Clinical Study On The Treatment Of Minimal Residual Myeloid Leukemia With YiQi BuShen Granules

Background:Minimal residual leukemia(MRL) is the state that residual trace of leukemia cells in vivo,which has been complete remission after the treatment of acute leukemia. It is the root cause of leukemia relapse and it is also one of the major factors that impact the long-term survival of patients with acute leukemia.Modern medicine studies find that the immune function in patients with acute leukemia becomes lower. When comes to the stage of minimal residual leukemia a3fter the complete remission, the immune function is still lower than normal although has recovered than before. All these indicate that patients with minimal residual leukemia still have deficiencies in immune function.Nowadays,the methods to treat the minimal residual leukemia are mainly bone marrow transplantation,maintenance the consolidation chemotherapy, cytokine-induced killer cell immunoglobulin therapy,and Traditional Chinese Medicine therapy,etc.Along with the gradual improvement of the chemotherapy program about Leukemia,the new application of anti-leukemia agents,a variety of hematopoietic stem cell transplants carried out,as well as the strengthening of symptomatic treatment,the complete remission rate in acute leukemia have been much improved,and the disease-free survival and overall survival of majority patients is significantly prolonged.However,there are still some patients who suffer from relapse after complete remission.According to our experience in diagnosis and treatment for many years,we consider that the patients in the stage of minimal residual leukemia have less pathogenic factors after complete remission and less healthy qi as a result of radiotherapy and chemotherapy.It is characterized by " deficiency of healthy qi and left of pathogenic factors ".We can see the patients suffer from fatigue,dizziness, weakness in lumber and knees,easy to sweat,red tongue or fat tongue body with tooth trace,as well as pulse tiny and fast.All of these are considered by" both deficiency of qi and yin ".Therefore to support the healthy qi and to reconstruct and recover the immune function of patients with minimal residual leukemia is the key to treat this disease.Yiqi Bushen granules(formerly named Fuzheng kangbai granules),summed up by the Hematologists in Xiyuan Hospital of China Academy of Traditional Chinese Medicine from long-term clinical practice,contains some kinds of Traditional Chinese Medicine to support qi and strengthen yin,and is most appropriate to treat minimal residual leukemia.It is proved by clinical and experimental studies that this prescription can help support the body healthy qi,raise the immunity of patients,significantly increase CD3, improve the disorders of CD4 and CD8,improve lymphocyte transformation rate and can significantly improve the patient's immune function to prevent or delay the relapse of leukemia,extend the clinical complete remission and survival time,and enhance the quality of patients' lives.Based on the foregoing theory and research results,we did a further study on the influence of Yiqi Bushen granules on the long-term survival and immune function of MRL patients.On the one hand,we had a multi-center clinical study of a large sample by randomized,double-blind,placebo-controlled methods,and had a long-term follow-up in MRL patients of the Yiqi Bushen granules and the placebo group,and then calculated the 3 and 5-year's continuous complete remission rate and survival rate by Kaplan-Meier method and compared the two groups by log-rank method;On the other hand,we made use of the flow cytometry to detect the peripheral blood T,B lymphocytes,NK cells,Th/Tc ratio,non-HLA restricted cytotoxic T cells,γδT cells, NKT cells,dendritic cells and so on.From which we analyzed the immune function in MRL patients and the changes after using Yiqi Bushen granules.We hope it could help us to treat MRL patients better by Traditional Chinese Medicine in the future time.There are two parts in this article.Section one:Clinical study on the treatment of minimal residual myeloid leukemia with Yiqi Bushen granulesObjective:To observe the affection of Yiqi Bushen granules on 3 and 5-year's continuous complete remission rate and survival rate in patients with minimal residual leukemia.Methods:It was a randomized,double-blind,multi-center controlled clinical study.There were total of 104 cases of patients,of which a total of 48 cases were in the treatment group,with 24 cases of male and 24 cases of female;a total of 56 cases were in the control group,with 32 cases of men and 24 cases of women.Yiqi Bushen granules were used to the treatment group and the malt speculation granules were used to the control group.Both were used continuously for 3 months with 1 bag a time,2 times a day.The originally planned chemotherapy was still to be consolidated.Besides,we also had 16 patients for open test,of which 8 cases were male and the other 8 cases were female.All of the patients were in the treatment group,and took a long-term of Yiqi Bushen granules.The follow-up began since the day when patients had been treated over 3 months.For the death patients the follow-up ended on the date of death,and for the survival patients it ended on November 20,2008.Results:In 104 cases of patients,the treatment group had 9 cases lost,28 cases