Peripheral Blood Stem Cell Transplantation Recipients Research Articles

The Area Under Tacrolimus Concentrations on Day 14-28 Is the Independent Predictor of the Development of Chronic Gvhd in Patients without Severe Acute Gvhd after Unrelated Allogeneic HSCT

Introduction: In unrelated allogeneic hematopoietic stem cell transplantation (UR-SCT), chronic graft-versus-host disease (GVHD) is a critical complication that affects not only patients' quality of life but also post-transplant outcome. Acute GVHD is a major risk factor for the subsequent development of chronic GVHD. The combination of tacrolimus and short-term methotrexate (TAC+sMTX) has been widely used as a GVHD prophylaxis for UR-SCT in Japan. Previous reports have shown that tacrolimus blood concentrations early after transplantation are associated with the development of acute GVHD, but not with that of chronic GVHD. On the other hand, among UR-SCT recipients who did not develop severe acute GVHD, the relationship between tacrolimus blood concentrations and the development of chronic GVHD remains unclear. Methods: To examine the association between tacrolimus blood concentrations and post-transplant outcomes, the area under the tacrolimus concentration on day 0-14 (AUTC 0-14) and day 14-28 (AUTC 14-28) was calculated simply as the sum of the area of the trapezoid for the corresponding period ( Figure). Tacrolimus was initiated by continuous intravenous administration from day -1 in all patients, and no patients were switched to oral administration prior to day 28. Short-term methotrexate was administered at 10 mg/m 2 on day 1 and 7 mg/m 2 on day 3, day 6, and day 11. Among all 151 adult patients with hematopoietic malignancies who underwent first UR-SCT with GVHD prophylaxis of TAC+sMTX between 2010 and 2022 at the Jikei University Hospital, the following were excluded from the analysis: developing grade III-to-IV acute GVHD, using prednisolone or methyl-prednisolone ≥0.5 mg/kg within day 100, engraftment failure, death before day 100, and relapse before day 100. Results: A total of 68 patients were included in the analysis. Median age was 50.5 (range, 16-68) years. Twenty-seven (40%) patients had acute myeloid leukemia, and 18 (27%) had acute lymphoblastic leukemia. Fifty-five (81%) were in complete remission/chronic phase/early stage. The donor source consisted of 42 (62%) bone marrow transplantation (BMT), 20 (29%) cord blood transplantation (CBT), and 6 (9%) peripheral blood stem cell transplantation (PBSCT). BMT recipients transplanted from 22 (52%) HLA 8/8 matched donor, 19 (45%) HLA 7/8 matched donor, and one (3%) HLA 6/8 matched donor. CBT recipients transplanted from 15 (75%) HLA 4/6 matched donor and 5 (25%) HLA 5/6 matched donor. PBSCT recipients transplanted from 5 (83%) HLA 8/8 matched donor and one (17%) HLA 7/8 matched donor. Fifteen (22%) patients were administered additional low-dose anti-thymocyte globulin (ATG) as GVHD prophylaxis. Fifteen male patients transplanted from female donors (22%). Thirty-nine (57%) patients received myeloablative conditioning regimen. The median time from UR-SCT to neutrophil engraftment was 19 days (range, 11-34). Regarding acute GVHD, 46 patients (68%) developed none, 13 patients (19%) developed grade I, and 9 patients (13%) developed grade II. The median observation period for all 68 patients was 48.2 months (4.0 years). The 4-year cumulative incidence (CI) of chronic GVHD was 51%, of which 24% were moderate-to-severe. The CI of moderate-to-severe chronic GVHD was not associated with age, disease status, donor source, HLA incompatibility, ATG use, female to male, intensity of conditioning regimen, and grade I-to-II acute GVHD development. AUTC 14-28 <200 was the only risk factor (AUTC 14-28<200: 32% vs AUTC 14-28≥200: 11%; p=0.047). Multivariate analysis also showed that AUTC 14-28 <200 was the independent factor for development of moderate-to-severe chronic GVHD ( p=0.04). In all 68 patients, 4-year CI of relapse was 20%, 4-year CI of non-relapse mortality was 10%, 4-year GVHD-free, relapse-free, survival (GRFS) was 50%, and 4-year Overall survival was 80%, all of which did not differ between AUTC 14-28 <200 and AUTC 14-28 ≥200 groups. Conclusion: In UR-SCT, our data showed that AUTC 14-28 <200 may be an independent risk factor for developing moderate-to-severe chronic GVHD, even in patients who did not develop severe acute GVHD.

