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CML

(Chronic Myeloid Leukemia)

Relevant Articles About Chronic Myeloid Leukemia (CML)
Cancer Research and Clinical Trials

RELATED :ALL (Acute Lymphoblastic Leukemia):AML (Acute Myeloid Leukemia):CLL (Chronic Lymphocytic Leukemia)

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CML (Chronic Myeloid Leukemia)BosutinibImatinibCompletedArgentinaBelgiumBrazilCanadaChileChinaColombiaFranceGermanyHong KongHungaryIndiaItalyJapanKorea, Republic ofLatviaLithuaniaMexicoPolandRussian FederationSingaporeSouth AfricaSpainTaiwanThailandTurkeyUkraineUnited KingdomUnited States10NCT00574873Phase 3
Compare Bosutinib To Imatinib In Subjects With Newly Diagnosed Chronic Phase Philadelphia Chromosome Positive CML

Compare Bosutinib To Imatinib In Subjects With Newly Diagnosed Chronic Phase Philadelphia Chromosome Positive CML

CML (Chronic Myeloid Leukemia)AsciminibBosutinibActiveNot RecruitingArgentinaAustraliaBrazilBulgariaCanadaCzechiaFranceGermanyHungaryIsraelItalyJapanKorea, Republic ofLebanonMexicoNetherlandsRomaniaRussian FederationSaudi ArabiaSerbiaSpainSwitzerlandTurkeyUnited KingdomUnited States 8NCT03106779 Phase 3
Study of Efficacy of CML-CP Patients Treated With ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs

Study of Efficacy of CML-CP Patients Treated With ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs

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Lymphomas and Leukemias Cancer Cells
Lymphoma

ac4C RNA Modification and Epigenetic Therapies in DLBCL

KEY TAKEAWAYS The study aimed to investigate NAT10's role and mechanisms in DLBCL using clinical samples and various assays. The results showed the essential role of ac4C RNA modification mediated by NAT10 in DLBCL and provided insights into novel epigenetic-based...

Jul 5, 2024

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Cancer Cell Cycle Control: Integrating Gene Regulation and Therapy

KEY TAKEAWAYS

  • The study aimed to understand how drug effects relate to cancer cell diversity to find effective combination therapies.
  • The results revealed insights into gene regulation and support sequential WEE1 and low-toxicity pre-BCR inhibitor therapy.

Targeted therapies that exploit cancer cell vulnerabilities show promise for improving patient outcomes and reducing chemotherapy side effects. However, the efficacy of precision therapies is partly limited by tumor cell heterogeneity. Understanding how drug effects are linked to the diversity of cancer cell states is crucial for identifying effective combination therapies to prevent disease recurrence.

Alena Malyukova and the team aimed to understand how G2/M checkpoint inhibition affects cell fate in acute lymphoblastic leukemia (ALL) to improve combination therapies.

Researchers characterized the effect of G2/M checkpoint inhibition in ALL, demonstrating that WEE1 targeted therapy affects cell fate decision regulatory circuits. They observed the highest inhibition of proliferation recovery in ALL cells with KMT2A rearrangements. Using single-cell RNA-seq and ATAC-seq on RS4, 11 cells harboring KMT2A::AFF1 were treated with the WEE1 inhibitor AZD1775, and they found a diversification of cell states.

A fraction of cells showed strong activation of p53-driven processes linked to apoptosis and senescence and disruption of a core KMT2A-RUNX1-MYC regulatory network. In this WEE1 inhibition-induced cell state diversification, some cells transitioned to a drug-tolerant state, characterized by activation of transcription factors regulating pre-B cell fate, lipid metabolism, and pre-BCR signaling in a reversible manner. Sequential treatment with BCR-signaling inhibitors dasatinib or ibrutinib, or metabolism perturbation by fatostatin or AZD2014, effectively countered drug tolerance by inducing cell death and repressing stemness markers.

