Primary systemic amyloidosis, also known as light chain-associated amyloidosis (AL amyloidosis), is a plasma cell disease caused by the extracellular deposition of monoclonal immunoglobulin light chains or light chain fragments in the form of abnormal amyloid fibrillary structures, which can involve multiple tissues and organs throughout the body, causing multi-organ dysfunction and death. Patients with AL amyloidosis have a poor prognosis, with an average survival of 6-15 months for untreated patients and a 10-year survival rate of less than 5%. (AHSCT). Conventional chemotherapy with drugs such as Marfan and hormones has a slow onset and low complete remission rate, and has limited effect on improving the prognosis of AL amyloidosis. In contrast, AHSCT treatment can achieve high hematologic and organ response, and its 5-year survival rate can reach 60%, which is one of the most effective treatment options for AL amyloidosis. To date, the foreign literature has reported long-term follow-up results of more than 800 patients with AL amyloidosis treated with AHSCT, with a median survival of more than 10 years for those who achieved complete remission [4]. However, there are few studies in this area in China, with only sporadic case reports [5], and there is a lack of experience related to AHSCT treatment in patients with AL amyloidosis in China. Subjects and methods: Object From July 2010 to January 2011, 13 cases of AL amyloidosis (8 males), aged 35-63 (median age 54) years, with a disease duration of 2 to 43 months (median time 9 months), were treated with AHSCT at the All Army Institute of Nephrology, Nanjing General Hospital, Nanjing Military Region, from July 2010 to January 2011, all patients presented with renal disease as the first manifestation and were clearly diagnosed by renal puncture. Immunofluorescence staining showed λ light chain deposition in renal tissue in 11 cases and κ light chain deposition in 2 cases. All patients were diagnosed with AL amyloidosis by percutaneous nephron puncture, and further biopsies of rectal mucosa, skin and bone marrow, cardiac ultrasound, electrocardiogram, liver ultrasound and alkaline phosphatase (AKP) were performed to determine organ involvement, and glomerular filtration rate, cardiac function, lung function, liver function and co-morbidities were also evaluated. The criteria for organ involvement were adopted from those developed at the 10th International Symposium on Amyloidosis [6]. Patient inclusion criteria were: age <65 years, serum creatinine (Scr) <2 mg/dl, alkaline phosphatase <3 times the upper limit of normal, bilirubin <2 mg/dl, physical status score (Eastern Tumor Collaborative Group criteria [7]) <2, cardiac function grade I-II, and ejection fraction >55%. Stem cell mobilization and collection Stem cells were mobilized with granulocyte colony-stimulating factor (G-CSF) alone, G-CSF dosage was 5-10 μg/kg/d, CD34+ cell count was detected after 4 days of continuous use, collection was started when CD34+ cell count >15 cells/μL, peripheral blood stem cells were collected using Fresenius blood cell separator, blood volume was treated with 11-14 L per collection, target value of collection After collection, the stem cells were mixed with cell lyophilization solution (ratio of saline: 10% dimethyl sulfoxide: 20% human albumin = 3:1:1) in equal proportions and then packed into 50 ml/bag and frozen in liquid nitrogen for storage. Stem cell transplantation process Stem cell transplantation was performed within 2-4 weeks after successful stem cell collection. The pretreatment regimen was high-dose Marfalan, which was divided into three doses of 100, 140 and 200 mg/m2 according to patient risk stratification [8]. The low-risk group (200 mg/m2 of Marfalan) was defined as no cardiac involvement, no more than two total organs involved, creatinine clearance >51 ml/min, and collected CD34+ cell count >2.5 × 106/kg; the intermediate-risk group (140 mg/m2 of Marfalan) was defined as one or two organs involved (including cardiac or creatinine clearance <51 ml/min), and collected CD34+ cell count >2.5×106/kg; high risk group (Marfalan 100mg/m2) defined as three or more organs involved (including heart), or CD34+ cell count collected was 2~2.5×106/kg. stem cell transfusion was performed 48h after Marfalan infusion, i.e. day 0, +1 day administration of G-CSF was started to stimulate hematopoiesis. Evaluation of efficacy and adverse reactions Patient efficacy was judged according to the criteria developed at the 10th International Symposium on Amyloidosis, and was divided into two categories: hematological reactions and organ reactions. Adverse reactions were evaluated according to the Common Terminology Criteria for Adverse Reactions (CTCAE v3.0). Statistical analysis Statistical software SPSS 13.0 was used, and the mean ± standard deviation ( ±S) was used to describe normally distributed measures, median was used to describe non-normally distributed measures, and percentages were used to describe count data. Results Pre-transplant condition The number of involved organs was 1-3 (mean 2.0±0.58) (only vital organs such as kidney, heart, liver and nervous system were counted), all patients had kidney involvement, and the remaining involved organs were heart, liver and peripheral nerves in that order. Blood monoclonal immunoglobulin types were predominantly λIgG. 4 patients were treated with AHSCT directly after diagnosis, and the rest had received different regimens of chemotherapy before transplantation, with a regimen of bortezomib combined with dexamethasone (BD) predominating. Scr: serum creatinine; AKP: alkaline phosphatase; BD: bortezomib combined with dexamethasone; TD: thalidomide combined