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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. [ABSTRACT FROM AUTHOR]

Human pegivirus-1 (HPgV-1) is a lymphotropic human virus, typically considered nonpathogenic, but its infection can sometimes cause persistent viremia both in immunocompetent and immunosuppressed individuals. In a viral discovery research program in hematopoietic stem cell transplant (HSCT) pediatric patients, HPgV-1 was detected in 3 out of 14 patients (21.4%) using a target enrichment next-generation sequencing method, and the presence of the viruses was confirmed by agent-specific qRT-PCR assays. For the first time in this patient cohort, complete genomes of HPgV-1 were acquired and characterized. Phylogenetic analyses indicated that two patients had HPgV-1 genotype 2 and one had HPgV-1 genotype 3. Intra-host genomic variations were described and discussed. Our results highlight the necessity to screen HSCT patients and blood and stem cell donors to reduce the potential risk of HPgV-1 transmission. [ABSTRACT FROM AUTHOR]

• Allogeneic stem cell transplant (SCT) is curative for patients with severe thalassemia. It can be safely performed with a sequence of a pretransplant immunosuppressive therapy (PTIS) of pulse fludarabine and dexamethasone, followed by a reduced-intensity regimen of fludarabine and i.v. busulfan, as well as peripheral blood progenitor transplant with post-transplant cyclophosphamide-based immunosuppression. • Patients with very high titers of anti-donor-specific antibodies (1:3000) further benefited from the addition of bortezomib and Rituxan to the PTIS phase to alleviate antibody-mediated graft rejection. • With this approach, SCT now be safely carried out using both matched and mismatched (aka haploidentical) donors, with a 3-year event-free and overall survival of 95%, regardless of donor type, and without having any increased risk for mortality in patients who are older than 7 years and having hepatomegaly (i.e., the Lucarelli group III high-risk subset). • This demonstrates that there is no reason to take the risk(s) of total body irradiation to secure engraftment in this group of patients who are at high risk for graft failure. 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. [ABSTRACT FROM AUTHOR]

Immune reconstitution of T cells has been proven to be a protective factor against cytomegalovirus (CMV) reactivation in patients post-hematopoietic stem cell transplant. Recently, more evidence has suggested that natural killer (NK) cells also play role in the protection against CMV reactivation in these patients. CMV-specific T cells and CMV-reactive NK cells from pediatric patients undergoing hematopoietic stem cell transplant were examined by flow cytometry. These cells were defined as cells producing interferon gamma (IFNγ) upon stimulation with CMV antigens. This study demonstrated that NK cells reactive to CMV do exist in pediatric patients after stem cell transplant. These cells vigorously responded to stimulation with CMV peptides (pp65 and IE1) and to a lesser extent to CMV whole lysate by secretion of IFNγ. Patients with CMV reactivation tended to have less CMV-reactive NK cells than those without. Reconstitution of CMV-reactive NK cells, together with CMV-specific T cells, may play a role in the control of CMV infections in patients after stem cell transplant. • NK cells reactive to CMV reconstituted after pediatric HSCT • CMV reactive NK cells responded vigorously to CMV peptides • CMV reactive NK cells tended to be higher in patients without CMV reactivation [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The total body irradiation (TBI)-based myeloablative conditioning regimen for allogeneic stem cell transplantation has been developed to overcome treatment failure and to improve overall survival of pediatric leukemia. The present study retrospectively reports the safety and success of this treatment regimen. Objective: The objective was to report the safety and success of this treatment program based on the evaluation of effectiveness and complications from treatment, overall and disease free survival rate of patients and prognostic factors that might affect survival outcome. Material and Method: Forty-four pediatric leukemic patients received the TBI-based myeloablative conditioning regimen for allogeneic stem cell transplantation at Ramathibodi Hospital between 1997 and 2011. The data were evaluated for clinical outcome. Results: With the median follow-up period at 5.9 years (ranging from 0.3 to 16.7 years), 29 cases (65.9%) were alive, 15 cases (34.1%) died. The Kaplan-Meier estimated that the overall survival rate was 72.5% after three years, 70% after five years, and 63.0% after 10 years. The diseases free survival rates at 3, 5 and 10 years were 85.5%, 82.5%, and 82.5%, respectively. Significantly, lower survival rate was observed in patients with relapsed disease prior to transplantation and in patients with no remission of disease after transplantation. Conclusion: The TBI-based myeloablative conditioning regimen for allogeneic stem cell transplantation can be applied to management of selected pediatric leukemic patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

