Pediatric Allogeneic Hematopoietic Stem Cell Research Articles

A systematic review of acute kidney injury in pediatric allogeneic hematopoietic stem cell recipients.

The process of allogeneic HSCT in children is associated with frequent AKI and mortality, but the epidemiology is not widely reported. The aim of this review was to summarize the available evidence on incidence, risk factors, timing, and prognosis of AKI in children following HSCT. We systematically reviewed all observational studies reporting incidence and outcomes of AKI in pediatric allogenic HSCT recipients. The minimum criteria for AKI were defined as an increase in sCr ≥ x1.5 or urine output ≤0.5 mL/kg/min over six h. Medline and Embase were searched until March 2014. From 993 electronic records, five were eligible for inclusion (n = 571 patients). The average incidence of AKI within the first 100 days following HSCT was 21.7% (range 11-42%), and the average time of onset was 4-6 wk post-transplant. Risk factors for AKI included cyclosporine toxicity, amphotericin B and foscarnet, SOS, and having a mismatched donor. There were conflicting reports on whether AKI was associated with the development of CKD. AKI is a common and potentially life-threatening complication following HSCT in children. Further quality observational studies are needed to accurately determine the epidemiology and prognosis of AKI in this population.

Risk factors for hemorrhagic cystitis in pediatric allogeneic hematopoietic stem cell transplant recipients.

Hemorrhagic cystitis (HC) results in significant morbidity among hematopoietic stem cell transplant (HSCT) recipients. Several potential causes for HC have been postulated, including viral infection, but definitive evidence is lacking, particularly in pediatric HSCT patients. Ninety pediatric HSCT recipients were prospectively tested on a weekly basis for adenovirus (ADV) and BK virus (BKV) by quantitative real-time polymerase chain reaction in blood and urine samples. Results were correlated with the occurrence of grade II-IV HC. The odds ratio (OR) of HC (95% confidence interval) for BKV ≥1×10(9) copies/mL of urine was 7.39 (1.52, 35.99), with a P-value of 0.013. Those with acute graft-versus-host disease (aGVHD) also had higher odds of developing HC, with an OR of 5.34. Given a 20% prevalence rate of HC, positive and negative predictive values of 29% and 95% were seen with a cutoff of 10(9) copies/mL. BK viremia did not reach significance as a risk factor for development of HC (P=0.06). Only 8 patients showed ADV viruria and 7 showed ADV viremia; all had low viral loads and 4 had no evidence of HC. HC in pediatric HSCT is correlated most strongly to elevated urinary viral load of BKV and to aGVHD, but less strongly to BK viremia.

Use of the Japanese Live Attenuated High-Titer Varicella Vaccine in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Recipients

