%), non-Hodgkin’s lymphoma (8.7%), lung cancer (8.6%), and other specified and unspecified types of non-Hodgkin’s lymphoma (7.8%). Most prevalent cancers in cluster 2 were lung cancer (13.1%), prostate cancer (11.6%), breast cancer (8.5%), colon cancer (7.9%), and kidney cancer (5.5%). In cluster 3, lung cancer (15.6%), prostate cancer (9.3%), multiple myeloma (8.9%), lymphoid leukemia (7.6%), and other specified and unspecified types of non-Hodgkin’s lymphoma were more prevalent. Furthermore, in cluster 4, myeloid leukemia (27.7%), non-Hodgkin’s lymphoma (20.1%), multiple myeloma (14.8%), lymphoid leukemia (12.4%), and other specified and unspecified types of non-Hodgkin’s lymphoma (10.4%) were the most prevalent cancers. Patients grouped in Cluster 3 had higher percentages of cardiovascular risk factors and comorbidities such as hypertension, diabetes, hyperlipidemia, kidney diseases, and pulmonary hypertension. Cardiovascular outcomes were naturally more frequent in cluster 3. Conclusion: Although cardiovascular disease and cancer have previously been linked to share pathophysiology, our study emphasizes that commonality between two seemingly different diseases may all be secondary to shared underlying cardiovascular risk factors.

APAL2020SC Pediatric Acute Leukemia (PedAL) Screening Trial - Developing New Therapies for Relapsed Leukemias

Background: Outcomes for children with relapsed acute myeloid leukemia (AML) and subgroups with relapsed acute lymphoblastic leukemia (ALL) remain poor, and therapeutic options are limited. There is no standard of care for relapsed disease, and data collection after relapse is lacking. In recent years, extensive molecular studies of pediatric leukemias have advanced target identification and clinical trial development. Such studies have shown that pediatric leukemias are biologically distinct from adult leukemias. The current paradigm of requiring new agent studies in adults prior to conducting pediatric trials is thus not appropriate. However, the rarity of relapsed leukemia in children makes the conduct of randomized registration trials for new agents infeasible. Recognizing that impactful progress requires international collaboration, the Leukemia & Lymphoma Society is sponsoring the Pediatric Acute Leukemia (PedAL) Initiative in North America, Australia and New Zealand. In parallel, the European Pediatric Acute Leukemia (EuPAL) Foundation has established a registry for pediatric relapsed leukemia. The principal goal of this international PedAL/EuPAL collaboration is to establish a data-driven developmental therapeutics program for children with relapsed/refractory leukemias. Trial Summary: A central component of the PedAL Initiative is the screening protocol APAL2020SC (NCT04726241), which serves as the entry point for associated therapeutic sub-trials. The primary aims of APAL2020SC are (1) to use clinical and biological characteristics to screen for eligibility for therapeutic sub-trials; and (2) to maintain a longitudinal data registry and biobank for relapsed leukemia. Eligible patients are <22 years old and have one of the following leukemias in first or greater relapse, or primary refractory: AML, myeloid leukemia of Down syndrome, T-ALL, mixed phenotype acute leukemia, and KMT2A-rearranged B-ALL. Additional eligible diagnoses include any B-ALL in second or greater relapse, and de novo or relapsed treatment-related AML. All leukemia specimens are profiled by multiparameter flow cytometry (MFC) at a central lab (Hematologics). Families have the option to submit biospecimens for banking. Patients with myeloid leukemia also have molecular testing through Foundation Medicine. Clinical data collected include demographics, cytomolecular features at diagnosis, prior treatment and post-relapse treatment. Patients are encouraged to submit follow-up bone marrow samples for central MFC. The MFC assay determines lineage and blast percent and quantifies expression of markers relevant to therapeutic sub-trials. Trial Progress: APAL2020SC opened in April 2022. As of July 25, 2023, 148 patients have enrolled and 97 have had leukemia confirmed centrally. The distribution of diagnoses is shown in Table 1. All patients had blast enumeration and target expression assessed by MFC at study entry and when follow-up samples were provided. Of the patients with myeloid leukemia (n=71), targeted DNA/RNA sequencing was successful for 69%. The distribution of AML-associated alterations is shown in Table 2. Of the patients with confirmed leukemia at enrollment, 79% submitted at least 1 follow-up sample, and 77% submitted a sample for biobanking. To date, two therapeutic trials have opened that require enrollment to the screening trial. APAL2020D/ITCC101 is a randomized phase III study comparing fludarabine-cytarabine (FLA) to FLA-venetoclax. APAL2020E/PEPN2113 is a phase 1 study of the E-selectin inhibitor uproleselan in combination with FLA. Pediatric-specific therapeutic trials for menin inhibitors and other new agents are in development. The study is collecting treatment information for children who do not enroll on a subtrial, with the goal of describing current practices and outcomes (Table 2). Conclusion: APAL2020SC will accrue patients with relapsed acute leukemias and treatment-related AML for 5 years. This protocol will promote clinical trial development by engaging industry partners and providing a single entry point to therapeutic studies with biological rationale. APAL2020SC and the EuPAL Foundation registry will generate a large, comprehensive and longitudinal dataset that will inform future trials. The biobank component will support innovative translational research to feed the pipeline of new agents.

