scholarly journals Bcr-Abl Tyrosine Kinase Inhibitors in the Treatment of Pediatric CML

2020 ◽  
Vol 21 (12) ◽  
pp. 4469 ◽  
Author(s):  
Francesca Carofiglio ◽  
Antonio Lopalco ◽  
Angela Lopedota ◽  
Annalisa Cutrignelli ◽  
Orazio Nicolotti ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Quality Data ◽  
Term Therapy ◽  
High Quality Data ◽  
Abl Tyrosine Kinase ◽  
Long Term Therapy

The therapeutic approach to Chronic Myeloid Leukemia (CML) has changed since the advent of the tyrosine kinase inhibitor (TKI) imatinib, which was then followed by the second generation TKIs dasatinib, nilotinib, and, finally, by ponatinib, a third-generation drug. At present, these therapeutic options represent the first-line treatment for adults. Based on clinical experience, imatinb, dasatinib, and nilotinib have been approved for children even though the studies that were concerned with efficacy and safety toward pediatric patients are still awaiting more specific and high-quality data. In this scenario, it is of utmost importance to prospectively validate data extrapolated from adult studies to set a standard therapeutic management for pediatric CML by employing appropriate formulations on the basis of pediatric clinical trials, which allow a careful monitoring of TKI-induced adverse effects especially in growing children exposed to long-term therapy.

scholarly journals Patient-Initiated Discontinuation of Tyrosine Kinase Inhibitor for Chronic Myeloid Leukemia

2020 ◽  
Vol 2020 ◽  
pp. 1-4
Author(s):  
Stephen E. Langabeer ◽  
Rehman Faryal ◽  
Michael O’Dwyer ◽  
Sorcha Ní Loingsigh
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Major Advance ◽  
Patient Anxiety ◽  
Molecular Monitoring ◽  
Treatment Free Remission

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.

scholarly journals The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia

2012 ◽  
Vol 2012 ◽  
pp. 1-19 ◽  
Author(s):  
Gabriela Nestal de Moraes ◽  
Paloma Silva Souza ◽  
Fernanda Casal de Faria Costas ◽  
Flavia Cunha Vasconcelos ◽  
Flaviana Ruade Souza Reis ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Resistance Mechanisms ◽  
Imatinib Resistance ◽  
Abl Tyrosine Kinase ◽  
Alternative Drug

Chronic myeloid leukemia (CML) is a clonal hematopoietic disorder characterized by the presence of the Philadelphia chromosome which resulted from the reciprocal translocation between chromosomes 9 and 22. The pathogenesis of CML involves the constitutive activation of the BCR-ABL tyrosine kinase, which governs malignant disease by activating multiple signal transduction pathways. The BCR-ABL kinase inhibitor, imatinib, is the front-line treatment for CML, but the emergence of imatinib resistance and other tyrosine kinase inhibitors (TKIs) has called attention for additional resistance mechanisms and has led to the search for alternative drug treatments. In this paper, we discuss our current understanding of mechanisms, related or unrelated to BCR-ABL, which have been shown to account for chemoresistance and treatment failure. We focus on the potential role of the influx and efflux transporters, the inhibitor of apoptosis proteins, and transcription factor-mediated signals as feasible molecular targets to overcome the development of TKIs resistance in CML.

scholarly journals BCR-ABL Tyrosine Kinase Inhibitors: Which Mechanism(s) May Explain the Risk of Thrombosis?

TH Open ◽  
2018 ◽  
Vol 02 (01) ◽  
pp. e68-e88 ◽  
Author(s):  
Hélène Haguet ◽  
Jonathan Douxfils ◽  
Christian Chatelain ◽  
Carlos Graux ◽  
François Mullier ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Clinical Data ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Risk Minimization ◽  
Abl Tyrosine Kinase ◽  
Atherosclerosis Development ◽  
Abl Tyrosine Kinase Inhibitor ◽  
Platelet Functions

