Model-Informed Precision Dosing of Intravenous Busulfan in Thai Pediatrics Undergoing Hematopoietic Stem Cell Transplantation.

BACKGROUND: Conditioning bifunctional agent, busulfan, is commonly used on children before hematopoietic stem cell transplantation. Currently, at the Ramathibodi hospital, Bangkok, Thailand, initial dosing is calculated according to age and body surface area, and 7 samples per day are used for therapeutic drug monitoring (TDM). This study aimed to identify the best strategies for individual dosages a priori from patient characteristics and a posteriori based on TDM. METHODS: The pharmacokinetic data set consisted of 2018 plasma concentrations measured in 135 Thai (n = 135) pediatric patients (median age = 8 years) and were analyzed using a population approach. RESULTS: Body weight, presence of malignant disease, and genetic polymorphism of Glutathione S-transferase Alpha-1 (GSTA1) were predictors of clearance. The optimum sampling times for TDM concentration measurements were 0.25, 2, and 5 hours after a 3-hour infusion. This was sufficient to obtain a Bayesian estimate of clearance a posteriori. Simulations showed the poor performance of a priori formula-based dose calculations with 90% of patients demonstrating a 69%-151% exposure interval around the target. This interval shrank to 85%-124% if TDM was carried out only at day 1 and to 90%-116% with TDM at days 1 and 3. CONCLUSIONS: This comprehensive study reinforces the interest of TDM in managing interindividual variability in busulfan exposure. Therapeutic drug monitoring can reliably be implemented from 3 samples using the Bayesian approach, preferably over 2 days. If using the latter is not possible, the formulas developed herein could present an alternative in Thai patients.

Ambulatory blood pressure monitoring in children and adolescents post-hematopoietic stem cell transplantation.

BACKGROUND: One of the long-term complications after hematopoietic stem cell transplantation (HSCT) is hypertension (HT). Previous studies showed that 10-15% of children post-HSCT had office HT, but only a few studies used ambulatory blood pressure monitoring (ABPM). The present study was aimed at exploring the frequency and factors associated with ABPM HT in children post-HSCT. METHODS: Patients aged ≥ 6 years who survived ≥ 2 years after HSCT were enrolled. Clinical and ABPM data were reviewed. ABPM HT was defined according to the 2022 American Heart Association guidelines. Factors associated with HT were analyzed by logistic regression. RESULTS: Ninety-eight (60 males) patients with a mean age of 15.1 years and a median follow-up time at 4.5 years after HSCT were included. Fifteen patients (15.3%) had ABPM HT (2 ambulatory HT and 13 masked HT). The ABPM HT group had a significantly older age (19 vs. 14 years), a higher proportion of males (87% vs. 57%), a higher office systolic BP index (0.93 vs. 0.85), a higher office diastolic BP index (0.96 vs. 0.82) and a higher proportion of current use of prednisolone and tacrolimus than those in the normal ABPM group. Multivariate analysis revealed that office diastolic BP index was associated with ABPM HT. Left ventricular mass index was significantly correlated with ABPM but not with office BP parameters. CONCLUSIONS: HT in children post-HSCT was not uncommon and most could not be detected with office BP measurement. A diastolic BP index can be used as a screening tool for HT. A higher resolution version of the Graphical abstract is available as Supplementary information.

Germline HAVCR2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis.

