M.B. Bradley

Reduced intensity allogeneic umbilical cord blood transplantation in children and adolescent recipients with malignant and non-malignant diseases.

There is a significant amount of morbidity and mortality following myeloablative umbilical cord blood transplantation (UCBT). Reduced intensity (RI) conditioning offers an alternative to myeloablative conditioning before UCBT. We investigated RI-UCBT in 21 children and adolescents with malignant (n=14), and non-malignant diseases (n=7). RI conditioning consisted of fludarabine (150–180 mg/m2) with either busulfan (⩽8 mg/kg)+rabbit antithymocyte globulin (R-ATG; n=16) or cyclophosphamide+R-ATG±etoposide (n=5). Human leukocyte antigen match: 4/6 (n=13), 5/6 (n=5) and 6/6 (n=3). The median total nucleated cell and CD34+ cell dose per kilogram were 3.58 × 107 and 2.54 × 105, respectively. The median time for neutrophil and platelet engraftment was 17.5 and 52 days, respectively. There were six primary graft failures (chronic myelogenous leukemia (CML), β-thalassemia, hemophagocytic lymphohistiocytosis (HLH) and myelodysplastic syndrome (MDS)). The probability of developing grade II to grade IV acute graft-versus-host disease (GVHD) and chronic GVHD was 28.6 and 16.7%, respectively. Incidence of transplant-related mortality (TRM) was 14%. The 5 years overall survival (OS) in all patients was 59.8%. The 5 years OS for patients with average versus poor-risk malignancy was 77.8 versus 22.2% (P=0.03). RI-UCBT may result in graft failure in specific high-risk chemo-naïve patients (CML, β-thalassemia, HLH and MDS), but in more heavily pretreated pediatric and adolescent recipients results in rapid engraftment and may be associated with decreased severe GVHD and TRM.

A comparison of immune reconstitution and graft-versus-host disease following myeloablative conditioning versus reduced toxicity conditioning and umbilical cord blood transplantation in paediatric recipients

Immune reconstitution appears to be delayed following myeloablative conditioning (MAC) and umbilical cord blood transplantation (UCBT) in paediatric recipients. Although reduced toxicity conditioning (RTC) versus MAC prior to allogeneic stem cell transplantation is associated with decreased transplant‐related mortality, the effects of RTC versus MAC prior to UCBT on immune reconstitution and risk of graft‐versus‐host disease (GVHD) are unknown. In 88 consecutive paediatric recipients of UCBT, we assessed immune cell recovery and immunoglobulin reconstitution at days +100, 180 and 365 and analysed risk factors associated with acute and chronic GVHD. Immune cell subset recovery, immunoglobulin reconstitution, and the incidence of opportunistic infections did not differ significantly between MAC versus RTC groups. In a Cox model, MAC versus RTC recipients had significantly higher risk of grade II–IV acute GVHD [Hazard Ratio (HR) 6·1, P = 0·002] as did recipients of 4/6 vs. 5–6/6 HLA‐matched UCBT (HR 3·1, P = 0·03), who also had significantly increased risk of chronic GVHD (HR 18·5, P = 0·04). In multivariate analyses, MAC versus RTC was furthermore associated with significantly increased transplant‐related (Odds Ratio 26·8, P = 0·008) and overall mortality (HR = 4·1, P = 0·0001). The use of adoptive cellular immunotherapy to accelerate immune reconstitution and prevent and treat opportunistic infections and malignant relapse following UCBT warrants further investigation.

A pilot study of reduced toxicity conditioning with BU, fludarabine and alemtuzumab before the allogeneic hematopoietic SCT in children and adolescents

We report the results of a pilot study of a BU–fludarabine–alemtuzumab (BFA)-reduced toxicity conditioning (RTC) followed by allogeneic hematopoietic SCT (AlloHSCT) in 12 children and adolescents (<21 years) with malignant and non-malignant diseases. Stem cell sources were: two unrelated cord blood, one unrelated BM, two related and seven unrelated PBSC. Positive CD34 selection was performed in five unrelated PBSC grafts. RCT was carried out with BFA, and GVHD prophylaxis was FK506 and mycophenolate mofetil. The median time for neutrophil and platelet engraftment was 16 and 31 days, respectively. The P of developing ⩾grade II, ⩾grade III aGVHD and cGVHD was 41.6, 25 and 9%, respectively. Only 1 out of 12 developed ⩾grade III toxicity. There was one primary and no secondary graft failure. Mixed donor chimerism on day 100 and 1 year was median 99 and 96%, respectively; ⩾90% of recipients achieved ⩾80% donor chimerism. The 3-year overall survival (OS) in all patients was 91.7±8% (100% for malignant vs 80% for non-malignant diseases, ns). In all, 11 (91%) patients remain alive at median 2.8 (0.3–6.8) years. RTC followed by AlloHSCT, based on BFA conditioning, is feasible and tolerable in children and adolescents, and results in prompt achievement of durable mixed donor chimerism and excellent OS.

