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Busulfan (Bu) is widely used in conditioning regimens for infants undergoing allogeneic hematopoietic progenitor cell transplantation (HPCT), but the best approach to administer Bu in this population is still unknown. Here, we report a single-center experience of the use of a test dose to guide dose adjustment of intravenous (i.v.) Bu therapy in infants. Between 2004 and 2013, 33 infants younger than 1 year with nonmalignant conditions received allogeneic peripheral blood or cord blood HPCT after a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, antithymocyte globulin, and 2 single daily doses of i.v. Bu. Pharmacokinetic results of a test dose of i.v. Bu (.8 mg/kg) were used to determine the dose of 2 single daily i.v. Bu regimen doses, adjusted to target an area under the curve (AUC) of 4000 μMol*minute per day in a first cohort (n = 12) and 5000 μMol*minute in a second cohort (n = 21). The mean Bu clearance in our infant patients was found to be 3.67 ± 1.03 mL/minute/kg, and the test dose clearance was highly predictive of the regimen dose clearance. The mean AUC achieved after the first single daily regimen dose was 3951 ± 1239 in the AUC 4000 cohort and 4884 ± 766 for the AUC 5000 cohort. No patient in either cohort developed hepatic sinusoidal obstructive syndrome or seizures attributable to Bu. Primary graft failure occurred in 4 patients and secondary graft failure occurred in 3, predominantly in the AUC 4000 cohort (6 of 7). Among the engrafted patients (n = 28), 16 achieved full donor chimerism and 9 patients attained stable mixed chimerism. Overall survival of patients at 6 years after transplantation was 59.5% for the AUC 4000 cohort and 85.4% for the AUC 5000 cohort, with primary graft failure in the first cohort being a major contributor to morbidity. Logistic regression analysis showed that the risk of graft failure increased significantly if cord blood hematopoietic progenitor cells were used or if total Bu exposure was below 4000 μMol*minute per day for 2 days. The difference in clinical outcomes between the 2 cohorts supports the conclusion that targeting a higher Bu AUC of 5000 μMol*minute per day for 2 days improves donor engraftment in infants with nonmalignant conditions undergoing RIC HPCT without increasing toxicity. Measuring i.v. Bu pharmokinetics using a test dose allows timely adjustment of single daily regimen doses and optimization of total Bu exposure, resulting in an effective and safe regimen for these infants. [ABSTRACT FROM AUTHOR]

Abstract: Allogeneic hematopoeitic progenitor cell transplantation (HPCT) is a curative therapy for pediatric patients with both malignant and nonmalignant diseases. Single or multiple benign exostoses or osteochondromas have been reported after total body irradiation (TBI), as well as after focal irradiation. Patients exposed to TBI at a young age are at highest risk of developing exostoses. The objective of this institutional review board–approved study was to look at potential factors, besides radiation, that may play a role in development of exostoses. All patients who underwent allogeneic and autologous HPCT at a single institution between March 1992 and December 2003 and who developed an exostosis identified by clinical findings or as an incidental finding on a radiologic study were included. A case-control design matched patients with controls who had the same stem cell source. [Copyright &y& Elsevier]

Post-hematopoietic stem cell transplantation (hsCT) chimerism monitoring is important to assess relapse and therapeutic intervention. The purpose of our study is to compare two methods variable number tandem repeats (VNTR) vs. quantitative real- time polymerase chain reaction (qpCR) in terms of determining chimerism. 127 (peripheral blood n = 112, bone marrow n = 15) samples were simultaneously tested by VNTR using apO-B, D1s80, D1s111, D17s30, gene loci sRY and Zp3 and qpCR using 34 assays (Ca001-Ca034) that are designed to a bi-allelic insertion/deletion (indel) polymorphism in the human genome. samples were separated in three subsets: total WBC, T-cell and Myeloid cells. extraction of DNa was performed then quantified. We analyzed column statistics, paired t-test and regression analysis for both methods. There was complete correlation between the two methods. The simplicity and rapidity of the test results from the qpCR method is more efficient and accurate to assess chimerism. [ABSTRACT FROM AUTHOR]

