Precision tyrosine kinase inhibitor dosing in chronic myeloid leukemia?
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ABSTRACT:
SUBMITTER: Saglio G
PROVIDER: S-EPMC6518890 | biostudies-literature | 2019 May
REPOSITORIES: biostudies-literature
Publications
Precision tyrosine kinase inhibitor dosing in chronic myeloid leukemia?
Saglio Giuseppe G Fava Carmen C Gale Robert Peter RP
Haematologica 20190501 5
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Project description:The introduction of tyrosine kinase inhibitors (TKI) has revolutionised the management of patients with chronic myeloid leukemia (CML) over the last twenty years, but despite significant improvements in survival, patients exhibit long-term side effects that impact on quality of life. A major advance in CML management has been the ability to discontinue TKI therapy achieving a treatment-free remission (TFR), yet this option is only available to eligible patients who present with low-risk disease and who subsequently attain deep and sustained molecular responses. A case is described of a patient with CML who self-initiated stopping of TKI therapy when in a less than optimal molecular remission. Despite this action, the patient continues to experience a TFR with prospective close molecular monitoring performed. It is emphasized that this approach may lead to ineffective treatment discontinuation, molecular relapse, and increased patient anxiety. As TFR for patients with CML moves from clinical trials into routine clinical practice, emphasis is placed on adherence to (evolving) guidelines critical to ensure optimal counselling, selection, monitoring, and continued management of patients whether TFR is successful or not.
| S-EPMC7125505 | biostudies-literature
Project description:Relapse of chronic myeloid leukemia (CML) is triggered by stem cells with a reconstituting capacity similar to that of hematopoietic stem cells (HSCs) and CML stem cells are a source of resistance in drug therapy with tyrosine kinase inhibitors (TKIs). Ecotropic viral integration site 1 (EVI1), a key transcription factor in HSC regulation, is known to predict poor outcomes in myeloid malignancies, however, incapability of prospective isolation of EVI1-high leukemic cells precludes the functional evaluation of intraindividual EVI1-high cells. Introduction of CML into Evi1-internal ribosomal entry site (IRES)-green fluorescent protein (GFP) knock-in mice, a versatile HSC-reporter strain, enables us to separate Evi1-high CML cells from the individual. Evi1-IRES-GFP allele models of CML in chronic phase (CML-CP), by retroviral overexpression of BCR-ABL and by crossing BCR-ABL transgenic mice, revealed that Evi1 is predominantly enriched in the stem cell fraction and associated with an enhanced proliferative as well as a leukemia-initiating capacity and that Evi1-high CML-CP cells exhibit resistance to TKIs. Overexpressing BCR-ABL and NUP98-HOXA9 in Evi1-IRES-GFP knock-in mice to model CML in blast crisis (CML-BC), in which Evi1-high cells turned to be a major population as opposed to a minor population in CML-CP models, showed that Evi1-high CML-BC cells have a greater potential to recapitulate the disease and appear resistant to TKIs. Furthermore, given that Evi1 heterozygosity ameliorates CML-CP and CML-BC development and that the combination of Evi1 and BCR-ABL causes acute myeloid leukemia resembling CML-BC, Evi1 could regulate CML development as a potent driver. In addition, in human CML-CP cases, we show that EVI1 is highly expressed in stem cell-enriched CD34+CD38-CD90+ fraction at single-cell level. This is the first report to clarify directly that Evi1-high leukemic cells themselves possess the superior potential to Evi1-low cells in oncogenic self-renewal, which highlights the role of Evi1 as a valuable and a functional marker of CML stem cells.
| S-EPMC4217142 | biostudies-literature
Project description:BackgroundTyrosine kinase inhibitor (TKI)-based therapy is a recommended treatment for patients with chronic myeloid leukemia (CML). However, a considerable group of CML patients do not respond well to the TKI therapy. Challenging to overcome this problem, we tried to discover molecular signatures in gene expression profiles to discriminate the responders and non-responders of TKI therapy.MethodsWe collected three microarray datasets of CML patients having total 73 responders and 38 non-responders. Statistical analysis was performed to identify differentially expressed genes (DEGs) as gene signature candidates from integrated microarray datasets. The classification performance of these genes and further selected discriminator gene sets was tested by using random forest and iterative backward variable selection methods.ResultsWe identified a set of genes including CTBP2, NADK, AZU1, CTSH, FSTL1, and HDLBP showing the highest accuracy more than 69.44 % to classify TKI response in CML patients. Interestingly, four genes of them are on the signaling pathway of cell proliferation. This set of genes showed much higher performance than the average performance of other genes in downstream signaling of TKI target, BCR-ABL.ConclusionsIn this study, we could find a set of potential companion diagnostic markers for TKI treatment and, at the same time, the potential of gene expression analysis to enhance the coverage of companion diagnostics.
