A pilot study of continuous imatinib vs pulsed imatinib with or without G-CSF in CML patients who have achieved a complete cytogenetic response

Drummond, Mark; Heaney, Nicholas; Kaeda, Jaspal; Nicolini, Franck E.; Clark, Richard E.; Wilson, George; Shepherd, Patricia; Tighe, Jane; McLintock, Lorna; Hughes, Timothy P.; Holyoake, Tessa L.

doi:10.1038/leu.2009.43

Cited by 35 publications

(28 citation statements)

References 6 publications

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“…26). For chronic myeloid leukemia (CML), stimulation with cytokines like granulocyte colony-stimulating factor (G-CSF) and IFN-a was presented to induce proliferation of the dormant stem cell compartment (30,31). In this study, due to FdUrd stimulation, myeloma stem-like cells appeared to acquire an injury-and repair-activated state characterized by cell cycling accompanied with high metabolic turnover rates.…”

Section: Discussionmentioning

confidence: 93%

Breaking the Invulnerability of Cancer Stem Cells: Two-Step Strategy to Kill the Stem-like Cell Subpopulation of Multiple Myeloma

Morgenroth

Vogg

Zlatopolskiy

et al. 2014

Molecular Cancer Therapeutics

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Section: Discussionmentioning

confidence: 93%

Breaking the Invulnerability of Cancer Stem Cells: Two-Step Strategy to Kill the Stem-like Cell Subpopulation of Multiple Myeloma

Morgenroth

Vogg

Zlatopolskiy

et al. 2014

Molecular Cancer Therapeutics

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“…27 The recently reported failure of a clinical trial employing G-CSF to eradicate minimal residual disease following imatinib therapy 28 may be related to a selective resistance of leukemic cells to be mobilized by G-CSF and/or to a regimen ineffective at doing so. It is well known that AMD3100 is more potent than G-CSF at inducing normal hematopoietic stem cell mobilization.…”

Section: Discussionmentioning

confidence: 99%

Bone marrow mesenchymal stromal cells non-selectively protect chronic myeloid leukemia cells from imatinib-induced apoptosis via the CXCR4/CXCL12 axis

Vianello¹,

Villanova²,

Tisato³

et al. 2010

Haematologica

152

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The online version of this article has a Supplementary Appendix. BackgroundResidual chronic myeloid leukemia disease following imatinib treatment has been attributed to the presence of quiescent leukemic stem cells intrinsically resistant to imatinib. Mesenchymal stromal cells in the bone marrow may favor the persistence and progression of leukemia by preserving the proliferation and self-renewal capacities of the malignant progenitor cells. Design and MethodsBV173 or primary chronic myeloid leukemia cells were co-cultured with human mesenchymal stromal cells and imatinib-induced cell death was then measured. The roles of pro-and antiapoptotic proteins and chemokine CXCL12 in this context were evaluated. We also studied the ability of BV173 cells to repopulate NOD/SCID mice following in vitro exposure to imatinib and mesenchymal stromal cells. ResultsWhilst imatinib induced dose-dependent apoptosis of BV173 cells and primary chronic myeloid leukemia cells, co-culture with mesenchymal stromal cells protected both types of chronic myeloid leukemia cells. Molecular analysis indicated that mesenchymal stromal cells reduced caspase-3 activation and modulated the expression of the anti-apoptotic protein Bcl-XL. Furthermore, chronic myeloid leukemia cells exposed to imatinib in the presence of mesenchymal stromal cells retained the ability to engraft into NOD/SCID mice. We observed that chronic myeloid leukemia cells and mesenchymal stromal cells express functional levels of CXCR4 and CXCL12, respectively. Finally, the CXCR4 antagonist, AMD3100 restored apoptosis by imatinib and the susceptibility of the SCID leukemia repopulating cells to the tyrosine kinase inhibitor. ConclusionsHuman mesenchymal stromal cells mediate protection of chronic myeloid leukemia cells from imatinib-induced apoptosis. Disruption of the CXCL12/CXCR4 axis restores, at least in part, the leukemic cells' sensitivity to imatinib. The combination of anti-CXCR4 antagonists with tyrosine kinase inhibitors may represent a powerful approach to the treatment of chronic myeloid leukemia.

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“…As mentioned above, the use of targeted antibodies, together with other anti-leukemic drugs, may be one possible (encouraging) approach. An alternative approach to overcome LSC quiescence is to apply LSC-priming agents such as cytokines (G-CSF, IL-3, SCF, others) in order to induce cycling of LSC prior to drug exposure [145,146]. Another strategy to overcome LSC resistance may be to combine cytotoxic drugs or TKI with MDR-1 inhibitors (e.g.…”

Section: Development Of Lsc-eradicating Drug Therapiesmentioning

confidence: 99%

Targeting of Leukemia-Initiating Cells to Develop Curative Drug Therapies: Straightforward but Nontrivial Concept

Valent¹

2011

CCDT

124

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The concept of leukemic stem cells (LSC) is increasingly employed to explain the biology of various myeloid neoplasms and to screen for essential targets, with the hope to improve drug therapy through elimination of disease-initiating cells. Although the stem cell hypothesis may apply to all neoplasms, leukemia-initiating cells have so far only been characterized in some detail in advanced acute (AML) and chronic myeloid leukemia (CML). An intriguing observation is that although expressing various targets, LSC often remain unresponsive against most drugs, presumably because of 'intrinsic' resistance. Moreover, LSC represent heterogeneous populations of cells, grow in separate subclones, and acquire numerous defects, which points to substantial genetic instability and stem cell plasticity. The situation is complicated by the fact that stem cell evolution is a step-wise process with variable latency periods, so that many LSC-derived subclones remain small (undetectable) at diagnosis, but later, during therapy, may expand to a dominant clone and clinically overt relapsing disease. Finally the interaction between LSC and the microenvironment may contribute to stem cell function and LSC resistance. Taking all these considerations into account, the application of broadly acting targeted drugs and of drug combinations has been proposed in order to better suppress or even eliminate LSC in AML and CML. The current article provides a summary of our knowledge on LSC in various myeloid neoplasms with special reference to novel arising treatment concepts.

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A pilot study of continuous imatinib vs pulsed imatinib with or without G-CSF in CML patients who have achieved a complete cytogenetic response

Cited by 35 publications

References 6 publications

Breaking the Invulnerability of Cancer Stem Cells: Two-Step Strategy to Kill the Stem-like Cell Subpopulation of Multiple Myeloma

Breaking the Invulnerability of Cancer Stem Cells: Two-Step Strategy to Kill the Stem-like Cell Subpopulation of Multiple Myeloma

Bone marrow mesenchymal stromal cells non-selectively protect chronic myeloid leukemia cells from imatinib-induced apoptosis via the CXCR4/CXCL12 axis

Targeting of Leukemia-Initiating Cells to Develop Curative Drug Therapies: Straightforward but Nontrivial Concept

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