Chronic Myeloid Leukemia Patients Research Articles

CML in the very elderly: the impact of comorbidities and TKI selection in a real-life multicenter study

Tyrosine kinase inhibitors (TKIs) have greatly improved chronic myeloid leukemia (CML) treatments, with survival rates close to the general population. Yet, for the very elderly, robust data remains limited. This study focused on assessing comorbidities, treatment approaches, responses, and survival for elderly CML patients. Our study was conducted on 123 elderly (≥ 75 years) CML patients across four centers in Israel and Moffitt Cancer Center, USA. The median age at diagnosis was 79.1 years, with 44.7% being octogenarians. Comorbidities were very common; cardiovascular risk factors (60%), cardiovascular diseases (42%), with a median age-adjusted Charlson Comorbidity Index (aaCCI) of 5. Imatinib was the leading first-line therapy (69%), while the use of second-generation TKIs increased post-2010. Most patients achieved a major molecular response (MMR, 66.7%), and half achieved a deep molecular response (DMR, 50.4%). Over half (52.8%) of patients moved to second-line, and nearly a quarter (23.5%) to third-line treatments, primarily due to intolerance. Overall survival (OS) was notably longer in patients with an aaCCI score below 5, and in patients who attained DMR. Contrary to expectations, the Israeli cohort showed a shorter actual life expectancy than projected, suggesting a larger impact of CML on elderly survival. In summary, imatinib remains the main initial treatment, but second-generation TKIs are on the rise among elderly CML patients. Outcomes in elderly CML patients depend on comorbidities, TKI type, response, and age, underscoring the need for personalized therapy and additional research on TKI effectiveness and safety.

BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors.

BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors.

Variant-specific BCR::ABL1 quantification discrepancy in chronic myeloid leukemia.

Accurate quantification of the BCR::ABL1 fusion gene in whole blood is pivotal for the clinical management of chronic myeloid leukemia (CML) patients. The fusion protein encoded by BCR::ABL1 can vary in size, depending on the BCR and/or ABL1 gene breakpoint. The vast majority of CML patients have a p210 BCR::ABL1 fusion gene (M-BCR), which can be attributed to the presence of either e14a2 (b3a2) or e13a2 (b2a2) mRNA transcript junctions. Twenty-five CML samples were analyzed in two different ISO15189-accredited centers that both use an Europe Against Cancer-based quantitative polymerase chain reaction (qPCR) protocol. Reanalysis of the sample set with transcript-specific standard curves and digital droplet PCR (ddPCR) were performed. qPCR quantification revealed a significant (up to 1 log) difference specifically for the e13a2 transcript variant in contrast to e14a2 transcripts (Hodges-Lehman 4.29; p < 0.001). Reanalysis of the sample set with transcript-specific standard curves abolishes the initial transcript-specific difference (Hodges-Lehman 0.003; p = 0.8192). Comparison of transcript-specific qPCR results of both centers with ddPCR, an absolute quantification method, showed a statically significant association, especially in the lower range, indicating the clinical utility of transcript-specific or absolute quantification methods. Our data show that differences between transcript-specific quantification might exist between centers, leading to potential clinical impact on the follow-up of CML patients. The use of transcript-specific standard curves for qPCR quantification, or absolute quantification, can significantly reduce these differences. Specific attention should be applied to the interpretation of quantification differences of CML patients that switch between diagnostic centers.

Mutations in Genes Producing Nitric Oxide and Hydrogen Sulfide and Their Connection With Apoptotic Genes in Chronic Myeloid Leukemia.