| S-EPMC4989900 | biostudies-literature
Project description:Asciminib, a "Specifically Targeting the ABL Myristoyl Pocket" inhibitor, is a new drug in the treatment of tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia (CML). Hemocytopenias associated with asciminib are common adverse events documented by clinical trials. We report a case of precipitous-onset pancytopenia with the initiation of asciminib treatment in a patient with TKI-resistant CML. This case had a confounding array of laboratory findings that evidenced a drug-induced hemophagocytic component. We hope that our case stimulates further reporting of similar cases to enhance the understanding of the pathophysiology underlying asciminib-induced hemocytopenias.
| S-EPMC10401557 | biostudies-literature
Project description: Not available
| S-EPMC10728762 | biostudies-literature
Project description:Ponatinib, the only third-generation pan-BCR::ABL1 inhibitor with activity against all known BCR::ABL1 mutations including T315I, has demonstrated deep and durable responses in patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to prior second-generation (2G) TKI treatment. We present efficacy and safety outcomes from the Ponatinib Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and CML Evaluation (PACE) and Optimizing Ponatinib Treatment in CP-CML (OPTIC) trials for this patient population. PACE (NCT01207440) evaluated ponatinib 45 mg/day in CML patients with resistance to prior TKI or T315I. In OPTIC (NCT02467270), patients with CP-CML and resistance to ≥2 prior TKIs or T315I receiving 45 or 30 mg/day reduced their doses to 15 mg/day upon achieving ≤1% BCR::ABL1IS or received 15 mg/day continuously. Efficacy and safety outcomes from patients with CP-CML treated with ≥1 2G TKI (PACE, n = 257) and OPTIC (n = 93), 45-mg starting dose cohort, were analyzed for BCR::ABL1IS response rates, overall survival (OS), progression-free survival (PFS), and safety. By 24 months, the percentages of patients with ≤1% BCR::ABL1IS response, PFS, and OS were 46%, 68%, and 85%, respectively, in PACE and 57%, 80%, and 91%, respectively, in OPTIC. Serious treatment-emergent adverse events and serious treatment-emergent arterial occlusive event rates were 63% and 18% in PACE and 34% and 4% in OPTIC. Ponatinib shows high response rates and robust survival outcomes in patients whose disease failed prior to 2G TKIs, including patients with T315I mutation. The response-based dosing in OPTIC led to improved safety and similar efficacy outcomes compared with PACE.
| S-EPMC9804741 | biostudies-literature
Project description:IntroductionAlthough consistent use of tyrosine kinase inhibitors (TKIs) confers significant improvements in long-term survival for individuals with chronic myeloid leukemia (CML), only 70% of CML patients are adherent to TKIs. Understanding the factors that contribute to non-adherence and establishing dynamic adherence patterns in this population are essential aspects of targeted drug monitoring and intervention strategies.MethodsNewly diagnosed CML patients were identified in the MarketScan database and relevant covariate values extracted. Proportion of days covered (PDC) per 30-day interval was used to calculate adherence over a 12-month follow-up period. We conducted a latent profile analysis (LPA) on these PDC estimates to identify distinct, dynamic patterns of TKI adherence. Identified trajectories were grouped into four clinically relevant categories and predictors of membership in these categories were determined via multinomial logistic regression.ResultsFour broad adherence categories were identified from the LPA: never adherent, initially non-adherent becoming adherent, initially adherent becoming non-adherent, and stable adherent. Results from the subsequent multinomial logistic regression indicated that younger age, female sex, greater monthly financial burden, fewer comorbidities, fewer concomitant medications, year of diagnosis, higher starting dose, TKI type, and a longer duration from diagnosis to treatment were significantly associated with membership in at least one of the three non-stable adherent groups.ConclusionSelect sociodemographic and clinical characteristics were found to predict membership in clinically meaningful groups of longitudinal TKI adherence. These findings could have major implications for informing personalized monitoring and intervention strategies for individuals who are likely to be non-adherent.
