Autologous Stem Cell Transplantation Treatment And New Induction Chemotherapy For Patients With Al Amyloidosis

PART ONE:Renal involvement in AL amyloidosis:the clinical and prognosis outcomes in a Chinese single centerBackground:Renal is the most common affected organ in AL(immunoglobulin light chain) amyloidosis, but data on clinical picture and survival of patients with renal AL amyloidosis are usually limited, especially in Chinese patients.Methods:The patients with biopsy-proven AL amyloidosis in Jinling hospital from March2003to August2011were studied, all patients had renal involvement. The clinical and laboratory information were collected from diagnosis to death or until the last available clinical control. The patients survival and renal outcomes were also analyzed, and the relationships between clinical parameters and were assessed.Results:245patients were studied.153patients were male, the median age at diagnosis was56years. The most common affect organs were intestinal tract (55.9%) and heart(46.7%) besides renal. Proteinuria was the major clinical feature of these patients,the mean24-hours proteinuria was4.86±4.32g,25%patients had renal insufficiency at diagnosis. The mean time of follow-up was20.5months(range1-98),111patients were dead, the median survival time of all patients was33.6months, the patients with heart involvement, hepatic involvement, hypotension and renal insufficiency had worse survival, and specific therapy can improve the survival. The1,2,3and5-year cumulative survival rate, calculated by Kaplan-Meier method, were68.3%、52.7%、47.8%and30.7%respectively. Multivariate COX analysis showed the age, hepatic involvement, cardic involvement, the rate of plasma cell in bone marrow can and specific therapy can significantly influence survival in these patients. The median time of renal survival was45months, the1,2,3and5-year renal survival rate were78.6%、69.6%、63.2%and36.9%respectively, Multivariate COX analysis showed the serum creatinine and hypotension were the important risk fators of renal failure.Conclusion:Our results first demonstrated the clinical picture and survival of Chinese patients with renal AL amyloidosis. These patients were usually combined with intestinal tract and heart involvement, the survival of our cohort was poor, and the heart involvement, hepatic involvement, hypotension, renal insufficiency and specific therapy can significantly influence survival. The high serum creatinine level and hypotension at diagnosis implied the bad renal outcome. PART TWO:The efficiency and safety of autologous stem cell transplantation for primary systemic amyloidosisObjective:To evaluate the short time efficiency and safety of autologous hematopoietic stem cell transplantation(AHSCT) in primary systemic amyloidosis(AL).Methodology:A total of13patients with biopsy-proven amyloidosis shown to be immunoglobulin light-chain type were enrolled on this study form July2010to Jan2011. The method of mobilization was granulocyte-colony-stimulating factor (G-CSF) alone. The patients received AHSCT in2-6weeks after collection. The condition regimen was high dose melphalan, the dose adjusted to100,140and200mg/m2according to patient stratification. The assessment of organ involvement and treatment response was according to the consensus opinion from the12th international symposium on amyloid and amyloidosis.Results:There were8males and5females in our series, the age was from35to63years old (median54yr). the course of disease was from2to43months(median9m), the primary clinical symptoms of these patients was nephritic syndrome, The clonal light chain subtype, classified by immunohistochemical staining, was κ in2patients and λ in11patients. The involved organ number was1～3(2.0±0.58), Amyloid was seen clinically in the kidneys (100%), heart (76.9%), liver(15.4%), and peripheral nerves (7.7%).4patients were untreated before AHSCT, while others were received induction therapy. All patients were collected enough stem cells, the main complications of collections were hypocalcemia, hypopotassaemia and thrombocytopenia, the number of CD34+cells was2.0-8.36(4.02±2.01)×106/kg. all patients had successful engraftment, All patients achieved a granulocyte count of500/L between day9and day13(median9d), achieved an untransfused platelet count of20,000/L from day10to day21(13.69±2.56). The major complication of peri-transplantation period were nausea/vomiting(84.6%), mucositis(76.9%), fever(53.8%), arrhythmia(53.8%), acute renal injury(46.2%) and diarrhea(30.8%). The uncommon complication were acute liver injury, hepatic rupture, pleural effusion, sepsis and so on. One patients died of transplant-related hepatic rupture at the day21, the treatment related mortality was7.7%in day100. After follow up for4-10months,8patients achieved hematologic response,5had complete response and3had partial response.7patients achieved organ response,3cases had renal and heart response,4had renal response only.Conclusion:The AHSCT was an efficiency and safety treatment for AL in selected patients, the hematologic and organ response rate was high. Though the complications of peri-transplantation were common, the fatal complications was rare. The long-term outcomes need future observation. PART THREE:Induction chemotherapy with bortezomib and dexamethasone followed by autologous stem cell transplantation can improve both the hematologic and organ response rate for patients with AL amyloidosisPurpose:The use of bortezomib alone and in combination with steroids has shown efficacy in primary systemic amyloidosis (AL amyloidosis), however, its role in combination with high-dose melphalan and autologous stem cell transplantation (HDM/SCT) is unknown. In this study, we evaluated bortezomib in combination with dexamethasone (BD) for induction chemotherapy prior to HDM/SCT. Patients and Methods:We conducted a prospective study comparing induction therapy consisting of two BD cycles followed by HDM/SCT (Group1) with HDM/SCT alone (Group2) in the treatment of patients with naive AL amyloidosis. The efficacy and toxicity of each treatment was evaluated.Results:Thirty-three patients were enrolled in this study, sixteen in Group1and seventeen in Group2. The patients presented with comparable disease severity and time from diagnosis to transplantation in the two treatment groups. The overall hematological response rates (ORR) were obtained for fifteen (93.8%) Group1and nine (52.9%) Group2patients (HR=3.41, P=0.004), and the complete hematological response rates were68.8%(11/15) for Group1and17.6%(3/17) for Group2(HR=4.95, P=0.016). Group1patients also achieved better renal response (87.5vs.35.3%, HR=3.74, P=0.008) and a better heart response (40vs.20%) without major adverse events related to BD therapy. After a median follow-up of twelve months (range:4-24months), overall survival was significantly higher in Group1(P=0.045).Conclusions:Our preliminary data suggest that induction chemotherapy with BD can significantly improve both the hematologic and organ response rates in patients with AL amyloidosis who undergo the HDM/SCT procedure.