Andolina JR, Kletzel M, Tse WT, Jacobsohn DA, Duerst RE, Schneiderman J, Helenowski I, Rademaker A, Chaudhury S. Allogeneic hematopoetic stem cell transplantation in pediatric myelodysplastic syndromes: Improved outcomes for de novo disease. Pediatr Transplantation 2011: 15: 334-343. © 2011 John Wiley & Sons A/S. We report 23 consecutive pediatric patients with MDS who received allogeneic HSCT on IRB approved protocols between 1992 and 2009 at Children's Memorial Hospital (Chicago, IL). Nine patients had de novo MDS, whereas 14 patients had treatment-related MDS. All patients had a documented cytogenetic abnormality, and monosomy 7/7q− was seen in 12 patients (52%). Fourteen of 23 patients received a myeloablative conditioning regimen; RIC regimens were used for the remaining nine. Five patients relapsed post-transplant, including four patients who received RIC transplant and four patients with treatment-related MDS. For the entire group, estimated five-yr RFS and OS were 47% and 50%, respectively. Treatment-related MDS was associated with decreased RFS in comparison with de novo MDS (33% vs. 70%, p = 0.05). Five-year OS rates reached 80% for those with de novo MDS. RIC regimens were associated with decreased three-yr RFS in comparison with myeloablative regimens (22% vs. 68%, p = 0.02). There was no correlation of survival with blast count at diagnosis, IPSS score, cytogenetic abnormality, donor type, or HLA match. Larger series are needed to confirm prognostic factors so that higher-risk patients can be targeted with novel approaches. [ABSTRACT FROM AUTHOR]

C-reactive protein (CRP) is an acute phase reactant that is a reliable marker of systemic inflammation and has been associated with increased morbidity and mortality following hematopoietic stem cell transplantation (HSCT) in adults. In this study, we evaluated whether early elevations of CRP were associated with various complications and nonrelapse mortality following HSCT in pediatric patients. Seventy pediatric patients had CRP levels drawn at regular time points during the first week following their transplants. Patients were followed for 100 days following transplant, and transplant-related complications were documented. Patients who subsequently developed severe infections had higher median CRP values than those without severe infections (median 8.03 mg/dL versus 1.64 mg/dL, P = .0008) as did those who suffered nonrelapse mortality compared with those who did not (12.6 mg/dL versus 2.44 mg/dL, P = .02). These findings suggest that elevated CRP values may be useful as a marker of individual pediatric patients with a higher risk for treatment-related morbidity and mortality. [Copyright &y& Elsevier]

Abstract: We studied 30 pediatric patients with malignant (n = 16) or nonmalignant (n = 14) conditions. The preparative regimen consisted of fludarabine, intravenous (IV) busulfan (Bu) for 2 daily doses, and antithymocyte globulin before stem cell transplantation. A test dose of IV Bu (0.8 mg/kg), anticipated to target an area under the concentration-time curve (AUC) of 800 to 1200 μmol·min, was followed later by 2 daily doses adjusted according to the pharmacokinetics (PK) to target an AUC of 3200 to 4800 μmol·min. The median test dose AUC was 953 μmol·min (range, 439-1315 μmol·min). The median AUC of single daily doses was 3798 μmol·min (range, 1511-7254 μmol·min). PK-based dose modification was required in 20 patients: 12 were adjusted to a higher dose, and in 8 the dose was decreased. Nausea and vomiting were noted in 15 patients. No patient developed hepatic veno-occlusive disease or seizures. Full donor chimerism was attained in 20 patients (mean of 24.5 days), 3 achieved partial chimerism, 5 did not engraft, and in 2 it is too early to assess chimerism. Acute graft-versus-host disease developed in 11 patients, grades I to II developed in 10 patients, and grade III developed in 1. Four patients died of infection and 5 of progressive disease. Thus, PK of a test dose of IV Bu provided information to adjust subsequent daily doses of IV Bu: this resulted in a regimen that was feasible, safe, and convenient for administration to children. [Copyright &y& Elsevier]

