Marta González-Vicent

Outcome of pandemic H1N1 infections in hematopoietic stem cell transplant recipients.

During 2009, a new strain of A/H1N1 influenza appeared and became pandemic. A prospective study was performed to collect data regarding risk factors and outcome of A/H1N1 in hematopoietic stem cell transplant recipients. Only verified pandemic A/H1N1 influenza strains were included: 286 patients were reported, 222 allogeneic and 64 autologous recipients. The median age was 38.3 years and the median time from transplant was 19.4 months. Oseltamivir was administered to 267 patients and 15 patients received zanamivir. One hundred and twenty-five patients (43.7%) were hospitalized. Ninety-three patients (32.5%) developed lower respiratory tract disease. In multivariate analysis, risk factors were age (OR 1.025; 1.01–1.04; P=0.002) and lymphopenia (OR 2.49; 1.33–4.67; P<0.001). Thirty-three patients (11.5%) required mechanical ventilation. Eighteen patients (6.3%) died from A/H1N1 infection or its complications. Neutropenia (P=0.03) and patient age (P=0.04) were significant risk factors for death. The 2009 A/H1N1 influenza pandemic caused severe complications in stem cell transplant recipients.

High-dose chemotherapy with autologous stem cell rescue for children with high risk and recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors

Current treatment for high risk and recurrent medulloblastoma (MB) and supratentorial primitive neuroectodermal tumors (stPNET) has a very poor prognosis in children. High dose chemotherapy (HDCT) and autologous stem cell rescue have improved survival rates. We present 19 patients (thirteen classified in the high risk group and six patients with recurrent disease) that received HDCT and autologous stem cell rescue.In the high risk group [Med Pediatr Oncol 38 (2002) 83], all patients underwent neurosurgical debulking. Standard chemotherapy was prescribed in 10 patients. Radiotherapy was given to 4 patients (all older than 4 years old). In the recurrence disease group [Childs Nerv Syst 15 (1999) 498], five patients underwent surgery. Radiotherapy was given to those who were not previously irradiated. The HDCT in twelve patients consisted of busulfan 4 mg/kg/day, orally over 4 days in 6-hourly divided doses and melphalan at a dose of 140 mg/m2/day by intravenous infusion over 5 min on day −1. Three patients additionally received thiotepa 250 mg/m2/day intravenously over 2 days and four patients additionally received topotecan 2 mg/m2/day over 5 days by intravenous infusion over 30 min. The other seven patients received busulfan and thiotepa at the same doses.Patient’s stem cells were mobilized with granulocyte colony-stimulating factor at a dose of 12 μg/kg twice daily subcutaneously for four consecutive days. Cryopreserved peripheral blood progenitor cells were re-infused 48 h after completion of chemotherapy. With a median follow-up of 34 months (range 5–93) eight complete responses and one partial response were observed. Three patients died of treatment-related toxicities (15%). The 2 year event-free survival was 37.67 ± 14% in all patients and 57 ± 15% for the high risk group.Therefore we conclude that HDCT may improve survival rates in patients with high risk/recurrent MB and stPNET despite treatment toxicity.

KIR-HLA receptor-ligand mismatch associated with a graft-versus-tumor effect in haploidentical stem cell transplantation for pediatric metastatic solid tumors.

Killer immunoglobulin‐like receptors (KIRs) on natural killer cells (NKs) recognize groups of human leukocyte antigen (HLA) class I alleles. Cells without an inhibitory HLA ligand may trigger NK activation. Reduced risk of relapse has been reported in malignant hematologic diseases after haploidentical transplantation when HLA ligands against the inhibitory KIRs present in the donor were absent in the recipient. We performed haploidentical transplant in three children with refractory solid tumors. Our results showed that beneficial antitumor effects could be observed in the presence of inhibitory KIR–HLA mismatch. These preliminary results suggest a possible association between disease control and NK cell alloreactivity. Pediatr Blood Cancer 2009;53:120–124.

Increasing incidence of invasive aspergillosis in pediatric hematology oncology patients over the last decade: a retrospective single centre study.

