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The red cell distribution width (RDW) is a standard variable reported in the complete blood count. It has been found to have a consistent relationship to life expectancy in older individuals, prognosis in patients with cardiovascular disease, outcome in those with hematological and non-hematological neoplasms and in a variety of medical circumstances such as non-cardiovascular or cancer related critical illness and postoperative outcome from various procedures. This report reviews some of the key medical publications establishing these relationships with RDW. The precise pathobiological processes that explain the predictive value of the RDW in this wide array of circumstances or why an alteration in erythropoiesis (exaggerated red cell size variation) occurs is uncertain. The possible role of inflammation has been one hypothesis considered, but not established.

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Acute myelogenous leukemia (AML) is one of the most lethal cancers, lacking a definitive curative therapy due to essential constraints related to the toxicity and efficacy of conventional treatments. This study explores the co-adjuvant potential of Lippia alba essential oils (EO) for enhancing the effectiveness and selectivity of two chemotherapy agents (cytarabine and clofarabine) against AML cells. EO derived from L. alba citral chemotype were produced using optimized and standardized environmental and extraction protocols. Rational fractionation techniques were employed to yield bioactive terpene-enriched fractions, guided by relative chemical composition and cytotoxic analysis. Pharmacological interactions were established between these fractions and cytarabine and clofarabine. The study comprehensively evaluated the cytotoxic, genotoxic, oxidative stress, and cell death phenotypes induced by therapies across AML (DA-3ER/GM/EVI1+) cells. The fraction rich in citral (F2) exhibited synergistic pharmacological interactions with the studied chemotherapies, intensifying their selective cytotoxic, genotoxic, and pro-oxidant effects. This shift favored transitioning from necrosis to a programmed cell death phenotype (apoptotic). The F2-clofarabine combination demonstrated remarkable synergistic anti-leukemic performance while preserving cell integrity in healthy cells. The observed selective antiproliferative effects may be attributed to the potential dual prooxidant/antioxidant behavior of citral in L. alba EO.

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OBJECTIVES: Chronic myeloid leukemia (CML) is characterized by the Philadelphia chromosome, leading to the BCR::ABL1 fusion gene and hyper-proliferation of granulocytes. Tyrosine kinase inhibitors (TKIs) are effective, and minimal residual disease (MRD) monitoring is crucial. Digital PCR platforms offer increased precision compared to quantitative PCR but lack comparative studies. METHODS: Eighty CML patient samples were analyzed in parallel using digital droplet PCR (ddPCR) (QXDx™ BCR-ABL %IS Kit) and chip digital PCR (cdPCR) (Dr. PCR™ BCR-ABL1 Major IS Detection Kit). RESULTS: Overall, qualitative and quantitative agreement was good. Sensitivity analysis showed positive percentage agreement and negative percentage agreement were both ≥90 %, and the quadratic weighted kappa index for molecular response (MR) level categorization was 0.94 (95 %CI 0.89, 0.98). MR levels subgroup analysis showed perfect categorical agreement on MR level at MR3 or above, while 35.4 % (17/48) of patient samples with MR4 or below showed discordant categorizations. Overall, Lin's concordance correlation coefficient (CCC) for the ratio of %BCR::ABL1/ABL1 converted to the International Scale (BCR::ABL1 IS) was almost perfect quantitative agreement (Lin's CCC=0.99). By subgroups of MR levels, Lin's CCC showed a quantitative agreement of BCR::ABL1 IS decreased as MR deepened. CONCLUSIONS: Both cdPCR and ddPCR demonstrated comparable performance in detecting BCR::ABL1 transcripts with high concordance in MR3 level or above. Choosing between platforms may depend on cost, workflow, and sensitivity requirements.

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Introduction: Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by the reciprocal translocation of chromosomes 9 and 22, which leads to a chimeric gene product known as BCR-ABL. Some studies have shown a higher incidence of secondary malignancies than the one seen in the general population in patients with CML. Hepatocellular carcinoma (HCC) is rarely reported in association with CML and/or CML-related treatment. Case Presentation: We describe a case of a patient with no history of liver disease and CML on imatinib for 10 years, who presented with worsening right upper quadrant abdominal pain. Imaging revealed a large hepatic mass highly suspicious of malignancy that later was confirmed to be HCC after biopsy. The patient was bracketed with advanced stage HCC (BCLC stage C) and given her advanced age and poor performance status; palliative care was offered. Conclusion: Patients with CML have a common association with secondary malignancies. This is the first case report based on our extensive review of available literature that HCC was diagnosed in a patient with CML on treatment with imatinib without any clear or usual underlying cause.