Background: Hematopoietic stem cell transplantation (HSCT) recipients carry a high risk of primary varicella and varicella-zoster virus (VZV) reactivation. VZV infections can be fatal, and VZV reactivation can be complicated by postherpetic neuralgia, which worsens the recipients’ post-HSCT quality of life. VZV vaccines may prevent such infections; however, international vaccination guidelines do not recommend VZV vaccination of HSCT recipients because few data regarding safety among HSCT recipients are available. In Japan, we use a high-titer Oka stain vaccine for varicella vaccination and zoster prevention in the elderly; the plaque forming unit (PFU) value of this vaccine is as high as the zoster vaccine used in the U.S. Data regarding the safety of zoster vaccine in HSCT recipients is limited; therefore, we report our experience with this high-titer zoster-equivalent varicella vaccine in pediatric allogeneic HSCT recipients.Patients and Methods: Forty-seven pediatric allogeneic HSCT recipients who underwent transplantation at the Saitama Children’s Medical Center from 2000-2011 were vaccinated with live vaccines and their antibody titers were evaluated after vaccination. Among the 47 recipients, the Japanese high-titer varicella vaccine was administered to 32 recipients. Since establishing the live vaccine initiation criteria in 2009, allogeneic HSCT recipients were considered as recipients for live vaccines, including the varicella vaccine, if 24 months had passed after HSCT without active chronic GVHD or required immunosuppression. In addition, recipients were required to have a lymphocyte count >1500/μl or CD4 cell count >700/μl if they were <6 years and a lymphocyte count >1000/μl or CD4 cell count >500/μl if they were >6 years, normal phytohemagglutinin response, and serum IgG level >500 mg/dL. Before 2009, time for vaccination depended on each doctor’s judgment. Patients were given a single dose of the Biken varicella vaccine containing a minimum of 23,000 PFUs. We use EIA to measure the antibody titer and defined seropositivity as a titer >6.0. The time to evaluate the antibody titer was not fixed. We retrospectively collected the clinical data of recipients and laboratory data by reviewing the medical records.Results: The 32 recipients, who received the Japanese varicella vaccine, underwent HSCT at a median age of 5.15 years (range: 0.5-16.4 years) and were vaccinated at a median of 20.65 months (range: 4.8-112.1 months) after HSCT. Twenty and 11 patients had received myeloablative and nonmyeloablative conditioning, respectively. Nine patients received related-donor transplant, of which eight were bone marrow and one was peripheral blood. Twenty-three patients received unrelated-donor transplant, of which 14 were bone marrow and nine were cord blood. Antithymocyte globulin was administered to four patients. Eighteen of the 32 patients (56.3%) were seropositive after vaccination. Of the 26 patients, whose vaccination histories and pre-transplantation histories were available, eight were affected by natural disease, six had been immunized, and 12 had not been immunized. At vaccination, the median lymphocyte count was 3201/μl (range: 817-6630/μl) and the median IgG value was 880 mg/dL (range: 233-1461 mg/dL). There was no significant risk factor associated with vaccine failure. We experienced one case of varicella because of wild type VZV and no cases of zoster after vaccination during a median follow-up period of 4.8 years (range: 0.4-11.3 years); the single patient developed varicella 13 days after vaccination, immediately after an influenza virus infection. Whereas, two cases of varicella and one case of zoster developed before vaccination. Of the other 15 recipients, who did not receive varicella vaccine, three varicella and two zoster developed in three recipients.Conclusion: We safely vaccinated pediatric allogeneic HSCT recipients with the Japanese high-titer varicella vaccine. This finding could encourage the use in the U.S. of zoster vaccines such as Zostavax@, which contains similarly high PFUs, and low-titer varicella vaccines such as Varivax@. However, the efficacy of high-titer varicella vaccines for preventing VZV reactivation in this population remains unclear. Further studies are warranted to elucidate the efficacy and difference between low-titer and high-titer varicella and zoster vaccines. DisclosuresNo relevant conflicts of interest to declare.

Abstract B29: Increased vertebral marrow adiposity in long-term survivors of pediatric allogeneic hematopoietic stem cell transplant is associated with deficits in trabecular microarchitecture

Abstract Background: As treatment-related mortality following allogeneic hematopoietic stem-cell transplantation (alloHSCT) declines, a major unmet need is the identification and prevention of late effects. Long-term survivors of hematologic malignancies requiring alloHSCT show impaired bone density and structure with excess whole body adiposity (Mostoufi-Moab, JBMR, 2012). Marrow adipocytes share common mesenchymal stem cells (MSC) with bone-forming osteoblasts, with an inverse relation between MSC differentiation into osteoblasts or adipocytes. The impact of alloHSCT and total body irradiation (TBI) on marrow adipose tissue (MAT) and trabecular bone microarchitecture (TBA) has not been addressed. Methods: Magnetic resonance spectroscopic imaging (MRSI) and high-resolution structural imaging were used to quantify vertebral MAT and distal tibia TBA on a 1.5 Tesla magnet. Twenty-five alloHSCT recipients with underlying diagnosis of acute leukemia, ages 12-24 years, were enrolled, a median of 11 years (range 5-19) after alloHSCT and TBI, and compared with age-, sex- and race-matched healthy controls. Results: AlloHSCT survivors had lower height Z-scores (-1.39 ± 0.98 vs. -0.04 ± 0.98; p &amp;lt; 0.001), compared with controls, while BMI Z-scores did not differ. Overall, greater MAT was associated with lower bone volume fraction (BVF), R = -0.57, p &amp;lt; 0.001. AlloHSCT was associated with higher mean (± SD) vertebral fat fraction (59.0 ± 11.3 vs. 29.3 ± 9.9; p &amp;lt; 0.001) and trabecular deficits including lower bone volume fraction (β -0.01; 95% CI -0.12, -0.00; p=0.02) and evidence of abnormal microarchitecture [greater erosion (p=0.01) with a more rod like structure (p=0.02)], vs. controls. TBA deficits were more pronounced in female alloHSCT recipients. Growth hormone deficiency was not associated with MAT or bone deficits. Conclusion: Survivors of childhood alloHSCT after TBI demonstrate marked increases in vertebral MAT combined with abnormal trabecular bone microarchitecture. Future studies are needed to determine the metabolic effects and fracture implications of excess MAT, and to identify therapies for improved bone accrual following childhood alloHSCT. Citation Format: Sogol Mostoufi-Moab, Wenli Sun, Jeremy Magland, Elizabeth Isaacoff, Nancy J. Bunin, Jill P. Ginsberg, Felix Wehrli, Justine Shults, Mary B. Leonard. Increased vertebral marrow adiposity in long-term survivors of pediatric allogeneic hematopoietic stem cell transplant is associated with deficits in trabecular microarchitecture. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B29.