Effect of Cryopreservation in Unrelated Bone Marrow and Peripheral Blood Stem Cell Transplantation in the Era of the COVID-19 Pandemic: An Update from the Japan Marrow Donor Program

During the COVID-19 pandemic, donor grafts are frequently cryopreserved to ensure that a graft is available before starting a conditioning regimen. However, there have been conflicting reports on the effect of cryopreservation on transplantation outcomes. Also, the impact of cryopreservation may differ in bone marrow (BM) transplantation (BMT) and peripheral blood stem cell (PBSC) transplantation (PBSCT). In this retrospective study, we analyzed the clinical data of both cryopreserved unrelated BMTs (n = 235) and PBSCTs (n = 118) and compared these with data from a large control cohort without cryopreservation including 4133 BMTs and 720 PBSCTs. Among the patients with cryopreserved grafts, 10 BMT recipients (4.3%) and 3 PBSCT recipients (2.5%) did not achieve neutrophil engraftment after transplantation, including 4 of the former and all 3 of the latter who died early before engraftment. In a multivariate analysis, cryopreservation was not associated with neutrophil engraftment in BMT but significantly delayed neutrophil engraftment in PBSCT (hazard ratio [HR], .82; 95% confidence interval [CI], .69 to .97; P = .023). There was an interaction with borderline significance between cryopreservation and the stem cell source (P = .067). Platelet engraftment was delayed by cryopreservation after both BMT and PBSCT. Only 2 cryopreserved grafts (<1%) were unused during the study period. The cryopreservation of unrelated donor BM and PBSC grafts is associated with a slight delay in neutrophil and platelet engraftment but an acceptable rate of graft failure. PBSC grafts may be more sensitive to cryopreservation than BM grafts. Cryopreservation is a reasonable option during COVID-19 pandemic, provided that the apheresis and transplantation centers are adept at cryopreservation.© 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Comparison of cryoprotectants in hematopoietic cell infusion-related adverse events.

The standard cryoprotectant for human cellular products is dimethyl sulfoxide (DMSO), which is associated with hematopoietic cell infusion-related adverse events (HCI-AEs) in hematopoietic stem cell transplantation including peripheral blood stem cell (PBSC) transplantation (PBSCT). DMSO is often used with hydroxyethyl starch (HES), which reduces DMSO concentration while maintaining the postthaw cell recovery. The cryoprotectant medium CP-1 (Kyokuto Pharmaceutical Industrial) is widely used in Japan. After mixture of a product with CP-1, DMSO and HES concentrations are 5% and 6%, respectively. However, the safety profile of CP-1 in association with HCI-AEs has not been investigated. To compare CP-1 with other cryoprotectants, we conducted a subgroup analysis of PBSCT recipients in a prospective surveillance study for HCI-AEs. Moreover, we validated the toxicity of CP-1 in 90 rats following various dose administration. The PBSC products cryopreserved with CP-1 (CP-1 group) and those with other cryoprotectants, mainly 10% DMSO (non-CP-1 group), were infused into 418 and 58 recipients, respectively. The rate of ≥grade 2 HCI-AEs was higher in the CP-1 group, but that of overall or ≥grade 3 HCI-AEs was not significantly different, compared to the non-CP-1 group. Similarly, after propensity score matching, ≥grade 2 HCI-AEs were more frequent in the CP-1 group, but the ≥grade 3 HCI-AE rate did not differ significantly between the groups. No significant toxicity was detected regardless of the CP-1 dose in the 90 rats. Infusion of a CP-1-containing PBSC product is feasible with the respect of HCI-AEs.

Antithymocyte Globulin Potentially Could Overcome an Adverse Effect of Acute Graft-versus-Host Disease in Matched-Related Peripheral Blood Stem Cell Transplantation

Previous Japanese studies have shown that bone marrow transplantation (BMT) is associated with better survival compared with peripheral blood stem cell transplantation (PBSCT) from a matched related donor (MRD). PBSCT recipients have shown higher incidences of severe graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) compared with BMT recipients. In recent years, the efficacy and safety of antithymocyte globulin (ATG) for PBSCT recipients has been evaluated worldwide. In the present study, we aimed to compare BMT and PBSCT recipients to identify current improvements and unmet needs among MRD PBSCT recipients. In addition, we evaluated the impact of ATG administration on the outcomes of PBSCT recipients. We retrospectively analyzed patients age ≥16 years with acute leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia who underwent their first BMT or PBSCT from an MRD between 2009 and 2018 in Japan. A total of 3599 transplantations were performed (BMT, n=1218; PBSCT without ATG [PBSCT-ATG(-)], n=2288; PBSCT with ATG [PBSCT-ATG(+)], n=93). The PBSCT-ATG(-) group had a higher NRM (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.08 to 1.57; P=.005) and lower overall survival (OS) (HR, 1.16; 95% CI, 1.04 to 1.30; P=.011) compared with the BMT group. Furthermore, the PBSCT-ATG(-) group had higher incidences of grade III-IV, stage 2-4 gut, high-risk, and steroid-refractory acute GVHD compared with the BMT group. Acute GVHD had a negative impact on NRM and OS. The PBSCT-ATG(-) group also was associated with an elevated risk of chronic GVHD (HR, 1.89; 95% CI, 1.24 to 2.57; P < .001) and extensive chronic GVHD (HR, 1.44; 95% CI, 1.23 to 1.68; P < .001). The incidences of acute GVHD, chronic GVHD, and NRM and chronic GVHD-free relapse-free survival rates were comparable between the PBSCT-ATG(+) and BMT groups. The OS of patients with acute GVHD was similar in the 3 donor groups. Patients treated with reduced-intensity conditioning in the PBSCT-ATG(+) group had a higher relapse rate and lower OS rate compared with those in the BMT group. In this Japanese cohort, standard calcineurin inhibitor-based GVHD prophylaxis was not sufficient for recipients of MRD PBSCT because of the high incidence of severe acute GVHD. Prophylactic ATG was found to be a promising strategy against GVHD.

