Myeloablative allogeneic hematopoietic stem cell transplantation in elderly patients

This study aimed to evaluate the outcome following myeloablative allogeneic hematopoietic stem cell transplantation (SCT) among patients older than 50 yr of age. A total of 215 patients with a median age of 57 yr underwent allogeneic hematopoietic SCT for early (41%) or advanced (59%) hematologic malignancies. After a median follow-up of 36 months a 10-yr survival estimate of 56 +/- 6% could be assessed for patients in early disease stages while patients with advanced diseases showed a significantly decreased survival probability of 31 +/- 5% (p < 0.0002). Transplant related mortality (TRM) at day 100 and 365 post-transplant was 13% and 30% for early but increased to 21% and 49% for advanced disease stages. As major determinants of TRM advanced disease stage (p < 0.0001) and occurrence of grades II-IV graft-vs.-host disease (GVHD) (p < 0.0001) were identified. These results show that hematopoietic SCT following myeloablative conditioning is also applicable to elderly patients whereas disease stage and high-grade GVHD represent the essential prognostic factors for outcome.     

Pharmacokinetics of intravenous mycophenolate mofetil after allogeneic blood stem cell transplantation

BACKGROUND: Mycophenolate mofetil (MMF) has shown synergistic effects in combination with cyclosporin A (CsA) in prevention of acute graft versus host disease (GvHD) after allogeneic blood stem cell transplantation (BSCT) in preclinical animal models. After having measured low plasma levels of the active metabolite mycophenolic acid (MPA) in recipients of allogeneic blood stem cell transplants after oral administration of MMF, we initiated a phase I/II study evaluating different dose levels of the intravenous (i.v.) formulation together with standard dose CsA. METHODS: A total of 15 patients received i.v. MMF in two split doses for 21 d after allogeneic BSCT from related (n=9) and unrelated (n=6) donors. Total daily doses of 25, 28, 31 and 34 mg/kg were investigated in 3-5 patients at each dose level. Plasma concentrations of MPA and its metabolite mycophenolic acid glucuronide (MPAG) were measured by high-performance liquid chromatography (HPLC). RESULTS: Mean trough blood levels of MPA ranged between 68.8 and 340 ng/mL with a median of 146.7 ng/mL. The mean MPA AUC0-12 h after first dose ranged between 19349+/-5087 ng * h/mL and 25705+/-3042 ng * h/mL and correlated with the dose level of MMF. The incidence of acute GvHD>grade I was 40%. No dose limiting toxicities were observed. CONCLUSIONS: The application of i.v. MMF is safe at a weight-adjusted dose between 25 and 34 mg/kg after allogeneic BSCT. The measured trough blood levels of MPA in patients after BSCT were ten times lower than in healthy volunteers. The toxicity induced by the conditioning therapy seems to negatively influence the pharmacokinetic behavior of MMF, MPA and MPAG.     

Treatment of X-linked childhood cerebral adrenoleukodystrophy by the use of an allogeneic stem cell transplantation with reduced intensity conditioning regimen

Childhood cerebral form of X-linked adrenoleukodystrophy (X-ALD) is a rapidly progressive demyelinating condition affecting the cerebral white matter, which rapidly leads to total disability and death. The only known curative treatment for this condition is allogeneic hematopoietic stem cell transplantation (HSCT). Procedure-related toxicity is assumed to be the cause of death of patients with X-ALD. Three cases of ALD successfully transplanted with the use of non-myeloablative fludarabine based conditioning are described. Patients showed smooth peri-bone marrow transplantation course with fast and stable engraftment. In the 3- to 5 yr follow-up period, patients showed no deterioration in their clinical and neurological condition. Levels of very long chain fatty acids were very variable and had a tendency to decrease in at least one of the three patients. In another patient, an improvement of magnetic resonance imaging changes was found. Non-myeloablative HSCT should be considered as an early treatment for X-ALD.     

Non-myeloablative allogeneic stem cell transplantation for metastatic renal cell carcinoma

Between 1999 and 2004, 11 patients with metastatic renal cell carcinoma (RCC) underwent non-myeloablative stem cell transplantation (NST) with conditioning using fludarabine-based regimens in two institutions of Korea. Among 11 patients, only one patient showed partial response (response rate: 9%), three showed stable disease, and six progressive disease. Three patients developed acute graft-versus-host disease (GVHD), and among them, one developed grade III acute GVHD which caused early death at day 60 after transplantation, and this patient showed partial response at day 30. Six patients developed chronic GVHD, three limited, and three extensive GVHD, respectively. Survival after one yr was 18% in transplanted patients. Median overall survival for entire cohort was 4.3 months. Eight patients died from progressive disease and three (27%) from treatment-related mortality. Only one patient survived 51.2 months after NST with slowly progressive disease. This patient received donor lymphocyte infusion three times after NST and achieved complete donor chimerism. NST does not lead to durable response and prolonged overall survival in the majority of patients with RCC in our series.     