We describe the experience with reduced intensity transplants (RIT) in pediatric patients and review the basis for this approach using adult examples and series of patients. We report the experience with RIT in two pediatric studies. [ABSTRACT FROM AUTHOR]

Vitamin C deficiency in developed countries is typically observed in patients with unique clinical conditions such as cystic fibrosis or anorexia nervosa, or in patients on long-term tube feeds. We report here a clinical observation in six pediatric and adolescent patients (median age 17.5 yr, range 9.8-23.5 yr) with chronic GVHD with mucous membrane involvement found to be vitamin C deficient. These patients' baseline serum vitamin C levels ranged from <0.12 to 0.94 mg/dL (normal value 0.20-1.90 mg/dL), with a mean level 0.56 ± 0.36 mg/dL and a median level 0.6 mg/dL. Among these patients, signs and symptoms of mucositis failed to respond to standard chronic GVHD therapy. After receiving treatment with 2000 mg of ascorbic acid by mouth, daily patients displayed increased serum vitamin C levels. Clinically, this correlated with a remarkable improvement in patients' mucositis and ability to eat. [ABSTRACT FROM AUTHOR]

The author discusses the manuscript regarding the treatment for high risk solid tumors in children having myeloablative chemotherapy and autologous hematopoietic progenitor stem cell (HPC) transplantation. He says that the true effect of autologous HPC in treatment cancer can be determined by performing randomize trials which compares the standard therapy to the use of high-dose therapy. He mentions that therapy and radiation received by patients should be considered.

Aim: Chimerism analysis post HPCT has become an essential tool for the surveillance of engraftment, graft rejection or relapse. MDC is a dynamic process reflecting the competition of multiple coexisting cell populations. In the setting of a second HPCT it may be difficult to assess the percentage of donor chimerism or the risk of relapse. A retrospective study on chimerism within the framework of MDC was demonstrated in the recipient’s graft. Methods: We studied 13 patients (9 males, 4 females), median age of 9 (1-16) years, who received a 2nd HPCT for acute leukemias (ALL n=9, AML n=3, Infant Leukemia n=1) who relapsed after the 1st HPCT. All patients achieved complete remission with full donor chimerism (FDC) of the 1st donor prior to the 2nd HPCT. AlleleSEQR™ qPCR (RUO) was used in this analysis. The technology follows the comparative ΔΔ CT method for relative PCR quantification with the known DNA quantity in a reference sample. Our stepwise approach to MDC analysis began with identifying the correct reference sample for pre transplant evaluation. Assessment of individual possible informative markers for: recipient, 1st donor and 2nd donor were performed. There were two combinations to be measured: recipient vs. 2nd donor and 1st donor vs. 2nd donor. Results: All cases engrafted and recovered their counts of ANC>500 /μl in a median of 18.5 (10-25) days and un-sustained platelets >20.0 /μl in 19 (0-54) days. Chimerism was evaluated weekly for the first 100 days. Three patterns were observed: a) FDC + 2nd donor (n=8) (62%), b) MDC without recipient (n=3) (23%) and c) MDC + recipient (n=2) (15%). Of 13 patients, three relapsed 2 with pattern C and 1 in pattern A. Conclusions: It is imperative to identify the informative assays for all 3 genotypes in order to assess MDC and its outcome properly. This study provided a novel approach in the interpretation of MDC. Presence of recipient cells post second HPCT illustrated a higher chance of relapse. [Copyright &y& Elsevier]

ADV has emerged as an important pathogen in children undergoing allogeneic HPCT. A prospective study of the epidemiology of ADV infection and preemptive therapy of high risk ADV infections in children undergoing HPCT was undertaken. Cultures of throat, urine, and stool for viral pathogens and plasma for ADV PCR were obtained prior to transplantation, weekly for the first 100 days, and then monthly for one yr. Children developing high-risk ADV infections were treated preemptively with cidofovir 1 mg/kg/day given three times weekly for three wk. A case-controlled study was performed to identify risk factors for high-risk ADV infections. Seven (18%) of the 38 subjects developed high-risk ADV infections usually within 100 days of HPCT and were preemptively treated with i.v. cidofovir at a dose of 1 mg/kg/dose three times weekly for nine doses. High-risk ADV infections resolved in all seven patients without renal toxicity. CMV viremia occurred in two of seven patients during or shortly after therapy with cidofovir. A case–control study did not identify any risk factors that achieved statistical significance. Treatment with a modified dosing regimen of cidofovir was well-tolerated and high-risk ADV infections resolved in all patients. [ABSTRACT FROM AUTHOR]

