2,730 results on '"Chronic myeloid leukaemia"'
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2. Late presentation of chronic myeloid leukaemia patients in a low-income country: the prognostic implications and impact on treatment outcome.
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Nelson, Elisha A., Ahmed, Ibrahim O., Bolarinwa, Rahman A., Adeagbo, Babatunde A., Adegbola, Adebanjo J., Salawu, Lateef, Bolaji, Oluseye O., and Durosinmi, Muheez A.
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CHRONIC myeloid leukemia , *PROGNOSIS , *LOW-income countries , *TERTIARY care , *TREATMENT failure , *PROTEIN-tyrosine kinase inhibitors , *DASATINIB - Abstract
Background: In Nigeria, since 2002, Imatinib mesylate (glivec®) has been available freely to chronic myeloid leukaemia (CML) patients but only at a tertiary health care centre in the southwestern part of the country. Despite this, it is not readily accessible to many patients due to the distance and other challenges including low socioeconomic status and political problems, preventing timely access to specialist care. This study evaluated the effect of the baseline characteristics on the prognostic implication and treatment outcome of CML patients in Nigeria. Method: This study retrospectively evaluated the baseline characteristics, clinical presentations and treatment outcomes of 889 CML patients over 18 years (2002–2020). Of these, 576 (65%) patients had complete information with up-to-date BCR::ABL1 records. These 576 patients were categorized based on their responses to Imatinib therapy into three groups viz.; Optimal response (OR) defined as BCR::ABL1 ratio of < 0.1% or major molecular remission (≥ 3-log reduction of BCR::ABL1 mRNA or BCR::ABL1 ratio of < 0.1% on the International Scale), Suboptimal response (SR) with BCR::ABL ratio of 0.1–1%, and Treatment failure (TF) when MMR has not been achieved at 12 months. The variables were analyzed using descriptive and inferential statistics and a p-value < 0.05 was considered statistically significant. Results: The result revealed a median age of 37 years at diagnosis with a male-to-female ratio of 1.5:1. The majority (96.8%) of the patients presented with one or more symptoms at diagnosis with a mean symptom duration of 12 ± 10.6 months. The mean Sokal and EUTOS scores were 1.3 ± 0.8 and 73.90 ± 49.09 respectively. About half of the patients presented with high-risk Sokal (49%) and EUTOS (47%) scores. Interestingly, both the Sokal (r = 0.733, p = 0.011) and EUTOS (r = 0.102, p = 0.003) scores correlated positively and significantly with the duration of symptoms at presentation. Based on response categorization, 40.3% had OR while 27.1% and 32.6% had SR and TF respectively. Conclusion: This study observed a low optimal response rate of 40.3% and treatment failure rate of 32.6% in our CML cohort while on first-line Imatinib therapy. This treatment response is strongly attributable to the long duration of symptoms of 12 months or more and high Sokal and EUTOS scores at presentation. We advocate prompt and improved access to specialist care with optimization of tyrosine kinase inhibitor therapy in Nigeria. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Risk factors determining adherence to tyrosine kinase inhibitors in chronic myeloid leukaemia.
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Del Rosario García, Betel, Viña Romero, María Micaela, González Rosa, Virginia, Alarcón Payer, Carolina, Oliva Oliva, Leonor, Merino Alonso, Francisco Javier, Nazco Casariego, Gloria Julia, and Gutiérrez Nicolás, Fernando
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THERAPEUTIC use of antineoplastic agents , *PATIENT compliance , *RISK assessment , *OUTPATIENT services in hospitals , *PROTEIN-tyrosine kinase inhibitors , *SCIENTIFIC observation , *SOCIOECONOMIC factors , *INDEPENDENT variables , *QUESTIONNAIRES , *LOGISTIC regression analysis , *CHRONIC myeloid leukemia , *CANCER patients , *DESCRIPTIVE statistics , *LONGITUDINAL method , *DASATINIB , *RESEARCH , *DRUGS , *SOCIODEMOGRAPHIC factors , *IMATINIB , *NILOTINIB , *DATA analysis software , *HOSPITAL pharmacies , *EDUCATIONAL attainment , *EMPLOYMENT - Abstract
Objective: Tyrosine kinase inhibitors (TKIs) have successfully changed the natural course of chronic myeloid leukaemia (CML). Although they are highly effective drugs, their clinical benefit is conditioned by adherence. This study aims to analyse the adherence of CML patients treated with TKIs and to identify the main factors influencing their adherence to TKIs treatment. Material and methods: An 8-month prospective, observational, multicentre study which included patients diagnosed with CML on treatment with TKIs attending the outpatient departments (OPD) of the Pharmacy Services of the participating hospitals. Adherence was assessed using two methods: the Simplified Medication Adherence Questionnaire (SMAQ) and the register of treatment dispensations from the OPDs. To analyse the predictors of adherence, a questionnaire was developed to report demographic and socio-economic information on the patients. Results: A total of 130 patients enrolled in this study. Adherence rate was 56.9% (n = 74) among individuals, not conditioned by the type of drug used: imatinib (54.8%), nilotinib (63.6%) or dasatinib (54.3%) (p = 0.67). The patient educational level (p = 0.047) and employment status (p = 0.028) were predictors of non-adherence to treatment. Conclusions: Adherence is one of the most relevant parameters affecting the effectiveness of highly effective chronic treatments. Approximately half of our patients showed inadequate adherence to treatment with TKIs, with employment status and the individual's level of education emerging as the determining factors. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Haematopoietic stem cell transplantation after reduced intensity conditioning in children and adolescents with chronic myeloid leukaemia: A prospective multicentre trial of the I‐BFM Study Group.
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Pichler, Herbert, Sedlacek, Petr, Meisel, Roland, Beier, Rita, Faraci, Maura, Kalwak, Krzysztof, Ifversen, Marianne, Müller, Ingo, Stein, Jerry, Vettenranta, Kim, Kropshofer, Gabriele, Kolenova, Alexandra, Karlhuber, Susanne, Glogova, Evgenia, Poetschger, Ulrike, Peters, Christina, Suttorp, Meinolf, Matthes‐Leodolter, Susanne, and Balduzzi, Adriana
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HEMATOPOIETIC stem cell transplantation , *CHRONIC myeloid leukemia , *TEENAGERS , *PROTEIN-tyrosine kinase inhibitors , *GRAFT versus host disease - Abstract
Summary: This prospective multicentre trial evaluated the safety and the efficacy of a thiotepa/melphalan‐based reduced intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT) in children and adolescents with chronic myeloid leukaemia (CML) in chronic phase (CP). Thirty‐two patients were transplanted from matched siblings or matched unrelated donors. In 22 patients, HSCT was performed due to insufficient molecular response or loss of response to first‐ or second‐generation tyrosine kinase inhibitor (TKI), with pretransplant BCR::ABL1 transcripts ranging between 0.001% and 33%. The protocol included a BCR::ABL1‐guided intervention with TKI retreatment in the first year and donor lymphocyte infusions (DLI) in the second‐year post‐transplant. All patients engrafted. The 1‐year transplant‐related mortality was 3% (confidence interval [CI]: 0%–6%). After a median follow‐up of 6.3 years, 5‐year overall survival and event‐free survival are 97% (CI: 93%–100%) and 91% (CI: 79%–100%) respectively. The current 5‐year leukaemia‐free survival with BCR::ABL1 <0.01% is 97% (CI: 88%–100%) and the current TKI‐ and DLI‐free survival is 95% (CI: 85%–100%). The incidence of chronic graft‐versus‐host disease (GvHD) was 32%, being severe in four patients (13%). At last follow‐up, 31 patients are GvHD‐free and have stopped immunosuppression. RIC HSCT following pretreatment with TKI is feasible and effective in children and adolescents with CP‐CML with an excellent disease‐free and TKI‐free survival. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Clinical outcomes of chronic myeloid leukaemia patients taking asciminib through a Managed Access Programme (MAP) in Australia.
