HLA相合同胞异基因外周血造血干细胞移植治疗急性白血病

背景：HLA相合同胞间异基因外周血造血干细胞移植是治疗急性白血病的一种有效方法。 目的：评价HLA相合异基因外周血造血干细胞移植治疗急性白血病的临床疗效及并发症。 方法：25例急性白血病患者接受HLA相合同胞的异基因外周血造血干细胞移植,其中急性髓系白血病20例,急性淋巴细胞白血病5例。预处理方案为BU+CY方案或CY+TBI方案,移植物抗宿主病预防采用环孢素A+吗替麦考酚酯+短程甲氨蝶呤。 结果：最短随访2个月,最长随访80个月。患者均获造血重建,中性粒细胞≥0.5×10⁹ L^-1的时间为10~18 d,血小板≥20× 10⁹ L^-1的时间为10~37 d。主要并发症：感染败血症12例,巨细胞病毒感染9例,带状疱疹病毒感染3例,发生急性移植物抗宿主病10例,慢性移植物抗宿主病11例,出血性膀胱炎4例。至随访结束,17例无病生存,8例死亡。提示HLA相合同胞异基因外周血造血干细胞移植是治疗急性白血病安全有效的方法。     

Impact of donor and recipient sex and parity on outcomes of HLA-identical sibling allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (SCT) may cure patients with hematologic malignancies, but it carries significant risks. Careful donor selection is an important component of the clinical transplantation decision-making process and includes evaluation of HLA typing and other criteria, the most controversial of which is parity. We examined the effect of donor sex and parity on outcomes of HLA-identical sibling SCT. Because the effect of recipient sex/parity has never been explicitly evaluated, we also analyzed the effect of recipient sex/parity on outcomes of transplantation. We found that (1) parous female donors result in an increased risk of chronic graft-versus-host disease (GVHD) in all recipients, (2) the magnitude of this increased risk is similar in male and female recipients, and (3) nulliparous female donors increase the risk of chronic GVHD in male recipients to a degree comparable to that from parous donors. A decrease in the risk of relapse was not observed, and there was no effect on overall survival, acute GVHD, or transplant-related mortality. Recipient parity had no independent effect on any endpoint. Until the effects of pregnancy on the maternal immune system are better understood, it is appropriate whenever possible to avoid parous female donors and to choose male donors for male recipients in HLA-identical related donor SCT.     

M-CSF levels during peripheral blood stem cell harvest and autologous stem cell transplantation

Plasma macrophage colony-stimulating factor(M-CSF) levels were determined during peripheral blood stem cell harvest and autologous stem cell transplantation(PBSCT). Plasma of 10 patients were analyzed by using ELISA system. The average peak values during PBSCT were quite higher than those during harvest(20,092 vs 1,681 pg/ml). Peak values were observed mainly around leukocyte nadir(Phase II) during harvest. On the other hand, they were detected just after pretreatment(Phase I) during PBSCT courses. Moreover, samples showing extremely high M-CSF values(Phase I) were associated with increase in serum LDH levels. These data suggest that plasma M-CSF in Phase I are mainly derived from chemotherapy-induced cellular damage during PBSCT courses, and there might be different mechanisms to raise M-CSF around the nadir of leukocytes. It is necessary to elucidate the biological meanings of M-CSF.     

Reduced-intensity stem cell transplantation in children and adolescents: the Mexican experience.

A group of 21 consecutive patients aged 4-20 (median 13) years was prospectively allografted using a reduced intensity preparative regimen. The group included both malignant (acute lymphoblastic leukemia, acute myelogenous leukemia, and chronic myelogenous leukemia) and nonmalignant (aplastic anemia, Diamond-Blackfan anemia, thalassemia major and adrenoleukodystrophy) conditions. Follow-up times ranged between 16 and 1038 days. Four of 21 patients (9.5%) developed acute graft-versus-host disease, and 2 of them died, whereas limited chronic graft-versus-host disease was observed in 2 of 15 cases. The 100-day mortality was 19%. Median overall survival was above 1038 days, whereas the 34-month survival was 55%. These data show that reduced intensity stem cell transplantation in children permits rapid engraftment from siblings with little toxicity.     

