Chronic Myeloid Leukemia Research Articles

Health-related quality of life and symptoms of chronic myeloid leukemia patients after discontinuation of tyrosine kinase inhibitors: results from the EURO-SKI Trial.

Limited data is available on the health-related quality of life (HRQoL) and symptoms of patients with chronic myeloid leukemia (CML) who are in treatment-free remission (TFR). We herein report HRQoL results from the EURO-SKI trial. Patients who had been on tyrosine kinase inhibitors (TKIs) therapy for at least 3 years and achieved MR4 for at least 1 year were enrolled from 11 European countries, and the EORTC QLQ-C30 and the FACIT-Fatigue questionnaires were used to assess HRQoL and fatigue respectively. Patients were categorized into the following age groups: 18-39, 40-59, 60-69 and ≥70 years. Of 728 patients evaluated at baseline, 686 (94%) completed HRQoL assessments. The median age at TKI discontinuation was 60 years. Our findings indicate that HRQoL and symptom trajectories may vary depending on specific age groups, with younger patients benefiting the most. Improvements in patients aged 60 years or older were marginal across several HRQoL and symptom domains. At the time of considering TKI discontinuation, physicians could inform younger patients that they may expect valuable HRQoL benefits. Considering the marginal improvements observed in patients aged 60 years or above, it may be important to further investigate the value of TFR compared to a lowest effective dose approach in this older group of patients.

CRISPR-based rapid molecular diagnostic tests for fusion-driven leukemias

AbstractFusion oncogenes can be cancer-defining molecular alterations that are essential for diagnosis and therapy selection.1,2 Rapid and accessible molecular diagnostics for fusion-driven leukemias such as acute promyelocytic leukemia (APL), Philadelphia chromosome–positive acute lymphoblastic leukemia, and chronic myeloid leukemia (CML) are unavailable, creating a barrier to timely diagnosis and effective targeted therapy in many health care settings, including community hospitals and low-resource environments. We developed CRISPR-based RNA-fusion transcript detection assays using SHERLOCK (specific high-sensitivity enzymatic reporter unlocking) for the diagnosis of fusion-driven leukemias. We validated these assays using diagnostic samples from patients with APL and CML from academic centers and dried blood spots from low-resource environments, demonstrating 100% sensitivity and specificity. We identified assay optimizations to enable the use of these tests outside of tertiary cancer centers and clinical laboratories, enhancing the potential impact of this technology. Rapid point-of-care diagnostics can improve outcomes for patients with cancer by expanding access to therapies for highly treatable diseases that would otherwise lead to serious adverse outcomes due to delayed or missed diagnoses.

Nilotinib vs dasatinib in achieving MR4.5 for de novo chronic myeloid leukemia: the randomized JALSG CML212 study

AbstractDeep molecular response (DMR) is a prerequite for treatment-free remission (TFR) in chronic myeloid leukemia in chronic phase (CML-CP). The JALSG (Japan Adult Leukemia Study Group) conducted a prospective randomized phase 3 CML212 study for de novo CML-CP to compare the cumulative achievement of molecular response 4.5 (MR4.5; international scale BCR::ABL1 ≤0.0032%) by 18 months between nilotinib and dasatinib treatment as a primary end point. A total of 454 patients were randomly assigned to the 300 mg nilotinib twice daily arm or to the 100 mg dasatinib daily arm (both n = 227). BCR::ABL1 messenger RNA levels were monitored every 3 months. Study treatment was stopped if the patients were judged as failure according to the European LekemiaNet 2009 criteria or showed intolerance. The cumulative achievement rates of MR4.5 by 18 months were 32.6% (95% confidence interval [CI], 26.5-39.1) in the nilotinib arm and 30.8% (95% CI, 24.9-37.3) in the dasatinib arm with no significant difference (P = .66). The cumulative achievement rates of early molecular response, complete cytogenetic response, and major molecular response by 12, 18, 24, and 36 months were almost the same between the 2 arms. There was no significant difference in progression-free survival (PFS) or overall survival (OS) between the 2 arms by log-rank tests (PFS, P = .58; OS, P = .64). These results suggest that nilotinib and dasatinib would be equally effective for patients with de novo CML-CP. This trial was registered in the University Hospital Medical Information Network Clinical Trials Registry as #UMIN000007909.

Clinical Validation of the Somatic FANCD2 Mutation (c.2022-5C>T) as a Novel Molecular Biomarker for Early Disease Progression in Chronic Myeloid Leukemia: A Case-Control Study.

