Is modulation of multidrug resistance a viable strategy for acute myeloid leukemia?

Larson, Richard A.

doi:10.1038/sj.leu.2402809

Cited by 11 publications

(7 citation statements)

References 35 publications

(27 reference statements)

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“…Several major studies, particularly Cancer and Leukemia Group B (CALGB) 9621 [2,3] and the French ALFA 9000 studies [4], have shown that higher doses of DNR (80 or 90 mg/m 2 ) can be administered safely. Recently, there are two major prospective studies compared DNR 90 mg/m 2 with 45 mg/m 2 in the induction regimen.…”

Section: New Regimens For Induction Therapy Of Newly Diagnosed Amlmentioning

confidence: 99%

Novel agents and regimens for acute myeloid leukemia: 2009 ASH annual meeting highlights

Zhu

Liu

2010

J Hematol Oncol

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Prognostic markers, such as NPM1, Flt3-ITD, and cytogenetic abnormalities have made it possible to formulate aggressive treatment plans for unfavorable acute myeloid leukemia (AML). However, the long-term survival of AML with unfavorable factors remains unsatisfactory. The latest data indicate that the standard dose of daunorubicin (DNR) at 45 mg/m2 is inferior to high dose 90 mg/m2 for induction therapy. The rates of complete remission and overall survival are significantly better in the high dose induction regimen. New regimens exploring the new liposomal encapsulation of Ara-C and DNR as well as addition of gemtuzumab ozogamicin monoclonal antibody have been studied. New agents, including the nucleoside analogues (clofarabine, sapacitabine, elacytarabine), FLT3 inhibitor (sorafenib), farnesyl-transferase inhibitor (tipifarnib), histone deacetylase inhibitor (vorinostat), lenalidomide, as well as DNA methyltransferase inhibitors (decitabine, azacitidine), were recently reported for AML treatment in the 2009 ASH annual meeting. This review also summarizes the updates of the clinical trials on novel agents including voreloxin, AS1413, behenoylara-C, ARRY520, ribavirin, AZD1152, AZD6244, and terameprocol (EM-1421) from the 2009 ASH annual meeting.

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Section: New Regimens For Induction Therapy Of Newly Diagnosed Amlmentioning

confidence: 99%

Novel agents and regimens for acute myeloid leukemia: 2009 ASH annual meeting highlights

Zhu

Liu

2010

J Hematol Oncol

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“…Morphologically, elderly blasts have less granulation and fewer Auer rods (Hassan & Rees, 1990), and biologically, elderly AML has a more immature stem cell-like phenotype (Fialkow et al, 1981), resulting in increased cytopenias and toxicity with treatment (Stephan et al, 1998). Elderly patients have overexpression of the multidrug resistance 1 (MDR1) gene (Leith et al, 1997(Leith et al, , 1999Appelbaum et al, 2006;Roboz, 2007;Sekeres, 2008;Kuendgen & Germing, 2009), which encodes an efflux pump, permeability glycoprotein (Pgp), that extrudes chemotherapeutics from the cell and increases treatment resistance (Leith et al, 1997;van der Kolk et al, 2002;Larson, 2003;Solary et al, 2003;Mahadevan & List, 2004;Burnett & Mohite, 2006). MDR1 over-expression correlates with a reduced CR rate, OS and DFS, and is associated with relapsed and refractory disease, secondary AML and adverse cytogenetics (Wood et al, 1994;Willman, 1996;Leith et al, 1999;Pinto et al, 2001;Baer et al, 2002;Larson, 2003;van der Holt et al, 2005;Burnett & Mohite, 2006;Estey, 2007;Dombret et al, 2008).…”

Section: Biological Factors Versus Host Factorsmentioning

confidence: 99%

“…Elderly patients have overexpression of the multidrug resistance 1 (MDR1) gene (Leith et al, 1997(Leith et al, , 1999Appelbaum et al, 2006;Roboz, 2007;Sekeres, 2008;Kuendgen & Germing, 2009), which encodes an efflux pump, permeability glycoprotein (Pgp), that extrudes chemotherapeutics from the cell and increases treatment resistance (Leith et al, 1997;van der Kolk et al, 2002;Larson, 2003;Solary et al, 2003;Mahadevan & List, 2004;Burnett & Mohite, 2006). MDR1 over-expression correlates with a reduced CR rate, OS and DFS, and is associated with relapsed and refractory disease, secondary AML and adverse cytogenetics (Wood et al, 1994;Willman, 1996;Leith et al, 1999;Pinto et al, 2001;Baer et al, 2002;Larson, 2003;van der Holt et al, 2005;Burnett & Mohite, 2006;Estey, 2007;Dombret et al, 2008). Finally, gene expression profiling in elderly AML has resulted in the identification of distinct subgroups that vary by outcome, supporting a molecular basis for poor clinical outcomes in elderly patients (Wilson et al, 2006;Raponi et al, 2008;de Jonge et al, 2009;Rao et al, 2009) (Table I).…”

Section: Biological Factors Versus Host Factorsmentioning

confidence: 99%

Acute myeloid leukaemia in the elderly: a review

Pollyea¹,

Kohrt²,

Medeiros³

2011

Br J Haematol

133

125

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SummaryThe majority of patients with acute myeloid leukaemia (AML) are elderly. Advancements in supportive care and regimen intensification have resulted in improvements in clinical outcomes for younger AML patients, but analogous improvements in older patients have not been realized. While outcomes are compromised by increased comorbidities and susceptibility to toxicity from therapy, it is now recognized that elderly AML represents a biologically distinct disease that is more aggressive and less responsive to therapy. Some patients tolerate and benefit from intensive remission‐induction approaches, while others are best managed with less aggressive strategies. The challenge is to differentiate these groups based on host‐related and biological features, in order to maximize the therapeutic benefit and minimize toxicity. As more is understood about the complicated pathogenesis and molecular basis of AML, there are more opportunities to develop and test targeted therapies. Elderly patients, with their narrow therapeutic window, are well positioned to derive a benefit from these novel agents, and therefore, despite a difficult past, there are reasons to be optimistic about the future of elderly AML.

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“…MDR-1 blockade using cyclosporine A or PSC 833 is not of proven benefit [153,154] and may either increase toxicity or necessitate dose reduction and hence reduce overall chemotherapy exposure [193,194].…”

Section: New Cytotoxic Agentsmentioning

confidence: 99%