Vascular Endothelium Changes After Conditioning in Hematopoietic Stem Cell Transplantation: Role of Cyclophosphamide and Busulfan

Vascular endothelial injury, a feature of some complications of hematopoietic stem cell transplantation (HSCT), is characterized by increased endothelial cells. We investigated that classical pretreatment drugs in HSCT could result in vascular endothelial injury in mice. Six-to eight-week-old female BALB/c mice were divided into a control group, a cyclophosphamide group (60 mg/kg per day for 2 days) and a busulfan group (4 mg/kg per day for 4 days). We observed the general state of health and regularly counted the number of white blood cells. Circulating endothelial cells and their progenitors were estimated by flow cytometry. Morphologic endothelial changes were analyzed with optical and transmission electron microscopy. After conditioning with cyclophosphamide or busulfan, white blood cells fell to a low number with injuries noted on hematoxylin and eosin-stained pathology sections. Circulating endothelial cells and their progenitors peaked significantly higher than in the control group. Vascular endothelial injuries were observed in the 2 experimental groups by transmission electron microscopy. These data support the hypothesis the vascular endothelial injury occurs during conditioning with cyclophosphamide or busulfan for HSCT, with simultaneous mobilization of endothelial progenitor cells.     

Outcomes of Busulfan,Fludarabine, and 400 cGy Total Body Irradiation Compared With Busulfan and Fludarabine Reduced-Intensity Conditioning Regimens for Allogeneic Stem Cell Transplantation in Adult Patients With Hematologic Diseases: A Single-Center Experience

BackgroundReduced intensity conditioning (RIC) regimens decrease the risk for nonrelapse mortality (NRM) in adult patients undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies but increase the risk for relapse. The aim of this study was to compare the outcomes of fludarabine–total body irradiation (TBI) with fludarabine among patients with hematologic diseases.Patients and MethodsThis retrospective study of 137 patients with different hematologic malignancies compared the outcomes of 63 patients who received a conventional RIC regimen with 2 days of IV busulfan (3.2 mg/kg/d × 2 days) and fludarabine with 74 patients who received the same regimen plus 400 cGy of fludarabine and busulfan (FB)-TBI divided in 2 doses over 1 day (200 cGy BID). Median follow-up was 4.62 years.ResultsThe donors were either HLA-matched siblings (36%) or HLA-matched unrelated donors (64%). The FB-TBI showed trends toward improvement in progression-free survival (PFS) and overall survival (OS) over FB (5-year PFS rates 50% vs 34%, P = .06, and 5-year OS rate 53% vs 39%, P = .13). Acute graft-vs-host disease (aGVHD), relapse, and NRM were similar between the 2 groups. The 5-year cumulative incidence of chronic GVHD (cGVHD) was lower in the FB-TBI group compared with the FB group (29% vs 52%, P = .003). Multivariable analysis revealed that grade III-IV aGVHD was the only independent risk factor for worse OS (P = .001) in both groups. A high disease risk index was possibly associated with inferior OS (P = .07) in both groups.ConclusionsThe FB-TBI is a safe and effective intensified RIC regimen for adult patients with hematologic malignancies. It predicted a lower risk for cGVHD and showed possibly improved PFS and OS compared with FB.     

Successful Treatment of Both Acute Leukemia and Active Crohn's Disease After Allogeneic Hematopoietic Stem Cell Transplantation Using Reduced-Intensity Conditioning With Fludarabine and Busulfan: A Case Report

Background

A 32-year-old man diagnosed with acute myelomonocytic leukemia (M4) concurrently had active Crohn's disease (CD) that was refractory to azathioprine and anti-tumor necrosis factor.

Case Report

He underwent an allogeneic bone marrow transplantation from a one HLA-DR allele-mismatched unrelated donor to achieve the first complete remission of leukemia. The conditioning regimen consisted of fludarabine (180 mg/m²) and busulfan (8.0 mg/kg) without T-cell depletion. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and mycophenolate mofetil. Cefotaxime was prescribed for a secondary bacterial infection in a perianal abscess before the start of conditioning chemotherapy. Although low-grade diarrhea persisted, there were no signs of either acute GVHD or CD in the mucosal biopsy specimens on day 24. Complete remission of leukemia and near remission of CD were sustained for 20 months after transplantation without any immunosuppressive drug.