Rash in Patients after T-Cell-Depleted Peripheral Blood Stem Cell Transplantation: Eosinophilia and Pruritus Do Not Distinguish Acute Graft-Versus-Host Disease from Drug Rash

Background: The incidence and severity of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT) is decreased with T-cell depletion. However, ~14% of these T-cell depleted (TCD) recipients will have aGVHD with skin involvement (Barba et al. 2017). Furthermore, alloHSCT recipients are at increased risk for drug eruptions and infectious exanthems (Byun et al. 2011). While histopathologic differences have been reported between aGVHD and non-aGVHD rash in TCD recipients (Fischer et al. 2015), skin biopsies alone are insufficient to determine rash etiology. As such, distinguishing inflammatory non-aGVHD rashes from aGVHD of the skin after TCD HSCT remains challenging and relies on clinical presentation. While peripheral eosinophilia is seen in both aGVHD and drug hypersensitivity, rashes that present with concomitant eosinophilia after HSCT are often suspected to have a drug-induced etiology. We sought to assess the incidence and features of aGVHD and non-aGVHD rashes within 1 year after TCD alloHSCT, as well as common etiologies of non-aGVHD rash. These findings may guide clinicians in earlier diagnosis and management of non-aGVHD rash.Methods: Using a clinical research database, 243 adult patients were identified who received alloTCD peripheral blood stem cell transplantation (PBSCT) at a single institution between 2008 and 2011. All patients had CD34+ hematopoietic progenitor cells selected using: the Isolex 300i Magnetic Cell, followed by additional T-cell rosetting with neuraminidase-treated sheep erythrocytes or using the CliniMACS CD34+ Reagent System (Table 1). Given decreased incidence of aGVHD with Isolex versus CliniMACS (Barba et al. 2017), we established Isolex and CliniMACS TCD groups and assessed aGVHD and non-aGVHD rash within these two CD34+ selection modalities. To identify non-aGVHD patients with skin rash, charts were reviewed from date of HSCT through 1 year post HSCT by review of dermatology visit notes or by extraction of International Classification of Diseases-9 (ICD-9) codes for skin lesion or rash (Table 2); skin infections and chronic GVHD rashes were excluded. Acute GVHD was diagnosed with histological confirmation when clinically indicated. Rash characteristics, including pruritus and peripheral eosinophilia at onset of rash, were collected from charts of both non-aGVHD and aGVHD rash patients.Results: Among 243 TCD PBSCT transplant recipients, 152 patients (63%) were identified with skin rash within 1 year after HSCT. Of these patients, 43 had aGVHD rash and 109 had non-aGVHD rash. The majority of aGVHD rashes had skin stage III aGVHD regardless of CD34+ selection method (Table 3). For patients with non-aGVHD rash, etiologies included inflammatory conditions (Table 4). TCD by Isolex led to non-aGVHD rash development at a median onset of 60 days and aGVHD rash at a median onset of 71 days; while TCD by CliniMACS led to non-aGVHD rash development at a median onset of 56.5 days and aGVHD rash at a median onset of 75 days. Of patients who had recorded complete blood counts at onset of rash, elevated percent eosinophilia (% eosinophils >7%) was present in 10% of Isolex and 5% of CliniMACS non-aGVHD rashes versus 3% of Isolex and 4% of CliniMACS aGVHD rashes. Peripheral eosinophilia was not associated with aGVHD versus non-aGVHD skin rash post TCD HSCT (p≥0.99) nor when separated by CD34+ selection method (Isolex p=0.673; CliniMACS p≥0.99). While non-aGVHD skin rash patients had higher incidence of pruritus compared to aGVHD skin rash, pruritus was not a significant predictor of aGVHD versus non-aGVHD skin rash (p=0.20) nor when separated by CD34+ selection modality (Isolex p=0.188; CliniMACS p=0.469).Conclusions: In our case series of 243 TCD PBSCT recipients of whom 152 had skin rashes, over three-quarters of all non-aGVHD skin rashes with clear etiologies were attributed to drug eruptions. Our results suggest that the commonly utilized feature of peripheral eosinophilia may not be helpful in differentiating between aGVHD and drug rashes after TCD alloHSCT. Additionally, pruritus at rash onset was not helpful in distinguishing cause of rash as due to aGVHD or non-aGVHD after TCD alloHSCT. Based on these data, if clinical scenario supports GVHD associated rash, the presence of peripheral eosinophilia or pruritus should not delay initiation of therapy for GVHD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Granulocyte Colony-Stimulating Factor Use after Autologous Peripheral Blood Stem Cell Transplantation: Comparison of Two Practices

