Clinical Study On The Prevention And Treatment Of Bortezomib-related Peripheral Neuropathy By Yiqi Yangxue Tongluo Prescription

Background Multiple myeloma((MM))is a hematological tumor caused by malignant clones of cancerous plasma cells which are highly dependent on proteasome function,and its incidence ranks second in lymphohematopoietic system tumors.Although new drugs,targeted therapy and immunotherapy are constantly introduced,they are still incurable.The advent of proteasome inhibitors which represented by Bortezomib,has brought real-world survival benefits to patients and significantly changed the outcome and the fate of MM patients.However,due to the high recurrence rate caused by prolonged treatment interval or cessation of treatment,more emphasis is placed on the survival benefits of continuous treatment and deep remission.In China,with the tilt of local health insurance policies and the listing of domestic Bortezomib,more and more patients can accept chemotherapy based on Bortezomib.However,many MM patients were forced to reduce or even stop treatment due to the Bortezomib induced peripheral neuropathy(BIPN).Unfortunately,up to now,there are not many effective prevention and treatment programs for BIPN.Traditional Chinese medicine(TCM)is a huge treasure house,which has been paid more and more attentions by researchers at home and abroad because of its low price,little side effect and definite clinical effect.TCM may be one of the effective means for the prevention and treatment of BIPN,but it still needs to be further confirmed by a large number of studies.According to the clinical characteristics of BIPN,We think that it belongs to the category of "arthralgia","numbness" and "non-benevolence".Its common pathogenesis is caused by qi deficiency of Rong Wei,condensation of "cold","toxin" and "blood stasis",treatment of tonifying qi and blood,giving consideration to dredging yang,and making good use of drugs for introducing menstruation.At the same time of treatment,traditional Chinese medicine puts more emphasis on the prevention before disease.Through the auxiliary treatment of traditional Chinese medicine in the early stage of our research group,it was found that the traditional Chinese medicine prescription based on the treatment principle of replenishing qi,nourishing blood and dredging collaterals could improve the clinical symptoms of BIPN patients,and the incidence of BIPN in some patients with prophylactic use of traditional Chinese medicine decreased significantly,which aroused the interest of our research group to carry out further clinical research.Objective To summarize the prescription characteristics of traditional Chinese medicine for the prevention and treatment of BIPN and optimize the prescription for prevention and treatment of BIPN through data mining,to observe the efficacy and safety of agreement prescription in the clinical prevention and treatment of BIPN in patients with multiple myeloma,and to explore the possible mechanism,so as to provide clinical basis for the treatment of BIPN with traditional Chinese medicine.Methods1.A total of 42 patients with MM were treated with Bortezomib in the Department of Hematology,Jiangsu Hospital of traditional Chinese Medicine from June 2016 to February 2018.All the prescriptions of traditional Chinese medicine combined with traditional Chinese medicine decoction for oral prevention and treatment of BIPN during chemotherapy were retrospectively analyzed.SPSS 25 software was used for frequency and cluster analysis,and IBM SPSS Modeler 18 software was used for association rule analysis.On the basis of our group's previous clinical efficacy of traditional Chinese medicine in the treatment of BIPN,according to the above data mining results,combined with literature,based on the principle of Yiqi Yangxue Tongluo prescription to optimize the prevention and treatment of BIPN.2.A total of 60 patients with MM were enrolled in the Department of Hematology of Jiangsu Hospital of traditional Chinese Medicine,the Department of Hematology of Taizhou Hospital of traditional Chinese Medicine and the Department of Hematology of the second people's Hospital of Huaian City from February 2018 to June 2020.Among them,30 patients in the prevention group were from the Department of Hematology of Jiangsu Hospital of traditional Chinese Medicine,and 30 patients in the control group were from the Department of Hematology of Taizhou Hospital of traditional Chinese Medicine and the Department of Hematology of the second people's Hospital of Huaian City.Therapy based on Bortezomib.Prescription