Clinical Impact of the New Bone Marrow Blasts Cutoff Defined By the International Classification Consortium (ICC) in Myeloid Neoplasms with Mutated TP53 gene

Introduction: The recent ICC introduced a novel category denominated “myeloid neoplasms with mutated TP53” (MN- TP53) that includes: 1) myelodysplastic syndromes (MDS- TP53) in cases with multi-hit TP53 or mutated TP53 with complex karyotype, and blasts <10%; 2) MDS/acute myeloid leukemia (MDS/AML- TP53) in those with TP53 mutations and blasts between 10-19% and 3) AML- TP53 in patients with TP53 mutations and blasts ≥ 20%. In all the aforementioned groups, a variant allele frequency (VAF) >10% of TP53 gene is required for inclusion. As opposite to ICC, the WHO 2022 classification does not recognize this mutated group as a distinct entity, maintaining the 20% blast count as the boundary between MDS and AML, with no intermediate category. The objective of this study was to assess, in a multicentric series, whether the 10% blast cutoff has clinical implications in the MN- TP53 category. Methods: All patients diagnosed with MDS and AML with MN- TP53 criteria according to ICC between 2009-2023 were included from four Spanish centers. TP53 gene status was assessed by Next-Generation Sequencing. Results: A total of 107 patients were included: 25 (23.4%) MDS- TP53, 17 (15.9%) MDS/AML- TP53, and 65 (60.7%) AML- TP53. The median age at diagnosis was 70 years (interquartile range, IQR: 65-78) and 54 (50.5%) were male. Among all patients, 83 (77.6%) presented a complex karyotype. After a median follow-up of 6.2 months, 84 patients (78.5%) died, resulting in a median overall survival (OS) of 7.9 months. The median OS for the MDS- TP53, MDS/AML- TP53 and AML- TP53 groups was 12.9, 14.3 and 5.4 months, respectively (p=0.025) (Figure 1). Paired comparisons showed similar OS between MDS- TP53 and MDS/AML- TP53 groups (p=0.5) but shorter OS in AML- TP53 group when confronted with MDS/AML- TP53 (p=0.03) or AML- TP53 with MDS- TP53 (p=0.052). In addition to potential outcome dissimilarities, clinical characteristics at baseline were also compared (Table 1). Again, there were no differences between the MDS- TP53 and MDS/AML- TP53 groups at diagnosis. Intensity of chemotherapy treatment and frequency of allogenic hematopoietic stem cell transplant (alloHSCT) were also analyzed. One important difference between MDS- TP53 and MDS/AML- TP53 was that 4% and 29% of cases underwent alloHSCT, respectively. To assess the potential impact of allotransplant in this cohort, the survival analysis was repeated censoring the OS at the infusion date. The OS between groups MDS- TP53 and MDS/AML remained comparable (p=0,98). Conclusions: In our cohort, patients with MDS- TP53 and MDS/AML- TP53 exhibit similar clinical behavior, in contrast to AML- TP53, suggesting that the newly proposed 10% blasts cutoff is not adding clinical value to the management of these entities.

