Chen-Yang Fan ,Li-Xiang Yan ,Xing-Li Wang ,Wei-Feng Zhang ,Lei Zhao ,Fang Yao ,Xiang-Dong Yang*

1First Teaching Hospital of Tianjin University of Traditional Chinese Medicine,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion,Tianjin 300380,China.

Abstract Objective: To investigate the characteristics of TCM syndromes in elderly patients with acute myeloid leukemia (AML) at the onset,and to analyze the main syndrome types and their correlation with age,percentage of bone marrow blasts,and genetic prognostic stratification.Methods: A retrospective analysis was performed on 159 AML patients aged over 60 years who were diagnosed and treated in our hospital,and the clinical data were collected and analyzed statistically.Results: In 159 elderly AML patients,the main clinical symptoms were fatigue,poor appetite,conscious fever,and various hemorrhages.The main syndromes were Ying(42.01%),Wei(31.25%),Essential (14.81%) and Blood(11.69%);the syndromes are divided into Qi and Yin deficiency (32.70%),Qi and blood deficiency(30.19%),true Yin deficiency (28.03%) and Qi heat and blood (8.81%).The age difference between the two groups was statistically significant (P ＜ 0.001),and the multiple comparison results showed that the age of the Qi-blood deficiency group was younger than the true-Yin deficiency group and the Qi-Yin deficiency group;the percentage of bone marrow blasts was statistically significant in the three groups at the initial diagnosis (P ＜0.05),multiple comparison results showed that the percentage of bone marrow blasts in the true Yin deficiency group was higher than that in the Qi-blood deficiency group and the Qi-Yin deficiency group;the genetic prognostic stratification of the three groups was statistically significant (P ＜0.05),multiple comparisons.The results showed that the genetic prognosis of the true Yin deficiency group was poorer than that of the Qi and blood deficiency group and the Qi and Yin deficiency group.Conclusion: The most common clinical symptoms of elderly AML patients are fatigue,the disease is located in the bone marrow,and the disease is Ying,Wei,essence,and blood.With the increase in the patient's age,the TCM syndrome types tend to be more insufficiency of true Yin and deficiency of both Qi and Yin,and the prognosis of patients with insufficiency of true Yin is poor.It provides a directional scientific basis for the treatment of senile AML with integrated traditional Chinese and Western medicine.

Keywords: acute myeloid leukemia;traditional Chinese medicine syndrome;Qi and Yin deficiency;syndrome differentiation and treatment

Background

The incidence of acute myeloid leukemia (AML) in the elderly (age ≥60 years) is 12 times that of other adult AML patients,and the 5-year overall survival rate of elderly patients is as low as 3-8%[1].The main treatment method for elderly AML patients is chemotherapy due to their physical factors,and hematopoietic stem cell transplantation cannot be performed,and the infection and anemia are more severe during the period of bone marrow suppression after chemotherapy.At this time,Chinese medicine adjuvant therapy has become the focus of clinical research.

Disease syndrome differentiation,one of the two major systems of syndrome differentiation,is the "essence of pathological changes,"which is the link between external symptoms and inner syndrome types and is the basis for qualitative syndrome types to guide medication.At present,there are many research results on the syndrome types of elderly AML at the onset of the disease,and no consensus has been reached.In this paper,the pathological characteristics of AML are divided into Ying,Wei,essence,and blood.Starting from the clinical symptoms,combined with the pathological characteristics,the syndrome rules of elderly AML in the onset period are clarified,and its dialectical characteristics are explored.Correlation analysis was performed on key prognostic indicators to guide clinical efficacy.

Materials and methods

Ethical approval

All the participants signed informed consent form.The study was approved by the hospital's ethics committee (IRM-DWLL-2020174)and signed informed consent was provided by patients or their families.

Normal information

This study collected elderly AML patients aged ≥60 years who were admitted to the Department of Hematology of the First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine from January 2015 to December 2020 and were newly diagnosed in our department.

Diagnostic criteria

The diagnostic criteria for AML refer to the 2021 edition of the"Guidelines for the Diagnosis and Treatment of Adult Acute Myeloid Leukemia (Non-Acute Promyelocytic Leukemia) in China" [2].The diagnostic points meet one of the following two points:(1) Peripheral blood or bone marrow blasts ≥20%;(2) Blasts ＜20%,patients with reproducible cytogenetic abnormalities t(8;21)(q22;q22),inv(16)(p13q22) or t(16;16)(p13;q22) and t(15;17)(q22;q12).

Inclusion criteria

(1) Meet the above AML diagnostic criteria;(2) Age greater than or equal to 60 years old;(3) Sign informed consent.

Exclusion criteria

(1) Patients who have not used chemotherapy such as cytotoxic drugs or targeted drugs after diagnosis,but only use hydroxyurea or supportive symptomatic treatment;(2) Patients who have undergone hematopoietic stem cell transplantation.

