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BACKGROUND: Leukocytosis and thrombocytosis often follow splenectomy in blunt trauma patients, complicating the postoperative identification of infection. While the platelet count to white blood cell ratio provides diagnostic assistance to discern between expected laboratory alterations and infection, diagnoses such as leukemia are often overlooked. CASE PRESENTATION: A 53-year-old Hispanic male presented with abdominal pain, nausea, tachycardia, and focal peritonitis 4 days after being assaulted and struck multiple times in the abdomen. Initial white blood cell count was 38.4 × 109/L, platelet count was 691 × 109/L, and lipase was 55 U/L. Computed tomography abdomen/pelvis demonstrated a hematoma encasing the distal pancreas and abutting the stomach and colon. Emergent laparotomy revealed a nearly transected pancreas and devascularized colon, necessitating a distal pancreatectomy, splenectomy, and colonic resection with primary anastomosis. Postoperatively, he had a persistently elevated leukocytosis, thrombocytosis, segmented neutrophils, eosinophilia, and basophilia (peak at 70, 2293, 64, 1.1, and 1.2 × 109/L, respectively). Despite sepsis workup, including repeat computed tomography, no source was identified. Hematology/oncology was consulted for concern for hematologic etiology, with genetic testing and bone marrow biopsy performed. The diagnosis of breakpoint cluster-Abelson gene-positive chronic myeloid leukemia was made based on genetic tests, including polymerase chain reaction and fluorescence in situ hybridization analysis, which confirmed the presence of the Philadelphia chromosome. Bone marrow biopsy suggested a chronic phase. The patient was treated with hydroxyurea and transitioned to imatinib. CONCLUSIONS: Thrombocytosis following splenectomy is a common complication and a plate count to white blood cell count ratio   50 × 109/L) and thrombocytosis (> 2000 × 109/L) may suggest something more ominous, including chronic myeloid leukemia , particularly when elevated granulocyte counts are present. Chronic myeloid leukemia workup includes peripheral smear, bone marrow aspiration, and determination of Philadelphia chromosome. Post-splenectomy vaccines are still indicated within 14 days; however, the timing of immunization with cancer treatment must be considered. Tyrosine kinase inhibitors are the first-line therapy and benefits of pretreatment with hydroxyurea for cytoreduction remain under investigation. Additionally, tyrosine kinase inhibitors have been associated with gastrointestinal perforation and impaired wound healing, necessitating heightened attention in patients with a new bowel anastomosis.

Background: Chronic Myeloid Leukemia (CML), accounting for 15–20% of adult leukemia cases, is marked by the Philadelphia chromosome, resulting from the t(9;22)(q34;q11) translocation. This leads to uncontrolled cell proliferation and survival. Imatinib therapy lowers BCR-ABL levels, influencing telomere-associated proteins and increasing telomerase accessibility, indirectly boosting its activity. This study investigates the effects of MST-312 and imatinib, both individually and combined, on a CML cell line. Methods: The K562 cells were subjected to different doses of MST-312 and imatinib, including four combination concentrations. Cell viability and metabolic activity were measured using trypan blue and MTT assays at 24-, 36-, and 48-h post-treatment. Flow cytometry (AnnexinV/PI) assessed cell apoptosis after 36 h of treatment with MST-312 and imatinib, both individually and in combination. The expression levels of Bax, Bcl-2, hTERT, P21, P53, and c-Myc were determined via qRT-PCR. Results: Both MST-312 and imatinib independently reduced cell viability in a dose- and time-dependent manner. Their combination further decreased cell viability compared to monotherapy. Treatment of K562 cells with MST-312 and imatinib for 36 h increased Bax expression and the Bax/Bcl-2 ratio while decreasing Bcl-2 expression. Combined treatment significantly reduced hTERT ansd P21 gene expression compared to imatinib alone. Conclusions: The combination of MST-312 and imatinib shows potential as a CML therapy. However, further research and clinical trials are necessary to validate these findings and determine their clinical relevance. [ABSTRACT FROM AUTHOR]

The coexistence of chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL) in the same patient is exceedingly rare, with only a few cases reported in the literature. Here, we report a patient with CML who, having achieved a major molecular response with imatinib, subsequently developed CLL, which necessitated the concomitant administration of ibrutinib. [ABSTRACT FROM AUTHOR]

Quantitation of BCR-ABL1 with the quantitative reverse transcriptase polymerase chain reaction (RT-PCR) is very important in monitoring chronic myeloid leukemia (CML), which relies on an RNA reference material. A genomic RNA reference material (RM) containing the BCR-ABL1 P210 fusion mutation was developed, and an absolute quantitative method based on one-step reverse transcription digital PCR (RT-dPCR) was established for characterizing the RM. The proposed dPCR method demonstrates high accuracy and excellent analytical sensitivity, as shown by the linear relationship (0.94 < slope < 1.04, R2≧0.99) between the measured and nominal values of b2a2, b3a2, and ABL1-ref within the dynamic range (104–101 copies/reaction). Homogeneity and stability assessment based on dPCR indicated that the RM was homogeneous and stable for 24 months at −80 °C. The RM was used to evaluate inter-laboratory reproducibility in eight different laboratories, demonstrating that participating laboratories could consistently produce copy concentrations of b3a2 and ABL1-ref, as well as the BCR-ABL1/ABL1 ratio (CV < 2.0%). This work suggests that the RM can be employed in establishing metrological traceability for detecting mutations in the BCR-ABL1 fusion gene, as well as in quality control for testing laboratories. [ABSTRACT FROM AUTHOR]

Resistance to therapy is a major clinical obstacle to treatment of cancer and communicable diseases. Drug selection in treatment of patients where the disease is showing resistance to therapy is often guided by IC50 or fold-IC50 values. In this work, through a model of the treatment of chronic myeloid leukaemia (CML), we contest using fold-IC50 values as a guide for treatment selection. CML is a blood cancer that is treated with Abl1 inhibitors, and is often seen as a model for targeted therapy and drug resistance. Resistance to the first-line treatment occurs in approximately one in four patients. The most common cause of resistance is mutations in the Abl1 enzyme. Different mutant Abl1 enzymes show resistance to different Abl1 inhibitors and the mechanisms that lead to resistance for various mutation and inhibitor combinations are not fully known, making the selection of Abl1 inhibitors for treatment a difficult task. We developed a model based on information of catalysis, inhibition and pharmacokinetics, and applied it to study the effect of three Abl1 inhibitors on mutants of the Abl1 enzyme. From this model, we show that the relative decrease of product formation rate (defined in this work as "inhibitory reduction prowess") is a better indicator of resistance than an examination of the size of the product formation rate or fold-IC50 values for the mutant. We also examine current ideas and practices that guide treatment choice and suggest a new parameter for selecting treatments that could increase the efficacy and thus have a positive impact on patient outcomes. Author summary: Resistance to drug treatments is a major problem in treating diseases. Choosing the right drug for a patient who shows resistance to treatment is a tricky business. Using a model of the treatment of chronic myeloid leukaemia (CML), we challenge the current methods of using IC50 values to guide treatment selection. CML is a blood cancer that is treated with drugs called Abl1 inhibitors. Around one in four patients will show resistance to the first treatment they are given. The Abl1 inhibitors target the Abl1 enzyme, mutations in this enzyme are the most common cause for drug resistance. Different drugs work better for different mutations, but how this happens is not fully understood, which makes choosing treatment difficult. We developed a model based on how the Abl1 enzyme works, how the inhibitor affects the enzyme, and drug concentrations in patients. The model shows that the relative decrease in the efficacy of the enzyme (which we named "inhibitory reduction prowess") better indicates which drugs should be selected for which mutation than the usual current methods. We also examine other factors that guide treatment choice and suggest a new method for selecting treatments that could have a positive impact on patients. [ABSTRACT FROM AUTHOR]

Summary The TOPASE study was set up to evaluate the outcomes of chronic myeloid leukaemia [CML] patients treated with ponatinib (PON) in a real‐world setting in France. One hundred and twenty CML patients, 105 in chronic phase (CP), 8 in accelerated phase (AP) and 7 in blastic phase (BP) were included. Fifty‐one (49%) of the CP‐CML patients were in third line of treatment. The trigger for PON initiation in CP‐CML was ‘poor response’ in 67 patients, ‘poor tolerance’ in 28 patients and ‘response enhancement’ in seven patients. The median dose at initiation was 30 mg/day [Q1; Q3 = 15; 30] in CP‐CML and 45 mg/day [Q1; Q3 = 30; 45] in AP/BP‐CML. Of 98 CP‐CML evaluable patients, 72 (73.5%) were considered as responders (MMR) at one time point at least once, especially for those in second line of treatment and/or presenting a T315I mutation. Ninety‐six of 120 (80%) patients reported at least one adverse event. An arterial occlusive event (AOE) was reported in 11 patients (9.2%). Thus, these real‐life data confirm the potency of ponatinib in resistant or intolerant patients with an acceptable safety profile in non‐selected patients.NCT number: NCT04048564. [ABSTRACT FROM AUTHOR]