The study concluded that gene regulatory programs associated with cell cycle and cell fate regulation are tightly connected. It provides a rationale for the sequential administration of WEE1 inhibitors with low-toxicity inhibitors of pre-BCR signaling or metabolism.

No funding information was available.

Source: https://pubmed.ncbi.nlm.nih.gov/38822412/

Malyukova A, Lahnalampi M, Falqués-Costa T, et al. (2024). “Sequential drug treatment targeting cell cycle and cell fate regulatory programs blocks non-genetic cancer evolution in acute lymphoblastic leukemia.” Genome Biol. 2024 May 31;25(1):143. doi: 10.1186/s13059-024-03260-4. PMID: 38822412; PMCID: PMC11143599.

Ibrutinib Induces Atrial Arrhythmia via PI3K Pathway

KEY TAKEAWAYS

  • The study aimed to understand the precise mechanism behind ibrutinib-induced atrial fibrillation in patients with CLL.
  • The results revealed that the ibrutinib’s off-target effect on PI3K-AKT-mTOR causes connexin degradation, promoting autophagy and atrial arrhythmia.

Ibrutinib has been associated with an increased risk of atrial fibrillation (AF) in patients with chronic lymphocytic leukemia (CLL). However, the precise mechanism behind this effect is not yet fully understood.

Huiyuan Qin and the team aimed to determine the incidence of new-onset atrial fibrillation (AF) in patients with CLL receiving ibrutinib and elucidate its underlying mechanism.

Researchers investigated the prevalence of new-onset AF in patients with CLL undergoing treatment with ibrutinib. They utilized optical mapping to elucidate the proarrhythmic effects of ibrutinib on HL-1 cells.

Furthermore, fluorescence staining and western blot analysis were employed to compare the expression levels of connexins 43 and 40 between the ibrutinib-treated group and the control group. To characterize autophagy phenotypes, they utilized western blotting to assess the levels of autophagy-related proteins.

The study employed transmission electron microscopy (TEM) to visualize autophagosomes and used a transfected mCherry-GFP-LC3 virus to label autophagosomes and lysosomes. Additionally, hydroxychloroquine, an autophagy inhibitor, was administered to counteract ibrutinib-induced degradation of Cx43 and Cx40.

About 2.67% of patients experienced atrial arrhythmias following the administration of ibrutinib. HL-1 cells subjected to ibrutinib treatment displayed decreased conduction velocity and a heightened occurrence of reentry-like arrhythmias compared to the control group.

Furthermore, the expression of connexins 43 and 40 was reduced, accompanied by an increase in autophagy markers in HL-1 cells treated with ibrutinib. The inhibition of autophagy led to the upregulation of connexins 43 and 40.

The off-target impact of ibrutinib on the PI3K-AKT-mTOR signaling pathway resulted in the degradation of connexins and the onset of atrial arrhythmia by inducing autophagy.

Funding was provided by the National Nature Science Foundation of China.

Source: https://pubmed.ncbi.nlm.nih.gov/38812314/

Qin H, Zheng B, Lin Z, et al. (2024). “Ibrutinib Contributes to Atrial Arrhythmia through the Autophagic Degradation of Connexins by Inhibiting the PI3K-AKT-mTOR Signaling Pathway.” Front Biosci (Landmark Ed). 2024 May 22;29(5):201. doi: 10.31083/j.fbl2905201. PMID: 38812314.

Real-World CLL/SLL Treatment Trends and Healthcare Costs

KEY TAKEAWAYS

  • The study aimed to investigate the real-world treatment patterns, healthcare resource utilization, and economic burden of patients with CLL or SLL in the US.
  • Researchers noticed a significant shift in targeted therapies in CLL treatment and the significant economic burden on patients with CLL/SLL.

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia among US adults and has experienced a rapidly evolving treatment landscape. Yet, current data on treatment patterns in clinical practice and economic burden are limited.

Xiaoqin Yang and the team aimed to provide an up-to-date description of real-world characteristics, treatments, and costs of patients with CLL or small lymphocytic lymphoma (SLL).