临床病例讨论（step by step）——自体干细胞移植后发热、呼吸困难

 植入综合征 (ES) 系造血干细胞移植过程中严重并发症,主要发生在造血干细胞移植后中性粒细胞恢复早期。ES以发热、皮疹、非心源性肺水肿为主要特征。ES以往与高移植相关死亡率相关,多数患者死于呼吸衰竭和多器官功能不全。早期诊断并合理应用皮质激素可以显著降低移植相关死亡率。本文报道了一个年轻女性NHL患者,在自体外周血干细胞移植后粒细胞恢复早期出现发热、呼吸困难、肺水肿,早期诊断为ES并及时应用皮质激素后病情获得完全缓解。     

Allogeneic stem cell transplantation with peripheral blood stem cells mobilized by pegylated G-CSF.

Mobilization of stem cells with pegylated granulocyte colony-stimulating factor (peg-G-CSF) modulates donor T- and natural killer T-cell (NKT-cell) functions, thus separating graft-versus-host from graft-versus-leukemia disease in animal models. We report a phase I/II study that analyzed the feasibility of mobilizing stem cells from normal donors with peg-G-CSF and the ability of these cells to restore hematopoiesis in allogeneic transplant recipients after myeloablative conditioning. Administration of 6 mg of peg-G-CSF resulted in suboptimal stem cell mobilization, with a peak peripheral blood CD34+ count of 29+/-5/microL. Apheresis 4 days after peg-G-CSF yielded 2.7+/-.4x10(6) CD34+ cells/kg recipient weight, and all donors required a second collection on day 5 to yield a total of 4.2+/-.5x10(6) CD34+ cells/kg recipient weight. After escalation of the dose to 12 mg, the peak CD34+ count was 99+/-11/microL and 12 of 13 donors collected sufficient stem cells for transplantation in a single apheresis (8.9+/-1.4x10(6) CD34+ cells/kg recipient weight). Late transient increases in serum hepatic transaminases were noted, but other side effects (predominantly bone pain) were otherwise similar to those seen in donors mobilized with standard G-CSF. Median neutrophil and platelet engraftments occurred on days 18 and 14, respectively, after transplantation and were identical to those seen with in recipients of grafts mobilized with standard G-CSF. With a median follow-up of 357 days, the incidence of grade II-IV acute graft-versus-host disease was 50% and there have been no relapses to date. Mobilization of stem cells with peg-G-CSF in normal donors is feasible and 12 mg results in mobilization characteristics similar to those of standard G-CSF.     

自体外周血干细胞移植治疗周围神经损伤

背景：关于神经干细胞对周围神经损伤的治疗已有多篇报道,但外周血干细胞对周围神经损伤治疗鲜有报道。 目的：探讨自体外周血干细胞移植治疗周围神经损伤使失神经骨骼肌重获神经再支配的临床应用。 方法：应用外周血干细胞治疗周围神经损伤6例,同时与周围神经损伤单纯行神经断端吻合或神经移植10例比较。2组患者术后常规肌注鼠神经生长因子一两个疗程,同时给予针灸、理疗、经皮电刺激治疗及功能康复训练。 结果与结论：两组患者随访均超过6个月。干细胞移植组运动神经传导速度和感觉神经传导速度的恢复率要明显高于单纯神经吻合组。提示周围神经损伤后给予修复局部用外周血干细胞移植能够使远端失神经骨骼肌早期重新获得神经再支配。     

Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients.

