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Blood, 14 May 2009, Vol. 113, No. 20, pp. 4824-4825.
Tipifarnib and etoposide for older AML patients: from bench to bedsideCARDARELLI HOSPITAL ITALY
In this issue of Blood, Karp and colleagues describe preclinical and clinical effects of the combination of tipifarnib with etoposide. The study represents an admirable example of successful translation of in vitro data to a phase 1 clinical trial.
In the study by Karp et al, preclinical data clearly demonstrated that tipifarnib inhibits signaling downstream of mTOR and enhances the antiproliferative effects of etoposide (E) in AML cell lines and clinical specimens, suggesting a role for Rheb, a small G protein that deserves further investigation, as far as its role into leukemogenesis is concerned.7 In addition, the authors showed that treatment with T+E in vivo is accompanied by drug-induced increases in histone H2AX phosphorylation and, to a lesser extent, DNA fragmentation in AML marrow blasts. This was coupled with the suggestion that achievement of complete remission (CR) may be associated with modest but measurable increases in both parameters. While the precise mechanisms leading to synergism of the combination remains to be clarified, these findings represent the biologic background of a multicenter clinical trial aiming at demonstration of the safety and potential efficacy of T+E in elderly AML patients, who are not candidates for conventional induction treatment on the basis of both host clinical features and unfavorable disease biology. It is noteworthy that the proportion of patients 75 years or older in this study was 65% and more than 50% of them had adverse cytogenetics. Finally, 55% of patients had secondary AML. Overall, of the 84 patients receiving T+E, 21 (25%) achieved CR, with a median CR duration of 9.8 months. Patients achieving CR had a median age of 77 years and their median survival was 22 months, with 14 (67%) surviving more than 1 year and 9 (43%) still living at 15.5+ to 36+ months. These data compare favorably with results achievable after conventional chemotherapy as well as with those reported by using single agent T or T + low-dose ARA-C. Previous study of single agent T had considered a 21-day schedule, which was not feasible in combination with E. In contrast, the same etoposide schedule was better tolerated when tipifarnib was administered for 14 days, with acceptable occurrence and severity of mucositis, a well-known effect of etoposide, and neurotoxicity. In conclusion, the above data, along with recently published results achieved with other new drugs such as clofarabine and cloretazine,8 demonstrate encouraging therapeutic results in a previously very difficult to treat patient population of poor risk older AML patients. It is now time to allocate these patients into upfront experimental clinical trials that avoid unnecessary toxicity, not counterbalanced by substantial clinical benefit. The search of preclinical and clinical models, based on the combination of new agents with old drugs as in the study by Karp et al, could represent a successful model for future therapeutic approaches in AML in the elderly and would be extended to high-risk relapsed patients, independent of age.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
REFERENCES
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| Copyright © 2009 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