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Invasive aspergillosis (IA) is a potentially life-threatening complication of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). We conducted a systematic review and meta-analyses of studies on acute leukemia in children aged 0-17 years since 2000. Findings were reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We included 24 studies with 3,661 ALL patients and 1,728 AML patients. IA cumulative incidence varied (0%-10% for ALL and 0%-18% for AML) across the studies. Pooled cumulative IA incidences were estimated at 3.2% (95% CI: 1.8% - 5.8%) in ALL and 5.2% (95% CI: 3.1% - 8.6%) in AML, with corresponding case-fatality-rates of 13.3% (95% CI: 6.3% - 25.9%) and 7.8% (95% CI: 0.7% - 51.2%), respectively. Our analysis highlights the impact of IA in childhood leukemia, underscoring the need to address strategies for prevention, early detection, and treatment of IA in pediatric leukemia.

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OBJECTIVE: To investigate the anti- chronic myelogenous leukemia (CML) activity of Nur77-specific agonist Csn-B combined with imatinib by promoting Nur77 expression, and explore the potential role of its signaling pathway. METHODS: Firstly, CCK-8 and Transwell assay were used to detect the inhibitory effects of Csn-B, imatinib, and their combination on the proliferation and migration of K562 cells. Furthermore, the apoptosis rate of K562 cells treated with Csn-B, imatinib, and their combination was detected by flow cytometry. The expression levels of Nur77, Pim-1, Drp1, p-Drp1 S616, Bcl-2 and Bax in K562 cells were detected by Western blot. Finally, the expression levels of reactive oxygen species (ROS) in K562 cells treated with Csn-B, imatinib and their combination were detected by immunofluorescence assay. RESULTS: The level of Nur77 in CML patients decreased significantly compared with normal population in dataset of GSE43754 (P < 0.001). Csn-B combined with imatinib could significantly inhibit the proliferation and migration of K562 cells (both P < 0.001), and induce apoptosis (P < 0.001). Csn-B promoted Nur77 expression in K562 cells, and synergistically enhanced imatinib sensitivity when combined with imatinib. Csn-B combined with imatinib could significantly enhanced ROS levels in K562 cells and mitochondria compared with single-drug treatment (both P < 0.001). CONCLUSION: Csn-B combined with imatinib can enhance ROS expression and induce apoptosis of K562 cells through Nur77/Pim-1/Drp1 pathway.

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In the treatment of chronic myeloid leukemia (CML), resistance to BCR-ABL inhibitors makes it difficult to continue treatment and is directly related to life expectancy. Therefore, asciminib was introduced to the market as a useful drug for overcoming drug resistance. While combining molecular targeted drugs is useful to avoid drug resistance, the new BCR-ABL inhibitor asciminib and conventional BCR-ABL inhibitors should be used as monotherapy in principle. Therefore, we investigated the synergistic effect and mechanism of the combination of asciminib and imatinib. We generated imatinib-resistant cells using the human CML cell line K562, examined the effects of imatinib and asciminib exposure on cell survival using the WST-8 assay, and comprehensively analyzed genetic variation related to drug resistance using RNA-seq and real-time PCR. A synergistic effect was observed when imatinib and asciminib were combined with or without imatinib resistance. Three genes, GRRP1, ESPN, and NOXA1, were extracted as the sites of action of asciminib. Asciminib in combination with BCR-ABL inhibitors may improve the therapeutic efficacy of conventional BCR-ABL inhibitors and prevent the development of resistance. Its dosage may be effective even at minimal doses that do not cause side effects. Further verification of this mechanism of action is needed. Additionally, cross-resistance between BCR-ABL inhibitors and asciminib may occur, which needs to be clarified through further validation as soon as possible.