Mesenchymal stem cells (MSCs) are found in a variety of tissues, including human bone marrow; secrete hematopoietic cytokines; support hematopoietic progenitors in vitro; and possess potent immunosuppressive properties. We hypothesized that cotransplantation of culture-expanded MSCs and hematopoietic stem cells (HSCs) from HLA-identical sibling donors after myeloablative therapy could facilitate engraftment and lessen graft-versus-host disease (GVHD); however, the safety and feasibility of this approach needed to be established. In an open-label, multicenter trial, we coadministered culture-expanded MSCs with HLA-identical sibling-matched HSCs in hematologic malignancy patients. Patients received either bone marrow or peripheral blood stem cells as the HSC source. Patients received 1 of 4 study-specified transplant conditioning regimens and methotrexate (days 1, 3, and 6) and cyclosporine as GVHD prophylaxis. On day 0, patients were given culture-expanded MSCs intravenously (1.0-5.0 x 10(6)/kg) 4 hours before infusion of either bone marrow or peripheral blood stem cells. Forty-six patients (median age, 44.5 years; range, 19-61 years) received MSCs and HLA-matched sibling allografts. MSC infusions were well tolerated, without any infusion-related adverse events. The median times to neutrophil (absolute neutrophil count > or = 0.500 x 10(9)/L) and platelet (platelet count > or = 20 x 10(9)/L) engraftment were 14.0 days (range, 11.0-26.0 days) and 20 days (range, 15.0-36.0 days), respectively. Grade II to IV acute GVHD was observed in 13 (28%) of 46 patients. Chronic GVHD was observed in 22 (61%) of 36 patients who survived at least 90 days; it was extensive in 8 patients. Eleven patients (24%) experienced relapse at a median time to progression of 213.5 days (range, 14-688 days). The probability of patients attaining disease- or progression-free survival at 2 years after MSC infusion was 53%. Cotransplantation of HLA-identical sibling culture-expanded MSCs with an HLA-identical sibling HSC transplant is feasible and seems to be safe, without immediate infusional or late MSC-associated toxicities. The optimal MSC dose and frequency of administration to prevent or treat GVHD during allogeneic HSC transplantation should be evaluated further in phase II clinical trials.     

外周血造血干细胞移植治疗3例重型β地中海贫血和1例特发性溶血性贫血

目的探讨异基因外周血造血干细胞移植(allogeneic peripheral blood stem cell transplantation,Allo-PBSCT)治疗遗传性溶血性贫血(hereditary haemolytic     

Infectious complications after autologous CD34-selected peripheral blood stem cell transplantation.

CD34 selection of peripheral hematopoietic blood stem cell products has been applied to reduce the risk of relapse after an autologous transplantation. However, CD34 selection is also associated with a significant reduction in T-cells, natural killer cells, and monocytes, and these reductions may influence immune reconstitution and thus increase the risk for infections. An increased incidence of cytomegalovirus (CMV) disease in patients receiving CD34-selected transplants has been reported. In this study, the incidence rate of infections other than CMV is reported in 32 patients who underwent myeloablative therapy followed by the infusion of CD34-selected autologous peripheral blood stem cells (PBSC) and compared to the rate in a contemporaneous group of 273 patients who received unselected autologous PBSC during the same time period. Infection surveillance and prevention strategies were identical between the 2 groups. More non-CMV infections occurred in the recipients of CD34-selected PBSC than in recipients of unselected PBSC (78% versus 30%, P < .0001). The differences in the rates of viral infections were mainly due to dermatomal and disseminated varicella-zoster virus (VZV) (any VZV, 26% versus 4%, P = .002; disseminated VZV, 11% versus 0.3%, P = .03) and parainfluenza 3 virus infections (13% versus 3%, P = .04). Bacterial infections were also more common among CD34-selected PBSC transplant recipients (34% versus 16%, P = .01), whereas fungal infections were not significantly different between the groups. In multivariable logistic regression models, the effect of CD34 selection on infection risk remained significant for viral infections and overall non-CMV infections. Infection-related mortality was not significantly different between the groups. In conclusion, the incidence of viral and bacterial infections appears to be increased in recipients of CD34-selected autologous PBSC transplants. Because the risk for infections approaches that seen in allogeneic transplant recipients, infection surveillance, diagnostic work-up, and prevention strategies similar to those used in allogeneic recipients are warranted.     

Immunotherapy with rituximab during peripheral blood stem cell transplantation for non-Hodgkin's lymphoma.