Background: Chronic myeloid leukemia (CML) results from chromosomal translocation t(9;22) leading to the formation of the BCR-ABL fusion oncogene. CML has three stages: the chronic phase (CP), the accelerated phase (AP), and the blast crisis (BC). Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML. TKIs work well in CP-CML, and these patients have a survival rate similar to the normal population, but TKIs are less effective in advanced-phase CML. Even with current advances in treatment, BC-CML patients have an average overall survival of less than a year. Early recognition of CML patients at risk of disease progression can help in timely interventions with appropriate TKIs or other therapeutic modalities. Although some markers of disease progression like BCR-ABL kinase domain, ASXL1, and GATA2 mutations are available, no universal and exclusively specific molecular biomarkers exist to early diagnose CML patients at risk of CML progression for timely therapeutic interventions to delay or minimize blast crisis transformation in CML. A recent study found that all BC-CML patients harbored the FANCD2 (c.2022-5C>T) mutation. Therefore, the current study was designed to detect this FANCD2 mutant in AP-CML (early progression phase) and to clinically validate its potential as a novel molecular biomarker of early CML progression from CP to AP. Methods: Our study comprised 123 CP-CML (control group) and 60 AP-CML patients (experimental group) from 2 oncology centers, from January 2020 to July 2023. Mean hemoglobin level, WBC count, platelet count, treatment type, hepatomegaly, splenomegaly, and survival status of AP-CML patients were significantly different from those of CP-CML patients. However, as these clinical parameters cannot help in the early detection of patients at risk of CML progression, there was a need for a clinically validated biomarker of AP-CML. DNA was extracted from the patients' blood samples, and the FANCD2 gene was sequenced using an Illumina NextSeq500 next-generation sequencer (NGS). Results: The NGS analysis revealed a unique splice-site mutation in the FANCD2 gene (c.2022-5C>T). This mutation was detected in the majority (98.3%) of AP-CML patients but in none of the CP-CML patients or healthy control sequences from genomic databases. The mutation was confirmed by Sanger sequencing. FANCD2 is a member of the Fanconi anemia pathway genes involved in DNA repair and genomic stability, and aberrations of this gene are associated with many cancers. Conclusions: In conclusion, our study shows that the somatic FANCD2 (c.2022-5C>T) mutation is a new molecular biomarker for early CML progression. We recommend further clinical validation of this biomarker in prospective clinical trials.

<i>De novo</i> design and virtual screening of potential Bcr-Abl tyrosine kinase inhibitors using deep learning and molecular modeling technologies

De novo design and virtual screening of small-molecule compounds with a high potential inhibitory activity against the Bcr-Abl tyrosine kinase playing a key role in the pathogenesis of chronic myeloid leukemia (CML) were carried out by an integrated computational approach including technologies of deep learning and molecular modeling. As a result, according to the calculation data we identified 5 compounds exhibiting low values of binding free energy to the enzyme comparable with those predicted for imatinib, nilotinib and ponatinib, anticancer drugs widely used in the clinic to treat patients with CML. It was shown that these compounds are able to form stable complexes with the ATP-binding sites of the Bcr-Abl tyrosine kinase and its mutant form T315I, which is confirmed by the analysis of the profiles of binding affinity and intermolecular interactions responsible for their energy stabilization. Based on the obtained data, these compounds, which have been generated by the deep learning neural network, are assumed to form promising basic structures for development of new effective drugs for treatment of patients with CML.

Imatinib Mesylate Causes Potential Cardiac Dysfunction in Patients With Chronic Myeloid Leukemia: the Results of a Case-control Study.

Unlike second-generation tyrosine kinase inhibitors, effects of imatinib on the cardiovascular (CV) system are debatable. The current case-control study aimed to evaluate the CV effects of imatinib in patients with chronic myeloid leukemia (CML) using non-invasive 2D-echocardiography testing. Patients with CML ≥ 13 years attending the adult haematology clinic of a tertiary care hospital in north India were prospectively enrolled over 1.5 years. The study population (n = 110) consisted of 35 newly diagnosed patients (treatment-naïve group) and 75 patients under imatinib therapy ≥ 1 year (treated group). All the eligible patients were subjected to 2D-echocardiography to calculate pulmonary artery systolic pressure (PASP), left ventricular ejection fraction (LVEF) and deceleration time (DT). These parameters were compared between the two groups. P-value < 0.05 was considered statistically significant. The median age of study population was 40 years (range, 13-73) and M:F ratio was 1.14:1. Both the groups had similar demographics at the diagnosis including CV risk factors. The median PASP of the treated group was 2 mm Hg higher than the treatment-naïve group (25 vs 23 mm Hg, p-value = 0.919). The median LVEF of the treated group was 3.2% lower than the treatment-naïve group (58.5% vs 61.72%, p-value = 0.577). The median DT of the treated group was 7 ms shorter than treatment-naïve group (211 vs 204 ms, p-value = 0.411). Imatinib causes potential cardiac dysfunction in patients with CML. Large scale prospective follow-up trials in the same cohort of patients are needed to validate the findings of our study.

