P669: ANALYSIS OF FACTORS INFLUENCING THE DECISION TO STOP TKI TREATMENT IN CML PATIENTS IN DEEP MOLECULAR RESPONSE
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ABSTRACT:
SUBMITTER: Semerad L
PROVIDER: S-EPMC10429555 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Project description: Not available
| S-EPMC6046500 | biostudies-literature
Project description:Longitudinal monitoring of BCR-ABL transcript levels in peripheral blood of CML patients treated with tyrosine kinase inhibitors (TKI) revealed a typical biphasic response. Although second generation TKIs like dasatinib proved more efficient in achieving molecular remission compared to first generation TKI imatinib, it is unclear how individual responses differ between the drugs and whether mechanisms of drug action can be deduced from the dynamic data. We use time courses from the DASISION trial to address statistical differences in the dynamic response between first line imatinib vs. dasatinib treatment cohorts and we analyze differences between the cohorts by fitting an established mathematical model of functional CML treatment to individual time courses. On average, dasatinib-treated patients show a steeper initial response, while the long-term response only marginally differed between the treatments. Supplementing each patient time course with a corresponding confidence region, we illustrate the consequences of the uncertainty estimate for the underlying mechanisms of CML remission. Our model suggests that the observed BCR-ABL dynamics may result from different, underlying stem cell dynamics. These results illustrate that the perception and description of CML treatment response as a dynamic process on the level of individual patients is a prerequisite for reliable patient-specific response predictions and treatment optimizations.
| S-EPMC6098052 | biostudies-literature
Project description:Numerous combinations of signaling pathway blockades in association with tyrosine kinase inhibitor (TKI) treatment have been proposed for eradicating leukemic stem cells (LSCs) in chronic myeloid leukemia (CML), but none are currently clinically available. Because targeting protein kinase Cδ (PKCδ) was demonstrated to eliminate cancer stem cells (CSCs) in solid tumors, we evaluated the efficacy of PKCδ inhibition in combination with TKIs for CML cells. We observed that inhibition of PKCδ by a pharmacological inhibitor, by gene silencing, or by using K562 CML cells expressing dominant-negative (DN) or constitutively active (CA) PKCδ isoforms clearly points to PKCδ as a regulator of the expression of the stemness regulator BMI1. As a consequence, inhibition of PKCδ impaired clonogenicity and cell proliferation for leukemic cells. PKCδ targeting in K562 and LAMA-84 CML cell lines clearly enhanced the apoptotic response triggered by any TKI. A strong synergism was observed for apoptosis induction through an increase in caspase-9 and caspase-3 activation and significantly decreased expression of the Bcl-xL Bcl-2 family member. Inhibition of PKCδ did not modify BCR-ABL phosphorylation but acted downstream of the oncogene by downregulating BMI1 expression, decreasing clonogenicity. PKCδ inhibition interfered with the clonogenicity of primary CML CD34+ and BCR-ABL-transduced healthy CD34+ cells as efficiently as any TKI while it did not affect differentiation of healthy CD34+ cells. LTC-IC experiments pinpointed that PKCδ inhibition strongly decreased the progenitors/LSCs frequency. All together, these results demonstrate that targeting of PKCδ in combination with a conventional TKI could be a new therapeutic opportunity to affect for CML cells.
| S-EPMC8038300 | biostudies-literature
Project description:Tyrosine kinase inhibitors (TKIs) have improved outcomes of chronic myeloid leukemia (CML). However, 20-30% of patients require second-line TKIs following suboptimal response. The cost and adverse events limit their use in resource-constraint settings. We conducted a pilot study to ascertain the benefit of adding pioglitazone to TKIs with suboptimal response in real-world resource-constraint settings. In this pragmatic pilot study from 01 Jan 2017 to 31 July 2021, CML patients from a tertiary care center in North India with sub-optimal response to TKIs were additionally given pioglitazone after ruling out imatinib resistance mutation (n - 31). Pioglitazone was stopped if there was disease progression on follow-up, and second-line TKI was started. The data were analyzed with the intention-to-treat principle using JMP Ver.15.1.1. The median age of the study population was 54y (27-82), who were followed up for a median duration of 1023.5d (59-1117). Pioglitazone showed the benefit of one-log reduction in BCR-ABL in 89.7% of the study participants. 1y, 2y and 3y-PFS were 92.57%, 76.5%, and 68.3% respectively. During follow-up period, the disease progressed in 38.7%, of which two succumbed. No adverse events to Pioglitazone were documented. This study proved that adding Pioglitazone to the existing TKI regime in CML with sub-optimal response can benefit. The addition of Pioglitazone was well tolerated.Graphical abstractSupplementary informationThe online version contains supplementary material available at 10.1007/s12288-022-01561-x.
| S-EPMC9868211 | biostudies-literature
Project description:Chronic myeloid leukaemia (CML) is a clonal haemopoietic stem cell (HSC) disorder associated with the BCR-ABL oncogene, which encodes a constitutively active tyrosine kinase. We have demonstrated the existence of CML HSC which are resistant to the tyrosine kinase inhibitors (TKI). We have hypothesised that CML stem cells are dependent on key survival pathways that are induced by TKI treatment. In order to elucidate these key survival pathways, we have investigated the transcriptional differences between CML stem/progenitor cells (CD34+38-) treated with TKIs (imatinib, dasatinib and nilotinib) at different time points (8 hours and 7 days, in the absence of growth factors) and by carrying out RNA profiling for the different populations. CD34+38- cells were isolated from chronic phase patient samples. >100ng of total RNA was amplified prior to analysis that was carried out with Affymetrix Human Gene 1.0 ST array.