Conclusions

Allogeneic heamtopoietic stem cell transplantation with reduced-intensity conditioning is a possible therapeutic option for patients with severe and/or refractory CD.     

Effect of Salvage Chemotherapy Before Donor Lymphocyte Infusion in Patients With Relapse After Allogeneic Hematologic Stem Cell Transplantation

ObjectivesAllogeneic hematopoietic stem cell transplantation (AHSCT) is an important treatment option in hematologic malignancies. Relapse after AHSCT is an indicator of poor prognosis. These patients may be treated with donor lymphocyte infusion (DLI). The chemotherapy given before DLI increases the success of the treatment by reducing the burden of disease. The aim of this study is to investigate post-DLI graft vs host disease (GvHD) and survival based on the course of chemotherapy given before DLI.MethodsA total of 23 patients who received DLI because of relapsed disease after AHSCT were enrolled. All of the patients received 1 or more courses of cytoreductive chemotherapy before DLI.ResultsComplete remission (CR) after DLI remained in 78.2% of all patients. There is no difference between 1 or multiple courses of chemotherapy in terms of CR (55.6% vs 44.4%; P = .21). During follow-up after DLI, although it did not reach statistical significance (P = .09), the patients receiving single-course chemotherapy tended to have longer survival (36.1 vs 4.3 months, respectively). Four patients who received multiple courses of chemotherapy were lost because of infection-related disease (pneumonia, sepsis) while they were in CR. GvHD development was more frequent in patients receiving multiple courses of chemotherapies (60% of all GvHD patients).ConclusionIt has been demonstrated that reducing the tumor burden by multiple-cycle chemotherapy does not have any advantage in terms of CR and does not improve the overall survival.     

Nosocomial BK Polyomavirus Infection Causing Hemorrhagic Cystitis Among Patients With Hematological Malignancies After Hematopoietic Stem Cell Transplantation

BK polyomavirus (BKPyV) is recognized as a pathogen that causes diseases such as hemorrhagic cystitis and nephritis after allogeneic hematopoietic stem cell transplantation (HSCT) or renal transplantation. BKPyV‐associated disease is thought to occur through reactivation under immunosuppression. However, the possibility of its nosocomial transmission and the clinical significance of such transmission have not been elucidated. During a 6‐month period, nine adult patients (median age: 47 years) who had hematological disorders and who were treated with HSCT (n = 7) or chemotherapy (n = 2) in a single hematology department developed hemorrhagic cystitis due to BKPyV infection. The polymerase chain reaction products of BKPyV DNA obtained from each patient were sequenced. Of the nine patients, six had subtype I, 2 had subtype IV, and 1 had subtype II or III. In the alignment of sequences, four and two of the six subtype I strains were completely homologous (100%). These results strongly suggest that BKPyV has the potential to cause nosocomial infection within a medical facility, especially among recipients of HSCT. Further studies are clearly warranted to elucidate the route(s) of BKPyV transmission in order to establish optimal infection control.     

Precise Nursing of Six Patients Who Underwent Second Allogeneic Hematopoietic Stem Cell Transplantation

This study aimed to summarize the experience of precise nursing in 6 patients who experienced failed allogeneic hematopoietic stem cell transplantations (allo-HSCTs) that underwent second allo-HSCT salvage treatment. The key points of nursing care included strictly implementing infection prevention and control measures to prevent secondary infections, precise symptom management to improve the graft survival rate of patients, formulating reasonable nutrition programs to meet their requirements, and paying attention to the psychological care of patients to enhance their self-confidence in overcoming diseases. The patients developed different degrees of complications in the process of transplantation. During the transplantation, 2 patients had oral mucositis, 2 had hemorrhagic cystitis, 3 had a perianal infection, and one had lower gastrointestinal bleeding. After careful treatment and nursing, the neutrophils transplanted in the 6 patients were alive at a median of 16.5 (13-20) days after the second allo-HSCT, and the patients were successfully transferred out of the laminar flow chamber.     