composition of prevention agreement:Radix Astragali 30g,Radix Paeoniae Alba 15g,Radix angelicae Sinensis 10g,Cinnamomum chinensis 10g,Asarum 3g,Papaya 15g,Shenjin Grass 15g,Wushao Snake 10g,Glycyrrhiza uralensis 10g,The traditional Chinese medicine was uniformly dispensed and fried by the TCM pharmacy of Jiangsu Provincial Hospital,and each 200ml was taken orally in the morning and evening,4 weeks as a course of treatment and 3 courses of treatment.The indexes such as WBC,Hb,PLT,NLR,LMR,RDW,MPV,AST,ALT,BUN,Scr,ALB,GLO,UA,LDH,Ca2+,serum ?2-MG,NCI-CTC AE PN grade,peripheral neuropathy scale score and TCM symptom score before and after treatment in the prevention group and the control group before and after treatment were statistically described and analyzed by SPSS25.0.3.A total of 30 patients with BIPN were included in the Department of Hematology,Jiangsu Hospital of traditional Chinese Medicine and the Department of Hematology,Taizhou Hospital of traditional Chinese Medicine from February 2018 to June 2020.the prescription was composed of:Radix Astragali 30g,Radix Paeoniae Alba 15g,Radix angelicae Sinensis 10g,Cinnamomum chinensis 10g,Asarum 3g,Papaya 15g,Shenjin Grass 15g,Wushao Snake 10g,Glycyrrhiza uralensis 10g,Radix aconiti lateralis preparata 10g,Dried ginger 6g,Evodia 5g.Traditional Chinese medicine was dispensed and fried by Jiangsu Provincial Hospital of traditional Chinese Medicine and Taizhou Hospital of traditional Chinese Medicine.200ml was taken orally in the morning and evening,4 weeks as a course of treatment,for a total of 3 courses.WBC,Hb,PLT,NLR,LMR,RDW,MPV,AST,ALT,BUN,Scr,ALB,GLO,UA,LDH,Ca2+,serum ?2-MG,SF,CRP,NCI-CTC AE PN grade,peripheral neuropathy scale score,TCM syndrome score and QoL score of health-related quality of life of patients were evaluated before treatment and after 3 courses of treatment.The difference was statistically significant(P<0.05).The level of serum nerve growth factor was measured before and after 3 courses of treatment,and compared with healthy patients,P<0.05.The sensation,motor nerve conduction velocity and amplitude of 4 patients with NCI-CTC PN grade 1-4 were detected by electromyography to evaluate the type and degree of nerve injury.Results1.The data mining results of prevention and treatment of BIPN with traditional Chinese medicine in this study group were as follows:a total of 286 traditional Chinese medicines were used in 42 patients with MM,of which 10 with high frequency and frequency were Radix Astragali,Radix Paeoniae Alba,Asarum,Glycyrrhiza uralensis,Atractylodes macrocephala,Angelica sinensis,Poria cocos,Salvia miltiorrhiza,Guizhi.More than half of the patients used a total of 20 traditional Chinese medicines,namely,Radix Astragali,Radix Paeoniae Alba,Asarum,Glycyrrhiza,Atractylodes,Angelica,Poria,Salvia miltiorrhiza,Guizhi,Fructus evodiae,Codonopsis,Rabdosia rubescens,calcined oyster,safflower,cat's claw,papaya,deer grass,Panax notoginseng powder and angelica;the network diagram of association rules shows that Radix Astragali,Radix Paeoniae Alba,Asarum and Angelica are the most closely related and belong to the core drugs.The highest degree of support for the second-order association is Radix Astragali+Radix Paeoniae Alba,the highest degree of support for the third-order correlation is Radix Paeoniae Alba+Asarum+Radix Astragali,and the highest degree of support for the fourth-order correlation is Guizhi+Angelica+Radix Paeoniae Alba+ Radix Astragali.Cluster analysis establishes the basic prescription:Huangqi Guizhi Wuwu decoction,Danggui Sini decoction,Danggui Buxue decoction,Buyang Huanwu decoction and Sijunzi decoction.On this basis,we further optimized the prevention agreement(Radix Astragali,Radix angelicae Sinensis,Radix Paeoniae Asarum,Asarum papaya,Radix Glycyrrhizae)and the treatment agreement(Radix Aconiti,dried ginger,Evodia,Radix Evodiae,Radix Astragali,Radix.2.The clinical results of prevention agreement prescription intervention on BIPN of MM patients:2.1 The clinical data of sex,age,classification,DS stage,ISS stage,bone destruction,renal insufficiency,WBC,Hb,PLT,NLR,LMR,RDW,MPV,AST,ALT,BUN,Scr,ALB,GLO,UA,LDH,Ca2+and serum ?2-MG between the prevention group and the control group before treatment were compared(P>0.05).There was no statistical difference in baseline characteristics between the two groups,and the two groups were comparable.2.2 In prevention group,there was no significant difference in WBC,NLR,PLT,ALB,Scr and Ca2+ before and after using prevention agreement prescription,but there was significant difference in