Perspectives on Drug Development for the Treatment of Chronic Myeloid Leukemia in Pregnant Patients and Patients Who Are Breastfeeding.

Tyrosine kinase inhibitors (TKI) have improved the outcome and life expectancy of patients with chronic myeloid leukemia (CML). Patients are diagnosed with CML at younger ages, and patients treated for CML may become pregnant or choose to breastfeed. The information available to date on the safety of TKIs during pregnancy and lactation and the optimal management of these patients is largely anecdotal, based on personal or small-group experience, and heterogeneous. A panel of interested parties was convened by U.S. Food and Drug Administration to analyze the current data and discuss possible solutions. Possible solutions include prospective data collection, in clinical trials and in routine clinical practice, a more uniform and specific data collection, and greater coordination among involved entities. As patients with cancer are living longer, frequently receiving therapies for extended periods of time (or for life), data on appropriate management of patients through different reproductive phases of life are needed. It is thus time to change our approach for how to study treatment of cancer (including CML) during pregnancy or breastfeeding to develop evidence-based guidelines for safe and effective patient care.

Enhanced Antitumor Activity by the Combination of Dasatinib and Selinexor in Chronic Myeloid Leukemia.

Chronic myeloid leukemia is a hematological malignancy characterized by the abnormal proliferation of leukemic cells. Despite significant progress with tyrosine kinase inhibitors, such as Dasatinib, resistance remains a challenge. The aim of the present study was to investigate the potential of Selinexor, an Exportin-1 inhibitor, to improve TKI effectiveness on CML. Human CML cell lines (LAMA84 and K562) were treated with Selinexor, Dasatinib, or their combination. Apoptosis, mitochondrial membrane potential, and mitochondrial mass were assessed using flow cytometry. Real-time RT-PCR was used to evaluate the expression of genes related to mitochondrial function. Western blot and confocal microscopy examined PINK and heme oxygenase-1 (HO-1) protein levels. Selinexor induced apoptosis and mitochondrial depolarization in CML cell lines, reducing cell viability. The Dasatinib/Selinexor combination further enhanced cytotoxicity, modified mitochondrial fitness, and downregulated HO-1 nuclear translocation, which has been associated with drug resistance in different models. In conclusion, this study suggests that Dasatinib/Selinexor could be a promising therapeutic strategy for CML, providing new insights for new targeted therapies.

The therapeutic and biomarker significance of ferroptosis in chronic myeloid leukemia.

The relationship between ferroptosis and the progression and treatment of hematological tumors has been extensively studied, although its precise association with chronic myeloid leukemia (CML) remains uncertain. Multi-transcriptome sequencing data were utilized to analyze the ferroptosis level of CML samples and its correlation with the tumor microenvironment, disease progression, and treatment response. Machine learning algorithms were employed to identify diagnostic ferroptosis-related genes (FRGs). The consensus clustering algorithm was applied to identify ferroptosis-related molecular subtypes. Clinical samples were collected for sequencing to validate the results obtained from bioinformatics analysis. Cell experiments were conducted to investigate the therapeutic efficacy of induced ferroptosis in drug-resistant CML. Ferroptosis scores were significantly lower in samples from patients with CML compared to normal samples, and these scores further decreased with disease progression and non-response to treatment. Most FRGs were downregulated in CML samples. A high ferroptosis score was also associated with greater immunosuppression and increased activity of metabolic pathways. Through support vector machine recursive feature elimination (SVM-RFE), least absolute shrinkage selection operator (LASSO), and random forest (RF) algorithms, we identified five FRGs (ACSL6, SLC11A2, HMOX1, SLC38A1, AKR1C3) that have high diagnostic value. The clinical diagnostic value of these five FRGs and their effectiveness in differentiating CML from other hematological malignancies were validated using additional validation cohorts and our real-world cohort. There are significant differences in immune landscape, chemosensitivity, and immunotherapy responsiveness between the two ferroptosis-related molecular subtypes. By conducting cellular experiments, we confirmed that CML-resistant cells are more sensitive to induction of ferroptosis and can enhance the sensitivity of imatinib treatment. Our study unveils the molecular signature of ferroptosis in samples from patients with CML. FRG identified by a variety of machine learning algorithms has reliable clinical diagnostic value. Furthermore, the characterization of different ferroptosis-related molecular subtypes provides valuable insights into individual patient characteristics and can guide clinical treatment strategies. Targeting and inducing ferroptosis holds great promise as a therapeutic approach for drug-resistant CML.