Administration of granulocyte colony-stimulating factor (G-CSF) after autologous peripheral blood stem cell transplantation (PBSCT) is generally recommended to reduce the duration of severe neutropenia; however, data regarding the optimal timing of G-CSFs post-transplantation are limited and conflicting. This retrospective study was performed at NewYork-Presbyterian/Weill Cornell Medical Center between November 5, 2013, and August 9, 2016, of adult inpatient autologous PBSCT recipients who received G-CSF empirically starting on day +5 (early) versus on those who received G-CSF on day +12 only if absolute neutrophil count (ANC) was <0.5 × 109/L (ANC-driven). G-CSF was dosed at 300 µg in patients weighing <75 kg and 480 µg in those weighing ≥75 kg. One hundred consecutive patients underwent autologous PBSCT using either the early (n = 50) or ANC-driven (n = 50) G-CSF regimen. Patient and transplantation characteristics were comparable in the 2 groups. In the ANC-driven group, 24% (n = 12) received G-CSF on day +12 and 60% (n = 30) started G-CSF earlier due to febrile neutropenia or at the physician's discretion, 6% (n = 3) started after day +12 at the physician's discretion, and 10% (n = 5) did not receive any G-CSF. The median start day of G-CSF therapy was day +10 in the ANC-driven group versus day +5 in the early group (P < .0001). For the primary outcome, the median time to neutrophil engraftment was 12 days (interquartile range [IQR] 11-13 days) in the early group versus 13 days (IQR, 12-14 days) in the ANC-driven group (P = .07). There were no significant between-group differences in time to platelet engraftment, 1-year relapse rate, or 1-year overall survival. The incidence of febrile neutropenia was 74% in the early group versus 90% in the ANC-driven group (P = .04); however, there was no significant between-group difference in the incidence of positive bacterial cultures or transfer to the intensive care unit. The duration of G-CSF administration until neutrophil engraftment was 6 days in the early group versus 3 days in the ANC-driven group (P < .0001). The median duration of post-transplantation hospitalization was 15 days (IQR, 14-19 days) in the early group versus 16 days (IQR, 15-22 days) in the ANC-driven group (P = .28). Our data show that early initiation of G-CSF (on day +5) and ANC-driven initiation of G-CSF following autologous PBSCT were associated with a similar time to neutrophil engraftment, length of stay post-transplantation, and 1-year overall survival.

Comparison of unrelated cord blood transplantation and HLA-identical sibling peripheral blood stem cell transplantation for the treatment of adult hematological malignancies

目的比较单份清髓非血缘脐血移植（UCBT）与HLA相合同胞外周血干细胞移植（PBSCT）治疗成人恶性血液病的疗效。方法自2011年4月1日至2015年12月31日，共81例单份清髓UCBT与57例HLA相合同胞PBSCT患者入组进行比较。所有患者均采用清髓性预处理方案，环孢素A联合霉酚酸酯预防移植物抗宿主病（GVHD）。结果移植后42 d（+42 d）UCBT组中性粒细胞累积植入率为95.0%（95%CI 87.0%~98.1%），同胞PBSCT组为100%（P=0.863）。+100 d UCBT组血小板累积植入率低于同胞PBSCT组[87.3%（95%CI 76.8%~93.1%）对98.2%（95%CI 87.3%~99.7%），P=0.005]。+100 d UCBT组Ⅱ~Ⅳ度急性GVHD、Ⅲ/Ⅳ度急性GVHD的累积发生率分别为18.2%（95%CI 9.1%~26.4%）、10.4%（95%CI 3.3%~16.9%），同胞PBSCT组分别为8.9%（95%CI 1.1%~16.1%）、7.1%（95%CI 1.4%~13.7%），差异均无统计学意义（P=0.142，P=0.521）。UCBT组3年慢性GVHD、广泛型慢性GVHD累积发生率均低于同胞PBSCT组[14.9%（95%CI 5.2%~23.5%）对35.2%（95%CI 19.4%~47.8%），P=0.008；11.2%（95%CI 2.9%~18.7%）对31.4%（95%CI 16.2%~43.9%），P=0.009]。UCBT组、同胞PBSCT组3年移植相关死亡率（TRM）差异无统计学意义[30.1%（95%CI 19.2%~41.7%）对23.2%（95%CI 13.1%~35.0%），P=0.464]。UCBT组3年疾病复发率低于同胞PBSCT组[12.9%（95%CI 6.6%~21.5%）对24.3%（95%CI 13.5%~36.8%），P=0.039]。UCBT、同胞PBSCT组3年总生存率、无病生存率差异均无统计学意义[58.6%（95%CI 45.4%~69.7%）对54.8%（95%CI 39.9%~67.4%），P=0.634；57.0%（95%CI 44.0%~68.0%）对52.4%（95%CI 38.2%~64.9%），P=0.563]。UCBT组3年无GVHD及复发生存（GRFS）率高于同胞PBSCT组[55.7%（95%CI 44.1%~65.8%）对42.9%（95%CI 29.8%~55.3%），P=0.047]。结论对于成人恶性血液病，UCBT与HLA相合同胞PBSCT具有相似的急性GVHD发生率、TRM、总生存率和无病生存率，但UCBT组具有较低的慢性GVHD发生率及疾病复发率。

Efficacy and safety of moxifloxacin as antibacterial prophylaxis for patients receiving autologous haematopoietic stem cell transplantation: a randomised trial

