Chronic myeloid leukemia: Second‐line drugs of choice

Gambacorti‐Passerini, Carlo; Cordani, Nicoletta

doi:10.1002/ajh.24247

Cited by 34 publications

(37 citation statements)

References 65 publications

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“…Point mutations within the ABL kinase domain (eg, Y235F/H, E255K/V, T315I, and H396P/R) are associated with IM‐resistance . To counter this, second and third generation TKI (eg, dasatinib, nilotinib, bosutinib, and ponatinib) were developed . Alternatively, multiple studies suggest that overexpression of BCR/ABL‐dependent or ‐independent signaling pathways correlates with resistance to or efficacy of TKI, regardless of the point mutations mentioned above .…”

Section: Introductionmentioning

confidence: 99%

Altered intracellular signaling by imatinib increases the anti‐cancer effects of tyrosine kinase inhibitors in chronic myelogenous leukemia cells

et al. 2017

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Tyrosine kinase inhibitors (TKI), including imatinib (IM), improve the outcome of CML therapy. However, TKI treatment is long‐term and can induce resistance to TKI, which often leads to a poor clinical outcome in CML patients. Here, we examined the effect of continuous IM exposure on intracellular energy metabolism in K562 cells, a human Philadelphia chromosome‐positive CML cell line, and its subsequent sensitivity to anti‐cancer agents. Contrary to our expectations, we found that continuous IM exposure increased sensitivity to TKI. Cancer energy metabolism, characterized by abnormal glycolysis, is linked to cancer cell survival. Interestingly, glycolytic activity was suppressed by continuous exposure to IM, and autophagy increased to maintain cell viability by compensating for glycolytic suppression. Notably, increased sensitivity to TKI was not caused by glycolytic inhibition but by altered intracellular signaling, causing glycolytic suppression and increased autophagy, as evidenced by suppression of p70 S6 kinase 1 (S6K1) and activation of AMP‐activated protein kinase (AMPK). Using another human CML cell line (KCL22 cells) and BCR/ABL+ Ba/F3 cells (mimicking Philadelphia chromosome‐positive CML cells) confirmed that suppressing S6K1 and activating AMPK increased sensitivity to TKI. Furthermore, suppressing S6K1 and activating AMPK had a synergistic anti‐cancer effect by inhibiting autophagy in the presence of TKI. The present study provides new insight into the importance of signaling pathways that affect cellular energy metabolism, and suggests that co‐treatment with agents that disrupt energy metabolic signaling (using S6K1 suppressors and AMPK activators) plus blockade of autophagy may be strategies for TKI‐based CML therapy.

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Section: Introductionmentioning

confidence: 99%

Altered intracellular signaling by imatinib increases the anti‐cancer effects of tyrosine kinase inhibitors in chronic myelogenous leukemia cells

et al. 2017

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“…In recent years, the discovery of a variety of genetic alterations in different malignancies leading to oncogenesis has provided insight into the complexity of tumorigenesis and the development for target‐specific therapies with the objective of improving clinical outcomes . Among them, the breakthrough of the BCR‐ABL fusion in patients with chronic myeloid leukemia has become a paradigm for personalized or precision medicine . In current clinical practice, personalized cancer therapy is well established for a number of gene targets, including various kinase encoded genes .…”

mentioning

confidence: 99%

“…(1) Among them, the breakthrough of the BCR-ABL fusion in patients with chronic myeloid leukemia has become a paradigm for personalized or precision medicine. (2) In current clinical practice, personalized cancer therapy is well established for a number of gene targets, including various kinase encoded genes. (1) The anaplastic lymphoma kinase (ALK) gene encodes a transmembrane receptor tyrosine kinase (RTK), which belongs to the insulin receptor superfamily.…”

mentioning

confidence: 99%

The role of anaplastic lymphoma kinase in pediatric cancers

Takita

2017

Cancer Science

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The anaplastic lymphoma kinase (ALK) gene was initially identified as a fusion partner of the nucleophosmin gene in anaplastic large‐cell lymphoma with t(2;5)(p23;q35) translocation, and then described with different genetic abnormalities in a number of tumors. Although ALK is known to be involved in the pathogenesis of neuroblastoma through activating mutations or gene amplification, its role in the pathogenesis of other pediatric cancers is still elusive. In addition to neuroblastoma, the high‐grade amplification of ALK has been described in a subset of rhabdomyosarcoma cases. Normal ALK protein expression is restricted to the nervous systems of adult mammals, but the aberrant expression of ALK has been observed in a variety of pediatric cancers, including glioma and Ewing sarcoma. The discovery of oncogenic activation of ALK in neuroblastoma suggests that this cancer could be potentially treated with an ALK inhibitor, as could other cancers, such as non‐small‐cell lung cancer and anaplastic large‐cell lymphoma. However, cellular responses to mutant ALK are complex when compared to rearranged ALK, and treatment remains a challenge. This review focuses on the biology of ALK in pediatric cancers and possible therapeutic strategies for ALK‐associated tumors.

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“…In terms of efficiency, complete cytogenetical response (CCyR) rates were 44–53% for dasatinib and 31–45% for nilotinib, while MMR rates of 29–43% and 28% are reported for dasatinib and nilotinib, respectively [20–22]. Bosutinib after imatinib failure demonstrated CCyR rates of 41–48% [20, 23] and MMR rates of 64%.…”

Section: Second- and Later-line Treatmentsmentioning

confidence: 99%

“…Bosutinib after imatinib failure demonstrated CCyR rates of 41–48% [20, 23] and MMR rates of 64%. Ponatinib data refer [24] to a highly pretreated population with 58% patients having received three and more TKIs prior to this ponatinib.…”

Section: Second- and Later-line Treatmentsmentioning

confidence: 99%

Short overview on the current treatment of chronic myeloid leukemia in chronic phase

Schmidt

2016

memo

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SummaryThis short review on current treatment options in chronic myeloid leukemia (CML) in the chronic phase summarizes the latest version of the ELN treatment recommendations dating from 2013 and indicates treatment situations not yet reflected in these recommendations. Daily practice in CML management is complicated by the recently observed treatment-emergent vascular and pulmonary adverse events in second- or later-generation tyrosine kinase inhibitors (TKIs), the lack of guidance with respect to the best TKI for initial treatment, as well as the optimal TKI sequence because no prospective randomized comparative data for second- and third-generation TKIs are available. Physicians have to balance the efficacy issues and safety aspects of the respective TKI and consider patient-specific factors such as comorbidities. Patients with any cardiovascular or pulmonary disease or treatment-requiring cardiovascular risk factor should receive nilotinib or ponatinib only if risk factors and comorbidities are treated accordingly and are further monitored. If these comorbidities are insufficiently controlled, other TKIs might be preferred. Dasatinib treatment should be critically evaluated in patients with pulmonary disease and other TKIs might be preferred in this setting. For as long as CML treatment is considered to be maintained lifelong, and no survival benefit for later-generation TKIs has been demonstrated, safety issues dominate the choice of treatment options. The concept of discontinuing TKI treatment after achieving a deep molecular response might in future change these considerations.

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Chronic myeloid leukemia: Second‐line drugs of choice

Cited by 34 publications

References 65 publications

Altered intracellular signaling by imatinib increases the anti‐cancer effects of tyrosine kinase inhibitors in chronic myelogenous leukemia cells

Altered intracellular signaling by imatinib increases the anti‐cancer effects of tyrosine kinase inhibitors in chronic myelogenous leukemia cells

The role of anaplastic lymphoma kinase in pediatric cancers

Short overview on the current treatment of chronic myeloid leukemia in chronic phase

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