Germline HAVCR2 mutations are frequently detected in subcutaneous panniculitis-like T-cell lymphoma (SPTCL) patients with/without hemophagocytic lymphohistiocytosis (HLH) but factors associated with variable manifestations remain undetermined. To evaluate clinical variations and associated factors in SPTCL and/or HLH with/without HAVCR2 mutations, we performed direct sequencing of HAVCR2 exon 2 using DNA from patients with SPTCL or idiopathic HLH/HLH-like systemic illnesses, defined by HLH alone without secondary causes. The systematic review and individual patient data (IPD) level meta-analysis which included the present and previously published studies reporting HAVCR2 mutations in SPTCL with/without HLH populations was subsequently conducted using random-effects meta-analysis and multivariate logistic regression. Among 34 patients enrolled, ten of 28 SPTCL patients developed HLH/HLH-like systemic illnesses. Six cases with HAVCR2Y82C mutation manifested with HLH without panniculitis. Male sex (P=0.03) and age <18 years (P=0.04) were associated with HLH, corresponding to the inverse correlation between age and HLH-2004 score (r=-0.40; P=0.02). Homozygous HAVCR2Y82C mutation was more common in the presence of HLH compared with the absence (75.0% vs. 44.4%; P=0.02). Using IPD from the present and the other three eligible cohorts (N=127), male sex, heterozygous and homozygous/compound heterozygous HAVCR2 mutations were associated with HLH by the adjusted odds ratio of 2.93 (95% confidence interval [CI]: 1.22-7.06), 4.77 (95% CI: 1.05-21.63) and 8.48 (95% CI: 2.98-24.10), respectively. Patients with male sex and/or germline HAVCR2 mutations showed an increased risk of developing HLH. Younger patients tended to manifest with HLH, while older patients typically presented with SPTCL with less frequent HLH/HLH-like systemic illnesses.

Effective T-cell replete haploidentical stem cell transplantation for pediatric patients with high-risk hematologic disorders.

OBJECTIVES: Patients with high-risk hematologic diseases require intensive modalities, including high-dose chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Haploidentical T-cell-replete transplantation is a logical choice because of the limited availability of matched sibling donors and the prolonged time needed to identify matched unrelated donors in Thailand. METHODS: The clinical outcomes data of 43 patients undergoing allo-HSCT were reviewed. All patients had high-risk hematologic malignancies, were younger than 20 years, and were in complete cytological remission at the time of allo-HSCT. We used two different conditioning regimens: total body irradiation (TBI) combined with cyclophosphamide, fludarabine, and melphalan (n = 23) and thiotepa combined with fludarabine and busulfan (n = 20). All patients received a graft-versus-host disease prophylaxis regimen consisting of cyclophosphamide, mycophenolate mofetil, and a calcineurin inhibitor or sirolimus. RESULTS: There was no difference in engraftment between patients receiving either of the regimens. After a median follow-up of 35.8 (range, 0.6-106.2) months, the overall survival (OS) and event-free survival (EFS) rates were 62.4% and 54.7%, respectively. OS and EFS were comparable between the respective regimens. CONCLUSIONS: We conclude that thiotepa-based conditioning has similar efficacy and tolerability as TBI-based conditioning for haploidentical HSCT with post-transplant cyclophosphamide.

Comprehensive and long-term outcomes of enzyme replacement therapy followed by stem cell transplantation in children with Gaucher disease type 1 and 3.

BACKGROUND: Gaucher disease (GD) is a lysosomal storage disorder, characterized by hepatosplenomegaly, pancytopenia, bone diseases, with or without neurological symptoms. Plasma glucosylsphingosine (lyso-Gb1), a highly sensitive and specific biomarker for GD, has been used for diagnosis and monitoring the response to treatment. Enzyme replacement therapy (ERT) is an effective treatment for the non-neurologic symptoms of GD. Neuronopathic GD (type 2 and 3) accounts for 60%-70% of the Asian affected population. METHODS: We explored combination therapy of ERT followed by hematopoietic stem cell transplantation (HSCT) and its long-term outcomes in patients with GD type 3 (GD3). RESULTS: Four patients with GD3 and one with GD type 1 (GD1) underwent HSCT. The types of donor were one matched-related, one matched-unrelated, and three haploidentical. The age at disease onset was 6-18 months and the age at HSCT was 3.8-15 years in the patients with GD3. The latest age at follow-up was 8-22 years, with a post-HSCT duration of 3-14 years. All patients had successful HSCT. Chronic graft-versus-host disease occurred in one patient. The enzyme activities were normalized at 2 weeks post HSCT. Lyso-Gb1 concentrations became lower than the pathological value. All of the patients are still alive and physically independent. Most of them (4/5) returned to school. None of the patients with GD3 had seizures or additional neurological symptoms after HSCT, but showed varying degrees of cognitive impairment. CONCLUSIONS: ERT followed by HSCT could be considered as an alternative treatment for patients with GD3 who have a high risk of fatal neurological progression.

