Abstract
Effective treatment options for patients with lower-risk myelodysplastic syndromes (MDS) are limited. However, around one-third of patients experience transformation to acute myeloid leukemia, and absent transformation, complications of chronic cytopenias (including infection), and iron-overload syndromes can be fatal. Although 5-azacitidine, decitabine, and lenalidomide have improved treatment options for patients with MDS, these are not routinely used in patients with lower-risk disease. Histone deacetylase (HDAC) enzymes are overexpressed in several tumor types including MDS, and regulate transcriptional and post-transcriptional processes. Vorinostat (Zolinza®) has been shown to inhibit class I and II HDAC enzymes, and has been approved by the FDA for the treatment of cutaneous manifestations of T-cell lymphoma in patients with persistent or recurrent disease, on or following 2 prior systemic therapies. Vorinostat induces cell-cycle arrest, apoptosis, or differentiation in a variety of cultured transformed cell lines, and has demonstrated activity against leukemias in in vivo non-clinical models and in phase I and II clinical trials. Efficacy data in these early phase trials prompted an investigation of vorinostat monotherapy in lower-risk MDS. The potency and tolerability of vorinostat suggest it may be effective in the treatment of MDS. Here, we report preliminary results of a randomized phase II study evaluating once-daily and three-times-daily (tid) intermittent dosing schedules of vorinostat in patients with low and intermediate-1 risk MDS. Primary objectives included assessment of the efficacy, safety, and tolerability of vorinostat. Eligible patients were aged ≥18 years, had either previously untreated disease, or were ≥4 weeks from any prior treatment regimen (including growth factors). Patients’ performance status was ≤2 on the ECOG performance scale, they had adequate organ function, and were either red blood cell transfusion dependent or had a hemoglobin level of ≤11g/dL at the time of screening, or had platelets ≤100 × 109/L at the time of screening. Eligible patients were assigned to 1 of 2 oral dosing regimens: vorinostat 400 mg daily or vorinostat 200 mg tid. Treatment was administered over a 21-day cycle (14 days’ therapy and 7 days’ rest), with patients receiving up to 8 cycles, or until the patient experienced unacceptable toxicity, disease progression, or withdrew consent. In total, 18 patients (12 male, 6 female; mean age 67.4 years) have been randomized, including 5 with low-risk MDS and 13 with intermediate-1 risk MDS, as defined by the International Prognostic Scoring System. Of the patients enrolled, 12 (3 low-risk and 9 intermediate-1 risk MDS) were evaluable for response and have received between 2 and 6 cycles of treatment. Stable disease has been reported in all 12 patients, with a reported duration of between 22–146 days (low-risk MDS) and 1–136 days (intermediate-1 risk MDS). A total of 11/18 (61%) patients have discontinued, 2 due to adverse events (1 event of grade 4 neutropenia [unrelated to study medication] and 1 event of grade 3 neuropathy [drug related]), 1 due to deviation from protocol, 4 due to lack of efficacy, 3 due to physician decision, 1 due to progressive disease, and 1 because of withdrawal of consent. Most adverse events were gastrointestinal disorders: diarrhea in 10 patients (7 grade 1, 3 grade 2), nausea in 9 patients (6 grade 1, 3 grade 2), and vomiting in 6 patients (5 grade 1, 1 grade 2). Grade 4 neutropenia, anemia, and thrombocytopenia were observed in 2, 1, and 1 patients, respectively; however these were unrelated to study medication. Data from this study indicate that vorinostat administered in a 21-day cycle has acceptable safety and tolerability.
S. pseudintermedius and S. aureus lineages with transmission ability circulate as causative agents of infections in pets for years