BTK acts as a modulator of the response to imatinib in chronic myeloid leukemia.

The use of tyrosine kinase inhibitors, such as imatinib, against the chronic myeloid leukemia (CML)-causing kinase BCR::ABL1 has become the model for successful targeted therapy. Nevertheless, drug resistance remains a clinical problem. Analysis of genome-wide expression and genetic aberrations of an in vitro imatinib-resistant CML cell line revealed downregulation of Bruton's tyrosine kinase (BTK), predominantly associated with B cell malignancies, and a novel BTK kinase domain variant in imatinib resistance. This raised the question of the role of BTK in imatinib-resistant CML. In the present study, BTK downregulation and the presence of the BTK variant c.1699_1700delinsAG p.(Glu567Arg) were confirmed in imatinib resistance in vitro. Similarly, BTK inhibition or small interfering RNA-mediated BTK knockdown reduced imatinib susceptibility by 84 and 71%, respectively. BTK overexpression was detrimental to CML cells, as proliferation was significantly reduced by 20.5% under imatinib treatment. In addition, BTK rescue in imatinib-resistant cells restored imatinib sensitivity. The presence of the BTK p.(Glu567Arg) variant increased cell numbers (57%) and proliferation (37%) under imatinib exposure. These data demonstrate that BTK is important for the development of imatinib resistance in CML: Its presence increased drug response, while its absence promotes imatinib resistance. Moreover, the BTK p.(Glu567Arg) variant abrogates imatinib sensitivity. These findings demonstrate a context-dependent role for BTK as an oncogene in B cell malignancies, but as a tumor suppressor in other neoplasms.

Treatment-free remission after third-line therapy with asciminib in chronic myeloid leukemia with an atypical e19a2 BCR::ABL1 transcript and T315I mutation

Treatment-free remission after third-line therapy with asciminib in chronic myeloid leukemia with an atypical e19a2 BCR::ABL1 transcript and T315I mutation

Long-term dynamics of epidemiological characteristics of some chronic leukemia and lymphoma in Moscow before, during and after the pandemic of the new coronavirus infection COVID-19. Epidemiologic study

Background. The COVID-19 pandemic, which swept the world in 2020–2021, had a significant impact on the epidemiological picture of hematological malignancies. Aim. To study the dynamics of epidemiological indicators of five chronic hemoblastoses in Moscow over a 12-year period, and also to assess the impact of the COVID-19 pandemic on these indicators. Materials and methods. A population-based study was conducted for five types of oncohematological diseases: multiple myeloma, Hodgkin's lymphoma, follicular lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia. The annual rates of morbidity, mortality, prevalence of these nosologies, overall survival, and expected overall survival were calculated. Gender and age characteristics for each disease were determined. Results and discussion. The present study showed a uniform increase in the incidence and prevalence of five hematological malignancies between 2012 and 2019. Convincing evidence of an increase in mortality and a decrease in the number of diagnosed cases in comparison with the expected figures for these hematological malignancies in 2020–2021 was presented. A greater reduction was shown for cases diagnosed at early stages compared to later ones. During the pandemic, a significant increase in mortality was recorded among patients with chronic lymphocytic leukemia and multiple myeloma, while in cohorts of patients with chronic myeloid leukemia and Hodgkin lymphoma it increased slightly. The return of morbidity, mortality and prevalence rates to the original dynamics in 2022–2023 has been demonstrated. Conclusion. This study demonstrated the features of the regional pattern of incidence, mortality, prevalence and gender-age characteristics of five hematological malignancies and provided the changes in the indicators dynamics of different hematological malignancies during the COVID-19 pandemic.

