scholarly journals Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update

2019 ◽  
Vol 20 (24) ◽  
pp. 6141 ◽  
Author(s):  
Luana Bavaro ◽  
Margherita Martelli ◽  
Michele Cavo ◽  
Simona Soverini
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Dismal Prognosis

Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene, which encodes a constitutive active tyrosine kinase considered to be the pathogenic driver capable of initiating and maintaining the disease. Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1, some patients may not respond (primary resistance) or may relapse after an initial response (secondary resistance). In a small proportion of cases, development of resistance is accompanied or shortly followed by progression from chronic to blastic phase (BP), characterized by a dismal prognosis. Evolution from CP into BP is a multifactorial and probably multistep phenomenon. Increase in BCR-ABL1 transcript levels is thought to promote the onset of secondary chromosomal or genetic defects, induce differentiation arrest, perturb RNA transcription, editing and translation that together with epigenetic and metabolic changes may ultimately lead to the expansion of highly proliferating, differentiation-arrested malignant cells. A multitude of studies over the past two decades have investigated the mechanisms underlying the closely intertwined phenomena of drug resistance and disease progression. Here, we provide an update on what is currently known on the mechanisms underlying progression and present the latest acquisitions on BCR-ABL1-independent resistance and leukemia stem cell persistence.

scholarly journals Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4820
Author(s):  
Raquel Alves ◽  
Ana Cristina Gonçalves ◽  
Sergio Rutella ◽  
António M. Almeida ◽  
Javier De Las De Las Rivas ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Fusion Gene ◽  
Computational Prediction ◽  
Tki Resistance

Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.

scholarly journals Role of anti-apoptotic pathways activated by BCR/ABL in the resistance of chronic myeloid leukemia cells to tyrosine kinase inhibitors.

2013 ◽  
Vol 60 (4) ◽  
Author(s):  
Katarzyna Danisz ◽  
Janusz Blasiak
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
Chronic Phase

Chronic myeloid leukemia (CML) is a hematological stem cell disorder characterized by the excessive proliferation of the myeloid lineage. In its initial chronic phase, the myeloid progenitor cells expand and demonstrate apparently normal differentiation. The disease may then transform into the accelerated phase, usually associated with resistance to therapy, and finally, into acute leukemic progression phase - blast crisis. Abnormal myeloid cells produce progenitors, which have lost their ability to differentiate, but retain the capacity to proliferate. The molecular hallmark of CML is the Philadelphia chromosome, resulting from reciprocal chromosome translocation, t(9;22)(q34;q11), and containing the BCR/ABL fusion gene, producing the BCR/ABL protein with a constitutive tyrosine kinase activity. BCR/ABL-positive cells have faster growth and proliferation over their normal counterparts and are resistant to apoptosis. Introduction of imatinib (IM), a tyrosine kinase inhibitor, revolutionized the therapy of CML, changing it from a fatal disease into a chronic disorder. However, some patients show a primary resistance to IM, others acquire such resistance in the course of therapy. Therefore, a small number of leukemic stem cells retains self-renewal capacity under IM treatment. Because BCR/ABL is involved in many signaling pathways, some of them may be essential for resistance to IM-induced apoptosis. The PI3K/AKT, Ras and JAK/STAT signaling pathways are involved in resistance to apoptosis and can be activated by BCR/ABL. Therefore, they can be candidates for BCR/ABL-dependent pro-survival pathway(s), allowing a fraction of CML cells to withstand treatment with tyrosine kinase inhibitors.

scholarly journals Thrombotic microangiopathy in dasatinib-treated patients with chronic myeloid leukemia

2019 ◽  
Vol 4 (1-2) ◽  
pp. 41-45 ◽  
Author(s):  
Takeo Koshida ◽  
Sylvia Wu ◽  
Hitoshi Suzuki ◽  
Rimda Wanchoo ◽  
Vanesa Bijol ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Kinase Inhibitors ◽  
Thrombotic Microangiopathy ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kidney Biopsy ◽  
Kinase Inhibitor ◽  
Target Effect

Dasatinib is the second-generation tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia. Proteinuria has been reported with this agent. We describe two kidney biopsy–proven cases of dasatinib-induced thrombotic microangiopathy that responded to stoppage of dasatinib and using an alternate tyrosine kinase inhibitor. Certain specific tyrosine kinase inhibitors lead to endothelial injury and renal-limited thrombotic microangiopathy. Hematologists and nephrologists need to be familiar with this off-target effect of dasatinib.

scholarly journals A Retrospective Analysis about Frequency of Monitoring in Italian Chronic Myeloid Leukemia Patients after Discontinuation

2020 ◽  
Vol 9 (11) ◽  
pp. 3692
Author(s):  
Matteo Dragani ◽  
Giovanna Rege Cambrin ◽  
Paola Berchialla ◽  
Irene Dogliotti ◽  
Gianantonio Rosti ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Molecular Response ◽  
Molecular Monitoring ◽  
Delay In Diagnosis ◽  
Number Of Patients

