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Neuroblastoma (NB) is a heterogeneous extracranial tumor occurring in childhood. A distinctive feature of NB tumors is their neuroendocrine ability to secrete catecholamines, which in turn, viaβ-adrenergic receptors ligation, may affect different signaling pathways in tumor microenvironment (TME). It was previously demonstrated that specific antagonism of β3-adrenergic receptor (β3-AR) on NB tumor cells affected tumor growth and progression. Here, in a murine syngeneic model of NB, we aimed to investigate whether the β3-AR modulation influenced the host immune system response against tumor. Results demonstrated that β3-AR antagonism lead to an immune response reactivation, partially dependent on the PD-1/PD-L1 signaling axis involvement. Indeed, β3-AR blockade on tumor-infiltrating lymphocytes (TILs) dampened their ability to secrete IFN-γ, which in turn reduced the PD-L1 expression, caused by TILs infiltration, on NB tumor cells. Further investigations, through a genomic analysis on NB patients, showed that high ADRB3 gene expression correlates with worse clinical outcome compared to the low expression group, and that ADRB3 gene expression affects different immune-related pathways. Overall, results indicate that β3-AR in NB TME is able to modulate the interaction between tumor and host immune system, and that its antagonism hits multiple pro-tumoral signaling pathways.

This article reviews the primary goals and achievements of the Italian Association for Pediatric Hematology-Oncology (Associazione Italiana Ematologia Oncologia Pediatrica [AIEOP]), a national cooperative group that has been working for children and adolescents with cancer in Italy since 1975.

•Pediatric high-risk (HR) neuroblastoma (NB) patients face a grim prognosis.•Allo-HCT with reduced intensity conditioning (RIC) may represent a consolidation option.•Allo-HCT with RIC for HR NB was feasible and associated with a 5-year TRM of 29.4%.•Poor prognosis (5-year DFS 11.8%) persists for disease recurrence/progression.

Patients given allogeneic hematopoietic stem cell transplantation (alloHSCT) present an increased incidence of long-term toxicities that can be attributed to the preparative regimen. We retrospectively analyzed in a population of 670 children receiving allo-HSCT for acute leukemia the occurrence of different late effects in function of the choice made between total body irradiation (TBI) and busulfan, as part of the preparative regimen. In univariable analysis, we found that patients treated with TBI developed cataract in 24% of the cases compared with 4% in patients treated with BU (p?=?0.0001) and that the incidence of secondary malignant neoplasia (SMN) was higher in patients treated with TBI (18%) as compared with those prepared to the allograft with a Bu-based regimen (0%) (p?=?0.019). Conditioning regimen did not show a statistically significant correlation with the occurrence of all the other investigated late effects. In multivariable analysis, TBI remained associated with the occurrence of cataracts (Relative Risk: 0.33 p?=?0.012) and secondary malignancies (Relative Risk 3.96?×?10e-6 p?

Abstract: Neuroblastoma (NB) is the most frequently observed among extracranial pediatric solid tumors. It displays an extreme clinical heterogeneity, in particular for the presentation at diagnosis and response to treatment, often depending on cancer cell differentiation/stemness. The frequent presence of elevated hematic and urinary levels of catecholamines in patients affected by NB suggests that the dissection of adrenergic system is crucial for a better understanding of this cancer. β3-adrenoreceptor (β3-AR) is the last identified member of adrenergic receptors, involved in different tumor conditions, such as melanoma. Multiple studies have shown that the dysregulation of the bioactive lipid sphingosine 1-phosphate (S1P) metabolism and signaling is involved in many pathological diseases including cancer. However, whether S1P is crucial for NB progression and aggressiveness is still under investigation. Here we provide experimental evidence that β3-AR is expressed in NB, both human specimens and cell lines, where it is critically involved in the activation of proliferation and the regulation between stemness/differentiation, via its functional cross-talk with sphingosine kinase 2 (SK2)/S1P receptor 2 (S1P2) axis. The specific antagonism of β3-AR by SR59230A inhibits NB growth and tumor progression, by switching from stemness to cell differentiation both in vivo and in vitro through the specific blockade of SK2/S1P2signaling.