Screening for ELANE, HAX1 and GFI1 gene mutations in children with neutropenia and clinical characterization of two novel mutations in ELANE gene.

BACKGROUND: Congenital neutropenia is a rare disease. Recurrent infections since young age are the presentation. The most common mutation causing severe congenital neutropenia (SCN) and cyclic neutropenia (CyN) is the ELANE gene. The objectives of this study were to screen the three common genetic mutations of ELANE, HAX1 and GFI1 in children with chronic neutropenia and to describe the clinical characteristics of children who had the mutations. METHODS: Infants having ANC < 1,000/cu mm or children aged > 1 year having ANC < 1,500/cu mm at least 3 times in 3 months were enrolled in the study. Patients who had acquired neutropenia due to infection, immune deficiency, or drugs were excluded. The ELANE gene was first studied; and if mutations were not identified, the HAX1 and GFI1 genes were further examined. RESULTS: A total of 60 patients were enrolled in the study. The median (range) age, ratio of female to male, ANC, and last follow-up age were 9.2 (0.5-45.2) months, 1:1.2, 248 (0-1,101) /cu mm, and 19.9 (3.5-202.3) months, respectively. Infections were noted in 67.3% of all patients. ELANE gene mutation was found in only four patients (6.7%), and the rest (56 patients) showed no mutations in the HAX1 and GFI1 genes. In patients without mutations, 66.0% had normal ANC during the follow-up, with a median (range) age for normal ANC of 19.8 (4.0-60.0) months. Two novel mutations p. Ala79del (c.234_236del) and p. Val197GlufsTer18 (c.589_590insAGGCCGGC) were identified, and they respectively cause SCN and CyN. Patients with the two novel mutations presented with several episodes of infection, including pneumonia, sepsis, abscess, otitis media, and gum infection. CONCLUSION: The genetic screening for ELANE, HAX1, and GFI1 gene mutations in 60 patients with chronic neutropenia could identify four patients (6.7%) with ELANE gene mutation and two novel mutations, p. Ala79del in exon 3 and p. Val197GlufsTer18 in exon 4 causing SCN; and CyN, respectively.

Factors affecting residents' internal motivation, grit, and well-being.

BACKGROUND: Residents completing competency-based medical education for postgraduate training face many challenging situations that may compromise their well-being or result in exhaustion or burnout. Factors described in self-determination theory and grit are important for residents' achievement of learning outcomes and well-being. This study explored the relationships among internal motivation, grit, well-being, and related factors among non-Western Asian residents. METHODS: We conducted an explanatory sequential mixed-methods survey-based study to explore correlations among satisfaction with basic psychological needs, grit, and well-being from September to November 2021 among residents at Ramathibodi Hospital, Mahidol University, Thailand. Data were collected with the Basic Psychological Needs Scale, Short Grit Scale, and World Health Organization-Five Well-Being Index. Next, participants with the highest and lowest scores for each scale were purposively invited to participate in semi-structured interviews. Interview data underwent thematic analysis and data collection continued until saturation was reached. RESULTS: In total, 245 residents (51% major ward, 65% female) completed the survey. There were strong associations between internal motivation, grit, and well-being (r = 0.46-0.90). Female residents had higher autonomy and relatedness scores than males (p = 0.04 and p = 0.01, respectively), and residents with less family responsibility had higher relatedness scores than other residents (p = 0.01). Residents who got more sleep had higher autonomy, relatedness, and well-being scores than those that slept less (p < 0.05). Residents who exercised > 5 times/week had higher well-being scores than other residents (p < 0.01). Thirty residents completed interviews. The thematic analysis revealed internal motivation, grit, and well-being were promoted by a supportive learning environment, a well-designed curriculum, actions and personalities of faculty members, and good personal factors. CONCLUSION: Internal motivation is significantly correlated with residents' grit, well-being, gender, family burdens, exercise, and sleep hours. Priority should be given to promoting internal motivation, grit, and well-being among residents by enhancing a positive learning environment, creating well-designed curricula, fostering good characteristics and actions among faculty members, and supporting residents' personal lives.