ABSTRACT The introduction of tyrosine kinase inhibitors has considerably improved the life expectancy (LE) for patients with chronic myeloid leukemia (CML). Evaluating health‐related quality of life within the treatment pathway remains crucial. Using the Swedish CML register, we included 991 adult patients with chronic‐phase (CP) CML diagnosed 2007 to 2017, with follow‐up until 2018. We developed a multistate model to estimate the loss in LE (LLE) and loss in quality‐adjusted life expectancy (LQALE) for the patient population compared to the general population, along with the respective proportions of losses relative to the general population. All patients with CP‐CML had a relatively low reduced LE but with larger LQALE. The maximum LLE within age/sex subgroups was 5.7 years (general population LE: 43.2 years vs. CP‐CML LE: 37.5 years) for females diagnosed at age 45 years, with LQALE of 12.0 quality‐adjusted life years (QALYs) (general population QALE: 38.2 QALYs vs. CP‐CML QALE: 26.3 QALYs). Across all ages, the proportions of LLE ranged from 9% to 15%, and the proportions of LQALE were 29% to 33%. Despite a low LLE, our findings reveal a greater LQALE for patients with CP‐CML. Further improvements in management of CP‐CML are thus warranted to successfully address the prevailing medical needs. [ABSTRACT FROM AUTHOR]

HIV-1 infection cannot be cured due to long-lived viral reservoirs formed by latently infected CD4+ T cells. "Shock and Kill" strategy has been considered to eliminate the viral reservoir and achieve a functional cure but the stimulation of cytotoxic immunity is necessary. Ponatinib is a tyrosine kinase inhibitor (TKI) clinically used against chronic myeloid leukemia (CML) that has demonstrated to be effective against HIV-1 infection in vitro. Several TKIs may induce a potent cytotoxic response against cancer cells that makes possible to discontinue treatment in people with CML who present long-term deep molecular response. In this longitudinal study, we analyzed the capacity of ponatinib to induce an antiviral response against HIV-1 infection in peripheral blood mononuclear cells (PBMCs) obtained from people with CML previously treated with imatinib for a median of 10 years who changed to ponatinib for 12 months to boost the anticancer response before discontinuing any TKI as part of the clinical trial NCT04043676. Participants were followed-up for an additional 12 months in the absence of treatment. PBMCs were obtained at different time points and then infected in vitro with HIV-1. The rate of infection was determined by quantifying the intracellular levels of p24-gag in CD4+ T cells. The levels of p24-gag+ CD4+ T−cells were lower when these cells were obtained during and after treatment with ponatinib in comparison with those obtained during treatment with imatinib. Cytotoxicity of PBMCs against HIV-infected target cells was significantly higher during treatment with ponatinib than during treatment with imatinib, and it was maintained at least 12 months after discontinuation. There was a significant negative correlation between the lower levels of p24-gag+ CD4+ T−cells and the higher cytotoxicity induced by PBMCs when cells were obtained during and after treatment with ponatinib. This cytotoxic immunity was mostly based on higher levels of Natural Killer and Tγδ cells seemingly boosted by ponatinib. In conclusion, transient treatment with immunomodulators like ponatinib along with ART could be explored to boost the antiviral activity of cytotoxic cells and contribute to the elimination of HIV-1 reservoir. [ABSTRACT FROM AUTHOR]

Background: Chronic myeloid leukaemia (CML) is a type of blood cancer that begins in the hematopoietic stem cells. It is primarily characterized by a specific chromosomal aberration, the Philadelphia chromosome. While the fusion gene is a major contributor to CML, several other genes including ADGRE2, that are reported as highly expressed in hematopoietic stem cells and could be utilized as a therapeutic marker in leukemic patients are implicated in the disease's progression. Until recently, little research had been conducted to identify single nucleotide polymorphisms (SNPs) associated with CML. Therefore, this study aims to investigate the influence of non-synonymous variants on the structure and function of the gene encoding adhesion G protein-coupled receptor E2, ADGRE2, and to evaluate their association with CML and its clinical and pathological characteristics. Methods: Non-synonymous SNPs of ADGRE2 were retrieved from the ENSEMBL, COSMIC, and gnomAD genome browsers, and the pathogenicity of deleterious variants was assessed using several established computational tools, including SIFT, CADD, REVEL, PolyPhen, and MetaLR. Results: Various in silico analyses explored the impact of damaging SNP on the function, stability, and structure of EGF-like modules containing mucin-like hormone receptor-like2 (EMR2) protein encoded by the ADGRE2 gene. Genotype analysis was performed on collected blood samples, revealing that altered genotype TT of variant rs765071211 (C/T) was associated significantly with CML patients compared to the control. Further in vitro and in vivo analyses suggest that this SNP holds potential for clinical translation. [ABSTRACT FROM AUTHOR]

BACKGROUND RESULTS CONCLUSION Advanced glycation end products (AGEs) are compounds formed by non‐enzymatic processes in the Maillard reaction and can cause various chronic diseases. This study explores the AGE formation process in a glucose–amino acid system under both wet‐ and dry‐heating conditions, and analyzes the effect of cysteine in AGE formation.Under wet‐heating conditions, Nε‐carboxymethyllysine (CML) and Nε‐carboxyethyllysine (CEL) concentrations rose for the initial 90 min and subsequently declined after 120 min; after 90 min of heating, the maximum yields in the absence of cysteine were 1151.04 ± 14.01 and 3386.90 ± 26.55 ng mL−1, respectively. The concentration of pyrraline (Pyr) increased after 30 min and then decreased after 60 min with a maximum yield of 777.68 ± 23.36 ng mL−1. However, in dry‐heating models, the AGE concentrations consistently increased with increasing heating time; the maximum yields for CML, CEL and Pyr were 468.66 ± 10.96, 1993.57 ± 14.81 and 1085.74 ± 58.06 ng mL−1, respectively. The addition of cysteine showed an inhibitory effect on AGE formation, especially for Pyr in the dry‐heating model, with inhibition rates ranging from 17.14% to 95.60%.Although wet‐heating models produced more CML and CEL, they produced less Pyr than dry‐heating models. The AGE formation in wet‐heating models positively correlated with the reaction rate; however, the dry‐heating reaction demonstrated a more complex relationship between reaction rate and reaction protocol. Moreover, cysteine exhibited a significant inhibitory effect on AGE production, and the degree of inhibition was proportional to the cysteine concentration. This study provides important insights into the mechanisms for AGE formation under various heating conditions, such as those representing baking (dry‐heating) and steaming conditions (wet‐heating). © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions De novo chronic myeloid leukemia in blastic phase (CML‐BP) showing lymphoid immunophenotype mimics Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph‐positive ALL). Although upfront allogeneic hematopoietic cell transplantation (HCT) is considered in both diseases, it is not yet clear whether the transplant outcomes are also similar.Using a registry database, the transplant outcomes between de novo CML‐BP and Ph‐positive ALL in negative‐minimal residual disease (MRD), positive MRD, and nonremission cohorts were compared, respectively. All of the included patients had received tyrosine kinase inhibitor therapy before HCT and underwent HCT between 2002 and 2021. Regarding Ph‐positive ALL, patients with p210 transcripts were excluded because there was concern that this group might include patients with de novo CML‐BP.Although most of the outcomes were comparable, in patients with positive MRD at HCT, de novo CML‐BP was significantly associated with superior disease‐free survival (DFS) (hazard ratio [HR] 0.6, p = .0032), overall survival (HR 0.66, p = .027), and a lower risk of relapse (HR 0.48, p = .0051). In subgroup analyses, BCR::ABL1 mutation status had a significant interaction with the disease (p for interaction = .0027). De novo CML‐BP seemed to be associated with superior disease‐free survival in a BCR::ABL1 mutation‐positive cohort, whereas this association was not observed in a mutation‐negative cohort.Considering previous reports that showed inferior outcomes for de novo CML‐BP compared to Ph‐positive ALL, the data suggested that allogeneic HCT could overcome the poor prognosis of de novo CML‐BP. These findings highlight the importance of distinguishing de novo CML‐BP from Ph‐positive ALL. [ABSTRACT FROM AUTHOR]

