Evolving treatment strategies for patients newly diagnosed with chronic myeloid leukemia: the role of second-generation BCR–ABL inhibitors as first-line therapy

Shami, Paul J.; Deininger, Michael

doi:10.1038/leu.2011.217

Cited by 41 publications

(39 citation statements)

References 108 publications

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“…One point is the choice of the first TKI. [162][163][164] Two trials have shown an initial superiority of second-generation TKIs vs imatinib, with significant differences in response but not yet in outcome. [9][10][11][12][13] They justify placing nilotinib and dasatinib in the front-line setting but do not justify the exclusion of imatinib.…”

Section: Discussionmentioning

confidence: 99%

European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013

Baccarani

Deininger

Rosti

et al. 2013

Blood

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Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, <1% at 6 months, and ≤0.1% from 12 months onward define optimal response, whereas >10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome–positive [Ph+] >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.

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Section: Discussionmentioning

confidence: 99%

European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013

Baccarani

Deininger

Rosti

et al. 2013

Blood

1,736

2,099

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“…The Food and Drug Administration-approved multi-kinase inhibitors dasatinib and bosutinib inhibit both ABL and SRC kinases and are used for the treatment of imatinib-resistant and -sensitive BCR-ABL-positive malignancies. 29,30 Interestingly, both drugs very potently inhibit LCK activity in vitro with IC 50 values of ~1-2 nM. 31,32 We showed that NUP214-ABL1 activity is inhibited by dasatinib in in vitro kinase assays, that proliferation of NUP214-ABL1-positive cells is inhibited by dasatinib and that dasatinib inhibits NUP214-ABL1-positive leukemogenesis in mouse xenografts and primary NUP214-ABL1-positive T-ALL lymphoblasts.…”

Section: Genementioning

confidence: 99%

NUP214-ABL1-mediated cell proliferation in T-cell acute lymphoblastic leukemia is dependent on the LCK kinase and various interacting proteins

et al. 2013

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ABSTRACTtics that target therapy-resistant cells, much effort has been invested in identifying novel proteins or pathways that are required for BCR-ABL-mediated transformation.11 An important example is the observation that certain SRC family kinases are critical signaling proteins in BCR-ABL1-positive B-ALL and advanced CML. [12][13][14][15] Indeed, the SRC family kinase LYN is over-expressed in ABL1 kinase inhibitor-resistant CML blast crisis and knockdown of LYN induces apoptosis in these cells.14 In addition, proteins interacting with BCR-ABL1 were recently identified, 16 which may allow the identification of therapeutically relevant critical interactors. In contrast, unbiased studies of the NUP214-ABL1 signaling network are lacking and critical signaling pathways and interactors that can be therapeutically targeted may previously have been missed.We fear that, as for BCR-ABL1, resistance to ABL1 inhibitors may develop readily in NUP214-ABL1-positive T-ALL. Although clinical experience with ABL1 inhibitors in NUP214-ABL1-positive T-ALL is limited, a recent report on a NUP214-ABL1-positive patient who had imatinib added to his therapeutic scheme did indeed show that the patient, after obtaining a rapid remission, had a fatal relapse. 17 In this study, we aimed to identify novel therapeutic targets in NUP214-ABL1-positive T-ALL by using two approaches. First, we investigated the therapeutic potential of SRC family kinases. In addition, we performed an unbiased mass spectrometry and short interfering (si)RNA-based screen to identify proteins that are critical for the survival and proliferation of NUP214-ABL1-positive T-ALL cells. Methods ConstructsHemagglutinin(HA)-tagged NUP155 and SMC4 cDNAs were synthesized (Genscript) and cloned into the XhoI and EcoRI restriction sites of pMSCV-puro (Clontech). NUP214-ABL1 and BCR-ABL1 constructs are described elsewhere. 7Cell culture ALL-SIL, K-562, KE-37, RPMI-8402, JURKAT, SUP-T1, RLD-1 and L-5178-Y cell lines (obtained from DSMZ) were cultured in RPMI-1640 medium with 20% fetal calf serum (FCS). NA10073 and NA10075 cell lines were established from mouse T-ALL leukemias induced in a NUP214-ABL1 bone marrow transplant assay 7 and were cultured in RPMI-1640 with 20% FCS. HEK293T cells (from DSMZ) were cultured in RPMI-1640 with 10% FCS. Transfections were performed using Turbofect reagent (Fermentas). ImmunoblottingSamples were processed according to standard procedures using the following antibodies: anti-FYN (Fyn3), anti-LCK (3A5), anti-ABL1 (24-11) and anti-ERK2 (Santa Cruz Biotechnology); anti-NUP155 (ab73292) (Abcam); anti-phospho-SRC family (Tyr416), anti-phospho-ABL1 (Tyr245), anti-SMC4 (D14E2) and anti-MAD2L1 (D8A7) (Cell Signaling); anti-HA tag (12CA5) (Roche) and peroxidase-labeled anti-mouse/anti-rabbit antibodies (Amersham). Short interfering RNA knockdownHuman T-ALL cell lines were electroporated on a Genepulser Xcell instrument (Biorad) with 400 nM siRNA. For mouse T-ALL cell lines, two electroporations were performed with a 24-h interval. Viable cell number...

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“…1 In 2011, the overwhelming majority of patients diagnosed and treated in the chronic phase (CML-CP) can expect long-term survival with good quality of life. In fact, life expectancy of patients with CML-CP who have maintained a complete cytogenetic response on imatinib for 2 years is identical to that of an aged-matched control.…”

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confidence: 99%

Stem cell persistence in chronic myeloid leukemia

Deininger

2012

Leukemia Suppl

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Tyrosine kinase inhibitors (TKIs) of BCR-ABL have turned chronic myeloid leukemia (CML) from a deadly disease into a chronic ailment. Unfortunately, evidence is accumulating that TKIs are not curative, since CML stem cells are not addicted to BCR-ABL, and persist despite TKI therapy. On closer view this is not surprising, as it reflects fundamental principles of CML pathogenesis. Strategies to eradicate CML stem cells will most likely be based on synthetic lethality though parallel inhibition of BCR-ABL and other critical pathways.

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Evolving treatment strategies for patients newly diagnosed with chronic myeloid leukemia: the role of second-generation BCR–ABL inhibitors as first-line therapy

Cited by 41 publications

References 108 publications

European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013

European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013

NUP214-ABL1-mediated cell proliferation in T-cell acute lymphoblastic leukemia is dependent on the LCK kinase and various interacting proteins

Stem cell persistence in chronic myeloid leukemia

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