Decades of Improvement in Cardiovascular Morbidity and Mortality in Leukemia Patients Reversed in 2020: Covid? Novel Agents? Neither?

Introduction: The incidence of many types of leukemia increases with age. Intensive induction chemotherapy containing cytarabine and an anthracycline has been part of the upfront and salvage treatment of AML for decades. Regimens for the treatment of ALL are also often anthracycline-based. Anthracyclines are associated with a significant risk of cardiotoxicity including anthracycline-related left ventricular dysfunction. Comprehensive baseline evaluation of cardiac function and risk may lead to better risk stratification and selection of patients who are best suited to anthracycline-based therapy. With the advent of more effective, yet less chemo-intense regimens for the management of older or unfit adults with leukemia, for example hypomethylator and venetoclax-based combinations, which gained widespread use with their accelerated approval in November 2018, one would hypothesize decreased rates of cardiovascular complications associated with the treatment of adult leukemia. To further investigate this hypothesis, we performed a nationwide analysis for adults age 25 and older with leukemia of all types and their associated cardiovascular disease related mortality. Methods: We utilized the Wide-ranging Online Data for Epidemiologic Research from the CDC. Patients were identified using ICD codes: C91 (Lymphoid leukaemia, C92 (Myeloid leukaemia), C93 (Monocytic leukaemia), C94 (Other leukaemias of specified cell type), and C95 (Leukaemia of unspecified cell type) with an underlying cause of death I00-I99 (Diseases of the circulatory system). Data was reviewed between 1999 to 2020 and included patients who were aged ≥25. We analyzed the age adjusted mortality rate (AAMR) per 100,000 people and stratified the data by sex, race/ethnicity, and geographical location within the USA by census region. Results: There were a total of 19,368 cardiovascular related deaths in leukemia patients between 1999 and 2020. There has been a decreasing trend in overall mortality associated with cardiovascular diseases from 1999 to 2019, falling from 4.6 to 3.9 deaths per 100,000 people, with an annual percent change of -2.89% (Figure 1). Both sexes mirrored this trend, with female mortality rates improving from 3.4 to 2.7 (APC -3.26%) and male rates from 6.5 to 5.6 (APC -3.07%) between 1999 and 2019. In 2020, it was observed that leukemia patients had an increased cardiovascular related mortality: 4.5 AAMR overall, 3.0 AAMR in females, and 6.5 AAMR in males . There was not a statistically significant difference in mortality changes by race (Table 1). Conclusion: Our study reveals a decrease in mortality rates from cardiovascular disease in leukemia patients from 1999 to 2018 followed by a relatively sharp increase noted in 2020. The steady improvements noted from the early 2000s to the 2010s may be attributable to awareness of known toxicities that led to enhanced screening and active monitoring for cardiovascular complications. Electrocardiograms, echocardiograms, and cardiotoxic markers including troponins and natriuretic peptides have served as diagnostic and risk-stratification tools. In 2020 leukemia patients exhibited a sudden increase in mortality across all sub-groups. One may postulate that this is related to COVID-19-related complications/delays in treatment, however, another possible explanation may be incompletely recognized toxicities of novel therapeutics. Interestingly, preclinical data have demonstrated that venetoclax treatment resulted in cardiac damage as evidenced by major changes in histopathology and markedly elevated cardiac enzymes and hypertrophic genes markers. Moreover, a drastic increase in oxidative stress, as well as inflammatory and apoptotic markers, with a remarkable decline in the levels of Bcl-2 has been observed (AlAsmari et al Int J Mol Sci 2022). Clearly, continued monitoring and further exploration is needed to identify the reason or reasons for the noted 2020 phenomenon. Continued data collection in the post-Covid vaccine era is likely to help to further elucidate the reasons for the unexpected uptick in cardiovascular-related morbidity and mortality in our leukemia patients.