Blood eosinophilia as a marker of favorable outcome after allogeneic stem cell transplantation

Eosinophilia is observed in a variety of disorders including acute and chronic graft-versus-host disease (GVHD). The clinical records of 237 patients who underwent allogeneic stem cell transplantation (allo-SCT) were retrospectively reviewed. Eosinophilia, defined as a relative eosinophil count>4% within the first 100 days, was observed in 135 patients (57%). The incidence of grades II-IV acute GVHD was significantly higher in patients without eosinophilia than in those with eosinophilia (68% vs. 43%; P<0.001). The incidence of chronic GVHD was significantly higher in patients without eosinophilia than in those with eosinophilia (73% vs. 56%; P=0.011). Relapse rate was similar between patients with and without eosinophilia (33% vs. 27%; P=0.438). The probability of nonrelapse mortality was 10% in patients with eosinophilia, which was significantly lower than that in patients without eosinophilia (31%; P<0.001), and the overall survival (OS) at 3 years was 67% in patients with eosinophilia, which was significantly higher than that in patients without eosinophilia (51%; P=0.003). Multivariate analysis identified older age, high-risk disease, acute GVHD, sex disparity between patient and donor, and the absence of eosinophilia as significant factors for reduced OS. These data lead us to conclude that eosinophilia after allo-SCT may serve as a favorable prognostic marker.     

Impact of cyclosporine‐A concentration in T‐cell replete haploidentical allogeneic stem cell transplantation

This paper aims to study whether cyclosporine‐A (CSA) levels have an impact on the clinical outcome of patients with T‐cell replete haploidentical allogeneic hematopoietic stem cell transplantation (allo‐HSCT). We analyzed 140 consecutive patients who had been given T‐cell replete haploidentical allo‐HSCT in our institute to assess the effect of CSA concentration in the early stages of allo‐HSCT on clinical outcomes, such as hematopoietic recovery, acute graft vs host disease (aGVHD), infection, disease‐free survival (DFS), and overall survival (OS). The median concentrations of CSA in the blood in the 1st, 2nd, 3rd, and 4th week after allo‐HSCT were 218, 235, 263, and 270 ng/mL, respectively. Additionally, 46%, 40%, 27%, and 18% of the patients had CSA blood levels below 200 ng/mL during those weeks. In total, 39 patients developed aGVHD (grade II‐IV), for a cumulative incidence of 27.8%, at a median of 32 days. Patients having a low CSA concentration (below 200 ng/mL) in the 3rd week had a higher cumulative incidence of grade II‐IV aGVHD (P = .02). In addition, multivariate logistic regression analysis showed that low CSA concentration (below 200 ng/mL) in the 3rd week was an independent risk factor of grade II‐IV aGVHD (P = .02; odds ratio = 2.66; 95% CI, 1.15‐6.17). However, CSA levels during the first 4 weeks did not have a significant impact on the patients’ hematopoietic recovery, infection, DFS, and OS. Our data indicated that adequate management of CSA levels during the peri‐engraftment period might improve clinical outcomes for those with T‐cell replete haploidentical allo‐HSCT.     

A rare complication after allogeneic stem cell transplantation: post‐transplant erythrocytosis

Post‐transplant erythrocytosis is an infrequent complication and has been reported after allogeneic hematopoietic stem cell transplantation (allo‐HSCT) in aplastic anemia, acute myeloid leukemia, and chronic myeloid leukemia. The pre‐disposing factors and treatment are not clearly defined. We present 11 post‐transplant erythrocytosis cases. More studies should be conducted to distinguish the pathogenesis and follow‐up for this rare complication.     