Wilms tumor (WT) treatment regimens are curative for more than 80% of patients, but those with relapsed or refractory disease continue to have poor outcomes. High-dose chemotherapy followed by autologous stem cell rescue is often utilized although outcomes remain variable. We report on HD-ASCR outcomes in 24 patients with relapsed or refractory Wilms tumor. Three-year disease free and overall survival are 46% and 60%, respectively, which is similar to those reported for conventional salvage therapies. These outcomes suggest that conventional salvage therapies should be employed for relapsed and refractory WT rather than HD-ASCR. [ABSTRACT FROM AUTHOR]

The Primary Immune Deficiency Treatment Consortium (PIDTC) is enrolling children with severe combined immunodeficiency (SCID) to a prospective natural history study. We analyzed patients treatedwith allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2014, including 68 patientswith typical SCID and 32 with leaky SCID, Omenn syndrome, or reticular dysgenesis. Most (59%) patients were diagnosed by newborn screening or family history. The 2-year overall survivalwas 90%, but was 95%for thosewhowere infection-free at HCTvs 81%for those withactive infection (P5.009). Other factors, including thediagnosis of typical vs leaky SCID/Omenn syndrome, diagnosis via family history or newborn screening, useofpreparative chemotherapy, or thetypeof donorused, did not impact survival. Although 1-year post-HCT median CD4 counts and freedom from IV immunoglobulin were improved after the use of preparative chemotherapy, other immunologic reconstitution parameters were not affected, and the potential for late sequelae in extremely young infants requires additional evaluation. After a T-cell-replete graft, landmark analysis at day 1100 post-HCT revealed that CD3 < 300 cells/μL, CD8 < 50 cells/μL, CD45RA < 10%, or a restricted Vb T-cell receptor repertoire (<13 of 24 families) were associated with the need for a second HCT or death. In the modern era, active infection continues to pose the greatest threat to survival for SCID patients. Although newborn screening has been effective in diagnosing SCID patients early in life, there is an urgent need to identify validated approaches through prospective trials to ensure that patients proceed to HCT infection free. [ABSTRACT FROM AUTHOR]

The article focuses on a study regarding children with chronic myeloid leukemia (CML) and long term of effect of tyrosine kinase inhibitor (TKI) therapy and hematopoietic stem cell transplantation (HSCT). Topics discussed include significantly less number of percentage of CML in the pediatric population, introduction of the TKI imatinib by the U.S. in 1988, development of short term TKI toxicity, and improvement in overall survival of patients.