AbstractImatinib, the first-in-class BCR-ABL tyrosine kinase inhibitor (TKI), had been a revolution for the treatment of chronic myeloid leukemia (CML) and had greatly enhanced patient survival. Second- (dasatinib, nilotinib, and bosutinib) and third-generation (ponatinib) TKIs have been developed to be effective against BCR-ABL mutations making imatinib less effective. However, these treatments have been associated with arterial occlusive events. This review gathers clinical data and experiments about the pathophysiology of these arterial occlusive events with BCR-ABL TKIs. Imatinib is associated with very low rates of thrombosis, suggesting a potentially protecting cardiovascular effect of this treatment in patients with BCR-ABL CML. This protective effect might be mediated by decreased platelet secretion and activation, decreased leukocyte recruitment, and anti-inflammatory or antifibrotic effects. Clinical data have guided mechanistic studies toward alteration of platelet functions and atherosclerosis development, which might be secondary to metabolism impairment. Dasatinib, nilotinib, and ponatinib affect endothelial cells and might induce atherogenesis through increased vascular permeability. Nilotinib also impairs platelet functions and induces hyperglycemia and dyslipidemia that might contribute to atherosclerosis development. Description of the pathophysiology of arterial thrombotic events is necessary to implement risk minimization strategies.

scholarly journals Is going for cure in chronic myeloid leukemia possible and justifiable?

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 122-128 ◽  
Author(s):  
François-Xavier Mahon
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Clinical Results ◽  
Major Question ◽  
Abl Tyrosine Kinase ◽  
Show Evidence ◽  
Abl Tyrosine Kinase Inhibitor

Abstract After more than a decade of treatment of chronic myeloid leukemia (CML) patients with the BCR-ABL tyrosine kinase inhibitor imatinib, and despite the impressive clinical results of this targeted therapeutic, many questions remain unresolved. One major question is how to cure CML, and the next step for the future will be to address this key issue. CML is a good model of cancer. The fact that the majority of CML patients who respond very well but discontinue tyrosine kinase inhibitors later show evidence of molecular recurrence focuses attention on the need for further research on leukemic stem cells. The challenge now is to understand why, after stopping treatment, the leukemia recurs in some patients but not in others. If we win this battle, this progress will certainly benefit the treatment and management of other leukemias and solid tumors and will validate this new topic.

scholarly journals Leukemic stem cell persistence in chronic myeloid leukemia patients with sustained undetectable molecular residual disease

Blood ◽  
2011 ◽  
Vol 118 (13) ◽  
pp. 3657-3660 ◽  
Author(s):  
Jean-Claude Chomel ◽  
Marie-Laure Bonnet ◽  
Nathalie Sorel ◽  
Angelina Bertrand ◽  
Marie-Claude Meunier ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Long Term Culture ◽  
Cell Assays ◽  
Risk Of Disease

Abstract Sustained undetectable molecular residual disease (UMRD) is obtained in a minority of patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. It remains unclear whether these patients are definitively cured of their leukemia or whether leukemic stem cells (LSCs) persist in their BM. We have evaluated the presence of BCR-ABL–expressing marrow LSCs in 6 patients with chronic myeloid leukemia with sustained UMRD induced by IFN-α (n = 3), imatinib mesylate after IFN-α failure (n = 2), and dasatinib after imatinib intolerance (n = 1). Purified CD34+ cells were used for clonogenic and long-term culture-initiating cell assays performed on classic or HOXB4-expressing MS-5 feeders. Using this strategy, we identified BCR-ABL–expressing LSCs in all patients. Interestingly, long-term culture-initiating cell assays with MS-5/HOXB4 stromal feeders increased detected numbers of LSCs in 3 patients. The relation between LSC persistency and a potential risk of disease relapse for patients with durable UMRD (on or off tyrosine kinase inhibitor therapy) warrants further investigation.

scholarly journals Tyrosine Kinase Inhibitor–Associated Cardiovascular Toxicity in Chronic Myeloid Leukemia

2015 ◽  
Vol 33 (35) ◽  
pp. 4210-4218 ◽  
Author(s):  
Javid J. Moslehi ◽  
Michael Deininger
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Rational Approach ◽  
Full Potential ◽  
T315i Mutation ◽  
Pulmonary Arterial