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Clinical experience with tyrosine kinase inhibitors (TKIs) over the past two decades has shown that, despite the apparent therapeutic benefit, nearly 30% of patients with chronic myelogenous leukemia (CML) display primary resistance or intolerance to TKIs, and approximately 25% of those treated are forced to switch TKIs at least once during therapy due to acquired resistance. Safe and effective treatment modalities targeting leukemic clones that escape TKI therapy could hence be game changers in the professional management of these patients. Here, we aimed to investigate the efficacy of a novel therapeutic oligonucleotide of unconventional design, called ASP210, to reduce BCR-ABL1 mRNA levels in TKI-resistant CML cells, with the assumption of inducing their apoptosis. Imatinib- and dasatinib-resistant sublines of BCR-ABL1-positive MOLM-7 and CML-T1 cells were established and exposed to 0.25 and 2.5 µM ASP210 for 10 days. RT-qPCR showed a remarkable reduction of the target mRNA level by >99% after a single application. Cell viability was monitored daily by trypan blue staining. In response to the lack of driver oncoprotein BCR-ABL1, TKI-resistant CML cells underwent apoptosis regardless of the presence of the clinically relevant T315I mutation by day 5 after redosing with ASP210. The effect was selective for cancer cells, indicating a favorable safety profile for this therapeutic modality. Furthermore, the spontaneous uptake and high intracellular concentrations of ASP210 suggest its potential to be effective at relatively low doses. The present findings suggest that ASP210 is a promising therapeutic avenue for patients with CML who fail to respond to TKI therapy.NEW & NOTEWORTHY Effective treatment modalities targeting leukemic clones that escape tyrosine kinase inhibitor (TKI) therapy could be game changers in the professional management of patients displaying primary resistance, intolerance, or acquired resistance to TKIs. Although delivering authentic innovations today is more complex than ever, we developed a highly potent and safe oligonucleotide-based modality against BCR-ABL1 mRNA named ASP210 that effectively induces cell death in BCR-ABL1-positive TKI-resistant cells while sparing BCR-ABL1-negative healthy cells.

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Imatinib is a tyrosine kinase inhibitor (TKI) and is a commonly used medication for treatment of chronic myelogenous leukemia (CML). Aplastic anemia is a very uncommon complication of Gleevec, and only a few cases are reported in the literature. We present a case of a 63-year-old Asian female who was initiated on imatinib for treatment of CML with good response in cell counts. Four months after Gleevec initiation, the patient was admitted to the hospital with extreme fatigue and noted to have severe pancytopenia. Patient received multiple blood transfusions. Finally, the patient underwent bone marrow biopsy, which showed concern for aplastic anemia with marked hypocellular bone marrow. Gleevec was held, blood counts were monitored, and supportive care was given. Patient had slow recovery of her blood counts. There remains scarcity of data on this topic and no criteria exist to predict the myelosuppression with TKI therapy. Our case report aims to reemphasize the need for increased research on myelosuppression with TKI therapy.

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Eosinophilic esophagitis (EoE) is an immune/antigen-mediated disease with an increasing incidence over the last decade. Clinicopathological remission can be achieved through different treatment options but often requires chronic therapy. To our knowledge, this is the first report of EoE wherein the patient (a 54-year-old man) achieved histological remission after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia. Overall, despite the success of EoE treatment in this case, further studies are needed to establish allogeneic HSCT as a curative option for EoE.