| S-EPMC8110595 | biostudies-literature
Project description:We investigated the impact of carrying more than one BCR-ABL1 mutation in 207 patients with chronic myeloid leukemia (102 chronic, 61 accelerated, and 44 blast phase) post-imatinib failure. Seven (8%) of 92 patients carrying mutations had more than one mutation: 4 (4%) in chronic phase, 2 (2%) in accelerated phase, and one (1 %) in blast phase. The cytogenetic response rate to second generation TKIs for patients with no, one, or more than one mutation was 88%, 69%, 50% (P=0.03) in chronic phase, 54%, 42%, 50% in accelerated phase (P=0.67), and 35%, 25%, 0% (P=0.63) in blast phase, respectively. No differences were observed in event free survival or overall survival in accelerated or blast phase according to their mutational status. However, the 4-year event free survival rates among patients in chronic phase with no, one, or more than one BCR-ABL1 mutation were 56%, 49%, and 0%, respectively (P=0.02), with overall survival rates of 91%, 69%, and 75%, respectively (P=0.13). In conclusion, patients with more than one BCR-ABL1 mutation fare worse than those with no or one mutation.
| S-EPMC3105655 | biostudies-literature
Project description:BackgroundCurrent recommendations for monitoring patients with chronic myeloid leukemia (CML) provide recommendations for response assessment and treatment only at 3, 6, 12, and 18 months. These recommendations are based on clinical trial outcomes computed from treatment start. Conditional survival estimates take into account the changing hazard rates as time from treatment elapses as a continuum.Patients and methodsWe performed conditional survival analyses among patients with CML to improve prognostication at any time point during the course of therapy. We used 2 cohorts of patients with CML in chronic phase: 1 treated in the frontline DASISION (Dasatinib versus Imatinib Study in Treatment - Naïve CML) phase III study (n = 519) and another treated after imatinib treatment had failed in the dasatinib dose-optimization phase III CA180-034 study (n = 670). Conditional survival estimates were calculated. A modified Cox proportional hazards model was used to build a prognostic nomogram.ResultsAs the time alive or free from events from commencement of treatment increased, conditional survival estimates changed. No differences were observed regarding future outcomes between patients treated with imatinib or dasatinib in the frontline setting for patients with the same breakpoint cluster region-abelson 1 (BCR-ABL1) transcript levels evaluated at the same time point. Age older than 60 years greatly affected future outcomes particularly in the short-term. Conditional survival-based nomograms allowed the prediction of future outcomes at any time point.ConclusionIn summary, we designed a calculator to predict future outcomes of patients with CML at any time point during the course of therapy.
| S-EPMC4099320 | biostudies-literature
Project description:Comorbidities at diagnosis among patients with chronic myeloid leukemia in chronic phase (CML-CP) may affect their overall survival (OS) rate even in the tyrosine kinase inhibitor (TKI) era. However, the prognostic impact of comorbidities in patients with CML-CP treated with a second-generation TKI (2GTKI) has not been elucidated. We evaluated the effect of comorbidities on survival using the Charlson Comorbidity Index (CCI) in patients with CML-CP treated with imatinib or a 2GTKI (nilotinib and dasatinib). From April 2010 to March 2013, 506 patients with CML-CP were registered for the population-based cohort study, and 452 with a median age of 56 y were assessable. Treatment groups included 139 patients receiving imatinib, 169 receiving nilotinib, and 144 receiving dasatinib. Comorbidities were diagnosed in 99 patients. CCI scores were stratified as follows: 2, 353 patients; 3, 72 patients; and ≥4, 27 patients. Treatment response did not vary relative to CCI scores. However, across the entire cohort, the OS rate was significantly lower among patients with higher CCI scores than in those with a CCI score of 2 (94.4% in score 2, 89.0% in score 3, and 72.8% in score ≥4; P < .001). Multivariate analysis identified a CCI score of ≥4 as a strong adverse prognostic factor for OS rather than the disease-specific risk factor, older age, performance status, or selection of TKI (Wald test, P < .01). Our results demonstrated that comorbidities at diagnosis were the most important predictive factor for successful treatment, regardless of the TKI type used in CML-CP. This trial was registered at UMIN-CTR as 00003581.
| S-EPMC7541002 | biostudies-literature