Tyrosine kinase targeted treatment of chronic myelogenous leukemia and other myeloproliferative neoplasms

Ajit Bisen, David F. Claxton

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Myeloproliferative neoplasms (MPNs) include Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) and the Ph- diseases primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET). Since FDA approval of imatinib in 2001, CML treatment has been focused on tyrosine kinase inhibitors. With these targeted therapies, imatinib-resistant CML has emerged as a major problem. Second generation tyrosine kinase inhibitors (TKIs) have allowed for effective treatment of some patients with imatinib resistance, but bcr-abl mutants such as T315I remain problematic. Additional agents are in development and are discussed here. New clinical issues with TKI treatment include premature termination of therapy due to adverse-effects, the cost of therapy, and the apparently indefinite duration of treatment in patients who have achieved complete molecular response (CMR). In contrast to Ph+ CML, targeted therapy for Ph- MPNs is novel and of less clear therapeutic potential. New insights into Ph- MPNs include alterations in the JAK-STAT signaling pathway, particularly as mediated by the JAK2 V617F mutation. The recent development of multiple JAK2 inhibitors has provided hope for the rational and effective management of these disorders. Recently, ruxolitinib was approved as therapy for PMF. Current data suggests, however, that given its vital cell signaling function, the therapeutic benefit of targeting Jak kinases in general, or JAK2 specifically may be less than that derived from ABL-directed TKI treatment of CML. This review focuses on the current treatment options for CML and Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) and limitations faced in current clinical practice.

Original languageEnglish (US)
Pages (from-to)179-196
Number of pages18
JournalAdvances in Experimental Medicine and Biology
Volume779
DOIs
StatePublished - 2013

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Protein-Tyrosine Kinases
Chromosomes
Neoplasms
Cell signaling
Therapeutics
Phosphotransferases
Philadelphia Chromosome
Polycythemia Vera
Primary Myelofibrosis
Imatinib Mesylate
Costs
Essential Thrombocythemia

Keywords

  • Bafetinib
  • BCR-ABL
  • Blastic phase
  • Bosutinib
  • CML
  • CYT387
  • Cytogenetic response
  • Cytopenia
  • Dasatinib
  • DCC-2036
  • DNA repair
  • Erythropoiesis
  • GNF-5
  • Hydoxyurea
  • Imatinib
  • JAK2
  • Lenalidomide
  • Lestaurtinib
  • Leukemia
  • Myelofibrosis
  • Myeloproliferative neoplasms
  • Nilotinib
  • OCT-1
  • Philadelphia chromosome
  • PIGF
  • Polycythemia vera
  • Ponatinib
  • QT-prolongation
  • Resistance
  • Ruxolitinib
  • SB1518
  • STAT
  • TG101348
  • Thrombopoietin
  • TKI

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Tyrosine kinase targeted treatment of chronic myelogenous leukemia and other myeloproliferative neoplasms. / Bisen, Ajit; Claxton, David F.

In: Advances in Experimental Medicine and Biology, Vol. 779, 2013, p. 179-196.

Research output: Contribution to journalArticle

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AU - Claxton, David F.

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AB - Myeloproliferative neoplasms (MPNs) include Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) and the Ph- diseases primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET). Since FDA approval of imatinib in 2001, CML treatment has been focused on tyrosine kinase inhibitors. With these targeted therapies, imatinib-resistant CML has emerged as a major problem. Second generation tyrosine kinase inhibitors (TKIs) have allowed for effective treatment of some patients with imatinib resistance, but bcr-abl mutants such as T315I remain problematic. Additional agents are in development and are discussed here. New clinical issues with TKI treatment include premature termination of therapy due to adverse-effects, the cost of therapy, and the apparently indefinite duration of treatment in patients who have achieved complete molecular response (CMR). In contrast to Ph+ CML, targeted therapy for Ph- MPNs is novel and of less clear therapeutic potential. New insights into Ph- MPNs include alterations in the JAK-STAT signaling pathway, particularly as mediated by the JAK2 V617F mutation. The recent development of multiple JAK2 inhibitors has provided hope for the rational and effective management of these disorders. Recently, ruxolitinib was approved as therapy for PMF. Current data suggests, however, that given its vital cell signaling function, the therapeutic benefit of targeting Jak kinases in general, or JAK2 specifically may be less than that derived from ABL-directed TKI treatment of CML. This review focuses on the current treatment options for CML and Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) and limitations faced in current clinical practice.

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KW - BCR-ABL

KW - Blastic phase

KW - Bosutinib

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KW - CYT387

KW - Cytogenetic response

KW - Cytopenia

KW - Dasatinib

KW - DCC-2036

KW - DNA repair

KW - Erythropoiesis

KW - GNF-5

KW - Hydoxyurea

KW - Imatinib

KW - JAK2

KW - Lenalidomide

KW - Lestaurtinib

KW - Leukemia

KW - Myelofibrosis

KW - Myeloproliferative neoplasms

KW - Nilotinib

KW - OCT-1

KW - Philadelphia chromosome

KW - PIGF

KW - Polycythemia vera

KW - Ponatinib

KW - QT-prolongation

KW - Resistance

KW - Ruxolitinib

KW - SB1518

KW - STAT

KW - TG101348

KW - Thrombopoietin

KW - TKI

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