Ganciclovir inhibits human adenovirus replication and pathogenicity in permissive immunosuppressed Syrian hamsters.

Adenovirus infections of immunocompromised patients can develop into deadly multiorgan or systemic disease. The virus is especially threatening for pediatric allogeneic hematopoietic stem cell transplant recipients; according to some studies, 10% or more of these patients succumb to disease resulting from adenovirus infection. At present, there is no drug approved for the treatment or prevention of adenovirus infections. Compounds that are approved to treat other virus infections are used off-label to combat adenovirus, but only anecdotal evidence of the efficacy of these drugs exists. Ganciclovir, a drug approved for the treatment of herpesvirus infection, was previously reported to be effective against human adenoviruses in vitro. To model adenovirus infections in immunocompromised humans, we examined ganciclovir's efficacy in immunosuppressed Syrian hamsters intravenously infected with type 5 human adenovirus (Ad5). This animal model is permissive for Ad5 replication, and the animals develop symptoms similar to those seen in humans. We demonstrate that ganciclovir suppresses Ad5 replication in the liver of infected hamsters and that it mitigates the consequences of Ad5 infections in these animals when administered prophylactically or therapeutically. We show that ganciclovir inhibits Ad5 DNA synthesis and late gene expression. The mechanism of action for the drug is not clear; preliminary data suggest that it exerts its antiadenoviral effect by directly inhibiting the adenoviral DNA polymerase. While more extensive studies are required, we believe that ganciclovir is a promising drug candidate to treat adenovirus infections. Brincidofovir, a drug with proven activity against Ad5, was used as a positive control in the prophylactic experiment.

Immunologic Resolution of Human Chronic Graft-versus-Host Disease

To determine the role of regulatory T lymphocytes (Tregs) in the pathogenesis of human chronic graft-versus-host disease (GVHD) and its clinical resolution, we evaluated long-term recipients of pediatric allogeneic hematopoietic stem cell transplantation (HSCT). Seventy-one recipients were evaluated, 30 of whom had a history of chronic GVHD, including 16 with active chronic GVHD and 14 with resolved chronic GVHD. There were no significant clinical differences and no differences in the frequency of Tregs (CD4+, CD127−, CD25+) between the recipients with active chronic GVHD and those with resolved chronic GVHD. Using the Miyara/Sakaguchi classification scheme to identify functional Tregs, a decreased frequency of functional resting Tregs (rTregs) was identified in recipients with active chronic GVHD (P = .009 compared with normal donors; P = .001 compared with HSCT recipients without history of chronic GVHD; P = .005 compared with recipients with resolved chronic GVHD). The frequency and number of recent thymic emigrants in rTregs were normal in recipients with resolved chronic GVHD, but persistently decreased in recipients with active chronic GVHD. These results support the hypothesis that the reestablishment of normal numbers of functional rTregs is required for the clinical resolution of chronic GVHD.

Paolo Perseghin, biography.