Introduction: The bone marrow examination is an essential investigation in the diagnosis and management of many haematological disorders. The integration of all investigations, including peripheral blood analysis, bone marrow aspirate, and trephine biopsy findings, along with supplementary tests such as immunophenotyping, cytogenetic analysis, and molecular genetic studies, is crucial for arriving at a final diagnosis. Aim: To assess the presence of reticulin fibres in bone marrow biopsy sections in haematological malignancies, to evaluate the grade of BMF associated with haematological malignancies and to assess the role of angiogenesis using IHC markers in various haematological malignancies. Materials and Methods: A cross-sectional study was conducted in the Department of Pathology at the National Institute of Pathology, Safdarjung Hospital, New Delhi, India in 2009 for a duration of 18 months. Thirty-eight patients with a diagnosis of Acute Myeloid Leukaemia (AML), Acute Lymphoblastic Leukaemia (ALL), Chronic Myeloid Leukaemia (CML), and Chronic Lymphoproliferative Disorder (CLPD) were studied. Bone marrow biopsies were taken, fixed in 10% formalin, and decalcified in 10% Ethylene Diamine Tetraacetic Acid (EDTA). Routine paraffin embedding was performed, and serial sections of 4 µm were obtained on poly-L-lysine-coated slides for Immunohistochemistry (IHC) {Vimentin, Vascular Endothelial Growth Factor (VEGF), CD-34, Smooth Muscle Actin (SMA)}. The presence of reticulin fibres in the bone marrow biopsy sections was assessed using two special stains: Gomori's Silver Impregnation and Masson's Trichrome. Fibrosis was quantified according to the Baurmeister 0-4 grading system of Bone Marrow Fibrosis (BMF). Results: The results of the present study suggest that Endothelial to Mesenchymal Transition (EndMT) may play a role in the pathogenesis of BMF. Various grades of fibrosis were observed, with 15 cases (39.47%) in Grade 3, followed by 11 cases (28.95%) in Grade 2, 8 cases (21.05%) in Grade 1, and 4 cases (10.53%) in Grade 4. Conclusion: BMF was a significant finding even in the early stages of the majority of the lesions studied and was closely linked with angiogenesis. This study showed that angiogenesis plays an important role in the pathogenesis of haematological neoplasms and that VEGF is a prominent stimulus in the majority of these disorders. Additionally, this study suggests that EndMT has a possible role in the pathogenesis of BMF. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by excessive proliferation of myeloid cells. The COVID-19 pandemic has raised concerns regarding the impact of SARS-CoV-2 on patients with malignancies, particularly those with CML. This study aimed to investigate the effects of SARS-CoV-2 proteins on CML cell viability and the protective role of vitamin K2 (VK2) in conjunction with imatinib. Experiments conducted on K562 CML cells demonstrated that the SARS-CoV-2 envelope protein induces cytotoxicity and activates caspase 3/7, which are key markers of apoptosis. VK2 mitigated these cytotoxic effects and decreased cytokine production while inhibiting colony formation. Furthermore, the combination of VK2 with imatinib significantly reduced cellular proliferation, diminished mitochondrial membrane potential, and markedly suppressed colony formation. These findings suggest that VK2 protects CML cells from SARS-CoV-2-induced cytotoxicity and enhances the therapeutic efficacy of imatinib, presenting a potential strategy to improve CML treatment during the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

This study investigates COVID-19 outcomes and immune response in chronic myeloid leukemia (CML) patients post-SARS-CoV-2 vaccination, comparing effectiveness of various vaccine options. Data from 118 CML patients (85 in Brazil, 33 in the US) showed similar infection rates prior (14% Brazil, 9.1% US) and post-vaccination (24.7% vs. 27.3%, respectively). In Brazil, AstraZeneca and CoronaVac were the most commonly used vaccine brands, while in the US, Moderna and Pfizer-BioNTech vaccines dominated. Despite lower seroconversion in the Brazilian cohort, all five vaccine brands analyzed prevented severe COVID-19. Patients who received mRNA and recombinant viral vector vaccines (HR: 2.20; 95%CI 1.07–4.51; p <.031) and those that had achieved at least major molecular response (HR: 1.51; 95% CI 1.01–3.31; p <.0001) showed higher seroconversion rates. Our findings suggest that CML patients can generate antibody responses regardless of the vaccine brand, thereby mitigating severe COVID-19. This effect is more pronounced in patients with well-controlled disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment outcomes in chronic myeloid leukemia (CML) have improved in recent years because of the use of tyrosine kinase inhibitors. However, treatment responses to myeloid blast-phase CML (MBP-CML) are still unsatisfactory. In this paper, we summarize the biological mechanisms of progression to MBP and the most frequently used treatment regimens for MBP-CML. We also review why some patients develop resistance to tyrosine kinase inhibitors. Myeloid blast-phase chronic myeloid leukemia (MBP-CML) is a rare disease with a dismal prognosis. It is twice as common as lymphoid blast-phase CML, and its prognosis is poorer. Despite the success with tyrosine kinase inhibitors in the treatment of chronic-phase CML, the same does not hold true for MBP-CML. In addition to the Philadelphia chromosome, other chromosomal and molecular changes characterize rapid progression. Although some progress in elucidating the biology of MBP-CML has been made, there is need to discover more in order to develop more satisfactory treatment options. Currently, most common treatment options include tyrosine kinase inhibitors (TKIs) as monotherapy or in combination with acute myeloid leukemia-based intensive chemotherapy regimens. Some patients may develop resistance to TKIs via BCR-ABL1-dependent or BCR-ABL1-independent mechanisms. In this paper, we provide an overview of the biology of MBP-CML, the current treatment approaches, and mechanisms of resistance to TKIs. In order to improve treatment responses in these patients, more emphasis should be placed on understanding the biology of myeloid blastic transformation in CML and mechanisms of resistance to TKIs. Although patient numbers are small, randomized clinical trials should be considered. [ABSTRACT FROM AUTHOR]

Introduction: Chronic myeloid leukemia (CML) is a hematological malignancy with an excellent prognostic outcome. After the advancements in CML treatment and the introduction of different tyrosine kinase inhibitors (TKIs), the life expectancy of CML patients has become equivalent to that of the general population. As a result, coronary artery disease is anticipated to be the leading cause of death among CML patients. Moreover, TKI use is associated with a risk of endothelial dysfunction, thrombosis, and cardiovascular events, including myocardial infarction. In this study, we compare the outcomes of percutaneous coronary intervention (PCI) in patients with CML to their matched non-CML counterparts. Method: This is a retrospective cohort study using the Nationwide Readmission Database from January 2016 to December 2020. Adults with or without CML hospitalized for acute myocardial infarction and underwent PCI were included. The patients were identified using ICD-10 codes. The primary outcomes were in-hospital mortality and 30-day readmission rates. The secondary outcomes were PCI complications rates. Results: Out of 2,727,619 patients with myocardial infarction, 2,124 CML patients were identified. A total of 888 CML patients underwent PCI. CML patients were significantly older (mean age: 68.34 ± 11.14 vs. 64.40 ± 12.61 years, p < 0.001) than non-CML patients without a difference in sex distribution. Hypertension (85.45% vs. 78.64%), diabetes (45.48% vs. 37.29), stroke (11.84% vs. 7.78) at baseline were significantly higher in the CML group. Prior myocardial infarction events (20.51% vs. 15.17%) and prior PCI procedure (24.47% vs. 16.89%) were significantly higher in the CML group. CML patients had a significantly longer hospital stay (4.66 ± 4.40 vs. 3.75 ± 4.62 days, p = 0.001). The primary outcomes did not differ between the comparison groups. The risk of post-PCI complications did not differ between the comparison groups in the propensity matched analysis except for coronary artery dissection (odds ratio [OR]: 0.10; 95% confidence interval [CI]: 0.02–0.65, p = 0.016) and ischemic stroke (OR: 0.35; 95% CI: 0.14–0.93, p = 0.034) which were lower in the CML group. Conclusion: This analysis showed no statistically significant difference in mortality, 30-day readmission, and post PCI complications rates between CML and non-CML patients. However, interestingly, CML patients may experience lower coronary artery dissection and ischemic stroke events than those without CML diagnosis. [ABSTRACT FROM AUTHOR]

Summary: Olverembatinib is a novel orally administered third-generation tyrosine kinase inhibitor (TKI) with definitive responses in T315I-mutant chronic myeloid leukemia (CML) patients. However, its value in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) remained unclarified. In this multiple-center study, 20 patients with de novo Ph + ALL were treated with olverembatinib-based regimens as frontline therapy. All patients acquired complete remission (CR) after induction. 85% of patients achieved complete molecular response (CMR) within three months, contributed mainly by the addition of blinatumomab. A total of 45% of patients experienced mild hematological treatment-related adverse events (TRAEs). Olverembatinib-based treatment led to promising outcomes in de novo Ph + ALL patients but warranted further studies to investigate the best-combined strategy. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia presenting de novo in the blast phase (CML-BP) is a rare diagnosis among pediatric malignancies. We report on a 16-year-old male who presented with CML-BP lymphoid at diagnosis. He was treated with shortened acute lymphoblastic leukemia induction plus the tyrosine kinase inhibitor (TKI) imatinib followed by dasatinib. After achieving molecular remission (MR), hematopoietic stem cell transplantation (HSCT) was performed early after diagnosis. Despite prophylactic dasatinib, he relapsed 3 months later with the kinase domain mutation T315I. Multiple therapeutic approaches including ponatinib, blinatumomab, a 2nd HSCT from a different donor, donor lymphocyte infusions, and high-dose asciminib all resulted in subsequent relapse. Another molecular response was achieved by combining ponatinib plus asciminib with chemotherapy. In this situation, CD19-directed CAR-T cells (Kymriah®) were administered for compassionate use and tolerated without adverse events. Compared to all prior therapies, CAR T-cells maintained remission. After 12 months of follow-up, complete B-cell aplasia and low numbers of CAR-T cells are detectable in the peripheral blood, potentially mediating long-term disease control. [ABSTRACT FROM AUTHOR]

