Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring

Abstract

CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL1 fusion oncogene, which in turn translates into a BCR-ABL1 oncoprotein. Frontline therapy: Four tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, dasatinib, and bosutinib are approved by the United States Food and Drug Administration for first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses; this has not translated into improved long-term survival, because of the availability of effective salvage therapies. Salvage therapy: For patients who fail frontline therapy, second-line options include second and third generation TKIs. Second and third generation TKIs, although potent and selective, exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities, disease stage, and BCR-ABL1 mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP who have failed at least 2 TKIs, and for all patients in CML advanced phases.

Toward the potential cure of leukemias in the next decade

“…[46][47][48][49][50] CML is characterized by the translocation of genetic material between the long arms of chromosomes 9 and 22 [t(9;22) (q34; q11)], resulting in the creation of Cancer November 15, 2018 the breakpoint cluster region-Abelson tyrosine protein kinase 1 (BCR-ABL1) fusion gene-which causes CML. The discovery of the activity of interferon α in 1983, and the later addition of homoharringtonine (now known as omacetaxine and approved by the US Food and Drug Administration [FDA] for the treatment of CML in 2012) and low-dose cytarabine resulted in a complete cytogenetic response rate (0% Ph-positive metaphases) of 20% to 30% and an improvement of the median survival to 6 to 7 years.…”

“…The discovery of the activity of interferon α in 1983, and the later addition of homoharringtonine (now known as omacetaxine and approved by the US Food and Drug Administration [FDA] for the treatment of CML in 2012) and low-dose cytarabine resulted in a complete cytogenetic response rate (0% Ph-positive metaphases) of 20% to 30% and an improvement of the median survival to 6 to 7 years. [46][47][48][49][50] Treatment-free remission as an endpoint recently has emerged as an important consideration, particularly among younger patients who wish to discontinue therapy. [46][47][48][49][50] CML is characterized by the translocation of genetic material between the long arms of chromosomes 9 and 22 [t(9;22) (q34; q11)], resulting in the creation of Cancer November 15, 2018 the breakpoint cluster region-Abelson tyrosine protein kinase 1 (BCR-ABL1) fusion gene-which causes CML.…”

Tyrosine kinase inhibitors and interferon‐α increase tunneling nanotube (TNT) formation and cell adhesion in chronic myeloid leukemia (CML) cell lines

“…To investigate the effects of TKIs on TNT formation, the K562 and Kcl-22 cells were treated with pre-apoptotic concentrations of imatinib, nilotinib, bosutinib, ponatinib, or dasatinib ( Figure 1A), kinase inhibitors currently in use as CML therapy. 58 TNT quantification was performed as earlier described for acute myeloid leukemia (AML) cells. 31 The K562 and Kcl-22 cells formed very low numbers of TNTs without treatment ( Figure 1A), however, 24 hours imatinib treatment resulted in a significant increase in TNT formation in both K562 (2.67 to 8.5 TNTs/100 cells, P-value <.001) and Kcl-22 cells (0.16 to 5.67 TNTs/100 cells P-value < .001) ( Figure 1A).…”

Relationship of oxidative stress in the resistance to imatinib in Tunisian patients with chronic myeloid leukemia: A retrospective study

“…Chronic myeloid leukemia (CML) is a malignant myeloproliferative disorder caused by the BCR‐ABL dysfunctional protein . The development of inhibitors specifically of the BCR‐ABL tyrosine kinase activity as a therapeutic agent has revolutionized CML treatment .…”