Relapse of acute lymphoblastic leukemia (ALL) may occur in extramedullary sites, mainly central nervous system (CNS) and testis. Optimal post-remissional treatment for isolated extramedullary relapse (IEMR) is still controversial. We collected data of children treated with hematopoietic stem cell transplantation (HSCT) for ALL IEMR from 1990 to 2015 in Italy. Among 281 patients, 167 had a relapse confined to CNS, 73 to testis, 14 to mediastinum, and 27 to other organs. Ninety-seven patients underwent autologous HSCT, 79 received allogeneic HSCT from a matched family donor, 75 from a matched unrelated donor, and 30 from an HLA-haploidentical donor. The 10-year overall survival was 56% and was not influenced by gender, ALL blast immune-phenotype, age, site of relapse, duration of first remission, and type of HSCT. In multivariable analysis, the only prognostic factors were disease status at HSCT and year of transplantation. Patients transplanted in third or subsequent complete remission (CR) had a risk of death 2.3 times greater than those in CR2. Children treated after 2000 had half the risk of death than those treated before that year. Our results suggest that both autologous and allogeneic HSCT may be considered for the treatment of pediatric ALL IEMR after the achievement of CR2.

Traditionally, hematopoietic stem cell transplantation (HSCT) from both HLA-matched related and unrelated donors (UD) has been used for treating children with acute leukemia (AL) in need of an allograft. Recently, HLA-haploidentical HSCT after αβ T-cell/B-cell depletion (αβhaplo-HSCT) was shown to be effective in single-center studies. Here, we report the first multicenter retrospective analysis of 127 matched UD (MUD), 118 mismatched UD (MMUD), and 98 αβhaplo-HSCT recipients, transplanted between 2010 and 2015, in 13 Italian centers. All these AL children were transplanted in morphological remission after a myeloablative conditioning regimen. Graft failure occurred in 2% each of UD-HSCT and αβhaplo-HSCT groups. In MUD vs MMUD-HSCT recipients, the cumulative incidence of grade II to IV and grade III to IV acute graft-versus-host disease (GVHD) was 35% vs 44% and 6% vs 18%, respectively, compared with 16% and 0% in αβhaplo-HSCT recipients (P< .001). Children treated with αβhaplo-HSCT also had a significantly lower incidence of overall and extensive chronic GVHD (P< .01). Eight (6%) MUD, 32 (28%) MMUD, and 9 (9%) αβhaplo-HSCT patients died of transplant-related complications. With a median follow-up of 3.3 years, the 5-year probability of leukemia-free survival in the 3 groups was 67%, 55%, and 62%, respectively. In the 3 groups, chronic GVHD-free/relapse-free (GRFS) probability of survival was 61%, 34%, and 58%, respectively (P< .001). When compared with patients given MMUD-HSCT, αβhaplo-HSCT recipients had a lower cumulative incidence of nonrelapse mortality and a better GRFS (P< .001). These data indicate that αβhaplo-HSCT is a suitable therapeutic option for children with AL in need of transplantation, especially when an allele-matched UD is not available.

Spinal cord involvement (SCI) is a rare feature of posterior reversible encephalopathy syndrome (PRES), especially in children. SCI is generally symptomatic, and may have a different outcome compared with encephalic localization of PRES. We reported about two cases of SCI in pediatric patients with PRES, after multimodal anticancer therapies, including radiotherapy, chemotherapy and targeted agents.

Malignant meningioma has a bad prognosis. Surgery and radiotherapy are the most effective therapeutic options, without an established role for chemotherapy. We report a case of 2-year-old male child with diagnosis of postoperative relapse of a malignant meningioma. Considering the rapid progression, the young age and the lack of effective therapeutic alternatives, the patient underwent multidisciplinary anticancer treatment with a protocol made for soft tissue sarcomas (EpSSG NRSSTS 2005 protocol), with positive outcome. This case represents a successful management of an anaplastic meningioma with a multimodal treatment, including chemotherapy, in a pediatric patient.