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Chee, Lynette, Lee, Nora, Grigg, Andrew, Chen, Melissa, Schwarer, Anthony, Szer, Jeff, Ratnasingam, Sumita, Raj, Sonia, Lukito, Pohan, Yeung, David, Hughes, Timothy, and Shanmuganathan, Naranie
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THERAPEUTIC use of antineoplastic agents , *DRUG allergy , *MANAGED care programs , *DRUG resistance in cancer cells , *PROTEIN-tyrosine kinase inhibitors , *CHRONIC myeloid leukemia , *TREATMENT effectiveness , *ONCOGENES - Abstract
Asciminib is a novel allosteric STAMP (specifically targets the ABL myristoyl pocket) inhibitor of the BCR::ABL1 oncogene. Real‐world clinical outcomes of patients with tyrosine kinase inhibitor (TKI)‐resistant/intolerant chronic myeloid leukaemia (CML) in Australia on the Managed Access Programme for asciminib showed higher molecular responses for those with intolerance versus resistance ± intolerance to their last TKI. There remains a clinical need to improve outcomes in patients with CML who have resistance to multiple TKIs, especially in the ponatinib‐pretreated cohort. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Late presentation of chronic myeloid leukaemia patients in a low-income country: the prognostic implications and impact on treatment outcome
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Elisha A. Nelson, Ibrahim O. Ahmed, Rahman A. Bolarinwa, Babatunde A. Adeagbo, Adebanjo J. Adegbola, Lateef Salawu, Oluseye O. Bolaji, and Muheez A. Durosinmi
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Chronic myeloid leukaemia ,Low-income country ,Sokal score ,Imatinib Mesylate ,Treatment outcomes ,Medicine ,Biology (General) ,QH301-705.5 ,Science (General) ,Q1-390 - Abstract
Abstract Background In Nigeria, since 2002, Imatinib mesylate (glivec®) has been available freely to chronic myeloid leukaemia (CML) patients but only at a tertiary health care centre in the southwestern part of the country. Despite this, it is not readily accessible to many patients due to the distance and other challenges including low socioeconomic status and political problems, preventing timely access to specialist care. This study evaluated the effect of the baseline characteristics on the prognostic implication and treatment outcome of CML patients in Nigeria. Method This study retrospectively evaluated the baseline characteristics, clinical presentations and treatment outcomes of 889 CML patients over 18 years (2002–2020). Of these, 576 (65%) patients had complete information with up-to-date BCR::ABL1 records. These 576 patients were categorized based on their responses to Imatinib therapy into three groups viz.; Optimal response (OR) defined as BCR::ABL1 ratio of
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- 2024
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- View/download PDF
7. Cardiovascular events in CML patients treated with Nilotinib: validation of the HFA-ICOS baseline risk score
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Fiona Fernando, Maria Sol Andres, Simone Claudiani, Nazanin Zounemat Kermani, Giulia Ceccarelli, Andrew J. Innes, Afzal Khan, Stuart D. Rosen, Jane F. Apperley, Alexander R. Lyon, and Dragana Milojkovic
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Chronic myeloid leukaemia ,TKI ,Nilotinib ,CV toxicity ,Risk stratification ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The therapeutic landscape of chronic myeloid leukaemia (CML) has been transformed by tyrosine kinase inhibitors (TKI). Nilotinib, showed higher rates of major molecular response than imatinib, however associated with higher cardiovascular (CV) toxicity. We sought to describe the CV events associated with nilotinib in a real-world population and assess the predictive value of the HFA-ICOS risk score. Methods The HFA-ICOS baseline risk was calculated for patients with CML treated with nilotinib beween 2006 and 2021. The primary end point was the incidence of all CV events. The secondary end point was the incidence of ischaemic events. Survival analysis evaluated the risk (hazard ratio [HR]) of events stratified by baseline risk category, whilst on nilotinib therapy. Results Two hundred and twenty-nine eligible patients were included. The incidence of CV events was 20.9% (95% CI: 15.7–26.2%) following a median duration of treatment of 34.4 months. The secondary end point occurred in 12.7% (95% CI: 8.4–16.9%) of the population. Patients with higher HFA-ICOS baseline score had higher rates of CV events (low: 11.2%, medium: 28.2% [HR: 2.51, 95% CI: 1.17–5.66], high/very high: 32.4% [HR: 3.57, 95% CI: 1.77–7.20]) and ischaemic events (low: 5.20%, medium: 17.9% [HR: 2.19, 95% CI: 0.97–4.96], high/very high: 21.6% [HR: 3.9, 95% CI: 1.91–7.89]). In patients who did not have a CV event, the median total dose at last follow up or cessation of nilotinib therapy was lower when compared to the total daily median dose of nilotinib in patients who had a CV event (450 mg vs. 600 mg, p = 0.0074). Conclusions The HFA-ICOS risk stratification tool is an efficient discriminator at low, medium and high/very high risk of developing cardiovascular events, with an overall positive trend towards increasing cardiotoxicity rates with rising risk catergories. This study provides evidence to support the use of this predictive tool in nilotinib treated patients.
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- 2024
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8. Study to Evaluate Chronic Myeloid Leukemia Treatment Landscape and Real-life Treatment Outcomes in Hungary: Analysis of National Health Insurance Fund Database
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- 2023
9. A Study To Describe The Real World Use Of Bosutinib In The UK And Netherlands
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pH Associates
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- 2023
10. Higher prevalence of harbouring BCR::ABL1 in first-degree relatives of chronic myeloid leukaemia (CML) patients compared to normal population
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Jew Win Kuan, Anselm Ting Su, Sai-Peng Sim, and Siow Phing Tay
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Chronic myeloid leukaemia ,BCR:ABL1 ,Pre-clinical ,Asymptomatic ,Normal ,Familial ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The role of familial influence in chronic myeloid leukaemia (CML) occurrence is less defined. Previously, we conducted a study to determine the prevalence of harbouring BCR::ABL1 in our local adult normal population (designated as StudyN). We present our current study, which investigated the prevalence of harbouring BCR::ABL1 in the normal first-degree relatives of local CML patients (designated as StudyR). We compared and discussed the prevalence of StudyR and StudyN to assess the familial influence in CML occurrence. Methods StudyR was a cross-sectional study using convenience sampling, recruiting first-degree relatives of local CML patients aged ≥ 18 years old without a history of haematological tumour. Real-time quantitative polymerase chain reaction standardised at the International Scale (BCR::ABL1-qPCRIS) was performed according to standard laboratory practice and the manufacturer’s protocol. Results A total of 96 first-degree relatives from 41 families, with a mean age of 39 and a male-to-female ratio of 0.88, were enrolled and analysed. The median number of relatives per family was 2 (range 1 to 5). Among them, 18 (19%) were parents, 39 (41%) were siblings, and 39 (41%) were offspring of the CML patients. StudyR revealed that the prevalence of harbouring BCR::ABL1 in the first-degree relatives was 4% (4/96), which was higher than the prevalence in the local normal population from StudyN, 0.5% (1/190). All four positive relatives were Chinese, with three of them being female (p > 0.05). Their mean age was 39, compared to 45 in StudyN. The BCR::ABL1–qPCRIS levels ranged between 0.0017%IS and 0.0071%IS, similar to StudyN (0.0023%IS to 0.0032%IS) and another study (0.006%IS to 0.016%IS). Conclusion Our study showed that the prevalence of harbouring BCR::ABL1 in the first-degree relatives of known CML patients was higher than the prevalence observed in the normal population. This suggests that familial influence in CML occurrence might exist but could be surpassed by other more dominant influences, such as genetic dilutional effects and protective genetic factors. The gender and ethnic association were inconsistent with CML epidemiology, suggestive of a higher familial influence in female and Chinese. Further investigation into this topic is warranted, ideally through larger studies with longer follow-up periods.
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- 2024
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11. The FABD domain is critical for the oncogenicity of BCR/ABL in chronic myeloid leukaemia
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Renren Zheng, Wei Wei, Suotian Liu, Dachuan Zeng, Zesong Yang, Jie Tang, Jinfeng Tan, Zhenglan Huang, and Miao Gao
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F-actin binding domain ,BCR/ABL ,Chronic myeloid leukaemia ,Oncogenicity ,p73 ,Medicine ,Cytology ,QH573-671 - Abstract
Abstract Background Abnormally expressed BCR/ABL protein serves as the basis for the development of chronic myeloid leukaemia (CML). The F-actin binding domain (FABD), which is a crucial region of the BCR/ABL fusion protein, is also located at the carboxyl end of the c-ABL protein and regulates the kinase activity of c-ABL. However, the precise function of this domain in BCR/ABL remains uncertain. Methods The FABD-deficient adenovirus vectors Ad-BCR/ABL△FABD, wild-type Ad-BCR/ABL and the control vector Adtrack were constructed, and 32D cells were infected with these adenoviruses separately. The effects of FABD deletion on the proliferation and apoptosis of 32D cells were evaluated by a CCK-8 assay, colony formation assay, flow cytometry and DAPI staining. The levels of phosphorylated BCR/ABL, p73, and their downstream signalling molecules were detected by western blot. The intracellular localization and interaction of BCR/ABL with the cytoskeleton-related protein F-actin were identified by immunofluorescence and co-IP. The effect of FABD deletion on BCR/ABL carcinogenesis in vivo was explored in CML-like mouse models. The degree of leukaemic cell infiltration was observed by Wright‒Giemsa staining and haematoxylin and eosin (HE) staining. Results We report that the loss of FABD weakened the proliferation-promoting ability of BCR/ABL, accompanied by the downregulation of BCR/ABL downstream signals. Moreover, the deletion of FABD resulted in a change in the localization of BCR/ABL from the cytoplasm to the nucleus, accompanied by an increase in cell apoptosis due to the upregulation of p73 and its downstream proapoptotic factors. Furthermore, we discovered that the absence of FABD alleviated leukaemic cell infiltration induced by BCR/ABL in mice. Conclusions These findings reveal that the deletion of FABD diminished the carcinogenic potential of BCR/ABL both in vitro and in vivo. This study provides further insight into the function of the FABD domain in BCR/ABL.
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- 2024
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12. Mismatched related donor allogeneic haematopoietic cell transplantation compared to other donor types for Ph+ chronic myeloid leukaemia: A retrospective analysis from the Chronic Malignancies Working Party of the EBMT.