Peripheral blood stem cell grafts from patients with lymphoma are often contaminated with neoplastic cells. Administration of a lymphoma-specific monoclonal antibody before collecting stem cells may be one way of reducing the contamination. Similarly, an antibody after transplantation at a time of minimal residual disease may increase the efficacy of the procedure. The objective of this study was to determine the safety of using rituximab as both an in vivo purging agent and a posttransplantation adjuvant. Eligible patients with lymphoma received 375 mg/m2 rituximab intravenously IV) on day 1, 2.5 g/m2 cyclophosphamide IV on day 4, and 10 microg/kg per day filgrastim starting on day 5 and continuing until completion of leukapheresis. Patients subsequently received a standard preparative regimen and then received 375 mg/m2 rituximab IV 7 days after platelet independence was achieved. Twenty-five patients (14 men, 11 women; median age, 51 years) were enrolled. Of the 25 patients, 23 received transplants after at least 2.0 x 10(6) CD34+ cells/kg were harvested. As determined with a sensitive polymerase chain reaction assay, 6 of 7 stem cell products tested were free of tumor contamination. All patients engrafted promptly, and the rituximab infusions were well tolerated. Transient neutropenia of uncertain etiology occurred in 6 patients a median of 99.5 days post-transplantation. An additional patient developed progressive pancytopenia. Rituximab used as an in vivo purging agent and adjuvant immunotherapy with peripheral blood stem cell transplantation for non-Hodgkin's lymphoma is a well-tolerated regimen. However, the ultimate determination of efficacy will require the results of ongoing studies.     

父母供者外周血单倍体移植治疗儿童难治性重型再生障碍性贫血

背景：在中国,儿童患者获得人类白细胞抗原相合同胞供者较困难,而以父母供者较多。 目的：回顾性分析父母供者外周血单倍体造血干细胞移植治疗儿童复发难治性重型再生障碍性贫血的疗效及安全性。 方法：纳入17例无人类白细胞抗原相合同胞及相合非血缘供者,且免疫抑制疗效不佳的复发难治性儿童重型再生障碍性贫血患者,行父母供者外周血单倍体造血干细胞移植。采用“氟达拉滨+环磷酰胺＋兔抗人胸腺细胞球蛋白抗体”预处理方案,应用环孢素+吗替麦考酚酯+甲氨蝶呤三联短程预防移植物抗宿主病。 结果与结论：①患者17例中16例(94%)获得造血重建,中性粒细胞≥0.5×109 L-1和血小板≥20×109 L-1的中位时间分别为13(11-15) d和17(12-28) d。②急性移植物抗宿主病发生率47%(8/17),其中Ⅰ-Ⅱ度29%(5/17),Ⅲ-Ⅳ度18%(3/17)。慢性移植物抗宿主病发生率41%(7/17)。③中位随访268(43-753) d,12例存活,总生存率为71%(12/17),死亡5例(29%),均为移植相关死亡,其中1例植入失败死于皮肤真菌感染,1例死于移植物抗宿主病,3例死于肺部重症感染。无患儿移植后复发。④结果显示,无人类白细胞抗原相合同胞及相合非血缘供者,且免疫抑制疗效不佳的复发难治性儿童重型再生障碍性贫血患者,父母供者外周血单倍体造血干细胞移植是一种安全有效的挽救治疗方法。 中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程     

自体外周血造血干细胞移植后淋巴细胞亚群的恢复

目的探讨自体外周血造血干细胞移植(auto-PBSCT)后免疫重建的规律。方法测定血液肿瘤患者auto-PBSCT前后淋巴细胞各亚群的绝对值。结果部分亚群在移植前低于正常。移植后各细胞亚群恢复时间不同,其中NK细胞在6个月恢复;B细胞在9个月恢复正常。T细胞总数在9个月恢复正常,其中主要为CD3 CD8 细胞。CD3 CD4 细胞在18个月恢复,而CD4 CD28 细胞在2年内仍未恢复。CD3 CD8 细胞在移植后早期有所下降,在3个月时恢复并高于正常,至9个月时逐渐下降至正常。CD3 CD8 细胞的主要部分是免疫表型呈活化的T细胞,即CD8 HLA-DR 细胞和CD8 CD38 细胞。两者分别在1个月和3个月时高于正常,在9个月时恢复正常。结论血液肿瘤患者移植前即存在淋巴细胞亚群异常的前提下,移植后NK细胞最先恢复,其次为B细胞,T细胞各亚群中CD3 CD8 细胞恢复较早,其中主要为活化T细胞。     