Bariatric surgery is increasingly performed to treat severe obesity. As a result of anatomical and physiological changes in the gastrointestinal tract, the pharmacokinetics (PK) of oral drugs can be altered, affecting their efficacy and safety. This includes the class of tyrosine kinase inhibitors (TKIs) which are used to treat chronic myeloid leukemia (CML). This case series describes the clinical course of four CML cases with a history of bariatric surgery. The patients used various TKIs (nilotinib, dasatinib, bosutinib, ponatinib, and imatinib) for which 15 drug levels were measured. The measured TKI concentrations were in part subtherapeutic, and highly variable when compared to mean levels measured in the general population. Multiple drug levels were measured in these patients, as the clinicians were aware of the possible impact of bariatric surgery. The drug levels were used as additional input for clinical decision-making. All four patients required TKI switches and/or dose modifications to achieve an effective and tolerable treatment. Eventually, adequate clinical and molecular remissions were achieved in all cases. In summary, TKI concentrations of patients undergoing bariatric surgery may be subtherapeutic. Moreover, there is substantial interindividual and intraindividual variation, which may be explained by the complex interference of bariatric surgery and associated weight loss. For clinical practice, therapeutic drug monitoring is advised in patients with a history of bariatric surgery in case of suboptimal response or loss of response. [ABSTRACT FROM AUTHOR]

Patients with chronic myeloid leukemia (CML) who have failed conventional tyrosine kinase inhibitors (cTKIs) and asciminib constitute a complex group of patients with few therapeutic options. A retrospective descriptive multicenter observational study was carried out including patients with CML who had presented a therapeutic failure to ≥ 2 cTKIs and asciminib, and had received or were not candidates to ponatinib. Of the 19 patients enrolled, 8 patients failed asciminib due to intolerance and 11 due to resistance. The most common strategy for intolerant patients was to initiate a previously administered cTKI (6/8) with dose adjustments or symptomatic management of adverse events (AEs). Of the patients who failed due to resistance, only patients who underwent progenitor transplantation achieved profound long-term responses. A frequent strategy was to use ponatinib (4/11) in patients previously considered non-candidates, with poor responses in patients in whom dose reductions were used, and severe AEs in patients at standard doses. In the remaining patients, cTKIs and other agents (interferon, hydroxyurea, citarabine, busulfan) were used with poor responses. Patients who progressed to advanced stages had a dismal prognosis. With a median follow-up of 11.2 months, overall survival of the global cohort was 73%; 100% for intolerant patients, 71% for resistant patients and 25% for those who discontinue asciminib in accelerated/blastic phase. [ABSTRACT FROM AUTHOR]

Venetoclax is a BH3 mimetic that was recently approved for the treatment of acute myeloid leukemia (AML) treatment. However, the effect of venetoclax on AML remains limited, and a novel strategy is required. Here, we demonstrate for the first time that the cytotoxic effect of venetoclax drastically increased when by combined with the naturally occurring flavonoid quercetin. Combined treatment with venetoclax and quercetin caused most of AML KG-1 cells to exhibit a condensed morphology. Cell cycle analysis revealed that the combination strongly induced cell death. Caspase inhibitor blocked this cell death, and the combination induced poly (ADP-ribose) polymerase (PARP) cleavage, indicating that apoptosis was the primary mechanism. These effects were also observed in another AML cell line Kasumi-1 but not in chronic myeloid leukemia (CML) K562 cells. Public data analysis demonstrated that B-cell/CLL lymphoma 2 (Bcl-2) expression is increased in AML cells compared to other malignant tumors, and the survival and the growth of AML cell line depends on Bcl-2. We found that quercetin increased Bcl-2-associated X protein (Bax) expression in KG-1. Our study provides a novel function for quercetin and presents a promising strategy for AML treatment using venetoclax. [ABSTRACT FROM AUTHOR]

Fast, accurate damage assessment of numerous buildings for large areas is vital for saving lives, enhancing decision‐making, and expediting recovery, thereby increasing urban resilience. The traditional methods, relying on expert mobilization, are slow and unsafe. Recent advances in machine learning (ML) have improved assessments; however, quantum‐enhanced ML (QML), a rapidly advancing field, offers greater advantages over classical ML (CML) for large‐scale data, enhancing the speed and accuracy of damage assessments. This study explores the viability of leveraging QML to evaluate the safety of reinforced concrete buildings after earthquakes, focusing on classification accuracy only. A QML algorithm is trained using simulation datasets and tested on real‐world damaged datasets, with its performance compared to various CML algorithms. The classification results demonstrate the potential of QML to revolutionize seismic damage assessments, offering a promising direction for future research and practical applications. [ABSTRACT FROM AUTHOR]

Pityriasis rosea is an acute, self‐limited exanthem that typically occurs in adolescence and young adulthood, classically featuring ovoid erythematous and scaly lesions on the trunk and proximal extremities. While its cause is not definitively known, the classic form of pityriasis rosea may result from the reactivation of latent human herpesvirus (HHV) infections (HHV‐6 and HHV‐7). Interestingly, drug eruptions that clinically and/or histopathologically resemble pityriasis rosea have also been reported. These pityriasis rosea‐like drug eruptions tend to occur at an older age and have a shorter duration than the classic type. As there are different management paradigms, the distinction between classic pityriasis rosea and the mimicking drug eruption is important to recognize. Herein, we report a case of a pityriasis rosea‐like drug eruption that occurred in association with imatinib mesylate treatment for chronic myeloid leukemia. We also review the clinicopathologic features of reported cases of pityriasis rosea‐like drug eruption, including those due to imatinib. While the clinical morphology of the cutaneous drug‐related eruption mimics the lesions seen in classic pityriasis rosea, the presence of unique histopathologic findings, including necrotic keratinocytes, interface dermatitis, and eosinophils, may aid in distinction. [ABSTRACT FROM AUTHOR]

Precise and reliable predictive parameters to accurately identify chronic myeloid leukemia (CML) patients who can successfully discontinue their tyrosine kinase inhibitor (TKI) treatment are lacking. One promising parameter is depth of molecular response measured by BCR::ABL1 digital PCR (dPCR). The aim of this study was to validate a previously described prediction cutoff of 0.0023%IS and to assess the value of dPCR for treatment‐free remission (TFR) prediction in relation to other clinical parameters. A droplet‐based dPCR assay assessed BCR::ABL1 %IS prior to TKI discontinuation. The primary endpoint was molecular recurrence (MolR) by 36 months. A total of 186 patients from Canada, Germany, and the Netherlands were included. In patients with a first TKI discontinuation attempt (n = 163), a BCR::ABL1 dPCR < and ≥0.0023%IS had a MolR probability of 33% and 70%, respectively. Patients treated less than 6 years with a BCR::ABL1 dPCR <0.0023%IS had a MolR probability of 31%. After correction for treatment duration, both high dPCR value and the use of imatinib (vs. second‐generation TKI) were significantly associated with a higher risk of MolR (HR of 3.66, 95%CI 2.06–6.51, p <.001; and 2.85, 95%CI 1.25–6.46, p =.013, respectively). BCR::ABL1 dPCR was not associated with TFR outcome after second TKI discontinuation, however, with the limitation of a small number of patients analyzed (n = 23). In conclusion, BCR::ABL1 digital PCR based on the cutoff of 0.0023%IS is a valuable predictive tool to identify CML patients with a high probability of TFR success after first TKI discontinuation, including patients treated for less than 6 years. [ABSTRACT FROM AUTHOR]