Background Despite advances in chronic myeloid leukemia (CML) genetics, the role of nitric oxide (NO) and hydrogen sulfide (H2S) gene mutations and their relationship to apoptotic genes is unclear. Therefore, this study investigated NO- and H2S-producing genes' mutations and their interactions with apoptotic genes using Sanger sequencing and next-generation sequencing (NGS). Methodology A complete blood count (CBC) was carried out to measure the total number of white blood cells, while IL-6 levels were assessed in both control and CML patients using an ELISA technique.Sanger sequencing was used to analyzemutations in the CTH and NOS3 genes, whereas NGS was applied to examine mutations on all chromosomes. Results White blood cell (WBC) and granulocyte counts were significantly higher in CML patients compared to controls (p<0.0001), and monocyte counts were similarly higher (p<0.05). Interleukin-6 (IL-6) levels were significantly elevated in CML patients thancontrols (p<0.0001), indicating a possible link to CML etiology or progression. Multiple mutations have been identified in both genes, notably in CTH exon 12 and the NOS3genes VNTR, T786C, and G894T. This study also measured IL-6 concentrations using IL-6 assays, identifying its potential as a CML prognostic diagnostic. WBC counts, granulocyte counts, and mid-range absolute counts, or MID counts, were significantly higher in CML patients than in normal control individuals. NGS identified 1643 somatic and sex chromosomal abnormalities and 439 actively expressed genes in CML patients. The findings imply a genomic landscape beyond the BCR-ABL1 mutation in CML development compared to other databases. Conclusion In conclusion, this study advances the understanding of the genetic characteristics of CML by identifying mutations in the NO- and H2S-producing genes and their complex connections with genes involved in apoptosis. The comprehensive genetic profile obtained by Sanger sequencing and NGS provides possibilities for identifying novel targets for therapy and personalized treatments for CML, therefore contributing to developments in hematological diseases.

The treatment of patients with chronic myeloid leukemia chronic phase combined with myelofibrosis with tyrosine kinase inhibitors: A Chinese population-based study.

e18524 Background: Chronic myeloid leukemia (CML) is a type of hematological malignancy characterized by the excessive proliferation of myeloid cells. Studies have shown that the presence of MF in CML patients has been associated with TFR. Identifying and assessing MF in CML patients at the time of diagnosis can provide valuable information for treatment planning and prognostic evaluation. Methods: The study enrolled 1757 CML-CP patients with pathological results of bone marrow biopsy. Patients with incomplete information from laboratory tests and medical records were excluded. The study was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine and conducted in accordance with the Declaration of Helsinki. CML was diagnosed according to National Comprehensive Cancer Network (NCCN) 2023 version. Results: Patients with MF were found to be older (p&lt;0.001) and had higher leukocyte (p&lt;0.001) and platelet counts (p&lt;0.001). They were also more likely to experience anemia (p&lt;0.001), splenomegaly (p&lt;0.001), patients with myelofibrosis had a higher percentage of eosinophils (p&lt;0.001) and basophils (p&lt;0.001) and had a higher proportion of peripheral blood blast cells (p&lt;0.001) compared to patients without myelofibrosis. However, there was no significant difference in the male-to-female ratio between the two groups (p=0.690). Patients with MF were more unlikely to achieve certain treatment milestones, including a 3-month early molecular response (3M-EMR) (p&lt;0.001), 6-month BCR-ABLIS ≤ 1% (p&lt;0.001), and 12-month major molecular response (12M-MMR) (p&lt;0.001). The proportion of medium/high-risk patients, as determined by Sokal score (p&lt;0.001), Hasford score (p&lt;0.001), ELTS score (p&lt;0.001), and EUTOS score (p=0.002), was significantly increased in patients with MF (Table 1). Patients with MF had lower OS and PFS compared to patients without MF, indicating a potentially worse prognosis for those with MF. Patients with MF 10-year cumulative incidences of imatinib-therapy failure (p&lt;0.001). However, there was no statistically significant difference in the treatment failure rate with different second-generation TKIs (p=0.222). CML-CP patients with MF who were treated with different TKIs were found that second-generation TKIs were more likely to achieve a 3-month EMR(p=0.009), 6-month BCR-ABLIS ≤ 1% (p=0.019), and 12-month MMR(p=0.015) compared to imatinib. Conclusions: Based on the available data, the results suggest that MF is indeed a poor prognostic factor for patients with CML. This finding highlights the importance of considering MF as a factor in assessing the outlook for CML patients. These findings indicate that second-generation TKIs are more effective in achieving molecular responses compared to imatinib, particularly in the context of myelofibrosis.

