Management of chronic myeloid leukaemia: current treatment options, challenges, and future strategies.

ABSTRACTSmall molecule therapy is a critical component of targeted anticancer treatment, with tyrosine kinase inhibitors (TKIs) being the first compounds to treat the clonal Chronic Myelogenous Leukaemia (CML) translocation t (9;22) (q34; q11) effectively since 2001. TKIs, such as imatinib, have improved the 10-year survival rate of CML patients to 80%. They bind the BCR::ABL1 kinase and inhibit downstream signaling pathways. However, therapy failure may be seen in 20-25% of CML patients due to intolerance or inadequacy related to BCR::ABL1 dependent or independent mechanisms. This review aimed to summarize current treatment options involving TKIs, resistance mechanisms and the prospective approaches to overcome TKI resistance. We highlight BCR::ABL1-dependent mechanisms of TKI resistance by reviewing clinically-documented BCR::ABL1 mutations and their consequences for TKI binding. In addition, we summarize BCR::ABL1 independent pathways, including the relevance of drug efflux, dysregulation of microRNA, and the involvement of alternative signaling pathways. We also discuss future approaches, such as gene-editing techniques in the context of CML, as potential therapeutic strategies.

The Mediating Role of Bullying and Victimisation on the Relationship Between Problematic Internet Use and Substance Abuse Among Adolescents in the UK: The Parent-Child Relationship as a Moderator.

Over the last decade, research into the negative effects of problematic internet use has greatly increased. The current study adopted a mediation-moderation model in exploring the relationship between problematic internet use and substance abuse (drinking, drug use, and smoking tobacco cigarettes) among 1,613 adolescents (aged 10-16) in the UK. The findings of the study revealed a significant positive correlation between problematic internet use and substance abuse, which is mediated by traditional and cyber bullying and victimisation. Furthermore, the parent-child relationship was found to be a protective factor that moderated the correlation between problematic internet use and substance abuse and the correlation between problematic internet use and traditional bullying. The study emphasises the critical need to reduce problematic internet use among adolescents as a risk factor for involvement in bullying as perpetrators and victims, in addition to substance abuse. Furthermore, the findings of the study highlight the importance of a good parent-child relationship as a protective factor among adolescents. In light of the findings of the study, interventions for reducing problematic internet use taking into account bullying and the parent-child relationship are needed among adolescents.

Predictive value of tyrosine phosphatase receptor gamma for the response to treatment tyrosine kinase inhibitors in chronic myeloid leukemia patients.

Protein tyrosine phosphatase receptor gamma (PTPRG) is a member of the receptor-like family protein tyrosine phosphatases and acts as a tumor suppressor gene in different neoplasms. Recent studies reported the down-regulation of PTPRG expression levels in Chronic Myeloid Leukemia disease (CML). In addition, the BCR-ABL1 transcript level is currently a key predictive biomarker of CML response to treatment with Tyrosine Kinase Inhibitors (TKIs). The aim of this study was to employ flow cytometry to monitor the changes in the expression level of PTPRG in the white blood cells (WBCs) of CML patients at the time of diagnosis and following treatment with TKIs. WBCs from peripheral blood of 21 CML patients were extracted at diagnosis and during follow up along with seven healthy individuals. The PTPRG expression level was determined at protein and mRNA levels by both flow cytometry with monoclonal antibody (TPγ B9-2) and RT-qPCR, and BCR-ABL1 transcript by RT-qPCR, respectively. PTPRG expression was found to be lower in the neutrophils and monocytes of CML patients at time of diagnosis compared to healthy individuals. Treatment with TKIs nilotinib and Imatinib Mesylate restored the expression of PTPRG in the WBCs of CML patients to levels observed in healthy controls. Moreover, restoration levels were greatest in optimal responders and occurred earlier with nilotinib compared to imatinib. Our results support the measurement of PTPRG expression level in the WBCs of CML patients by flow cytometry as a monitoring tool for the response to treatment with TKIs in CML patients.

Aberrant DNA methylation of PTPRG as one possible mechanism of its under-expression in CML patients in the State of Qatar.

BACKGROUND: Several studies showed that aberrant DNA methylation is involved in leukemia and cancer pathogenesis. Protein tyrosine phosphatase receptor gamma (PTPRG) expression is a natural inhibitory mechanism that is downregulated in chronic myeloid leukemia (CML) disease. The mechanism behind its downregulation has not been fully elucidated yet. AIM: This study aimed to investigate the CpG methylation status at the PTPRG locus in CML patients. METHODS: Peripheral blood samples from CML patients at time of diagnosis [no tyrosine kinase inhibitors (TKIs)] (n = 13), failure to (TKIs) treatment (n = 13) and healthy controls (n = 6) were collected. DNA was extracted and treated with bisulfite treatment, followed by PCR, sequencing of 25 CpG sites in the promoter region and 26 CpG sites in intron-1 region of PTPRG. The bisulfite sequencing technique was employed as a high-resolution method. RESULTS: CML groups (new diagnosed and failed treatment) showed significantly higher methylation levels in the promoter and intron-1 regions of PTPRG compared to the healthy group. There were also significant differences in methylation levels of CpG sites in the promoter and intron-1 regions amongst the groups. CONCLUSION: Aberrant methylation of PTPRG is potentially one of the possible mechanisms of PTPRG downregulation detected in CML.