Patients receiving high-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) are at high risk of infections, especially bacteraemia. A prospective, double-blind, randomised, placebo-controlled, single-centre, pilot study was performed on oral moxifloxacin 400mg versus placebo for preventing bacteraemia in PBSCT recipients. Patients received moxifloxacin or placebo for the duration of neutropenia or until emergence of fever or other infections necessitating intravenous antibiotic treatment. Of 68 patients included in the trial, 2 were excluded from the trial before taking their first dose. The remaining 66 patients were eligible for evaluation in the intention-to-treat analysis set. Neutropenia with an absolute neutrophil count of <500cells/μL developed in 30 moxifloxacin-treated patients (88.2%) and 21 patients in the placebo group (65.6%) (P<0.03). Nine patients (26.5%) and eight patients (25.0%), respectively, were prematurely discontinued from study treatment. Breakthrough bacteraemia occurred in 3 moxifloxacin-treated patients (8.8%) and 9 patients in the placebo group (28.1%) (P=0.042). The time period until fever was 9.5 days [95% confidence interval (CI) 8.06–10.94 days) and 7.69 days (95% CI 6.51–8.85 days), respectively (P=0.0499). There was no difference in adverse events or toxicities between the groups. Moxifloxacin prevented bacteraemia and shortened febrile episodes in patients receiving autologous PBSCT. No significant increase of adverse events in the moxifloxacin arm was observed, possibly due to the rather small sample size.

Comparison of stem cell sources in the severity of dry eye after allogeneic haematopoietic stem cell transplantation

AimsTo compare the incidence and severity of dry eye (DE) after allogeneic haematopoietic stem cell transplantation (HSCT) according to the stem cell source. The authors specifically focused on patients who...

Children with acute leukemia: A comparison of outcomes from allogeneic blood stem cell and bone marrow transplantation

The relative merits of peripheral blood stem-cell transplantation (PBSCT) versus bone marrow transplantation (BMT) for children with standard and high-risk hematologic malignancies remain unclear. In a retrospective study, we compared allogeneic PBSCT (n = 30) with BMT (n = 110) in children with acute leukemia between January 2001 and September 2006. Median age for PBSCT was 9 years versus 8 years for BMT. Descriptive statistics were used to summarize the demographic and medical variables. The unadjusted probabilities of disease-free survival were estimated using the Kaplan-Meier method. The association of graft-source and time to each of the study endpoints was estimated by Cox's regression model and the occurrence of graft-versus-host disease (GvHD) was included as a time-dependent covariate. Time to neutrophil engraftment and platelet independence was faster after PBSCT than BMT (neutrophils 15.0 days vs. 17.0 days, P < 0.001; platelets, 21.0 days vs. 27.0 days, P = 0.034). The cumulative incidence of grades II-IV acute GvHD at 100 days was 10.4% (SE 5.6%) after PBSCT and 15.1% (SE 3.5%) after BMT (P = NS). The cumulative incidence of chronic GvHD was 13.8% (SE 6.3%) after PBSCT and 11.3% (SE 3.1%) after BMT (P = NS). One-year disease-free survival was 37.9% (SE 9.0%) for PBSCT recipients versus 65.1% (SE 4.6%) after BMT (P = 0.005) but this difference was not sustained in multivariate analysis. Thus, only disease risk and pre-transplant CMV seropositivity were significant predictors of disease-free survival. We conclude that PBSCT for children produces faster engraftment without increased risk of acute or chronic GvHD.

The Costs and Cost-Effectiveness of Allogeneic Peripheral Blood Stem Cell Transplantation versus Bone Marrow Transplantation in Pediatric Patients with Acute Leukemia

In a retrospective study, we evaluated the cost and cost-effectiveness of allogeneic peripheral blood stem cell transplantation (PBSCT) (n = 30) compared with bone marrow transplantation (BMT) (n = 110) in children with acute leukemia after 1 year of follow-up. Treatment success was defined as disease-free survival at 1 year posttransplantation. For patients at standard risk for disease, the treatment success rate was 57.1% for PBSCT recipients and 80.3% for BMT recipients (P = not significant [NS]). The average total cost per treatment success at 1 year in the standard-risk disease group was $512,294 for PBSCT recipients and $352,885 for BMT recipients (P = NS). For patients with high-risk disease, the treatment success rate was 18.8% for PBSCT recipients and 23.5% for BMT recipients (P = NS). The cumulative average cost was $457,078 in BMT recipients and $377,316 in PBSCT recipients (P = NS). Point estimates of the incremental cost-effectiveness ratio (ICER) indicate that in patients with standard-risk disease, allogeneic BMT had lower costs and greater effectiveness than PBSCT (ICER, -$687,108; 95% confidence interval [CI], $2.4 million to dominated). For patients with high-risk disease, BMT was more effective and more costly, and it had an ICER of $1.69 million (95% CI, $29.7 million to dominated) per additional treatment success. The comparative economic evaluation provides support for BMT in standard-risk patients, but much uncertainty precludes a clear advantage of either treatment option in patients with high-risk disease. More studies using larger and randomized controlled trials are needed to confirm the long-term cost-effectiveness of each procedure.

Unrelated Cord Blood Transplantation after Nonmyeloablative Conditioning: Single Institutional Retrospective Comparison with Bone Marrow or Peripheral Blood Stem-Cell Transplants.

