Hypercytokinemia-induced metabolic encephalopathy in a multiple myeloma patient on hemodialysis undergoing autologous stem cell transplantation: Clinical response after plasma exchange

We report here a 50-years old female with multiple myeloma-associated chronic renal failure who underwent high-dose chemotherapy supported by autologous hematopoietic stem cell transplantation. She developed progressive encephalopathy on day 5 progressing to coma despite hemodialysis and no obvious organ failure. She finally recovered after a single 1-liter plasma exchange. The final diagnosis was metabolic encephalopathy due to hypercytokinemia, particularly high serum TNF levels. We discuss here the pathogenesis and raise an alert for monitoring cytokine levels in patients with renal failure undergoing high-dose chemotherapy.     

Beta-2-microglobulin level predicts outcome following autologous hematopoietic stem cell transplantation in patients with multiple myeloma

Despite the widespread use of high-dose therapy combined with autologous hematopoietic stem cell transplantation (autoHSCT), the outcomes of multiple myeloma (MM) treatment remain variable. The aim of this study was to define pretransplantation factors that influence outcomes following autoHSCT in patients with MM. Eighty-one MM patients, aged 51 years (range 31-70 years), undergoing first autoHSCT were included in the analysis. Thirty patients were in complete remission and 51 were in partial remission. The conditioning regimen was based mainly on melphalan (200 mg/m(2) intravenous [iv]). The following factors were tested for their prognostic significance: beta-2-microglobulin (B2M), lactate dehydrogenase, monoclonal protein level, bone marrow plasma cell percentage (PL), hemoglobin level, age, interval from diagnosis to autoHSCT, and number of transplanted CD34-positive cells. The transplant-related mortality at day 100 was 3.7% (3/81). The incidence of progression at 9.2 years was 71% for patients with elevated B2M, and 32% for those where B2M was within normal limits (P = .02.) The probability of PFS was decreased for patients with B2M > or = versus < normal limits (29% vs 68%; P = .02) and PL > or = versus < 5% (0% vs 45%; P = 0.03). In a multivariate analysis B2M remained the only factor associated with increased risk of progression (relative risk [RR] = 3.3; P = .03) and reduced probability of PFS (RR = 3.3; P = .03). We concluded that B2M level measured at first autoHSCT was a useful predictor for progression and PFS in MM patients.     

Retrospective analysis of the efficacy and influencing factors of autologous hematopoietic stem cell transplantation for multiple myeloma

This study aims to review the clinical efficacy and factors affecting the treatment of multiple myeloma (MM) by autologous hematopoietic stem cell transplantation (ASCT). The clinical data of 47 patients with MM from the Department of Hematology of Henan Cancer Hospital from September 2010 to July 2018 were retrospectively analyzed. At pre‐transplantation of autologous cells, 25.5% were in complete remission (CR), 14.9% were in very good partial remission (VGPR) and 59.6% were in partial remission (PR). Among these cases, one case had PR after three recurrences. At post‐transplantation, 51% were in CR, including two cases who received double transplantations, 27.7% were in VGPR, and 21.3% were in PR. The median follow‐up time was 27.6 months (4–96 months). The 3‐year progression free survival (PFS) and overall survival (OS) were 47.9% and 79.6%, respectively. The Analysis of variance (ANOVA) results revealed that factors that affected OS were international staging system (ISS) stage (P = 0.002), CR and VGPR post‐transplantation (P = 0.002), while factors that affected PFS were ISS stage (P = 0.005), pre‐transplant induction therapy (P = 0.032), and disease risk stratification (P = 0.017). The curative effects for PFS were CR and VGPR pre‐transplantation (P = 0.013) and post‐transplantation (P = 0.011). The Cox multivariate regression analysis revealed that ISS stage and CR and VGPR post‐transplantation were independent prognostic factors of OS. At post‐transplantation, CR and VGPR, ISS stage, and pre‐transplant induction therapy were independent prognostic factors for PFS. In conclusion, ASCT can improve the clinical efficacy and survival rate of MM patients. ISS stage, CR and VGPR post‐transplantation are independent prognostic factors of OS and PFS, while pre‐transplant induction therapy is an independent prognostic factor for PFS.     