Research methods

Concerning "Traditional Chinese Medicine Diagnostics," "Expert Consensus on the Diagnosis and Treatment of Aged Acute Myeloid Leukemia (Non-Acute Promyelocytic Leukemia) with Integrated Traditional Chinese and Western Medicine" [3],etc.,the elderly AML information collection scale was formulated.Professionals who have undergone unified training collect the basic information of AML patients,the results of a bone biopsy,physical examination at the first visit to our hospital,TCM symptoms,and signs,TCM syndromes and corresponding dialectics for this scale,and classify them.Random sampling was performed on the summarised AML syndrome types,and correlation analysis was performed on TCM syndrome types and age,the percentage of newly diagnosed bone marrow blasts,and genetic prognostic typing.

Statistical methods

The statistical software uses SPSS26.0 and uses frequency (rate) to describe the distribution of each index in different TCM syndrome types.The Kruskal-Wallis nonparametric test was used to compare the ordered data between groups,the χ2test was used to compare the dichotomous data between groups,and the Bonferroni adjustment method was used for multiple comparisons.P＜0.05 indicated a statistically significant difference.

Results

A total of 159 elderly AML patients were collected from the Department of Hematology,The First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine.The age of 159 AML patients was(68.57±7.10)years old,53.46%were male and 46.54%were female.

Among the 159 elderly patients with AML,the most frequent symptom at the initial diagnosis in our hospital was fatigue,followed by poor appetite,conscious fever,various bleeding,edema,and sweating (Table 1).

Table 1 Distribution of clinical symptoms in myelosuppression stage in elderly patients with AML

According to the clinical identification of 159 elderly AML patients by several TCM hematology experts,the main disease classifications in this study are Ying,wei,essence,and blood.Dema,dry skin,lack of food,dry stools,and night sweats and sweating;conscious fever and sore throat and dry cough belong to wei;fatigue,insomnia,tinnitus,dizziness belong to essence;delirium,mania,and bleeding belong to blood (Table 2).

Among the 159 elderly AML patients,more than 20% of the TCM syndromes were Qi-Yin deficiency and Qi-blood deficiency and true Yin deficiency (Table 3).

159 elderly AML patients were grouped by TCM syndromes with a frequency of more than 20% during the myelosuppression period,45 cases in each group and the overall distribution was shown with age,percentage of newly diagnosed bone marrow blasts,and genetic prognostic typing (Table 4).

In addition,the Kruskal-Walls nonparametric test method was used,and the results showed that the age of onset of the patients in the true Yin deficiency group was higher than that in the Qi and Yin deficiency group (P＜0.05).The age of onset in the true Yin deficiency group was significantly higher than that in the Qi and blood deficiency group(P＜0.001).

In addition,using Kruskal-Walls nonparametric test,the results showed that the percentage of newly diagnosed bone marrow blasts in the patients with true Yin deficiency group was significantly higher than that in the Qi and blood deficiency group (P＜0.05),and there was no statistical difference between the other groups (P＞0.05)(Table 5).

According to the "Guidelines for the diagnosis and treatment of acute myeloid leukemia(non-acute promyelocytic leukemia) in adults in China",the genetic prognosis grouping was carried out according to the cytogenetic and molecular genetic changes of AML cells at the initial diagnosis of AML patients.Group 3,namely poor prognosis,moderate prognosis,and good prognosis (Table 6).

Table 2 AML syndrome distribution

Table 3 AML syndrome type distribution

Table 4 The distribution and correlation analysis of AML syndrome types and first-diagnosis age in the elderly

Table 5 The distribution and correlation analysis of AML syndrome types and bone marrow blast cells in the elderly

Table 6 Distribution and correlation analysis of syndrome types and genetic prognosis of AML in the elderly

Using Kruskal-Walls nonparametric test,the results showed that the genetic prognosis of patients in the true Yin deficiency group was significantly worse than that in the Qi and blood deficiency group (P＜0.05),and there was no statistical difference between the other groups(P＞0.05).

Discussion

AML is a heterogeneous clonal disease that is a hematopoietic malignancy caused by mutations in hematopoietic stem progenitor cells.The necessary condition for the diagnosis of the disease is bone marrow blast cells ≥ 20%.The percentage of blast cells often indicates the stage of the patient's disease progression.The higher the percentage,the faster the disease progression [4].According to clinical studies,age is proportional to AML mortality [5].The median age of onset of AML is as high as 68 years old [6],and the elderly are the majority of the onset of AML.According to the consensus of several frontier clinical experts of traditional Chinese and Western medicine,traditional Chinese medicine has a significant effect on the adjuvant treatment of elderly AML in the period of bone marrow suppression after chemotherapy [3].Compared with antibiotics,the prevention and treatment of complications in the bone marrow suppression stage of elderly AML have fewer adverse reactions and lower prices.Therefore,it is necessary to study the TCM syndrome types and their correlation with age,bone marrow blast cells,genetic prognostic stratification,and remission after chemotherapy.