Background: Unrelated cord blood transplantation (CBT) has emerged as an effective therapy for treating patients with advanced or high-risk hematologic diseases who have no suitable related or unrelated donor. In older patients or those with extensive prior therapy or other clinical features, nonmyeloablative regimens have been used to reduce the risk of regimen-related toxicity and transplantation-related mortality (TRM). Several studies have been reported on the use of unrelated CBT using various reduced-intensity conditioning regimens.Objectives: This study aimed to evaluate the safety and efficacy of unrelated CBT after nonmyeloablative conditioning using fludarabine, cyclophosphamide and single fraction of total body irradiation of 200 cGy, compared with bone marrow transplantation (BMT) or peripheral blood stem-cell transplantation (PBSCT) for adult Japanese patients with hematologic diseases and relate those to biological and procedural factors.Patients and Methods: Clinical data were collected retrospectively on 70 adults with hematologic disease who received unrelated CBT (n=19) or BMT from unrelated donors (n=27), or PBSCT from related donors (n=24) between August 2000 and June 2008 in our institution. All patients received nonmyeloablative conditioning regimens including fludarabine. The median period of follow-up for survivors was 253 days after CBT, 364 days after BMT and 692 days after PBSCT, respectively. We analyzed the hematopoietic recovery, incidence of graft-versus-host disease (GVHD), risks of TRM and relapse, and disease-free survival (DFS) using Cox proportional hazards models.Results: Comparisons of characteristics in 3 groups showed similar distributions for age, gender ratio, diagnosis, risk of disease at the transplant. Compared with BMT and PBSCT (BMT/PBSCT) recipients, CBT recipients had more previous history of hematopoietic stem cell transplantation (HSCT), less human leukocyte antigen-matched donor and less methotrexate (MTX)-containing GVHD prophylaxis. Multivariate analysis demonstrated slow neutrophil (P<0.01) and platelet (P<0.01) recoveries in CBT compared with BMT/PBSCT. The cumulative incidence of grade II to IV acute GVHD in CBT recipients were significantly higher than those in PBSCT recipients (60% versus 23%, P=0.02), but not significantly different from BMT recipients. The cumulative incidence of extensive-type of chronic GVHD at 1 year in CBT recipients was not significantly different from BMT/PBSCT recipients. No statistically differences were seen in TRM (22% in CBT, 24% in BMT and 9% in PBSCT recipients at 1 years), relapse (38% in CBT, 32% in BMT and 40% in PBSCT recipients at 1 years) and DFS (46% in CBT, 50% in BMT and 46% in PBSCT recipients at 1 years) among 3 groups. Risk of disease at the transplant was the only factor for DFS result (standard versus high, P<0.01).Conclusion: These data suggest that unrelated cord blood (UCB) after this nonmyeloablative conditioning could be a safe and effective stem cell source similar to bone marrow or mobilized peripheral blood for adult Japanese patients, and also support the use of UCB as a strategy for extending the availability of transplantation therapy, particularly for older patients without suitable related or unrelated blood or bone marrow donor.

Donor cell leukemia after allogeneic peripheral blood stem cell transplantation: a case report and literature review

A 49-year-old male developed recurrent acute myeloid leukemia 27 months after allogeneic peripheral blood stem cell transplantation (PBSCT) from an HLA-identical brother. The immunophenotype of the blastic cell population was incompatible with that of the pre-transplant blast cells; a mutation in C/EBPA gene was found in the pre-transplant blast cells that was not present in the post-transplant blast cells, and short tandem repeat analysis of marrow cells, which included 71% blasts, showed complete donor chimera. Thus, this recipient developed donor cell leukemia (DCL). The donor was healthy when DCL developed in the recipient as well as before donation of the peripheral blood stem cells. Only five cases of DCL after PBSCT have been reported in the literature. As a mechanism for the development of DCL, a vigorous proliferative demand on the donor cells, which often correlates with a higher likelihood of replication error or mutation, has been proposed. Peripheral blood stem cells might have an advantage in that they are associated with a low incidence of DCL development because PBSCT recipients receive a higher total cell dose than recipients of bone marrow or cord blood cells.

Factors influencing varicella zoster virus infection after allogeneic peripheral blood stem cell transplantation: low‐dose acyclovir prophylaxis and pre‐transplant diagnosis of lymphoproliferative disorders

Varicella zoster virus (VZV) infection is one of the frequent opportunistic infections after allogeneic bone marrow transplantation, with a high incidence of 30-50%. However, no data have been reported on VZV infection after allogeneic peripheral blood stem cell transplantation (PBSCT). We report a retrospective analysis of VZV infection in 192 allogeneic PBSCT recipients. Twenty-seven patients (14%) received long-term prophylaxis of low-dose acyclovir (200 mg twice daily orally > or =3 months) for recurrent oral (n=21) or genital herpes simplex virus infection (n=5) or for a previous history of recurrent VZV infection (n=1). Forty-two patients (22%) developed VZV infections: localized (n=37) and disseminated infection (n=5). The incidence of VZV infection at 1 and 3 years was 19.3+/-3.3% and 36.8+/-5.2%, respectively. Complications included post-herpetic neuralgia (n=18, 43%), secondary bacterial infections (n=3), and intracranial hemorrhage (n=1) with 2 deaths. A higher risk factor for VZV infection was pre-transplant diagnosis of a lymphoproliferative disorder (LPD): chronic lymphocytic leukemia, Hodgkin's disease, or non-Hodgkin's lymphoma (P=0.021, 52.5% in LPD vs. 32.6% in non-LPD group). The use of low-dose acyclovir prophylaxis (P=0.043, 14.7% in acyclovir vs. 41.6% in nonacyclovir group) was found to be protective. Although no VZV infection episodes were noted during the period of acyclovir prophylaxis, 3 episodes of VZV infection were noted after acyclovir cessation. The incidence of VZV infection after PBSCT was high at 36.8%, with patients transplanted for LPDs at higher risk. The long-term use of low-dose acyclovir may be protective for VZV infection, although it does not completely prevent rebound of late VZV infection.

