Homoharringtonine and Low-Dose Cytosine Arabinoside Combined with G-CSF or GM-CSF Administered in Patients with Advanced Myelodysplastic Syndromes and Relapsed or Refractory Acute Myeloid Leukemia.

Abstract

According to the FAB classification of myelodysplastic syndromes (MDS), subgroups of refractory anemia with excess blasts(RAEB) and refractory anemia with excess blasts in transformation(RAEB-t) are considered as high-risk MDS or advanced MDS which tend to involve into acute myeloid leukemia(AML). Even though various strategies have been in use, chemotherapy remains the main treatment option. With low remission rates, short duration of remission and high relapse rates, conventional chemotherapy for high-risk MDS and AML transforming from MDS is generally unsatisfactory. Relapsed or refractory AML, geriatric AML and secondary AML have a poor response to the classical induction chemotherapy. Studies indicate that CRs have occurred(8∼56%) at the cost of a high incidence of deaths from toxicity(24%∼64%). Although allogeneic stem cell transplantation could potentially be curative, it is appropriate for only a small subset of patients. This challenges us to work towards new reasonable therapeutic strategies. In vitro, studies have confirmed that granulocyte colony stimulating factor(G-CSF) can enhance the cytotoxic effects of S-phase-specific drugs such as Ara-C by the mechanism of driving myeloid leukemic cells of resting G0-phase into the cell cycle as well as intensifying the metabolism of Ara-C and anthracyclines in the leukemic cell. Recently the regimen of low-dose Ara-C and aclarubicin in combination with G-CSF(CAG regimen) has presented both well-tolerated and highly effective in treating the above categories of AML and MDS. The reported overall CR rate is 35∼75%. We designed a combination chemotherapy of homoharringtonine, low-dose cytarabine and G-CSF or GM-CSF(HAG priming regimen) for remission induction in this study which enrolled 42 patients with advanced MDS or AML between January 2002 and July 2005. 42 patients who received HAG chemotherapy were followed up till April 2006. Clinical and laboratory data of all these patients, which concerned with a)medical interventions including induction chemotherapy, post-remission treatment, and management of complications, etc; b)follow up for conditions of remission, relapse-free survival and overall survival after HAG induction therapy; c)adverse events following HAG induction therapy, were recorded in detail. Among Forty appraisable patients, 20 of them (50%) achieved complete remission (CR), including 66.7% patients with MDS-RAEB and 46.2% patients with refractory or relapsed AML. The fact of 80% patients with AML-M1 achieved CR, demonstrates a better response than those with other subtypes of AML. The overall response rate was 52.5%. After a follow-up of 6—47 months(median 23) from the date of remission, the median times of relapse-free survival and overall survival were 7.0±1.1 and 28±12.3 months, respectively. Meanwhile, these patients aged under 60-year-old who have achieved complete remission and received regular post-remission treatment showed a better survival rate. Myelosuppression was the most significant toxicity. More than 80% of patients experienced neutropenia or thrombocytopenia of grade III to IV after the first induction therapy. The incidences of infection and hemorrhage in the total of 64 induction courses were 43.8%(28/64) and 37.5%(24/64), respectively. Nonhematologic adverse-effects were minimal.