Successful discontinuation of tyrosine kinase inhibitors has been achieved in patients with chronic-phase chronic myeloid leukemia (CML). Careful molecular monitoring after discontinuation warrants safe and prompt resumption of therapy. We retrospectively evaluated how molecular monitoring has been conducted in Italy in a cohort of patients who discontinued tyrosine kinase inhibitor (TKI) treatment per clinical practice. The outcome of these patients has recently been reported—281 chronic-phase CML patients were included in this subanalysis. Median follow-up since discontinuation was 2 years. Overall, 2203 analyses were performed, 17.9% in the first three months and 38.4% in the first six months. Eighty-six patients lost major molecular response (MMR) in a mean time of 5.7 months—65 pts (75.6%) during the first six months. We evaluated the number of patients who would experience a delay in diagnosis of MMR loss if a three-month monitoring schedule was adopted. In the first 6 months, 19 pts (29.2%) would have a one-month delay, 26 (40%) a 2-month delay. Very few patients would experience a delay in the following months. A less intense frequency of monitoring, particularly after the first 6 months off treatment, would not have affected the success of treatment-free remission (TFR) nor put patients at risk of progression.

Recurrent bone marrow aplasia secondary to nilotinib in a patient with chronic myeloid leukemia: A case report

2012 ◽  
Vol 18 (4) ◽  
pp. 440-444 ◽  
Author(s):  
Prathima Prodduturi ◽  
Anamarija M Perry ◽  
Patricia Aoun ◽  
Dennis D Weisenburger ◽  
Mojtaba Akhtari
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Bone Marrow Aplasia ◽  
Line Therapy ◽  
Grade 3

Nilotinib is a potent tyrosine kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL), which has been approved as front-line therapy for newly diagnosed chronic myeloid leukemia in chronic phase and as second-line therapy after imatinib failure in chronic or accelerated phase chronic myeloid leukemia. Tyrosine kinase inhibitors have been associated with myelosuppression and grade 3 or grade 4 cytopenias are not uncommon in chronic myeloid leukemia patients treated with these drugs. There are a few reports of imatinib-associated bone marrow aplasia, but to our knowledge only one reported case of bone marrow aplasia associated with nilotinib. Herein, we report a 49-year-old male patient with chronic phase chronic myeloid leukemia, who developed severe bone marrow aplasia due to nilotinib. Possible mechanisms for this significant adverse drug reaction are discussed along with a review of literature.

scholarly journals Tyrosine Kinase Inhibitor Therapy for Chronic Myeloid Leukemia: Approach to Patients with Treatment-Naive or Refractory Chronic-Phase Disease

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 121-127 ◽  
Author(s):  
Catherine C. Smith ◽  
Neil P. Shah
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Rapid Development ◽  
Chronic Phase ◽  
The United States ◽  
Medical Needs ◽  
Treatment Naïve

Abstract The 21st century ushered in the dawn of a new era of targeted therapeutics and a dramatic shift in the management of chronic-phase chronic myeloid leukemia (CP-CML) patients. Groundbreaking scientific and translational studies have led to the rapid development and approval of several effective BCR-ABL tyrosine kinase inhibitors (TKIs). In the United States, there are currently 3 approved BCR-ABL TKIs for newly diagnosed CP-CML patients. It is anticipated that clinical outcomes will continue to improve as more TKIs that address unmet medical needs are approved. However, to achieve this goal, it is critical to carefully monitor and optimally manage patients. To this end, the latest seminal clinical trial results of approved and investigational BCR-ABL TKIs and some of the salient unique features of each of these agents are summarized herein.

scholarly journals Krónikus myeloid leukaemia miatt 2003 és 2019 között a Semmelweis Egyetem Belgyógyászati és Onkológiai Klinikáján kezelt betegek adatainak elemzése

2021 ◽  
Vol 162 (32) ◽  
pp. 1297-1302
Author(s):  
Júlia Weisinger ◽  
Ilona Tárkányi ◽  
Eid Hanna ◽  
Ágnes Kárpáti ◽  
Zsolt Nagy ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Treatment Change