The treatment of brain tumors and neurodegenerative diseases, represents an ongoing challenge. In Central Nervous System (CNS) the achievement of therapeutic concentration of chemical agents is complicated by the presence of distinct set of efflux proteins, such as ATP-Binding Cassette (ABC) transporters localized on the Blood-Brain Barrier (BBB). The activity of ABC transporters seems to be a common mechanism that underlies the poor response of CNS diseases to therapies. The molecular characterization of Breast Cancer Resistance Protein (BCRP/ABCG2), as an ABC transporter conferring multidrug resistance (MDR), has stimulated many studies to investigate its activity on the BBB, its involvement in physiology and CNS diseases and its role in limiting the delivery of drugs in CNS. In this review, we highlight the activity and localization of BCRP on the BBB and the action that this efflux pump has on many conventional drugs or latest generation molecules used for the treatment of CNS tumors and other neurodegenerative diseases.

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 CD8T lymphocytes and the achieving of the 10th percentile of normal CD4T 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 CD8T lymphocytes in overall survival.

Acute lymphoblastic leukemia (ALL) in second complete remission is one of the most common indications for allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients. We compared the outcome after HCST of adolescents, aged 14 to 18 years, with that of children (ie, patients < 14 years of age). Enrolled in the study were 395 patients given the allograft between January 1990 and December 2007; both children (334) and adolescents (61) were transplanted in the same pediatric institutions. All patients received a myeloablative regimen that included total body irradiation in the majority of them. The donor was an HLA-identical sibling for 199 patients and an unrelated volunteer in the remaining 196 patients. Children and adolescents had a comparable cumulative incidence of transplantation-related mortality, disease recurrence, and of both acute and chronic graft-versus-host disease. The 10-year probability of overall survival and event-free survival for the whole cohort of patients were 57% (95% confidence interval, 52%-62%) and 54% (95% confidence interval, 49%-59%), respectively, with no difference between children and adolescents. This study documents that adolescents with ALL in second complete remission given HSCT in pediatric centers have an outcome that does not differ from that of patients younger than 14 years of age.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for patients with relapsed acute myeloid leukemia. In this retrospective, multicenter study, we analyzed the outcome of 63 children (median age, 7 y; range, 0.2 to 17) who received unmanipulated allo-HSCT in second complete remission. Either a matched family donor or an unrelated donor was used in 29 (46) and 34 (54) patients, respectively. The stem cell source was bone marrow in 53 children (84), peripheral blood in 7 (11), and cord blood in 3 patients (5). Preparative regimen included total body irradiation in 25 patients (40). The 5-year estimates of overall survival and leukemia-free survival were 53 95 confidence interval (CI) 39-66 and 49 (95 CI 35-63), respectively, whereas the cumulative incidence of relapse and transplant-related mortality (TRM) were 26 (95 CI 16-41) and 25 (95 CI 15-40), respectively. In multivariate analysis, the use of a matched family donor predicted a better probability of LFS relative risk (RR) 2.29, P0.05. Both chronic graft-versus-host disease occurrence and age at diagnosis greater than 11 years were associated with an increased TRM (RR 8.08, P0.04 and RR 4.38, P0.05, respectively). These results indicate that allo-HSCT is a procedure able to rescue a significant proportion of children with acute myeloid leukemia in second complete remission, especially if an human leukocyte antigen-compatible relative is employed as donor. Both leukemia recurrence and TRM contributed to treatment failure. Optimization of donor selection and of strategies for both prophylaxis and treatment of graft-versus-host disease may improve the results of unrelated donor allo-HSCT.