Liver Transplantation Followed by Allogeneic Hematopoietic Stem Cell Transplantation for Atypical Mevalonic Aciduria

Mevalonic aciduria because of mutations of the gene for mevalonate kinase causes limited synthesis of isoprenoids, the effects of which are widespread. The outcome for affected children is poor. A child with severe multisystem manifestations underwent orthotopic liver transplantation at age 50 months for the indication of end‐stage liver disease. This procedure corrected liver function and eliminated portal hypertension, and the patient showed substantial improvement in neurological function. However, autoinflammatory episodes continued unabated until hematopoietic stem cell transplantation was performed at 80 months. Through this complex therapy, the patient now enjoys a high quality of life without significant disability.     

Kidney Disease After Allogeneic Hematopoietic Stem Cell Transplantation Is Associated With Decreased Physical Function

Objective/BackgroundAllogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved outcomes and prognosis, but it has many complications and is associated with impaired physical function. To solve this problem, it is necessary to further analyze the factors that cause the decline in physical function. In the present study, we hypothesized that kidney disease following allo-HSCT would be associated with impaired physical function, in addition to conventional factors, and tested this hypothesis retrospectively.MethodsThirty-one patients who underwent allo-HSCT at the Department of Hematology in our hospital from January 2016 to October 2021 were included in the analysis. Correlation analysis and stepwise multiple regression analysis with change in 30-second sit to stand test (Δ30-s STS) as the dependent variable were performed to identify predictors of physical function decline from pretransplant to discharge.ResultsThe mean age of participants was 43.9 years (SD = 11.8), the mean time from transplant to discharge was 103.1 days (SD = 35.0), and approximately 30% of patients had kidney disease following allo-HSCT. All patients were ambulatory and independent at discharge, but 30-s STS was significantly reduced (P < .001). Among various factors, age (β = ?0.464, P < .05), total corticosteroid dose (β = ?0.380, P < .05), and kidney disease after allo-HSCT (β = ?0.307, P < .05) were the independent predictors of Δ30-s STS (R² = 0.592, adjusted R² = 0.547, F = 13.072, P < .01).ConclusionKidney disease after allo-HSCT is one of the factors that may contribute to poor physical function, and patients who experience this condition may require additional follow-up to improve physical function.     

Micafungin Does Not Influence the Concentration of Tacrolimus in Patients After Allogeneic Hematopoietic Stem Cell Transplantation

Background

Tacrolimus is commonly used in stem cell transplant recipients for prophylaxis of graft-vs-host disease. Micafungin is widely used as a strong antifungal agent in empirical therapy in patients with febrile neutropenia. Both tacrolimus and micafungin are substrates of cytochrome P450 3A4 in vitro. Therefore, there is risk of drug interaction with concomitant administration of these drugs.

Objective

To estimate the drug interaction of tacrolimus and micafungin by evaluating the pharmacokinetics in 6 patients who had undergone allogeneic stem cell transplantation.

Results

The mean (SD) concentration-dose ratio of tacrolimus in all patients at 1, 4, 8, and 24 hours after concomitant administration of micafungin was 607 ± 306, 653 ± 328, 699 ± 340 and 671 ± 403 (ng/mL)/(mg/kg/d), respectively, and without micafungin was 756 ± 314 (ng/mL)/(mg/kg/d). The percentage of the concentration-dose ratio in patients treated with tacrolimus and micafungin vs patients treated with tacrolimus alone was 98%, 105%, 112%, and 108% at 1, 4, 8, and 24 hours, respectively. For both tacrolimus and micafungin, the 90% confidence intervals for the primary pharmacokinetic parameters (ie, the concentration-dose ratio at each point) ranged from 80% to 125%.

