Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Kantarjian, Hagop M.; Cortés, Jorge E.; Rosée, Paul La; Hochhaus, Andreas

doi:10.1002/cncr.24928

Cited by 41 publications

(37 citation statements)

References 87 publications

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“…This goal was confirmed through both computational modeling and in vitro experiments. Alternative treatments for CML are still needed because of the inability to eliminate CML stem cells, resistance to small molecule inhibitors, and ineffective treatment of advanced stages of the disease (25,(52)(53)(54)(55). Given the importance the coiled coil domain has in the regulation of Bcr-Abl activity, it has long been hypothesized that this domain could be used therapeutically.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Bcr-Abl Coiled Coil Oligomerization by Design

Dixon

Pendley

Bruno

et al. 2011

Journal of Biological Chemistry

105

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Oligomerization is an important regulatory mechanism for many proteins, including oncoproteins and other pathogenic proteins. The oncoprotein Bcr-Abl relies on oligomerization via its coiled coil domain for its kinase activity, suggesting that a designed coiled coil domain with enhanced binding to Bcr-Abl and reduced self-oligomerization would be therapeutically useful. Key mutations in the coiled coil domain of Bcr-Abl were identified that reduce homo-oligomerization through intermolecular charge-charge repulsion yet increase interaction with the Bcr-Abl coiled coil through additional salt bridges, resulting in an enhanced ability to disrupt the oligomeric state of Bcr-Abl. The mutations were modeled computationally to optimize the design. Assays performed in vitro confirmed the validity and functionality of the optimal mutations, which were found to exhibit reduced homo-oligomerization and increased binding to the Bcr-Abl coiled coil domain. Introduction of the mutant coiled coil into K562 cells resulted in decreased phosphorylation of Bcr-Abl, reduced cell proliferation, and increased caspase-3/7 activity and DNA segmentation. Importantly, the mutant coiled coil domain was more efficacious than the wild type in all experiments performed. The improved inhibition of Bcr-Abl through oligomeric disruption resulting from this modified coiled coil domain represents a viable alternative to small molecule inhibitors for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Disruption of Bcr-Abl Coiled Coil Oligomerization by Design

Dixon

Pendley

Bruno

et al. 2011

Journal of Biological Chemistry

105

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“…L'avvento degli inibitori di seconda generazione disegnati proprio per superare tale resistenza ha rappresentato un ulteriore passo avanti nella cura della LMC. Questi infatti, pur avendo come target primario sempre BCR-ABL, presentano una più alta affinità per il sito catalitico in modo da legarsi in maniera più stabile al BCR-ABL [1] .…”

Section: Discussioneunclassified

“…Nonostante gli ottimi risultati, una quota di pazienti sviluppa resistenza. In questi casi l'uso degli inibitori di seconda generazione, inibitori più potenti di imatinib, rappresenta una valida alternativa [1].…”

Section: Introduzioneunclassified

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Nilotinib efficacy in a patient resistant to imatinib

Luciano

2015

CMI

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Imatinib, a BCR-ABL inhibitor, is the standard of care for the first-line treatment of patients with chronic-phase CML. Despite the optimal results, some patients develop resistance to imatinib. For these patients, the second-generation tyrosine kinase inhibitors represent effective therapeutic options. Here, we describe a report about a young patient with CML developing resistance to imatinib due to BCR-ABL kinase domain mutations. After six months of treatment with imatinib 400 mg daily, the patient had complete cytogenic response, while at 12 months he had a sub-optimal molecular response, that is a "warning" according to the European LeukemiaNet guidelines (both 2006 and 2009). At 29 months, persisting the sub-optimal molecular response, we decided to increase the imatinib dose up to 800 mg daily. Even after the dose escalation, the patient couldn't achieve a major molecular response. Therefore we subjected him to a mutation screening, that highlighted L248V mutation. After switching to nilotinib the patient has resulted in complete cytogenic response and major molecular response.

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“…Adverse effects grade 1 to 2 must be treated; on the contrary, they may affect the long-term compliance. They must be timely solved to prevent, if possible, stopping imatinib treatment [53].…”

Section: Intolerancementioning

confidence: 99%

Mexican Guidelines for the Diagnosis and Treatment of Chronic Myeloid Leukaemia

Cervera¹,

Godínez²,

Sosa³

et al. 2013

JCT

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Background: This document includes recommendations and guidelines issued by a group of Mexican researchers and specialists gathered in the First National Colloquium for the Diagnosis and Management of Chronic Myeloid Leukaemia (CML) by initiative of Instituto Nacional de Cancerología and with the support of the Leukaemia Department of the MD Anderson Cancer Center. Mexico lacks of updated information taken from its own reality on the diagnosis and treatment of CML and other haematological disorders; besides, there are no national guidelines. Aim: To publish a consensus document with guidelines for the management of CML adjusted to the national environment and overall characteristics. Method: The participants answered a DELPHI questionnaire about the overall aspects of the disease, aiming to target controversial topics, discuss them in the colloquium, and to agree on the best ones. After those meetings, a final document was drawn up. Results: The group presents recommendations for definition, diagnosis, prognosis, monitoring, and treatment of CML in Mexico. Conclusions: Having consensus guidelines for the clinical management of CML in our country will enable the consensual practice of Mexican specialists regarding the clinical approach to CML, as well as optimize the resources which allow the rational planning of the medical care strategies.

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Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Cited by 41 publications

References 87 publications

Disruption of Bcr-Abl Coiled Coil Oligomerization by Design

Disruption of Bcr-Abl Coiled Coil Oligomerization by Design

Nilotinib efficacy in a patient resistant to imatinib

Mexican Guidelines for the Diagnosis and Treatment of Chronic Myeloid Leukaemia

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