Paolo Perseghin received his medical degree from the University of Pavia Medical School, where he completed his clinical training in Clinical and Laboratory Haematology in 1985 and in Infectious Diseases in 1991. During the same period, he received training in both donor and therapeutic apheresis at The Blood Transfusion Center at IRCCS San Matteo in Pavia. He is a member of several scientific societies in the field of transfusion medicine, apheresis and cell therapies and serves as a reviewer for several high-ranked journals. He has received grants from Italian Health Authorities to support his research in donor and therapeutic apheresis and in the field of cellular therapies and regenerative medicine. He has teaching appointments in post-graduate specialization schools at the University of Milano-Bicocca School of Medicine, and since 2009, at the II° level master in “Stem cell transplantation and cellular therapies” at the University of Florence School of Medicine. Since 2009 he has also been a member of the ad-hoc committee (CNS/CNT) for the upgrading of the National Law in Transfusion Medicine. From 2007 to 2013 he served as the general secretary of the Italian Society of Apheresis and Cell Manipulation (SIDEM). Since 1997 he has been the head of the Therapeutic Apheresis Unit and Cryobiology Lab at San Gerardo Hospital in Monza, Italy, a JACIE accredited facility for both adult and pediatric autologous and allogeneic hematopoietic stem cell transplantation, and a staff member within the GMP cell factory “S. Verri” at the same institution. His main scientific interests in recent years have been to ascertain the effectiveness (and biologic effects) of extracorporeal photochemotherapy in patients with acute and chronic GvHD, the use of platelet lysate in regenerativemedicine, and the introduction of new devices in both donor and therapeutic apheresis. He has authored or co-authored more than 80 papers published in peer-reviewed journals and he has served as a speaker or chairman in national and international congresses and symposia.

Frequent Occurrence of Cytomegalovirus Retinitis During Immune Reconstitution Warrants Regular Ophthalmic Screening in High-Risk Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients

Although cytomegalovirus (CMV) retinitis (CMVR) is a well-recognized complication after allogeneic hematopoietic stem cell transplantation (HSCT), standard operating procedures for ophthalmic monitoring are variable. In particular, authors perceived a greater risk of CMVR after pediatric HSCT for inherited immunodeficiencies, in patients who often have pretransplantation viremia. This study was therefore performed to identify high-risk pediatric HSCT recipients who would benefit from regular ophthalmic monitoring. During a 5-year study period, we retrospectively analyzed findings in 56 of 304 consecutive HSCT recipients (age range, 0.5-197 months) in whom significant CMV viremia developed (CMV level at PCR, ≥4000 copies/mL). All HSCT recipients with significant CMV viremia underwent retinal examination weekly (inpatients) or every other week (outpatients), with examinations performed by a skilled ophthalmologist. CMVR developed in 13 (4%) of 304 HSCT recipients, 23% (13 of 56) of those with significant CMV viremia. Pretransplant viremia (odds ratio, 11.3; P < .01), acute (grade ≥2) graft-vs-host disease (odds ratio, 8.2; P < .02) and mismatched graft (odds ratio, 8; P < .02) were identified as independent risk factors. Compared with other invasive CMV diseases, CMVR was more often a late-onset disease, occurring at a median of 199 days after HSCT. At diagnosis, a significantly higher CD4 T-cell count (≥200/µL; P < .03) and a lower CMV load (P < .004) was observed in children with CMVR, compared with those in whom lung, gut, or liver CMV disease developed. We report an increased risk of CMVR in high-risk pediatric HSCT recipients. This form of CMV disease differs from other invasive CMV disease in its relationship to immune reconstitution and viral dynamics. We have studied the relationship between these variables and suggested a risk-stratified ophthalmic screening strategy.

Assessment of Aspergillus‐specific PCR as a screening method for invasive aspergillosis in paediatric cancer patients and allogeneic haematopoietic stem cell recipients with suspected infections

Invasive aspergillosis (IA) remains difficult to diagnose in immunocompromised patients, because diagnostic EORTC/MSG criteria are often not met. As biomarkers might elucidate the pathogen, we analysed the performance of an Aspergillus PCR assay in blood for diagnosis of IA in immunocompromised paediatric patients with suspected infections. Ninety-five haemato-oncological paediatric patients were included over a period of 3 years, the underlying diseases consisting of acute leukaemia, solid tumours, non-malignant immunocompromising disorders and haematopoietic stem cell transplantation recipients. We retrospectively analysed 253 consecutive episodes of suspected infections. Thirty-eight patients had possible IA, none of the patients fulfilled EORTC/MSG criteria of probable/proven IA. PCR positivity was observed in 97/967 analyses. Sensitivity, specificity, positive and negative predictive value of the PCR per episode were 34%, 78%, 31% and 81% using possible IA as endpoint. Taken together, an undirected blood screening by Aspergillus-specific PCR is of little diagnostic value in a heterogenous paediatric patient cohort. Harnessing PCR for diagnosis of IA should thus be focused on blood analyses of more homogenous high-risk patients and/or analyses of bronchoalveolar lavage, tissue or cerebrospinal fluid specimens.