Conclusion

We conclude that there is no drug interaction between tacrolimus and concomitantly administered micafungin in stem cell transplantation recipients.     

异基因造血干细胞移植术后并发口腔粘膜炎患者的护理

21例接受异基因造血干细胞移植术的患者在移植术后并发口腔粘膜炎(OM)．对其进行护理。结果13例(61．9％)发生不同程度的OM。其中Ⅰ度2例。Ⅱ度7例,Ⅲ度3例。Ⅳ度1例。严重程度与术后OM发生时间相关,发生时间越早,OM越严重．愈合时间越长。经综合治疗、护理后。OM均于3～46d痊愈。提示加强观察与护理能够降低OM的发生率。减轻或缩短OM病程,提高患者的生活质量。     

数字减影全脑血管造影术的护理配合

回顾性总结46例数字减影全脑血管造影术的护理配合。提出术前全面评估病情、做好健康教育及心理护理，术中注重全身肝素化、严格执行无菌技术，密切观察术中、术后病情变化。积极采取有效的抢救措施是成功配合脑血管造影术的关键。     

异基因造血干细胞移植亲缘供者的护理

针对61例捐献造血干细胞供者的特点,进行心理疏导和术前做好身体和皮肤准备;术中保持静脉通路通畅,严格无菌操作,行全程心电监护;术毕防止穿刺点出血和感染等健康指导,结果均顺利完成造血干细胞采集,无1例发生并发症,住院4~10d出院。提示供者捐献造血干细胞是安全的。     

The Impact of Early Rehabilitation on the Duration of Hospitalization in Patients After Allogeneic Hematopoietic Stem Cell Transplantation

Background

We examined the relationship between the improved physical activity by early rehabilitation and the duration of hospitalization among patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Methods

Thirteen allo-HSCT patients with myeloablative conditioning regimens (group A) and 13 patients with nonmyeloablative conditioning regimens (group B) were assessed retrospectively in this study. All patients received physical exercise immediately after neutrophil engraftment at the class 10,000 bioclean room (class 10,000). The mean daily steps at class 10,000 were measured as a substitute for the amount of physical activity, and the duration of hospitalization as one of the clinical outcomes.

Results

The degree of physical activity showed a negative correlation with the duration of hospitalization in group A (r = −.71; P = .0071), regardless of complications such as acute graft-versus-host disease, infections, and cytomegalovirus reactivation. However, there was no significant association in group B (r = .09; P = .77).

Conclusion

The improved physical activity through early rehabilitation may be an independent, favorable prognostic factor for allo-HSCT patients with myeloablative conditioning regimens.     

单倍体相合造血干细胞移植联合间充质干细胞输注治疗异染性脑白质营养不良

目的探讨单倍体相合造血干细胞移植联合间充质干细胞输注治疗异染性脑白质营养不良的疗效。方法 7岁患儿,采用单倍体相合造血干细胞移植联合间充质干细胞输注的方法,经氟达拉滨、马利兰、环磷酰胺和抗人胸腺细胞球蛋白方案进行预处理,供者应用G-CSF动员和联合免疫抑制剂(包括环胞菌素A、氨甲喋呤、霉酚酸酯、CD25单抗)预防移植物抗宿主病。造血重建后,每周输注脐带来源的间充质干细胞1次,连续4周。结果患儿造血重建迅速,11 d时中性粒细胞0.5×109/L、血小板20×109/L;14 d时血白细胞芳基硫酸酯酶A水平明显上升;28 d时达正常水平。患者无急性GVHD发生。移植后1个月经植入证据检测,证实为完全供者造血,神经系统症状逐渐恢复。结论单倍体相合造血干细胞移植,联合间充质干细胞输注,治疗异染性脑白质营养不良,安全、有效,血白细胞芳基硫酸酯酶A水平回升迅速。这种新型疗法可能是治疗缺乏HLA全相合供者的异染性脑白质营养不良疾病患者的可靠选择。     

同种反应性NK细胞在异基因干细胞移植治疗实体性肿瘤中的作用

干细胞移植(stem cell transplantation,SCT)是一种新兴技术,在多个临床领域有着广泛的应用.干细胞移植在肿瘤治疗领域的应用可分为两类:即大剂量化疗/放疗联合自体干细胞移植(autologous stem cell transplantation,Auto-SCT)和异基因干细胞移植(allogeneic stem cell transplantation,Allo-SCT)两大类.     

