Antithymocyte Globulin/antilymphocyte Globulin Plus Kidney-nourishing Chinese Medicinal

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Xudong Tang, et al

Abstract

OBJECTIVE:

To explore the effect of anti-thymocyte globulin (ATG)/antilymphocyte globulin (ALG) plus kidney-nourishing Chinese medicinal (KNCM) on severe aplastic anemia (SAA).

METHODS:

Twenty-five subjects of severe aplastic anemia were treated with ATG/ALD plus KNCM between 1992 and 2009, and the clinical data before and after treatment were collected and analyzed.

RESULTS:

Of the 25 patients, 9 were nearly cured, 6 were improved, 5 were in remission, and 5 failed. The overall effective rate was 80.0%. The 3-year, 5-year, 10-year, 15-year survival rates were respectively 98.6%, 97.3%, 97.3%, 67.5%, and the median survival time was 180 months. Compared to the conditions before administering the medication of ATG/ ALG plus KNCM, after 2 weeks, the reticulocyte was first improved (P=0.001); one month later, followed by palette (P=0.037); two months later, by the neutrophil cell in peripheral blood (P=0.001); three months later, then by the hemoglobin (P=0.012). By conducting a 1-year follow-up, 1 case of complication--paroxysmal nocturnal hemoglobinuria (PNH) was identified, and the patient is still alive today.

CONCLUSION: ATG/ALG plus KNCM had a better effect on SAA and could improve patients' survival rate.

Keywords: Anemia, aplastic; Reinforcing kidney; Drugs, Chinese herbal; antilymphocyte serum; anti-thymocyte serum

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INTRODUCTION

Severe aplastic anemia (SAA) is a condition that may acutely develop and have a relatively high mortality rate. It is a refractory illness of hematological diseases. Studies showed that most aplastic anemias were caused by immune disorders.1 The very severe aplastic anemia (VSAA), a much more serious condition, is characterized by a higher death rate and is often accompanied by heavy infection and internal hemorrhage. 20 years ago, the mortality rate of VSAA was nearly 100%. Based on VSAA's nature of acute onset, rapid development, progressive anemia, high fever, and severe hemorrhage, it was defined and discussed as "Ji Lao", "Re Lao" or "Xue Zheng" in Traditional Chinese Medicine (TCM). In 2004, the Hematological Committee of the Chinese Association of the Integration of Traditional and Western Medicine defined SAA as "Ji Sui Lao" in terms of TCM theory. The department of Xiyuan Hospital has been engaged in the research into AA and it has treated the illness with the integration of TCM and Western Medicines since the 1950s2-3 and proposed kidney-nourishing as the primary principle in AA's treatment with TCM, which has been acknowledged as a better scheme for chronic aplastic anemia. Starting from the 1990s, anti-thymocyte globulin (ATG)/antilymphocyte globulin (ALG) plus kidney-nourishing Chinese medicinal (KNCM) has been used as the first-line treatment for SAA and VSAA. Up to date, few reports have been published on VSAA's treatment with ATG/ALG plus KNCM. In this paper, we report our results of treating VSAA with the integration of TCM with Western Medicine from 1992 to 2009.

METHODS

Subjects

Twenty-seven subjects of type-I VSAA were recruited by the Department of Hematology of Xiyuan Hospital of the Chinese Academy of Chinese Medicine Sciences. 2 of them dropped out after ATG was administered for 2 months due to financial issues. 25 subjects, 17 males and 8 females were treated and evaluated. Their ages ranged from 7 to 61 years with a median age of 29, and the disease courses ranged from 1 to 6 months with a median course of 1.1 months. 11 cases were treated with ATG (of them, 5 with horse anti-human antibody; 6 with rabbit anti-human antibody) and 14 cases were treated with ALG.

Diagnostic criteria

VSAA was diagnosed with Camitta's criteria (1925) for SAA plus neutrophil count which was less than 0.2 × 109 /L.