Bloodstream bacterial infections in thalassemic pediatric and adolescent patients after hematopoietic stem cell transplantation.

BACKGROUND: Thalassemic patients usually require regular blood transfusions; however, HSCT can provide a cure. Incidence of IBI in pediatric patients post-HSCT is still scant. OBJECTIVES: This study aimed to explore whether thalassemic patients had a different incidence of post-HSCT IBI compared with patients with other underlying diseases. Factors associated with IBI in the pediatric population undergoing HSCT were also investigated. METHODS: In this retrospective cohort study, clinical data of pediatric patients who underwent HSCT during the period from 2011 to 2016 were reviewed and analyzed. The primary outcome was incidence of IBI within 1-year post-HSCT. RESULTS: Of 123 patients, 53 were thalassemic. IBI was diagnosed in 23 patients within 1 year after HSCT (incidence: 19.5 episodes/1000 patients/month). The IBI incidence was lower in thalassemic patients than in patients with other underlying diseases (6.9 vs. 31.6 episodes/1000 patients/month). Having thalassemia as an underlying disease was the only factor associated with lower IBI in pediatric post-HSCT patients (hazard ratio: 0.245; 95% confidence interval, 0.080-0.748). In post-HSCT thalassemic patients, IBI mostly occurred within 100 days after HSCT, and most of these cases had catheter-related blood stream infection. The risk of IBI tended higher for haploidentical HSCT, but this difference was not statistically significantly different. CONCLUSION: The IBI incidence after HSCT was lower in thalassemic patients than in those with other underlying diseases. Catheter-related blood stream infection was the major IBI in these patients. IBI was not a major complication in thalassemic pediatric patients undergoing HSCT.

Haploidentical Hematopoietic Stem Cell Transplantation in Thalassemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only established treatment that is potentially curative, but it is limited by the availability of donors and the medical condition of the patient. To expand the donor pool to include haploidentical related donors, we introduced a program consisting of a pharmacologic pre transplant immune suppression phase (PTIS) and two courses of dexamethasone (DXM) and fludarabine (FLU) followed by pre transplant conditioning with intravenous FLU busulfan (BU) and post transplant graft-vs.-host disease (GvHD) prophylaxis with cyclophosphamide (CPM), tacrolimus, and mycophenolate mofetil. We transplanted 83 consecutive transfusion-dependent patients with thalassemia; the 3-year projected overall and event-free survival is over 96.0%, and there have been no secondary graft failures. Of the first 31 patients, we had two graft failures, both of them occurring in patients with extremely high titers of anti-donor-specific human leukocyte antigen (HLA) antibodies [anti-donor specific antibodies (DSAs)], but after adjusting the PTIS to include bortezomib (BORT) and rituximab (RIX) for patients with high titers of anti-DSAs and using pharmacologic dose guidance for BU, we had no graft failures in the last 52 patients. Six (7.0%) of 83 patients developed severe GvHD. We conclude that this is a safe and efficacious approach to allogeneic HSCT in thalassemia.

Successful haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide in a child with X-linked chronic granulomatous disease: A first report in Asia.

BACKGROUND: HLA-matched hematopoietic stem cell transplantation (HSCT) is the curative treatment for chronic granulomatous disease (CGD). OBJECTIVE: To report a case of X-linked CGD with active infection successfully treated by haploidentical HSCT with post-transplant high dose cyclophosphamide (PTCY). METHODS: A 5-year-old Thai boy with CGD was undergone for haploidentical HSCT using PTCY with correction of the phagocytic function. He presented with Chromobacterium violaceum liver abscess at the age of 9 months and experienced recurrent perianal abscess and invasive pulmonary aspergillosis even receiving antimicrobial prophylaxis. PTCY was given on day 3 and 4, after CD34+ cells infusion. RESULTS: The peripheral blood-nucleated cell chimerism showed 100% on day 16 and remained 100%. Dihydrorhodamine (DHR) assay on day 108 and day 214 showed normal results. Currently at 22 months post HSCT, he does not receive antibiotic and anti-fungal prophylaxis. CONCLUSIONS: Haploidentical HSCT with PTCY could be an effective treatment option for children with CGD.