They performed an inclusive analysis utilizing retrospective data from the Optum Clinformatics DataMart database (January 2013 to December 2021). Adults with diagnosis codes for CLL/SLL on two different dates were selected, and an adapted algorithm identified lines of therapy (LOT). Treatment patterns were stratified by the index year pre- and post-2018. Healthcare resource utilization and costs were evaluated per patient-years.

About 18,418 patients with CLL/SLL were identified. Of these, 5,226 patients (28%) received treatment with at least 1 line of therapy (LOT), while 1,728 patients (9%) received treatment with at least two LOT. Among patients diagnosed with CLL between 2014 and 2017 and receiving at least one LOT (N = 2,585), 42% utilized targeted therapy, and 30% utilized chemoimmunotherapy in the first line (1L).

In contrast, among patients diagnosed with CLL between 2018 and 2021 (N = 2,641), these proportions rose to 54% and 16%, respectively. Total costs were approximately 3.5 times higher and 4.9 times higher compared to baseline costs among patients treated with 1L+ and 3L+, respectively.

The study concluded that there has been a notable real-world change in the CLL treatment landscape, with targeted therapies being increasingly utilized as first-line treatments, comprising more than half of first-line regimens in recent years (2018-2021). Additionally, the study highlighted the substantial economic burden faced by patients with CLL/SLL.

This study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Source: https://pubmed.ncbi.nlm.nih.gov/38280190/

Yang X, Zanardo E, Lejeune D, et al. (2024). “Treatment Patterns, Healthcare Resource Utilization, and Costs of Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma in the US.” Oncologist. 2024 Mar 4;29(3):e360-e371. doi: 10.1093/oncolo/oyad324. PMID: 38280190; PMCID: PMC10911928.

Ibrutinib Induces Atrial Arrhythmia via PI3K Pathway

Ibrutinib Induces Atrial Arrhythmia via PI3K Pathway

KEY TAKEAWAYS

  • The study aimed to understand the precise mechanism behind ibrutinib-induced atrial fibrillation in patients with CLL.
  • The results revealed that the ibrutinib’s off-target effect on PI3K-AKT-mTOR causes connexin degradation, promoting autophagy and atrial arrhythmia.

Ibrutinib has been associated with an increased risk of atrial fibrillation (AF) in patients with chronic lymphocytic leukemia (CLL). However, the precise mechanism behind this effect is not yet fully understood.

Huiyuan Qin and the team aimed to determine the incidence of new-onset atrial fibrillation (AF) in patients with CLL receiving ibrutinib and elucidate its underlying mechanism.

Researchers investigated the prevalence of new-onset AF in patients with CLL undergoing treatment with ibrutinib. They utilized optical mapping to elucidate the proarrhythmic effects of ibrutinib on HL-1 cells.

Furthermore, fluorescence staining and western blot analysis were employed to compare the expression levels of connexins 43 and 40 between the ibrutinib-treated group and the control group. To characterize autophagy phenotypes, they utilized western blotting to assess the levels of autophagy-related proteins.

The study employed transmission electron microscopy (TEM) to visualize autophagosomes and used a transfected mCherry-GFP-LC3 virus to label autophagosomes and lysosomes. Additionally, hydroxychloroquine, an autophagy inhibitor, was administered to counteract ibrutinib-induced degradation of Cx43 and Cx40.

About 2.67% of patients experienced atrial arrhythmias following the administration of ibrutinib. HL-1 cells subjected to ibrutinib treatment displayed decreased conduction velocity and a heightened occurrence of reentry-like arrhythmias compared to the control group.

Furthermore, the expression of connexins 43 and 40 was reduced, accompanied by an increase in autophagy markers in HL-1 cells treated with ibrutinib. The inhibition of autophagy led to the upregulation of connexins 43 and 40.

The off-target impact of ibrutinib on the PI3K-AKT-mTOR signaling pathway resulted in the degradation of connexins and the onset of atrial arrhythmia by inducing autophagy.

Funding was provided by the National Nature Science Foundation of China.