with dexamethasone; MP: mafenamic acid combined with prednisone Transplantation parameters Stem cells were successfully collected in all patients with a mean number of 2 (1-3) collections, and the main complications during collection were hypocalcemia (38.5%), hypokalemia (61.5%) and platelet The main complications of the collection procedure were hypocalcemia (38.5%), hypokalemia (61.5%) and platelet depression (<50,000/ul) (30.7%), all of which could be recovered 2-3 days after the collection. The number of CD34+ cells collected ranged from 2.0 to 8.36×106/kg [(mean 4.02±2.01)×106/kg]. Marfalan dosage was mainly 100 mg/m2. Hematopoiesis was restored and reconstituted in all patients with a granulocyte deficiency period of 3-7 days (median time 4 days), neutrophil implantation time of 9-13 days (median time 9 days), and platelet implantation time of 10-21 (median time 13 days) days. Complications The main complications during transplantation are nausea and vomiting, mucositis, fever during granulocytosis, cardiac arrhythmia, acute kidney injury, diarrhea, etc. Other rare complications include acute liver injury, pleural effusion, sepsis and hepatic rupture and bleeding. The complications were predominantly grade 1 to 2, with relatively few complications of grade 3 and above (Table 3). 7 patients had granulomatous fever lasting 1 to 5 days (median time 2 days), which improved after antipyretic and antibiotic treatment. 1 case was clearly identified as E. coli sepsis, and the rest had no pathogenic evidence and no combined fungal infections. Among the patients with arrhythmias, 3 had atrial fibrillation, 2 had premature ventricular contractions, 1 had diphasic rhythm, and 1 had triple rhythm, which occurred mostly after retransfusion and lasted for 1-8 days (median time 3 days). 3 cases required antiarrhythmic drug treatment. One patient died within 100 days after transplantation due to hepatic rupture and bleeding, and the treatment related mortality (TRM) was 7.7%. One patient had unexplained thrombocytopenia at post-transplant follow-up and required regular platelet transfusions for maintenance. The rest of the patients did not develop complications during the follow-up. Efficacy evaluation: 8 cases (61.5%) achieved hematologic response at 4-10 months post-transplant follow-up, including 5 cases (38.5%) with complete remission, 3 cases (23%) with partial remission, 3 cases with stable disease, and 2 cases with disease progression. 7 cases (53.8%) achieved organ response, including 3 cases with renal and cardiac response, 4 cases with renal response, and the remaining patients had no organ response. CR: complete remission; PR: partial remission Discussion AL amyloidosis is a clonal proliferative plasma cell disease, the basic principle of treatment is to control plasma cell lesions by chemotherapy and to inhibit the synthesis of monoclonal immunoglobulin light chains [9]. MP (Marfalan combined with prednisone) regimen has been the standard therapy for the treatment of AL amyloidosis, with a long response time and less than 5% complete remission rate, despite the improved survival compared to untreated patients. Since its clinical use in the mid-1990s, AHSCT has improved the response rate to treatment and the prognosis of patients with AL amyloidosis has improved considerably [11]. This study summarizes the experience of AHSCT treatment in patients with AL amyloidosis at our center, with the aim of evaluating its initial efficacy and safety. Selection criteria for transplantation Currently, there are several international selection criteria for AHSCT in AL amyloidosis, mainly referring to the patient's age, general status, vital organ functional reserve and comorbidities, with the most stringent criteria proposed by Comenzo et al. The liver and kidney functional evaluation in this study extended the criteria, but with more stringent age restrictions. Regarding the evaluation of cardiac functional reserve, it mainly relies on the classification of cardiac function rather than septal thickness, because clinical observation revealed that some patients had normal cardiac function despite septal thickening, and both patients with septal thickness of 19 mm in this group successfully received AHSCT and achieved cardiac response. However, cardiac evaluation remains a crucial aspect of patient selection, as nearly half of patients with AL amyloidosis eventually die of heart failure or severe arrhythmias. Analysis of transplantation efficacy The results of the current major studies of AHSCT for AL amyloidosis are summarized in Table 7. From the results of the studies, the overall hematologic response was high, about 50-80%, with a CR of about 40-60%. From the results of the short-term follow-up of our patients, the hematological response rate was 61.5%, including a CR of 38.5%, with a mean onset of action of only 1.5 months. The overall response rate and CR rate in this group were slightly lower than those reported in the literature, which may be related to the shorter follow-up period. The organ response rates reported in the literature were all above 40%, and 53.8% of patients in our group achieved organ response, with the main organ of response being the kidney. The literature reports that renal response generally takes more than 1 year, but the average response time of patients in this group was only 2.4 months. Analysis of patients who obtained organ response suggests that the short response time may be related to the shorter disease duration, induction therapy received before transplantation and fewer organs involved, but further clinical observation is still needed. In this study, the observation period was short and no data related to