TY - JOUR
T1 - Clinical development of farnesyltransferase inhibitors in leukemias and myelodysplastic syndrome
AU - Kurzrock, Razelle
AU - Cortes, Jorge
AU - Kantarjian, Hagop
PY - 2002/10
Y1 - 2002/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0036814927&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036814927&partnerID=8YFLogxK
U2 - 10.1053/shem.2002.36925
DO - 10.1053/shem.2002.36925
M3 - Article
C2 - 12447848
AN - SCOPUS:0036814927
SN - 0037-1963
VL - 39
SP - 20
EP - 24
JO - Seminars in Hematology
JF - Seminars in Hematology
IS - 4 SUPPL. 3
ER -