输注供者自然杀伤细胞对小鼠单倍型相合造血干细胞移植的影响

目的 探讨输注供者自然杀伤(NK)细胞对小鼠单倍型相合造血干细胞移植的影响.方法 选取C57BL/6(H-2b)雄性小鼠为供者、CB6F1(H-2d/b)雌性小鼠为受者.移植前制备供者的骨髓细胞(BMC)、脾细胞(SC)及脾NK细胞,NK细胞经体外培养扩增和激活;所有受者均接受直线加速器X线全身照射(TBI)预处理.TBI后将受者分为4组(每组10只),分别进行单倍型相合造血干细胞移植.单纯TBI组:TBI后不输注细胞,仅作为对照;单纯BMC输注组:输注5×106个BMC;诱发GVHD组:输注5×106个BMC+1.5×107个SC;NK细胞输注组:输注5 x 106个BMC+1.5×107个SC+1×107个NK细胞,并腹腔注射100 ng重组人白细胞介素2(rhIL-2)和1μg rhIL-15,持续7 d.移植后观察各组受者GVHD的发生情况,并对各组受者进行组织病理学、供者细胞嵌合度和免疫功能重建等检测.另取TBI后受者20只,设白血病复发组和白血病治疗组,每组10只.白血病复发组:输注5×106个BMC+1×107个SC+2×106个白血病细胞株EL9611;白血病治疗组:在白血病复发组的基础上再输注1 x 107个NK细胞,并腹腔注射100 ng rhIL-2和1μg rhIL-15,持续7 d.观察两组受者白血病复发情况和移植后100 d的存活率.结果 单纯BMC输注组受者无GVHD发生,NK细胞输注组受者GVHD的评分和组织病理学改变均较诱发GVHD组轻(P<0.05)f诱发GVHD组的免疫功能重建较NK细胞输注组延迟.白血病复发组和白血病治疗组移植后100 d的存活率分别为20%和90%,两组比较,差异有统计学意义(P<0.01).结论 输注激活的供者NK细胞可以减轻小鼠单倍型相合造血干细胞移植后的GVHD,减少白血病复发,促进免疫功能重建.     

荧光原位杂交法检测造血干细胞移植后骨髓嵌合状态和微量残留病灶

目的 探讨荧光原位杂交（FISH）法在异基因造血干细胞移植（allo-HSCT）后检测供、受者骨髓嵌合状态和微量残留病灶（MRD）的作用。方法 2001年2月至2005年6月对83例患者进行allo-HSCT。对供者为异性的64例受者实施骨髓细胞性染色体着丝粒探针FISH法检测，评价供、受者骨髓嵌合状态及其动态改变；对供、受者性别相同而有特殊染色体异常的19例受者，应用相应的基因探针（BCR／ABL、AMIL1／ETO和MLL）对骨髓细胞行FISH法检测，评价微量残留病灶的发生。结果 64例异性allo-HSCT的受者中，50例供、受者骨髓嵌合度在99％以上；7例早期嵌合度偏低（96．2％～98．7％），在随访过程中逐渐上升至99％以上，移植后均未复发原病；另外7例嵌合度在随访过程中呈进行性下降，其中3例微量残留病灶在10％以上，均同时出现血液学复发；4例患者微量残留病灶在2％～5％之间，其中2例经快速停用免疫抑制剂后出现严重的移植物抗宿主病（GVHD）；1例在免疫抑制剂快速减量后骨髓嵌合度逐步上升至99．9％，目前仍处于完全缓解（CR）状态中；1例持续处于CR状态。19例供、受者性别相同的allo-HSCT受者中，16例移植后未检测到原来的异常核型；1例检测到10％的微量残留病灶，经免疫抑制剂减量4个月后降为1％，移植后1年仍在完全缓解中；2例分别在移植后1个月和4个月时出现原来的染色体异常。复查骨髓为原病复发，再次化疗未缓解。结论 应用FISH法检测allo-HSCT后骨髓嵌合状态和微量残留病灶，对判断植入、复发和指导早期干预性免疫治疗有重要意义。     

The impact of donor natural killer cell alloreactivity on allogeneic hematopoietic transplantation

Although natural killer (NK) cells are triggered to kill by many activating receptors, lysis of autologous cells is blocked by inhibitory receptors (called Killer cell Ig-like receptors or KIRs) which recognize epitopes shared by certain major histocompatibility complex (MHC) class I allele groups (called KIR ligands). As these inhibitory receptors are clonally distributed, they constituted a repertoire containing different allospecificities. Thus, the NK cells in the repertoire are lytic against allogeneic targets that do not express their inhibitory KIR ligands. In hematopoietic human-leukocyte-antigen (HLA)-haplotype mismatched transplantation, donor-vs-recipient alloreactive NK cells improve engraftment, decrease the incidence of leukemia relapse and do not cause Graft-vs-Host disease (GvHD). Pre-transplant molecular high-resolution HLA of recipient and donor, KIR genotyping of the donor and direct assessment of the donor NK repertoire identify donors with the potential for donor-vs-recipient NK cell alloreactivity.     