Late-Onset Noninfectious Pulmonary Complications After Pediatric Allogeneic Hematopoietic Stem Cell Transplantation

SESSION TITLE: Transplantation

Outcome of Pediatric Allogeniec Hematopoietic Stem Cell Transplantation for Nonmalignant Disease: A Single Center Experience

AbstractAbstract 4558 Background:The aim of this study was to determine the outcome of pediatric allogeneic hematopoietic stem cell transplantation (Allo-HSCT) for nonmalignant disease in our center. Method:Data were retrospectively collected for all patients (aged 0–18 years) who received allogeneic HSCT between May, 2005 and December, 2011. Outcomes according to the type of transplant, diagnosis, and transplant-related complications are reported. Result:Allo-HSCT was performed in 17 patients, (11 male; 6 female). Bone marrow Failure (7;41%) was the commonest nonmalignant disease followed by B-thalassemia major (4;24%) and others (6;35%). Only HLA-matched family donors were used. Most patients were conditioned with Busulfan/Cyclophosphamide/ATG. GVHD prophylaxis comprised mainly of cyclosporine and methotrexate. The median time to neutrophil engraftment was 20 (9–27) days. Two patients experienced graft failure. Four patients had Grade (I–III) aGVHD and no patient had grade (IV). Four patients (23%) had chronic GVHD. No patient had sinusoidal obstruction syndrome (SOS). Five patients had reactivation of CMV infection, which was treated and resolved in all of them. Only one patient died of sepsis. Overall survival (OS) and event free survival (EFS) were 94%, and 88% respectively. Conclusion:In this cohort of patients, bone marrow failure was the main reason for transplantation. The early results of HSCT were promising and consistent with published international data. Similarly, graft failure remains a concern. Disclosures:No relevant conflicts of interest to declare.

Acute graft‐versus‐host disease in pediatric allogeneic hematopoietic stem cell transplantation. Single‐center experience during 10 yr

a-GvHD may complicate allogeneic HSCT. In this retrospective single-center study, we evaluated incidence and risk factors of a-GvHD in 197 consecutive allogeneic pediatric HSCTs applying Glucksberg and NIH a-GvHD classifications. Among 179 eligible transplants, the cumulative incidence of grade 0-I a-GvHD was 48% and grade II-IV was 52%. None of the considered variables significantly influenced the incidence of grade II-IV a-GvHD. Malignancy and myeloablation were associated with an increased risk of classic a-GvHD (p < 0.01). Seventy-two percentage of children are alive, with a significant difference in OS and TRM between grade 0 and I vs. grade II and IV a-GvHD; this observation was reproduced in the non-malignant setting, while only a disparity in TRM was evidenced in children with malignancy. In our experience, the incidence of a-GvHD was similar, regardless of donor type. Myeloablation and malignant disease represented the only risk factors for classic a-GvHD. Our results highlight the need for a better prevention of this complication in the non-malignant setting.

Lung Function Before and After Pediatric Allogeneic Hematopoietic Stem Cell Transplantation

Pre-allogeneic hematopoietic stem cell transplantation (aHSCT) and post-aHSCT lung function of 41 eligible patients at Riley Hospital for Children were assessed to identify risk factors for post-aHSCT morbidity and mortality. One year post-aHSCT pulmonary function tests were significantly lower compared with baseline. These findings recovered at 2 years post-aHSCT. Refractory disease before aHSCT correlated with lower pulmonary function tests after aHSCT. Graft-versus-host disease was significantly associated with higher post-aHSCT residual volume. Importantly, low pre-aHSCT carbon monoxide diffusing capacity adjusted for hemoglobin and alveolar volume was predictive of death. Among survivors, lung function improves over time after pediatric aHSCT. Measurement of carbon monoxide diffusing capacity adjusted for hemoglobin and alveolar volume before pediatric aHSCT should be further investigated as a predictor of pulmonary dysfunction and mortality.