Treatment

Administration of ATG/ALG: ALG (swine anti-human T cell immunoglobulin, Wuhan Institute of Biological Products, P. R. China), intravenously guttae (iv gtt) 20-30 mg/(kg·d). ATG (horse anti-human T cell immunoglobulin, Genzyme Polyclonals S.A.S),iv gtt 8.3-13.4 mg/(kg·d); ATG (rabbit anti-human T cell immunoglobulin, Genzyme Polyclonals S.A.S), iv gtt 2.5-3.2 mg/(kg·d), ATG (rabbit anti-human T cell immunoglobulin, Fresenius Biotech GmbH), iv gtt 5- 7 mg/(kg·d). After hypersensitive tests of the subjects were confirmed negative, ATG/ALG was administered, iv gtt QD, to them for 5 days. Every time prior to the administration of ATG/ALG, 5 mg of Dexamethasone was administered by venous infusion and 25 mg of promethazine hydrochloride by intramuscular injection. Administration of KNCM: In terms of TCM theory, kidney deficiency can be classified as kidney-Yang deficiency and kidney-Yin deficiency. While the kidney was nourished, the spleen might be nourished and blood activated, related toxic elements eliminated depending on the outcome of pattern differentiation.

The commonly used Chinese medicinal were as follows: Radix Rehmannia, Fructus Corni, Polugonum Multiflorum Thunb, Fructus Psoralea, Cuscuta Chinensis Lam, Radix morinda Officinalis, Songaria Cynomorium and Herba Epimedii. The addition of extra medicinal was dependent on the outcome of pattern differentiation: for the pattern with manifest kidney deficiency, Fructus Mori, Glossy privet fruit, Mayflower solomonseal rhizome, and Barbury wolfberry fruit were added; for the pattern with manifest kidney-Yang deficiency, Rhizoma curculiginis and Herba distances were added. For the pattern accompanied by symptoms of spleen deficiency, Radix pseu Stellaria, Large head atractylodes rhizome, Common yam rhizome was added; for the pattern accompanied by the symptoms of blood deficiency, Astragalus membranaceus, Chinese angelica, Chinese peony, and Placenta hominins were added. For the pattern accompanied by blood stasis, Radix salvia miltiorrhiza, Millettia dielsiana, Leonurus heterophyllous, and Rhizoma linguistic chuanxiong were added; for the pattern accompanied by heat toxin, Smilax glabra, Taraxacum, Flos Lonicera, and Weeping forsythia fruit were added. The medicines were decocted and taken twice a day in the morning and evening respectively. The course of therapy was 6 months, and two consecutive courses were administered. After finishing the two courses, all patients who showed progression were required to be treated with the same regimen for at least 1 year or more.

Supportive and palliative treatment: All patients that underwent the above-mentioned treatment were orally administered Cyclosporin A. It was initially taken at the dose of 6 mg/(kg·d) BID, then the dose was modified in terms of blood drug concentration (to keep its trough concentration at 200-400 ng/mL). The treatment course was 6 months or more. After the hemogram was stable, the dose was slowly reduced, and finally, it ceased to be administered; Stanozolol (6-12 mg/d) or testosterone undecanoate capsule (120- 240 mg/d) was taken orally BID. After the peripheral hemogram became normal, the dose of medicine was reduced gradually and maintained for 3 years. The granulocyte-colony stimulating factor was administered at the dose of 5 μg/(kg·d) until the count of neutrophilic granulocytes was greater than 1×109 /L; Blood transfusion was performed when hemoglobin was below 60 g/L and the count of platelets was less than10 × 109 /L or when there was an increasing tendency of hemorrhage, the machine-collected pallet was transfused.

Prevention and treatment of adverse reaction: When ATG/ALG was used, patients were requested to stay in the wards with 100-grade air cleanliness to be kept away from infection. Their blood cell counts were examined every other day or daily when necessary. Depending on the outcome of the hemogram, bone marrow might be re-examined. Hypersensitiveness and serum disease were monitored during the administration of ATG/ALG. The symptoms watched were hypertrichosis, digestive tract disorders, hand tremor, periphery sensation decreasing, pyrexia, bleeding, skin itch, my salvia, ureterocele. Regularly hepatic and renal functions were examined, electrocardiogram and X-ray were performed, hemocluture was conducted, and chest CT performed if necessary.