Myeloablative conditioning and allogeneic hematopoietic stem cell transplant (alloHSCT) in children with acute myeloid leukemia (AML) in first complete remission (CR1) may be associated with significant acute toxicity and late effects. Reduced-intensity conditioning (RIC) and alloHSCT in children is safe, feasible, and may be associated with less adverse effects. Gemtuzumab ozogamicin (GO) induces a response in 30% of patients with CD33 + relapsed/refractory AML. The dose of GO is significantly lower when combined with chemotherapy. We examined the feasibility and toxicity of RIC alloHSCT followed by GO targeted immunotherapy in children with CD33 + AML in CR1/CR2. Conditioning consisted of fludarabine 30 mg/m 2 × 6 days, busulfan 3.2 to 4 mg/kg × 2 days ± rabbit antithymocyte globulin 2 mg/kg × 4 days followed by alloHSCT from matched related/unrelated donors. GO was administered ≥60 days after alloHSCT in 2 doses (8 weeks apart), following a dose-escalation design (4.5, 6, 7.5, and 9 mg/m 2 ). Fourteen patients with average risk AML received RIC alloHSCT and post-GO consolidation: median age 13.5 years at transplant (range, 1 to 21), male-to-female 8:6, and disease status at alloHSCT 11 CR1 and 3 CR2. Eleven patients received alloHSCT from 5-6/6 HLA-matched family donors: 8 received peripheral blood stem cells, 2 received bone marrow, and 1 received related cord blood transplantation. Three patients received an unrelated allograft (two 4-5/6 and one 9/10) from unrelated cord blood unit and bone marrow, respectively. Neutrophil and platelet engraftment was observed in all assessable patients (100%), achieved at median 15.5 days (range, 7 to 31) and 21 days (range, 10 to 52), respectively. Three patients received GO at dose level 1 (4.5 mg/m 2 per dose), 5 at dose level 2 (6 mg/m 2 per dose), 3 at dose level 3 (7.5 mg/m 2 per dose), and 3 at dose level 4 (9 mg/m 2 per dose). Three of 14 patients received only 1 dose of GO after alloHSCT. One patient experienced grade III transaminitis, which resolved; no grade IV transaminitis, no grade III/IV hyperbilirubinemia, or sinusoidal obstructive syndrome were observed. The second dose of GO was given at median of 143 days (range, 120 to 209) after alloHSCT. Probability of grades II to IV acute and chronic graft-versus-host disease were 21% and 33.5%, respectively. Probability of overall survival after RIC alloHSCT and GO consolidation at 1 and 5 years was 78% and 61%, respectively. Probability of 5-year event-free survival after RIC alloHSCT and GO consolidation in patients in CR1 was 78%. No dose-limiting toxicities probably or directly related to GO were observed in this cohort. This preliminary data demonstrate that RIC followed by alloHSCT and consolidation with GO appears to be safe in children and adolescents with CD33 + AML in CR1/CR2. A phase II trial is currently underway investigating this approach with a GO dose of 9 mg/m 2 per dose. [ABSTRACT FROM AUTHOR]

The safety and efficacy of reduced-intensity conditioning (RIC) regimens for the treatment of pediatric acute myeloid leukemia is unknown. We compared the outcome of allogeneic hematopoietic cell transplantation in children with acute myeloid leukemia using RIC regimens with those receiving myeloablative-conditioning (MAC) regimens. A total of 180 patients were evaluated (39 with RIC and 141 with MAC regimens). Results of univariate and multivariate analysis showed no significant differences in the rates of acute and chronic graft-versus-host disease, leukemia-free, and overall survival between treatment groups. The 5-year probabilities of overall survival with RIC and MAC regimens were 45% and 48%, respectively (P = .99). Moreover, relapse rates were not higher with RIC compared with MAC regimens (39% vs 39%; P = .95), and recipients of MAC regimens were not at higher risk for transplant-related mortality compared with recipients of RIC regimens (16% vs 16%; P = .73). After carefully controlled analyses, we found that in this relatively modest study population, the data supported a role for RIC regimens for acute myeloid leukemia in children undergoing allogeneic hematopoietic cell transplantation. The data also provided justification for designing a carefully controlled randomized clinical trial that examines the efficacy of regimen intensity in this population. [ABSTRACT FROM AUTHOR]