Quantifying the financial impact of treatment intolerance in chronic myeloid leukemia on oncology clinical practices: A mixed methods study.

e18520 Background: Tyrosine kinase inhibitors (TKIs) have changed the prognosis for patients with chronic myeloid leukemia (CML) to a chronic disease. However, adverse events related to TKI treatment intolerance frequently occur. While the impact of CML treatment intolerance on patient quality of life and cost to health insurers has previously been measured, the time and cost impact to oncology practices is unknown. This mixed methods study aimed to estimate the average time and cost to oncology practices per CML treatment intolerance episode. Methods: The study combined interviews of oncology practice staff with economic modeling. A convenience sample of oncology practice managers was interviewed between October 2023 - January 2024. Interviews aimed to identify and quantify the cost dimensions of addressing treatment intolerance in CML patients. Time impacts reported by respondents were converted into monetary terms using hourly compensation rates of staff needed to complete the identified task. Results: A total of 10 academic oncology practice managers participated in the study. Eight cost dimensions were identified including time spent on prior authorization for medication switch, patient communication, follow-up visits, and care coordination after inpatient stays. Estimated practice time and cost per treatment intolerance episode requiring hospitalization were 34 hours and $3,413 (Table), which were largely attributable to navigating payer prior authorization for medication switch (10 hours, $871), additional follow-up visits (8 hours, $858) and care coordination with inpatient team (9 hours, $782). Activities that could be coded for reimbursement represented only 31.9% of incurred cost. The time and cost per treatment intolerance episode requiring no hospitalization were 17 hours and $1,772. Other burdens not explicitly quantified included negative impact on patient satisfaction, staff morale and care continuity. Conclusions: CML treatment intolerance imposes additional resource and economic burden on oncology practices, and most of these activities are not reimbursed in the current healthcare system. [Table: see text]

Frequency of comedication of proton pump inhibitors with crystalline dasatinib in chronic myeloid leukemia and effects on TKI-bioavailability.

6561 Background: Tyrosine kinase inhibitors (TKI), including dasatinib, have profoundly improved clinical outcome in chronic myeloid leukemia (CML). However, solubility, bioavailability and systematic exposure of the crystalline formulation of dasatinib (Sprycel) is reduced at higher gastric pH levels. This is problematic for comedication with acid reducing agents as lower bioavailability may reduce clinical response. Methods: We investigated proton pump inhibitor (PPI) and TKI comedication, including dasatinib, in a large real world CML cohort. Furthermore, we assessed the influence of timing of PPI comedication on the absorption and bioavailability of dasatinib. Results: Using the Swedish CML- and Prescribed Drug-Registries, we identified 1,328 chronic phase CML patients, diagnosed 2002-2018. 1,261 (95%) had received specified/known TKI treatment and 685 of those (54%) were prescribed a PPI (ATC-code: “A02BC”) at some point after CML diagnosis. TKIs and PPIs prescribed within 12 months of CML diagnosis were prescribed by different HCPs in 66% of cases (284/432). Of the 388 patients treated with dasatinib, 91 (23.5%) received a concomitant PPI. The PPI prescription rate increased to 53% (204/388) in the dasatinib cohort after dasatinib treatment had ended. Further, we assessed the drug-drug interaction (DDI) in 18 healthy volunteers given crystalline dasatinib (100mg) alone or together with omeprazole (40mg, at steady state) administered 9 hours apart; a time point when a high effect on bioavailability is expected. Compared to dosing with crystalline dasatinib alone, Cmax and AUC0-24 were reduced by 96% and 88% by omeprazole comedication (Table). Conclusions: Despite warnings, comedication with PPI is common among dasatinib treated CML patients. Further, an even larger proportion of patients need PPI co-treatment, which however, cannot fully be administered due to its negative impact on dasatinib pharmacokinetics. Moreover, with an optimized study design, we observed a higher than previously reported negative interaction of PPI comedication on crystalline dasatinib bioavailability. This may compromise clinical efficacy and risk CML disease progression. For patients in need of PPI, selection of a non-crystalline, less pH-sensitive formulation of dasatinib therefore appears more appropriate. Clinical trial information: NCT06145217 . [Table: see text]