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Onida, Francesco, Gras, Luuk, Ge, Junran, Koster, Linda, Hamladji, Rose‐Marie, Byrne, Jenny, Avenoso, Daniele, Aljurf, Mahmoud, Robin, Marie, Halaburda, Kazimierz, Passweg, Jakob, Salmenniemi, Urpu, Sengeloev, Henrik, Apperley, Jane, Clark, Andrew, Reményi, Péter, Morozova, Elena, Kinsella, Francesca, Lenhoff, Stig, and Ganser, Arnold
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CHRONIC myeloid leukemia , *HEMATOPOIETIC stem cell transplantation , *STEM cell transplantation , *CELL transplantation , *PROTEIN-tyrosine kinases , *GRAFT versus host disease , *RETROSPECTIVE studies - Abstract
Summary: Allogeneic haematopoietic cell transplantation (allo‐HCT) remains an option for tyrosine kinase inhibitor‐resistant chronic myeloid leukaemia (CML) in first chronic phase (CP1) and high‐risk patients with advanced disease phases. In this European Society for Blood and Marrow Transplantation (EBMT) registry‐based study of 1686 CML patients undergoing first allo‐HCT between 2012 and 2019, outcomes were evaluated according to donor type, particularly focusing on mismatched related donors (MMRDs). Median age at allo‐HCT was 46 years (IQR 36–55). Disease status was CP1 in 43%, second CP (CP2) or later in 27%, accelerated phase in 12% and blast crisis in 18%. Donor type was matched related (MRD) in 39.2%, MMRD in 8.1%, matched unrelated (MUD) in 40.2%, and mismatched unrelated (MMUD) in 12.6%. In 4 years, overall survival (OS) for MRD, MMRD, MUD and MMUD was 61%, 56%, 63% and 59% (p = 0.21); relapse‐free survival (RFS) was 48%, 42%, 52% and 46% (p = 0.03); cumulative incidence of relapse (CIR) was 33%, 37%, 27% and 30% (p = 0.07); non‐relapse mortality (NRM) was 19%, 21%, 21% and 24% (p = 0.21); and graft‐versus‐host disease (GvHD)‐free/relapse‐free survival (GRFS) was 16%, 18%, 22% and 15% (p = 0.05) respectively. On multivariate analysis, MMRD use associated with longer engraftment times and higher risk of graft failure compared to MRD or MUD. There was no statistical evidence that MMRD use associated with different OS, RFS and incidence of GvHD compared to other donor types. [ABSTRACT FROM AUTHOR]
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- 2024
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13. The FABD domain is critical for the oncogenicity of BCR/ABL in chronic myeloid leukaemia.
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Zheng, Renren, Wei, Wei, Liu, Suotian, Zeng, Dachuan, Yang, Zesong, Tang, Jie, Tan, Jinfeng, Huang, Zhenglan, and Gao, Miao
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CHRONIC myeloid leukemia , *CHIMERIC proteins , *STAINS & staining (Microscopy) , *F-actin , *PROTEIN kinases , *CYTOPLASM - Abstract
Background: Abnormally expressed BCR/ABL protein serves as the basis for the development of chronic myeloid leukaemia (CML). The F-actin binding domain (FABD), which is a crucial region of the BCR/ABL fusion protein, is also located at the carboxyl end of the c-ABL protein and regulates the kinase activity of c-ABL. However, the precise function of this domain in BCR/ABL remains uncertain. Methods: The FABD-deficient adenovirus vectors Ad-BCR/ABL△FABD, wild-type Ad-BCR/ABL and the control vector Adtrack were constructed, and 32D cells were infected with these adenoviruses separately. The effects of FABD deletion on the proliferation and apoptosis of 32D cells were evaluated by a CCK-8 assay, colony formation assay, flow cytometry and DAPI staining. The levels of phosphorylated BCR/ABL, p73, and their downstream signalling molecules were detected by western blot. The intracellular localization and interaction of BCR/ABL with the cytoskeleton-related protein F-actin were identified by immunofluorescence and co-IP. The effect of FABD deletion on BCR/ABL carcinogenesis in vivo was explored in CML-like mouse models. The degree of leukaemic cell infiltration was observed by Wright‒Giemsa staining and haematoxylin and eosin (HE) staining. Results: We report that the loss of FABD weakened the proliferation-promoting ability of BCR/ABL, accompanied by the downregulation of BCR/ABL downstream signals. Moreover, the deletion of FABD resulted in a change in the localization of BCR/ABL from the cytoplasm to the nucleus, accompanied by an increase in cell apoptosis due to the upregulation of p73 and its downstream proapoptotic factors. Furthermore, we discovered that the absence of FABD alleviated leukaemic cell infiltration induced by BCR/ABL in mice. Conclusions: These findings reveal that the deletion of FABD diminished the carcinogenic potential of BCR/ABL both in vitro and in vivo. This study provides further insight into the function of the FABD domain in BCR/ABL. [ABSTRACT FROM AUTHOR]
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- 2024
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14. Expectations and outcomes of varying treatment strategies for CML presenting during pregnancy.
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Robertson, H. F., Milojkovic, D., Butt, N., Byrne, J., Claudiani, S., Copland, M., Gallipoli, P., Innes, A. J., Knight, K., Mahdi, A. J., Parker, J., Virchis, A., and Apperley, J. F.
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Summary Diagnosing chronic myeloid leukaemia (CML) during pregnancy is rare. Tyrosine kinase inhibitors (TKIs) have traditionally been contraindicated owing to their teratogenicity. Management decisions should consider the risks to mother and foetus of uncontrolled disease and teratogenic medications. Further cases are required to build upon the paucity of current literature. We report 22 cases of CML diagnosed during pregnancy from 2002 to date. Twenty‐one pregnancies resulted in healthy babies and one patient miscarried. Some patients remained untreated throughout pregnancy but the majority received one or both of interferon‐α and leucapheresis. One patient was started on imatinib at Week 26, and one on hydroxycarbamide in the third trimester. We report haematological parameters during pregnancy to provide clinicians with realistic expectations of management. There were no fetal abnormalities related to treatment during pregnancy. Seventeen patients achieved at least major molecular response on first‐line TKI. A diagnosis of CML during pregnancy can be managed without significant consequences for mother or child. Leucapheresis and interferon‐α are generally safe throughout pregnancy. Despite having been avoided previously, there is growing evidence that certain TKIs may be used in particular circumstances during the later stages of pregnancy. Future work should aim to further elucidate this safety profile. [ABSTRACT FROM AUTHOR]
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- 2024
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15. An in silico investigation of the haematological niche during normal and malignant haematopoiesis
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Forde, Eóghan Anthony, Dzierzak, Elaine, and Ottersbach, Katrin
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haematological niche ,normal haematopoiesis ,malignant haematopoiesis ,leukaemia stem cells ,LSCs ,chronic myeloid leukaemia ,CML ,abnormal chimeric BCR-ABL1 tyrosine kinase ,haematopoietic stem cell ,HSC ,tyrosine kinase inhibitors ,TKIs ,BMSC-dependent regulation ,Pituitary tumour-transforming ,PTTG1-LSC ,SCLtTA×BCR-ABL1 ,BCR-ABL1 ,CML BM microenvironment - Abstract
Eradicating leukaemia stem cells (LSCs) and curing stem cell-derived cancers is hugely challenging. This is exemplified in chronic myeloid leukaemia (CML), where the t(9;22)(q34;q11) chromosomal translocation results in an abnormal chimeric BCR-ABL1 tyrosine kinase in a haematopoietic stem cell (HSC). Treatment of CML with tyrosine kinase inhibitors (TKIs) targeting the BCRABL1 protein is considered an exemplar of precision medicine, but unfortunately, TKIs do not cure most patients. Hence, unmet clinical needs arise in CML through the persistence and propagation of LSCs that are not eradicated by TKI treatment as they yield a source of disease recurrence. The persistence of LSCs after TKI treatment is related to tyrosine kinaseindependent mechanisms which include intrinsic properties of LSCs determined by epigenetic alterations, dysregulated transcriptional networks, and mitochondrial/metabolic changes. Importantly, both leukemic and normal HSCs share these properties along with quiescence and self-renewal ability supported in specialised haematopoietic bone marrow (BM) niches. The BM mesenchymal cell (BMSC) plays an essential niche role in HSC and LSC maintenance. Therefore, a deeper understanding of BMSC-dependent regulation of CML LSCs is required to determine how CML manipulates the haematopoietic niche and protect LSCs from TKI treatment. In this thesis, I set out to identify genes downstream of established autocrine signalling loops which drive the persistence of CML LSCs in a BCRABL1 independent manner. I examined seventeen publicly available CML RNA-seq datasets obtained from the Gene Expression Omnibus for novel gene signatures (Chapter 3). To understand the possible bone marrow niche cell interactions, dataset samples from human primary CD34⁺ enriched normal donor and CML samples (Greater Glasgow and Clyde National Health Service) cultured alongside human stromal, myeloid, and Lymphoid CML cell lines were also examined. A Fluidigm platform was used for LSC-niche co-culture samples to verify the autocrine signalling loops identified from published RNA sequencing data (Chapter 4). Collectively, the analyses inferred the expected widespread disturbances of haemopoietic networks. Gene sets enriched in CML LSCs downstream of previously reported axes included IL-6, TGF-β-BMP, TNF-α as well as PI3KBMP and NF-κB- expression pathways. During this study, significantly expressed genes from both human CML LSCs and a murine model of CML were mined for overlapping genes of novel significance. These datasets allowed us to compare normal HSCs, highly proliferative LSCs, quiescent BCR-ABL⁺ LSCs, as well as CML cell lines, and murine CML cells. Gene enrichment for Pituitary tumour-transforming gene 1 (PTTG1) and its interacting protein (PTTG1IP) were found and CML co-cultures showed increased expression of PTTG1 transcriptional targets, c- Myc, p53, FGF2, p21, prolactin and MMP2. To confirm whether the cell source of expression was the LSC, or niche cells co-culture data were re-examined. We hypothesised that the BMSC niche harbours and selectively maintains LSC persistence through cellular secretion. Our findings reveal a role for the secretory BMP/TGF-β superfamily, particularly Activin signalling, during the progression of CML. These correspond with earlier observations in CML that propose a switch from BMP to ActivinA (INHBA) signalling during treatment resistance and progressive disease. Throughout the in-silico study, we explored the role of the TGF-β superfamily and ActivinA associated genes within the CML BM niche and how they could be involved in the augmentation of a PTTG1-LSC gene network. In Chapter 4-5 we report an unanticipated finding. When CML cells were cocultured with BMSCs, macrophage chemotaxis and activation pathways were upregulated. This highlights CMLs ability to recruit immune cells to their specialised niche. We explored CML immune cell datasets focusing on macrophages from CML and normal healthy BM samples. CML exposed macrophages provided strong evidence that the niche can provide AcitivinA secretion that drives Activin signalling during CML. Thus, macrophages could pose an interesting therapeutic target along with other niche-related adjuvant approaches for TKI-resistant patients or following treatment discontinuation. To unravel the insights, we observed during our in-silico analyses, we sought to determine the in vivo effects of the niche on CML-LSCs and the potential synergistic effect of the BM towards disease progression and relapse during therapy (Chapter 2). To achieve this, we employed a CML mouse model (SCLtTA×BCR-ABL1) in which BCR-ABL1 expression is mainly targeted to the haematopoietic population. Through this approach, our data established that BCR-ABL1 expression produced a myeloproliferative disorder (with a similar temporal onset) after BM transplantation into a large cohort of mice. From this observation, we could produce varying clinical scenarios that represent significant time points during the development and transformation of the CML BM microenvironment. With these cohorts, we developed protocols for bone digestion and whole-bone mount imaging allowing for endosteal and central marrow cell visualisation, providing the basis for single-cell studies localizing niche constituents within the BM. In summary, the re-analysis of existing CML transcriptomic datasets provided insights into BM niche pathways that are potentially involved in promoting the survival of a subset of quiescent BCR-ABL1⁺ LSCs via a BCR-ABLindependent mechanism.