Source: https://pubmed.ncbi.nlm.nih.gov/38812314/

Qin H, Zheng B, Lin Z, et al. (2024). “Ibrutinib Contributes to Atrial Arrhythmia through the Autophagic Degradation of Connexins by Inhibiting the PI3K-AKT-mTOR Signaling Pathway.” Front Biosci (Landmark Ed). 2024 May 22;29(5):201. doi: 10.31083/j.fbl2905201. PMID: 38812314.

Targeted IGHV SHM in CLL for Prognosis Integration

KEY TAKEAWAYS

  • The study aimed to investigate the efficacy of a targeted capture approach for determining SHM status in the IGHV gene in patients with CLL.
  • Researchers noticed that a targeted capture approach enables broad CLL prognostication via IGHV SHM integration in a single assay.

The somatic hypermutation (SHM) status of the immunoglobulin heavy variable (IGHV) gene is pivotal for assessing the prognosis and guiding treatment decisions in patients with chronic lymphocytic leukemia (CLL). However, the conventional method for determining SHM status, involving multiplex polymerase chain reaction (PCR) and Sanger sequencing of the immunoglobulin heavy locus, suffers from limitations such as low throughput, susceptibility to failure, and lack of compatibility with multiplexing other diagnostic assays.

Jennifer M Grants and the team aimed to address these challenges by exploring an alternative approach for assessing SHM status in patients with CLL.

They conducted an inclusive analysis wherein a DNA-targeted capture approach was devised and validated to detect SHM status in the IGHV gene. This method was integrated as a submodule within a larger next-generation sequencing (NGS) panel comprising probes for various genes associated with CLL prognosis and treatment, including ATM, BIRC3, CHD2, KLHL6, MYD88, NOTCH1, NOTCH2, POT1, SF3B1, TP53, and XPO1. Inputting FASTQ files, the assay yields a comprehensive report consistent with the European Research Initiative on CLL guidelines, detailing IGHV SHM status and V allele usage.

The approach was validated on 35 CLL patient samples, 34 of which had been characterized via Sanger sequencing. Using the NGS panel, IGHV SHM status was successfully identified in 34 out of 35 patients with CLL. Sensitivity and specificity were demonstrated to be 100% among the 33 CLL samples with both NGS and Sanger sequencing calls. Additionally, it was shown that this panel could be integrated with other targeted capture panels to detect prognostically relevant CLL single nucleotide variants, insertions/deletions, and copy number variants, particularly TP53 copy number loss.

The study concluded that a targeted capture approach for detecting IGHV SHM can seamlessly integrate into broader sequencing panels, thereby enabling comprehensive prognostication of CLL within a single molecular assay.

The study was sponsored by a Large Scale Applied Research Project funded by Genome Canada, Genome British Columbia, Canadian Institutes of Health Research, the British Columbia Cancer Foundation, and the Provincial Health Services Authority.

Source: https://pubmed.ncbi.nlm.nih.gov/38175592/

Grants JM, May C, Bridgers J, et al. (2024). “Chronic Lymphocytic Leukemia IGHV Somatic Hypermutation Detection by Targeted Capture Next-Generation Sequencing.” Clin Chem. 2024 Jan 4;70(1):273-284. doi: 10.1093/clinchem/hvad147. PMID: 38175592.

Enhancing CAR T-Cell Therapy in Leukemia: Beyond CD22

KEY TAKEAWAYS

  • The study aimed to evaluate the efficacy and safety of CAR T-cell therapy for individuals with r/r B-ALL.
  • The study concluded that CAR T-cell improvements are crucial for enhancing survival in acute leukemia, suggesting the exploration of new targets.

Pediatric cancer presents a challenging prognosis, particularly in cases of relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Although CAR T-cell therapy is an advanced treatment option, its efficacy remains controversial due to high relapse rates and adverse events.

Sebastian Emmanuel Willyanto and the team aimed to evaluate the effectiveness and safety of CAR T-cell therapy for individuals with r/r B-ALL.