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Background: Chronic myelogenous leukemia is a neoplastic proliferation of the granulocytic series. In Mexico, chronic myelogenous leukemia accounts for approximately 10% of all leukemias. Tyrosine-kinase inhibitors are considered front-line therapy in high-income countries, whereas allogeneic hematopoietic stem cell transplantation is a recognized therapeutic approach, mainly in low- and middle-income countries. Objective: To analyze the overall survival of persons with chronic myelogenous leukemia who have received tyrosine-kinase inhibitors or allogeneic hematopoietic stem cell transplantation in a medical center, since 1994, and briefly discuss the current indications of these treatments in the tyrosine-kinase inhibitors era. Methods: We retrospectively analyzed all patients with a diagnosis of chronic myelogenous leukemia treated in a medical center between 1994 and 2023; subsets of individuals who received an allogeneic hematopoietic stem cell transplantation or tyrosine-kinase inhibitors therapy as first-line treatment were analyzed. Results: 60 persons with chronic myelogenous leukemia were treated with allogeneic hematopoietic stem cell transplantation or tyrosine-kinase inhibitors: 35 received an allogeneic hematopoietic stem cell transplantation, whereas 25 were given tyrosine-kinase inhibitors. All patients who underwent an allogeneic hematopoietic stem cell transplantation engrafted successfully, and the procedure was completed on an outpatient basis in most cases (29/35). The median survival in allogeneic hematopoietic stem cell transplantation was 78.3 months (CI 95%: 0-205.6) and in persons given tyrosine-kinase inhibitors the median was not reached. Conclusion: Tyrosine-kinase inhibitors were significantly superior to allogeneic hematopoietic stem cell transplantation in prolonging the overall survival of persons with chronic myelogenous leukemia in our single institution experience.

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The implications of previous central nervous system (CNS) involvement in children with acute myeloid leukemia (AML) undergoing hematopoietic cell transplantation (HCT) remain inadequately understood. Patients with CNS disease require more upfront CNS-directed intrathecal therapy, but little is known about whether transplant conditioning regimens should be intensified or if previous CNS involvement impacts post-HCT outcomes. While total body irradiation (TBI) remains standard for pediatric acute lymphoblastic leukemia myeloablative conditioning, it has been largely replaced with chemotherapy-only myeloablation in pediatric AML, primarily due to toxicity and late effects associated with TBI. In the setting of previous CNS involvement, it has been suggested that TBI-based myeloablation may have advantages due to superior CNS tissue penetration and thus decreased rates of AML relapse post-HCT. We analyzed a publicly available dataset derived from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry to characterize the impact of TBI in HCT preparative regimens in pediatric AML patients with a history of CNS involvement. The study dataset was obtained from the CIBMTR data repository. The study cohort included patients aged ≤21 years who underwent initial allogeneic HCT with myeloablative conditioning for de novo AML in the first or second complete remission (CR) between 2008 and 2016, who provided consent for research. Patients with mismatched related donor transplants and noncalcineurin inhibitor graft-versus-host disease (GVHD) prophylaxis were excluded. The dataset was further modified by excluding patients with missing disease site data or those with non-CNS extramedullary disease. Patients were categorized as CNS-positive or -negative AML (AML-CNS(+) and AML-CNS(-), respectively) based on the disease status at diagnosis. The Cox regression model and Fine-Grey methods were employed to delineate the effects of TBI and CNS disease on key HCT outcomes. The study cohort comprised 550 pediatric AML patients, of which 25% (n = 136) were AML-CNS(+). CNS involvement was more prevalent in patients aged 0 to 3 years, patients who were in the second CR, and those with a mismatched unrelated donor or umbilical cord blood. AML-CNS(+) patients demonstrated a lower relapse rate (hazard ratio: 0.50, 95% confidence interval: 0.33 to 0.76) compared to AML-CNS(-) patients, with comparable disease-free survival (DFS) and overall survival (OS) (P = .10 and 0.20, respectively) in the two cohorts. The entire TBI-treated cohort showed an association with increased risks of grade 2 to 4 acute GVHD, bloodstream infections, and endocrine dysfunction. TBI use within the AML-CNS(+) cohort was associated with a lower relapse rate but increased risks of nonrelapse mortality and a trend of higher grade 3 to 4 acute GVHD. In this population-based analysis of pediatric patients with de novo AML undergoing HCT, TBI-based conditioning regimens did not confer an advantage in DFS or OS compared to non-TBI regimens, irrespective of CNS disease status. However, TBI use was associated with increased risks of short- and long-term comorbidities. These findings underscore the need for careful consideration of TBI in pediatric AML.