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- 2023
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16. The BCR::ABL1 tyrosine kinase inhibitors ponatinib and nilotinib differentially affect endothelial angiogenesis and signalling
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Zibrova, Darya, Ernst, Thomas, Hochhaus, Andreas, and Heller, Regine
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- 2024
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17. Side effects of treatment with tyrosine kinase inhibitors in patients with chronic myeloid leukaemia and the occurrence of depressive symptoms
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Katarzyna Gibek
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chronic myeloid leukaemia ,depressive disorders ,tyrosine kinase inhibitors ,Medicine - Published
- 2024
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18. Real-World Disease Management and Outcomes in Chronic Myeloid Leukaemia
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- 2023
19. Drug-induced chylothorax as a rare pleural complication in dasatinib therapy for chronic myeloid leukaemia.
- Author
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Ng, Isaac KS, Ruparel, Mamta, Chan, Esther HL, and Khoo, Kay Leong
- Subjects
CHRONIC myeloid leukemia ,CHYLOTHORAX ,THERAPEUTIC complications ,PROTEIN-tyrosine kinase inhibitors ,DRUG side effects ,PLEURAL effusions - Abstract
Chylothorax is a lymphatic chylous pleural effusion typically associated with traumatic (iatrogenic, non-iatrogenic) and non-traumatic (infections, malignancy, lymphatic disorders) aetiologies. Drug-induced chylothorax is uncommon and mostly reported in association with BCR-ABL tyrosine kinase inhibitor therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
20. How to improve treatment‐free remission eligibility in chronic myeloid leukaemia?
- Author
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Costa, Alessandro and Breccia, Massimo
- Subjects
- *
CHRONIC myeloid leukemia , *DISEASE risk factors , *PROTEIN-tyrosine kinase inhibitors , *PATIENT selection , *PROGNOSIS , *CHRONIC leukemia - Abstract
Summary: The achievement of treatment‐free remission (TFR) has become a significant clinical end‐point in the management of patients with chronic myeloid leukaemia (CML), providing an opportunity to discontinue therapy with tyrosine kinase inhibitors (TKIs) while maintaining deep molecular response (DMR). Early studies, such as the French STIM trial, have demonstrated that a portion of patients can maintain DMR after treatment cessation, with rates ranging from 40% to 50%, and most relapses occurring within the first 6 months. Key prognostic factors for successful TFR, including treatment duration, duration of DMR, risk scores, and transcript type, have been identified. Optimal patient selection for TFR remains a challenge, but recent research provides insights into potential strategies to increase TFR eligibility. Evidence suggests that early intervention switching to achieve optimal response, treatment combinations, proactive switch in the case of absence of DMR, dose‐optimization and induction‐maintenance approach can improve molecular responses and, consequently, enhance TFR eligibility. In this review, we report and discuss all the potential therapeutic strategies that may enhance eligibility for a first attempt at TFR, with a particular emphasis on potential future approaches. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
21. Condition Vasoregulation Function Endothelium in Patients With CML Getting TKI II Generation Bosutinib
- Published
- 2023
22. Bilateral retinal haemorrhages as primary ocular manifestation of chronic myeloid leukaemia - A case report
- Author
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Preeti Surpur, M Prabhushanker, G Geetha, and Nipun Bagrecha
- Subjects
chronic myeloid leukaemia ,pars plana vitrectomy ,preretinal haemorrhage ,white centred haemorrhages ,Ophthalmology ,RE1-994 - Abstract
Chronic myeloid leukaemia (CML) in a patient with pre-existing uncontrolled diabetes and hypertension is rarely encountered but must be detected early for appropriate management with systemic chemotherapy. Significant fundus finding mimic diabetic and hypertensive retinopathy, which makes the diagnosis of CML challenging. Early recognition and treatment of the underlying condition can prevent further vision loss and overall morbidity and mortality. Here, we report a case of bilateral retinal haemorrhages as one of the manifestations of CML.
- Published
- 2024
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- View/download PDF
23. Overcoming BCR::ABL1 dependent and independent survival mechanisms in chronic myeloid leukaemia using a multi-kinase targeting approach
- Author
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Caroline Busch, Theresa Mulholland, Michele Zagnoni, Matthew Dalby, Catherine Berry, and Helen Wheadon
- Subjects
Chronic myeloid leukaemia ,Leukaemic stem cells ,Bone morphogenetic protein ,Multi-kinase drug targeting ,Medicine ,Cytology ,QH573-671 - Abstract
Abstract Background Despite improved patient outcome using tyrosine kinase inhibitors (TKIs), chronic myeloid leukaemia (CML) patients require life-long treatment due to leukaemic stem cell (LSC) persistence. LSCs reside in the bone marrow (BM) niche, which they modify to their advantage. The BM provides oncogene-independent signals to aid LSC cell survival and quiescence. The bone-morphogenetic pathway (BMP) is one pathway identified to be highly deregulated in CML, with high levels of BMP ligands detected in the BM, accompanied by CML stem and progenitor cells overexpressing BMP type 1 receptors- activin-like kinases (ALKs), especially in TKI resistant patients. Saracatinib (SC), a SRC/ABL1 dual inhibitor, inhibits the growth of CML cells resistant to the TKI imatinib (IM). Recent studies indicate that SC is also a potent ALK inhibitor and BMP antagonist. Here we investigate the efficacy of SC in overcoming CML BCR::ABL1 dependent and independent signals mediated by the BM niche both in 2D and 3D culture. Methods CML cells (K562 cell line and CML CD34+ primary cells) were treated with single or combination treatments of: IM, SC and the BMP receptors inhibitor dorsomorphin (DOR), with or without BMP4 stimulation in 2D (suspension) and 3D co-culture on HS5 stroma cell line and mesenchymal stem cells in AggreWell and microfluidic devices. Flow cytometry was performed to investigate apoptosis, cell cycle progression and proliferation, alongside colony assays following treatment. Proteins changes were validated by immunoblotting and transcriptional changes by Fluidigm multiplex qPCR. Results By targeting the BMP pathway, using specific inhibitors against ALKs in combination with SRC and ABL TKIs, we show an increase in apoptosis, altered cell cycle regulation, fewer cell divisions, and reduced numbers of CD34+ cells. Impairment of long-term proliferation and differentiation potential after combinatorial treatment also occurred. Conclusion BMP signalling pathway is important for CML cell survival. Targeting SRC, ABL and ALK kinases is more effective than ABL inhibition alone, the combination efficacy importantly being demonstrated in both 2D and 3D cell cultures highlighting the need for combinatorial therapies in contrast to standard of care single agents. Our study provides justification to target multiple kinases in CML to combat LSC persistence.
- Published
- 2023
- Full Text
- View/download PDF
24. Observational Study in Adults With Imatinib-resistant/Intolerant Chronic Myeloid Leukemia Treated With Nilotinib (CML0609)
- Published
- 2022
25. How the latent geometry of a biological network provides information on its dynamics: the case of the gene network of chronic myeloid leukaemia.
