Application of Homoharringtonine in the Treatment of Acute Promyelocytic Leukemia.

Abstract

Objective Homoharringtonine (HHT) as the cytotoxic alkaloid has been demonstrated effective in the treatment of acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and myelodysplastic syndrome (MDS). To evaluate the efficacy of HHT in newly diagnosed acute promyelocytic leukemia (APL) and compare with anthracycline-based regimen in a randomized trial.Methods From January 2004 to January 2007, 39 new diagnosed acute promyelocytic leukemia patients (diagnosed according to MIC criteria) were randomized classified into two groups. Group A included 17 patients (6 males and 11 females), with a median age 37y. They received ATRA plus homoharringtonine as induction therapy. After achieved complete remission (CR), they received three courses HHT+AraC (HA) as consolidation therapy. Group B included 22 patients (11 males and 11females), with a median age 37y. They received ATRA plus daunorubicin-DNR or mitozantrone-MTZ as induction therapy. After achieved CR, patients in group two received three courses DNR+AraC (DA) or MTZ+AraC (MA) as consolidation therapy. ATRA (25mg/m2) was administered daily orally from day1 to day28, HHT (2.5mg/m2/d) was used from d4 (started from the use of ATRA) for seven days, DNR (40–45mg/m2/d) was used from d4 to d6 (since the use of ATRA). The doses of HHT and DNR used in consolidation were similar to that used in induction. The dose of AraC used in consolidation was 100mg to 150mg/m2/d (for seven days). After finish consolidation, all patients received ATRA and 6-MP (70mg/m2/d)+MTX (20mg/m2, 1 dosage per week) as maintenance therapy routinely. Bone marrow and PML/RARa fusion gene (RT-PCR and/or real time PCR) were analyzed after induction therapy and each consolidation therapy. Disease-free survival (DFS) and overall survival (OS) were estimated.Results In Group A (HHT group), all patients achieved hematological complete remission after induction therapy, CR rate was 100%. The CR rate of Group B (DNR group) was 92.9% (one early death). PML/RARa fusion gene became negative in 68.8% patients after HHT+ATRA induction, and 100% were negative after 1 course HA regimen consolidation therapy. In Group B (DNR group), they were 33.3% and 91.7%, respectively. The median DFS and OS in Group A (HHT group) and Group B (DNR group) are 72 (9∼129) weeks and 70 (7∼111) weeks, 81 (13∼133) weeks and 70.5 (2∼115) weeks, respectively. The two different regimens were both well tolerated.Conclusion HHT is an effective drug in the treatment of APL, HHT+ATRA can achieve a high CR rate and a higher rate of PML/RARa fusion gene negative after induction therapy. HHT containing regimen can shorten the time of PML/RARa fusion gene becoming negative (after one course of HA regimen consolidation, PML/RARa fusion gene becomes negative in all patients). In conclusion, HHT based regimen should be a new choice in treatment of APL that can achieve molecular remission. It can be used in the treatment of APL instead of DNR.