Prevention and treatment of serum sickness: After ATG/ALG treatment, Prednisone acetate was orally administered at the dose of 50 mg/d. If a serum sickness reaction occurred, prednisone acetate was replaced with methylprednisolone, which was administered at the dose of 40-200 mg/d, iv gtt for no more than one week, then its dose was gradually reduced. Once infection occurred, antibiotics were used. If hepatic function impairment occurred, Polyene Phosphatidylcholine and diammonium glycyrrhizinate were administered for liver protection purposes.

Effect evaluation

The efficacy evaluation criteria were formulated based on the evaluation standard formulated by the Fourth National Conference on Aplastic Anemia held in 1987,5 The efficacy was graded as a cure, remittance, improvement, and failure. And the first 3 grades, cure, remittance, and improvement, were considered to have an effect.

Data analysis

SPSS 13.0 was employed for data analysis. A Matched-pair sample t-test was performed to compare means before and after the treatment in the same group. The difference was considered significant if P-value was less than or equal to 0.05.

RESULTS

Effectiveness of ATG/ALG plus KNCM in the treatment of VSAA (Table 1)

Table 1 summarizes the information of the 25 VSAA patients treated with the therapy and followed up for 1 year or more after they finished the intervention.

The change of hemograms before and after the treatment of ATG/ALG plus KNCM (Table 2)

From Table 1, we can see that 2 months after the treatment, the neutrophil started to rise significantly (P= 0.001); that hemoglobin increased manifestly 3 months after treatment (P=0.012); that reticulocytes began to go up quickly 2 weeks after the treatment (P= 0.001); that platelet rose considerably 1month after the treatment (P=0.037).

Survival Curve for the treatment of ATG/ALG plus KNCM (Figure 1)

From Figure 1, we can see that, after the Treatment of ATG/ALG plus KNCM, the survival rate for 3 years, 5 years, 10 years and 15 years were 98.6%, 97.3%, 97.3%, 67.5% respectively..

Adverse reaction and long-term complication

Allergic response occurred in 23 VSAA cases after ATG/ALG was administered. Of all patients of serum sickness reaction; pyrexia occurred in 22 patients; skin rash in 21 patients; arthrodynia in 19 patients; and chest distress in 1 patient. After administered methylprednisolone, prolamine, and calcium gluconate, all symptoms were improved. The serum sickness reaction occurred as early as the first day after ATG/ALG was administered and the latest one occurred on the 30th day after ATG/ALG was given and the reaction lasted from 4-8h. The time period of follow-up ranged from 51 to 172 months. The median follow-up time was 104 months. During the follow-up period, patient 2 were reported the death. One relapsed and developed into PNH, who is still alive today.

DISCUSSION

VSAA is a life-threatening disorder that which the function of bone marrow is impaired. The condition leads to red marrow being replaced by yellow marrow which is specialized fat cells, and the decrease of the whole blood cells. In many cases, the etiology is considered to be idiopathic, but one known cause is an autoimmune disorder in which T lymphocytes attack the bone marrow.6 Aplastic anemia is sometimes associated with exposure to toxins such as benzene, or with the use of certain drugs, including chloramphenicol and carbamazepine. Exposure to ionizing radiation from radioactive materials or radiation-producing devices is also associated with the development of VSAA.

There are few records of VSAA in the ancient literature. However, Huangdi's Internal Classic has many descriptions of grouping symptoms such as pale, bleeding, and pyrexia. In Han Dynasty, Zhongjing Zhang first coined the word Xulao for the condition in Synopsis of Golden Chamber. In terms of TCM theory, VSAA is a long-term course illness characterized by the deficiency pattern staying throughout the whole course, which involves the deficiency of the heart, liver, spleen, lung, and kidney. Qi and blood deficiency appeared first, then kidney deficiency, and essence depletion follows. Although the condition involves the heart, liver, spleen, and kidney, the kidney has the closest relation to VSAA. Kidney deficiency is the key factor underlying the onset and development of VSAA.