- Author
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Lecca, Paola, Lombardi, Giulia, Latorre, Roberta Valeria, and Sorio, Claudio
- Subjects
GENE regulatory networks ,BIOLOGICAL networks ,HYPERBOLIC geometry ,INFORMATION networks ,METRIC geometry - Abstract
Background: The concept of the latent geometry of a network that can be represented as a graph has emerged from the classrooms of mathematicians and theoretical physicists to become an indispensable tool for determining the structural and dynamic properties of the network in many application areas, including contact networks, social networks, and especially biological networks. It is precisely latent geometry that we discuss in this article to show how the geometry of the metric space of the graph representing the network can influence its dynamics. Methods: We considered the transcriptome network of the Chronic Myeloid Laeukemia K562 cells. We modelled the gene network as a system of springs using a generalization of the Hooke’s law to n-dimension (n ≥ 1). We embedded the network, described by the matrix of spring’s stiffnesses, in Euclidean, hyperbolic, and spherical metric spaces to determine which one of these metric spaces best approximates the network’s latent geometry. We found that the gene network has hyperbolic latent geometry, and, based on this result, we proceeded to cluster the nodes according to their radial coordinate, that in this geometry represents the node popularity. Results: Clustering according to radial coordinate in a hyperbolic metric space when the input to network embedding procedure is the matrix of the stiffnesses of the spring representing the edges, allowed to identify the most popular genes that are also centres of effective spreading and passage of information through the entire network and can therefore be considered the drivers of its dynamics. Conclusion: The correct identification of the latent geometry of the network leads to experimentally confirmed clusters of genes drivers of the dynamics, and, because of this, it is a trustable mean to unveil important information on the dynamics of the network. Not considering the latent metric space of the network, or the assumption of a Euclidean space when this metric structure is not proven to be relevant to the network, especially for complex networks with hierarchical or modularised structure can lead to unreliable network analysis results. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
26. Discovery of 3-((3-amino-1H-indazol-4-yl)ethynyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (AKE-72), a potent Pan-BCR-ABL inhibitor including the T315I gatekeeper resistant mutant.
- Author
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El-Damasy, Ashraf K., Kim, Hyun Ji, Park, Jung Woo, Nam, Yunju, Hur, Wooyoung, Bang, Eun-Kyoung, and Keum, Gyochang
- Subjects
- *
CHRONIC myeloid leukemia , *INHIBITION of cellular proliferation , *BENZAMIDE , *AZOLES , *GATEKEEPERS , *CELL lines - Abstract
BCR-ABL inhibition is an effective therapeutic approach for the treatment of chronic myeloid leukaemia (CML). Herein, we report the discovery of AKE-72 (5), a diarylamide 3-aminoindazole, as a potent pan-BCR-ABL inhibitor, including the imatinib-resistant mutant T315I. A focussed array of compounds 4a, 4b, and 5 has been designed based on our previously reported indazole I to improve its BCR-ABLT315I inhibitory activity. Replacing the morpholine moiety of I with the privileged tail (4-ethylpiperazin-1-yl)methyl afforded 5 (AKE-72) with IC50 values of < 0.5 nM, and 9 nM against BCR-ABLWT and BCR-ABLT315I, respectively. Moreover, AKE-72 potently inhibited a panel of other clinically important mutants in single-digit nanomolar IC50 values. AKE-72 elicited remarkable anti-leukemic activity against K-562 cell line (GI50 < 10 nM, TGI = 154 nM). In addition, AKE-72 strongly inhibited the proliferation of Ba/F3 cells expressing native BCR-ABL or its T315I mutant. Overall, AKE-72 may serve as a promising candidate for the treatment of CML, including those harbouring T315I mutation. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
27. Effect of Imatinib treatment on renal anaemia in chronic myeloid leukemia patients.
- Author
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Singh, Avinash Kumar, Vidyadhari, Arya, Bhurani, Dinesh, Agrawal, Narendra, Ahmed, Rayaz, and Sharma, Manju
- Subjects
- *
KIDNEY disease risk factors , *GLOMERULAR filtration rate , *KIDNEYS , *KIDNEY function tests , *HEMOGLOBINS , *CHRONIC myeloid leukemia , *RISK assessment , *CANCER patients , *ANEMIA , *IMATINIB , *DATA analysis software , *STATISTICAL correlation , *LONGITUDINAL method , *DISEASE risk factors - Abstract
Purpose: In this study, we investigate renal function and anaemia during imatinib treatment in patients with chronic myeloid leukaemia. Methods: The patients with chronic myeloid leukaemia with chronic phase who had been treated with only imatinib for 12 months at Rajiv Gandhi Cancer Institute and Research Centre (New Delhi, India) were enrolled and prospectively analysed. The chronic renal impairment parameters, including estimated glomerular filtration rate and haemoglobin levels for anaemia from June 2020 to June 2022, were monitored in newly diagnosed in patients with chronic myeloid leukaemia-chronic phase. The data were analysed by SPSS software version 22. Results: In total 55 patients with chronic myeloid leukaemia chronic phase who had been on imatinib for 12 months were monitored. The mean estimated glomerular filtration rate was significantly decreased (74 ± 14 to 59 ± 12 mL/min/1.73m2, p < 0.001) with a decrease in mean haemoglobin levels after 12 months (10.9 ± 2.01 to 9.0 ± 1.02, p < 0.004). The decreased estimated glomerular filtration rate was negatively correlated with haemoglobin levels after 1 year of imatinib administration (correlation coefficient = 0.892, R2 = 0.7976, p < 0.05). Conclusion: We recommended close monitoring of renal function and haemoglobin levels in patients with chronic myeloid leukaemia patients. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
28. Overcoming BCR::ABL1 dependent and independent survival mechanisms in chronic myeloid leukaemia using a multi-kinase targeting approach.
- Author
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Busch, Caroline, Mulholland, Theresa, Zagnoni, Michele, Dalby, Matthew, Berry, Catherine, and Wheadon, Helen
- Subjects
- *
CHRONIC myeloid leukemia , *CELL culture , *CELL cycle regulation , *LEUCOCYTES , *ERYTHROCYTES , *MESENCHYMAL stem cells , *BLOOD coagulation , *BONE marrow - Abstract
Background: Despite improved patient outcome using tyrosine kinase inhibitors (TKIs), chronic myeloid leukaemia (CML) patients require life-long treatment due to leukaemic stem cell (LSC) persistence. LSCs reside in the bone marrow (BM) niche, which they modify to their advantage. The BM provides oncogene-independent signals to aid LSC cell survival and quiescence. The bone-morphogenetic pathway (BMP) is one pathway identified to be highly deregulated in CML, with high levels of BMP ligands detected in the BM, accompanied by CML stem and progenitor cells overexpressing BMP type 1 receptors- activin-like kinases (ALKs), especially in TKI resistant patients. Saracatinib (SC), a SRC/ABL1 dual inhibitor, inhibits the growth of CML cells resistant to the TKI imatinib (IM). Recent studies indicate that SC is also a potent ALK inhibitor and BMP antagonist. Here we investigate the efficacy of SC in overcoming CML BCR::ABL1 dependent and independent signals mediated by the BM niche both in 2D and 3D culture. Methods: CML cells (K562 cell line and CML CD34+ primary cells) were treated with single or combination treatments of: IM, SC and the BMP receptors inhibitor dorsomorphin (DOR), with or without BMP4 stimulation in 2D (suspension) and 3D co-culture on HS5 stroma cell line and mesenchymal stem cells in AggreWell and microfluidic devices. Flow cytometry was performed to investigate apoptosis, cell cycle progression and proliferation, alongside colony assays following treatment. Proteins changes were validated by immunoblotting and transcriptional changes by Fluidigm multiplex qPCR. Results: By targeting the BMP pathway, using specific inhibitors against ALKs in combination with SRC and ABL TKIs, we show an increase in apoptosis, altered cell cycle regulation, fewer cell divisions, and reduced numbers of CD34+ cells. Impairment of long-term proliferation and differentiation potential after combinatorial treatment also occurred. Conclusion: BMP signalling pathway is important for CML cell survival. Targeting SRC, ABL and ALK kinases is more effective than ABL inhibition alone, the combination efficacy importantly being demonstrated in both 2D and 3D cell cultures highlighting the need for combinatorial therapies in contrast to standard of care single agents. Our study provides justification to target multiple kinases in CML to combat LSC persistence. Plain English Summary: Blood is made in the spongy inner most section of the bone, called the bone marrow. The bone marrow is where normal blood stem cells live that are responsible for producing the different blood cell types; white blood cells (fight infections), red blood cells (carrying oxygen around the body), platelets (blood clotting) and other cells which support this process. Chronic myeloid leukaemia (CML) is a type of blood cancer that starts in the bone marrow. CML occurs when a normal blood stem cell becomes damaged, forming a leukaemia stem cell (LSC), leading to blood cancer. LSCs multiply and generate many faulty cancerous white blood cells that do not work properly. Patients are treated with a drug called imatinib, which reduces the number of cancerous cells circulating in the body. In many cases, this treatment is not enough to cure the disease because the bone marrow protects the LSCs from the drug meaning patients must remain on long term treatment. This work has discovered one of the ways in which the bone marrow protects LSCs from treatments and has used this knowledge to test new drugs that stop this protection. Our findings show that by combining two drugs, one that overcomes this protection and one that directly targets the cancerous cells, we can destroy more of the LSCs. These findings are a step closer towards a cure for CML and could improve treatment for patients in the future. 8kTkWYvNitSmKGMPj2Mgjo Video Abstract [ABSTRACT FROM AUTHOR]
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- 2023
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29. Comparison of Clinicopathological Parameters, and Treatment Responses in Younger and Older Chronic Myeloid Leukaemia Patients Treated with Imatinib.