ASC4REAL: Efficacy and tolerability comparison between ASCEMBL study, a phase 3 randomized clinical trial (RCT), and consolidated real-world (RW) experience with asciminib (ASC) in patients with CML beyond two TKIs.

e18519 Background: Despite advances in the management of chronic myeloid leukemia (CML), effective treatment options in later lines are limited. Treatment failure rates increase with each line of treatment and sequential tyrosine kinase inhibitor (TKI) therapy is associated with increased resistance. Importantly, almost all TKIs in the clinics target the ATP-binding site potentially resulting in off-target effects and long-term tolerability issues. Although data for ASC, a novel allosteric TKI targeting the myristoyl pocket, is emerging in the RW setting, low patient numbers in ASC RW studies hinders a robust comparison with the larger phase 3 RCT study. Methods: Post systematic literature search, data from 9 published or publicly presented RW studies was extracted. 319 CML patients that received ASC beyond 2 TKIs were included in this analysis. RW studies that had less than 10 patients were excluded. The results were then compared to estimates from the ASCEMBL study. Results: Compared to the RCT, RW studies showed similar or higher efficacy based on major molecular response (MMR) and deep molecular response (DMR) rates, achieved in shorter time. Rate of discontinuation of ASC was also lower in the RW setting. Similarly, some adverse events, specifically thrombocytopenia and arterial occlusive events (AOE) were lower, while some such as myalgia were higher in the RW setting when compared with the RCT. Conclusions: This analysis demonstrates ASC as an effective TKI for CML patients in the RW setting, supporting the results from the ASCEMBL RCT. [Table: see text]

Cardiovascular complications associated with asciminib use: A retrospective analysis.

6563 Background: Asciminib, a newly developed drug, has shown promising results in the treatment of several diseases. It is a cellular tyrosine kinase inhibitor (TKI) that specifically targets ABL myristoyl pocket (STAMP) inhibitor, responsible for the malignant growth and proliferation of leukemia cells in chronic myeloid leukemia (CML) patients, assuring a positive treatment of CML. However, as with all medications, there are possible side effects that must be carefully monitored. In comparison to Ponatinib (tyrosine kinase inhibitor) which is extensively used to treat CML and exhibits a cardiovascular risk profile, cardiovascular side effects with the use of Asciminib are rarely reported in literature, prompting its use in patients at a higher risk of these events. Through this study, we aim to highlight the cardiovascular complications associated with the use of Asciminib by integrating patient experience and clinical research. Methods: A publicly available FDA Adverse Events Reporting System (FAERS) database was utilized to review cardiovascular events associated with the use of Asciminib in patients with Chronic Myeloid leukemia (CML) between 2018-2023. Cardiovascular events such as coronary artery disease (CAD), peripheral arterial disease (PAD), and cerebrovascular accidents (CVA) were reviewed. The study focused only on adverse events reported by healthcare providers and observed in adults (above 18 years old). Results: We identified a total of 563 adverse events pertaining to the use of Asciminib in patients with CML. Of which, 63 were cardiovascular events, contributing to 11.2% of the total adverse events. Out of the reported cardiovascular side effects, 29 (46%) were due to CAD, 6 (9.5%) were due to PAD, and 28 (44.45%) were due to CVA. The mortality rate amongst patients who experienced cardiovascular side effects was 11%. Moreover, cardiovascular events contributed to 7% of all mortality associated with the use of Asciminib, with CAD contributing to most of the deaths. Conclusions: It is imperative to consider the potential of cardiovascular events in patients initiated on Asciminib. This study emphasizes the importance of using patient records and medical research to obtain complete information. Patients with underlying risk factors for the development of cardiovascular diseases should be thoroughly evaluated before drug initiation. The minimum threshold for drug discontinuation should be considered in patients with suspected heart disease.