Hematopoietic Cell Transplant-Composite Risk (HCT-CR): A Novel Predictor of Prognosis in Acute Leukemia Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

BackgroundAllogeneic hematopoietic stem cell transplantation (allo-HCT) is a curable treatment modality for hematologic disorders. Transplant-related mortality remains high despite prominent scientific and technologic improvements. In consideration with the potential impact of patient- and disease-related factors on transplant outcome, this retrospective study was performed to investigate the predictive role of pretransplant HCT-composite risk (HCT-CR) score in allo-HCT recipients.MethodsA total of 313 patients with acute leukemia (male/female: 192/121; median age, 36 [18-71] years) were included in this study. The study cohort was divided into 2 subgroups based on pretransplant HCT-CR categories. The HCT-CR^lo group included low-risk patients, and the HCT-CR^int-hi group consisted of intermediate-, high-, and very high-risk patients.ResultsIn the whole cohort, overall survival (OS) and 5-year OS were found to be 32.2% and 45.1%, respectively. Probability of OS was significantly better in the HCT-CR^lo group compared with the HCT-CR^int-hi group (P < .001). Leukemia-free survival (LFS) and 3-year LFS were 59.5% and 65.1%, respectively. Probability of LFS was better in the HCT-CR^lo group compared with the HCT-CR^int-hi group (P = .001). Nonrelapse mortality (NRM) and 3-year NRM were estimated to be 38.1% and 27.5%, respectively. Probability of NRM was significantly higher in the HCT-CR^int-hi group compared with the HCT-CR^lo group (P = .012). In multivariate analysis, HCT-CR was shown to have significant prognostic impact in acute lymphoblastic leukemia patients (P = .023; hazard ratio, 2.613; 95% CI, 1.142-5.982).ConclusionPretransplant evaluation of patient- and disease-related factors is essential for the accurate prediction of posttransplant survival. Further efforts to evolve current criteria for pretransplant risk assessment would eventuate in better transplant outcomes.     

2例B细胞非霍奇金淋巴瘤患者异基因造血干细胞移植联合利妥昔单抗治疗的护理

对2例B细胞非霍奇金淋巴瘤患者进行异基因造血干细胞移植,同时联合使用利妥昔单抗治疗.结果 移植后患者造血功能恢复顺利,中性粒细胞绝对数＞0.5×109/L恢复时间分别为+15 d和+16 d,血小板＞20×109/L恢复时间分别为+15 d和+17 d;移植后1个月复查纵隔及腹腔淋巴结消失;分别随访至移植后28个月和6个月,病情处于持续完全缓解状态.提出利妥昔单抗治疗时应严格掌握药物用法,移植期间严格落实各项护理措施,观察并及时处理各种并发症,可保证治疗顺利进行.     

Evaluation of Readmission in Children Receiving Allogeneic Hematopoietic Stem Cell Transplantation: An Institutional Experience

Background

Use of unrelated cord blood (UCB) has become increasingly popular as a stem cell source, given the rapid availability and decreased potential of graft-versus-host disease. We sought to ascertain whether the use of UCB transplantation for pediatric patients changed the rates of unscheduled readmission.

Methods

We analyzed the rate, causes, and evolution of hospitalization among patients receiving UCB versus matched sibling bone marrow. A retrospective analysis of the data from 54 patients who received a matched sibling hematopoietic stem cell transplantation (HSCT; n = 25; 46.3%) versus an unrelated cord blood transplantation (CBT; n = 29; 53.7%) was performed on subjects treated between 1998 and 2006. Patients who died before discharge (n = 4) were excluded from the readmission analysis.