异基因造血干细胞移植后严重的出血性膀胱炎多因素分析

目的 探讨异基因造血干细胞移植（allo-HSCT）后严重的（≥Ⅱ度）出血性膀胱炎（HC）的危险因素。方法 对1997年4月至2004年12月期间的114例allo-HSCT患者的资料进行回顾性分析。以预处理实施之日为观察起点，至移植后＋180 d随访中止。选择11个临床参数，即：年龄、性别、疾病类型、供者类型、预处理方案、移植时疾病状态、急性移植物抗宿主病（aGVHD）、aGVHD的预防、预处理方案中抗胸腺细胞球蛋白（ATG）的应用、中性粒细胞及血小板植活时间做Cox单因素分析。将在单因素分析中P＜0.1作为有统计学意义的因素进行Cox多因素回归分析。移植后180 d内HC累计发生率的计算应用Kaplan-Meier法。结果 （1）114例患者中有29例发生HC，＋180 d内HC的累计发生率为26％，其中Ⅱ级12例，Ⅲ级11例，Ⅳ级6例。（2）单因素分析表明，以下因素与HC的发生密切相关；男性（RR=2.885，P=0.021）、年龄≤25岁（RR=3.265，P=0.002）、Ⅲ～Ⅳ度aGVHD（RR=4.039，P=0.002）、非血缘供者（RR=4．347，P=0.000）、加强的GVHD预防方案（RR=2.218，P=0.045）、疾病进展期（RR=2.668，P=0.009）。（3）对上述有统计学意义的因素进行Cox多因素分析，只有男性（RR=2.993，95％CI 1.218～7.358；P=0.017）和非血缘供者（RR=4.478，95％CI 2.049～9.786；P=0.000）为HC的独立危险因素。结论 男性受者和非血缘供者的造血干细胞移植后发生HC的危险性显著增加。     

Glutathione S-transferase A1 polymorphisms and acute graft-vs.-host disease in HLA-matched sibling allogeneic hematopoietic stem cell transplantation

Busulfan and the metabolites of cyclophosphamide are conjugated with glutathione and catabolized by enzymes of the cytosolic glutathione S-transferases family. There are clearly linked single nucleotide polymorphisms in the promoter region of the glutathione S-transferase A1 gene (i.e., GSTA1*A, -567T, -69C and -52G; GSTA1*B, -567G, -69T and -52A). We assessed whether the clinical outcomes, including acute graft-vs.-host disease, of 61 patients with hematological malignancies, following HLA-matched sibling allogeneic stem cell transplantation using busulfan/cyclophosphamide conditioning are altered by glutathione S-transferase A1 genotypes. Globally, grade II-IV acute graft-vs.-host disease developed in 13 patients (21%). Grade II-IV acute graft-vs.-host disease developed in 15.2% of 46 patients with GSTA1*A/*A diplotype and in 40.0% of 15 patients with GSTA1*A/*B or GSTA1*B/*B diplotype (p = 0.04). Moreover, this relationship between GSTA1*A/*A diplotypes and lower incidence of acute graft-vs.-host disease was independent of the age, gender, stem cell source, and disease status. The incidences of acute skin graft-vs.-host disease were 7% (3/46) in patients with GSTA1*A/*A and 27% (4/15) in patients without GSTA1*A/*A (p = 0.009, univariate; p = 0.01, multivariate). Acute hepatic graft-vs.-host disease developed in 6 (13%) of 46 patients with the GSTA1*A/*A diplotype and in 4 (27%) of 15 patients without this diplotype (p = 0.09, univariate; p = 0.12, multivariate). Ten patients (16%) developed hepatic veno-occlusive disease. No significant difference was found in the incidence of hepatic veno-occlusive disease between patients with and without the GSTA1*A/*A diplotype (19.6% vs. 6.7%; p = 0.24). We conclude that the GSTA1*A/*A diplotype is an independent protective factor against acute graft-vs.-host disease, especially for skin graft-vs.-host disease, and probably for hepatic graft-vs.-host disease, in patients using busulfan/cyclophosphamide conditioning. The identification of glutathione S-transferase A1 genotypes prior to allogeneic stem cell transplantation could allow conditioning regimens and graft-vs.-host disease prophylaxis to be modified to improve outcome.     

Lack of evidence for a reciprocal interaction between bacterial and cytomegalovirus infection in the allogeneic stem cell transplantation setting

Pathogenic interactions between bacteria and cytomegalovirus (CMV) may potentially occur early after allogeneic stem cell transplantation (allo‐SCT). This possibility nevertheless has not been investigated in depth. This was a retrospective study that included 170 consecutive patients who underwent 173 allo‐SCTs. Both bacterial infection (most of which were bacteremic) and CMV DNAemia were detected in 78 allo‐SCTs (62.9%). In total, 51 and 32 episodes of bacterial infection preceded or occurred after CMV DNAemia detection, respectively. Both events were diagnosed concurrently in four allo‐SCTs. The cumulative incidence of bacterial infection (of any type) over the study period was comparable in patients with or without a preceding episode of CMV DNAemia (P = 0.321). Cox proportional hazards regression analysis failed to identify CMV DNAemia as a significant risk factor for bacterial infection. Likewise, the cumulative incidence of CMV DNAemia within the study period was not significantly different in patients with or without a preceding episode of bacterial infection (P = 0.189). Furthermore, the occurrence of bacterial infection within episodes of active CMV infection had no apparent impact on the kinetics of CMV DNAemia. Our data, thus, do not support the existence of a bidirectional synergistic effect between bacterial infection and active CMV infection in the allo‐SCT setting.     