The study conducted a literature search on 4 databases. Efficacy parameters focused on minimal residual disease negative complete remission (MRD-CR) and relapse rate (RR). Safety parameters included cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

The results revealed that anti-CD22 exhibited superior efficacy, displaying the highest rate of MRD-CR events and the lowest RR compared to anti-CD19. Combining CAR T-cell therapy with haploidentical stem cell transplantation improved RR.

Safety-wise, bispecific anti-CD19/22 showed the lowest CRS rate, while anti-CD22 demonstrated the fewest cases of ICANS. Analysis of costimulatory receptors indicated that adding CD28ζ to anti-CD19 CAR T-cell therapy demonstrated superior efficacy in reducing relapses, with favorable safety profiles.

The study concluded that selecting a more effective and safer CAR T-cell treatment is vital for enhancing overall survival in acute leukemia. Beyond the promising anti-CD22 CAR T-cell therapy, further exploration of costimulatory domains and new CD targets could potentially improve treatment effectiveness for individuals with r/r B-ALL.

Funding was provided by the World Class University Universitas Brawijaya.

Source: https://pubmed.ncbi.nlm.nih.gov/38738799/

Willyanto SE, Alimsjah YA, Tanjaya K, et al. (2024). “Comprehensive analysis of the efficacy and safety of CAR T-cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia: a systematic review and meta-analysis.” Ann Med. 2024 Dec;56(1):2349796. doi: 10.1080/07853890.2024.2349796. Epub 2024 May 13. PMID: 38738799.

Optimal PEGasparaginase Dosing for Infants With ALL

KEY TAKEAWAYS

  • The study aimed to investigate the pharmacokinetics of PEGasparaginase in infants with newly diagnosed ALL to determine optimal dosing strategies.
  • Researchers noticed that infants with ALL respond, like older children, to PEGasparaginase.

PEGasparaginase is known to be a critical drug for treating pediatric acute lymphoblastic leukemia (ALL); however, there is insufficient evidence to determine the optimal dose for infants who are less than one year of age at diagnosis.

Leiah J Brigitha and the team aimed to identify the pharmacokinetics of PEGasparaginase in infants with newly diagnosed ALL and gather insight into the clearance and dosing of this population.

They performed an inclusive analysis by including infants with ALL who received treatment with PEGasparaginase in a population pharmacokinetic assessment utilizing non-linear mixed effects modeling (NONMEM).

About 68 infants with ALL, contributing to a total of 388 asparaginase activity samples, were included in the study. PEGasparaginase doses varied from 400 to 3,663 IU/m2 and were administered intravenously or intramuscularly. Utilizing a one-compartment model with time-dependent clearance, modeled via a transit model, they found the best fit for the data.

Body weight demonstrated a significant correlation with both clearance and volume of distribution. The final model estimated a half-life of 11.7 days immediately post-administration, decreasing to 1.8 days after 14 days. Notably, clearance during post-induction treatment was 19.5% lower compared to the induction phase.

The study concluded that the pharmacokinetics of PEGasparaginase in infants diagnosed under one year of age with ALL closely resemble those of older children (1-18 years). Based on this finding, a recommended dosing regimen of 1,500 IU/m2 for infants without age-based dose adjustments is suggested. Furthermore, the implementation of therapeutic drug monitoring as standard practice is recommended to ensure optimal treatment outcomes.

The study was sponsored by the Cancer Plan Action 29 from the Belgian Federal Public Service of Health; the Flemisch League Against Cancer, vzw Kinderkankerfonds, and the Clinical Research Fund of the Ghent University Hospital.

Source: https://pubmed.ncbi.nlm.nih.gov/38538970/

Brigitha LJ, Mondelaers V, Liu Y, et al. (2024). “Pharmacokinetics of PEGasparaginase in Infants with Acute Lymphoblastic Leukemia.” Pharm Res. 2024 Apr;41(4):711-720. doi: 10.1007/s11095-024-03693-3. Epub 2024 Mar 27. PMID: 38538970.

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