Oxidative Protein Damage with Carbonyl Levels and Nitrotyrosine Expression after Chemotherapy in Bone Marrow Transplantation Patients

Protein oxidation is defined as the covalent modification of a protein, induced either directly by reactive oxygen species/reactive nitrogen species or indirectly by reaction with secondary by-products of oxidative stress. Protein carbonyls are the most commonly measured products of protein oxidation. Additionally, nitrotyrosine is a product of tyrosine nitration mediated by reactive nitrogen species such as peroxynitrite anion and nitrogen dioxide. Samples were collected before the preparative regimen (10 days before transplantation; day –10), on transplantation day (day 0), and after transplantation (days 7, 14, and 28) from 16 pediatric allogeneic hematopoietic stem cell transplantation (HSCT) patients. The erythrocyte 3-nitrotyrosine expression was shown to be significantly increased after chemotherapy. In accordance, the mean plasma carbonyl levels on days 14 and 28 were significantly higher than on the other days. High-dose chemotherapy applied in the preparative regimen of HSCT may be responsible for this long-term oxidation of plasma proteins. These results show that high-dose chemotherapy resulted in protein oxidation both in plasma and in erythrocytes in HSCT patients.

Lethal Pulmonary Complications After Pediatric Allogeneic Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) in children is accompanied by a transplant-related mortality of 10% to 30%, which is the result of lethal pulmonary complications (LPCs) in many cases. We retrospectively assessed prevalence and risk factors of LPC following 234 allogeneic HSCTs in 228 patients for malignant or nonmalignant diseases at a single institution. Pulmonary complications (PCs) were observed following 81 of 234 transplants (35%). LPCs were observed in 4% of HSCT within 100 days and in 14% within 5 years after HSCT. Late PCs after day 100 were lethal in 56% (22/39) of the patients with PCs, who are 11% (22/202) of all evaluable patients still alive after day +100. Causes of LPC after day 100 were viral (10 cases), bacterial (1 case), fungal (5 cases) pulmonary infection, or noninfectious (6 cases) PCs. Abnormal pretransplant pulmonary function test was not associated with an increased risk of LPC. Children older than 10 years and those undergoing a second HSCT had an increased incidence of overall LPC. T-cell depletion and mismatched donor HSCT (P = 0.001), but not age, were associated with an increased risk of lethal viral pneumonia. Transplant-related mortality up to 5 years after HSCT in children was associated with LPC in 14%. There were more late (>100 days) than early LPCs, predominantly due to infectious etiologies and affecting children >10 years of age.

CMX001 in the Peri-Engraftment Period Does Not Impair Neutrophil Recovery in Pediatric Allogeneic Hematopoietic Stem Cell Recipients

CMX001 in the Peri-Engraftment Period Does Not Impair Neutrophil Recovery in Pediatric Allogeneic Hematopoietic Stem Cell Recipients

The effectiveness of tacrolimus and minidose methotrexate in the prevention of acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation in children: a single-center study in Korea

BackgroundKnowledge of the roles of tacrolimus and minidose methotrexate (MTX) in the prevention of acute graft-versus-host disease (aGVHD) in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) is limited. We retrospectively evaluated the engraftment status, incidence of aGVHD and chronic GVHD (cGVHD), and toxicities of tacrolimus and minidose MTX in aGVHD prophylaxis in children undergoing allogeneic HSCT.MethodsSeventeen children, who underwent allogeneic HSCT and received tacrolimus and minidose MTX as GVHD prophylaxis from March 2003 to February 2011, were reviewed retrospectively. All the patients received tacrolimus since the day before transplantation at a dose of 0.03 mg/kg/day and MTX at a dose of 5 mg/m2 on days 1, 3, 6, and 11.ResultsOf the 17 patients, 9 received human leukocyte antigen (HLA)-matched related donor transplants, and 8 received HLA-matched, or partially mismatched unrelated donor transplants. The median time for follow-up was 55 months. The incidence of aGVHD in the related and unrelated donor groups was 22.2% and 42.9%, respectively. cGVHD was not observed. To maintain therapeutic blood levels of tacrolimus, the younger group (<8 years of age) required an increased mean dose compared to the older group (≥8 years) (P=0.0075). The adverse events commonly associated with tacrolimus included hypomagnesemia (88%), nephrotoxicity (23%), and hyperglycemia (23%).ConclusionTacrolimus and minidose MTX were well tolerated and effective in GVHD prophylaxis in pediatric patients undergoing allogeneic HSCT. Children <8 years of age undergoing HSCT required increased doses of tacrolimus to achieve therapeutic levels.

