Study of Intra-Venous Homoharringtonine (HHT) in the Treatment of Myelodysplastic Syndrome (MDS).

Homoharringtonine (HHT) is a plant alkaloid that inhibits protein synthesis, induces differentiation and apoptosis of myeloid cells. We initiated a phase II study of intra-venous HHT in patients (pts) diagnosed with MDS by WHO criteria to assess safety and efficacy of HHT in this setting. Responses were recorded according to the MDS response criteria defined by NCI working group. Pts received HHT 2.5 mg/m² by continuous 24-hour intravenous infusion daily for 7 days every 4 weeks until a) a complete remission (CR) was achieved, or b) failure to achieve a CR after 3 courses of therapy or c) unacceptable toxicities developed. The dose was increased to 3.0 mg/m² for pts with no response after the 1st course. Nine pts have been enrolled (6 male and 3 female). Median age was 70 yrs (range 55 to 84 yrs) and 4 pts had secondary MDS. Four pts had refractory anemia with excess blasts-1 (RAEB-1), 3 had RAEB-2, 1 had chronic myelomonocytic leukemia (CMML-1) and 1 had MDS/myeloproliferative disorder (MDS/MPD). IPSS score was intermediate-1 in 1 pt, intermediate-2 in 7 pts and high in 1 pt. Seven pts (78%) received only one cycle of HHT. One (11%) pt had a CR (including cytogenetic CR) that lasted for 67 days, 5 pts discontinued treatment due to lack of response and1 pt with stable disease decided to withdraw from the study. After a median follow-up of 54 days (range, 37 to 145 days) 2 pts have died, one on day 37 due to intracranial bleed secondary to thrombocytopenia and one on day 39 due to invasive fungal infection. Grade 2 toxicities included fatigue (4 pts), diarrhea (3 pts) and nausea (3 pts). Grade 3 cytopenias were seen in all pts and grade 3 nausea in 1 pt. Three pts had neutropenic fever. Treatment during first course was interrupted after 5 days of infusion in 1 pt due to grade 3 congestive heart failure (CHF). This pt received his second course of treatment without recurrence of CHF. In conclusion, HHT has modest activity in intermediate to high risk MDS. After first interim analysis, the study meets criteria for continued accrual.