Pilot Study of Lovastatin in Patients with Myelodysplastic Syndrome (MDS) Receiving Arsenic Trioxide (Trisenox®) Therapy.

Statins have been shown to impair processing of RAS proteins, which are signaling molecules mutated in some patients with MDS, and the addition of lovastatin to myeloid cell lines exposed to arsenic trioxide in vitro has suggested enhanced cytotoxicity. To address the hypothesis that statins may modulate the therapeutic effect of arsenic, we are conducting a pilot study for MDS treated by arsenic trioxide combined with lovastatin. Objectives are to estimate the response rate, and secondarily to describe safety. Patients with MDS by FAB diagnostic criteria are treated with arsenic trioxide 0.25 mg/kg IV twice weekly for 16 weeks, after initial dosing for 5 consecutive days in the first week. Lovastatin is given at 20 mg/day for 2 weeks, then 40 mg/day for 2 weeks, and finally 80 mg/day for 12 weeks. Toxicity is monitored continuously and reviewed by a local Data and Safety Monitoring Committee. Stopping rules include serious adverse events (SAE) definitions for evidence of myopathy (symptoms or CPK >2x upper limit of normal) or hepatocellular injury (transaminases >3x upper limit of normal). Nine patients have been enrolled to date, with sufficient follow up to assess efficacy and safety. Five of these 9 patients completed the planned 16-week regimen. One subject was removed from study because of a rapid rise in blast count before treatment, based on marrow exams in a brief interval between screening and enrollment. Three patients had study drugs stopped per the above stringent SAE definitions, for elevations of CPK in 1 and transaminases in 2 subjects -- these abnormalities were asymptomatic and resolved. Toxicities were otherwise tolerable and as expected, including QTc prolongation in 1 patient, which resolved after withholding arsenic trioxide for several days and drug resumption was uneventful, as well as grade <=2 fatigue, nausea and insomnia. Responses are assessed by IWG criteria. One patient had a minor erythroid response with need for packed red blood cell transfusion decreased by 50%. One patient had a minor platelet response documented as a net increase greater than 10,000/mm3 but less than 30,000/mm3. One patient showed progression of disease to AML before completing the trial. Remaining patients showed stable disease; one showed marked but non-sustained improvement in counts and suffered necrotizing faciitis after completing the study as a complication of a bone marrow biopsy. Preliminary findings in an additional patient after 8 weeks of therapy suggest an early response in multiple lineages and freedom from red cell transfusion. Tentative conclusions are that this combination of a statin and arsenic trioxide has activity in MDS, and toxicities are tolerable.