Hematopoietic Stem Cell Transplantation for Severe Thalassemia Patients from Haploidentical Donors Using a Novel Conditioning Regimen.

Patients with severe thalassemia commonly have a survival that is significantly shorter than that of the general population. Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only established treatment that is potentially curative, but it is limited by the availability of donors and the medical condition of the patient. To expand the donor pool to include haploidentical related donors, we introduced a program consisting of a pharmacologic pretransplant immune suppression phase (PTIS) and 2 courses of dexamethasone and fludarabine, followed by pretransplant conditioning with fludarabine-i.v. busulfan and post-transplant graft-versus-host disease (GVHD) prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil. We transplanted 83 consecutive transfusion-dependent patients with thalassemia (median age, 12 years; range, 1 to 28 years) with a minimum follow-up of 6 months (median, 15 months; range, 7 to 53 months); the 3-year projected overall and event-free survival is over 96%, and there have been no secondary graft failures. Of the first 31 patients, we had 2 graft failures, both of them occurring in patients with extremely high titers of anti-donor-specific HLA antibodies (anti-DSAs), but after adjusting the PTIS to include bortezomib and rituximab for patients with high titers of anti-DSAs and using pharmacologic dose guidance for busulfan, we had no graft failures in the last 52 patients. Six (7%) of 83 patients developed severe GVHD. We conclude that this is a safe and efficacious approach to allogeneic SCT in thalassemia, yielding results comparable to those available for patients with fully matched donors.

No differences in hemostatic and endothelial activations between haploidentical and matched-donor hematopoietic stem cell transplantation in thalassemia disease.

Hemostatic changes and endothelial activations have been recognized in ß-thalassemic patients after matched-donor hematopoietic stem cell transplantation (HSCT) but there are limited studies for haploidentical HSCT. This report demonstrates that the levels of hemostatic and endothelial markers, including thrombin antithrombin complex, prothrombin fragment, D-dimer, von Willebrand factor antigen and thrombomodulin levels, were not significantly different between haploidentical and matched-donor HSCT patients.

Various initial presentations of Epstein-Barr virus infection-associated post-transplant lymphoproliferative disorder in pediatric liver transplantation recipients: Case series and literature review.

PTLD is a rare but potentially life-threatening condition, which shows a higher prevalence in children than in adults. From 129 children who underwent LT, we reported 5 cases with biopsy-proven PTLD at a single teaching hospital. Four patients had shared clinical presentations including fever, lymphadenopathy, and splenomegaly. They were noted to be given a prolonged course of IS due to the management of comorbid complications such as acute cellular rejection or severe food allergy or eosinophilic gastrointestinal disease. The other one patient presented with upper gastrointestinal bleeding from gastric mass during an early post-transplantation period. Notably, hypoalbuminemia was noted in all reported patients. Similar to previous studies, both EBV serology mismatch between the donor and recipient with high EBV viral load were noted in all except one case, whose EBV serology was unknown before LT. At least one episode of CMV reactivation was also observed in 3 of 5 patients prior to the PTLD diagnosis. The histopathology revealed 1 of 5 early PTLD, 1 of 5 polymorphic PTLD, and 3 of 5 monomorphic PTLD. The treatment included IS withdrawal, chemotherapy, and/or rituximab. One patient died of multiorgan dysfunction, one remains in complete remission, and three patients are either still on treatment or await response evaluation. Even though most of our reported PTLD cases had shared manifestations with fever, lymphadenopathy, splenomegaly, EBV serology mismatch, and high EBV viral load, various initial presentations such as respiratory symptoms, hypoalbuminemia, and prolonged use of IS from other causes such as significant food allergy were noted.

Pediatric non-Hodgkin lymphoma: Characteristics, stratification, and treatment at a single institute in Thailand.