2018-01-20 | E-MTAB-2594 | biostudies-arrayexpress
Project description:BackgroundApproximately 5-20% of chronic myeloid leukemia (CML) patients demonstrate primary resistance or intolerance to imatinib. None of the existing predictive scores gives a good prognosis of TKI efficacy. Gene polymorphisms, expression and microRNAs are known to be involved in the pathogenesis of TKI resistance in CML. The aim of our study is to find new molecular markers of TKI therapy efficacy in CML patients.MethodsNewly diagnosed patients with Ph+ CML in chronic phase were included in this study. Optimal and non-optimal responses to TKI were estimated according to ELN 2013 recommendation. We performed genotyping of selected polymorphisms in 62 blood samples of CML patients, expression profiling of 33 RNA samples extracted from blood and miRNA profiling of 800 miRNA in 12 blood samples of CML patients.ResultsThe frequencies of genotypes at the studied loci did not differ between groups of patients with an optimal and non-optimal response to TKI therapy. Analysis of the expression of 34,681 genes revealed 26 differently expressed genes (p < 0.05) in groups of patients with different TKI responses, but differences were very small and were not confirmed by qPCR. Finally, we did not find difference in miRNA expression between the groups.ConclusionsUsing modern high-throughput methods such as whole-exome sequencing, transcriptome and miRNA analysis, we could not find reliable molecular markers for early prediction of TKI efficiency in Ph+ CML patients.
| S-EPMC6416830 | biostudies-literature
Project description: Not available
| S-EPMC7481600 | biostudies-literature
Project description:Purpose of reviewFor patients with chronic phase chronic myeloid leukemia (CP-CML), there is an increasing focus on personalization of therapy with dose modifications of tyrosine kinase inhibitors (TKIs) to reduce side effects and maintain efficacy. Dose reductions are also being considered in clinical trials prior to treatment-free remission (TFR) attempts.Recent findingsRecent retrospective analyses of large clinical trials show that dose modification/reduction is safe. Efficacy is generally maintained and side effects are improved. Clinical trials such as DESTINY have demonstrated that dose reduction is safe for patients in deep molecular remission and may be considered prior to a TFR attempt. Dose modifications are widely used to prevent and manage the toxicities of TKIs. With adequate monitoring, dose optimization is safe, reduces side effects, and improves quality-of-life for patients. Clinical trials of dose optimization are currently recruiting across all approved TKIs and will lead to further personalization of therapy for CP-CML patients in the future.
| S-EPMC6647386 | biostudies-literature
Project description:PurposeIn this scoping review, we evaluated existing literature related to factors influencing treatment decision-making for patients diagnosed with cancer in low- and middle-income countries, noting factors that influence decisions to pursue treatment with curative versus non-curative intent. We identified an existing framework for adult cancer developed in a high-income country (HIC) context and described similar and novel factors relevant to low-and middle-income country settings.MethodsWe used scoping review methodology to identify and synthesize existing literature on factors influencing decision-making for pediatric and adult cancer in these settings. Articles were identified through an advanced Boolean search across six databases, inclusive of all article types from inception through July 2022.ResultsSeventy-nine articles were identified from 22 countries across six regions, primarily reporting the experiences of lower-middle and upper-middle-income countries. Included articles largely represented original research (54%), adult cancer populations (61%), and studied patients as the targeted population (51%). More than a quarter of articles focused exclusively on breast cancer (28%). Approximately 30% described factors that influenced decisions to choose between therapies with curative versus non-curative intent. Of 56 reported factors, 22 novel factors were identified. Socioeconomic status, reimbursement policies/cost of treatment, and treatment and supportive care were the most commonly described factors.ConclusionsThis scoping review expanded upon previously described factors that influence cancer treatment decision-making in HICs, broadening knowledge to include perspectives of low- and middle-income countries. While global commonalities exist, certain variables influence treatment choices differently or uniquely in different settings. Treatment regimens should further be tailored to local environments with consideration of contextual factors and accessible resources that often impact decision-making.
| S-EPMC10524036 | biostudies-literature
Project description:In an emergency, making the correct decision is vital. It is a necessary element of professional nursing care, and the ability of nurses to make successful clinical decisions is the most critical element influencing care quality. The purpose of this study was to assess the factors influencing nurses' clinical decision-making in the emergency department of Palestinan hospitals. A cross-sectional study was targeted at all nurses working in emergency departments at the Palestinian hospitals. The study was completed with 227 nurses, and collecting data was performed with the Clinical Decision Making in Nursing Scale. Results of the study revealed that the average score for the total clinical decision-making score was 3.3 (SD = 0.23). The subscales of clinical decision making were "search for alternatives or options," "canvassing of objectives and values," "evaluation and reevaluation of consequences," and "search for information and unbiased assimilation of new information." Furthermore, multiple linear regression analysis revealed that degree and work hours accounted for 11.7% of the variance in clinical decision-making. The study confirmed the average score for clinical decision-making was slightly higher than the average score. Also, it approved that nursing degree and work hours were predictors of clinical decision-making among nurses in emergency departments.
| S-EPMC9893345 | biostudies-literature