Childhood B‐cell lymphomas (B‐NHLs) represent a group of aggressive malignancies that are amenable to high‐intensity chemotherapy regimens. In 1992, the Italian Association of Pediatric Hematology and Oncology (AIEOP) initiated a prospective clinical trial involving the diagnosis and treatment of childhood B‐NHL based on a well established strategy developed by the Berlin–Frankfurt–Munster Group.Between November 1992 and October 1997, 163 children who had B‐NHL were treated prospectively in the first national AIEOP trial. Disease staging was performed according to the St. Jude staging system, and treatment was assigned on the basis of risk group (R1, R2, or R3), which took into account disease stage and resectability and serum lactate dehydrogenase (LDH) levels.Of the 144 evaluable patients, 11 had Stage I disease, 35 had Stage II disease, 76 had Stage III disease, and 22 had Stage IV disease. Thirteen, 54, and 77 patients were included in risk groups R1, R2, and R3, respectively. The 10‐year overall survival (OS) and event‐free survival (EFS) rates for the overall population were 89.4% and 81.8%, respectively; the EFS rates for patients in risk groups R1, R2, and R3 were 100%, 86.9%, and 75.1%, respectively. Multivariate analysis indicated that age ≥ 10 years, disease histology other than Burkitt or Burkitt‐like lymphoma, and LDH levels ≥ 1000 international units per liter had negative prognostic value. Analysis of the toxicity (according to the World Health Organization grading system) associated with 710 of the 748 chemotherapy cycles administered revealed 855 cases of Grade 3 or 4 toxicity, with 73% being cases of hematologic toxicity. Toxic episodes were most common after the first chemotherapy cycle and were equally common in the R2 and R3 risk groups. To date, the development of a second malignancy has not been observed in any patient in the study cohort.Long‐term follow‐up of the current study (AIEOP LNH92) confirms the observation of a favorable outcome for patients with B‐NHL treated with short, intensive chemotherapy regimens and raises the possibility that non‐Burkitt or non‐Burkitt‐like histology and age ≥ 10 years may have negative prognostic value for patients with childhood B‐NHL. Cancer 2004. © 2004 American Cancer Society.

Survivors of childhood malignancies have an increased risk of developing second malignant neoplasms (SMN) due to their prior treatment and/or genetic susceptibility. A small proportion of SMNs are soft tissue sarcomas (STS), whose prognosis is generally thought to be poor, though publications on such patients' treatment and outcome is limited. The authors analyzed 25 patients who were registered for the Italian Cooperative Group protocols for pediatric STS from 1979 to 2000. The primary tumor was STS in five patients; Hodgkin disease in five patients; leukemia in four patients; retinoblastoma, neuroblastoma, and Wilms tumor in two patients each; and other tumor types in five patients. SMNs occurred after a median of 8 years (range, 1.9–15.0 years) and included rhabdomyosarcoma (RMS) in 4 patients, malignant peripheral nerve sheath tumor in 4 patients, extraosseous Ewing family tumor (EFT) in 4 patients, leiomyosarcoma in 3 patients, fibrosarcoma in 2 patients, synovial sarcoma in 2 patients, and other tumor types in 6 patients. Treatment generally was administered according to the guidelines for primary STS. Seven non-RMS patients with STS underwent surgery alone, whereas 18 patients received chemotherapy and 8 patients received radiotherapy. Retreatment was feasible with acceptable toxicity. Fifteen patients were alive in complete remission of their SMN at the time of last follow-up. Responses to chemotherapy and survival were satisfactory for patients with tumors such as RMS and EFT. Complete tumor resection was correlated with a favorable prognosis in patients with other types of STS and in patients with postirradiation sarcoma. Two patients developed a third malignancy. Although prior treatment may hinder the management of these patients, pediatric STS second malignancies can be cured using the same strategies used for de novo pediatric sarcomas. Long-term follow-up is mandatory given the risks of further malignancies and more severe, treatment-related side effects. Cancer 2004. © 2004 American Cancer Society.