异基因外周血干细胞移植后的心膈角髓肉瘤

背景：异基因造血干细胞移植是治愈白血病的主要方法,但经过异基因造血干细胞移植的患者仍面临着复发的风险,髓肉瘤为一种罕见的髓外复发方式,且临床疗效差,因此了解髓肉瘤的特点及治疗方法十分必要。 目的：分析异基因外周血干细胞移植后髓肉瘤的临床特点及治疗方法。 方法：异基因外周血干细胞移植后并发心膈角髓肉瘤患者1例,先后予手术切除肿块、化疗、放疗等联合方法治疗,观察临床疗效及相关并发症和生存情况。 结果与结论：患者在2个疗程的化疗过程中出现了败血症、真菌性肺炎及感染性休克等并发症,之后接受了纵隔放疗,髓肉瘤未再复发。无病生存25个月后出现中枢神经系统白血病。造血干细胞移植后髓肉瘤罕见且临床表现多变,主要依靠病理组织学和免疫组化检查确诊。可采用手术、化疗、放疗、二次移植和分子靶向治疗等方法,但个体化的治疗方案仍需进一步探讨。     

Improved outcome for peripheral blood stem cell transplantation for advanced primary myelodysplastic syndrome.

Stem cell transplantation for myelodysplastic syndrome (MDS) is characterized by high transplant-related mortality (TRM), especially in older patients and those with more advanced disease. Outcome after peripheral blood stem cell transplantation (PBSCT) may be superior to earlier results with bone marrow transplantation. Forty-three patients (aged 12-73 years; median, 49 years) received an HLA-identical sibling donor PBSCT. Twenty three patients aged < or =55 years without prohibitive comorbidity received myeloablative total body irradiation-based conditioning, followed by a T cell-depleted PBSCT and delayed add-back of donor lymphocytes. Older patients or those with comorbidities (n = 20) received reduced-intensity conditioning and an unmanipulated PBSCT. Thirty-seven (86%) had advanced disease (refractory anemia with excess blasts [n = 9], refractory anemia with excess blasts in transformation [n = 6], acute myelogenous leukemia [n = 13], or treatment-related MDS [n = 9]); 6 had low-risk MDS (refractory anemia or refractory anemia with ringed sideroblasts). The median follow-up was 18 months (range, 5-89 months). Actuarial probabilities of 3-year overall survival (OS), disease-free survival, relapse, and TRM were 64%, 59%, 26%, and 23%, respectively, for 34 primary MDS patients. The best results were in 19 patients younger than 50 years of age undergoing myeloablative PBSCT (actuarial probabilities of OS, disease-free survival, relapse, and TRM were 81%, 72%, 22%, and 7%, respectively). Although outcomes for all stages of primary MDS were improved, that for therapy-related MDS remained dismal, with 11% OS, because of a high relapse rate (89%).     

Mobilization and transplantation of peripheral blood stem cells

Two hundred nineteen patients underwent peripheral blood stem cell (PBSC) transplantation from 1990 to 1997. Stem cells were mobilized with cyclophosphamide (CY), or with CY plus Taxol or etoposide, followed by cytokines, and collected when leukocyte counts > or = 1,000/microl, or when CD34+ counts > or = 20/microl. On average, four to five collections were needed to obtain sufficient PBSC for engraftment. When CD34+ counts were used, the average number of collections decreased from 5.4 to 4.2. A discrepancy was noted in the extraction ratios and number of collections that depended on the optical density (I/O) setting of the leukapheresis machine. Patients collected at a setting of 100 had higher extraction ratios and required fewer collections (mean = 2.7) than those collected at 150 (mean = 4.4). This result was unexpected, because the entire mononuclear cell layer is collected at the higher I/O setting. Further analysis revealed that a larger volume of red cells was collected at 150 than at 100. These procedures used a small-volume collection chamber, so the chamber was apparently overloaded by RBC at the higher setting. More rapid recovery of neutrophil counts and platelet counts was seen in PBSC transplants than in autologous marrow transplants; moreover, PBSC transplant patients required fewer RBC and platelet transfusions. Sixteen out of 21 normal donors for allogeneic PBSC transplants gave adequate collections (> 2.5 x 10(6) CD34+ cells/kg), but three donors failed to yield > or = 1.5 x 10(6) CD34 cells/kg. This suggests an inherent difference among certain normal donors that may make PBSC mobilization difficult.     