Currently, in China, the primary treatment for VSAA is intensive immunosuppressive therapy (IST) such as ATG/ALG and CsA. The fatality rate in the early stage fell to 9.6%. According to some early literature, the efficiency rate of treating SAA with horse ATG only was 40%-50% and that with the combination of ATG and CsA was 70% in the treatment period between 3 and 6 months. The advantage of the combination of the medications is that ATG and CsA can act on different parts of the immune system. Today, ATG/CsA is still used in the regular treatment scheme for VSAA. A large number of cases studied in multi-centers proved that the effective rate of the treatment scheme was 70%7 with a 5-year survival rate up to 80%-90%.8 The research into the treatment of VSAA with kidney nourishing as the principal method for AA started in the 1960s. That the treatment of AA should focus on kidneys was first advocated by the Hematological Committee of the Chinese Association of the Integration of Traditional and Western Medicine at the National Conference on Blood Disease Treated by the integration of Chinese and Western Medicines held in 1986 in Dalian, China. In terms of TCM pattern differentiation for treatment, kidney deficiency patterns for AA were classified into three: Yang deficiency, Yin deficiency, both Yang and Yin deficiency. Ever since the beginning of the 1990s, a combination of KNCM and ATG/ALG for VSAA treatment was first used in Xiyuan Hospital in Beijing, China. In our experience of treating 25 VSAA patients, the total effective rate was 80.0%. The survival rate for 3 years, 5 years, 10 years, and 15 years were 98.6%, 97.3%, 97.3%, 67.5% respectively. The reticulocyte, platelet, neutrophil, and hemoglobin started to rise 2 weeks, 1 month, 2 months, and 3 months after the treatment respectively. The results suggested that kidney-nourishing medicinal played a vital role in the VSAA treatment and patients' survival time.

For the human body, ATG/ALG is a kind of heterogenous protein, it is mainly composed of IgG, which underlies allergy and serum sickness. Our study found that the symptoms could disappear within 2-4 days of all patients experiencing allergy (23/25,92.0% ), especially 2-8h after ATG/ALG is first used, by slowing down the iv-gtt speed of ATG/ALG or stopping using it and taking medication such as dexamethasone. Serum sickness is a systemic allergic disease caused by the blood circulation of an allergen. It would occur 7-14 days after ATG/ ALG was given.9 The main symptoms were pyrexia, rash, muscular soreness, and arthralgia. Prednisolone could bring serum sickness reaction under control at the dose of 40-200 mg/d and a larger dose was seldom used. No sequela was found. So ALG/ATG is safe in clinical practice.

The most important factor affecting the prognosis of the patients treated with ATG is relapse. In Europe, the reported rate was 30%-40%. The primary symptoms are red blood cell dependence and palette transfusion dependence, and CsA dependence recurring.6 The long-term (10 years) relapse rate is 33%, with a median relapse time of 570 days.10 Sometimes, a few VSAA patients, staying in remittance for ten years after IST therapy, developed into clonal diseases such as PNH, MDS, AML, and other tumors. The occurrence of PNH is 9% 11 and the 10-year cumulative incidence was 16%.12 Another study reported that the incidence of clonal disease was 10%-40%.13-14

In our study, 25 VSAA patients were followed up for at least 1-year, no relapse was found. Only 1 case developed into PNH. Probably, the fewer relapse cases were due to shorter follow-up periods. A Longer follow-up period will still be conducted. In spite of this, the treatment of VSAA with ATG/ALG kidney-nourishing plus Chinese medicinal showed promising efficacy. Moreover, up to date, no subjects have been found dead. Further study will try to explore how VSAA exerts its impact on complications.

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