Yiqibushen Particles Of Diseases And Diagnosis And Treatment Of Acute Myeloid Leukemia Minimal Residual Disease In Clinical Research

Leukemia is a hematologic malignancy with poor prognosis and high mortality. In China acute myeloid leukemia (AMD incidence rates are the highest. At present, chemotherapy may result in a complete response in 65 to 85 percent of newly diagnosed adult AML patients. And the survival at 5 years posttransplantation in these patients is 50 percent. Both chemotherapy and hematopoietic stem cell transplantation prolong survival remarkably. However, treatment-related toxicities, complications, drug resistance and recurrence lower the quality of life of these patients and even lead to death. Only about one quarter patients achieve long-term survival. Relapse remains the primary contributor to death which origins from minimal residual disease ( MRD) cells. Now there is no ideal treatment for MRD. Researches of Traditional Chinese Medicine are beginning to address this issue. Objective: To observe the deficiency of Qi and Yin syndrome and evaluate the immune function in patients with MRD in AML, investigate the safety, theraputic effects of Yiqi Bushen granule ( YQBSG ) on patients with MRD in AML and explore its possible mechanism so as to provide evidences for establishing the diagnosis and treatment criterion of MRD in AML with integrated traditional and western medicine and a useful drug. Methods: The large multicenter clinical study was prospective. Double-blind, placebo-controlled and randomized manner was adopted. Eligible patients were randomized to receive either YQBSG or placebo 13g as a single dose every 12 hours for 3 monthes with the addition of standard treatment for AML. According to the diagnosis criterion of the deficiency of Qi and Yin syndrome both treatment groups were divided into 2 subgroups—the deficiency of Qi and Yin syndrome group and the non-deficiency of Qi and Yin syndrome group. Morever, 30 healthy volunteers were recruited as normal control. Before and after treatment cumulative score of the deficiency of Qi and Yin syndrome was recorded. Blood cells were counted by automated hematology analyzer. The percentage and absolute value of circulating lymphocyte populations including T cells (CD3 ~+ CD19~-) , Th cells ( CD3~+ CD4~+ CD8~- ) , Ts cells( CD3 + CD4 CD8 + ) , non-HLA dependented cytotoxic T cells(CD3 + CD56+) , NK cells (CD3~CD56+) , B cells (CD3CD19 ) and Th/Ts ratio were detected by flow cytometry. The serum concentration of immunoglobulins A, G, M and complement 3 was tested using immunoturbidimetric assay. The karyotypes of bone marrow cells were analysed with conventional cytogenetic method. PML/RARa and AML1/ET0 fusion transcripts were detected using nested RT-PCR assay. Patients were followed at the end of the trial. Urine, stool, hepatic and renal function and electrocardiogram were checked and adverse events were recorded. The analysis was carried out using the SPSS11.0 statistical software. Results: l.From February 2004 to February 2006, 67 patients including 48 inpatients and 19 outpatients were entered into the trial at 7 third class grade A hospitals in China, of whom 11 were excluded and 56( 83.58% ) were included in this analysis. At the same time 30 healthy volunteers were recruited as normal control. 2.The distribution and baseline characteristics of patients between groups were resembled without statistical difference ( P>0.05 ) . 3.The deficiency of Qi and Yin syndrome was showed in 22 patients( 39.29% ) . 4.Generally, the numbers of peripheral blood lymphocytes, T cells, Th cells, Ts cells and NK cells of all the patients were lower than those of normal persons ( P<0.01 or 0.05 ) . The reduction in both the deficiency of Qi and Yin syndrome groups seemed more serious. The percentage of T cells and NK cells was normal but the Th/Ts ratio was inversed due to both a significant decrease in Th cells and an increase in Ts cells( P<0.01 or 0.05 ) . The percentage and counts of non-HLA dependented cytotoxic T cells and B cells were normal either whereas the serum concentration of immunoglobulins A, G, M and complement 3 was abnormal in 23 (41.07%) patients with MRD in AML and 8 (36.36%) patients with the deficiency of Qi and Yin syndrome. 5.After treatment the deficiency of Qi and Yin syndrome was relieved in YQBSG group compared with placebo group(P<0.05) . But there was no difference between the deficiency of Qi and Yin syndrome groups nevertheless ( P>0.05 ) . The percentage and numbers of T cells in YQBSG group, the counts of lymphocytes, T cells and NK cells and the percentage and numbers of non-HLA dependented cytotoxic T cells in YQBSG group withthe deficiency of Qi and Yin syndrome were improved (P<0.05 or 0.01 ) . However, there were still not differences compared with their respective controls ( P>0.05 ) . The numbers of Ts cells in patients were similar to those in normal control posttreatment (P>0.05) . There were not differences on chromosome aberrations (5/56) and fusion transcripts (11/56) including PML/RARa and AML1/ETO before and after treatment. When the research was finished all patients were followed. Three of the 56 patients died of relapse while the rests were still in complete remission. The median survivals for patients of YQBSG group, placebo group, YQBSG group with the deficiency of Qi and Yin syndrome and placebo group with the deficiency of Qi and Yin syndrome cound not be calculated. The survivals at 1 year posttreatment in patients were 95.83%, 95.45%, 100% and 100%, respectively. There were not significant differences between groups in survival ( P>0.05 ) . 6.The toxicities of YQBSG were evaluated by laboratory investigations including blood, urine and stool routine test, hepatic and renal founction and electrocardiogram and adverse events. Abnormal laboratory findings and adverse events caused by YQBSG were not observed. Conclusion: l.The data from this study is convincing. 2.The comparability of patients between groups is good. 3.The deficiency of Qi and Yin syndrome is often displayed in patients with MRD in AML (39.29%) . 4.The cellular immune function, humoral immune function and natural immune function of patients with MRD in AML are generally suppressed by chemotherapy and imbalanced. Patients with the deficiency of Qi and Yin syndrome appear more severe which indicates that this syndrome perhaps correalate with immunodeficiency. Immunologic recovery is slow following chemotherapy. B cells restore rapidly followed by NK cells and Ts cells while the numbers of Th cells are not normal until a long period. 5.YQBSG may relieve the deficiency of Qi and Yin syndrome and improve the counts of immunocytes including lymphocytes, T cells and NK cells from which patients can profit. But disappointedly, the therapeutic effects are not obvious and there is no advantage in favour of humoral immunoresponse. The effects on immune system of patients with the deficiency of Qi and Yin syndrome are better than with MRD in AML which implies that combination of disease andsyndrome is of potential benefit to therapy. The immediate effects of YQBSG on chromosomes, fusion genes and 1-year survival posttreatment are not found. Maybe the effects of YQBSG were covered by the favourable prognosis of the selected patients or maybe there were not effects on them at all. 6.Oral YQBSG is safe.