Delayed administration of G-CSF in both mobilization and post transplantation in autologous peripheral blood stem cell transplantation

Granulocyte colony stimulating factors (G-CSFs) play a very important role in the current technique of stem cell transplantation. The conventional timing of administration of G-CSF in both mobilization and post transplantation has been right after chemotherapy or right after transplantation. We have studied the effects of timing of administration of G-CSF in 21 patients who had autologous stem cell transplantation for breast cancer, lymphoma or nasopharyngeal cancer. Their stem cells were mobilized by chemotherapy followed by G-CSF, which were given on day +1 or day +5 after chemotherapy. The median peak percentage of CD34 positive cells harvested using both technique were 1.88 and 0.48% respectively. After transplantation, G-CSF were given on day +1 or day +6 after stem cell infusion until neutrophil recovery. The time until bone marrow recovery was significantly longer in the group with delayed administration of G-CSF (10 days versus 8 days). However, there was no difference in duration of neutropenic fever or hospital stay after transplantation. The transplantation outcome was also unaffected. We therefore concluded that G-CSF can be given in the delayed fashion in both mobilizing and post transplantation settings without jeopardizing the outcome and this would result in a significant cost saving.     

Roles of clinical laboratory monitoring in bone marrow and peripheral blood stem cell transplantation

Hematopoietic stem cell transplantation(HSCT) increase the chances of cure of many hematological malignancy. The clinical laboratory plays a major role in support of HSCT. Both transplantation-specific laboratory test(tissue typing, assessment of graft viability/rejection, evaluation of minimal residual disease, and measurement of immunosuppressive drugs) and routine clinical laboratory tests(biochemical, hematological, serological, urinary, bacteriological, and physiological examinations) are significant. Hematopoietic stem cells(HSC) are usually assessed as CD34+ cells, while immature cells determined by automated hematology analyzers can simply evaluate HCS. These automated immature cell counts are earlier markers of engraftment following transplantation than the traditional indicators(neutrophils and platelets). After transplantation, infections, regimen-related toxicities, graft-versus host disease, veno-occlusive disease, and thrombotic microangiopathy are the serious complications, which are causes of expected mortality and morbidity in HSCT. Clinical laboratory monitoring may contribute early diagnosis and treatment of the complications, resulting in prevention of the adverse events.     

Disturbance of pro-oxidative/antioxidative balance in allogeneic peripheral blood stem cell transplantation

High dose chemotherapy causes increased free radical formation and depletion of tissue antioxidants. Whether allogeneic hematopoietic stem cell transplantation (HSCT) has an effect on oxidative stress is uncertain. The aims of the study were to determine the effect of allogeneic HSCT on plasma concentrations of antioxidants and oxidative stress biomarkers, and to investigate their relationships with graft-versus-host disease (GVHD), conditioning regimens, and transplant-related mortality (TRM) in patients with hematological malignancies. Patients (n=25) undergoing allogeneic HSCT from HLA-matched sibling donors were enrolled in the study. Plasma oxidant and antioxidant status were measured at day -1 before transplantation and 30 days after HSCT. In both myeloablative (n=14) and non-myeloablative (n=11) transplant groups, the mean levels of plasma malondialdehyde (MDA) and nitric oxide (NO) increased after allogeneic HSCT (p <0.01), whereas superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities decreased compared with baseline values (p <0.01). No significant relationships were found between either the pretransplant or post-transplant mean levels of the oxidative stress parameters and the existence of graft-versus-host disease (GVHD), the type of conditioning regimen, or transplant related mortality (TRM). This study documents a significant disturbance of pro-oxidative/antioxidative balance in the plasma of patients undergoing allogeneic HSCT regardless of the intensity of the conditioning regimen.