The presence of a BCR-ABL mutant allele in CML does not always explain clinical resistance to imatinib

Khorashad, Jamshid S.; Anand, Mona; Marín, David; Saunders, S. J.; Al-Jabary, T; Iqbal, Ahmed; Margerison, S; Melo, Junia V.; Goldman, John M.; Apperley, Jane F.; Kaeda, Jaspal

doi:10.1038/sj.leu.2404137

Cited by 137 publications

(93 citation statements)

References 29 publications

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“…23 The most common cause of secondary imatinib resistance is point mutations in BCR-ABL that prevent effective binding of imatinib but may retain kinase activity. [35][36][37][38][39] These mutations are clustered primarily within the kinase domain of BCR-ABL (ABL exons 4-10). 40 They exhibit differential relative resistance to imatinib in vitro.…”

Section: Imatinib Nilotinib Dasatinibmentioning

confidence: 99%

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Kantarjian

Cortés

Rosée

et al. 2010

Cancer

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Identification of BCR‐ABL as the defining leukemogenic event in chronic myelogenous leukemia (CML) revolutionized the treatment of the disease. Imatinib, a potent BCR‐ABL inhibitor, is the standard of care for the first‐line treatment of patients with chronic‐phase CML because of its high long‐term response rates and favorable tolerability profile compared with previous standard therapies. However, resistance to imatinib develops in 2% to 4% of patients annually. For patients with acquired cytogenetic resistance to standard‐dose imatinib (400 mg daily), imatinib dose escalation (600‐800 mg daily) is an excellent first option for managing patients and achieving cytogenetic responses. However, for patients with primary resistance to imatinib, hematologic disease recurrence, or emergent BCR‐ABL kinase domain mutations, imatinib dose escalation may not be sufficient to control the disease. For these patients, the potent second‐generation tyrosine kinase inhibitors dasatinib and nilotinib are available. Both agents provide effective therapeutic options for patients with imatinib resistance or intolerance. For the current overview, the authors reviewed the data supporting the use of both dasatinib and nilotinib in imatinib‐resistant or imatinib‐intolerant patients, and they have highlighted the future of CML therapy. Overall, the article is intended to offer physicians a comprehensive review of the current literature and to provide data supporting various treatment options for patients with CML throughout the course of imatinib therapy and beyond. Cancer 2010. © 2010 American Cancer Society.

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Section: Imatinib Nilotinib Dasatinibmentioning

confidence: 99%

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Kantarjian

Cortés

Rosée

et al. 2010

Cancer

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“…Two recent frontiers in leukemia research are the emergence of imatinib-resistant CMLs [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77] and the discovery of mutations at the Jak2 kinase in certain myeloproliferative diseases. These topic areas document the importance of genetic approaches in leukemia and abnormal hematopoiesis research as they were discovered upon identification of the genetic mutations responsible for the hematopoietic neoplasia.…”

Section: Novel Hematopoietic Targets and Resistancementioning

confidence: 99%

Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

et al. 2008

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“…The best described is the t(14;19) involving the BCL3 gene, often associated with atypical morphology, unmutated VH genes and inferior prognosis. 4,6 The t(14;18)(q32;q21) and its variants, the t(2;18) (p11;q21) and t(18;22)(q21;q11), lead to overexpression of P-value was still non-significant when loss of response was analysed for experimental arms (pIM plus pIM-G) vs cIM (P ¼ 0.4). Abbreviations: CCyR, complete cytogenetic response; cIM, continuous IM; MMR, major molecular response; pIM, pulsed IM; pIM-G, pulsed IM plus G-CSF.…”

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confidence: 99%

“…F317L mutation comprised 83% of clone using methodology as published. 6 now being estimated at X20 years. Identifying a measurable depletion of the BCR-ABL þ -quiescent leukaemic stem cell pool may simply not be feasible over this period of time, which was chosen as a result of practical issues with running such a study and ethical concerns regarding the safety of IM dose interruption.…”

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confidence: 99%

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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

et al. 2009

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The presence of a BCR-ABL mutant allele in CML does not always explain clinical resistance to imatinib

Cited by 137 publications

References 29 publications

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

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

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