Chronic myeloid leukaemia

2020 ◽  
pp. 93-112
Author(s):  
Tariq I. Mughal
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Treatment Algorithm ◽  
Chromosome 9 ◽  
Balanced Translocation ◽  
Optimal Monitoring ◽  
Advanced Phase ◽  
Cytogenetic Remission ◽  
Initial Choice

Chronic myeloid leukaemia (CML) was recognized in the 1970s by Janet Rowley to be a genetically simple malignancy; resulting as a consequence of a balanced translocation between chromosome 9 and 22. This provided vital insights into the molecular aberration, in the 1990s, which ushered in the current ‘precision medicine’ era, not only for patients of CML, but for cancers in general. As a result, today, a personalized treatment algorithm is available for all newly diagnosed patients with CML. Treatment involves a choice of three first-line orally administered tyrosine kinase inhibitors (TKIs) and two effective next-line TKIs that should be used based on risk stratification, comorbidities, the side effects profile, and the BCR-ABL1 genotype. Regardless of the initial choice of TKI, the vast majority of patients achieve a durable complete cytogenetic remission, with a lifespan approaching that of the general population. In most instances the medication must be continued indefinitely, and a principal challenge now, is to develop strategies to stop TKIs safely and effectively. Challenges remain in how to achieve optimal monitoring of patients with CML on treatment and in achieving a better understanding of the mechanisms and treatment of patients with advanced phase disease. This chapter addresses these questions as well as the concomitant topical issues in CML.

Deletions Adjacent to BCR and ABL Breakpoints Occur in a Substantial Minority of Chronic Myeloid Leukaemia Patients with Masked Philadelphia Rearrangements.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2929-2929
Author(s):  
Valeria A. De Melo ◽  
Paul Kotzampaltiris ◽  
Elisabeth Nacheva ◽  
David Marin ◽  
Jane F. Apperley ◽  
...  
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Chronic Phase ◽  
Chromosome 9 ◽  
Significant Feature ◽  
Potential Side Effect ◽  
Translocation Breakpoints ◽  
Dual Colour

Abstract Chronic myeloid leukaemia (CML) results from the malignant transformation of haematopoietic stem cells by the BCR-ABL fusion gene, generated by a reciprocal translocation between chromosomes 9 and 22, the Philadelphia (Ph) translocation, or variations thereof. Common permutations of the Ph include translocations involving one or more additional chromosomes to 9 and 22 (“variant” Ph), and rearrangements resulting in cryptic insertion of chromosome 9 into chromosome 22, or vice versa, leaving apparently normal chromosomes 9 and 22 (“masked” Ph). Recently the development of new FISH techniques led to the identification of unexpected deletions at the Ph translocation breakpoints in approximately 15% of CML patients. The deletions, encompassing sequences 3′ of the BCR breakpoint and/or 5′ of the ABL breakpoint, were associated with a shorter duration of chronic phase and shorter survival in patients treated with interferon therapy, although their impact in patients treated with tyrosine kinase inhibitors is currently unclear. Interestingly, the incidence of deletions has been shown to vary for different cytogenetic subgroups of CML, with a significantly higher incidence of deletion in patients with a variant Ph translocation. The frequency of such events in patients with masked Ph rearrangements, however, has not yet been explored because of limitations inherent to the widely adopted dual-colour BCR-ABL FISH approach. We report the evaluation of 14 patients with masked Ph-positive CML for the presence of deletions extending 3′ from BCR and 5′ from ABL using two 3-colour BCR-ABL probes. Deletions were identified in 3 patients in total (21%), encompassing sequences 5′ to ABL in two of these and sequences 3′ to BCR in the remaining patient, thus demonstrating that the phenomenon is a significant feature of the masked Ph CML subgroup. Furthermore, our findings are consistent with the notion that loss of genomic material is a potential side effect of any DNA breakage event at the 9q34.1 and 22q11.2 chromosomal regions, regardless of the subsequent mechanism of chromosomal rearrangement.

scholarly journals Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yotaro Ochi ◽  
Kenichi Yoshida ◽  
Ying-Jung Huang ◽  
Ming-Chung Kuo ◽  
Yasuhito Nannya ◽  
...  
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Blast Crisis ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Genetic Alterations ◽  
Prognostic Impact ◽  
Genetic Abnormalities ◽  
Prior Use

AbstractBlast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.

scholarly journals Pharmacokinetics of Dasatinib

2019 ◽  
Vol 120 (2-3) ◽  
pp. 52-63 ◽  
Author(s):  
Jana Hořínková ◽  
Martin Šíma ◽  
Ondřej Slanař
Keyword(s):  
Cytochrome P450 ◽  
Chronic Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Gastric Ph ◽  
Simultaneous Administration ◽  
Essential Tool ◽  
Pharmacokinetic Properties

Tyrosine kinase inhibitors have recently become an essential tool in management of chronic myeloid leukaemia (CML). Dasatinib, a representative of those drugs, acts by inhibiting key proteins included in CML development, predominantly Bcr-Abl and Src. Its advantage is that it shows activity in many cases where other agents bring no improvement due to resistance. Pharmacokinetics of dasatinib has specific characteristics that may play an important role in achieving sufficient exposure in patients. Therefore, the key pharmacokinetic properties are summarized in this report. For example, dasatinib absorption is significantly influenced by gastric pH and its modulation can be a source of serious interactions, as well as simultaneous administration of drugs affecting cytochrome P450.

scholarly journals Treatment-Free Remission in Chronic Myeloid Leukaemia: Can We Identify Prognostic Factors?

2021 ◽  
Author(s):  
Hilbeen Hisham Saifullah ◽  
Claire Marie Lucas
Keyword(s):  
Prognostic Factors ◽  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Response ◽  
Predicting Success ◽  
Treatment Free Remission ◽  
Almost All ◽  
Tki Discontinuation

Following the development of tyrosine kinase inhibitors (TKI), the survival of patients with chronic myeloid leukaemia (CML) drastically improved. With the introduction of these agents, CML is now considered a chronic disease, for some patients. Taking into consideration the side effects, toxicity, and high cost, discontinuing TKIs became a goal for patients with chronic phase CML. Patients who achieved deep molecular response (DMR) and discontinued TKI, remained in treatment-free remission (TFR). Currently, the data from the published literature demonstrate that 40-60% of patients achieve TFR, with relapses occurring within the first six months. In addition, almost all patients who relapsed regained a molecular response upon re-treatment, indicating TKI discontinuation is safe. However, there is still a gap in the understanding the mechanisms behind TFR, and whether there are prognostic factors that can predict the best candidates who qualify for TKI discontinuation with a view to keeping them in TFR. Furthermore, the information about a second TFR attempt and the role of gradual de-escalation of TKI before complete cessation is limited. This review highlights the factors predicting success or failure of TFR. In addition, it ex-amines the feasibility of a second TFR attempt after the failure of the first one, and the current guidelines concerning TFR in clinical practice.

DI-104 Tyrosine kinase inhibitors in chronic myeloid leukaemia: use and safety profile

2014 ◽  
Vol 21 (Suppl 1) ◽  
pp. A112.1-A112
Author(s):  
CM Valencia Soto ◽  
F Artime Rodriguez-Hermida ◽  
S Cortés de Miguel ◽  
R López Sepúlveda ◽  
C Alarcón Payer ◽  
...  
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Tyrosine Kinase Inhibitors ◽  
Safety Profile ◽  
Kinase Inhibitors
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