Durable Transfusion Independence in Lower-Risk Myelodysplastic Syndrome (LR-MDS) Is Associated with Better Survival: A Population Level Analysis Based on a Large US Health Insurance Claims Database

CONCLUSIONS Red blood cell (RBC) transfusions are commonly used to treat patients with LR-MDS and anemia. RBC transfusion dependence (TD) is an impairment on patients' quality of life and associated with worsened survival (Lemos et al. Sci Rep. 2021). The few approved therapeutic options for LR-MDS have limited efficacy and durability. In this study, the baseline RBC-TD before first-line (1L) and second-line (2L) of therapy, durability of transfusion independence (TI), and associated survival among patients with LR-MDS treated with current standard-of-care therapies were assessed in a large US health insurance claims database. Optum Clinformatics ®, a large single-payer database of administrative health claims for members of large commercial and Medicare Advantage health plans, includes approximately 17-19 million annual covered lives, for a total of >76 million unique lives over a 9-year period. Patients with LR-MDS were identified through 5 relevant International Classification of Diseases, Tenth Revision (ICD-10) diagnosis codes (D46.0, D46.1, D46.9, D46.A, and D46.B) between Oct 2015 and Jun 2022 and were required to have no MDS/acute myeloid leukemia (AML) diagnosis and no use of higher-risk MDS or AML medication before their respective index diagnosis dates. As revised International Prognostic Scoring System or other risk score classification information was not available in the database, ICD-10 diagnosis codes were used as a proxy for the identification of LR-MDS; these codes have been used previously in published studies (Zeidan et al. Leuk Lymphoma. 2019). Lines of treatment were determined based on claims for MDS treatments contained in the database: erythropoietin stimulating agents (ESAs; darbepoetin, epoetin alfa), hypomethylating agents (HMAs; azacitidine, decitabine, decitabine-cedazuridine), lenalidomide, luspatercept, eltrombopag, and cyclosporine. Outcomes of interest included transfusion burden (RBC units [U] in 8 weeks), proportion of patients who were transfusion independent before and after different lines of treatment, time to 8- and 16-week continuous TI, Kaplan-Meier analysis of real-world progression-free survival (starting a next line of treatment, progression to higher-risk MDS or AML, and death were considered events), and overall survival. The analysis included 5662 patients with LR-MDS (median age, 79 years; 57% male; 76% non-Hispanic White, primarily covered by Medicare Advantage) who received ≥1 line of treatment. Overall, 66% and 17% of patients received frontline monotherapy with ESAs and HMAs, respectively. In the 16 weeks before 1L treatment initiation, 35% of patients received ≥1 RBC transfusion. During 1L treatment, 45% of patients received ≥1 RBC transfusion, of whom 49% received >3 U and 24% received >6 U during any 8-week period. 2L treatment consisted of ESA monotherapy (40%), HMA monotherapy (21%), luspatercept (9%), or a combination thereof (19%). In the 16 weeks before 2L treatment initiation, 49% of patients received ≥1 RBC transfusion, and 55% received transfusions during 2L treatment (Table). Among patients receiving ≥1 transfusion during 2L treatment, 61% and 31% had >3 and >6 U/8 weeks, respectively. Transfusion burden was greater for patients with ring sideroblast-positive disease and increased with subsequent lines of therapy. Among 612 patients who received ≥1 transfusion in the 16-week period before 2L, 33% achieved 16-week TI with subsequent therapies. Median real-world progression-free survival from start of 2L was 20.0 months in patients who achieved 16-week TI and 4.1 months in patients who did not ( P < .0001). The median overall survival from start of 2L was 23.4 months overall, and 37.9 months vs 9.3 months among responders becoming RBC-TI vs nonresponders, respectively ( P < .0001; Figure). Among patients with LR-MDS, 35% and 49% were RBC-TD before 1L and 2L of therapy, respectively. Achievement of TI was associated with improved survival, suggesting that RBC-TD is a modifiable predictor of clinical outcomes in LR-MDS. Despite the currently available therapies, RBC-TD after any line of therapy is associated with poorer outcomes. Our study results show that novel therapies that provide durable TI are expected to yield decreased progression and improved survival.

