NSAIDs are being evaluated for their chemopreventive activity in cancer. NSAIDs, such as salicylates, inhibit multiple signaling pathways, including those affecting NF-KB and AP-1. We have shown that salicylates can directly trigger apoptosis of AML cell lines in vitro and can act synergistically with daunorubicin to kill AML cells. These effects are not strictly dependent on NF- KB inhibition, but occur at concentrations within the therapeutic range for treating rheumatologic disorders. NSAIDs have been avoided in patients with hématologie malignancies because of their ability to impair platelet function, however, sodium salicylate (NaSal) does not have this property. This led us to evaluate the safety profile of NaSal in a phase I trial in adults with advanced MDS or AML. Patients (pts) take oral NaSal for six weeks, with repeated dose adjustments to maintain salicylate levels between 20-30 mg/dL, and limit salicylate-related toxicity. Pts are monitored with twiceweekly CBCs, serum chemistries and salicylate levels, and weekly histories, physical exams and coagulation tests. Four pts have been enrolled thus far: 2 with relapsed AML & 2 with advanced MDS. 3 pts attained salicylate levels above 20 mg/dL, a concentration of salicylate that can synergize with chemotherapy to trigger apoptosis of leukemic cells in vitro. Thus far, one MDS pt was removed from the study on day 37 because of evolution to AML; the salicylate level was 18 mg/dL at the time. Two pts have had grade III hepatotoxicity, one during an episode of febrile neutropenia. One pt, with baseline presbycusis, required dose reduction for grade III ototoxicity and vestibulotoxicity on day 35. None of these adverse events were associated with a salicylate level > 24 mg/dL. All toxicities resolved after discontinuation of salicylates. No patient developed platelet aggregation abnormalities, GI symptoms or guaiac positive stools. Two pts had evidence of a hématologie response to the drug; 1 had an increased platelet count, from 80,000/nL to 234,000/u.L and 1 pt had a prolongation in the interval between RBC transfusions (from 11 days to 22 days). Based on these preliminary results, we conclude that serum levels of salicylate that can synergize in vitro with chemotherapy are achievable in patients with AML/advanced MDS, although toxicities have been encountered during the six week duration of therapy. Adding salicylates to chemotherapy may increase its efficacy in patients with myeloid and other malignancies. Thus far, no bleeding complications have been seen; accrual is ongoing to provide additional safety/ PK data.
|Original language||English (US)|
|Issue number||11 PART II|
|State||Published - Dec 1 2000|
ASJC Scopus subject areas
- Cell Biology