Összefoglaló. Bevezetés: A krónikus myeloid leukaemia a diagnosztika fejlődésének és a tirozin-kináz-gátlók bevezetésének köszönhetően az elmúlt évtizedekben kiváló prognózisú betegséggé vált. Célkitűzés: A betegséggel kapcsolatos ismereteink nagy része klinikai vizsgálatokból származik, emiatt kiemelt szerepük van a nem szelektált beteganyagon végzett elemzéseknek. Módszer: Retrospektív elemzésünkben a Semmelweis Egyetem Belgyógyászati és Onkológiai Klinikáján 2003 és 2019 között tirozin-kináz-gátló kezelésben részesült betegek adatait tekintettük át. Eredmények: Klinikánkon összesen 88 beteg részesült terápiában, közülük 73 beteg az analízis időpontjában is kezelés alatt állt. A betegek 5 éves össztúlélése 86%, 5 éves progressziómentes túlélése 70% volt. 9 beteg halt meg, közülük 2 betegnél a halál oka a progrediáló alapbetegség volt. 38 betegnél volt szükség az első vonalban terápiaváltásra, a váltás oka akkor elsősorban az elégtelen terápiás válasz volt. A későbbi terápiaváltásokra elsősorban intolerancia miatt került sor. Az első vonalban a betegek több mint fele major molekuláris választ ért el, a jelenlegi kezelés mellett a betegek 85%-ánál major molekuláris választ detektáltunk. Megbeszélés: Adataink alapján az intézményünkben kezelt betegek túlélése és a betegek által elért terápiás válasz megfelel a nemzetközi adatoknak. Következtetés: Mivel nem válogatott beteganyagról van szó, a kapott eredmények pontosabb képet adhatnak a krónikus myeloid leukaemia tirozin-kináz-gátlóval történt kezelésének eredményeiről. Orv Hetil. 2021; 162(32): 1297–1302. Summary. Introduction: As a result of advances in diagnostic techniques and the introduction of tyrosine kinase inhibitors, the prognosis of chronic myeloid leukemia has improved over the last decades. Objective: Most of our knowledge about chronic myeloid leukemia results from clinical trials, therefore data derived from non-selected patient population is substantial. Method: Data of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors at the Department of Internal Medicine and Oncology, Semmelweis University, between 2003 and 2019 were analysed retrospectively. Results: 88 patients received treatment, 73 patients were on therapy at the time of the analysis. Overall survival at 5 years was 86%, progression-free survival at 5 years was 70%. 9 patients died, 2 of them due to progressive disease. 38 patients needed 2nd line therapy, the main reason of treatment change was failure of therapy. Subsequent treatment modifications were conducted mostly because of intolerance. More than half of the patients on 1st line treatment reached major molecular response and 85% of the patients on treatment at the end of the analysis are in major molecular response. Discussion: Based on our data, survival and therapeutic response of patients in our center are similar to the international results. Conclusion: This analysis provides real-world data about treatment results of chronic myeloid leukemia in the tyrosine kinase inhibitor era. Orv Hetil. 2021; 162(32): 1297–1302.

scholarly journals Use of tyrosine kinase inhibitor by patients with chronic myeloid leukemia at a public hematology institution in the state of Amazonas, Brazil

2020 ◽  
Vol 11 (4) ◽  
pp. 510
Author(s):  
Andreia D. MENEZES ◽  
Nelson A. FRAIJI
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Cross Sectional Study ◽  
Chi Square ◽  
Cross Sectional ◽  
The Right

Objectives: To evaluate the conditions of use of tyrosine kinase inhibitors and adherence by patients with chronic myeloid leukemia treated at a public hematology institution. Methods: This was an observational and cross-sectional study carried out from December 2015 to April 2016. Data collection was carried out through interviews with standardized questionnaires that assessed the socioeconomic and demographic profile, drug therapy and by the Morisky-Green test that assessed the green adherence. Patients over 18 years old who had been using one of the tyrosine kinase inhibitors for more than one month were included; imatinib, dasatinib or nilotinib and who signed the informed consert form, agreement to participate in study. Descriptive statistical analysis and chi-square test with Yates correction were performed. Results: 63 patients were interviewed, with a mean age of 50 years with a standard deviation of 15.95. being 60% men. As for knowledge about the aspects related to the use of inhibitors: 95.2% took at the right time, 93.7% did not use other medications concomitantly, 63.5% kept it in an appropriate place and 97% of the patients received prior guidance from the doctor about the use. As for information about treatment, 90.5% knew the purpose of taking the medication, 60% did not know the time of use, 83% did not know what would happen if they stopped taking it and 73% believed they could stop the treatment at some point. Adherence to treatment was identified 46% of patients. Conclusion: No statistically significant differences were found between having or not adherence, when compared with the studied variables.

Mechanisms of Resistance to Targeted Therapies in Acute Myeloid Leukemia and Chronic Myeloid Leukemia

2012 ◽  
pp. 685-689
Author(s):  
Catherine C. Smith ◽  
Neil P. Shah
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chronic Myeloid Leukemia ◽  
Targeted Therapies ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Oncogenic Signaling ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Clinical Resistance ◽  
Acute Myeloid

Overview: Small molecule kinase inhibitors of BCR-ABL in chronic myeloid leukemia (CML) and of FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in acute myeloid leukemia (AML) have been successful at achieving remissions in these diseases as monotherapy, but these leukemias do not initially respond in a subset of patients (primary resistance) and they progress in an additional group of patients after an initial response (secondary resistance). Resistance to these agents can be divided into mechanisms that allow reactivation kinase activity and those that bypass reliance on oncogenic signaling mediated by the target kinase. Elucidation of clinical resistance mechanisms to targeted therapies for patients can provide important insights into disease pathogenesis and signaling.

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