Evaluation of cytokine profile in the different phases of the autologous hematopoietic stem cell transplantation in patients with multiple myeloma

BackgroundThe autologous hematopoietic stem cell transplantation (ASCT) is of fundamental importance in the treatment of patients with multiple myeloma (MM). Nevertheless, due to its toxicity, it decreases the number of bone marrow cells available, altering the cell interactions and causing an imbalance between pro- and anti-inflammatory cytokines.MethodsThus, we determined the serum levels of pro- and anti-inflammatory cytokines in samples of patients with MM obtained from the different phases of ASCT.ResultsIn summary, the cytokines levels varied considering the different phases of ASCT. The levels of IL-1ra tend to increase in the post-apheresis period suggesting an anti-inflammatory role induced by the apheresis process. A response characterized by the increase in the concentrations of IL-5 and IL-8 was observed in the post-conditioning bone marrow aplasia phase. The rise in IL-5 levels was not correlated with any clinical or laboratory event in this framework; IL-8 was associated with positive blood cultures and seems to have an effect against microbial agents. The increase in the levels of IL-10 and IL-12 suggests a possible regulatory effect of the inflammatory response in the period of bone marrow recovery and IL-12 seems to be inversely associated with the presence of minimal residual disease.ConclusionsApheresis process seems to induce an anti-inflammatory response, followed by a pro-inflammatory response and a stimulus for granulocytes differentiation.     

Sex steroid ablation enhances lymphoid recovery following autologous hematopoietic stem cell transplantation

BACKGROUND: Autologous hematopoietic stem cell transplantation (auto-HSCT) patients experience long-term immunosuppression, which increases susceptibility to infection and relapse rates due to minimal residual disease (MRD). Sex steroid (SS) ablation is known to reverse age-related thymic atrophy and decline in B-cell production METHODS: This study used a congenic HSCT mouse model to analyze the effects of SS ablation (through surgical castration) on immune reconstitution and growth factor production following auto-HSCT. Bone marrow (BM) and thymic stromal cell (TSCs) populations were analyzed using RT-PCR and were tested for the production of growth factors previously implicated in immune reconstitution or age-relate immune degeneration RESULTS: Castration increased bone marrow (BM), thymic, and splenic cellularity following auto-HSCT. HSC number and common lymphoid precursor (CLP) frequency and number were increased in castrated mice. B cell precursor numbers were also significantly increased in the BM of these mice. Triple negative, double positive and single positive thymocytes were increased following HSCT and castration, as were thymic dendritic cells and natural killer T (NKT) cells. This enhanced lymphoid reconstitution of the primary immune organs leads to a significant increase in splenic T and B cells 42 days after HSCT. The molecular mechanisms behind the enhanced reconstitution were also studied. TGF-beta1 was decreased in castrated mice compared to sham-castrated controls in TSCs and BM cells. TSC production of IL-6 was also decreased in castrated mice CONCLUSIONS: These data suggest that sex steroid ablation significantly enhances lymphopoiesis following auto-HSCT providing a new strategy for posttransplant immune reconstitution.     

Chronic kidney disease after autologous stem cell transplantation: analysis of a single center experience

Purpose

Chronic kidney disease (CKD) after allogeneic hematopoietic stem cell transplantation (HSCT) has increasingly been reported. However, CKD after autologous HSCT, especially changes in renal pathology, has rarely been reported. This study aimed to evaluate the frequency of CKD among patients who received autologous HSCT for hematological and nonhematological disorders, and analyze its clinical and pathological features.

Methods

We performed a retrospective study to evaluate the frequency of CKD after autologous HSCT and analyzed clinical and pathological features of CKD. Clinical records of patients who underwent autologous HSCT at the First Affiliated Hospital of Guangxi Medical University between May 2000 and November 2010 were screened. Clinical data of those with kidney injury on presentation and follow-up were acquired from hospital records.

Results

A total of 41 patients who received autologous HSCT were identified. CKD developed in six patients (14.6 %). Among the six patients, all had various degrees of proteinuria and three patients had nephrotic syndrome. Impaired renal function occurred in three patients. Three patients with nephrotic syndrome received only prednisone. Two patients obtained complete remission, and one had partial remission. What is particularly worth mentioning is, in two patients who received renal biopsy in our study, the pathological changes were mesangial proliferative glomerulonephritis.

Conclusions

Mesangial proliferative glomerulonephritis may not be as uncommon as previously thought in CKD patients after autologous HSCT. Presentation of nephrotic syndrome is common in CKD after HSCT and prednisone alone are effective.     

Membranous glomerulonephritis after haematopoietic cell transplantation for multiple myeloma.