- Author
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Kamarudin, Ahmad Farhan, Palaniappan, Sivakumar, Raja Sabudin, Raja Zahratul Azma, Shuib, Salwati, Jamil, Siti Afiqah Muhamad, and Tumian, Nor Rafeah
- Subjects
- *
CHRONIC myeloid leukemia , *IMATINIB , *MEDICAL records , *RESOURCE-limited settings , *ADVERSE health care events , *CHRONIC leukemia - Abstract
Introduction: Differences in baseline characteristics and response to treatment in different age groups of patients with chronic myeloid leukaemia (CML) in resource-limited countries have not been extensively studied. We aimed to determine the differences in clinicopathological parameters at diagnosis and response to imatinib in adult CML patients with younger (under 60 years; YCML) and older (60 years and older; OCML) age treated at our institution from March 2001 to March 2021. Methods: A retrospective analysis of consecutive adult CML patients receiving imatinib was performed. Clinicopathological parameters and treatment response were reviewed and analysed using hospital medical records and electronic data reports. Results: The median age at diagnosis was 50 years. OCML patients (n=17) had significantly more comorbidities. The YCML group (n=50) generally had a palpable spleen >5cm from the costal margin, mild anaemia, hyperleukocytosis and thrombocytosis. A starting dose of 400 mg/day was observed in 84% of YCML and in 65% of OCML. Cumulative complete cytogenetic response was 50% in YCML versus 70.6% in OCML, p=0.158. OCML tended to have a higher percentage of major molecular response (MMR) (52.9% versus 32%) and a shorter time to MMR, 22 months (range 5-70) versus 35 months (range 8-53). OCML experienced more haematological and non-haematological treatment-related adverse events after imatinib therapy. Conclusion: Although OCML patients had more comorbidities and treatment intolerances, overall long-term treatment response was comparable to YCML. In OCML, a more personalised approach to initial and subsequent dosing of imatinib may be considered. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
30. Targeted Mass Spectrometry Reveals Interferon-Dependent Eicosanoid and Fatty Acid Alterations in Chronic Myeloid Leukaemia.
- Author
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Scott, Hannah C., Draganov, Simeon D., Yu, Zhanru, Kessler, Benedikt M., and Pinto-Fernández, Adán
- Subjects
- *
CHRONIC myeloid leukemia , *FATTY acids , *MASS spectrometry , *ARACHIDONIC acid , *TYPE I interferons , *PALMITIC acid , *STEARIC acid - Abstract
Bioactive lipids are involved in cellular signalling events with links to human disease. Many of these are involved in inflammation under normal and pathological conditions. Despite being attractive molecules from a pharmacological point of view, the detection and quantification of lipids has been a major challenge. Here, we have optimised a liquid chromatography–dynamic multiple reaction monitoring–targeted mass spectrometry (LC-dMRM-MS) approach to profile eicosanoids and fatty acids in biological samples. In particular, by applying this analytic workflow to study a cellular model of chronic myeloid leukaemia (CML), we found that the levels of intra- and extracellular 2-Arachidonoylglycerol (2-AG), intracellular Arachidonic Acid (AA), extracellular Prostaglandin F2α (PGF2α), extracellular 5-Hydroxyeicosatetraenoic acid (5-HETE), extracellular Palmitic acid (PA, C16:0) and extracellular Stearic acid (SA, C18:0), were altered in response to immunomodulation by type I interferon (IFN-I), a currently approved treatment for CML. Our observations indicate changes in eicosanoid and fatty acid metabolism, with potential relevance in the context of cancer inflammation and CML. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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31. Imatinib resistance in CML and its association with age & gender.
- Author
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Khan, Asma, Hakim, Zunera, Waheed, Akbar, Ibrar, Naila, Afzal, Ayesha, and Munir, Attiya
- Subjects
- *
IMATINIB , *CHRONIC myeloid leukemia , *CHI-squared test , *AGE groups , *LEUKOCYTE count - Abstract
Objective: To evaluate the association of gender and age with the resistance shown to Imatinib in CML with evaluation of WBCC in different age groups. Study Design: Cross Sectional Analytical study. Setting: Islamic International Medical College, Riphah International University, Islamabad, Pakistan. Patients were enrolled from the CML clinic in Holy Family Hospital, Rawalpindi. Period: January 2019 to December 2021. Material & Methods: Sampling technique was non probability consecutive sampling. We included 75 newly diagnosed CML patients, who were taking Imatinib 400 mg. Blood samples of all these patients were analysed at the start of treatment and also after 3 months to determine the complete haematological response (CHR) and patients were labelled as resistant who failed to achieve complete haematological response at this stage according to the Leukemia Net guidelines. Results: Our study demonstrates that 54.7% of the patients were Imatinib responders while 45.3 % patients were Imatinib resistant. Patients who were labelled as responders have shown complete haematological remission at 3 months of treatment. (Platelet Count < 450 x 10 9/L - WBCC < 10 x 10 9/L - Differential without Immature Granulocytes (MC, PMC, MB) and With Less Than 5% Basophils - Non-Palpable Spleen) A chi square test of independence was performed to examine the relation between gender and response and between age groups and response. The relationship between age groups and response is significant with p value of 0.003. While the relationship when determined between gender and response, it was found to be non-significant with p value of 0.08. It was also found out that WBC count in responders is at lowest in second age group and also highest in second age group in case of resistant patients that is age between 31-40 years. Conclusion: Imatinib resistance is common while treating patients with chronic myeloid leukemia. There is significant association with the different age groups and non-significant association with the gender in terms of response to the treatment of Imatinib. It was also found that age also effects the WBC count with Imatinib though it was not significant. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
32. Side effects of treatment with tyrosine kinase inhibitors in patients with chronic myeloid leukaemia and the occurrence of depressive symptoms.
- Author
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Gibek, Katarzyna
- Subjects
- *
KINASE inhibitors , *DRUG side effects , *CHRONIC myeloid leukemia , *MENTAL depression , *TREATMENT duration - Abstract
Introduction: The aim of the study was to check whether individual side effects of treatment with tyrosine kinase inhibitors (TKI) in patients suffering from chronic myeloid leukaemia (CML) contribute to the occurrence of depressive symptoms. In addition, it was decided to check whether there is any correlation between the age, sex, and duration of treatment and the intensity of depressive symptoms, in relation to the occurrence of individual side effects. Material and methods: The study included 91 patients with CML treated with TKI. The following questionnaires were used: a questionnaire created by the author, David Goldberg's general health questionnaire-28 (GHQ-28), and the four-dimensional symptom questionnaire (4DSQ). Results: Our research showed that fatigue (ß = 0.27; p = 0.007), nausea/indigestion (ß = 0.26; p = 0.008), bone and joint pain (ß = 0.21; p = 0.033), and abdominal pain (ß = 0.33; p = 0.001) were the most common side effects of TKI treatment resulting in increased depressive symptoms. Age and duration of treatment had a significant impact on the severity of depressive symptoms in patients experiencing specific side effects of TKI treatment. Conclusions: The results indicate the influence of the occurrence of TKI treatment side effects on the development of depressive symptoms. Patients' quality of life can be improved with the cooperation of medical staff in reducing/alleviating the side effects. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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33. Drug–drug interactions of protein kinase inhibitors in chronic myeloid leukaemia patients: A study using the French health insurance database.
- Author
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Pajiep, Marie, Lapeyre‐Mestre, Maryse, and Despas, Fabien
- Subjects
- *
PROTEIN kinase inhibitors , *CHRONIC myeloid leukemia , *DRUG interactions , *DRUG side effects , *HEALTH insurance , *NILOTINIB , *BENZODIAZEPINES - Abstract
The introduction of protein kinase inhibitors (PKIs) for chronic myeloid leukaemia (CML) has considerably improved prognosis of the disease but has also demonstrated a great potential for drug–drug interactions. Using the French health insurance databases, we aim to investigate the frequency, identify the associated factors and describe the potential consequences of potential drug–drug interactions (pPKI‐DIs) between PKIs and concurrent medications in CML. A retrospective cohort study has been performed among patients with CML identified in the French healthcare database from 2011 to 2014. A pPKI‐DI is defined as the presence of drugs listed as 'interacting' on the same day as PKI dispensing (co‐dispensing) or in its coverage period (co‐medication) during the first year of follow‐up. The list of interacting drugs is based on the summary of products characteristics (SPCs) and Thesaurus of interactions. We performed specific nested case–control comparisons to investigate the association between PKI‐DI and each of the three potential outcomes (death, hospitalisation for adverse drug reactions and switch to another PKI). We included 3480 patients; 1429 (41%) had a co‐dispensing pPKI‐DI, and 2153 (62%) had a co‐medication pPKI‐DI; 50% of the pPKI‐DIs were 'to be taken into account', and 17% were 'not recommended'. The PKI with the most interactions was imatinib, and additional common drug classes included statins, benzodiazepines and proton pump inhibitors. Multivariate analysis demonstrated that the use of a higher number of additional drugs, comorbidities at baseline, high number of prescribers and higher ages were potential risk factors. Nilotinib and dasatinib showed a tendency towards a higher risk of pPKI‐DI compared to imatinib. Despite the fact that some PKI‐DIs were potentially clinically relevant, we did not find any significant association with death, hospitalisation for adverse drug reactions and switching. These findings should increase awareness to help reduce the prevalence of PKI–drug interactions and thereby ensure better management of CML patients. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