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The management of elderly patients diagnosed with acute myelogenous leukemia (AML) is complicated by high relapse risk and comorbidities that often preclude access to allogeneic hematopoietic cellular transplantation (allo-HCT). In recent years, fast-paced FDA drug approval has reshaped the therapeutic landscape, with modest, albeit promising improvement in survival. Still, AML outcomes in elderly patients remain unacceptably unfavorable highlighting the need for better understanding of disease biology and tailored strategies. In this review, we discuss recent modifications suggested by European Leukemia Network 2022 (ELN-2022) risk stratification and review recent aging cell biology advances with the discussion of four AML cases. While an older age, >60 years, does not constitute an absolute contraindication for allo-HCT, the careful patient selection based on a detailed and multidisciplinary risk stratification cannot be overemphasized.

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Olfactory receptors (ORs), the largest family of G protein-coupled receptors (GPCRs), are ectopically expressed in cancer cells and are involved in cellular physiological processes, but their function as anticancer targets is still potential. OR2AT4 is expressed in leukemia cells, influencing the proliferation and apoptosis, yet the limited number of known OR2AT4 agonists makes it challenging to fully generalize the receptor's function. In this study, we aimed to identify new ligands for OR2AT4 and to investigate their functions and mechanisms in K562 leukemia cells. After producing the recombinant OR2AT4 protein, immobilizing it on a surface plasmon resonance chip, and conducting screening to confirm binding activity using 258 chemicals, five novel OR2AT4 ligands were discovered. As a result of examining changes in intracellular calcium by five ligands in OR2AT4-expressing cells and K562 cells, (-)-epigallocatechin gallate (EGCG) was identified as an OR2AT4 agonist in both cells. EGCG reduced the viability of K562 cells and induced apoptosis in K562 cells. EGCG increased the expression of cleaved caspase 3/8 and had no effect on the expression of Bax and Bcl-2, indicating that it induced apoptosis through the extrinsic pathway. Additionally, the initiation of the extrinsic apoptosis pathway in EGCG-induced K562 cells was due to the activation of OR2AT4, using an OR2AT4 antagonist. This study highlights the potential of EGCG as an anti-cancer agent against leukemia and OR2AT4 as a target, making it a new anti-cancer drug.

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Background: Limited data exist on when and how to stop antifungal treatment (AFT) in patients with invasive mold infections (IMIs) who are immunocompromised. Methods: This retrospective multicenter study included adult patients with acute myelogenous leukemia and proven/probable IMI (1 January 2010-31 December 2022) in 3 university hospitals. The primary objective was to describe AFT duration and adaptation. Secondary objectives were to investigate the reasons for AFT adjustments and prolongation. Results: In total 71 patients with 73 IMIs were identified; 51 (71.8%) had an allogeneic hematopoietic cell transplant. Most infections were invasive aspergillosis (IA; 49/71, 69%), followed by mucormycosis (12, 16.9%) and other (12, 16.9%); there were 2 mixed infections. Median treatment duration was 227 days (IQR, 115.5-348.5). There was no difference in AFT duration between patients with IA and non-IA IMI (P = .85) or by center (P = .92). Treatment was longer in patients with an allogeneic hematopoietic cell transplant vs not (P = .004). Sixteen patients (22.5%) had no therapy modifications. In 55 patients (77.5%), a median 2 changes (IQR, 1-3; range, 1-8) were observed. There were 182 reasons leading to 165 changes, associated with clinical efficacy (82/182, 44.5%), toxicity (47, 25.8%), and logistical reasons (22, 12.1%); no reason was documented in 32 changes (18.8%). AFT was continued beyond days 90 and 180 in 59 (83%) and 39 (54.9%) patients, respectively, mostly due to persistence of immunosuppression. Conclusions: AFT in patients with acute myelogenous leukemia and IMI is longer than that recommended by guidelines and is frequently associated with treatment adjustments due to variable reasons. More data and better guidance are required to optimize AFT duration and secondary prophylaxis administration according to immunosuppression.