Chronic graft-versus-host disease (cGVHD) remains the major cause of late morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). However, only a few studies specifically focused on children, and little information is available on the antileukemic effect of cGVHD and its impact on disease-free survival (DFS) in children. We retrospectively analyzed 696 children given allogeneic HSCT for malignant (n = 450) or nonmalignant (n = 246) diseases. The donor was an HLA-identical sibling in 461 cases and an alternative donor in 235. Bone marrow was the stem cell source in 647 cases, peripheral blood in 17, and cord blood (CB) in 32. cGVHD developed in 173 children (25%) at a median of 116 days after HSCT. Three-year cGVHD probability was 27%. In multivariate analysis, variables predicting cGVHD were donor and recipient age, grade II to IV acute GVHD, female donor for male recipient, diagnosis of malignancy, and use of total body irradiation; CB transplants had a very low risk of cGVHD (RR = 0.07,P = .0001). cGVHD occurrence increased transplant-related mortality (P < .05). Nevertheless, in hematologic malignancies, patients with cGVHD had a reduced relapse probability compared with children without cGVHD (16% ± 3% versus 39% ± 3%, P = .0001) and a better DFS (68% ± 4% versus 54% ± 3%, P = .01). The antileukemic effect of cGVHD was observed mainly in patients with acute lymphoblastic leukemia (ALL). This study provides novel data on cGVHD in childhood. Use of CB stem cells and preparative regimens without radiotherapy may prevent its development. In patients affected by ALL, cGVHD was associated with a strong graft-versus-leukemia effect, improving DFS.

Nineteen pediatric patients affected by acute lymphoblastic leukemia (ALL) were examined weekly with respect to 6-mercaptopurine nucleotide (6-MPN) and 6-thioguanine nucleotide (6-TGN) levels in erythrocytes during the course of maintenance treatment with 6-MP 50 mg/m2per d and results were related to various parameters of bone marrow function to assess, in the same individual, the level of reliability of 6-MP metabolites in predicting a later change in peripheral blood cell counts. Median values for 6-MPN and 6-TGN were 57 and 200 pmol/8 × 108erythrocytes, respectively, as measured by reversed-phase high-performance liquid chromatography (HPLC). 6-TGN levels in erythrocytes were inversely related with white blood cell count (r−0.463, p < 0.0001, n 361), absolute neutrophil count (r−0.386, p < 0.0001, n 347), erythrocyte (r−0.354, p < 0.0001, n 287), and platelet counts (r−0.24, p < 0.0001, n 319) in the majority of patients (n 10–12), while no correlation was found for 6-MPN. In the remaining children, no evidence of correlation was demonstrated between 6-TGN levels and myelotoxicity. The results confirm the role of 6-TGN as the reference cytotoxic metabolite for evaluating the exposure to 6-MP and identifying treatment compliance in ALL children but indicate the limits of a follow-up based solely on metabolite levels and suggest that a more correct approach remains the double monitoring of 6-TGN and blood cell count with differential.

Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine (6-MP) and methotrexate (MTX) was investigated in patients as well as in rats and in HL-60 human leukemic cells. Ten children affected by acute lymphoblastic leukemia (ALL) in remission received daily doses of 6-MP given at 25 mg/m2and i.v. infusion of high-dose MTX at 2 or 5 g/m2once every other week. When 6-MP was given alone, the mean peak plasma concentration (Cmax) and area under the curve (AUC) of 6-MP were 72.5 ng/ml and 225.3 hngml-1. Concurrent treatment with MTX at 2 or 5 g/m2resulted in a mean increase of 108% and 121% in the Cmaxand of 69% and 93% in the AUC, respectively. In rats treated with an oral dose of 6-MP at 75 mg/m2, MTX given i.p. at 5 g/m2produced mean increases of 110% and 230% in the Cmaxand AUC of 6-MP, respectively. In HL-60 human leukemic cells incubated with 6-MP at 250 ng/ml, the cumulative intracellular concentration of 6-thioguanine and 6-MP nucleotides was not significantly modified by treatment with 20 ug/ml of MTX. The present findings indicate that high-dose MTX enhances the bioavailability of 6-MP as evidenced by the observed increases in the plasma Cmaxand AUC of 6-MP in humans and animals.