Patched Homolog Gene (PTCHI) as a Reliable Marker for Predicting Imatinib Response in Chronic Phase Chronic Myeloid Leukemia Patients in Correlation with Early Response to First Line of Treatment Imatinib

Abstract Background Chronic myeloid leukaemia BCR-ABL1 + (CML) is a clonal disorder of a pluripotent stem cell. The disease accounts for around 15% of leukaemias and may occur at any age. The diagnosis of CML is rarely difficult and is assisted by the characteristic presence of the Philadelphia (Ph) chromosome. This results from the t (9;22) (q34; q11) translocation between chromosomes 9 and 22, as a result of which part of the oncogene ABL1 is moved to the BCR gene on chromosome 22. and part of chromosome 22 moves to chromosome 9. The abnormal chromosome 22 is the Ph chromosome. Aim of the Work To measure the level of PTCH1 in newly diagnosed CP-CML and to find correlation between the level of PTCH1in those patients and response to first line of treatment; imatinib and other prognostic factors Patients and Methods In our study there are 50 patients newly diagnosed cml recruited from hematology out patients clinic in ain shams university within duration august 2021 –april 2022.We have measured level of PTCH1 protein in newly diagnosed CP-CML and its follow up after 6months Results the studies show that 25% of patients discontinue imatinib due to lack of efficacy. A few years ago, two second-generation tyrosine kinase inhibitors (TKIs), Dasatinib and Nilotinib, were approved for first-line treatment, increasing the options available for patients diagnosed with CP- CML.Currently, the best way to adjust treatment to fit the severity of the disease is by assessing the response at different milestones. One milestone is the BCR-ABL1/ABL1 transcript level at 3 months; a level &amp;gt;10% 3 months after starting treatment has been related to a worse subsequent imatinib response. However, whether a change in therapy is warranted based on this single determination is controversial. Conclusion Patched homolog 1 gene (PTCH1) is marker for predicting first line of treatment imatinib response in chronic myeloid leukemia patients in chronic phase in correlation with response to imatinib. It is detected by PCR and proved to be a reliable marker to detect early imatinib response in chronic myeloid leukemia patients in chronic phase. In our study, we measured level of (PTCH1) in chronic myeloid leukemia patients in chronic phase using ELISA as a cost benefit in comparison to PCR in newly diagnosed cml patients on first line of treatment imatinib then follow up after 6 months. We found that it is a reliable marker, sensitive and specific to detect imatinib response.

P-423 Fertility outcomes of an egg donation program for hematologic cancer survivors: an 11-year retrospective cohort study

Abstract Study question What is the effectiveness of IVF/intracytoplasmic sperm injection with egg donation (IVF/ICSI-ED) in hematological cancer survivors (HCS) with reproductive desire and iatrogenic ovarian failure (IOF)? Summary answer The probability of clinical pregnancy and having a live birth does not significantly differ between women treated for hematological cancer and non-oncological patients using IVF/ICSI-ED. What is known already The most common hematological malignancies in women before or during reproductive age are lymphoma and leukemia. Oncological therapies cause premature ovarian failure, uterine fibrosis and infertility. Fertility preservation measures are not always possible or advisable. Egg vitrification in post-pubertal women has temporary implications as it requires ovarian stimulation; cryopreservation of ovarian tissue carries the risk of introducing back malignant cells. Fertility preservation is performed in 4-20% of cases: only 5% of patients have the chance to consult a reproductive specialist before cancer treatment. There are no published comparative studies on the effectiveness of ED in hematologic cancer survivors. Study design, size, duration We conducted a retrospective cohort study of 47 HCS with IOF, all of them nulliparous and without infertility diagnosis nor fertility preservation prior to oncological treatment and compared them with a control group (CG) of 19 infertile non-oncologic patients who underwent IVF/ICSI-ED with eggs from the same donors obtained during the same period of time (2012-2022). After evaluation by the center’s Oncofertility Committee, 45 HCS were eligible for IVF/ICSI-ED, and 23 agreed to undergo treatment. Participants/materials, setting, methods On the 47 patients HCS group we studied all the oncologic information: mean age at cancer diagnosis, mean age at IVF/ICS-ED treatment, type of tumor and oncologic treatment received. We compared the 23 patients HCS group with the 19 patients CG for: mean age of the egg recipient, mean age of the egg donor, single embryo transfers performed per patient, pregnancy and life bith rate per IVF/ICSI-ED treatment. We used chi-square statistic for the comparison. Main results and the role of chance The 47 women HCS group was aged between 25 to 50 years. The mean age at cancer diagnosis was 25.9 ± 7.6 years. The most frequent neoplasms were Hodgkin lymphoma (46.8%), non-Hodgkin lymphoma (21.2%), acute myeloid leukemia (12.7%), chronic myeloid leukemia (10.6%), other leukemias (8.5%). Lymphomas (68%) predominated over leukemias (32%). In this group 95.8% of the HCS were treated with chemotherapy: 21.2% as monotherapy, 14.8% combined with radiotherapy, 6.3% with surgery, and 6.3% with tyrosine kinase inhibitors (TKIs). Bone marrow transplantation was required in 46.8% of cases. At least 5 years elapsed from diagnosis to evaluation by the Oncology Committee. The mean egg recipient age was 36.5 ± 4.9 years for the HCS group and 41.3 ± 2.6 years for the CG (p &amp;lt; 0.05); there were no significant differences in the egg donor’s mean age (26.5±4.5 Vs 26.1±4.9, p=ns). We found no significant differences between the HCS and the CG in the mean single embryo transfers performed per patient (1.7 Vs 1.9, p=ns), in the pregnancy rate per ED cycle (88.4% vs 89.4%, p=ns), nor in the live birth rate per ED cycle (73% vs 64%, p=ns). Limitations, reasons for caution The retrospective nature of the study, the small number of cases and the under-recording of data in the medical history are the main limitations of this study. Wider implications of the findings It is important to have a comprehensive understanding of cancer therapies on fertility so that both doctors and patients can make informed decisions. Fertility preservation methods must be proposed before initiating oncological treatment, so multidisciplinary teamwork and timely referral to reproductive medicine centers specialized in fertility preservation are recommended. Trial registration number Not applicable