Busulfan is widely used as a chemotherapy treatment before hematopoietic stem-cell transplantation (HSCT). However, the response of busulfan is highly variable and unpredictable, whereby the pharmacogenetic interference of glutathione S-transferase (GST) has strong evidence in Caucasians and some adult Asians but not in pediatric Asian patients. This study was aimed at investigating the associations of GST genetic polymorphisms with variations in the pharmacokinetic (PK) properties of busulfan in pediatric Asian patients. This retrospective cohort study recruited 92 pediatric patients. The polymorphism of GSTA1 was genotyped by Sanger sequencing, and GSTM1 and GSTP1 were genotyped by real-time PCR. Drug concentration and PK estimation were identified using an LC-MS/MS method and a noncompartmental model. Statistical analysis was performed by R software. Out of 92 patients, 48 (53%) were males, the mean age was 8.4 ± 5.12 years old, and the average weight was 26.52 ± 14.75 kg. The allele frequencies of GSTA1*B and of GSTM1 and GSTP1* deletions were 16.9%, 68.5%, and 21.2%, respectively. Patients with GSTA1*B had a statistically significant impact on the PK of busulfan, whereas those with GSTM1 and GSTP1 did not (p > 0.05). The carriers of GSTA1*B showed a significant difference compared to noncarriers in terms of t1/2 (for first dose: 161.9 vs. 134.3 min, p = 0.0016; for second dose: 156.1 vs. 129.8, p = 0.012), CL (88.74 vs. 124.23 mL/min, p = 0.0089), Cmax (4232.6 vs. 3675.5 ng/mL, p = 0.0021), and AUC (5310.6 vs. 4177.1 µM/min, p = 0.00033). The augmentation of AUC was around 27.1% in patients carrying the GSTA1*B variant. The GSTA1 polymorphism was significantly associated with variations of the pharmacokinetic properties of busulfan treatment in pediatric Asian patients. [ABSTRACT FROM AUTHOR]

We retrospectively analysed the outcomes of 127 children with acquired severe aplastic anaemia ( SAA) who had received haematopoietic stem cell transplantation ( HSCT) between 2000 and 2011 in one of the 10 Asia Pacific institutions. Fifty-three were matched sibling donor ( MSD) and 74 were alternative donor ( AD), including 22 matched unrelated donor, 32 mismatched unrelated donor and 20 mismatched related donor. With a median follow up 45·5 months (13-139) and when compared to the MSD group, AD recipients had more grade II- IV acute graft-versus-host disease (a GVHD; 14·3% vs. 32·8%, P = 0·029), but similar grade III- IV a GVHD (10·2% vs. 12·5%, P = 0·774), graft failure ( GF) (15·1% vs. 15·5%, P = 0·658) and 5-year overall survival (90·6% vs. 83·7%, P = 0·251). As a source of stem cell, peripheral blood stem cells ( PBSC) resulted in less GF (18% vs. 9·1% P = 0·013), similar grade II-IV a GVHD (28·1% vs. 17·4%, P = 0·258), chronic GVHD (25·8% vs. 29·3%, P = 0·822) and similar outcomes (89·7% vs. 82·4%, P =0 ·665) when compared to bone marrow ( BM). In univariate analysis, GF ( P < 0·001) and grade II- IV a GVHD ( P = 0·009) were predictors of poor survival. In multivariate analysis, only GF was associated with poor survival ( P = 0·012). The outcome of AD and PBSC HSCT were comparable to that of MSD and BM HSCT in the Asia Pacific region. [ABSTRACT FROM AUTHOR]