BACKGROUND: In the modern era of chemotherapy, the outcome of pediatric non-Hodgkin lymphoma (NHL) continues to improve internationally. Limited data such as information on epidemiology and survival, however, are available in Asian countries. METHODS: Children (≤15 years old) diagnosed with histologically proven NHL from 1998 to 2014 were retrospectively analyzed. RESULTS: In total, 114 patients were enrolled; they were predominantly male (65.8%) and had advanced disease (stage III, IV; 71.9%). Of these, 22.8% had Burkitt lymphoma, 20.2% had diffuse large B-cell lymphoma, 21.1% had lymphoblastic lymphoma, 20.2% had large cell lymphoma, and 15.8% had peripheral T-cell lymphoma. Twenty-nine patients died, especially of uncontrolled disease (62.1%) and infection (20.7%). During a median follow up of 78.4 months, Kaplan-Meier 5 year event-free and overall survival rates were 71.5% ± 4.3% and 74.8% ± 4.1%, respectively, regardless of subtype. B symptoms (i.e. systemic symptoms of fever, night sweats, and weight loss that can be associated with both Hodgkin's lymphoma and non-Hodgkin's lymphoma) and advanced disease had a significant negative impact on 5 year survival. No other prognostic factor was found, but survival tended to have a negative correlation with age. CONCLUSIONS: Pediatric NHL is aggressive, with a high prevalence of peripheral T-cell lymphoma. The present treatment stratification seems to be effective compared with that used in developed countries.

Correction to: Exploring burnout and the association with the educational climate in pediatric residents in Thailand.

Following publication of the original article.

Exploring burnout and the association with the educational climate in pediatric residents in Thailand.

BACKGROUND: This study, undertaken in Bangkok, Thailand, explored the extent to which paediatric residents in a non-Western setting experienced burnout and the potential association with factors in the medical educational climate and work-related quality of life. METHODS: An exploratory sequential mixed methods design was employed in a cross-sectional study. The initial, quantitative phase used the validated Maslach Burnout Inventory, the Postgraduate Hospital Educational Environmental Measure (PHEEM) and Work-Related Quality of Life scale (WRQoL). Regression analysis was used to identify the correlation between burnout and educational climate. Thereafter, residents in all years with high levels of burnout on subscales were interviewed individually. RESULTS: Forty-one paediatric residents completed the three questionnaires. None had high levels related to burnout in all three domains (emotional exhaustion, high level of depersonalization and perceived low personal accomplishment), seven (17%) showed high levels in two out of three domains. Emotional exhaustion and educational climate (perceptions of role autonomy, perceptions of teaching, perceptions of social support) were correlated with work-related quality of life. In the interviews, the main themes related to burnout were inappropriate tasks, teachers and teaching styles, the perception of knowledge insecurity relating to task performance, time dimensions, life crisis during training, role expectations and work allocation clarity, and facilities such as accommodation. CONCLUSIONS: The study, in a non-Western setting, demonstrated a positive relation between educational climate and work-related quality of life. To help reduce the risk of burnout, the following factors were identified: minimize unnecessary or duplicated workload, schedule time arrangements to avoid extension of regular duty hours, and clearly define role expectations. The impact of inappropriate tasks, teachers and teaching styles (including unsafe environment) on the incidence of burnout was also highlighted. Additional studies focusing on teaching styles, safe learning climate and mistreatment in a non-Western context are needed.

Viral-specific T-cell response in hemorrhagic cystitis after haploidentical donor stem cell transplantation.

Viral hemorrhagic cystitis (HC) after hematopoietic stem cell transplantation (HSCT) can be devastating. Standard treatment modalities have not been well established, but immune reconstitution may be necessary for sustained viral clearance. We studied five pediatric patients who developed viral HC after haplo-identical HSCT. All patients developed virus-specific CD4- and CD8-positive T cells, and the emergence of these viral-specific T cells was temporally associated with successful viral clearance.

Curative Stem Cell Transplantation for Severe Hb H Disease Manifesting From Early Infancy: Phenotypic and Genotypic Analyses.