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Abelson tyrosine kinase (Abl) is regulated by the arrangement of its regulatory core, consisting sequentially of the SH3, SH2, and kinase (KD) domains, where an assembled or disassembled core corresponds to low or high kinase activity, respectively. It was recently established that binding of type II ATP site inhibitors, such as imatinib, generates a force from the KD N-lobe onto the SH3 domain and in consequence disassembles the core. Here, we demonstrate that the C-terminal αI-helix exerts an additional force toward the SH2 domain, which correlates both with kinase activity and type II inhibitor-induced disassembly. The αI-helix mutation E528K, which is responsible for the ABL1 malformation syndrome, strongly activates Abl by breaking a salt bridge with the KD C-lobe and thereby increasing the force onto the SH2 domain. In contrast, the allosteric inhibitor asciminib strongly reduces Abl's activity by fixating the αI-helix and reducing the force onto the SH2 domain. These observations are explained by a simple mechanical model of Abl activation involving forces from the KD N-lobe and the αI-helix onto the KD/SH2SH3 interface.

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OBJECTIVE: To analyze the efficacy and safety of flumatinib, a second-generation tyrosine kinase inhibitor (TKI) independently developed in China, in patients with chronic myelogenous leukemia in chronic phase (CML-CP) who falied first-line and second-line treatment. METHODS: The clinical data of 30 CML-CP patients treated with flumatinib in Lianyungang First People's Hospital from January 2020 to September 2022 were collected retrospectively. Among them, 15 patients who received imatinib first-line treatment but failed treatment were included in the second-line group, and the other 15 patients who failed second-line treatment with nilotinib or dasatinib were included in the third-line group. The hematological and molecular responses of the patients in the two groups at 3, 6 and 12 months of treatment, and the event-free survival (EFS) and adverse reactions of patients at the end of follow-up were statistical analyzed. RESULTS: At 3, 6, and 12 months of treatment, 10, 11, and 12 patients in the second line group achieved major molecular response (MMR), which was higher than that of 3, 4, and 5 patients in the third line group (P =0.010, P =0.011, P =0.010). At 3 months of treatment, 12 and 13 patients achieved complete hematological response (CHR) and early molecular response (EMR) in the second-line group, which was higher than that of 9 and 13 patients in the third-line group, but the difference between the two groups was not statistically significant (P =0.232, P =1.000); At 6 and 12 months of treatment, 6 and 7 patients in the second-line group achieved MR4.5, which were higher than of 3 and 2 cases in the third-line group, but the difference was not statistically significant (P =0.427, P =0.713). The hematological adverse reactions of patients in the second-line group during treatment the period were mainly grade 1-2 thrombocytopenia and anemia, and no grade 3-4 of adverse reactions occurred. In the third-line group, there were 2 cases of grade 1-2 thrombocytopenia, grade 1-2 anemia and white blood cell 3 cases were reduced each, 1 case of grade 3-4 anemia, 2 cases of grade 3-4 neutropenia. The non-hematological adverse reactions in the second-line group were rash (2 cases), headache (1 case), diarrhea (1 case), fatigue (1 case), limb pain (1 case). There were 1 cases of diarrhea, 1 cases of nausea, and 1 cases of edema in the third-line group. There was no statistical significance in hematological and non-hematological adverse reactions between the two groups of patients (P >0.05). At the end of follow-up, the EFS rate of patients in the second-line group was higher than that in the third-line group (100% vs 93.3%), but the difference was not statistically significant (P =0.317). CONCLUSION: The second-generation TKI flumatinib independently developed in China, has good curative effect and safety for CML-CP patients who failed first-line and second-line treatment.

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A 3-year-old boy was referred to our hospital with splenomegaly. Blood tests revealed hyperleukocytosis and bone marrow examination showed major BCR::ABL1 fusion, leading to the diagnosis of chronic myelogenous leukemia (CML). Due to intolerance, the tyrosine kinase inhibitor (TKI) was changed from imatinib to dasatinib to nilotinib. The patient achieved molecular remission but became markedly short in stature, measuring 129.3 cm (height standard deviation score [SDS] -3.3) at the age of 12. TKI therapy was discontinued at age 12 years and 10 months, which was 9 years and 8 months after the start of TKI and 1 year and 6 months after achievement of MR4.0, as discontinuation before epiphyseal closure would not improve short stature. At 2 years and 6 months after discontinuation, the patient's height improved to 156.1 cm (SDS-2.0) without relapse. Growth suppression by TKIs is a problem in the management of pediatric CML. This case illustrates how improvement in severe short stature can be achieved by discontinuing TKI therapy before epiphyseal closure.

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