Surveillance of Nosocomial Sepsis and Pneumonia in Patients with a Bone Marrow or Peripheral Blood Stem Cell Transplant: A Multicenter Project

For surveillance of nosocomial bloodstream infections (BSIs) and pneumonia during neutropenia in adult patients who have undergone bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT), a multicenter study--the Hospital Infection Surveillance System for Patients with Hematologic/Oncologic Malignancies (ONKO-KISS)--was initiated in Germany in 2000. Nosocomial infections were identified in neutropenic patients by means of Centers for Disease Control and Prevention definitions for laboratory-confirmed BSI and modified criteria for pneumonia. During the first 38-month period of the study (i.e., through December 2003), a total of 1899 patients associated with 28,273 neutropenic days were investigated. Of these, 1173 (62%) had undergone allogeneic and 726 (38%) had undergone autologous BMT or PBSCT. The mean duration of neutropenia was 14.9 days (9.6 and 18.1 days after autologous and allogeneic transplantation, respectively). Overall, 395 BSIs and 168 cases of pneumonia were identified. The pooled mean site-specific incidence density per 1000 neutropenic days was 14.0 for BSI (12.4 and 18.9 for the allogeneic and autologous transplantation groups, respectively) and 5.9 for pneumonia (6.1 and 5.6 in the allogeneic and autologous transplantation groups, respectively). After allogeneic transplantation, 22.4 BSIs per 100 patients and 11.0 cases of pneumonia per 100 patients occurred, whereas 18.2 BSIs per 100 patients and 5.4 cases of pneumonia per 100 patients occurred after autologous transplantation. The majority (57%) of pathogens associated with BSI were coagulase-negative staphylococci. The ongoing ONKO-KISS project provides unprecedented reference data about the incidence of pneumonia and sepsis among BMT recipients and PBSCT recipients in Germany. These data will be used for further evaluation of the impact of hygiene measures and therapeutic regimens for these patients.

Surveillance of nosocomial infections in adult recipients of allogeneic and autologous bone marrow and peripheral blood stem-cell transplantation.

To identify overall and site-specific rates of nosocomial infections (NIs) during the neutropenic, as compared to the non-neutropenic stage of treatment in adult recipients of allogeneic and autologous bone marrow transplantation (BMT) and peripheral blood stem-cell transplantation (PBSCT), a prospective, 54-month study was started at the Haematological Stem Cell Transplantation Unit of the University Hospital of Freiburg, Germany. NI types were identified using modified CDC definitions. A total of 351 patients (14 256 in-patient days, 5026 neutropenic days) were investigated (316/90% allogeneic, 35/10% autologous; BMT: 119 patients, PBSCT: 234 patients). The mean length of neutropenia was 14.3 days (range: 0-66). Antimicrobial prophylaxis for allogeneic transplantation consisted of ciprofloxacin, trimethoprim/sulpha-methoxazole, fluconazole, and metronidazole. In total, 239 NIs were identified in 169 patients (48.1%), and of these 171 (71.5%) occurred during neutropenia (34.0 NIs per 1000 days at risk). The main pathogens were coagulase-negative staphylococci (36.3%), Clostridium difficile (20.4%), and enterococci (10.0%). Site-specific incidence densities during neutropenia vs non-neutropenia were: 13.9 vs 1.6 bloodstream infections (all central line-associated), 11.9 vs 1.8 pneumonias, 3.0 vs 2.9 gastroenteritis, and 1.6 vs 0.3 urinary tract infections. The greatest number of NI in BMT and PBSCT recipients is acquired during neutropenia, and multicentre surveillance programmes should focus on this.

G-CSF modulates cytokine profile of dendritic cells and decreases acute graft-versus-host disease through effects on the donor rather than the recipient.

Allogeneic peripheral blood stem cell transplantation (PBSCT) is increasingly used instead of bone marrow transplantation, particularly in HLA identical sibling pairs. Despite the presence of significantly increased numbers of T cells in the PBSC graft, acute graft-versus-host disease (GVHD) is not increased. We have investigated whether granulocyte-colony stimulating factor (G-CSF) administration to PBSCT recipients, both with and without donor G-CSF pretreatment, further modulates acute GVHD in a murine model of PBSCT. Recipients of G-CSF mobilized splenocytes showed a significantly improved survival (P<0.001) and a reduction in GVHD score and serum LPS levels compared with control recipients. G-CSF treatment of donors, rather than recipients, had the most significant effect on reducing levels of tumor necrosis factor (TNFalpha) 7 days after transplantation. As a potential mechanism of the reduction in TNFalpha, we demonstrate G-CSF decreased dendritic cells TNFalpha, and interleukin-12 production to lipopolysaccharide. In conclusion, G-CSF modulates GVHD predominantly by its effects on donor cells, reducing the production of TNFalpha. G-CSF treatment of bone marrow transplantation recipients, without pretreatment of the donor, does not have an impact on acute GVHD.