IntroductionFor patients in need of an allograft and lacking an HLA-identical sibling, hematopoietic stem cell transplantation (HSCT) from an unrelated donor (UD) is the standard of care. In the recent few years, αβ T-cell and B-cell depleted HLA-haploidentical HSCT (αβhaplo-HSCT) is becoming a widely employed alternative to UD-HSCT in patients with acute leukemia. We, thus, decided to conduct a retrospective analysis on the outcome of patients given either αβhaplo-HSCT or UD HSCT in the same time period, namely October 2010-December 2015, in one of the 13 centers affiliated with the Italian-HSCT pediatric network.

Background:Established indications for Hematopietic Stem Cell Transplantation (HSCT) in SCN include transformation to acute leukemia (AL) and/or myelodisplasia (MDS) and G-CSF resistance (need for >20mcg/kg/d). Indication for HSCT also appears appropriate in patients with poor response to G-CSF (10-20 mcg/kg/d) and, as a consequence, a high incidence of infectious events. Indication is less clear in cases requiring a G-CSF doses up to 10 mcg/kg but with good control of infections.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

The chromosomal translocation t(8;14)(q24;q32) represents a specific tumor marker in Burkitt's lymphoma (BL). This chromosomal aberration involves the MYC oncogene on chromosome 8 and the immunoglobulin heavy-chain (IgH) locus on chromosome 14. We have previously demonstrated that this genetic abnormality can be used as a marker of Minimal Disseminated Disease (MDD) in BL (Mussolin et al, JCO, 2007). The aim of the study was to assess of the prevalence of MDD in BL at diagnosis in children enrolled in the AIEOP LNH-97 clinical protocol and the evaluation of its impact on prognosis.We established a simplified long-distance PCR (LD-PCR) assay which can amplify up to 15-20 Kb DNA sequence making it possible to detect the t(8;14) at the genomic level with the sensitivity of 10-4. The assay was based on 4 separate PCR reactions in which one primer complementary to the first exon of the MYC gene is used with one of four primers for the IgH locus (1 for the JH region and 1 for each of the 3 constant regions).LD-PCR was applied to prospectively study 124 BL biopsies and detected a specific PCR product in 88 of them (71%). Of the 88 positive BL patients we studied both the tumor and the bone marrow (BM) at diagnosis in 76: BM was positive by LD-PCR in 25 patients (33%), whereas only 10 (13%) were positive at the standard morphological and/or immunophenotypical analyses. Most of the MDD positive patients (88%) belonged to the R4 Risk Group according to BFM definition (stage III or stage IV according to St. Jude staging classification and LDH≥1000 U/l). The 3-year progression-free survival (PFS) was 68% (SE 10%) in MDD positive R4 patients compared with 96% (SE 4%) in MDD negative R4 patients (p= 0.02), whereas there was no difference in PFS between children with morphological involvement of BM at diagnosis versus those who had negative BM (PFS=62.5% (SE 17%) vs. PFS= 87% (SE 6%), respectively, p= 0.09). By multivariate analysis (including MDD, gender, LDH, CNS involvement) MDD was predictive of higher risk of failure (Hazard Ratio: 8.4 , p= 0.04).We demonstrated that MDD identifies a poor prognosis subgroup among high risk Burkitt's lymphoma patients. We suggest that a more effective risk-adapted therapy, possibly including anti-CD20 monoclonal antibody, should be considered in these patients.No relevant conflicts of interest to declare.