Purpose: The choice of characterization model has the potential to profoundly influence LCA results and conclusions. It is therefore a requirement of ISO 14044:2006 that the selection of characterization model shall be both justified and consistent with goal and scope. The purpose of this article was to examine current practices regarding the characterization of GHG emissions and reporting as CO2 equivalent emissions. Methods: A survey of practice was conducted across articles recently published in the International Journal of Life Cycle Assessment. Each article was examined using seven predetermined questions covering reporting of CO2 equivalent emissions and justification of climate metric used, interpretation of results in relation to climate measures or goals, and the implications of choosing an alternative climate metric. Results and discussion: Of the sample of 85 articles, more than half reported GHG emissions as CO2 equivalent emissions. Of these, 81% unambiguously reported the climate metric used. Most often, there was no justification for the choice of a characterization model. Where a justification was given, the most common reason was alignment with the requirements of a program or PCR document. In some cases, the choice of characterization model was determined by the choice of impact assessment method (e.g., CML, ReCiPe). In other cases, the choice of characterization model was based on the desire to compare results to other studies. It is noted that none of the abovementioned reasons is scientific justification related to a stated climate objective. Not surprisingly, most studies made no attempt to interpret results reported as CO2 equivalent emissions in relation to climate measures or goals, and most did not discuss the potential implications of alternative climate metrics. For almost half of the articles, the choice of climate metric was assessed as potentially having major implications for decision-making or comparison to alternative systems. Conclusions: Based on this survey, it is evident that key aspects of ISO 14044:2006 are routinely not being followed. When GHG emissions are aggregated into a single impact category indicator result, there is a loss of transparency about climate impacts over time and the potential to unknowingly trade short-term climate benefits against the exacerbation of the difficulties of achieving long-term climate stabilization. As such, whenever GHG emissions are reported as CO2 equivalent emissions, it is imperative that the choice of characterization model is unambiguously reported and justified, that results are interpreted in relation to environmental outcomes, and that the potential implications of selecting alternative models are discussed. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Methods Results Conclusion Fluorescently labeled aerolysin (FLAER) is widely used for the identification of paroxysmal nocturnal hemoglobinuria (PNH) clones in peripheral blood (PB) samples. However, there are only a few reports on the differential fluorescent intensity of FLAER in normal bone marrow (BM) cell subpopulations. The purpose of this study was to evaluate FLAER expression during normal and pathological hematopoiesis, to map the critical existence of non‐PNH FLAER‐dim cells.A total of 54 BM aspirates were prospectively analyzed with FLAER‐based flow cytometric (FC) protocols, during their routine work‐up. These were obtained from patients with the following diagnoses: PNH (3), infections/reactive (5), myelodysplastic syndromes (MDS) (7), myelodysplastic/myeloproliferative neoplasms (MDS/MPN) (4), chronic myelogenous leukemia (CML) (3), acute myelogenous leukemia (AML) at diagnosis (20), AML in measurable residual disease (MRD) assessment (7), and B‐cell acute lymphoblastic leukemia (B‐ALL) in MRD assessment (5). The applied protocols consisted of FLAER, HLA‐DR, CD14, CD33, CD34, CD66b, CD38, CD117, CD64, CD45, and FLAER, CD66c, CD14, CD33, CD34, CD66b, CD123, CD16, CD64, and CD45, respectively. FLAER expression was assessed in CD34++/CD38‐ and CD34+/CD38+ stem cells, CD34‐/CD117+/HLA‐DR+/CD33+ myeloid precursors, and CD64+/CD14‐/HLA‐DR+ monocyte precursors but also in mature myeloid cells.All patients revealed an intermediate FLAER intensity in CD34++/CD38‐ stem cells, with a discrete FLAER‐negative subpopulation observed only in maturing CD34+/CD38+ stem cells of patients with PNH. The lowest FLAER intensity was noticed in CD34‐/CD117+/HLA‐DR+/CD33+ myeloid precursors, not only in patients with PNH but also in PNH‐negative BM aspirates. An ascending FLAER intensity was further observed during monocytic and granulocytic maturation, with a discrete FLAER‐negative population in CD64+/CD14‐/HLA‐DR+ monocyte precursors and maturing neutrophils and monocytes of patients with PNH only. The maturation pattern of FLAER expression was further confirmed in a patient with acute promyelocytic leukemia treated with all‐trans retinoic acid (ATRA), where FLAER was concurrently upregulated with CD66b in a consecutive series of PB samples tested over a 20‐day‐period after diagnosis.The application of FLAER in PNH‐positive and PNH‐negative reactive or malignant BM aspirates identified normally expected non‐PNH FLAER‐dim CD34‐/CD117+/HLA‐DR+/CD33+ myeloid precursors in all samples. A specific FLAER‐associated maturation pattern was observed, which is proposed for further study within MRD and diagnostic protocols. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Young female patients with chronic myeloid leukemia (CML) often face challenges becoming pregnant due to the teratogenicity of tyrosine kinase inhibitors (TKIs).The authors conducted a nationwide survey of female patients with CML who experienced pregnancy between 2002 and 2020.Information for 70 pregnancies in 49 patients was obtained. There were three types of pregnancies: CML onset during pregnancy (n = 9), unplanned pregnancy mostly during treatment with a TKI (n = 25), and planned pregnancy during treatment‐free remission (TFR) or treatment with interferon‐alpha (IFN‐α) (n = 36). The median duration from CML diagnosis to pregnancy in patients with planned pregnancy was significantly longer than that in patients with unplanned pregnancy (10.6 years vs. 4.1 years, p < .001). In 48 pregnancies that resulted in childbirth, TFR and treatment with IFN‐α were chosen in 26 and 17 pregnancies, respectively. Sustained major or deeper molecular response was observed in 18 of 26 pregnancies with TFR. The patients who fulfilled the requirements for TKI therapy discontinuation by European LeukemiaNet recommendations achieved a TFR rate of 77% in pregnancy. Treatment with IFN‐α might be effective for patients who are in complete cytogenetic response or deeper response (response rate, 76%).Pregnancy by TFR or treatment with IFN‐α could be a safe and feasible way for patients with CML. However, a substantial duration of treatment with a TKI before conception may be needed for planned pregnancy. Planning and evaluation for pregnancy should be considered at the time of CML onset for female patients with childbearing potential. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) is a major cause of chronic myeloid leukemia (CML) relapse, therapeutic failure, and a poor prognosis. However, Agaricus blazei Murill (AbM) is a mushroom that might have anticancer and other medicinal properties. Therefore, this study aimed to determine the effects of combining the acidic RNA protein complex FA‐2‐b‐β extracted from AbM with imatinib (IM) on MDR in the K562/ADR leukemia cell line in vitro and in xenograft mouse models. The combination of FA‐2‐b‐β and IM significantly inhibited cell proliferation and promoted apoptosis in K562/ADR cells compared with either alone. Western blotting (WB) revealed that the combination significantly reduced p‐PI3K, p‐AKT, and p‐mTOR protein expression. The combination also inhibited tumor growth in mice with K562/ADR xenografts. These findings suggested that FA‐2‐b‐β enhances the effects of IM on K562/ADR cell proliferation and apoptosis, potentially by inhibiting the PI3K/AKT/mTOR pathway and downregulating P‐glycoprotein (P‐gp) expression. [ABSTRACT FROM AUTHOR]

Objective To investigate the dynamics of NK cells and Treg cells, as well as their potential prognostic significance in relation to TKI discontinuation among patients diagnosed with chronic myeloid leukemia （CML）. Methods In this study, a total of 200 patients diagnosed with CML were randomly selected and divided into two groups: the discontinuation group （n = 100） and the non-discontinuation group （n = 100）. Within the discontinuation group, patients were further categorized into a recurrence subgroup （n = 41） and a non-recurrence subgroup （n = 59）. Clinical data and follow-up information of these patients were retrospectively analyzed. Logistic regression analysis was performed to investigate the impact of various variables on patient outcomes following drug discontinuation, as well as to explore independent factors influencing recurrence in these individuals. Receiver operating characteristic （ROC） curve analysis was employed to assess the predictive value of NK cells and Treg cells for TKI discontinuation outcomes. A significance level of P < 0.05 was considered statistically significant. Results The proportion of patients treated with interferon in the discontinuation group was significantly higher than that in the non-discontinuation group （P < 0.05）. Moreover, the former group exhibited a significantly higher number of NK cells （P < 0.05） and Treg cells （P < 0.01） compared to the latter group. Compared to the recurrence group, there was a significant increase in the proportion of patients using interferon in the non-recurrence group （P < 0.05）, along with longer durations of TKI treatment and deep molecular response （DMR） duration （P < 0.05）. The number of NK cells and Treg cells in the non-recurrence group was significantly higher than that in the recurrence group （P < 0.01）. Logistic regression analysis found that the use of interferon （OR = 1.25, 95% CI: 1.11 ~ 2.03, P < 0.001）, duration of DMR （OR = 1.16, 95% CI: 1.08 ~ 1.92, P < 0.05）, NK cells （OR = 1.64, 95% CI: 1.14 ~ 2.28, P < 0.01）, and Treg cells （OR = 1.83, 95% CI: 1.15 ~ 2.42, P < 0.01） were all influencing factors for the recurrence of patients after drug discontinuation. The results of ROC curve analysis showed that the AUC of NK cells combined with Treg cells for predicting the recurrence of TKI after discontinuation was 0.892 （95% CI: 0.857 ~ 0.927, P < 0.001）. Conclusion The frequencies of NK cells and Treg cells were significantly elevated in patients who remained recurrence-free following TKI discontinuation, highlighting the potential predictive value of combined NK cell and Treg cell analysis for drug cessation in CML patients. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Methods Results Conclusion Asciminib, a novel allosteric BCR::ABL1 inhibitor, targets the ABL1 myristoyl pocket to potentially reduce toxicity and enhance efficacy. It is approved for Philadelphia chromosome‐positive chronic‐phase chronic myeloid leukemia (CML‐CP) in patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs) or those with the T315I mutation.This retrospective analysis evaluated patients with CML treated with asciminib under a managed‐access program across eight Israeli centers from July 2019 to August 2022. We assessed treatment responses, toxicities, event‐free survival (EFS), and overall survival (OS) using Kaplan–Meier methods.The study included 30 patients who had received a median of three prior TKIs, with 73% starting asciminib due to intolerance. After a median follow‐up of 7.1 months, 85% of those without prior complete cytogenetic response (CCyR) achieved CCyR, and 60% previously not in major molecular response (MMR) attained MMR. Resistance was rare (10%), with no cardiovascular events reported despite high baseline comorbidity (73%). Median EFS was 47 months; median OS was not reached.Asciminib demonstrates significant efficacy and tolerability in heavily pretreated patients with CML‐CP, with no new cardiovascular events observed. Further long‐term studies are necessary to explore its full cardiovascular impact. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm in which all the patients has the translocation (9;22) that generates de BCR::ABL1 tyrosine kinase. Despite this disease possessing a good biomarker (BCR::ABL1 transcripts level) for diagnosis and prognosis, many studies has been performed to investigate other molecules, such as the long noncoding RNAs (lncRNAs) and mRNAs, as potential biomarkers with the aim of predicting a change in BCR::ABL1 levels and as an associated biomarker. A RNAseq was performed comparing 6 CML patients with high BCR::ABL1 expression with 6 healthy control individuals, comprising the investigation cohort to investigate these molecules. To validate the results obtained by RNAseq, samples of 87 CML patients and 42 healthy controls were used in the validation cohort by RT-qPCR assays. The results showed lower expression of HOTAIR and PTGS2 in CML patients. The HOTAIR expression is inversely associated with BCR::ABL1 expression in imatinib-treated CML patients, and to PTGS2 showing that CML patients with high BCR::ABL1 expression showed reduced PTGS2 expression. [ABSTRACT FROM AUTHOR]