There is scanty information about invasive aspergillosis (IA) in the pediatric population. A review of IA at Hospital Infantil Universitario Niño Jesús between 1996 and 2006 was undertaken to analyze incidence, risk factors, and treatment response. Twenty patients were diagnosed with probable or proven IA during the study period, with a cumulative incidence of 1.96%. Incidence was higher in hematopoietic stem cell transplantation (HSCT) recipients: 2.26% (3.5% in allogeneic HSCT and 1.2% in autologous HSCT). A significative increase in IA incidence was observed along the study period (P=0.013), although this increase did not reach signification if only proven cases were compared (P=0.058). Most patients presented multiple risk factors for IA (87% more than 1, and 47% more than 3). The most frequently described risk factor was chemotherapy (90%), after by long-term neutropenia (90%), and corticotherapy (75%). Main locations of the infection were pulmonary (8 patients), cutaneous (3 patients) and intestinal (3 patients). Six patients presented disseminated IA. Initial response to treatment was 55%, although 3 of these cases had a subsequent episode. Global antifungal response, at the end of the follow-up, was 45%. IA-related mortality was 55%. Global mortality was 90%. Only 2 patients (isolated cutaneous IA cases) survived. Seven patients died due to their underlying malignant disease without active fungal disease. Incidence of IA in oncology children is increasing, and in adults. In our experience, IA is a marker of poor outcome even for patients who initially respond to antifungal treatment.

Unrelated cord blood transplantation for severe combined immunodeficiency and other primary immunodeficiencies

HCT is currently the treatment of choice for children with severe primary immunodeficiencies (PIDs). Frequently, these patients lack an HLA-identical sibling donor, and umbilical cord blood (UCB) transplantation may be an option; however, experience in this field remains scant. Fifteen children with PID (SCID 11, X-linked lymphoproliferative syndrome 2, Omenns syndrome 1, Wiskott–Aldrich syndrome 1) received a UCB transplant. The donor was unrelated in 14 cases and related in 1. Median age at transplant was 11.6 months (range, 2.9–68.0) and median weight 7 kg (range, 4–21). Thirteen patients were conditioned with busulphan and cyclophosphamide and 2 with fludarabine and melphalan. Nine patients received antithymocyte globulin. Median NC × 107/kg infused was 7.9 (range, 2.9–25.0) and median CD34 × 105/kg 2.9 (range, 1.0–7.9). All patients engrafted. Median days to >0.5 × 109/l neutrophils was 31. Eight patients developed acute graft-versus-host disease (GvHD) grades II–IV and one chronic GvHD. Viral and fungal infections were frequent. Four patients died: three from GvHD grade IV complicated by infection and one from progressive interstitial lung disease. Five-year survival was 0.73±0.12. All surviving patients presented complete immunologic reconstitution. No patient is intravenous immunoglobulin (IVIg) replacement therapy-dependent. UCB transplantation is a valid option for children with PID who lack an HLA-identical sibling donor.

Granulocyte colony-stimulating factor alone at 12 μg/kg twice a day for 4 days for peripheral blood progenitor cell priming in pediatric patients

In children, the optimal mobilization schedule for harvesting peripheral blood progenitor cells (PBPC) is an issue of continuous research. We have studied a schedule based on high and daily divided doses of G-CSF (12 μg/kg body weight twice daily) for 4 days for PBPC priming. Toxicity related to G-CSF was observed in 13 patients (23%), mainly mild bone pain and myalgia. The median CD34+cell number collected was 4.4 (0.4–35 × 106/kg body weight), with 46 patients achieving 2 × 106/kg body weight (83.6%) after a single large volume leukapheresis. In conclusion, this mobilization schedule allows safe and efficient collection of the minimum target CD34+ cell dose in most pediatric patients by only one procedure.

Transient donor cell-derived myelodysplastic syndrome with monosomy 7 after unrelated cord blood transplantation

Abstract:  Donor cell leukaemia or myelodysplastic syndromes are extremely rare complications that have been observed not only after haematopoietic transplantation with progenitor cells harvested from bone marrow and peripheral blood, but also after cord blood transplantation. We describe the early onset of monosomy 7 in donor cells after cord blood transplantation in a patient diagnosed with myelodysplastic syndrome 3 months after transplantation. Fluorescent in situ hybridisation analysis performed in a cryopreserved aliquot of the cord blood showed 2.5% of nuclei with monosomy 7. The cord blood donor was studied and he showed neither peripheral blood cytopenias nor cytological or cytogenetic features of myelodysplasia. The cell blood counts (CBC) of the girl have improved over 2 yr while decreasing the percentage of monosomic cells. The monosomic clone has finally disappeared and the CBC are finally normal. This case of transient monosomy 7 started very early after engraftment emphasises the relevance of clonal instability of specific progenitor cells in the early engraftment, and host immune status, in cytogenetic abnormalities founded in donor cell‐derived MDS and acute leukaemia. Moreover, the clinical follow‐up of this patient, recommends a more conservative treatment for this clonal disease early developed after transplantation.