Childhood obesity has more than tripled in the past 30 years. The prevalence of overweight and obese children has also increased in the pediatric cancer setting, causing substantial concern over proper chemotherapeutic dosing in this population. The purpose of this study was to determine if children with an increased body mass index (BMI) have an alteration in busulfan pharmacokinetics during hematopoietic stem cell transplant (HSCT) conditioning. We retrospectively reviewed data on busulfan pharmacokinetics (PK) on HSCT subjects (subjects were part of a prospective study previously reported by our group at Children’s Memorial Hospital) to determine appropriateness of dosing. Subjects were divided into appropriate BMI categories (<25th percentile, 25th-85th percentile, ≥85th percentile) and busulfan PK dosing was analyzed (test dose, regimen dose, area under the curve [AUC], and clearance). The dosing based on PK test dose data of children with BMI ≥85% was compared against the package insert dosing recommendations of using adjusted ideal body weight (AIBW) in obese patients to determine which dosing schema was most accurate. Children with high BMIs had higher AUCs when dosing on actual weight then their normal or low BMI counterparts. This indicates that children with a high BMI require less drug (2.9 mg/kg using actual body weight) to achieve the same AUC as children with normal BMI (4.0 mg/kg) or low BMI (3.6 mg/kg). Using the recommended AIBW dosing schema, 53% of the patients with high BMIs would have had regimen dose AUCs ≥20% over/under the target; whereas with the PK test dose method, only 16% of the patients with high BMIs had regimen dose AUCs ≥20% over/under the target. PK testing continues to be the gold standard for busulfan dosing in children. Particular vigilance should be paid to PK monitoring in high BMI categories because of the potential risk of imprecise dosing when using the AIBW schema. [ABSTRACT FROM AUTHOR]

WT1 gene expression has been proposed as a useful marker of minimal residual disease in leukaemia. Its utility in paediatric haematopoietic stem cell transplantation (HSCT) has not been studied. We studied the prognostic value of WT1 expression in peripheral blood prior to HSCT in 36 children with acute myeloid leukaemia (AML). Samples were obtained 2 weeks pre-transplant to determine the level of WT1 expression. WT1 expression was normalized using K562 cells as a control and a relative value of 0·5 was chosen as the cut-off point between high and low WT1 expression. The median level of pre-transplant WT1 expression in the 36 patients was 0·09 (range 0·0001–11·0), with 11patients having WT1 ≥ 0·5 and 25, WT1 < 0·5. After HSCT, 76% of patients with high pre-transplant WT1 expression relapsed, in contrast to 0% of the patients with low WT1 expression. Those with high WT1 expression had significantly lower 5-year event-free survival (EFS) (18%, 95% CI 0–40%) as compared to those with low WT1 expression (68%, 95% CI 50–86%, P = 0·007). Multivariate analysis showed that pre-transplant WT1 level is the only significant prognostic factor for the difference in EFS. Our finding suggests that elevated WT1 gene expression before HSCT in paediatric AML predicts relapse and poor long-term EFS. A larger prospective study is warranted to compare the value of high WT1 expression and other markers of minimal residue disease in predicting clinical outcomes after HSCT. [ABSTRACT FROM AUTHOR]

Myeloablative conditioning (MAC) regimens decrease the risk of relapse in pediatric patients undergoing hematopoietic stem cell transplant (HCT) but cause significant toxicities: transplant-related mortality (TRM) and late effects. Therefore, a MAC regimen that decreases toxicity has the potential to improve overall survival (OS). Busulfan (Bu), fludarabine (Flu), anti-thymocyte globulin (ATG) and 400 cGy of total body irradiation (TBI), a reduced toxicity, MAC regimen was used in pediatric patients. To evaluate the safety and toxicity of this regimen. Secondary objectives included determining OS at 2 and 5 years, and incidence of relapse and GVHD. We prospectively evaluated 40 patients ≤21 years of age undergoing HCT for high-risk leukemias who received dose-adjusted Bu, Flu, ATG and TBI. Bu pharmacokinetics were measured after a test dose and regimen dose 1 to target AUC of 4000-5000 uMol*min/day. Patients were treated between October 2008 and June 2018 (Table 1). OS was 67% and 51% at 2 and 5 years post-HCT, respectively. OS at 2 and 5 years was 70% and 55% for patients with myeloid disease versus 56% and 37% for patients with lymphoid disease, respectively (p=0.18) (Figure 1). Relapse occurred in 11 (28%) at a median of 7 months. TRM was 8% and 13% at 100 days and 1 year post-HCT, respectively. All patients engrafted. >Grade II acute GVHD was seen in 9 (23%); chronic GVHD was seen in 16 (40%). There was no significant impact of age, disease type, donor source or type on HCT outcomes. Long-term toxicities noted were ovarian insufficiency in 8, and short stature, hypothyroidism and learning disabilities in 2 each. Evaluation of Bu AUCs and multivariate analyses are still ongoing. Reduced toxicity, MAC regimen was well tolerated with a low incidence of TRM. This regimen shows a trend toward better efficacy in patients with myeloid disease, however larger studies are needed. [ABSTRACT FROM AUTHOR]