Background: Treatment-free remission (TFR) is a new long-term goal for treating selected patients with chronic myeloid leukemia in the chronic phase (CML-CP). Still, the appropriate group in which TFR can be attempted and the factors influencing it have not yet been identified. This meta-analysis aimed to explore TFR in CML-CP patients who achieved a deep molecular response (DMR) before Tyrosine kinase inhibitors (TKIs) discontinuation and to explore possible factors influencing TFR and the safety of discontinuation. Methods: We performed a systematic review and single-arm meta-analysis with a systematic search of published literature up to September 2023 in PubMed, Embase, Web of Science, Cochrane Library, and CNKI databases. The assessment was performed using the MINORS scale. Random-effects models were used to calculate outcome metrics, including overall mean TFR rates at 12 and 24 months and subgroup differences. Data synthesis and analysis were done by Stata17.0 software. Results: A total of 19 single-arm trials involving 2336 patients were included in this meta-analysis, with an overall mean TFR rate of 59% [95CI:0.56–0.63] at 12 months and 55% [95CI:0.52–0.59] at 24 months, and no CML-related deteriorations or deaths reported during the TFR period. Our subgroup analysis showed that better TFR was associated with prior interferon therapy (P = 0.003), and molecular response depth MR5.0 (P = 0.020). Conclusion: Our study demonstrated that prior interferon therapy and attainment of a molecular response depth of MR5.0 or greater were associated with higher TFR rates, with patients who attained MR5.0 or greater achieving a TFR rate of up to 62% in the second year after TKI discontinuation. Considering the high heterogeneity of the included trials, the above influences still require further validation and more detailed subgroup analysis in future discontinuation trials. Systematic review registration:https://www.crd.york.ac.uk/prospero/ (Registration No. CRD42023471334). [ABSTRACT FROM AUTHOR]

Background: Since the development of the first‐generation Tyrosine Kinase Inhibitor (TKI), it has played a crucial role in the treatment of BCR::ABL1‐positive acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML). However, ABL1 kinase domain (ABL1 KD) mutations confer resistance to several TKIs. These mutations have been extensively studied in chronic myeloid leukemia (CML) but less so in BCR::ABL1‐positive acute lymphoblastic leukemia (ALL). Methods: Our study aimed to analyze the the ABL1 KD mutations in 97 consecutive newly‐diagnosed adults with BCR::ABL1‐positive ALL before therapy, in cytogenetic complete remission and at relapse with next generation sequencing (NGS). The relationship between ABL1 KD mutations and TKI selection was also analyzed. Results: Previously unreported ABL1 KD mutations R239G, F401V/L, R516L and K262T were the most prevalent in pre‐therapy and cytogenetic remission samples, whereas T315I/P and P‐loop mutations were most prevalent in relapse samples. R239G, F401V/L, R516L and K262T are related to the BCR::ABL1 structure, whereas T315I/P and P‐loop mutations directly alter kinase activity. BaF3 cells transfected with ABL1 KD F401V, K262T, R239G, or R516L mutations were resistant to imatinib but strongly inhibited by olverembatinib with IC50 values of 0.73 to 1.52nM. Meanwhile, olverembatinib had advantages in increasing complete molecular response (CMR) and good prognosis. Conclusion: Overall, our findings indicate the prevalence and impact of new ABL1 KD mutations in BCR::ABL1‐positive ALL patients, highlighting the necessity for effective therapies targetingthese mutations. [ABSTRACT FROM AUTHOR]

Background: Approximately one‐third of US adults have a tattoo, and the prevalence is increasing. Tattooing can result in long‐term exposure to carcinogens and inflammatory and immune responses. Methods: We examined tattooing and risk of hematologic cancers in a population‐based case–control study with 820 cases diagnosed 2019–2021 and 8200 frequency‐matched controls, ages 18–79 years. We calculated odds ratios (OR) and 95% confidence intervals (CI) using multivariable‐adjusted logistic regression models. Results: The prevalence of tattooing was 22% among Hodgkin lymphoma (HL) cases, 11% among non‐Hodgkin lymphoma (NHL) cases, 16% among myeloid neoplasm cases, and 15% among controls. Though there were no clear patterns of associations between ever receiving a tattoo and risk of HL, NHL, or myeloid neoplasms overall, in analyses restricted to ages 20–60 years, ever receiving a tattoo (OR 2.06 [95% CI 1.01, 4.20]) and receiving a tattoo 10+ years prior (OR 2.64 [95% CI 1.23, 5.68]) were associated with an aggregated group of rarer mature B‐cell NHLs. We also observed elevated risks for a 10+ year latency for myelodysplastic syndromes and chronic myeloid leukemia (OR 1.48 [95% CI 0.40, 5.41], and OR 1.24 [95% CI 0.45, 3.43], respectively). Conclusions: Though estimates were imprecise, we found some suggestive evidence that tattooing may be associated with an increased risk of certain hematologic cancer subtypes. With an estimated 46% prevalence of tattooing in US individuals ages 30–49, additional studies are needed to understand the degree to which these exposures may be associated with hematologic cancer risk. [ABSTRACT FROM AUTHOR]

Background: Subsequent short‐latency leukemias are well‐described among survivors of childhood cancer. However, late (5–14.9 years from diagnosis, LL) and very late (≥15 years from diagnosis, VLL) subsequent leukemias have not been well studied. We assessed risk factors, prevalence, and outcomes for LL and VLL in the Childhood Cancer Survivor Study cohort. Methods: Subsequent leukemias, among 25,656 five‐year survivors, were self‐reported and confirmed by pathology review. Standardized incidence ratios (SIR) and cumulative incidences were calculated, and relative risks (RR) were estimated using Cox regression for exposures. Results: Seventy‐seven survivors developed subsequent leukemia, 49 survivors with LL (median time from diagnosis 7.8 years, range 5.0–14.5 years) and 28 with VLL (median time from diagnosis 25.4 years, range 15.9–42.8 years), with a cumulative incidence of 0.23% (95% CI 0.18%–0.30%) 20 years from diagnosis for all subsequent leukemias. The most common leukemia subtypes were acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia. Compared to the general population, survivors were at increased risk, for developing LL (SIR 9.3, 95% CI 7.0–12.1) and VLL (SIR 5.9, 95% CI 3.9–8.4). In multivariable relative risk analyses, cumulative epipodophyllotoxin dose >4000 mg/m2 was associated with increased risk for LL and VLL (RR 4.5, 95% CI 2.0–9.9). Conclusions: In this large series of late subsequent leukemias, survivors of childhood cancer are at increased risk, with no evidence of plateau over time. We observed most risk among survivors who received high cumulative doses of epipodophyllotoxins. Ongoing consideration for this late effect should continue beyond 10 years. [ABSTRACT FROM AUTHOR]

Ribavirin and its analogues exhibit an in vitro antiproliferative effect in cancer cells. In this work, we studied the biological activities of a number of alkyl/aryloxymethyl derivatives of ribavirin's aglycon—1,2,4-triazole-3-carboxamide. Alkyl/arylxymethyl derivatives of 1,2,4-triazole-3-carboxamide with substitutions at the fifth or first position of the triazole ring, were synthesized and their antiproliferative and antimicrobial effects were assessed. For both series, the presence of an antiproliferative effect was investigated, and 1-alkyl/aryloxymethyl derivatives were shown an antimicrobial potential against a Gram-positive bacteria Micrococcus luteus and Gram-negative bacterium Pseudomonas aeruginosa. The obtained results showed that the n-decyloxymethyl derivatives induced leukemia cell death at low micromolar concentrations. We confirmed that n-decyloxymethyl derivatives of ribavirin inhibited the cell cycle progression and induced an accumulation of leukemia cells in the subG1-phase. The molecular docking results suggest that alkyl/aryloxymethyl derivatives may act by inhibiting translation initiation, due to interference with eIF4E assembly. The outcome results revealed that active derivatives (1- or 5-n-decyloxymethyl-1,2,4-triazole-3-carboxamides) can be considered as a lead compound for anticancer treatments. [ABSTRACT FROM AUTHOR]