P-364 Impact on fertility outcomes in survivors after hematopoietic stem cell transplantation for benign and malignant hematologic disorders: a systematic review and meta-analysis

Abstract Study question What is the prevalence of infertility after hematopoietic stem cell transplantation (HSCT) in females and males up to the age of 1 year? Summary answer The overall prevalence of infertility (95% CI) in women treated with HSTC is 64% (0.58-0.70) and in men 39% (0.31-0.47). What is known already HSCT is a well-established treatment that has significantly increased survival in haematological malignancies and also benign diseases since its introduction in the 1980s. The use of high-dose chemotherapy and radiotherapy, myeloablative conditioning, combined with HSCT exposes serious long-term complications, including gonadal dysfunction and infertility. The risk of ovarian and testicular damage seems to be very high. Therefore, the European Society for Blood and Marrow Transplantation (EBMT) had recommended in 2015 to consider fertility preservation measures in children and adolescents requiring HSCT. However, the data on which this recommendation was based was limited and heterogeneous. Study design, size, duration The systematic review and meta-analysis is part of the FertiTOX project (www.fertitox.com) which aims to close the gap of data regarding gonadotoxicity of cancer therapies to enable more accurate counselling regarding fertility preservation. A systematic literature search was conducted in Medline, Embase and Cochrane in November 2023, considering papers published since 2000. Participants/materials, setting, methods A total of 1632 records were identified for abstract screening. Only females and males without recurrent disease and follow up of more than one year were considered. For the systematic review, 68 studies fulfilled the criteria. For the meta-analysis, studies with &amp;lt; 10 patients were excluded. Infertility was defined in females as very low AMH, hypergonadotropic hypogonadism, amenorrhoea and/or need for hormone replacement therapy and in males as low inhibin B and/or azoospermia. Main results and the role of chance In total, 68 out of 1632 studies were included in the final analysis. Malignant diseases were mainly acute myeloid / lymphoblastic leukemia, chronic myeloid leukemia/ lymphocytic leukemia and non-hodgkin’s and hodgkin’s lymphoma. Benign diseases were sickle cell disease, Fanconi anaemia, and β-thalassemia major. In the meta-analysis, 56 studies were included, comprising 1853 female malignant cases, 241 female benign cases, 1871 male malignant cases, and 226 male benign cases. The analysis, employing a random-effects model for estimating prevalence and its 95% confidence interval, revealed that the overall pooled prevalence of infertility exceeded 30% in all groups. The prevalence of infertility was highest in female malignant cases (65%, 95% CI: 0.58-0.71). In women with benign diseases it was 61% (95% CI: 0.48-0.73). In males with malignant diseases it reached 41% (95% CI: 0.32 to 0.51) and with benign diseases 31% (95% CI: 0.19 to 0.46). Heterogeneity of data was high as shown by female as shown by the malignant cases of 83% and benign cases of 65% in women and the malignant cases of 91% and benign cases of 74% in males. Limitations, reasons for caution The heterogeneity of the included studies due to treatment variations and diverse characteristics of the study populations with large age ranges, did not allow further subgroup analyses. Thus, an individual and reliable fertility prognosis is still difficult to give. Wider implications of the findings The results of this meta-analysis support the clinical necessity of fertility preservation counselling in females and males undergoing HSCT treatment. Further prospective studies addressing the individual impact of the HSCT treatment on gonadal function are needed Trial registration number The study protocol was registered at the international Prospective Register of Systematic Reviews, PROSPERO (Registry number CRD42023486928).