Adenovirus infection in paediatric allogeneic stem cell transplantation recipients is a major independent factor for significantly increasing the risk of treatment related mortality

Adenovirus infection is a significant complication in paediatric AlloSCT recipients with a mortality rate for disseminated adenovirus that may exceed 80%. We sought to determine the incidence, risk factors, and associated outcomes of adenovirus infection in 123 consecutive paediatric AlloSCT recipients. Adenovirus was diagnosed by antigen detection or viral culture, and was defined by isolation of virus with presence of correlating clinical symptoms. The probability of developing adenovirus infection was 12·3% (CI95 6·0–18·6). There were no statistically significant differences in probability of adenovirus infection in univariate analysis of risk factors including donor source, use of ATG/Alemtuzumab, ≥Grade II GVHD, among others (age, diagnosis, conditioning regimen). Probability of overall survival for patients that experienced adenovirus infection was 15·4% vs. 50% for those without adenovirus (P = 0·0286). In multivariate analysis, the most important risk factor for an increased risk of death was adenovirus infection [HR 3·15 (CI95 1·6–6·18) P = 0·0009]. In this series of paediatric AlloSCT recipients, the development of adenovirus infection was the leading multivariate predictor of treatment‐related mortality. Enhanced surveillance with adenovirus PCR and identification of the risk factors associated with poor outcomes from adenovirus infection may identify patients that may benefit from pre‐emptive therapeutic interventions including adenovirus‐specific cellular immunotherapies.

Pericardial effusion post-SCT in pediatric recipients with signs and/or symptoms of cardiac disease.

The objective of this study was to assess the incidence, risk factors, outcome and impact on OS of pericardial effusion (PEF) in a cohort of 156 pediatric SCT recipients. The mean age was 8.15±6.25 years. In all, 74% of the patients had malignant disease and 35% of the patients received autologous stem cell grafts. Twenty-three subjects developed effusion at 2.75±3.54 months after SCT. The overall probability of developing a PEF after SCT was 16.9%. In the multivariate analysis of risk factors associated with time to PEF, increased age, allogeneic risk status and conditioning type, were all significant factors. In a multivariate analysis of time to death, PEF, CMV status and risk status were all independent risk factors. PEF, however, had the highest HR of 3.334. Of the 23 patients with PEF, 19 died (82.6%); however, none died as a direct result of pericardial tamponade. In summary, our results suggest that PEF is a significant risk factor for post transplant mortality. These results suggest a need for more frequent evaluation and monitoring for development of PEF. Studies are needed to determine the etiology of, and new therapeutic strategies for, PEF in the post-SCT population.

The pharmacokinetics and safety of twice daily i.v. BU during conditioning in pediatric allo-SCT recipients

Intravenous BU divided four times daily (q6 h) has been shown to be safe and effective in pediatric allo-SCT recipients. Though less frequent dosing is desirable, pharmacokinetic (PK) data on twice daily (q12 h) i.v. BU administration in pediatric allo-SCT recipients is limited. We prospectively examined the PK results in a cohort of pediatric allo-SCT recipients receiving i.v. BU q12 h as part of conditioning before allo-SCT. BU levels were obtained after the first dose of conditioning. PK parameter analysis (n=49) yielded the following 95% confidence intervals (CI95): weight-normalized volume of distribution: 0.65–0.73 L/kg; t1/2: 122–147 min; weight-normalized clearance (CLn): 3.4–4.3 mL/min/kg; and area under the curve: 1835–2180 mmol × min/L. From these results, a steady state concentration was calculated with CI95 between 628–746 ng/mL. Comparison between recipients ⩽4 vs >4 years old revealed significant differences in t1/2 (mean: 115 vs 146 min, P=0.008) and CLn (mean: 4.4 vs 3.5 mL/min/kg, P=0.038). Intravenous BU q12 h had a comparable PK to i.v. BU q6 h PK seen in the literature, and in pediatric allo-SCT recipients, is a feasible, attractive alternative to i.v. q6h dosing.

Preliminary results of gemtuzumab ozogamicin (GO) during myeloablative conditioning for allogeneic stem cell transplantation (AlloSCT) or following reduced intensity alloSCT (RI-AlloSCT) in children with AML

7038 Background: CD33 is expressed in 80–90% of childhood AML. GO, an immunotoxin targeting CD33, induces remission in 20–30% of relapsed/refractory childhood AML. Standard myeloablative conditioning (MAC) for AlloSCT in children with standard risk AML (SR-AML) is BU/CY. However, this regimen may be associated with 32% transplant related mortality (TRM) and 25% risk of relapse in SR-AML (Woods et al, Blood, 2001). Outcome following AlloSCT for high risk (HR) AML (≥CR3, induction failure [IF], refractory disease) is dismal (≤10% OS). There is a need for novel therapy during conditioning and after AlloSCT that can reduce TRM and relapse in SR-AML and improve outcome in HR-AML. Methods: We have performed 2 phase I studies of GO. In the first study of CD33+ HR-AML GO was dose escalated on day - 14 (3–7.5 mg/m2) prior to BU /CY MAC regimen. In the 2nd study of CD33+ SR-AML 2 doses of GO (4.5- 9 mg/m2) were administered ≥60d post reduced intensity conditioning (RIC) AlloSCT (8 wks apart). Results: In the HR-AML...