Patients with chronic myeloid leukemia (CML) respond to tyrosine kinase inhibitors (TKIs); however, CML leukemic stem cells (LSCs) exhibit BCR::ABL kinase-independent growth and are insensitive to TKIs, leading to disease relapse. To prevent this, new therapies targeting CML-LSCs are needed. Rates of mitochondria-mediated oxidative phosphorylation (OXPHOS) in CD34+CML cells within the primitive CML cell population are higher than those in normal undifferentiated hematopoietic cells; therefore, the inhibition of OXPHOS in CML-LSCs may be a potential cure for CML. NK-128 (C33H61NO5S) is a structurally simplified analog of JCI-20679, the design of which was based on annonaceous acetogenins. NK-128 exhibits antitumor activity against glioblastoma and human colon cancer cells by inhibiting OXPHOS and activating AMP-activated protein kinase (AMPK). Here, we demonstrate that NK-128 effectively suppresses the growth of CML cell lines and that the combination of imatinib and NK-128 is more potent than either alone in a CML xenograft mouse model. We also found that NK-128 inhibits colony formation by CD34+ CML cells isolated from the bone marrow of untreated CML patients. Taken together, these findings suggest that targeting OXPHOS is a beneficial approach to eliminating CML-LSCs, and may improve the treatment of CML. [ABSTRACT FROM AUTHOR]

Background: Chronic myeloid leukemia (CML) can manifest ocular complications stemming from hematologic irregularities or direct infiltration of neoplastic cells. This article details the case of a patient with newly diagnosed CML exhibiting elevated platelet counts (PLT) who developed panuveitis accompanied by retinal vascular occlusion. Case presentation: A 52-year-old woman experienced a notable decline in vision in her left eye over a 2-week period. Classical anterior uveitis, vitreous cavity opacity, optic nerve edema, and retinal vascular obstruction were observed. The right eye exhibited papilledema and retinal vein tortuosity. Despite admission, the condition of both eyes deteriorated, accompanied by a continuous increase in PLT. She was diagnosed with CML based on bone marrow biopsy and chromosomal examination. Following platelet apheresis therapy and chemotherapy, the condition of her right eye significantly improved, but the left eye's condition remained irreversible. Conclusions: This is a rare case of newly diagnosed CML presenting with diverse ocular manifestations in both eyes. The disparate outcomes in eyes with varying lesion stages underscore the importance of prompt diagnosis. [ABSTRACT FROM AUTHOR]

Introduction: Leukemic stem cells (LSCs) are the transcriptionally low/silent cells which are resistant to the tyrosine kinase inhibitor. These have been found to play a pivotal role in disease relapse in chronic myeloid leukemia (CML) cases. The present study evaluated the correlation of absolute CML‐LSC count in the peripheral blood (PB) at diagnosis and achievement of major molecular response (MMR) at 12 months in patients of CML‐CP. Methods: This was a prospective, observational, non‐interventional single center study including newly diagnosed adult (>18 yrs) CML‐CP patients. Absolute CD26 + CML‐LSC quantification was done by multiparametric flow cytometry. Patients were treated with Imatinib treatment and subsequently monitored at 3‐month intervals for BCR::ABL transcript levels. MMR was defined as a BCR::ABL1 transcript level of less than 0.1% on international scale. Results: A total of 89 patients were enrolled in the study out of which 40.5% achieved MMR at 12 months. There was a significant difference in the median absolute CML‐LSC count of the patients who achieved MMR at 12 months as compared to those who did not (58.5 vs 368.1 cells/μL; p value <0.001). Using a ROC analysis, a count of <165.69 CML LSC/μL was identified to have a sensitivity of 83.8% and specificity of 72.4%, in predicting the MMR at 12 months. Conclusion: Absolute CML‐LSC count at diagnosis in the PB predicts the MMR achievement at 12 months. An absolute count of less than 165 cells/μL is highly predictive of achieving MMR at 12 months. [ABSTRACT FROM AUTHOR]

Objective: We aimed to establish capsaicin as a potent natural chemotherapeutic agent in chronic myeloid leukemia by unveiling anti-cancer mechanisms, concentrating at pro-apoptotic and anti-proliferative effects on K562 cells. Methodology: After REC approval, this research proceeded with culturing K562 cells and treatment with serial concentrations of capsaicin for calculation of subsequent 50% Inhibitory Concentration (IC50) values via MTT [3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay, expression analysis of gene, comparative analysis of relative gene fold (intrinsic biomarkers caspase-3, caspase-9) as apoptosis mediator biomarkers followed by Quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR). Anti-proliferative activity was confirmed via Nitric Oxide (NO) releasing Assay. Results: For K562 cells, the IC50 of capsaicin (12.1 µM) showed high gene expression of intrinsic pro-apoptotic biomarkers caspase-3 and caspase-9 with the relative gene fold of 12.1 and 13.9 respectively. Persistent peaks of NO levels confirmed the anti-proliferative potential of the compounds. Strongest growth inhibitory activity was seen at the peak time of 100-120 min. Conclusion: Capsaicin proved to be a strong pro-apoptotic and anti-proliferative phytochemical agent leading to therapeutic effects against K562 cells. Further studies would help in identifying key molecular intricacies by which capsaicin exhibits diversified anti-cancer potential. [ABSTRACT FROM AUTHOR]

The document provides information on the Jahrestagung der Deutschen, Österreichischen und Schweizerischen Gesellschaften für Hämatologie und Medizinische Onkologie, taking place from October 11-14, 2024, in Basel. It includes abstracts, editor information, and a list of contributors. The content covers a wide range of topics related to oncology research and treatment, such as bone metastases, lymphomas, solid tumors, and supportive therapies. The document also addresses specific issues like COVID-19 and cancer, immunotherapy, and the use of artificial intelligence in medicine. [Extracted from the article]

Nilotinib, a tyrosine kinase inhibitor that targets the Abelson tyrosine kinase (c-Abl) signaling pathway, is FDA-approved to treat chronic myeloid leukemia. Nilotinib has properties indicative of a possible utility in neuroprotection that have prompted exploration of repurposing the drug for the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD). AD is a progressive age-related neurodegenerative disorder characterized by the deposition of extracellular amyloid-β plaques and intracellular neurofibrillary tangles. It is incurable and affects approximately 50 million patients worldwide. Nilotinib reduces c-Abl phosphorylation, amyloid-β levels, and dopaminergic neuron degeneration in preclinical AD models. This study explores the effects of nilotinib on amyloid processing and mitochondrial functioning in the SH-SY5Y human neuroblastoma cell line. SH-SY5Y cells were exposed to nilotinib (1, 5, and 10 µM). Real-time PCR and immunoblot analysis were performed to quantify the expression of genes pertaining to amyloid-β processing and neuronal health. Nilotinib did not significantly change APP, BACE1, or ADAM10 mRNA levels. However, BACE1 protein was significantly increased at 1 µM, and ADAM10 was increased at 10 µM nilotinib without affecting APP protein expression. Further, nilotinib treatment did not affect the expression of genes associated with neuronal health and mitochondrial functioning. Taken together, our findings do not support the efficacy of nilotinib treatment for neuroprotection. [ABSTRACT FROM AUTHOR]

Platelets are essential blood components that maintain hemostasis, prevent excessive bleeding, and facilitate wound healing. Reduced platelet counts are implicated in various diseases, including leukemia, hepatitis, cancer, and Alzheimer's disease. Enhancing megakaryocytic differentiation is a promising strategy to increase platelet production. Compound K (CK), a major bioactive metabolite of ginsenosides from Panax ginseng, has demonstrated anti-cancer and neuroprotective properties. In this study, we investigated the effects of CK on megakaryocytic differentiation and apoptosis in chronic myeloid leukemia (CML) cell lines K562 and Meg-01. CK treatment significantly upregulated the mRNA expression of key megakaryocytic differentiation markers, including CD61, CD41, and CD42a, and promoted the formation of large, multinucleated cells in K562 cells. Additionally, flow cytometry analysis revealed that CK at 5 µM induced apoptosis, a critical process in thrombocytopoiesis, in both K562 and Meg-01 cells. RT2 Profiler PCR array analysis further identified a marked increase in the expression of genes associated with the activation of the NLRP3 inflammasome in CK-treated K562 and Meg-01 cells. This study is the first to demonstrate that CK promotes megakaryocytic differentiation and apoptosis through the activation of the ERK/EGR1 and NLRP3 inflammasome pathways. These findings suggest that CK may enhance platelet production, indicating its potential as a therapeutic candidate for platelet-related disorders and other associated diseases. [ABSTRACT FROM AUTHOR]

Histone H1 is involved in the regulation of chromatin structure. Human somatic cells express up to seven subtypes. The variability in the proportions of somatic H1s (H1 complement) is one piece of evidence supporting their functional specificity. Alterations in the protein levels of different H1 subtypes have been observed in cancer, suggesting their potential as biomarkers and that they might play a role in disease development. We have developed a mass spectrometry-based (MS) parallel reaction monitoring (PRM) assay suitable for the quantification of H1 subtypes. Our PRM method is based on the quantification of unique peptides for each subtype, providing high specificity. Evaluation of the PRM performance on three human cell lines, HeLa, K562, and T47D, showed high reproducibility and sensitivity. Quantification values agreed with the electrophoretic and Western blot data, indicating the accuracy of the method. We used PRM to quantify the H1 complement in peripheral blood samples of healthy individuals and chronic myeloid leukemia (CML) patients. In CML, the first line of therapy is a tyrosine kinase inhibitor, imatinib. Our preliminary data revealed differences in the H1 complement in CML patients between imatinib responders and non-responders. These results support further research to determine if the H1 content or subtype composition could help predict imatinib response. [ABSTRACT FROM AUTHOR]