EE507 Frontline TKI Strategies for Chronic Myeloid Leukemia Patients: Balancing Outcomes and Costs in Pursuit of Treatment-Free Remission and Dose Reduction

EE507 Frontline TKI Strategies for Chronic Myeloid Leukemia Patients: Balancing Outcomes and Costs in Pursuit of Treatment-Free Remission and Dose Reduction

Value of combining biological age with assessment of individual frailty to optimize management of cancer treated with targeted therapies: model of chronic myeloid leukemia treated with tyrosine kinase inhibitors (BIO-TIMER trial)

BackgroundIn the era of targeted therapies, the influence of aging on cancer management varies from one patient to another. Assessing individual frailty using geriatric tools has its limitations, and is not appropriate for all patients especially the youngest one. Thus, assessing the complementary value of a potential biomarker of individual aging is a promising field of investigation. The chronic myeloid leukemia model allows us to address this question with obvious advantages: longest experience in the use of tyrosine kinase inhibitors, standardization of therapeutic management and response with minimal residual disease and no effect on age-related diseases. Therefore, the aim of the BIO-TIMER study is to assess the biological age of chronic myeloid leukemia or non-malignant cells in patients treated with tyrosine kinase inhibitors and to determine its relevance, in association or not with individual frailty to optimize the personalised management of each patient.MethodsThe BIO-TIMER study is a multi-center, prospective, longitudinal study aiming to evaluate the value of combining biological age determination by DNA methylation profile with individual frailty assessment to personalize the management of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Blood samples will be collected at diagnosis, 3 months and 12 months after treatment initiation. Individual frailty and quality of life will be assess at diagnosis, 6 months after treatment initiation, and then annually for 3 years. Tolerance to tyrosine kinase inhibitors will also be assessed during the 3-year follow-up. The study plans to recruit 321 patients and recruitment started in November 2023.DiscussionThe assessment of individual frailty should make it possible to personalize the treatment and care of patients. The BIO-TIMER study will provide new data on the role of aging in the management of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors, which could influence clinical decision-making.Trial registrationClinicalTrials.gov, ID NCT06130787; registered on November 14, 2023.

An association between Dasatinib, elevated left atrial pressure and pleural effusion

BackgroundTyrosine kinase inhibitors (TKI), such as Dasatinib, are effective in the treatment of chronic myeloid leukemia (CML) but associated with development of pleural effusions (PE). The relationship between haemodynamic parameters identified on transthoracic echocardiogram (TTE) such as elevated estimated left atrial pressure (LAP), and PE development is unknown. This study aims to describe associations between Dasatinib, elevated LAP and PE. MethodsThis was a retrospective study of 71 CML patients who underwent TTE during treatment with various TKIs. Descriptive analysis was performed to identify associations between TKI use, PE and elevated LAP on TTE. Multivariate logistic regression was performed to identify predictors of elevated LAP. ResultsThere were 36 patients treated with Dasatinib, 15 Nilotinib, and 20 Imatinib. Those treated with Dasatinib had higher rates of elevated LAP (44% vs 7% Nilotinib vs 10% Imatinib, p < 0.01) and PE (39% vs 7% vs 0%, p < 0.01). In the 15 patients who developed PE, 14 (93%) patients were treated with Dasatinib. Patients with PE had higher rates of elevated LAP (67% vs 16%, p < 0.01). Nineteen (26.8%) patients in the entire cohort had elevated LAP. After multivariate adjustment, Dasatinib (OR 33.50, 95% CI = 4.99–224.73, p < 0.01) and age (OR 1.12, 95% CI = 1.04–1.20, p < 0.01) were associated with elevated LAP. ConclusionsAmong patients with CML, there was an association between Dasatinib use, PE and elevated LAP on TTE. These findings are hypothesis generating and further studies are required to evaluate the utility of elevated LAP on TTE as a novel marker for prediction and surveillance of PE.