Prophylactic use of zoledronic acid to prevent early bone loss is safe and feasible in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation

Osteopenia and osteoporosis are well-known consequences of allogeneic stem cell transplantation (allo-SCT). The role of prophylactic zoledronic acid on bone turnover following allo-SCT has not been well characterized. We prospectively studied the role of prophylactic use of zoledronic acid on bone metabolism in 17 patients with acute myeloid leukemia (AML) undergoing allo-SCT over a period of three yr (2006-2009). We measured bone mineral density using dual energy X-ray absorptiometry (DXA) scanning and the markers of bone turnover by urinary N-terminal telopeptide (uNTX) and serum osteocalcin levels prior to and serially following transplantation. All patients received 4 mg of zoledronic acid (Zometa, Novartis Pharmaceuticals Corp., Basel, Switzerland) intravenously prior to starting conditioning regimen and at six months after SCT. DXA scores did not change significantly in any patient over time (p > 0.05). uNTX progressively decreased over time (p < 0.001) and serum osteocalcin stabilized after six months. No patient developed osteonecrosis of the jaw. In conclusion, in this prospective pilot study, prophylactic use of zoledronic acid to prevent early bone loss was found to be safe and feasible in patients with AML undergoing allo-SCT during the immediate post-transplantation period.     

The relationship between body mass index and outcomes in leukemic patients undergoing allogeneic hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is being used increasingly in an attempt to cure many hematological disorders. Obesity has become a world wide phenomenon and is a known risk factor for numerous medical conditions, but its role in transplant outcomes remained controversial. Total of 192 patients with acute leukemia who underwent sibling HLA matched HSCT were analyzed to find the effect of pre-transplant body mass index (BMI) on transplant outcomes such as time to engraftment, infections, graft vs. host disease (GvHD), and overall survival (OS) for the period of three yr (April 2006-March 2009). There was a significant correlation between higher pre-transplant BMI and shorter engraftment time (p = 0.010); but no relation between BMI and GvHD, infection, and OS was found. The results of this study showed that patients with higher BMI may have a shorter engraftment time; but lower, although not significant, survival rate compared to non-obese patients.     

Lactobacillus rhamnosus GG probiotic enteric regimen does not appreciably alter the gut microbiome or provide protection against GVHD after allogeneic hematopoietic stem cell transplantation

Graft‐versus‐host disease (GVHD) is a major adverse effect associated with allogeneic stem cell transplant. Previous studies in mice indicated that administration of the probiotic Lactobacillus rhamnosus GG can reduce the incidence of GVHD after hematopoietic stem cell transplant. Here we report results from the first randomized probiotic enteric regimen trial in which allogenic hematopoietic stem cell patients were supplemented with Lactobacillus rhamnosus GG. Gut microbiome analysis confirmed a previously reported gut microbiome association with GVHD. However, the clinical trial was terminated when interim analysis did not detect an appreciable probiotic‐related change in the gut microbiome or incidence of GVHD. Additional studies are necessary to determine whether probiotics can alter the incidence of GVHD after allogeneic stem cell transplant.     

Comparative outcomes of reduced intensity and myeloablative allogeneic hematopoietic stem cell transplantation in patients under 50 with hematologic malignancies

We have conducted a direct comparison of the outcomes of reduced intensity and myeloablative conditioning in younger adults with hematological malignancies<50 yr. One hundred and five patients received transplants from human leukocyte antigen (HLA)-matched donors, via either reduced intensity (n=35) or myeloablative conditioning (n=70). The median ages of the reduced intensity and myeloablative groups were 36 and 33 yr (p=0.014). Neutrophil engraftment (i.e. time to absolute neutrophil count>0.5x10(9)/L) occurred more rapidly in the reduced intensity group (median: 10 d; range: 0-21 d) than in the myeloablative group (median: 18 d; range: 11-38 d; p<0.0001). The incidence of grades 2-4 acute graft-vs.-host disease were similar between the reduced intensity and myeloablative groups, at 17% vs. 24% respectively (p=0.40). The cumulative incidence of day 100 non-relapse mortality was 18% in the reduced intensity group, and 21% in the myeloablative group (p=0.88). The overall two-yr survival rates were 43% in the reduced intensity group, and 35% in the myeloablative group (p=0.72). In conclusion, reduced intensity transplantation yielded outcomes comparable with those of myeloablative transplantation in patients under 50 with hematological malignancies.     