Most people with Hb H disease live normal lives; however, a minority of cases requires lifelong regular transfusions. An atypical form of nondeletional Hb H disease was reported in a Thai boy, characterized by severe persistent hemolytic anemia since the age of 2 months. Molecular diagnosis revealed the apparent compound heterozygosity for the Southeast Asian (- -(SEA)) and α2 polyadenylation (polyA) signal (AATAAA>AATA- -) deletions. The proband was successfully treated with allogeneic hematopoietic stem cell transplantation (HSCT). Accurate phenotypic and genotypic diagnosis in atypically severe Hb H disease is helpful for the understanding of its pathophysiology, the institution of appropriate management, and provision of genetic counseling and prenatal diagnosis. Hematopoietic stem cell transplantation is a potentially curative treatment option for this severe α-thalassemia (α-thal) syndrome.

The use of hematocrit level for predicting the efficiency of peripheral blood CD34(+) cell collection after G-CSF Mobilization in Healthy Donors.

Recently, peripheral blood stem cell (PBSC) has been widely used and replaced bone marrow (BM) as the stem cell source in allogeneic hematopoietic stem cell transplantation (HSCT) because of a more rapid engraftment, easier accessibility, and lower risk of donor complications. We, therefore, report the predicting factors for the high PBSC harvest yields in 50 healthy donors. Among the 50 donors, median collected CD34(+) cell number was 4.6 × 10(6/) kg (1.5-16.3 × 10(6) /kg). Number of circulating CD34+ cells and hematocrit (HCT) level increased parallelly whereas peripheral CD34+ cell numbers were decreased with increasing donor age. In univariate analysis, HCT level≥ 35.5% at the time of PBSC collection was significantly associated with high PBSC number (≥ 5.0 × 10(6) cells/kg) and donor aged <30 years was significantly associated with collected CD34+ cells ≥ 6.0 × 10(6) /kg, P = 0.03. HCT level ≥35.5% was an independent parameter for high WBC count (≥50 × 10(9) /L), P < 0.05. None of donor who had both HCT < 35.5% and WBC < 50 × 10(9) /L had circulating CD34+ cells ≥ 5.0 × 10(6) /kg. Platelet count ≥ 200 × 10(9) /L was found significantly in donors with WBC ≥ 40 × 10(9) /L (P = 0.03) and HCT ≥ 35.5%, P < 0.05. Collected PBSC number tended to be higher in our donors with high levels of HCT, WBC, and platelet. We also found that HCT and platelet levels in our donors decreased after receiving G-CSF administration compared with the initial complete blood counts (CBC) results. We, therefore, concluded that HCT level at the time of initiation leukapheresis was an important predictor for PBSC collection yields.

Outcomes of thalassemia patients undergoing hematopoietic stem cell transplantation by using a standard myeloablative versus a novel reduced-toxicity conditioning regimen according to a new risk stratification.

Improving outcomes among class 3 thalassemia patients receiving allogeneic hematopoietic stem cell transplantations (HSCT) remains a challenge. Before HSCT, patients who were ≥ 7 years old and had a liver size ≥ 5 cm constitute what the Center for International Blood and Marrow Transplant Research defined as a very high-risk subset of a conventional high-risk class 3 group (here referred to as class 3 HR). We performed HSCT in 98 patients with related and unrelated donor stem cells. Seventy-six of the patients with age < 10 years received the more conventional myeloablative conditioning (MAC) regimen (cyclophosphamide, busulfan, ± fludarabine); the remaining 22 patients with age ≥ 10 years and hepatomegaly (class 3 HR), and in several instances additional comorbidity problems, underwent HSCT with a novel reduced-toxicity conditioning (RTC) regimen (fludarabine and busulfan). We then compared the outcomes between these 2 groups (MAC versus RTC). Event-free survival (86% versus 90%) and overall survival (95% versus 90%) were not significantly different between the respective groups; however, there was a higher incidence of serious treatment-related complications in the MAC group, and although we experienced 6 graft failures in the MAC group (8%), there were none in the RTC group. Based on these results, we suggest that (1) class 3 HR thalassemia patients can safely receive HSCT with our novel RTC regimen and achieve the same excellent outcome as low/standard-risk thalassemia patients who received the standard MAC regimen, and further, (2) that this novel RTC approach should be tested in the low/standard-risk patient population.