Technical challenges for standardization of molecular monitoring in chronic myeloid leukaemia in developing countries

Quantification of BCR-ABL after treatment with tyrosine kinase inhibitors is an important therapeutic indicator for patients with chronic myeloid leukaemia (CML). An international scale (IS) for BCR-ABL was established in 2012 to improve the comparability of results between different laboratories. BCR-ABL measurement is technically challenging, especially in developing countries where the process of standardization isn’t easily available. The aim of this study was to assess the technical advantages of reporting results on the IS using the GeneXpert BCR-ABL assay, compared to the RQ-PCR standard method currently recommended by the European Leukaemia Network but not standardised in our laboratory and to compare the results obtained by both methods. BCR-ABL transcript quantification was performed in 51 samples from CML patients by both methods. The operator hands-on time was reduced using the automated method. A good linear correlation was observed in the results between the two methods. The concordance at logarithmic intervals reached 64%. When the major molecular response (MMR) and the early molecular response (EMR) were analysed, 90% and 80% agreement, respectively, were achieved. However, the discordances in the remaining cases could have misled the therapeutic approach if only a standard method was used. The complexity of the process to establish a laboratory-specific conversion factor in developing countries can be overcome by the use of the GeneXpert automated system, which represents a rapid, accurate and reliable clinical tool to correctly define molecular responses on the IS and to allow clinicians to achieve better patient management.

Real World Outcomes with Treatment Free Remission in Chronic Myeloid Leukemia-Experience from a Tertiary Care Cancer Centre.

Chronic myeloid leukaemia (CML) is caused by balanced translocation t(9::22)(q34;q11) resulting in formation of pathogenic BCR-ABL fusion gene. Tyrosine kinase inhibitors (TKI) have revolutionised the treatment of CML. Ongoing treatment with TKI leads to side effects and has financial impact. Teratogenic potential of TKI and growth disturbance also represent an important challenge. Thus, TKI discontinuation in form of treatment free remission (TFR) has emerged as a new and important therapeutic goal. In this retrospective study, we reviewed CML patients who were kept on TFR. Inclusion criteria was patient age ≥ 18years diagnosed with CML in chronic phase who met the criteria for TFR and opted for same and who were in DMR but stopped TKI for any reason. We analysed the data for baseline characteristics, molecular relapse (MR), survival without molecular relapse (SWMR), TFR duration and factors affecting MR. We included 38 patients in this analysis. Thirty five (92%) patients were treated with imatinib at diagnosis. Median duration of TKI treatment was 135months. 37 patients (97.5%) achieved DMR on TKI and median time from TKI initiation to DMR was 96months. Median duration of DMR prior to TKI discontinuation was 41months. TKI was discontinued after counselling for TFR in 26 patients (68%) while it was discontinued due to intolerance in 10 patients (29%). At median molecular follow up of 25months, nine patients (23.7%) had molecular relapse. Median SWMR was not reached and 2year estimated SWMR was 65.2% (95%CI,47.2- 83.2). Of all relapses, 5/9 (55.5%) occurred in the first six months of TFR. On univariate analysis, duration of TKI and duration of DMR were predictive of molecular relapse. On multivariate analysis, none of these factors were found to be significant. This retrospective study suggests that for CML CP patients achieving deep molecular response, discontinuing TKI therapy in real-world settings may be feasible while potentially achieving comparable outcomes.

Kinetics of BCR::ABL1 transcript levels and molecular relapse after tyrosine kinase inhibitors discontinuation in chronic myeloid leukemia patients: preliminary results from the DES-CML study.

Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of patients with chronic myeloid leukemia. Patients who achieve sustained deep molecular response are eligible for treatment discontinuation. DES-CML is an ongoing, phase 2 multicentric discontinuation trial. Adult patients with CML in chronic phase with typical BCR::ABL1 transcripts, stable deep molecular response (MR4.5 IS) for two years, and no previous resistance were eligible. Patients underwent a phase of TKI dose de-escalation for six months before discontinuation. TKI was reintroduced at the previous dose if the patient lost major molecular response (MMR) at any time. This study aimed to assess the impact of BCR-ABL transcript kinetics during TKI de-escalation and discontinuation phases on treatment-free survival. So far, the study recruited 41 patients, and 38 patients discontinued therapy (4 were in the second discontinuation attempt). Eleven patients lost MMR, one during the de-escalation phase and ten after discontinuation. 24-month treatment-free survival was 66% (95% CI: 48-84%) in a median follow-up of 7 (1-30) months. No patient lost hematological response or had disease progression. A higher rate of molecular relapses occurred in patients with fluctuating BCR::ABL1 levels after the discontinuation phase (with loss of MR4.5, but no loss of MMR) (P=0.04, HR-4.86 (1.03-22.9) but not confirmed in the multivariate analysis. The longer duration of TKI treatment (P=0.03, HR-1.02, 95%CI - 1.00-1.04) and MMR (P=0.004, HR-0.95, 95%CI - 0.92-098) were independent factors of a lower relapse rate.