Leukemia is located in the bone marrow.According to ancient Chinese medicine books,essence,blood,and marrow can be transformed into each other [7].Essence refers to the most essential part of Qi.Essence and Qi have basically the same concept and are the foundation of human beings.Therefore,when AML is in essence,theories and clinical experience can lead to fatigue,tinnitus,deafness,dizziness (without phlegm),insomnia,and anxiety belong to the category of the essence.Regarding the nature of the disease as blood,one is that Qi deficiency is difficult to generate blood,and it consumes blood to move blood;the other is that blood and heat fight each other and cause heat and blood stasis.The "Emperor's Classic of Internal Medicine" puts forward the assumption that Yingwei uses the theory of Yin and yang to explain the hypothesis of the theory of Qi and blood [8].Sickness Yuwei refers to a class of syndromes characterized by fever,aversion to cold,sore throat,and dry cough.It nourishes the organs and tissues,balances Yin and Yang,and enhances the body's resistance and other functions.It circulates in the blood vessels to ensure the stability of the human body’s functions.It nourishes the whole body,liver,and kidney.Symptoms such as anorexia,edema,dense stools,dry skin,excessive sweating,and night sweat all fall under the category of Ying.To sum up,Yin,essence and blood belong to Yin,and Wei and essence are also classified as Qi.Therefore,the main syndromes of elderly AML patients are summarized as deficiency of both Qi and Yin,deficiency of Qi and blood,and deficiency of true Yin.In addition,the theory of traditional Chinese medicine believes that "the kidney stores the essence and controls the bone to generate the marrow" is a summary of the "Nei Jing" in the long-term practice process,which is in line with the laws of life and the correct conclusion of many clinical practices [9,10].The relationship is also closer.The relationship between kidney and leukemia needs to be further summarized.

The results of this study show that:according to the clinical symptoms of elderly AML patients,they are classified as disease-related Ying,essence,Wei,blood.Dema,dry skin,lack of food,dry stools,and night sweats and sweating;conscious fever and sore throat and dry cough belong to Wei;fatigue,insomnia,tinnitus,dizziness belong to essence;delirium,mania,and bleeding belong to blood.The incidence of elderly AML patients is more common in Ying,essence,Wei,and blood.It is concluded that the frequency of syndrome types from high to low is:Qi and Yin deficiency,Qi and blood deficiency,and true Yin deficiency.First of all,AML is due to"liver Qi failure" and "Tiangui depletion" due to the age of over 60 years old,which reduces the reserve of various functions of the body,increases the vulnerability of the body,and depletes the true Yin.From the perspective of traditional Chinese medicine,AML is usually caused by phlegm-dampness,blood stasis,damp-heat,and other pathogenic Qi that injure the bone marrow and brew into toxins,such as heat toxin,blood stasis,dampness,and phlegm.Damaged,the human body's nourishing essence and blood belong to the category of Yin,and the Yin-jin Yin fluid also plays a role in moisturizing and nourishing.Dai H,et al [11,12] confirmed that the Yin-nourishing method,such as Zuogui Buxue Shengsui Decoction or Shengma Biejia Decoction combined with chemotherapy has obvious clinical effect in the treatment of AML.According to this study,in the process of diagnosis and treatment of elderly AML,the age at first diagnosis,bone marrow blast cell count,and genetic prognostic stratification are all important indicators that affect the clinical prognosis and treatment effect of patients.Types of Qi and blood tend to be more prone to deficiency of true Yin and deficiency of both Qi and Yin.Patients with a deficiency of Qi and blood have a good genetic prognosis and a low percentage of marrow blasts.They should be actively treated,and it is important to cooperate with Codonopsis,Astragalus,Angelica,and Rehmannia.Older patients should pay more attention to the adjuvant treatment of traditional Chinese medicine that nourishes true Yin,nourishes Qi and restores pulse,and invigorates body fluid and nourishes blood.Patients should be closely observed in clinical practice.In case of five upset heat,hot flashes and night sweats,and red tongue,timely and close symptoms should be observed.Take medication and observe vital signs to prevent adverse events.

Conclusion

To sum up,the most common clinical symptoms of 159 elderly AML patients were fatigue.The disease was located in the bone marrow.The symptoms were summarized as Ying,Wei,essence,and blood.The more frequent syndromes were deficiency of Qi and Yin,and Qi and blood.Deficiency and lack of true Yin.In this study,the patients in the true Yin deficiency group and the Qi and Yin deficiency group were older,and the prognosis of the patients in the true Yin deficiency group was worse than that in the other groups.This paper pioneered the use of Ying,Wei,essence,and blood as the link of disease to summarize clinical symptoms into syndrome types,which gave more innovative tips for clinical Chinese medicine use in elderly AML patients when they were onset,and improved clinical efficacy.However,due to the lack of historical data and regional limitations in this study,a prospective,multi-regional,and large-scale clinical study can be carried out in the next step to further explore the combination of different chemotherapy regimens or gene mutation types with TCM symptomatic medication,and develop an integrated traditional Chinese and Western medicine.The best regimen for the treatment of AML in the elderly.