For most patients with chronic myeloid leukemia, tyrosine kinase inhibitors (TKIs) have turned a fatal disease into a manageable chronic condition. Imatinib, the first BCR-ABL1 TKI granted regulatory approval, has been surpassed in terms of molecular responses by the second-generation TKIs nilotinib, dasatinib, and bosutinib. Recently, ponatinib was approved as the only TKI with activity against the T315I mutation. Although all TKIs are associated with nonhematologic adverse events (AEs), experience with imatinib suggested that toxicities are typically manageable and apparent early during drug development. Recent reports of cardiovascular AEs with nilotinib and particularly ponatinib and of pulmonary arterial hypertension with dasatinib have raised concerns about long-term sequelae of drugs that may be administered for decades. Here, we review what is currently known about the cardiovascular toxicities of BCR-ABL1 TKIs, discuss potential mechanisms underlying cardiovascular AEs, and elucidate discrepancies between the reporting of such AEs between oncology and cardiovascular trials. Whenever possible, we provide practical recommendations, but we concede that cause-directed interventions will require better mechanistic understanding. We suggest that chronic myeloid leukemia heralds a fundamental shift in oncology toward effective but mostly noncurative long-term therapies. Realizing the full potential of these treatments will require a proactive rational approach to minimize long-term cardiovascular and cardiometabolic toxicities.

Tyrosine kinase inhibitor nilotinib induced palmoplantar erythrodysesthesia: A rare case

2022 ◽  
pp. 107815522110724
Author(s):  
Muzeyyen Aslaner Ak ◽  
Pelin Ertop Doğan ◽  
Birsen Sahip
Keyword(s):  
Side Effects ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Palmoplantar Erythrodysesthesia

Introduction Nilotinib is a second generation Tyrosine Kinase inhibitor (TKI) used in the treatment of Chronic Myeloid Leukemia (CML). The development of tyrosine kinase inhibitors has transformed chronic phase chronic myeloid leukemia from a disease with a poor prognosis to a treatable chronic disease. Long-term treatment with tyrosine kinase inhibitors means that patients must be clinically managed and monitored for years. While under Nilotinib tretament, the development of palmoplantar erythrodyesthesia is a very rare condition compared to other oncological drugs. Case report A 66-year-old male patient, who was diagnosed with chronic phase CML in 2019 had been placed under imatinib treatment . He had major molecular response loss in 2021, and was started on second generation TKI nilotinib 2  ×  400mg/day, considering his comorbidities. We present a case of a 66-year-old patient with CML who developed palmoplantar erythrodysesthesia on the 21st day starting nilotinib treatment. Conclusion It is important to manage the side effects that develop in long-term treatments. Adverse events can have a negative impact on patient compliance and quality of life and lead to poor clinical outcomes Our case is the first to develop PPE after beginning nilotinib use. We present this phenomenon to raise awareness and ignite a review of management strategies.In this case, we wanted to emphasize the importance of managing side effects.

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 Tyrosine Kinase Inhibitor Induced Isolated Pericardial Effusion

2015 ◽  
Vol 8 (1) ◽  
pp. 88-93 ◽  
Author(s):  
Vineet Agrawal ◽  
Eric S. Christenson ◽  
Margaret M. Showel
Keyword(s):  
Primary Care ◽  
Pericardial Effusion ◽  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Early Recognition ◽  
Primary Care Providers ◽  
Incidence Rates ◽  
Term Therapy ◽  
Care Providers

Long-term therapy with tyrosine kinase inhibitors (TKI) has resulted in improved outcomes for patients suffering from Bcr-Abl fusion protein-harboring leukemias. As a result, a growing population of patients on TKI therapy present to their primary care providers. In this case, we report on the case of a 62-year-old male who presented with a symptomatic pericardial effusion. After pericardiocentesis, malignancy and infectious etiologies were excluded. The pericardial effusion was attributed to his TKI, with a transition of this medication to a different TKI. A repeat evaluation 1 month following the withdrawal of the offending agent showed no recurrence of his pericardial effusion on echocardiogram. In this report, we will highlight a rare but important side effect of TKI therapy before discussing its purported mechanisms and differing incidence rates. Early recognition of serosal inflammation related to long-term TKI therapy by primary care providers is important in preventing patient morbidity and mortality.

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