Incidence of Secondary Primary Malignancies after Long-Term Follow up of Multiple Myeloma Patients Treated with Autologous Stem Cell Transplantation - Report from Croatian Cooperative Group for Hematologic Malignancies (KroHem)

Background: Autologous stem cell transplantation (ASCT) after induction treatment is standard of care for multiple myeloma (MM) for the last 30 years. Two transplantations up-front (so-called tandem transplant) were standard of care for all MM patients. With the use of new antimyeloma agents (such as proteasome inhibitors, immunomodulators and especially monoclonal antibodies) this approach has changed and tandem transplant is now reserved mainly for patients with high-risk disease, defined by revised international staging system (R-ISS). There have been reports which cast further doubts on the value of the more aggressive tandem ASCT approach, as well as reports suggesting higher incidence of secondary primary malignancies (SPM) after high dose therapy and ASCT. Aims: To describe long-term outcomes of MM patients treated with ASCT (single, delayed, and tandem) and the rate of secondary primary malignancies. Methods: a retrospective analysis of outcomes of 577 MM patients who underwent 865 ASCT procedures between 1993 and 2017 was performed. Data were collected from 3 transplant centres and 9 other haematological centres in which MM patients were treated pre- and post-transplant. During that period treatment strategies changed significantly from single to tandem to salvage second ASCT. Results: there were 577 patients included. Median age at first transplant was 58 years (range 22 - 74). There were 295 female and 282 male patients. 346 patients received VAD (vincristine, doxorubicin, dexamethasone) and 231 received bortezomib and/or thalidomide (PI/IMiD) based regiments as induction therapy. All patients received high dose melphalan for pretransplant conditioning, 32 in combination with total body irradiation. Tandem ASCT (defined as second transplantation performed within 6 months after the first) was performed in 226 patients, single ASCT in 262 and salvage second (after relapse and/or progression) in 89 patients. Median overall survival (OS) for the entire group is 81.9 months and median progression free survival (PFS) 38.9 months. Tandem ASCT in comparison to single and second salvage transplantation resulted in statistically significant better OS (115 vs. 83 vs. 67 months respectively, p < 0.0001) and PFS (48 vs. 32. vs. 28 months respectively, p < 0.0001). There was no difference in outcomes regarding type of induction therapy, VAD vs. PI/IMiD based: median OS was 83 vs. 80 months, respectively (p=0.39) and median PFS was 39 vs. 38 months, respectively (p=0.15). 17.6% percent of patients who were treated with tandem ASCT are progression-free more than 10 years after the procedure while 10-year OS is 31.9%. 51 patients (8.8%) developed secondary malignancies (SPM). Most common SPM were lung carcinoma (10 patients), colorectal carcinoma (7 patients), myelodysplastic syndrome/acute myeloid leukaemia (6 patients), breast carcinoma (4 patients) and melanoma (4 patients). Of those 19 died due to SPM (3% of the entire patient group). There was no correlation between number of ASCT and SPM (p=0.87). Conclusion: in our group of patients tandem ASCT resulted in superior OS and PFS in comparison to single and/or salvage ASCT. Interestingly, we did not observe benefit of new drugs (PI/IMiD) in induction therapy regarding outcomes. This peculiar result might be due to rather late availability of these drugs in front line settings (bortezomib and thalidomide since 2015) and time period taken for analysis (up to 2018). SPM rate was similar to other reports and did not show significant correlation with number of ASCT. More than 15% of patients treated with tandem ASCT experienced very prolonged PFS and almost 32% had OS longer than 10 years.

Chronic Myeloid Leukemia (CML) with Permanent Hearing Loss

Objective: The present case study aims to discuss a rare case of chronic myeloid leukemia causing bilateral hearing impairment, tinnitus, and vertigo. Introduction: Chronic Myeloid Leukemia (CML) or chronic granulocytic leukemia is a type of blood cancer that affects the bone marrow. It results in an overproduction of immature White Blood Cells (WBCs) that typically happens throughout or after middle age, and adolescents are rarely affected. The genetic mutation that causes CML is known as the BCR-ABL fusion gene. Case Presentation: In this case report, a 30-year-old female presented to the hospital of Jazan, Saudi Arabia, with sudden hearing impairment and other symptoms, leading to a CML diagnosis. The patient had no prior hearing impairment background, and the otoscopic scanning was normal. The Pure Tone Audiometry (PTA) showed profound sensorineural hearing loss on both sides. Blood tests revealed hyperleukocytosis with marked neutrophilia, mild basophilia, and eosinophilia and a BCR-ABL quantitation of 85%. Bone marrow aspiration showed granulocytic hyperplasia, mild left-shifted maturation, and less than 1% blasts. Results: The patient was started with options including Tyrosine Kinase Inhibitors (TKIs) such as Imatinib, which target the BCR-ABL fusion gene, reducing the number of leukemia cells and improving her white blood cell count. However, her deafness persisted, and she became dependent on hearing aids. Discussion: CML presenting with hearing loss is rare, with only a few reported cases in the literature. It is believed to be related to the infiltration of leukemic cells in the inner ear or the microvascular complications associated with the disease. Hearing loss can be reversible or permanent, depending on the severity and duration of the disease. Treatment of CML with tyrosine kinase inhibitors such as Imatinib can improve the hematologic parameters, but the effect on hearing loss is uncertain.