long-term prognosis were available, but a case-control study comparing the differences between patients with AL undergoing AHSCT and other therapies showed that the former had a significantly better prognosis, further confirming the role of AHSCT in AL. The study also confirmed that patients who achieved hematologic CR after transplantation had a better prognosis, with a median survival of more than 10 years. CR: complete remission; PR: partial remission TRM causes and countermeasures TRM in patients with AL amyloidosis undergoing AHSCT is several times higher than in other diseases (e.g., multiple myeloma), with a TRM of 12-13% at 100 days post-transplant, even in experienced transplant centers. In a multicenter study, TRM was as high as 40% in patients with progressive organ damage. The main causes of death were heart failure, severe arrhythmias, multi-organ failure, infection, and gastrointestinal bleeding. Multifactorial analysis showed that pre-transplant creatinine level, number of organs involved and myocardial amyloidosis were important risk factors for TRM, in addition to a significant increase in TRM in patients with severe hypotension and physical status score >2 [24]. One patient died within 100 days after transplantation in our group, and the cause of death was liver hemorrhage, probably related to severe liver involvement and coagulation abnormalities in the patient. This complication is relatively rare and has only been reported as a case in the literature. The TRM of our patients was 7.7%, which was lower than that reported abroad and may be related to the small sample size, case selection and dose adjustment of Marfan. In order to reduce TRM, some scholars stratified patients according to the number and type of organs involved and adjusted the dosage of mafran to 100, 140 and 200 mg/m2. confirmation. This risk stratification scheme was also used in this study, which did have a positive effect on reducing the risk of transplantation, and patients in the low-dose mafran group also achieved a better outcome, so we believe that mafran dose adjustment still has some clinical significance. Analysis of transplantation-related complications Other common complications during the transplantation process include nausea, vomiting, diarrhea, mucositis, edema, liver and kidney function impairment, cardiac arrhythmia, bleeding and infection, among which the incidence of toxicity grade II or above is 26-91%. The occurrence of complications in our patients was similar to that reported in the literature, with nausea, vomiting, mucositis, fever during the granulomatous phase, and diarrhea remaining the main complications during treatment, especially the incidence of cardiac arrhythmia and acute kidney injury was higher. The literature reports the occurrence of acute renal insufficiency in about 2l%, 50% of which is reversible. Adverse reactions to Marfan are the main cause, with age, hypoproteinemia, massive proteinuria, and use of diuretics as high-risk factors. In another large group of studies, the incidence of renal failure after transplantation for AL amyloidosis was 5% (14/277). All patients in this group had renal involvement and manifestations of nephrotic syndrome, which may have led to a high incidence of acute kidney injury. All patients recovered to baseline levels of renal function, except for one patient who had continued progression of renal function and started dialysis treatment after six months. Cardiac complications are an important cause of TRM in patients with AL. In this group of patients, although no fatal cardiac complications occurred, seven patients developed various types of arrhythmias, three of which required antiarrhythmic drug therapy. These patients were themselves combined with cardiac involvement and the arrhythmias occurred mostly after stem cell transfusion back, the reasons for which were firstly related to the toxicity of their own amyloid deposition on cardiac myocytes [30] and secondly dimethyl sulfoxide has a toxic effect on cardiac amyloidosis of the myocardium [31]. Other rare complications include acute liver injury, pleural effusion and sepsis, all of which improved with appropriate treatment. Fewer complications occurred during post-transplant follow-up, one patient developed severe thrombocytopenia, which was considered to be related to factors such as the patient’s long duration of disease and previous treatment with marfalan. The rest of the patients showed no relevant complications during the follow-up. Summary: The results of this study suggest that AHSCT remains one of the most effective means of treating AL amyloidosis. For strictly selected patients with AL amyloidosis, AHSCT treatment has a high hematologic and organ response rate. Although the incidence of various transplant-related complications is high, fatal complications are rare. Short-term follow-up observations indicate the definite efficacy of AHSCT treatment with high patient response rates and rapid response times, but its long-term efficacy needs further observation. Comprehensive assessment of patients’ vital organ functions before transplantation and selection of suitable patients are important aspects to reduce TRM, while adjusting the dose of Marfalan according to patients’ risk stratification can enable some high-risk patients to receive transplantation successfully; the transplantation process should pay special attention to changes in vital organ functions such as heart, kidney and liver, and timely treatment to enable patients to safely pass the transplantation period. Therefore, for patients with AL amyloidosis, AHSCT treatment is not a safe and effective means and is worthy of clinical promotion and application.