Abstract: Infants with acute lymphoblastic leukemia (ALL) have a poor prognosis when treated with standard chemotherapy. A subset of these infants, particularly those with mixed-lineage leukemia (MLL) rearrangements, has a high likelihood of relapse. Hematopoietic stem cell transplantation (HSCT) performed early in first remission may improve outcome. We present the results of 16 patients with infant ALL who were treated with HSCT in first remission. Six patients were ≤6 months of age at diagnosis, 11 had an initial white blood cell count of >50000/μL, and all patients with determinable cytogenetics had a high-risk karyotype [t(4:11) abnormality or other MLL rearrangement]. All patients received 150 cGy of total body irradiation for 8 doses (1200 cGy). Fifteen of 16 patients received etoposide at 1000 mg/m2 as a continuous infusion over 24 hours and cyclophosphamide at 60 mg/kg/d for 3 days. Eight patients received HSCT from an HLA-identical sibling, and 8, from unrelated cord blood. Twelve (75%) patients remain long-term survivors (median follow-up, 4.7 years). Two patients, 1 of whom had minimal residual disease at HSCT, died after relapse following HSCT. Two patients died of transplant-related causes. The HSCT was well tolerated; 15 patients achieved neutrophil engraftment at a median of 16 days. Acute and chronic graft-versus-host disease were minimal in these patients. These results support the use of HSCT in the treatment of infant ALL, especially when used as consolidation in first remission. The risk of relapse seems to be decreased with this approach. Further work is being performed to determine the long-term effects from this therapy. [Copyright &y& Elsevier]

Measles inclusion body encephalitis (MIBE) is a disease of the immunocompromised host and typically occurs within 1 year of acute measles infection or vaccination. We report a 13-year-old boy who had chronic granulomatous disease and presented 38 days after stem cell transplantation with afebrile focal seizures that progressed despite multiple anticonvulsants. After an extensive diagnostic evaluation, brain biopsy was performed, revealing numerous intranuclear inclusion bodies consistent with paramyxovirus nucleocapsids. Measles studies including reverse transcriptase-- polymerase chain reaction and viral growth confirmed measles virus, genotype D3. Immunohistochemistry was positive for measles nucleoprotein. Despite intravenous ribavirin therapy, the patient died. MIBE has not been described in stem cell recipients but is a disease of immunocompromised hosts and typically occurs within 1 year of measles infection, exposure, or vaccination. Our case is unusual as neither the patient nor the stem cell donor had apparent recent measles exposure or vaccination, and neither had recent travel to measles-endemic regions. The patient had an erythematous rash several weeks before the neurologic symptoms; however, skin biopsy was consistent with graft-versus-host disease, and immunohistochemistry studies for measles nucleoprotein were negative. As measles genotype D3 has not been seen in areas where the child lived since his early childhood, the possibility of an unusually long latency period between initial measles infection and MIBE is raised. In addition, this case demonstrates the utility of brain biopsy in the diagnosis of encephalitis of unknown cause in the immunocompromised host. [ABSTRACT FROM AUTHOR]