Objectives To evaluate the outcome of pediatric patients with refractory or relapsed Hodgkin’s Disease (HD) who undergo high dose chemotherapy (HDCT) with autologous hemopoietic stem cell rescue (aSCT) and reported to BMT Registry of Italian Pediatric Hematology-Oncology Association Group (AIEOP). Methods From 1986 to 2004, 100 aSCT were performed in 91 pediatric patients, 45 male/35 female, with relapsed or primary refractory HD. At time of transplant the median age was 15 (6–18) years. Ten out 91 patients received a double program transplant. At the time of first transplant, 33 patients were in II CR, 35 in PR and 23 in more advanced phase of disease. First line therapy was a conventional treatment consisting of MOPP/ABVD and involved field radiotherapy for the majority of patients. Most of HDCT consisted of BCNU (38) or Thiotepa (35) based regimens, while TBI was delivered in only 2 cases. The source of stem cell was BM in 44 cases and peripheral blood in 66. A median number of 2.15 x 108/kg MNC (0.48–21.62) and 5.70 x 106/kg CD34+ cells (0.58–45.53) were infused. Pre treatment factors were analyzed by univariate analysis for prognostic significance for 5, 10 and 15-year overall survival (OS) and event free survival (EFS) Results. After a median follow-up of 6,6 (0,1–12) years the 5, 10 and 15-year OS rates were 67.4%, 58.9% and 58.9% respectively, while 5, 10 and 15-year EFS rates were 63.7%, 54.6% and 54.6% respectively. Twenty-nine out 91 patients relapsed after a median time of 9 (2–46) months. Second CR and HDCT regimens containing BCNU can offer a better but not statistically significant 5-year EFS (83.5% and 73.8% respectively). Peripheral blood stem cell sources determined a better significant outcome (5-year EFS 76.2% vs 50.2% p= 0.024). Transplant related toxicity was moderate and 100 days TRM was 3.0%. Discussion. More than half children with relapsed or refractory HD can be successfully treated with HDCT and aSCT, confirming the efficacy of this approach. Patients who undergo aSCT in II CR, conditioned with a BCNU containing HDCT and rescued with peripheral blood hemopoietic stem cell have a better outcome compared with those receiving any other treatment. Alternative treatment such as allogeneic SCT need to develop in patients with early relapse or chemo-resistant relapse after first line chemotherapy associated with a poorer outcome.

Leukemia recurrence is the most common cause of treatment failure in children with ALL. The prognosis relapsed ALL mainly depends on the site of recurrence, time between diagnosis and relapse and immune-phenotype, children with bone marrow relapse occurring within the first 30 months after diagnosis or with T-ALL being those with the worst prognosis. Allogeneic haematopoietic stem cell transplantation (HSCT) is considered the treatment of choice for many children with relapsed ALL. We report the outcome of 175 children with ALL in second complete remission given HSCT from either a relative or an unrelated donor (UD) in one of the Italian AIEOP Centers from1998 to 2002. Less than 10% of these patients had an isolated extra-medullary relapse. TBI was employed in the preparative regimen in 92% of patients. GVHD prophylaxis consisted of Cs-A alone in the vast majority of children transplanted from a relative, whereas the combination of Cs-A, short-term MTX and either ALG, or Campath-1G in a minority of cases, was used in children transplanted from an UD. The source of stem cells was bone marrow, cord blood and peripheral blood in 150, 20 and 5 children respectively. We used the Berlin-Frankfurt-Munster (BFM) classification of ALL relapses in childhood to subdivide patients according to site of relapse, time from diagnosis to relapse and immune-phenotype. This classification identifies 4 different groups of risk (S1, S2, S3 and S4), the latter being those including patients with the worst prognosis. The 5-year probability of disease-free survival (DFS) of patients transplanted from either a relative or an unrelated donor was 56% and 44% (P=0.05). However, the outcome of the 86 children transplanted from an HLA-identical sibling or an UD beyond 1998 was comparable, the 3-year Kaplan-Meier estimate of DFS being 62% and 59%, respectively. The cumulative incidence of transplant-related mortality (TRM) for patients transplanted either from a relative or from an UD was 15% and 33%, respectively. For children transplanted beyond 1998 we found a reduction in TRM, irrespectively of the type of donor employed. The 5-year cumulative incidence of relapse for patients transplanted either from a relative or from an UD was 30% and 23%, respectively (P=NS). The occurrence of grade I-III acute GVHD was associated with a reduction in the risk of leukemia recurrence, which translated into a significantly better probability of DFS as compared to children with absent or grade IV acute GVHD. Also chronic GVHD was associated with a significantly lower risk of disease recurrence and with a better DFS. Irrespectively of the type of donor emlpoyed, S1 and S2 patients had a significantly better outcome in comparison to those S3 and S4 groups. These data indicate that allogeneic HSCT is able to rescue a significant proportion of patients with ALL in 2nd CR. DFS of unrelated donor HSCT in children with ALL in 2nd CR has improved in the last few years, being comparable to that of patients transplanted from a matched family donor. This information, together with that on the prognostic relevance of BFM classification, is of value for counselling of patients with relapsed ALL. The GVHD-related graft-versus-leukemia effect is important for the eradication of the malignant clone.