Combination of an aurora kinase inhibitor and the ABL tyrosine kinase inhibitor asciminib against ABL inhibitor-resistant CML cells

The development of BCR::ABL1-targeting tyrosine kinase inhibitors (TKIs) has improved the prognosis of patients with chronic myeloid leukemia (CML). However, resistance to ABL TKIs can develop in CML patients due to BCR::ABL1 point mutations and CML leukemia stem cell (LSC). Aurora kinases are essential kinases for cell division and regulate mitosis, especially the process of chromosomal segregation. Aurora kinase members also promote cancer cell survival and proliferation. This study analyzed whether aurora kinases were regulated in the progression of CML. It also evaluated the efficacy of the ABL TKI asciminib and the aurora kinase inhibitor LY3295668. The expressions of AURKA and AURKB were higher in the CML cells compared with normal cells using a public database (GSE100026). Asciminib or LY3295668 alone inhibited CML cells after 72 h, and cellular cytotoxicity was increased. The combined use of Asciminib and LY3295668 increased superior efficacy compared with either drug alone. Colony formation was reduced by cotreatment with asciminib and LY3295668. In the cell-cycle analyses, LY3295668 induced G2/M arrest. Cell populations in the sub-G1 phase were observed when cotreating with asciminib and LY3295668. The combination treatment also changed the mitochondrial membrane potential. In addition, AURKA shRNA transfectant cells had increased asciminib sensitivity. Combining asciminib and aurora kinase inhibition enhanced the efficacy and is proposed as a new therapeutic option for patients with CML. These findings have clinical implications for a potential novel therapeutic strategy for CML patients.

Prognostic and predictive implications of Sokal scoring system in newly diagnosed Chronic Myeloid Leukemia patients

Objective: To assess the predictive utility of the Sokal scoring system for determining disease prognosis in newly diagnosed patients with chronic myeloid leukemia (CML). Methodology: This comparative cross-sectional study was conducted at the Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from September 2021 to September 2022. The study included all newly diagnosed Philadelphia-positive chronic myeloid leukemia (CML) patients. Patients with CML in the accelerated and blast phases, as well as those with atypical CML, were excluded. Gender was considered as a qualitative variable of interest, while platelet count, spleen size, age, and percentage of myeloblasts in the peripheral blood were the quantitative variables of interest. These variables were documented using preformed data sheets, and the prognostic class of each patient was recorded. Follow-up assessments were conducted after 3 months for patients who received the same tyrosine kinase inhibitor (TKI) therapy to avoid bias. Results: A total of 62 patients were included in the study, with a mean age of 46±5 years. According to the Sokal scoring system, 20 (32%) of 62 patients were classified as low-risk, 34 (54.8%) as intermediate-risk, and 8 (12.9%) as high-risk. Conclusion: The routine implication of traditional prognostic scoring systems, such as the Sokal score, is beneficial for stratifying CML patients into different risk groups due to its cost-effectiveness. Regression in Sokal score grades was observed after 3 months of TKI therapy.

Association between plasma imatinib levels and response to treatment of chronic myeloid leukemia in patients from Manaus, Brazil.

