A phase II trial of tipifarnib in myelofibrosis: Primary, post-polycythemia vera and post-essential thrombocythemia

R. A. Mesa, John K Camoriano, S. M. Geyer, W. Wu, Scott H Kaufmann, Candido E Rivera, C. Erlichman, J. Wright, Animesh D Pardanani, T. Lasho, C. Finke, C. Y. Li, Ayalew Tefferi

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Abstract

Patients with primary myelofibrosis (PMF) or post-polycythemia vera or post-essential thrombocythemia myelofibrosis (post-PV/ET MF) have limited therapeutic options. The farnesyltransferase-inhibitor tipifarnib inhibits in vitro proliferation of myeloid progenitors from such patients. In the current phase II clinical trial, single-agent oral tipifarnib (300 mg twice daily × 21 of 28 days) was given to 34 symptomatic patients with either PMF (n = 28) or post-PV/ET MF (n = 6). Median time to discontinuation of protocol therapy was 4.6 months; reasons for early termination (n = 19; 56%) included disease progression (21%) and adverse drug effects (18%). Toxicities (≥grade 3) included myelosuppression (n=16), neuropathy (n = 2), fatigue (n = 1), rash (n = 1) and hyponatremia (n = 1). Response rate was 33% for hepatosplenomegaly and 38% for transfusion-requiring anemia. No favorable changes occurred in bone marrow fibrosis, angiogenesis or cytogenetic status. Pre- and post-treatment patient sample analysis for in vitro myeloid colony growth revealed substantial reduction in the latter. Clinical response did not correlate with either degree of colony growth, measurable decrease in quantitative JAK2V617F levels or tipifarnib IC50 values (median 11.8 nM) seen in pretreatment samples. The current study indicates both in vitro and in vivo tipifarnib activity in PMF and post-PV/ET MF.

Original languageEnglish (US)
Pages (from-to)1964-1970
Number of pages7
JournalLeukemia
Volume21
Issue number9
DOIs
StatePublished - Sep 2007

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tipifarnib
Essential Thrombocythemia
Polycythemia Vera
Primary Myelofibrosis
Farnesyltranstransferase
Phase II Clinical Trials
Hyponatremia
Therapeutics
Growth
Exanthema
Cytogenetics
Inhibitory Concentration 50
Fatigue
Disease Progression
Anemia
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

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A phase II trial of tipifarnib in myelofibrosis : Primary, post-polycythemia vera and post-essential thrombocythemia. / Mesa, R. A.; Camoriano, John K; Geyer, S. M.; Wu, W.; Kaufmann, Scott H; Rivera, Candido E; Erlichman, C.; Wright, J.; Pardanani, Animesh D; Lasho, T.; Finke, C.; Li, C. Y.; Tefferi, Ayalew.

In: Leukemia, Vol. 21, No. 9, 09.2007, p. 1964-1970.

Research output: Contribution to journalArticle

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abstract = "Patients with primary myelofibrosis (PMF) or post-polycythemia vera or post-essential thrombocythemia myelofibrosis (post-PV/ET MF) have limited therapeutic options. The farnesyltransferase-inhibitor tipifarnib inhibits in vitro proliferation of myeloid progenitors from such patients. In the current phase II clinical trial, single-agent oral tipifarnib (300 mg twice daily × 21 of 28 days) was given to 34 symptomatic patients with either PMF (n = 28) or post-PV/ET MF (n = 6). Median time to discontinuation of protocol therapy was 4.6 months; reasons for early termination (n = 19; 56{\%}) included disease progression (21{\%}) and adverse drug effects (18{\%}). Toxicities (≥grade 3) included myelosuppression (n=16), neuropathy (n = 2), fatigue (n = 1), rash (n = 1) and hyponatremia (n = 1). Response rate was 33{\%} for hepatosplenomegaly and 38{\%} for transfusion-requiring anemia. No favorable changes occurred in bone marrow fibrosis, angiogenesis or cytogenetic status. Pre- and post-treatment patient sample analysis for in vitro myeloid colony growth revealed substantial reduction in the latter. Clinical response did not correlate with either degree of colony growth, measurable decrease in quantitative JAK2V617F levels or tipifarnib IC50 values (median 11.8 nM) seen in pretreatment samples. The current study indicates both in vitro and in vivo tipifarnib activity in PMF and post-PV/ET MF.",
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