Hb,LMR,RDW,MPV,AST,ALT,BUN,Scr,GLO,UA,LDH and serum ?2-MG(P<0.05).Among them,Hb and RDW increased after treatment,while LMR,MPV,GLO,UA,LDH and serum ?2-MG decreased.In the control group,there was no statistical difference in WBC,NLR,PLT,MPV,Scr,Ca2+,UA,LDH and serum ?2-MG(P>0.05),but there was significant difference in Hb,LMR,RDW,ALB and GLO(P<0.05).Among them,Hb and ALB increased after treatment,while LMR,RDW and GLO decreased.After treatment,there was no significant difference in WBC,Hb,PLT,LMR,NLR,ALB,GLO,Scr,UA,LDH and serum?2-MG between the prevention group and the control group(P>0.05),but there was significant difference in RDW,MPV and Ca2+(P<0.05).Among them,the RDW prevention group was higher than the control group,while MPV and Ca2+ in the prevention group were lower than those in the control group.2.3 Compared with the control group,the NCI-CTC AE PN level above grade 4 was 0 in the prevention group,23.3%in grade 1,6.7%in grade 2,and no patients with grade 3 or above.In the control group,grade 1 was 13.3%,grade 2 was 36.7%,grade 3 was 6.7%,P=0.012,and there was a statistical difference between the two groups.The median(upper and lower quartile)of the peripheral neuropathy scale in the prevention group was 2.5(1.75?4.25),compared with that of the control group 8.5(2.75?13.25),there was statistical difference,the median of TCM symptom score(upper and lower quartile)in the prevention group was 4(2.75?6),compared with the control group 9(6?15),the difference was statistically significant.3.Clinical results of treatment agreement prescription intervention on BIPN in patients with MM:3.1 Compared with the general data before treatment,there was no significant correlation between NCI-CTC AE PN grade and age,sex,DS stage,ISS stage,infection,autonomic neuropathy and recurrent patients(P>0.05),while NCI-CTC AE PN grade was significantly correlated with M protein type and renal function damage(P<0.05).There was no significant difference in the levels of WBC,Hb,PLT,NLR,LMR,RDW,MPV,AST,ALT,BUN,Cr,ALB,UA,LDH,Ca2+,?2-MG,SF and CRP before and after treatment(P>0.05),but there was significant difference in the levels of GLO before and after treatment(P<0.05).3.2 Before treatment,NCI-CTC AE PN grade 1 accounted for 31.8%,grade 2 accounted for 59.1%,grade 3 accounted for 9.1%,After treatment,there were no peripheral neuropathy(45.4%),grade 1(36.4%),grade 2(18.2%),and there were no patients with grade 3 or above peripheral neuropathy.3.3 Before treatment,the median(upper and lower quartile)quantitative score of TCM symptom classification was 12.50(7.75?15),and decreased to 5(2.75?8.25)after treatment,P=0.001,there was statistical difference.The median(upper and lower quartile)of the peripheral neuropathy scale was 9(4?11)before treatment and decreased to 3(1?7)after treatment(P<0.001).The median QoL score before treatment was 28(25?31),and it was 28.5(26?30)after treatment.There was no significant difference between the two groups(P<0.05).The NCI-CTC AE PN level decreased significantly after the intervention of the treatment agreement,and there was no significant difference between the two groups(P<0.05).3.4 The median level of serum NGF was 22.10(15.32?38.24)ng/L in patients before treatment,which was significantly lower than that in healthy controls 39.26(30.64?50.94)ng/L,and 37.02(19.65?59.37)ng/L after treatment(P<0.05),and there was no significant difference between patients after treatment and healthy controls(P>0.05).The nerve conduction velocity measured by electromyography showed that the sensory nerve was mainly damaged,the motor nerve was also involved in severe cases,and the damage of peripheral nerve was mainly caused by axon and myelin sheath.Conclusions1.Bortezomib-based regimen is effective in the treatment of MM,and the prevention and treatment agreement can effectively control BIPN by replenishing qi and nourishing blood,warming meridians and dredging collaterals.After 3 course of treatment,the incidence of PN decreased,and the symptoms of numbness,pain and cold were relieved,which is speculated to be related to the promotion of blood circulation and the improvement of blood supply and oxygen supply of nerve cells.2.The prescription of replenishing qi,nourishing blood and dredging collaterals can reduce the probability of interrupting or stopping treatment in patients with severe BIPN,and provide guarantee for continuous and standardized treatment in the later stage,so as to assist in prolonging the PFS of patients.3.Yiqi Yangxue Tongluo recipe has no obvious clinical adverse reactions in the process of prevention and treatment of BIPN.