34. SARS-CoV-2 Omicron BA.5.2-infection and COVID-19 in persons with chronic myeloid leukaemia.
- Author
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Cheng, Fang, Xiang, Hang, Gale, Robert Peter, Chen, Siyi, Qu, Jiao, Guo, Hao, Li, Qiubai, Zhang, Yanli, and Li, Weiming
- Subjects
- *
CHRONIC myeloid leukemia , *SARS-CoV-2 Omicron variant , *SARS-CoV-2 , *COVID-19 , *INTENSIVE care units , *CHRONIC leukemia - Abstract
Objective: A SARS-CoV-2 Omicron (BA.5.2) epidemic began in China in December, 2022 following stopping the zero COVID policy. Methods: We studied features of the epidemic in 1,121 persons with chronic myeloid leukaemia (CML). Results: 1103 (98%) were in chronic, 10 in accelerated and 8 in acute phases. 834 (74%) became infected almost all of whom met criteria for COVID-19. The most common symptoms were fever (91%), cough (90%) and fatigue (82%). 42 infected persons were asymptomatic. Most people quarantined at home and self-medicated. 22 were hospitalized for COVID-19. At admission 5 had mild, 14, moderate and 3, severe/critical disease according to World Health Organization (WHO) criteria. 5 received respiratory assistance, 3 were admitted to the intensive care unit (ICU) and 1 in accelerated phase died from COVID-19. Co-variates associated with a risk of COVID-19 in SARS-CoV-2-infected subjects include age ≥ 65 years, higher education level and imatinib therapy. Conclusion: In conclusion, most SARS-CoV-2 Omicron BA.5.2 infections in persons with CML resulted in COVID-19 most of which cases are mild with only 1 death. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
35. A rare case of an elderly male with progression to chronic myeloid leukaemia secondary to chronic lymphocytic leukaemia
- Author
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Sakditad Saowapa, Watsachon Pangkanon, Yaw Adu, Nattanicha Chaisrimaneepan, Diego Olavarria Bernal, Natchaya Polpichai, Pharit Siladech, and Jasmine Sekhon
- Subjects
coexisting cll/cml ,chronic lymphocytic leukaemia ,chronic myeloid leukaemia ,dasatinib ,Medicine - Abstract
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder characterised by an accumulation of monoclonal B lymphocytes, with an increased risk of secondary cancers. The coexistence of CLL and chronic myeloid leukaemia (CML) is a rare phenomenon, with three main types being classified: CML preceding CLL, CLL preceding CML and simultaneous occurrence. The coexistence of these chronic leukaemias poses a complex clinical challenge, with the underlying mechanisms of their association remaining enigmatic. Here, we present a report of an elderly male with a long history of CLL, who was subsequently diagnosed with secondary CML.
- Published
- 2024
- Full Text
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36. Treatment-Free Remission in Chronic Myeloid Leukemia
- Author
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Shanmuganathan, Naranie, Ross, David M., Gill, Harinder, editor, and Kwong, Yok-Lam, editor
- Published
- 2023
- Full Text
- View/download PDF
37. Graph Embedding of Chronic Myeloid Leukaemia K562 Cells Gene Network Reveals a Hyperbolic Latent Geometry
- Author
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Lecca, Paola, Re, Angela, Lombardi, Giulia, Latorre, Roberta Valeria, Sorio, Claudio, Kacprzyk, Janusz, Series Editor, Gomide, Fernando, Advisory Editor, Kaynak, Okyay, Advisory Editor, Liu, Derong, Advisory Editor, Pedrycz, Witold, Advisory Editor, Polycarpou, Marios M., Advisory Editor, Rudas, Imre J., Advisory Editor, Wang, Jun, Advisory Editor, Yang, Xin-She, editor, Sherratt, R. Simon, editor, Dey, Nilanjan, editor, and Joshi, Amit, editor
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- 2023
- Full Text
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38. Cancer Stem Cell Markers in Haematological Malignancies
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Ramos, S., Brenu, E. W., Islam, Farhadul, editor, and Lam, Alfred K., editor
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- 2023
- Full Text
- View/download PDF
39. Bilateral vision loss at high altitude: A diagnostic dilemma.
- Author
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Gupta, Radhika, Shukla, Apoorva, and Mathew, Blessy
- Subjects
CHRONIC myeloid leukemia ,VISION disorders ,TUMOR lysis syndrome ,ALTITUDES - Abstract
A young male patient of 22 years inducted at 11,000 feet altitude presented with a sudden onset bilateral diminution of vision associated with easy fatiguability and generalised weakness. Fundus examination revealed preretinal haemorrhages and Roth spots both eyes, owing to which differential diagnosis of high altitude retinopathy (HAR) and haematological disorders was considered. On systemic examination, he had pallor with massive splenomegaly. Haematological investigation revealed high total leucocyte count (TLC) 2.96 lac (normal 4000–11,000/uL) with peripheral blood smear showing increase in basophils, neutrophil precursors, myelocyte bulge, anaemia with no blasts suggestive of chronic myeloid leukaemia—chronic phase. Hence, a diagnosis of chronic myeloid leukaemia (chronic phase) with no features of tumour lysis syndrome was made. Patient was started on Tab hydroxyurea 50 mg twice a daily and managed by haemato-oncologist and required no further active ophthalmological intervention. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
40. Cardiovascular events in CML patients treated with Nilotinib: validation of the HFA-ICOS baseline risk score
- Author
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Fernando, Fiona, Andres, Maria Sol, Claudiani, Simone, Kermani, Nazanin Zounemat, Ceccarelli, Giulia, Innes, Andrew J., Khan, Afzal, Rosen, Stuart D., Apperley, Jane F., Lyon, Alexander R., and Milojkovic, Dragana
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- 2024
- Full Text
- View/download PDF
41. Higher prevalence of harbouring BCR::ABL1 in first-degree relatives of chronic myeloid leukaemia (CML) patients compared to normal population
- Author
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Kuan, Jew Win, Su, Anselm Ting, Sim, Sai-Peng, and Tay, Siow Phing
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- 2024
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42. Front-line Nilotinib Treatment of BCR-ABL+ Chronic Myeloid Leukaemia in Chronic Phase (CML0912)
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- 2022
43. Utilising stimulated Raman scattering microscopy to study intracellular distribution of label-free ponatinib in live cells
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Sepp, Kristel, Hulme, Alison, and Brunton, Valerie
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615.1 ,Raman microscopy ,drug imaging ,ponatinib ,chronic myeloid leukaemia ,Ponatinib imaging ,intracellular localisation - Abstract
Despite advancements in the drug discovery process, drug attrition rate in the late stages of clinical trials still remains high. Better understanding of drug efficacy in the pre-clinical stage would potentially translate into increased clinical trial success rate and reduce the economic burden of failed trials. However, visualising intracellular drug uptake and distribution at high resolution to improve the pre-clinical drug discovery process is still a challenge for scientists. Stimulated Raman scattering (SRS) microscopy represents a powerful imaging tool for visualising drug molecules inside cells with high resolution, without the need for additional labels, or nanoparticle sensors as used in many other optical imaging technologies. It provides Raman imaging with minimal spectral distortion and a quantitative output, allowing accurate determination of intracellular drug concentrations. Ponatinib is a clinically approved tyrosine kinase inhibitor that targets BCR-ABL and is used to treat chronic myeloid leukaemia (CML). Drug resistance is a widespread problem in CML treatment, where ponatinib resistant patients have very limited treatment options. Ponatinib has an alkyne moiety in its structure that makes it inherently Raman active in the cellular silent region of the Raman spectrum. In this thesis, SRS microscopy was used to image intracellular ponatinib label-free with high sensitivity and specificity in live human CML cell lines, in the context of ponatinib resistance. SRS imaging of ponatinib was optimised in Chapter 3, enabling ponatinib imaging at nanomolar treatment concentrations as well as determination of absolute ponatinib concentrations in both ponatinib sensitive and resistant CML cells. In Chapter 4, it was determined that ponatinib is sequestered into the lysosomes, with a higher lysosomal concentration found in drug resistant cells. This was associated with increased lysosome biogenesis. Target engagement studies showed that treatment with chloroquine reduced ponatinib accumulation in lysosomes, but did not resensitise cells to ponatinib, confirming a BCR-ABL independent resistance mechanism in this CML cell model. To demonstrate further utility of SRS microscopy, it was applied to spheroid imaging in Chapter 5. CML cell lines formed three-dimensional (3D) cell 'aggregates' rather than spheroids with tight cell-cell contacts, and could not be used for SRS imaging. However, spheroid growth was successfully optimised in a breast cancer cell line T47D; and live T47D spheroids were imaged using SRS microscopy.
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- 2021
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44. Discovery of 3-((3-amino-1H-indazol-4-yl)ethynyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (AKE-72), a potent Pan-BCR-ABL inhibitor including the T315I gatekeeper resistant mutant
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Ashraf K. El-Damasy, Hyun Ji Kim, Jung Woo Park, Yunju Nam, Wooyoung Hur, Eun-Kyoung Bang, and Gyochang Keum
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Chronic myeloid leukaemia ,aminoindazole ,diarylamides ,ABLT315I ,Imatinib resistance ,Therapeutics. Pharmacology ,RM1-950 - Abstract
BCR-ABL inhibition is an effective therapeutic approach for the treatment of chronic myeloid leukaemia (CML). Herein, we report the discovery of AKE-72 (5), a diarylamide 3-aminoindazole, as a potent pan-BCR-ABL inhibitor, including the imatinib-resistant mutant T315I. A focussed array of compounds 4a, 4b, and 5 has been designed based on our previously reported indazole I to improve its BCR-ABLT315I inhibitory activity. Replacing the morpholine moiety of I with the privileged tail (4-ethylpiperazin-1-yl)methyl afforded 5 (AKE-72) with IC50 values of < 0.5 nM, and 9 nM against BCR-ABLWT and BCR-ABLT315I, respectively. Moreover, AKE-72 potently inhibited a panel of other clinically important mutants in single-digit nanomolar IC50 values. AKE-72 elicited remarkable anti-leukemic activity against K-562 cell line (GI50 < 10 nM, TGI = 154 nM). In addition, AKE-72 strongly inhibited the proliferation of Ba/F3 cells expressing native BCR-ABL or its T315I mutant. Overall, AKE-72 may serve as a promising candidate for the treatment of CML, including those harbouring T315I mutation.