Results

A total of 50 patients were recruited for the analyses. Their median age was 6.7 years (range = 0.2-17 years). The median duration of hospitalization was 18 days shorter in the sibling HSCT group than in the unrelated CBT group. There were 89 readmissions in 25 patients (50%): 49 readmissions (55%) in the related HSCT and 40 (45%) in the unrelated CBT cohorts. Forty-two percent of readmissions were due to infections. Mortality following transplantation in 10 patients (19%) included sepsis (n = 3), intracranial hemorrhage (n = 1), pulmonary hemorrhage (n =1), and relapse (n = 5). Seven patients received HSCT from HLA-identical sibling donors and three from a cord blood donor.

Conclusion

For both groups, infection was the most common reason for readmission followed by graft failure and extramedullary relapse. Although the median hospital stay was shorter in the sibling donor group, some uncertainty exists as to whether the increased risk for readmission was related to proportionally more malignancies or to the severity of the illness. After HSCT, there was a frequent use of hospital resources: 46% of patients were hospitalized for a median of 11 days. The resulting health expenses seem to be useful, since 81% of subjects survived at 36-month follow-up.     

Effectiveness of Prophylactic Anti-HBV Therapy in Allogeneic Hematopoietic Stem Cell Transplantation with HBsAg Positive Donors

Use of hepatitis B surface antigen (HBsAg) positive donors for allogeneic hematopoietic stem cell transplantation (HSCT) causes serious hepatitis B virus (HBV)-related liver morbidity and mortality in the recipient. We compared the effectiveness of anti-HBV therapy in 29 recipients who underwent HSCT using HBsAg positive marrow (group I) against a historical control group of 25 patients who received HBsAg positive marrow without pre-HSCT prophylaxis (group II). Anti-HBV therapy consisted of lamivudine for HBsAg-positive donors and all recipients (n = 29) as well as HBV vaccination to all HBsAg-negative recipients (n = 10) before HSCT. After transplantation, HBV-related hepatitis was significantly higher in group II than group I recipients [12 of 25 recipients (48%) vs. 2 of 29 recipients (6.9%), p = 0.002] and in recipients whose donors had detectable serum HBV DNA by Digene Hybrid Capture II assay [8 of 14 recipients (57.1%) vs. 6 of 40 recipients (15.0%), p = 0.02]. Six recipients in group II and none in group I died of HBV-related hepatic failure (24.0% vs. 0%, p = 0.01). By multivariate Cox analysis, anti-HBV therapy effectively reduces post-HSCT HBV-related hepatitis (p = 0.01, adjusted hazards ratio 7.27, 95%CI 1.62-32.58). Our data support the use of prophylactic therapy in preventing HBV-related hepatitis after allogeneic HSCT from HBsAg-positive donor.     

Solid Organ Transplantation After Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective,Multicenter Study of the EBMT

To analyze the outcome of solid organ transplantation (SOT) in patients who had undergone allogeneic hematopoietic stem cell transplantation (HSCT), a questionnaire survey was carried out within 107 European Group of Blood and Marrow Transplantation centers. This study covered HSCT between 1984 and 2007 in Europe. Forty‐five SOT in 40 patients were reported. Fifteen liver, 15 renal, 13 lung, 1 heart and 1 skin transplantations were performed in 28 centers. Overall survival (OS) of patients after SOT was 78% at 5 years (95% confidence interval [CI], 64% to 92%). OS at 5 years was 100% for renal, 71% (95% CI, 46% to 96%) for liver and 63% (95% CI, 23% to 100%) for lung transplant recipients. The 2‐year‐incidence of SOT failure was 20% (95% CI, 4% to 36%) in patients with graft‐versus‐host disease (GvHD) and 7% (95% CI, 0% to 21%) in patients without GvHD before SOT. The relapse incidence for underlying malignant diseases was 4% at 5 years (95% CI, 0% to 12%). In summary, this study shows that selected patients receiving SOT after HSCT have a remarkably good overall and organ survival. These data indicate that SOT should be considered in selected patients with single organ failure after HSCT.