Reconstitution Rate of Absolute CD8+ T Lymphocyte Counts Affects Overall Survival After Pediatric Allogeneic Hematopoietic Stem Cell Transplantation

Immune reconstitution after allogeneic stem cell transplantation protects against opportunistic infections and disease relapse. Identifying the most protective lymphocyte subset would have implications of adoptive immunotherapy. We followed up a case series of 34 allogeneic transplantations for pediatric leukemias, aplastic anemias, or solid tumors. Regardless of baseline hematologic disorder, the speed of reconstitution of cytotoxic CD8 T lymphocytes and the achieving of the 10th percentile of normal CD4 T lymphocytes (but not B lymphocytes or natural killer cells) conditioned overall survival. The source of hematopoietic stem cells (peripheral blood vs bone marrow) and the occurrence of graft-versus-host disease (either acute or chronic) did not impact on immune reconstitution. Larger case series are needed to confirm the pivotal role of cytotoxic CD8 T lymphocytes in overall survival.

Nonpharmacologic Treatment of Chronic Graft-versus-Host Disease in Children and Adolescents

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many children with life-threatening diseases. One of the most significant long-term complications of transplantation is chronic graft-versus-host disease (cGVHD). Although the rates of cGVHD after HSCT are lower in the pediatric population than in adults, cGVHD remains a significant cause of morbidity and mortality. Medicines used to prevent and treat cGVHD remain unsatisfactory, with protracted use of immune suppression necessary and high rates of first-line treatment failure. Efforts to improve salvage treatment are urgently required. Nonpharmacologic strategies attempt to modulate the cellular inflammation response and possibly allow reduction or cessation of immunosuppressive drugs. Mesenchymal stromal cells (MSC) have been shown invitro to mediate a wide variety of immune responses. MSC have been used in the prophylaxis of acute GVHD (aGVHD) and for the treatment of established steroid refractory aGVHD and, more recently, in the management of cGVHD. Extracorporeal photochemotherapy (ECP) has shown promising efficacy in graft-versus-host disease, and may allow a significant reduction in the use of systemic steroids and other immunosuppressants, reducing long-term morbidity and mortality. The accumulated experience shows ECP to be well tolerated, with no clinically significant side effects.

Bone density and structure in long-term survivors of pediatric allogeneic hematopoietic stem cell transplantation

Children requiring allogeneic hematopoietic stem cell transplantation (alloHSCT) have multiple risk factors for impaired bone accrual. The impact of alloHSCT on volumetric bone mineral density (vBMD) and cortical structure has not been addressed. Tibia peripheral quantitative computed tomography (pQCT) scans were obtained in 55 alloHSCT recipients, ages 5 to 26 years, a median of 7 (range, 3-16) years after alloHSCT. pQCT outcomes were converted to sex- and race- specific Z-scores relative to age based on reference data in >700 concurrent healthy participants. Cortical section modulus (Zp; a summary measure of cortical bone structure and strength), and muscle and fat area Z-scores were further adjusted for tibia length for age Z-scores. AlloHSCT survivors had lower height Z-scores (-1.21 ± 1.25 versus 0.23 ± 0.92; p < 0.001), versus reference participants; BMI Z-scores did not differ. AlloHSCT survivors had lower trabecular vBMD (-1.05; 95% confidence interval [CI], -1.33 to -0.78; p < 0.001), cortical Zp (-0.63; 95% CI, -0.91 to -0.35; p < 0.001), and muscle (-1.01; 95% CI, -1.30 to -0.72; p < 0.001) Z-scores and greater fat (0.82; 95% CI, 0.54-1.11; p < 0.001) Z-scores, versus reference participants. Adjustment for muscle deficits eliminated Zp deficits in alloHSCT. Total body irradiation (TBI) was associated with lower trabecular vBMD (-1.30 ± 1.40 versus -0.49 ± 0.88; p = 0.01) and muscle (-1.34 ± 1.42 versus -0.34 ± 0.87; p < 0.01) Z-scores. Growth hormone deficiency (GHD) was associated with lower Zp Z-scores (-1.64 ± 2.47 versus -0.28 ± 1.24; p = 0.05); however, muscle differences were not significant (-1.69 ± 1.84 versus -0.78 ± 1.01; p = 0.09). History of graft versus host disease was not associated with pQCT outcomes. In summary, alloHSCT was associated with significant deficits in trabecular vBMD, cortical geometry, and muscle area years after transplantation. TBI and GHD were significant risk factors for musculoskeletal deficits. Future studies are needed to determine the metabolic and fracture implications of these deficits, and to identify therapies to improve bone accrual following alloHSCT during childhood.