The primary treatment for chronic myeloid leukemia (CML) involves first- and second-generation tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, bosutinib, and dasatinib. However, these medications are ineffective against mutations in the kinase domain of the ABL1 protein, particularly in the protein with the T315I mutation. To address this, ponatinib (PNT), a third-generation inhibitor, was developed. Despite its efficacy in treating the BCR-ABL1T315I mutation, the use of PNT was briefly suspended in 2013 due to serious adverse effects but was subsequently reintroduced to the market. During the drug discovery and development process, it is rare to consolidate all information into a single article, as is the case with ponatinib. This review aims to compile and chronologically organize the research on the discovery of ponatinib using medicinal chemistry tools and computational methods. It includes in silico calculations, such as the octanol/water partition coefficient (cLogP) via SwissAdme, and 2D maps of intermolecular interactions through molecular docking. This approach enhances understanding for both specialists and those interested in medicinal chemistry and pharmacology, while also contextualizing future directions for further optimizations of ponatinib, facilitating the development of new analogs of this crucial inhibitor for the treatment of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). [ABSTRACT FROM AUTHOR]

In the field of chronic myeloid leukemia (CML), new strategies are needed to increase the rate of successful treatment discontinuations, a crucial goal in this disease. Anti-PD-L1 checkpoint inhibitors are a promising therapeutic approach in CML after the demonstration of an increase of these inhibitory molecules in patients with CML. A phase Ib/II (NCT04793399, registration date March 11, 2021) open-label exploratory trial has been conducted to evaluate the safety of atezolizumab, a humanized anti-PD-L1 antibody, in combination with bosutinib in patients with newly diagnosed chronic phase CML. A total of 36 patients were planned to be enrolled, but the study had to be prematurely terminated due to safety concerns. Nine patients were included in the study, and only 8 went on to receive the combination with atezolizumab. There were a total of 44 adverse events (AEs) during the study period. The most frequent were gastrointestinal (50%), mostly mild (86% grade 1–2). The most serious AEs were hepatic. There were 17 hepatic AEs in 5 patients. Of the hepatic AEs 5 were during the bosutinib monotherapy phase and 12 during the combination phase (AST increase x4, ALT increase x4, blood bilirubin increase x1, alkaline phosphatase elevation x2, GGT increase x2), most of them grade 3–4. There were 2 patients who presented a dose-limiting toxicity; a grade 3 elevation of transaminases, that led to premature termination of the study. The combination of atezolizumab with bosutinib presents hepatotoxicity as a dose-limiting effect and therefore we do not recommend to explore this combination in future studies. [ABSTRACT FROM AUTHOR]

Introduction: Chronic myeloid leukemia is characterized by the dysregulated growth of granulocytes, driven by the Philadelphia chromosome translocation. The prevalence of CML is higher in men, with a median age of 57 years and a five-year survival rate of 85%. Tyrosine kinase inhibitors such as Imatinib have revolutionized CML treatment. However, resistance or intolerance to first-line Imatinib requires second-generation TKIs like Nilotinib and Dasatinib. This study aims to evaluate the response of patients treated with these TKIs at a hematology clinic. Methods: This retrospective study analyzed 100 randomly selected CML patients treated between 2020 and 2022. Data were collected on patient demographics, disease progression, treatment regimens, and response rates. Patients who started on Imatinib and later switched to second-line TKIs due to resistance or side effects were followed to assess treatment efficacy. Results: The cohort had a median age of 43 years, with 52% males and 48% females. Most patients (95%) initiated treatment with Imatinib, with 6% experiencing mild side effects and 4% severe side effects leading to treatment changes. In patients resistant to Imatinib, second-generation TKIs showed favorable responses: Dasatinib was effective in patients with advanced disease, while Nilotinib was useful for those intolerant to Imatinib. One patient resistant to both was successfully treated with Bosutinib, a third-generation TKI. Conclusion: Our findings highlight the efficacy of secondgeneration TKIs for managing Imatinib-resistant CML. Dasatinib and Nilotinib effectively managed disease progression, though side effects were a concern. The use of third-generation TKIs like Bosutinib provides additional therapeutic options for refractory cases. [ABSTRACT FROM AUTHOR]

The oral cavity is a frequent site for head and neck cancers, which rank as the sixth most common cancer globally, with a 5-year survival rate slightly over 50%. Current treatments are limited, and resistance to therapy remains a significant clinical obstacle. IsCT1, a membrane-active peptide derived from the venom of the scorpion Opisthacanthus madagascariensis, has shown antitumor effects in various cancer cell lines, including breast cancer and chronic myeloid leukemia. However, its hemolytic action limits its potential therapeutic use. This study aims to assess the antitumor and antiproliferative activities of synthetic peptides derived from IsCT1 (IsCT-P, AC-AFPK-IsCT1, AFPK-IsCT1, AC-KKK-IsCT1, and KKK-IsCT1) in the context of oral squamous cell carcinoma. We evaluated the cytotoxic effects of these peptides on tongue squamous cell carcinoma cells and normal cells, as well as their impact on cell cycle phases, the expression of proliferation markers, modulators of cell death pathways, and mitochondrial potential. Our results indicate that the IsCT1 derivatives IsCT-P and AC-AFPK-IsCT1 possess cytotoxic properties towards squamous cell carcinoma cells, reducing mitochondrial membrane potential and the proliferative index. The treatment of cancer cells with AC-AFPK-IsCT1 led to a positive modulation of pro-apoptotic markers p53 and caspases 3 and 8, a decrease in PCNA and Cyclin D1 expression, and cell cycle arrest in the S phase. Notably, contrary to the parental IsCT1 peptide, AC-AFPK-IsCT1 did not exhibit hemolytic activity or cytotoxicity towards normal cells. Therefore, AC-AFPK-IsCT1 might be a viable therapeutic option for head and neck cancer treatment. [ABSTRACT FROM AUTHOR]

Summary Third‐generation tyrosine kinase inhibitors (TKIs) have much potential for the treatment of BCR::ABL1‐positive leukaemia, particularly that harbouring the ABL1 T315I mutation. Olverembatinib (HQP1351), a novel third‐generation TKI, has favourable efficacy and safety profiles in chronic myeloid leukaemia. Here, we present the clinical findings from 31 BCR::ABL1‐positive acute lymphoblastic leukaemia (ALL) patients who received olverembatinib. Among the 14 patients with overt relapsed/refractory (R/R) disease (including 10 with the T315I mutation), 71.4% achieved an overall response. Of the other 17 patients with minimal residual disease (MRD)‐positive ALL (including 14 with the T315I mutation), 60.0% and 47.1% achieved MRD flow negativity and complete molecular remission, respectively. With a median follow‐up time of 16.3 months, the median event‐free survival and overall survival were 3.9 and 8.3 months respectively, in overt R/R patients, and 11.5 and 18.4 months in MRD‐positive patients. Allogeneic haematopoietic stem cell transplantation further improved outcomes among responders. The safety profile was generally manageable. This study suggests that olverembatinib‐based therapy is another promising option for BCR::ABL1‐positive ALL in addition to ponatinib, especially for patients with MRD‐positive disease and a single T315I mutation. [ABSTRACT FROM AUTHOR]

Background: Ponatinib is a third‐generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with robust activity in Philadelphia chromosome–positive leukemias. Herein, we report the long‐term follow‐up of the phase 2 trial of ponatinib in chronic myeloid leukemia in chronic phase. Methods: Patients received ponatinib 30 to 45 mg/day. The primary end point was the rate of 6‐month complete cytogenetic response (CCyR). The study was held in June 2014 because of the risk of cardiovascular toxicity, requiring patients to change TKI. Results: Fifty‐one patients were treated with ponatinib (median dose, 45 mg/day). Median age was 48 years (range, 21–75); 30 (59%) had baseline cardiovascular comorbidities. Median treatment duration was 13 months (range, 2–25). Fourteen patients (28%) discontinued ponatinib because of toxicities, 36 (71%) after the Food and Drug Administration warning/study closure, and one for noncompliance. Dasatinib was the most frequently chosen second‐line TKI (n = 34; 66%). Among 46 patients evaluable at 6 months, 44 (96%) achieved CCyR, 37 (80%) major molecular response, 28 (61%) MR4, and 21 (46%) MR4.5. The cumulative 6‐month rates of CCyR, major molecular response, MR4, and MR4.5 were 96%, 78%, 50%, and 36%, respectively. Durable MR4 ≥24 or ≥60 months was observed in 67% and 51% of patients, respectively. The 24‐month event‐free survival rate was 97%. After a median follow‐up of 128 months, the 10‐year overall survival rate was 90%. Eight patients (16%) had serious grade 2 to 3 cardiovascular adverse events, leading to permanent discontinuation in five (10%). Conclusion: Ponatinib yielded high cytogenetic and molecular responses in newly diagnosed chronic myeloid leukemia in chronic phase. Its use in the frontline setting is hindered by arterio‐/vaso‐occlusive and other severe toxicities. Treatment with ponatinib in the frontline setting of chronic myeloid leukemia in chronic phase was associated with high molecular response rates, with 12‐month cumulative rates of major molecular response and MR4 of 82% and 72%, respectively. However, it was associated with an increased incidence of toxicity, in particular serious grade 2‐3 cardiovascular adverse events in 16% of the patients. [ABSTRACT FROM AUTHOR]