Antibody responses to tetanus toxoid and Haemophilus influenzae type b conjugate vaccines following autologous peripheral blood stem cell transplantation (PBSCT)

Accelerated granulocyte and platelet recovery following peripheral blood stem cell transplantation (PBSCT) are well documented. We hypothesize that functional immunity may also be enhanced in PBSCT and performed a phase II trial of immunizations in patients with lymphoma undergoing autologous transplantation with peripheral blood stem cells or bone marrow. Seventeen BMT and 10 PBSCT recipients were immunized at 3, 6, 12, and 24-months post-transplantation with Haemophilus influenzae type b (HIB)-conjugate and tetanus toxoid (TT) vaccines. IgG anti-HIB and anti-TT antibody concentrations were measured and compared between the two groups. Geometric mean IgG anti-HIB antibody concentrations were significantly higher for PBSCT recipients compared to BMT recipients at 24 months post-transplantation (11.3 micrograms/ml vs 0.93 microgram/ml, P = 0.051) and following the 24 month immunization (66.2 micrograms/ml vs 1.30 micrograms/ml, P = 0.006). Similar results were noted for IgG anti-TT antibody with significantly higher geometric mean antibody concentrations in the PBSCT group at 24 months post-transplantation (182 micrograms/ml vs 21.6 micrograms/ml, P = 0.039). Protective levels of total anti-HIB antibody were achieved earlier in PBSCT recipients compared with those of BMT recipients. PBSCT recipients had higher antigen-specific antibody concentrations following HIB and TT immunizations. These results suggest enhanced recovery of humoral immunity in PBSCT recipients and earlier protection against HIB with immunization.

Phenotype of lymphocyte subsets after autologous peripheral blood stem cell transplantation.

The expression of CD45RA+ and CD45RO+ isoforms on T cells and the recovery of B lymphocytes and NK cells after autologous peripheral blood stem cell transplantation (PBSCT) were studied during the early period following transplantation. The same panel of monoclonal antibodies was used to analyze the lymphocyte subsets after allogeneic bone marrow transplantation (allo-BMT) and in cord blood. The CD4+ subsets regenerated differently from the CD8+ isoforms and the CD4+CD45RA+ subsets appears to be the only thymus-dependent regenerating population post-transplantation. Since the CD8+ CD45RA+ and CD8+ CD45RO+ isoforms recovered to normal levels within a month after PBSCT and within 3 months after allo-BMT, there seems to be no thymic influence on the regeneration of the immature CD8+CD45RA+ subset. The regeneration of the CD4+ cells was markedly delayed, but was faster in the PBSCT recipients, mainly because of the faster recovery of the mature CD4+ CD45RO+ subset. The pattern of surface antigens on T lymphocytes after transplantation did not resemble the antigen pattern on cord blood cells. The CD19+ CD20+ cells recovered earlier in the PBSCT group and remained compromised after allo-BMT during the time studied. The faster B lymphocyte regeneration correlates with the faster reconstitution of the mature CD4+CD45RO+ cells. The pattern of antigens CD38+, HLA-DR+, CD10+ on B lymphocytes of the recovery phase resembled the pattern on B cells of cord blood lymphocytes. The NK cells were not deficient at any time post-transplant in both groups.

Improved Immune Reconstitution After Allotransplantation of Peripheral Blood Stem Cells Instead of Bone Marrow

Clinical studies are evaluating possible advantages of allogeneic peripheral blood stem cell transplantation (PBSCT) over bone marrow transplantation (BMT). We compared immune reconstitution after PBSCT (n = 20) and BMT (n = 20) in terms of lymphocyte subset counts and proliferative in vitro responses to mitogens and recall antigens (follow-up: 5 to 11 months posttransplant). Additionally, 10 PBSC harvests and 10 marrow harvests were analyzed for their composition of immunocompetent cells. Compared with BMT patients, PBSCT recipients had PB counts of naive (CD4+CD45RA+) and memory (CD4+CD45RO+) helper T cells and of B cells (CD19+) that were elevated (P < .003, P < .001, and P < .004, respectively) and proliferative responses to phytohemagglutinin (P < .0001), pokeweed mitogen (P < .02), Tetanus toxoid (P < .0005), and Candida (P < .004) that were increased. PBSCT recipients received a mean of 188 (range, 44 to 280) x 10(6) naive helper T cells and 169 (range, 18 to 296) x 10(5) memory helper T cells per kilogram; the corresponding numbers for BMT recipients were 11 (range, 4 to 24) and 10 (range, 1 to 22) x 10(5) cells per kilogram, respectively. The question of whether the documented improved in vitro immune competence after PBSCT is associated with a lower incidence of infectious complications in vivo still needs further study.