Watcharananan SP, Kiertiburanakul S, Piyatuctsanawong W, Anurathapan U, Sungkanuparph S, Pakakasama S, Chantratita W, Hongeng S. Cytomegalovirus, adenovirus, and polyomavirus co-infection among pediatric recipients of allogeneic stem cell transplantation: Characteristics and outcome. Pediatr Transplantation 2010: 14:675–681. © 2010 John Wiley & Sons A/S. ADV and PMV infection have increasingly been documented as significant complications following allo-HSCT. Despite increasing recognition, characteristics and outcome of CMV, ADV, and PMV viral co-infection remain obscured. In this study, a retrospective quantitative PCR analysis of ADV, PMV (BKV and JCV) was performed from pediatric patients’ stored blood samples previously tested for CMV viremia after allo-HSCT. Clinical and virological characteristics and outcome among patients with and without viral co-infection were analyzed and compared. From 2001 to 2006, 219 blood samples from 69 patients were studied. Viral DNA was present in 119 samples (52.9%).The proportion of viremia was highest for BKV (30.6%), followed by CMV (20.9%), ADV (9.1%), and JCV (0.5%). Viral co-infection occurred in 17 patients (24.6%), with CMV/BKV as the most common type (11.6%), followed by CMV/ADV (4.3%) and ADV/BKV (2.9%). From multivariate analysis, factors associated with viral co-infection were acute GVHD (OR 4.57; 95% CI 1.9–10.96, p = 0.001), level of blood CMV viral load (OR 1.53; 95% CI 1.24–1.89, p < 0.001), and level of blood ADV viral load (OR 1.56; 95% CI 1.05–2.32, p = 0.027). Higher probability of developing viral disease was strongly associated with more types of virus detected in blood (p < 0.001). Significant difference in the causes of death was observed among patients with and without viral co-infection (p = 0.014). Infection (87.5%) was the major cause of death of patients with viral co-infection, whereas relapse of hematologic disease (70%) was the major cause of death of patients with mono-viral infection. Viral co-infection is a common and significant infectious complication in pediatric recipients of allo-HSCT. Blood monitoring of CMV, ADV, and BKV is suggested among pediatric patients who develop GvHD or who have rising of CMV or ADV viremia following allo-HSCT. [ABSTRACT FROM AUTHOR]

Background: Hematopoietic stem cell transplantation (HSCT) is the only curative treatment available to severe thalassemic patients. The treatment, however, is very costly, particularly in the context of low and middle income countries, and no studies have been carried out to explore its economic justifiability. This study aimed to estimate the cost-utility of HSCT compared with blood transfusions combined with iron chelating therapy (BT-ICT) for severe thalassemia in Thailand, and to investigate the affordability of HSCT using a budget impact analysis. Methods: A Markov model was used to estimate the relevant costs and health outcomes over the patients' lifetimes taking a societal perspective as recommended by Thailand's health technology assessment guidelines. All future costs and outcomes were discounted at a rate of 3% per annum. Primary outcomes of interest were lifetime costs, quality adjusted life years (QALYs) gained, and the incremental cost-effectiveness ratio (ICER) in Thai baht (THB) per QALY gained. Results: Compared to BT-ICT, the incremental cost-effectiveness ratio increased with patient age from 80,700 to 183,000 THB per QALY gained for related HSCT and 209,000 to 953,000 THB per QALY gained for unrelated HSCT among patients aged 1 to 15 years (US$1= 34 THB). The governmental budget impact analysis showed that providing 200 related HSCT to patients aged 1 to 10 years, in accordance with the current infrastructure limitations, would initially require approximately 90 million additional THB per year. Conclusions: At a societal willingness to pay of 100,000 THB per QALY gained, related HSCT was likely to be a cost-effective and affordable treatment for young children with severe thalassemia in Thailand. [ABSTRACT FROM AUTHOR]