Is Adherence to Imatinib Mesylate Treatment Among Patients with Chronic Myeloid Leukemia Associated with Better Clinical Outcomes in Qatar?

BACKGROUND: Despite the revolutionary success of introducing tyrosine kinase inhibitors (TKIs), such as imatinib mesylate (IM), for treating chronic myeloid leukemia (CML), a substantial proportion of patients' treatments fail. AIM: This study investigates the correlation between patient adherence and failure of TKIs' treatment in a follow-up study. METHODS: This is a follow-up study of a new cohort of CML patients. Adherence to IM is assessed using the Medication Event Monitoring System (MEMS 6 TrackCap, AARDEX Ltd). The 9-item Morisky Medication Adherence Scale, medication possession ratio (MPR) calculation, and the electronic medical records are used for identifying potential factors that influence adherence. Clinical outcomes are assessed according to the European Leukemia Net 2013 guidelines via reverse transcriptase quantitative polymerase chain reaction measurement of the level of BCR-ABL1 transcripts in peripheral blood. Response is classified at the hematological, cytogenetic, and molecular levels into optimal, suboptimal, or failure. RESULTS: A total of 36 CML patients (5 citizens and 31 noncitizen residents) consented to participate in the study. The overall mean MEMS score was 89. Of the 36 patients, 22 (61%) were classified as adherent (mean: 95) and 14 (39%) were classified as nonadherent (mean: 80.2). Adherent patients were significantly more likely to obtain optimal response (95%) compared to the nonadherent group (14.3%; P < 0.0001). The rate of poor adherence was as high as 39% using MEMS, which correlates with 37% treatment failure rate. The survey results show that 97% of patients increased the IM dose by themselves when they felt unwell and 31% of them took the missing IM dose when they remembered. Other factors known to influence adherence show that half of patients developed one or more side effects, 65% of patients experienced lack of funds, 13% of patients declared unavailability of the drug in the NCCCR pharmacy, and 72% of patients believed that IM would cure the disease. The MPR results reveal that 16% of patients had poor access to treatment through the hospital pharmacy. DISCUSSION AND CONCLUSION: This is the first prospective study to evaluate CML patients' adherence and response to IM in Qatar. The high rate of treatment failure observed in Qatar is explained by poor adherence. An economic factor (unaffordable drug prices) is one of the main causes of nonadherence and efforts should be made locally to improve access to medication for cancer diseases. Other risk factors associated with poor adherence could be improved by close monitoring and dose adjustment. Monitoring risk factors for poor adherence and patient education that include direct communication between the health-care teams, doctors, nurses, pharmacists, and patients are essential components for maximizing the benefits of TKI therapy and could rectify this problem. The preliminary results show that patients' response to treatment may be directly linked to patients' adherence to treatment. However, further in-depth and specific analysis may be necessary in a larger cohort.

Studying the Impact of Presence of Alpha Acid Glycoprotein and Protein Glycoprotein in Chronic Myeloid Leukemia Patients Treated with Imatinib Mesylate in the State of Qatar.

Despite the efficacy of imatinib mesylate (IM) in treating chronic myeloid leukemia (CML), there is a high degree of resistance. Alpha- 1-acid glycoprotein may reduce drug efficacy through its ability to interact with IM and blocks it from reaching its target, while protein glycoprotein (PGP) may reduce the intracellular concentration of the drug via an active pump mechanism. We thus investigated the correlation between AGP and PGP levels and the resistance/response to treatment. A total of 26 CML patients were investigated for AGP and PGP levels at diagnosis and during treatment. There was no significant difference or correlation between AGP levels and the different groups of patients. There was also no significant difference in the fluorescence intensities of PGP levels among the different patient groups. The resistance observed in our CML patient population could not be correlated with AGP and PGP levels. There was no significant pattern of AGP and PGP expression, irrespective of the response or resistance to treatment.

Evaluation of the Taguchi methods for the simultaneous assessment of the effects of multiple variables in the tumour microenvironment.

BACKGROUND: The control of proliferation, differentiation and survival of normal and malignant cells in the tumour microenvironment is under the control of a wide range of different factors, including cell:cell interactions, cytokines, growth factors and hormonal influences. However, the ways in which these factors interact are poorly understood. In order to compare the effects of multiple variables, experimental design becomes complex and difficult to manage. We have therefore evaluated the use of a novel approach to multifactorial experimental design, the Taguchi methods, to approach this problem. METHOD: The Taguchi methods are widely used by quality engineering scientists to compare the effects of multiple variables, together with their interactions, with a simple and manageable experimental design. In order to evaluate these methods, we have used a simple and robust system to compare a traditional experimental design with the Taguchi Methods. The effect of G-CSF, GM-CSF, IL3 and M-CSF on daunorubicin mediated cytotoxicity in K562 cells was measured using the MTT assay. RESULTS: Both methods demonstrated that the same combination of growth factors at the same concentrations minimised daunorubicin cytotoxicity in this assay. CONCLUSIONS: These findings demonstrate that Taguchi methods may be a valuable tool for the investigation of the interactions of multiple variables in the tumour microenvironment.