Evaluation of mortality among Marines, Navy personnel, and civilian workers exposed to contaminated drinking water at USMC base Camp Lejeune: a cohort study

BackgroundDrinking water at U.S. Marine Corps Base (MCB) Camp Lejeune, North Carolina was contaminated with trichloroethylene and other industrial solvents from 1953 to 1985.MethodsA cohort mortality study was conducted of Marines/Navy personnel who, between 1975 and 1985, began service and were stationed at Camp Lejeune (N = 159,128) or MCB Camp Pendleton, California (N = 168,406), and civilian workers employed at Camp Lejeune (N = 7,332) or Camp Pendleton (N = 6,677) between October 1972 and December 1985. Camp Pendleton’s drinking water was not contaminated with industrial solvents. Mortality follow-up was between 1979 and 2018. Proportional hazards regression was used to calculate adjusted hazard ratios (aHRs) comparing mortality rates between Camp Lejeune and Camp Pendleton cohorts. The ratio of upper and lower 95% confidence interval (CI) limits, or CIR, was used to evaluate the precision of aHRs. The study focused on underlying causes of death with aHRs ≥ 1.20 and CIRs ≤ 3.ResultsDeaths among Camp Lejeune and Camp Pendleton Marines/Navy personnel totaled 19,250 and 21,134, respectively. Deaths among Camp Lejeune and Camp Pendleton civilian workers totaled 3,055 and 3,280, respectively. Compared to Camp Pendleton Marines/Navy personnel, Camp Lejeune had aHRs ≥ 1.20 with CIRs ≤ 3 for cancers of the kidney (aHR = 1.21, 95% CI: 0.95, 1.54), esophagus (aHR = 1.24, 95% CI: 1.00, 1.54) and female breast (aHR = 1.20, 95% CI: 0.73, 1.98). Causes of death with aHRs ≥ 1.20 and CIR > 3, included Parkinson disease, myelodysplastic syndrome and cancers of the testes, cervix and ovary. Compared to Camp Pendleton civilian workers, Camp Lejeune had aHRs ≥ 1.20 with CIRs ≤ 3 for chronic kidney disease (aHR = 1.88, 95% CI: 1.13, 3.11) and Parkinson disease (aHR = 1.21, 95% CI: 0.72, 2.04). Female breast cancer had an aHR of 1.19 (95% CI: 0.76, 1.88), and aHRs ≥ 1.20 with CIRs > 3 were observed for kidney and pharyngeal cancers, melanoma, Hodgkin lymphoma, and chronic myeloid leukemia. Quantitative bias analyses indicated that confounding due to smoking and alcohol consumption would not appreciably impact the findings.ConclusionMarines/Navy personnel and civilian workers likely exposed to contaminated drinking water at Camp Lejeune had increased hazard ratios for several causes of death compared to Camp Pendleton.

A Quality by Design (QbD) driven gradient high performance liquid chromatography method development for the simultaneous estimation of dasatinib and nilotinib in lipid nanocarriers

Tyrosine kinase inhibitors (TKIs) are effective as a targeted treatment for chronic myeloid leukemia (CML), which can selectively suppress BCR-ABL1 kinase activity. CML therapy with TKIs combination has been supported by in-vitro, in-vivo, and patient-based data where the nilotinib-dasatinib co-administration has exerted superior anticancer efficacy with greater cellular uptake, less resistance to chemotherapy, and no additive adverse events encountered. Therefore, it is essential to develop a suitable analytical method for the simultaneous estimation of these drugs in the developed novel lipid nanocarriers like liposomes. Design of Experiment (DoE) has been implemented as a tool of QbD to systematically investigate the relation between the HPLC method attributes and analytical responses, i.e., chromatographic detection, quantification, and peak properties for dasatinib and nilotinib. An Ishikawa diagram is constructed to delineate possible influencing variables to the analytical performances. Afterward, 4 factors 2 level full factorial design (FFD) was employed to model and identify the main effects and interaction effects between the factors selected after the initial risk assessment. The suggested design space for optimized chromatographic conditions by QbD analysis is linear within the selected range of drug concentrations, accurate and precise, sensitive, and robust according to the ICH guidelines. The optimal method is comprised of a 1 mL/min flow rate of mobile phase (ACN and 20 mM KH2PO4 of pH 7.00) in gradient mode at 25 °C column temperature for 20 μL sample injection volume and detection wavelength fixed at 297 nm. Most importantly, this novel HPLC method is simple and selective enough to evaluate dasatinib and nilotinib content in the lipid nanocarriers.