Risk score for pediatric intensive care unit admission in children undergoing hematopoietic stem cell transplantation and analysis of predictive factors for survival.

The authors retrospectively analyzed postransplantation events in 198 children who underwent hematopoietic stem cell transplantation (HSCT) between 1998 and 2002 to obtain a risk score for pediatric intensive care unit (PICU) admission and to ascertain variables predicting a poor outcome. Thirty-six patients (18%) were admitted to the PICU. Median age was 9 years (range 1-18). On univariate analysis, variables significantly associated with PICU admission were male gender (P = 0.01), more than first complete remission (P = 0.003), allogeneic transplantation (P = 0.001), engraftment syndrome (P = 0.03), and acute graft-versus-host disease grade of at least two (P = 0.05). According to this, patients were divided in two levels of risk (low and high), with a respective probability of PICU admission of 8.8 ± 2.2% and 63.8 ± 8.8% (P < 0.0001). Seventeen (47%) patients were discharged from the PICU. The probability of event-free survival after PICU admission at 3 years was 24.2 ± 7%. On univariate analysis, variables with a negative impact on event-free survival were type of transplantation, inotropic support, a C-reactive protein level of at least 10 mg/dL, and a high O-PRISM score. On multivariate analysis, the only variable that influenced event-free survival was the O-PRISM score (≤10 points, 54.6 ± 15.3%; >10 points, 8.6 ± 5.8%; P = 0.007). In conclusion, the risk of PICU admission may be easily estimated using simple variables. A high O-PRISM score at the time of PICU admission predicts a dismal outcome.

A phase I/II trial of interleukin-15--stimulated natural killer cell infusion after haplo-identical stem cell transplantation for pediatric refractory solid tumors.

BACKGROUND AIMS Preliminary data suggest that T-cell-depleted haplo-identical stem cell transplantation (haplo-SCT) has a clinically beneficial allograft-versus-tumor effect associated with natural killer (NK) cell immune reconstitution. METHODS This phase I/II trial descriptively evaluates the feasibility of interleukin (IL)-15-stimulated NK cell infusion after haplo-SCT in pediatric patients with refractory solid tumors. RESULTS Six patients received an IL-15-stimulated NK cell infusion at 30 days after haplo-SCT. The mean number of infused NK cells per product was 11.3 × 10(6)/kg (range, 3-27 × 10(6)/kg). The T-cell count was <1 × 10(3)/kg in all patients (range, 0-0.75 × 10(3)/kg). No toxic effects related to IL-15--stimulated NK cell infusion were observed. Four of the six patients showed a clinical response (one achieved very good partial remission, two achieved partial remission and one had stable disease). One patient had progressive disease, and the response was not evaluated in the remaining patient. After a median follow-up period of 310 days, all patients had died: four of cancer relapse, one of cancer-associated thrombotic micro-angiopathy and one of acute graft-versus-host disease. CONCLUSIONS The adoptive transfer of allogeneic IL-15--stimulated NK cells might be feasible and safe in heavily pretreated pediatric patients with refractory solid tumors, though the advanced stage of disease and toxic effects of haplo-SCT may limit the efficacy of NK cell infusion in this population.

Peripheral blood progenitor cell collection adverse events for childhood allogeneic donors: variables related to the collection and safety profile.

The use of children as haematopoietic stem cell donors represents an ethical dilemma. For some investigators, this is even more questionable if the children underwent peripheral blood progenitor cell (PBPC) collection. Due to these controversies, information related to adverse events (AE) in paediatric donors and variables related to the collection is scanty. We analysed 152 PBPC collections, and compared the complications and results between young children, older children and adults. The pattern of AE was shown to vary according to the age of the donor. Older paediatric donors and adults had a higher incidence of complaints related to PBPC priming (54·3% vs. 79·7%, respectively) than the youngest children (12%). On the other hand, these donors had a lower incidence of AE during PBPC collection (19·6% older children, 37·3% adults) mainly related to hypocalcaemia, than the youngest donors, who suffered mainly cardiovascular complications due to hypovolaemia (51·7%). The only variables related to collected cell dose were total blood volume processed per donor body weight, and CD34+ cell count before apheresis. The donor/recipient body weight ratio predicted the outcome of collection in a single large volume leukapheresis. Donors with body weight ratio ≥0·75 had 4·69 times higher likelihood to reach the minimum target cell dose.