Renal involvement during graft-versus-host disease following haematopoietic cell transplantation for multiple myeloma has never been described. We report a case of a recipient who developed nephrotic syndrome and membranous glomerulonephritis 22 months after the graft and 6 months after cyclosporine withdrawal. Symptoms resolved when immunosuppressive therapy was reinstituted.     

Non-cryopreserved hematopoietic stem cell transplantation in multiple myeloma, a single center experience

Several clinical trials have shown the superiority of high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) over conventional dose therapy for patients with multiple myeloma. There is limited experience with non-cryopreserved autologous hematopoietic stem cell transplantation. Between January 2004 and February 2010, we treated 38 patients with myeloma (mean age = 50.6) with a preparative regimen of Melphalan 140-200 mg/m(2) and non-cryopreserved ASCT. All the apheresis products were kept in a conventional blood bank refrigerator at 4°C for 2 d before infusion. The median time to platelet count of >20 × 10(9) /L was 13 d (range 10-31). Also, the median time to absolute neutrophil count >0.5 × 10(9) /L was 11 d (range 9-21). All the 38 patients were engrafted and there was not graft failure in this study group. Twenty-nine of 38 (76.3%) patients are alive and without disease activity after a median follow-up of 31 months (range 6-77). Responses (complete and partial response) were seen in all the 38 patients. The median progression-free survival was 27 months with 95% confidence interval 23.52-30.48, whereas the median overall survival was 30 months. One hundred days transplant-related mortality was 0%. HDT and autologous transplantation without cryopreservation is an effective and safe method which simplifies the procedure and is feasible and cost saving in our patients.     

Renal transplant in plasma cell dyscrasias with lenalidomide treatment after autologous stem cell transplantation

Plasma cell dyscrasias (PCD) are a spectrum of diseases characterized by clonal proliferation of plasma cells secreting a monoclonal immunoglobulin. Although considered an incurable disease, a combination of autologous stem cell transplant with novel therapies, including lenalidomide, has improved the overall and progression‐free survival of these patients. Renal impairment is an important complication of the disease that, in some cases, progresses to end‐stage renal disease. Due to the characteristics of PCD, traditionally these patients have not been candidates for renal transplantation. However, treatment improvement allows a reconsideration of this perception, especially in younger patients with good performance status and treatment response. We report two cases of patients diagnosed with PCD undergoing renal transplantation after autologous stem cell transplantation, both cases under treatment with lenalidomide. We also report their perioperative management and their outcome.     

自体造血干细胞移植治疗周围动脉疾病的系统评价

目的评价自体造血干细胞移植治疗周围动脉疾病(peripheral arterial disease,PAD)的疗效和安全性。方法计算机检索中国生物医学文献数据库(CBM,1978年-2010年9月)、中国期刊全文数据库(CNKI,1979年-2010年9月)、MEDLINE(1950年-2010年9月)、Pubmed(1950年-2010年9月)、Embase(1970年-2010年9月)和Cochrane图书馆(2010年第4期),收集以自体造血干细胞移植为干预措施治疗PAD的随机对照试验(randomized controlled trials,RCTs),按照Cochrane系统评价方法,由2位研究者独立地对符合纳入标准的试验进行资料提取,并对纳入文献进行质量评估和对提取的有效数据进行Meta分析。结果有8个RCTs,共280例PAD患者322条肢体符合纳入标准,但大多数研究的方法学质量较差。Meta分析结果显示,自体造血干细胞移植治疗PAD较常规治疗能提高溃疡治愈率[RD=0.38,95%CI=(0.25,0.50)]、踝肱指数[MD=0.11,95%CI=(0.04,0.18)]、经皮氧分压[MD=7.33,95%CI=(3.14,11.51)]和无痛性行走距离[SMD=1.35,95%CI=(0.90,1.79)],可降低截肢率[RD=–0.19,95%CI=(—0.31,—0.07)]和静息痛评分[MD=—1.70,95%CI=(—2.15,—1.25)]。仅2个试验报道了自体造血干细胞移植治疗的不良反应,如肢体肿胀和血清磷酸激酶升高等。结论自体造血干细胞移植治疗PAD可能有一定疗效,但由于尚缺乏高质量的RCTs证据支持,其疗效尚不能作出最后结论,还需进行更多高质量RCTs才能得出肯定性结论。     

Chronic kidney disease after hematopoietic stem cell transplantation

Acute and chronic kidney diseases occur after hematopoietic stem cell transplantation. These are caused by the transplant itself, and the complications of transplant. Recent estimates show that near 15% of subjects undergoing hematopoietic stem cell transplantation will develop chronic kidney disease, which is a complication rate that can affect outcome and reduce survival. Investigation of the causes of chronic kidney disease is needed, as are ways to prevent, mitigate, and treat it.