Imatinib mesylate (IM) is the drug of choice for the treatment of chronic myeloid leukemia (CML). However, despite most of the results obtained with this therapy being positive, some patients still present a suboptimal therapeutic response or still develop some type of resistance. Therefore, the aim of this study was to evaluate IM plasma levels in CML patients treated at a referral unit in Manaus and correlate them with variables that might interfere with these levels. Data from 52 patients were obtained through a standardized questionnaire containing clinical, sociodemographic, lifestyle, and use of other medication information, as well as an estimate of therapeutic adherence. Additionally, blood collection was performed to measure the plasma concentration of the drug using the HPLC-UV technique. Molecular studies were done to identify the presence of polymorphism in the ABCG2 C421A membrane transporter. Most patients were male with a mean age of 52 ± 12.3 years (95% CI 49.0-55.9). There was a high variation in drug concentrations in the range from 0 to 4694 ng/mL, with a mean of 1558.59 ± 989.79 ng/mL (95% CI 1283.0-1834.1). Approximately two-thirds of patients were classified in the drug-level range considered therapeutic, and there was a correlation between plasma concentration and higher molecular response. Additionally, most individuals had the normal genotype for the ABCG2 C421A polymorphism but further studies should be performed to reveal the role of this variable in the outcome of the disease in this population.

Antileukemic potential of methylated indolequinone MAC681 through immunogenic necroptosis and PARP1 degradation

BackgroundDespite advancements in chronic myeloid leukemia (CML) therapy with tyrosine kinase inhibitors (TKIs), resistance and intolerance remain significant challenges. Leukemia stem cells (LSCs) and TKI-resistant cells rely on altered mitochondrial metabolism and oxidative phosphorylation. Targeting rewired energy metabolism and inducing non-apoptotic cell death, along with the release of damage-associated molecular patterns (DAMPs), can enhance therapeutic strategies and immunogenic therapies against CML and prevent the emergence of TKI-resistant cells and LSC persistence.MethodsTranscriptomic analysis was conducted using datasets of CML patients' stem cells and healthy cells. DNA damage was evaluated by fluorescent microscopy and flow cytometry. Cell death was assessed by trypan blue exclusion test, fluorescent microscopy, flow cytometry, colony formation assay, and in vivo Zebrafish xenografts. Energy metabolism was determined by measuring NAD+ and NADH levels, ATP production rate by Seahorse analyzer, and intracellular ATP content. Mitochondrial fitness was estimated by measurements of mitochondrial membrane potential, ROS, and calcium accumulation by flow cytometry, and morphology was visualized by TEM. Bioinformatic analysis, real-time qPCR, western blotting, chemical reaction prediction, and molecular docking were utilized to identify the drug target. The immunogenic potential was assessed by high mobility group box (HMGB)1 ELISA assay, luciferase-based extracellular ATP assay, ectopic calreticulin expression by flow cytometry, and validated by phagocytosis assay, and in vivo vaccination assay using syngeneic C57BL/6 mice.ResultsTranscriptomic analysis identified metabolic alterations and DNA repair deficiency signatures in CML patients. CML patients exhibited enrichment in immune system, DNA repair, and metabolic pathways. The gene signature associated with BRCA mutated tumors was enriched in CML datasets, suggesting a deficiency in double-strand break repair pathways. Additionally, poly(ADP-ribose) polymerase (PARP)1 was significantly upregulated in CML patients’ stem cells compared to healthy counterparts. Consistent with the CML patient DNA repair signature, treatment with the methylated indolequinone MAC681 induced DNA damage, mitochondrial dysfunction, calcium homeostasis disruption, metabolic catastrophe, and necroptotic-like cell death. In parallel, MAC681 led to PARP1 degradation that was prevented by 3-aminobenzamide. MAC681-treated myeloid leukemia cells released DAMPs and demonstrated the potential to generate an immunogenic vaccine in C57BL/6 mice. MAC681 and asciminib exhibited synergistic effects in killing both imatinib-sensitive and -resistant CML, opening new therapeutic opportunities.ConclusionsOverall, increasing the tumor mutational burden by PARP1 degradation and mitochondrial deregulation makes CML suitable for immunotherapy.

Myocardial Infarction in Chronic Myeloid Leukemia: Results from the Nationwide Readmission Database

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.