Clinical development of farnesyltransferase inhibitors in leukemias and myelodysplastic syndrome

Razelle Kurzrock, Jorge Cortes, Hagop Kantarjian

Research output: Contribution to journalArticle

Abstract

Farnesyltransferase inhibitors (FTIs) target multiple pathways including the Ras pathway implicated in the pathogenesis of some hematologic malignancies. R115777 and BMS-214662, selective FTIs in clinical development, exhibit preclinical activity against cell lines and tumor xenografts with or without ras mutations. Phase I dose-escalating trials at M.D. Anderson Cancer Center have explored the potential of these agents as monotherapy for leukemias and myelodysplastic syndrome (MDS). In 20 patients with MDS, two cycles of oral R115777 for 3 consecutive weeks followed by a 1-week rest produced an overall response rate of 30%, consistent with 29% reported in poor-prognosis acute leukemia or blast-phase chronic myelogenous leukemia (CML). Administration of BMS-214662 as a weekly intravenous infusion produced a decrease in bone marrow blasts of greater than 50% in 23% of patients with acute leukemia or MDS; 18% achieved normalization of blast counts to less than 5%. In both studies, most responding patients did not have ras mutations. The most common side effects at maximum tolerated doses of R115777 (400 mg twice daily) and BMS-214662 (118 mg/m2 weekly) were myelosuppression and nausea, respectively. Further evaluation of FTIs for hematologic malignancies clearly is warranted. Future research should address whether molecular techniques can identify patients most likely to respond to an FTI, optimal administration schedules for these agents, and the value of incorporating an FTI into combination regimens for difficult-to-treat hematologic malignancies.

Original languageEnglish (US)
Pages (from-to)20-24
Number of pages5
JournalSeminars in Hematology
Volume39
Issue number4 SUPPL. 3
DOIs
StatePublished - Oct 2002

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Farnesyltranstransferase
Myelodysplastic Syndromes
tipifarnib
Leukemia
Hematologic Neoplasms
Blast Crisis
Mutation
Maximum Tolerated Dose
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Tumor Cell Line
Heterografts
Intravenous Infusions
Nausea
Appointments and Schedules
Bone Marrow
7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine
Neoplasms

ASJC Scopus subject areas

  • Hematology

Cite this

Clinical development of farnesyltransferase inhibitors in leukemias and myelodysplastic syndrome. / Kurzrock, Razelle; Cortes, Jorge; Kantarjian, Hagop.

In: Seminars in Hematology, Vol. 39, No. 4 SUPPL. 3, 10.2002, p. 20-24.

Research output: Contribution to journalArticle

Kurzrock, Razelle ; Cortes, Jorge ; Kantarjian, Hagop. / Clinical development of farnesyltransferase inhibitors in leukemias and myelodysplastic syndrome. In: Seminars in Hematology. 2002 ; Vol. 39, No. 4 SUPPL. 3. pp. 20-24.
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