Optimizing Outcomes for Patients With Advanced Disease in Chronic Myelogenous Leukemia

Francis J. Giles, Daniel J. DeAngelo, Michele Baccarani, Michael Deininger, François Guilhot, Timothy Hughes, Michael Mauro, Jerald Radich, Oliver Ottmann, Jorge Cortes

Research output: Contribution to journalArticle

Abstract

The treatment of chronic myelogenous leukemia (CML) has been revolutionized by the development of the small-molecule tyrosine kinase inhibitor imatinib. The primary target for this drug is the oncogenic BCR-ABL kinase. Five-year survival rates for patients in chronic phase CML is now greater than 80%. Patients who have advanced beyond the chronic phase to the accelerated phase or blast crisis, however, have not faired as well. Progression occurs for a variety of reasons, including late diagnosis, slow response to imatinib, and the development of imatinib-resistant clones. Imatinib resistance has, in part, been addressed with the introduction of the new BCR-ABL inhibitors, namely dasatinib and nilotinib. These drugs have shown efficacy in CML patients with wild-type BCR-ABL and some BCR-ABL mutants that are imatinib-resistant. Unfortunately, some BCR-ABL mutations remain resistant to these therapies and will require the development of alternative treatments, and other mechanisms of imatinib resistance besides BCR-ABL mutation exist. In the future, genetic and pharmacologic tests may allow the clinician to predict response to imatinib. More aggressive therapies are being considered for high-risk patients, including increased dosage of the current tyrosine kinase inhibitors, along with combination therapies. Aggressive therapy holds promise, as the data suggest that responses are improved. Unfortunately, toxicities are also increased, and thus a balance must be found to ensure safety and compliance. This is especially important for young CML patients, who hopefully will remain in remission for decades. Polymerase chain reaction analysis has become of primary importance as a means of assessing disease burden, and given the idiosyncrasies of this technique, standards must be established to allow results to be compared across different institutions. Additionally, the nature of advanced disease is being explored. Intriguingly, genetic analysis of transformed blasts from patients in blast crisis has identified numerous members of the Wnt/B-catenin pathway and JunB as being activated. Increased activity of these pathways correlates with poor response and eventual disease progression. In addition to these data, evidence is emerging associating survival of the quiescent blast cell with Wnt activity, leading to the hope that Wnt inhibitors will increase the likelihood of eradicating these cells. Other areas such as microRNA profiling and DNA methylation patterns are likely to provide important information.

Original languageEnglish (US)
Pages (from-to)S1-S17
JournalSeminars in Oncology
Volume35
Issue numberSUPPL. 1
DOIs
StatePublished - Feb 1 2008
Externally publishedYes

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Blast Crisis
Protein-Tyrosine Kinases
Therapeutics
Leukemia, Myeloid, Chronic Phase
Catenins
Mutation
Delayed Diagnosis
DNA Methylation
Imatinib Mesylate
MicroRNAs
Pharmaceutical Preparations
Compliance
Disease Progression
Phosphotransferases
Survival Rate
Clone Cells
Safety
Polymerase Chain Reaction
Survival

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Giles, F. J., DeAngelo, D. J., Baccarani, M., Deininger, M., Guilhot, F., Hughes, T., ... Cortes, J. (2008). Optimizing Outcomes for Patients With Advanced Disease in Chronic Myelogenous Leukemia. Seminars in Oncology, 35(SUPPL. 1), S1-S17. https://doi.org/10.1053/j.seminoncol.2007.12.002

Optimizing Outcomes for Patients With Advanced Disease in Chronic Myelogenous Leukemia. / Giles, Francis J.; DeAngelo, Daniel J.; Baccarani, Michele; Deininger, Michael; Guilhot, François; Hughes, Timothy; Mauro, Michael; Radich, Jerald; Ottmann, Oliver; Cortes, Jorge.

In: Seminars in Oncology, Vol. 35, No. SUPPL. 1, 01.02.2008, p. S1-S17.

Research output: Contribution to journalArticle

Giles, FJ, DeAngelo, DJ, Baccarani, M, Deininger, M, Guilhot, F, Hughes, T, Mauro, M, Radich, J, Ottmann, O & Cortes, J 2008, 'Optimizing Outcomes for Patients With Advanced Disease in Chronic Myelogenous Leukemia', Seminars in Oncology, vol. 35, no. SUPPL. 1, pp. S1-S17. https://doi.org/10.1053/j.seminoncol.2007.12.002
Giles FJ, DeAngelo DJ, Baccarani M, Deininger M, Guilhot F, Hughes T et al. Optimizing Outcomes for Patients With Advanced Disease in Chronic Myelogenous Leukemia. Seminars in Oncology. 2008 Feb 1;35(SUPPL. 1):S1-S17. https://doi.org/10.1053/j.seminoncol.2007.12.002
Giles, Francis J. ; DeAngelo, Daniel J. ; Baccarani, Michele ; Deininger, Michael ; Guilhot, François ; Hughes, Timothy ; Mauro, Michael ; Radich, Jerald ; Ottmann, Oliver ; Cortes, Jorge. / Optimizing Outcomes for Patients With Advanced Disease in Chronic Myelogenous Leukemia. In: Seminars in Oncology. 2008 ; Vol. 35, No. SUPPL. 1. pp. S1-S17.
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