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- 2023
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45. How the latent geometry of a biological network provides information on its dynamics: the case of the gene network of chronic myeloid leukaemia
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Paola Lecca, Giulia Lombardi, Roberta Valeria Latorre, and Claudio Sorio
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network geometry ,graph embedding ,dynamical systems ,spring systems ,chronic myeloid leukaemia ,systems biology ,Biology (General) ,QH301-705.5 - Abstract
Background: The concept of the latent geometry of a network that can be represented as a graph has emerged from the classrooms of mathematicians and theoretical physicists to become an indispensable tool for determining the structural and dynamic properties of the network in many application areas, including contact networks, social networks, and especially biological networks. It is precisely latent geometry that we discuss in this article to show how the geometry of the metric space of the graph representing the network can influence its dynamics.Methods: We considered the transcriptome network of the Chronic Myeloid Laeukemia K562 cells. We modelled the gene network as a system of springs using a generalization of the Hooke’s law to n-dimension (n ≥ 1). We embedded the network, described by the matrix of spring’s stiffnesses, in Euclidean, hyperbolic, and spherical metric spaces to determine which one of these metric spaces best approximates the network’s latent geometry. We found that the gene network has hyperbolic latent geometry, and, based on this result, we proceeded to cluster the nodes according to their radial coordinate, that in this geometry represents the node popularity.Results: Clustering according to radial coordinate in a hyperbolic metric space when the input to network embedding procedure is the matrix of the stiffnesses of the spring representing the edges, allowed to identify the most popular genes that are also centres of effective spreading and passage of information through the entire network and can therefore be considered the drivers of its dynamics.Conclusion: The correct identification of the latent geometry of the network leads to experimentally confirmed clusters of genes drivers of the dynamics, and, because of this, it is a trustable mean to unveil important information on the dynamics of the network. Not considering the latent metric space of the network, or the assumption of a Euclidean space when this metric structure is not proven to be relevant to the network, especially for complex networks with hierarchical or modularised structure can lead to unreliable network analysis results.
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- 2023
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46. Cardiovascular risk in chronic myeloid leukaemia: A multidisciplinary consensus on screening and management.
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Milojkovic, Dragana, Lyon, Alexander R., Mehta, Priyanka, Dimitriadou, Evangelia, Choudhuri, Satarupa, Manisty, Charlotte, Cheshire, Nick, Crozier, Kirsty, Basker, Nanda, Amer, Karim, Purcell, Simon, Tan, Susan, and Clark, Richard E.
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CHRONIC myeloid leukemia , *MEDICAL screening , *MEDICAL personnel , *CARDIOVASCULAR diseases risk factors , *PROTEIN-tyrosine kinase inhibitors - Abstract
Introduction: Tyrosine kinase inhibitors (TKIs) have become the mainstay of treatment for chronic myeloid leukaemia (CML), but cardiovascular (CV) risk and exacerbation of underlying risk factors associated with TKIs have become widely debated. Real‐world evidence reveals little application of CV risk factor screening or continued monitoring within UK CML management. This consensus paper presents practical recommendations to assist healthcare professionals in conducting CV screening/comorbidity management for patients receiving TKIs. Methods: We conducted a multidisciplinary panel meeting and two iterative surveys involving 10 CML specialists: five haematologists, two cardio‐oncologists, one vascular surgeon, one haemato‐oncology pharmacist and one specialist nurse practitioner. Results: The panel recommended that patients commencing second‐/third‐generation TKIs undergo formal CV risk assessment at baseline, with additional investigations and involvement of cardiologists/vascular surgeons for those with high CV risk. During treatment, patients should undergo CV monitoring, with the nature and frequency of testing dependent on TKI and baseline CV risk. For patients who develop CV adverse events, decision‐making around TKI interruption, cessation or change should be multidisciplinary and balance CV and haematological risk. Conclusion: The panel anticipates these recommendations will support healthcare professionals in implementing CV risk screening and monitoring, broadly and consistently, and thereby help optimise TKI treatment for CML. [ABSTRACT FROM AUTHOR]
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- 2023
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47. Association of CYP3A5*3, CYP3A4*18 & CYP2B6*6 polymorphisms with imatinib treatment outcome in Azerbaijani chronic myeloid leukaemia patients.
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Asadov, Chingiz, Karimova, Nigar, Hasanova, Aypara, Bayramov, Bayram, Shirinova, Aytan, and Alimirzoyeva, Zohra
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- 2023
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48. An investigation of the use of app technology to support clinical management of patients with chronic myeloid leukaemia (CML).
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Khadam, Saffiya, Chu, Teresa, Deekes, Nigel, FitzGerald, David, Preston, Andrea, and Duncan, Nick
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- *
CLINICAL decision support systems , *CHRONIC myeloid leukemia , *MOBILE apps , *MEDICAL care , *CANCER patients , *SURVEYS , *QUESTIONNAIRES , *TECHNOLOGY , *PATIENT education , *TELEMEDICINE - Abstract
Introduction: The availability of healthcare apps to support patient self-management of various medical conditions, including cancer, has increased considerably in the past decade. However, there are limited published data on the role of apps in the management of chronic myeloid leukaemia (CML). The primary aim of this study was to investigate the current and future role of apps as a means of supporting patients with CML. Methods: A 31-item questionnaire was developed and distributed to patients via three on-line CML support groups. Results: Responses were received from 286 patients. There was an approximate 2:1 female: male split and the majority (54%, n = 155) resided in the United Kingdom. 91% (n = 260) of respondents were currently receiving drug treatment for their CML. 23.4% (n = 67) of respondents were aware that apps were available to support their CML management and 11.5% (n = 33) had experience of using such an app. 94.1% (n = 238) of those who had not used a patient support app in the past stated that they would consider using an app in the future to help manage their disease. App awareness was significantly higher amongst male patients (30.3% vs. 19.9%). Likelihood of being a current or previous app user was higher amongst younger patients (16.3% for <55 years old vs. 5.6% for ≥55 years old) whilst younger patients and those with a more recent diagnosis of CML were both more likely to be interested in using an app in the future. When asked about potential app functionality, a drug interaction checker was the feature of greatest interest to respondents. Conclusions: We have identified both a lack of awareness of and a low uptake of patient support apps amongst CML patients. Importantly, we have demonstrated a clear interest in CML-specific apps amongst this population. Based on the functionality that study participants were most interested in, we will work with health care professionals, app developers and patients to develop a new app to deliver holistic support to CML patients. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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49. CHALLENGES OF THE TREATMENT WITH TYROSINE KINASE INHIBITORS IN CHRONIC MYELOID LEUKEMIA - CASE PRESENTATION.
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BENEA, A. P., ILEA, A. M., and GAVRIS, C. M.
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PROTEIN-tyrosine kinase inhibitors , *CHRONIC myeloid leukemia , *CHRONIC leukemia , *TRANSIENT ischemic attack , *FEMORAL artery , *ISCHEMIC stroke , *ORAL drug administration - Abstract
We present the case of a 33-year-old male patient diagnosed with chronic phase chronic myeloid leukaemia in June 2008. According to treatment protocols enforced at that time, the patient started oral treatment with imatinib 400 mg/day, reaching a major molecular response (MMR) in 18-month time. The molecular response improved over the time, with an undetectable BCR-ABL1 transcript level after 36 -48 months of treatment. However, the profound molecular response did not last, requiring a switch to the second line of therapy after 75 months of imatinib. Taking nilotinib 400 mg x2/day, the patient achieved a major molecular response in 12 months, and after 18 months of treatment the level of BCR-ABL1 became undetectable. However, two vasooclusive events occurred in 2018 - a transient left parietal ischemic stroke and a left femoral artery occlusion - and in accordance with ESMO 2017 recommendations, nilotinib treatment was interrupted. The treatment free remission decision was made with monthly monitoring of the BCR-ABL1 transcript level, but since the 4th month of monitoring, the deep molecular response disappeared. Administration of dasatinib, the third tyrosine kinase inhibitor, resulted in a deep molecular response which currently lasted until now, during the 58 months of treatment. The presented case represents the evolution of the concept of treatment in this haemato-oncological disease during the last decade. [ABSTRACT FROM AUTHOR]
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- 2023
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50. Patient-guided dose reduction of tyrosine kinase inhibitors in chronic myeloid leukaemia (RODEO study): study protocol for a prospective, multicentre, single-arm trial
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Melissa F Djodikromo, Rosella PMG Hermens, Bart JF van den Bemt, Yolba Smit, Tim M Govers, Charlotte L Bekker, and Nicole MA Blijlevens
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Chronic myeloid leukaemia ,Tyrosine kinase inhibitors ,Dose reduction ,Shared decision making ,Patient-centred care ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Dose reduction of tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukaemia (CML) with an optimal response to TKIs may support cost-effective medication use by maintaining therapeutic effectiveness while reducing adverse events and medication costs. As the choice for dose reduction depends on patients’ individual needs and preferences, a patient-centred approach is warranted. Therefore, a study to evaluate the effectiveness of patient-guided dose reduction in patients with CML who are in a major or deep molecular response is designed. Methods This study is a prospective, multicentre, single-arm study. 147 patients with CML (aged ≥ 18 years) in chronic phase, who are treated with imatinib, bosutinib, dasatinib, nilotinib or ponatinib, and have reached at least major molecular response (defined as having BCR-ABL levels
- Published
- 2023
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