EBV-PTLDs affect as high as 20% of SCT recipients especially those with T-cell depleted grafts while high mortality rates were also noted. Adoptive allogeneic and autologous CTLs have a therapeutic potential in this setting. However, the process of expansion of these cells is tedious and time consuming in both allogeneic and autologous CTL generation. For the allogeneic SCT, another major obstacle is unavailability of donors especially in an unrelated SCT setting. The aim of the present study was therefore to investigate the efficacy of autologous CIK cells (CD3+ CD56+) against autologous EBV-LCLs from post-SCT pediatric patients. We could demonstrate that CIK cells can be generated within two wk and did show the significant cytotoxicity against autologous EBV-LCLs. CIK cells may provide a potent tool for use in post-transplantation adoptive immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Recently published reports indicate that the outcome of unrelated donor transplantations in patients with leukemia is currently comparable to that of transplantation from identical family donors. We investigated the possibly favorable outcomes of related and unrelated transplantation in children with severe thalassemia. We reviewed transplantation outcome in 49 consecutive children with severe thalassemia who underwent allogeneic stem cell transplantation with related-donor (n = 28) and unrelated-donor (n = 21) stem cells between September 1992 and May 2005 at the Faculty of Medicine, Ramathibodi Hospital, Mahidol University (Bangkok, Thailand). Analysis of engraftment, frequency of procedure-related complications, and thalassemia-free survival showed no advantage from use of related-donor stem cells. The 2-year thalassemia-free survival estimate for recipients of related-donor stem cells was 82% compared with 71% in the unrelated-donor stem cell group (P = .42). The present study provides evidence to support the view that it is quite reasonable to consider unrelated-donor stem cell transplantation an acceptable therapeutic approach in severe thalassemia, at least for patients who are not fully compliant with conventional treatment and do not yet show irreversible severe complications of iron overload. [Copyright &y& Elsevier]

Discusses a study which demonstrated that donor lymphocyte infusion can eliminate mixed chimerism in nonmyeloablative stem cell transplantation for correction of hyper-immunoglobulin M (HIM) syndrome. Recommended treatment for HIM; Study subjects and methods; Indication of the study findings.

Introduction Methods Results Conclusion Immune reconstitution (IR) kinetics of paediatric patients underwent haploidentical haematopoietic stem cell transplantation (HSCT) with post‐transplant cyclophosphamide (PTCy) have not been extensively studied. We compared IR patterns of children receiving HSCT from haploidentical (n = 92) and HLA‐matched donors (n = 36), and analysed risk factors for viral infection in these patients.We prospectively measured lymphocyte subset numbers before HSCT and at 1, 3, 6 and 12 months after HSCT. Blood cytomegalovirus (CMV), Epstein–Barr virus, adenovirus, BK virus (BKV) and urine adenovirus and BKV viral loads were measured at designated time points.The median numbers of total T and T helper cells at 1 month were significantly lower in the haploidentical group compared with the HLA‐matched group. Haploidentical HSCT recipients had significantly lower median numbers of several T cell subsets and B cells for 1 year after HSCT. The median NK cell count of the haploidentical group was lower at 1 month. BKV haemorrhagic cystitis, blood CMV and urine adenovirus reactivation were more frequently found in the haploidentical group. Post‐haploidentical HSCT patients receiving anti‐T lymphocyte globulin (ATG) had significantly lower median numbers of total T cells (at 1 month) and T helper cells (at 6 and 12 months) and higher rate of blood BKV reactivation compared with those without ATG.Paediatric patients who undergo haploidentical HSCT with PTCy are likely to have delayed IR and an increased risk of viral reactivation/infection compared with HLA‐matched HSCT. The addition of ATG to PTCy delayed T cell recovery and increased risk of BKV reactivation. [ABSTRACT FROM AUTHOR]

Abstract: Patients with class 3 thalassemia with high-risk features for adverse events after high-dose chemotherapy with hematopoietic stem cell transplantation (HSCT) are difficult to treat, tending to either suffer serious toxicity or fail to establish stable graft function. We performed HSCT in 18 such patients age ≥7 years and hepatomegaly using a novel approach with pretransplant immunosuppression followed by a myeloablative reduced-toxicity conditioning regimen (fludarabine and i.v. busulfan [Flu-IV Bu]) and then HSCT. The median patient age was 14 years (range, 10 to 18 years). Before the Flu-IV Bu + antithymocyte globulin conditioning regimen, all patients received 1 to 2 cycles of pretransplant immunosuppression with fludarabine and dexamethasone. Thirteen patients received a related donor graft, and 5 received an unrelated donor graft. An initial prompt engraftment of donor cells with full donor chimerism was observed in all 18 patients, but 2 patients developed secondary mixed chimerism that necessitated withdrawal of immunosuppression to achieve full donor chimerism. Two patients (11%) had acute grade III-IV graft-versus-host disease, and 5 patients had limited chronic graft-versus-host disease. The only treatment-related mortality was from infection, and with a median follow-up of 42 months (range, 4 to 75), the 5-year overall survival and thalassemia-free survival were 89%. We conclude that this novel sequential immunoablative pretransplantation conditioning program is safe and effective for patients with high-risk class 3 thalassemia exhibiting additional comorbidities. [Copyright &y& Elsevier]