Background Transplantation of allogeneic hemopoietic stem cells can cure several non-malignant disorders in children. Transplantation with reduced intensity preparation might achieve the same goals but with less toxicity. We undertook a pilot study to determine engraftment rates, kinetics of engraftment, toxicity, and acute graft-versus-host disease (GVHD) associated with a uniform reduced intensity hemopoietic stem-cell transplant (HSCT) regimen for children with non-malignant diseases. Methods We studied 13 pediatric patients with non-malignant disorders who underwent reduced intensity HSCT at Children's Memorial Hospital from January, 2000, to February, 2004. Stem-cell sources included unrelated donor, matched-sibling peripheral blood stem cells, and unrelated cord blood. A uniform preparative regimen was used, consisting of fludarabine, busulfan, and anti-thymocyte globulin. Major endpoints were engraftment, transplant-related mortality at day 100, short-term toxicities, and incidence of acute GVHD. Results 72% of evaluable patients achieved full donor engraftment. There was rapid reconstitution of platelets (median 13.5 days) and neutrophils (median 18 days). Short-term toxicities were minimal, as seen by a median length of hospital stay of 7 days (between days 0-100). Incidence of grade II-IV acute GVHD was 8%. Two patients died before day 100 from underlying disease and viral infection, respectively (day 100 transplant-related mortality of 15%). The 1-year overall survival was 84% (95% CI 64-100). Most patients with immunodeficiencies and metabolic disorders had excellent donor engraftment and disease resolution or stabilization, but most of those with hemoglobinopathies rejected their graft. Interpretation This reduced intensity regimen followed by HSCT provides a good alternative to myeloablative HSCT for children with non-malignant disorders, except for hemoglobinopathies, in which engraftment is poor. [ABSTRACT FROM AUTHOR]

Conclusions. Nonmyeloablative HSCT from HLA-matched siblings can offer immune reconstitution with-out hepatotoxicity in patients with X-HIM syndrome and preexisting cholangiopathy. Even with stable mixed chimerism after allogeneic HSCT, patients may be able to enjoy a normal phenotype. Nonmyeloablative HSCT warrants additional study in X-HIM syndrome. Pediat-rics 2004;113:e122--e127. URL: http://www.pediatrics.org/ cgi/content/full/113/2/e122; stem cell transplant, nonmy-eloablative, immunodeficiency, hyper-IgM, cholangiopathy. [ABSTRACT FROM AUTHOR]

Abstract: Umbilical cord blood (UCB) has become a frequent source of allogeneic hematopoietic stem cells for transplantation. Of theoretical concern is a potential decrease in the graft vs. leukemia (GvL) effect, given the lesser degree of graft vs. host disease (GvHD) with this donor source. We report a case of recurrent acute non-lymphoblastic leukemia (ANLL) following stem cell transplantation with unrelated mismatched UCB, which responded to the induction of GvHD. The response was documented both morphologically and by evaluation of chimeric engraftment by molecular DNA techniques. In addition, WT-1, a purported marker of minimal residual disease in acute leukemia, correlated with remission status in this patient. In summary, the GvL effect is seen with allogeneic UCB transplantation and has the potential to be induced along with GvHD. [ABSTRACT FROM AUTHOR]

Abstract: Hematopoietic stem‐cell transplantation (HSCT) is an effective mode of therapy in pediatrics for the treatment of both malignant and non‐malignant disorders. We compared the course of children transplanted with unrelated umbilical cord blood (UCB) to those transplanted with allogeneic sibling bone marrow (BM) for bone marrow failure syndromes. Thirteen patients with a median age of 6.3 years were transplanted for the following diseases between April 1992 and November 1997: myelodysplastic syndromes, aplastic anemia, Diamond–Blackfan anemia, myelofibrosis, paroxysmal nocturnal hemoglobinuria, osteopetrosis and dyskeratosis congenita. The stem cell source was BM in ten patients and UCB in three. We retrospectively examined the conditioning regimens, stem cell source and dose, days to engraftment, survival and complication rate to see whether there was a significant advantage in using one source over the other. The median time to an absolute neutrophil count > 500 per µL was 25 days for UCB patients and 16 days for BM patients. The median time to a platelet count > 20 000 per µL was 55 days for UCB patients and 22 days for BM patients. The 100‐day mortality was 66% in UCB patients and 20% in BM patients. The overall mortality rates were 66% and 40%, respectively. Three patients died prior to engraftment. Seven patients (54%) were still alive as of May 1999 with a median follow‐up of 1574 days post‐transplant. The patients transplanted with BM had faster engraftment and lower rates of graft‐versus‐host disease, 100‐day mortality and overall mortality. HLA‐matched sibling BM is preferred as a source but transplantation using unrelated UCB is still an option in treating pediatric bone marrow failure syndromes. [ABSTRACT FROM AUTHOR]