The Correlation Between Motivation and Self-Care Mangement Among Leukemia Patients Based on Orem's Theory

Introduction: Leukemia is one of the most diagnosed types of cancer and a cause of death worldwide. Patients who experience severe side effects of cancer treatment tend to experience less than optimal self-care management. Leukimia patients in treatment often complain of fatigue, weakness, lack of energy, and nausea which hinder them in self-care management. The purpose of this study was to determine the relationship between motivation and self-care management. Methods: This study used an analytic descriptive research design with a cross sectional approach. Population on this research were members of Chronic Granulocytic Leukemia (it is known as “ELGEKA”), East Java, Indonesia. The sample size was 69 respondents using purposive sampling. The independent variable was motivation and the dependent variable was self-care management. Data was analyzed using Spearman Rho analysis with level of significance 0.05. Results: The results of this study indicated that there was a relationship between motivation and self-care management (p=0.000) and (r=0,531). Discussion: Motivation has a significant relationship with self-care management in leukemia patients based on Orem's theory. The higher the motivation, the higher self-care management. Good self-care management involves nutrition and fluid management, physical activity, stress management, complementary therapy, information and support seeking, and medication adherence. Conclusion: Nurses have an important role in identifying and increasing patient motivation to carry out self-care management and changing their attitudes to improve health and disease care. The recommendation for future researchers is to develop research with interventions to improve self-care management in leukemia patients.

Metformin mitigates doxorubicin-induced cardiotoxicity via the AMPK pathway

To explore whether metformin reduces cardiotoxicity of doxorubicin through the AMPK pathway. We analyzed the data of 123 patients with myeloid leukemia, non-Hodgkin's lymphoma, or breast cancer receiving doxorubicin for phased chemotherapy, including 43 patients receiving combined treatment with metformin (test group) and 80 without metformin treatment (control group). The changes in plasma levels of CK-MB, LDH, and BNP, left ventricular ejection fraction (EF) and left ventricular fractional shortening (FS) of the patients were observed. The effect of treatments with metformin and doxorubicin, alone or in combination, on myocardial damage, cardiac function and myocardial cell apoptosis were also observed in C57BL/6 mice with AMPKα2 gene knockout (AKO). CK-MB, LDH and BNP levels increased and EF and FS decreased significantly in the control group after chemotherapy (P<0.05). In the test group, CK-MB, LDH and BNP levels were significantly lowered after the combined treatment (P<0.05), while EF and FS did not undergo obvious changes (P>0.05). CK-MB, LDH and BNP levels were lower and EF and FS were higher significantly in the test group than in the control group after the treatment (P<0.05). Doxorubicin treatment reduced FS in both wild-type and AKO mice, but the reduction was less obvious in AKO group (P<0.05). The combined treatment restored FS in wild-type mice (P<0.05) but not in AKO mice. Doxorubicin significantly increased LDH and cTnI levels in both wild-type and AKO mice, but with smaller increments in the latter (P<0.05); The combined treatment with metformin reduced doxorubicin-induced elevation of LDH and cTnI levels in the wild-type mice (P<0.05) but not in AKO group (P>0.05). Doxorubicin increased myocardial cell apoptosis in both mice (P<0.01) but less strongly in AKO mice (P<0.05). Chemotherapy with doxorubicin causes cardiotoxicity, which can be mitigated by combined treatment with metformin possibly through a mechanism involving the AMPK pathway.