The significance of cytomegalovirus viremia at day 100 or more following allogeneic hematopoietic stem cell transplantation

We conducted a single‐center retrospective review of patients who had received allogeneic hematopoietic stem cell transplantation (HSCT) between January 2003 and December 2007, to assess the incidence and risk factors for late CMV infection and evaluate its effects on outcomes. Twenty of 49 HSCT recipients (41%) developed CMV infection at day ≥100 after transplant. Univariable analysis showed that having a matched unrelated donor, having early CMV infection, having a diagnosis of lymphoma, and receipt of antithymocyte globulin were risks for developing late CMV. On multivariable analysis, the occurrence of CMV prior to day 100 and lymphoma conferred a significant risk for late CMV infection. Of the 20 patients with late CMV infection, two patients manifested CMV disease (10%). Despite the relatively low incidence of CMV disease, patients with late CMV infection had a 4.8‐fold increased risk of death compared to patients without late CMV. Identifying patients at increased risk for developing late CMV infection may be important for prompting more intensive monitoring of infection late after HSCT, particularly because this manifestation of CMV is associated with poorer outcomes.     

移植前铁过载对重型再生障碍性贫血异基因造血干细胞移植疗效的影响

目的  研究移植前铁过载对重型再生障碍性贫血（SAA）患者异基因造血干细胞移植（allo-HSCT）疗效的影响。方法  回顾性分析行首次allo-HSCT的80例SAA受者临床资料。根据有否铁过载,将受者分为铁过载组（20例）和无铁过载组（60例）。比较两组间受者移植后植入率、并发症发生情况及预后情况;采用Cox比例风险回归模型分析受者2年总生存率（OS）和180 d移植相关病死率（TRM）的影响因素。结果  无铁过载组的中性粒细胞植入率为98%（59/60）,明显高于铁过载组的75%（15/20）（P < 0.05）。无铁过载组的血小板植入率为90%（54/60）,明显高于铁过载组的65%（13/20）（P < 0.05）。无铁过载组血流感染发生率为23%（14/60）,明显低于铁过载组的40%（8/20）（P < 0.05）。无铁过载组受者术后180 d TRM为17%,明显低于铁过载组的45%（P < 0.05）。无铁过载组受者术后1、2年OS分别为82%、80%,均高于铁过载组的50%、44%（均为P < 0.05）。是否有铁过载是受者的OS和TRM的独立危险因素（均为P < 0.05）。结论  铁过载可影响SAA患者allo-HSCT移植后的OS和TRM。     

异基因造血干细胞移植患儿营养状况的纵向调查

目的了解异基因造血干细胞移植患儿营养状况的变化。方法分别于移植前、移植后30d、60d、100d对89例异基因造血干细胞移植患儿进行身高、体质量、体质指数(BMI)、三头肌皮褶厚度(TSF)、中上臂围(MUAC)、腰围(WC)等人体学测量,同时测量脂肪组织(FM)、体脂百分比(%BF)、去脂组织(FFM)及去脂组织百分比(%FFM)等人体成分,并进行生化指标白蛋白(ALB)、前白蛋白(PreALB)测量,比较异基因造血干细胞移植患儿营养状况的改变。结果人体学测量结果显示,在移植后100d内患儿体质量、BMI、TSF均呈现先降后升趋势,在移植后30d降至最低点,然后逐渐上升(P0.05,P0.01),WC在移植后100d内持续升高(P0.01);人体成分测量结果显示,%BF、FM在移植后60d内明显升高(均P0.05),%FFM在移植后60d内显著降低(P0.01);生化测量结果显示,ALB呈先升后降再上升的趋势,PreALB在移植后60d内显著上升(P0.01)。结论在异基因造血干细胞移植后30d内,多数人体学及人体成分测量指标下降;而在移植后60d则存在FFM丢失和FM不断蓄积的现象。不建议将ALB和PreALB作为评价造血干细胞移植患儿营养状况的可靠指标。