Abstract: The hypercoagulable state is well recognized in patients with severe β-thalassemia disease. One of the mechanisms of chronic hypercoagulable state is the abnormal expression of phosphatidylserine on red blood cells (RBC). This study aimed to determine the coagulable state in patients with severe β-thalassemia disease following successful stem cell transplantation (SCT). Subjects were classified into three groups: normal controls (NC), β-thalassemia disease receiving regular transfusion (Thal-RT) and β-thalassemia disease post SCT (Thal-SCT). Sixty eight subjects, aged 3–17years, consisting of 21 NC, 28 Thal-RT and 19 Thal-SCT were enrolled. After SCT, the annexin V level in Thal-SCT was normalized. At the median follow-up time of 70.3 (50.9-84.2) months after SCT, the levels of coagulation markers (thrombin antithrombin complex, prothrombin fragment and D-dimer) and anticoagulation proteins (protein C, S and antithrombin activities) returned to the levels similar to controls. [Copyright &y& Elsevier]

Patients diagnosed as ALL, AML or MDS with high-risk features need myeloablative conditioning regimen prior to SCT. Total body irradiation (TBI) contacting regimens have been commonly used, whereas thiotepa can mimic the effect of radiation. We would like to evaluate clinical outcomes and assess complications of haplo-identical SCT with post-transplant cyclophosphamide (PTCY) using TBI-based condition regimen (TBI-regimen) versus thiotepa (thio)-based conditioning regimen (Thio-regimen) in high-risk childhood hematologic malignancies. We retrospectively reviewed medical record of patients with high-risk hematologic malignancies, aged less than 20 years old, between August 2012 and September 2018. HLA studying of all patients and their parents were done by high-resolution technique searching for A, B, C, DR and DQ subunits. Parents with greater HLA matching or those with presence of KIR B haplotype were chosen to be a donor for patients. Patients received TBI-regimen (low-dose TBI, fludarabine, busulfan and melphalan) during August 2012 to April 2017. While patients received Thio-regimen (thio, fludarabine and busulfan) during March 2015 to September 2018 due to an availability of thio in Thailand. Patients were given unmanipulated stem cell products on day 0, then received PTCY, and continued either a calcineurin inhibitor or an mTOR inhibitor with mycophenolate as a graft-versus-host-disease (GvHD) prophylaxis regimen. Survival analysis was calculated by Kaplan-Meier analysis and log-rank test was used to compare variables. Forty-three patients (21 of male) were enrolled; 22, 19 and 2 patients were diagnosed as ALL, AML and MDS, respectively. Twenty-three patients received TBI-regimen, and 26 patients received mother derived stem cell products. Most of the donors had 5/10 or 6/10 HLA-matched. The median CD34+ cell dose was 9.24 (2.06-21.8) cells ×106/kg. One patient died from disseminated adenoviral infection prior to neutrophil engraftment. For 42 evaluable patients, the median time to neutrophil and platelet engraftment was 15 (12-26) days and 22 (12-100) days, respectively. At the median follow-up time of 18.5 (0.6-74.2) months, the overall survival rates of TBI-regimen and Thio-regimen were 63.68 and 61.98%, respectively (p=0.69), while the event-free survival rates of TBI-regimen and Thio-regimen were 68.82 and 66.67%, respectively (p=0.61). Viral infections, CMV, BKV and adenovirus, were the most common infectious complications and were comparable in both groups. Moreover, rates of acute and chronic GVHD in both groups were not significantly different. Relapse was the most common cause of death in both regimens while non-relapse mortality rates of both regimens were approximately 17%. Haplo-identical SCT in high-risk pediatric hematologic malignancies using Thio-regimen had comparable clinical outcomes and complications as those using TBI-regimen. [ABSTRACT FROM AUTHOR]