of continuous complete remission,3 cases of recurrence,8 cases of death,while the control group had 9 cases lost,34 cases of continuous complete remission,2 cases of recurrence,11 cases of death.The 3 and 5-year's continuous complete remission rates were 81.5%,72.5%in the treatment group and in the control group were 84.4%,71.5%.The 3 and 5-year's survival rates were 84.6%and 78.5%in the treatment group while in the control group were 84.4%,81.2%.Statistical analysis showed that two groups of continuous complete remission rates and survival rates were not significantly different(P = 0.750,0.938＞0.05).As for the open test,except for one case of relapse after remission,the remaining 15 cases were still in continuous complete remission status,the complete remission rates and survival rates could not be calculated.Further follow-up studies are needed in the future.Section 2:Analysis about the immune function of minimal residual leukemia patients and the effect of Yiqi Bushen granulesObjective:To Analyze the immune function in patients with MRL and the changes after the application of Yiqi Bushen granules.Methods:We detected the immune cells in 32 cases of MRL patients and 31 healthy controls by flow cytometry, and analyzed the immune function with EXPO32 software by taking FS vs SS doors. Results:MRL patients lymphocytes,T cells,Th cells,non-HLA-dependent cytotoxic T cells reduced in absolute value,B cells,NK cells decreased both in the percentage and absolute value;leukocytes,Tc cells and CD4+/CD8+ had no significant difference;the absolute value of NK cells significantly increased after treatment by Yiqi Bushen granules than before,but were still lower than the normal group.T cells and Non-HLA-dependent cytotoxic T cells absolute values were still lower than the normal group as well.Th cells percentage were significantly lower than before treatment and the normal group,the absolute values were also significantly lower than the normal group.Tc cells increased in percentage and CD4+/CD8+ was still lower than the normal group.Th1,Th0,Th2,Tc1,Tc0,Tc2 had no significant difference from the normal group.However,Tc1 was significantly higher than before,while Tc2 was significantly lower,and Th1 was significantly higher than the normal group after treatment,The percentages and absolute values of CD8+γδT+,γδT+CD161+in lymphocytes,γδT+CD161+in CD4-CD8-cells were significantly lower than the normal control group;γδT+CD161+in CD4+cells were also significantly lower in absolute terms.After treatment the percentage ofγδT+CD161- in lymphocytes became lower than before,however,it had no significant differences from those in the control group.The percentages and absolute values ofγδT+CD161+,γδT+in lymphocytes were lower than the normal control group.The percentages and absolute values ofγδT+CD161+ and the absolute value ofγδT+ in CD4-CD8-cells were also still lower than the normal group.The percentage and absolute terms of Va24+cell in CD4+cells,and the absolute values of Va24+CD161-,Va24+CD161+ in CD4+cells were lower than the normal control group.After treatment the percentage and absolute terms of CD4+Va24+ in lymphocytes,the absolute values of Va24+CD161-, Va24+CD161+,Va24+ in CD4+cells were still lower than normal group.The absolute values of CD45RA+CD45RO-,CD45RA+CD45RO+,CD4+CD45RO+, CD8+CD45RA+ in lymphocytes,CD45RA+CD45RO+,CD45RA-CD45RO+ in CD4+cells were significantly lower than the control group.The percentage and absolute value of CD45RA+CD45RO+ in CD8+cells were also significantly lower than those of the control group,while the percentage of CD45RA-CD45RO+ in CD8+cells increased significantly.CD45RA+CD45RO+ and CD4+CD45RA+ percentages in lymphocytes after treatment reduced further than pre-treatment and their percentages and the absolute values were still significantly lower than the normal control group.The CD45RA+CD45RO- percentage in CD8+cells was significantly higher than before,and with no significant difference from the normal group,while the CD45RA+CD45RO+ absolute value and percentage in CD8+cells was also lower than the normal control group.The absolute values of the CD4+CD45RO+ and CD8+CD45RA+ in lymphocytes,CD45RA+CD45RO+ and CD45RA-CD45RO+ in CD4+cells were still lower than the normal control group.Only the absolute values of CD8+CD28-,CD8-CD28+cell in lymphocytes were lower than the normal control group,all of the left were with no significant differences.PF+Gr-,PF-Gr+ absolute values in lymphocytes were significantly lower.The PF+Gr- percentages and absolute values in CD8+cells and CD56+cells were both lower.Tn CD8+cells,PF percentage was lower,while the PF-Gr+,Gr percentages and absolute terms were higher.In CD56+cells,PF percentages and absolute terms decreased,while PF+Gr+,Gr percentage increased.And after treatment,except for PF+Gr- percentage and absolute value in lymphocytes was lower than those of the control group either,the abnormal immune parameters mentioned above were still abnormal.Dendritic cells had no significant differences from the normal control group and there was no change after treatment.Conclusions:Minimal residual leukemia patients had abnormal immune function,charactered by lower and disorders of immune function,and the abnormal immune function had recovered after treatment.There were no obvious abnormalities in dendritic cells of patients with minimal residual leukemia.