MiR-15a targets the HSP90 co-chaperone Morgana in chronic myeloid leukemia

Morgana is a ubiquitous HSP90 co-chaperone protein coded by the CHORDC1 gene. Morgana heterozygous mice develop with age a myeloid malignancy resembling human atypical myeloid leukemia (aCML), now renamed MDS/MPN with neutrophilia. Patients affected by this pathology exhibit low Morgana levels in the bone marrow (BM), suggesting that Morgana downregulation plays a causative role in the human malignancy. A decrease in Morgana expression levels is also evident in the BM of a subgroup of Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) patients showing resistance or an incomplete response to imatinib. Despite the relevance of these data, the mechanism through which Morgana expression is downregulated in patients’ bone marrow remains unclear. In this study, we investigated the possibility that Morgana expression is regulated by miRNAs and we demonstrated that Morgana is under the control of four miRNAs (miR-15a/b and miR-26a/b) and that miR-15a may account for Morgana downregulation in CML patients.

S1P Signaling Genes as Prominent Drivers of BCR-ABL1-Independent Imatinib Resistance and Six Herbal Compounds as Potential Drugs for Chronic Myeloid Leukemia.

Imatinib (IM), a breakthrough in chronic myeloid leukemia (CML) treatment, is accompanied by discontinuation challenges owing to drug intolerance. Although BCR-ABL1 mutation is a key cause of CML resistance, understanding mechanisms independent of BCR-ABL1 is also important. This study investigated the sphingosine-1-phosphate (S1P) signaling-associated genes (SphK1 and S1PRs) and their role in BCR-ABL1-independent resistant CML, an area currently lacking investigation. Through comprehensive transcriptomic analysis of IM-sensitive and IM-resistant CML groups, we identified the differentially expressed genes and found a notable upregulation of SphK1, S1PR2, and S1PR5 in IM-resistant CML. Functional annotation revealed their roles in critical cellular processes such as proliferation and GPCR activity. Their network analysis uncovered significant clusters, emphasizing the interconnectedness of the S1P signaling genes. Further, we identified interactors such as BIRC3, TRAF6, and SRC genes, with potential implications for IM resistance. Additionally, receiver operator characteristic curve analysis suggested these genes' potential as biomarkers for predicting IM resistance. Network pharmacology analysis identified six herbal compounds-ampelopsin, ellagic acid, colchicine, epigallocatechin-3-gallate, cucurbitacin B, and evodin-as potential drug candidates targeting the S1P signaling genes. In summary, this study contributes to efforts to better understand the molecular mechanisms underlying BCR-ABL1-independent CML resistance. Moreover, the S1P signaling genes are promising therapeutic targets and plausible new innovation avenues to combat IM resistance in cancer clinical care in the future.

Subclinical Hypothyroidism Following Imatinib Use in Nigerian BCR::ABL1-positive Chronic Myeloid Leukemia Patients: A Prospective Cohort Study

Abstract BACKGROUND: Thyroid toxicity has been reported with tyrosine kinase inhibitors (TKIs) such as sunitinib and sorafenib, targeting angiogenic tyrosine kinase receptors. However, the effect of imatinib, a first-line TKI for chronic myeloid leukemia (CML) patients on the thyroid, has been inconclusive. Of note, imatinib remains the mainstay of treatment for BCR::ABL1-positive Nigerian CML patients. AIM: We evaluated the effect of imatinib mesylate on the thyroid and its function in BCR::ABL1 positive CML patients and assessed the effect of the continuous imatinib use on thyroid features. PATIENTS AND METHODS: This prospective cohort study included 50 imatinib-naive patients with BCR::ABL1-positive CML and 50 age- and sex-matched apparently normal controls without any underlying thyroid disorder or on any thyroid medication. Serum free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH) were measured at baseline for both the CML patients and the controls and were repeated at 1, 3, and 6 months for the CML patients while on imatinib therapy. RESULTS: Subclinical hypothyroidism was observed in 7 of 50 (14%) of the patients with CML at 6 months on imatinib. Six of these patients were female, while 1 was male. The mean values for the serum fT3 (pmol/L), serum fT4 (pmol/L), and TSH (μIU/mL) for the CML subjects versus controls were 4.22 ± 0.79 versus 4.31 ± 0.31 (t = −0.27 P = 0.532), 17.13 ± 2.49 vs. 16.39 ± 2.16 (t = 1.605 P = 0.112), and 1.58 ± 0.74 versus 1.63 ± 0.64 (t = −0.399 P = 0.691), respectively. CONCLUSION: This study confirmed subclinical hypothyroidism as an adverse effect of continuous imatinib use with a prevalence of 14% in Nigerian CML patients.