Background: These last 20 years, the activity of Italian blood banks and transfusion services has been modified and widened, following the evolution of transfusion medicine from the primary, prevailing interest for immunohematology towards new activities in diagnostic, clinical-therapeutic and research field. Notwithstanding this gradual transformation, blood collection activity and the production of hemocomponents in quantities proper to reach and/or keep a balance of self-sufficiency on a local and national level, keeps beeing a prior target, as it is the main task of National Health Department plans. The aim necessary to guarantee hemocomponent safety is very important also, as such as to meet public opinion expectations and law provisions in an efficient way. Blood safety can only be joined to adopting severe methodological criteria even upon donor’s selection stage, in order to avoid hemocomponents donation in the “window period” of HBV, HCV or HIV infections. Nevertheless the temporary donation suspension has a negative impact on subsequent donations by the deferred donors. Donors who do not meet any of the selection criteria in the screening process, may undergo quarantine plasmapheresis (QP) as an alternative to deferral, and QP units may be stocked, validated and released only if repeated donor’s screening tests are negative up to a maximum of 12 months after the risk event. Methods: Since 01/01/98 we have been collecting 600 mL QP units from donors who should have been deferred for one of the following reasons: 1) minor dental surgery (DS); 2) major or minor surgery (MMS); 3) sexual risk behaviours (SRB) (with a limit to: change of sexual partner or more than one partner); 4) health care work risk (HW); 5) other risk events (OR) (with a limit to: tattoo application, skin or ear piercing, acupuncture); 6) endoscopic examination (EE). QP units were daily listed, labelled and physically located and quarantined in monthly dedicated containers within a specific freezer. Results: From 01/01/98 to 06/30/04 we have been collecting 16,555 plasmapheresis units and 1,531 (9.25%) of these were QP donated by 1,053 donors. First time apheresis donors were 350 and 45% of them became repeat plasmapheresis donors. The causes for including donors into QP group have been in percentage respectively: 1) DS: 29.5; 2) MMS: 26; 3) SRB: 20.5; 4) OR: 19; 5) EE: 3; HW: 2. None of the QP units has been eliminated for seroconversion during or at the end of the quarantine period; QP units elimination percentages (0.69) for sanitary reasons (high ALT, HCV positive) soon after donation appear to be substantially superimposable in comparison to non-QP units (0.71). Conclusions: Our data shows that the provisions of this strategy, with a limit to some specific exclusion causes and joined to a proper logistical organization: 1) Does not generate an increase of elimination sanitary causes of plasmapheresis soon after donation. 2) Is highly efficient in improving plasma production safely, without sacrificing whole blood donations. 3) Greatly increases repeat plasmapheresis donor’s recruitment. 4) Prevents the negative impact on subsequent donations by the deferred donors. 5) Is a donor’s recruitment and a retention strategy which contributes to raise plasma production safely, even though restrictive changes to donation selection criteria continue to increase deferrals.