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The potential impact on patient outcome of different Minimal residual disease (MRD) levels at time of transplant in patients with lymphoblastic leukemia undergoing allogeneic hematopoietic SCT (HSCT) remains uncertain. In this study, we quantified MRD levels at time of transplant using multiparameter flow cytometry (MFC). Mononuclear cells from marrow aspirates were obtained from 102 adult and child patients before their conditioning regimen. Quantification of MRD levels was carried out by detecting patient-specific leukemia-associated immunophenotypes using four-color MFC. Thirty patients exhibited measurable levels of MRD at the time of transplant, with low levels (0.01 to p0.1%) in 12 cases, intermediate levels (40.1 to p1%) in 8 cases and high levels (41%) in 10 cases. The leukemia-free survival (LFS) rates were 65.9±7.0%, 42.9±15.7% and 0% for negative, low levels p0.1% and intermediate-high levels 40.1%, respectively (Po0.001, log-rank test). Overall survival (OS) was 52.3 ± 7.6%, 28.6 ± 13.8% and 0% for MRD-negative, low levels p0.1% and intermediate-high levels 40.1%, respectively (Po0.001, log-rank test). Multivariate Cox analysis confirmed that detection of leukemia cells by flow cytometry at transplant was the most significantly adverse factor for OS, LFS and EFS after transplant.

Summary:The use of peripheral blood stem cells (PBSC) in autolog- In order to determine if peripheral blood stem cells ous transplantation (PBSCT) has demonstrated advantages (PBSC) collected after priming with G-CSF in AML inover the use of marrow (ABMT) in several hematological first complete remission (CR) can be used for autologmalignancies and solid tumors. 1,2 In fact, a faster hematopoous transplantation and to evaluate the efficacy of early ietic reconstitution in PBSCT, resulting in lower infectious intensification therapy as in vivo purging, we studied 35 and haemorrhagic morbidity-mortality than in ABMT, has consecutive patients with AML in first CR. After stanbeen widely observed. 3,4 These advantages are particularly dard induction and consolidation chemotherapy, 24 of evident in patients autografted for acute myelogenous leuthem were treated with one (10 patients) or two (14 kemia (AML), in whom engraftment is slower than in acute patients) cycles of high-dose cytarabine plus etoposide lymphocytic leukemia, and further delays occur as a conseprior to PBSC collection. G-CSF was used as the primquence of purging or heavy chemotherapy administered ing agent. Of the 35 patients scheduled for peripheral before marrow cell harvest. 5,6 In addition, a lower freblood stem cell transplantation (PBSCT), three relapsed quency of neoplastic cells in peripheral blood has been before transplantation, and the 32 remaining underwent reported in this entity. 7,8 PBSCT. High-dose therapy consisted of either totalIn recent years, different methods of mobilization to body irradiation plus cyclophosphamide or busulphan obtain peripheral blood progenitors have been developed. plus cyclophosphamide. The median number of CD34 + High-dose cyclophosphamide or polychemotherapy alone cells infused was 3.24 × 10 6 /kg (range 0.15-14). The or associated with growth factors (mainly GM-CSF or Gmedian times to reach a PMN count of 0.5 × 10 9 /l and CSF) have generally yielded a good number of blood prea platelet count of 50 × 10 9 /l were 12 (8-28) and 30 (11-cursors, enough to assure an early engraftment. 9-12 How-345) days, respectively. There was no transplant-related ever, its use has been considerably reduced because of the mortality. Twelve patients relapsed between 2 and 21 dependence on 'timing' and the additional hematological months post-PBSCT. With a median follow-up of 28 and nonhematological toxicities. Lately, the capacity of a months, actuarial disease-free survival (DFS) is single growth factor to induce mobilization to peripheral 52.41 ؎ 9% in the intent-to-treat group and blood of hematopoietic precursors which are capable of 57.4 ؎ 9.8% in patients who underwent PBSCT. The restoring a complete and sustained hematopoiesis has freprobability of DFS is significantly higher for patients quently been reported. 13,14 Nevertheless, the presence of who receive early intensification therapy prior to both GM or G-CSF receptors in leukemic blast cells, the PBSC collection and PBSCT as compared with patients reported capa...

Summary:In 1989 we carried out a trial comparing allogeneic BMT to chemotherapy (CT) in 76 children with relapsed acute lymphoblastic leukaemia (ALL). Ten years on we have clinically revised outcome to firmly establish the role of each treatment, to analyse the importance of length of first remission and to provide long-term actuarial results for disease-free survival (DFS) and relapse rate in each group. For 21 patients within the transplantation group, probability of DFS and relapse are 42.8 ± 10.8% and 40.2 ± 11.7% (s.e.), respectively. In the chemotherapy group, probability of DFS is 10.0 ± 4.74% (P = 0.001) and probability of relapse 87.5 ± 5.2% (P = 0.0004). These results strongly reflect those at initial analysis, confirming a key role of BMT in the management of ALL in second remission. Moreover, on univariate analysis only two factors influenced DFS: treatment group and length of first complete remission (less or more than 30 months from first CR). Thus, it seems clear that the best therapeutic option in early relapse is BMT, whereas DFS in late relapse is at the limit of significance (P = 0.07), with a higher relapse rate in the CT group. Although encouraging results using intensified rotational combination chemotherapy have been published, prospective randomised studies are needed to assess with certainty the best therapeutic option in these patients. Keywords: BMT vs chemotherapy; childhood ALL; second CR; revisited In 1989, we concluded that allogeneic bone marrow transplantation (BMT) is the best alternative therapy for children with ALL who have relapsed in their marrow. 1 In that report, we prospectively studied 76 such patients, 21 of whom had a genotypically identical HLA donor and underwent allogeneic BMT. The remaining 55 patients who lacked a suitable donor, received conventional chemotherapy (CT). Probability of survival was significantly higher in the BMT group (47.1 ± 11.7% vs 9.2 ± 5.6%, P Ͻ 0.025). Probability of remaining in complete remission in the BMT group was 58.5% vs 10.9% in the chemotherapy group (P Ͻ 0.005).At the time of publication of those findings and as a consequence of the discouraging results initially obtained by some groups with BMT for ALL patients in second CR, 2,3 many controversies arose, such as whether or not these children should undergo allogeneic BMT. [4][5][6][7] In the last 10 years, despite the lack of well-designed randomised studies with large numbers of patients, all results seem to confirm that high-dose chemotherapy and bone marrow transplantation from an histocompatible donor afford a greater chance of leukaemia-free survival than does conventional chemotherapy. However, it has been recently pointed out 8 that indications for BMT in ALL are not fully established, because of publications involving small numbers of patients, difficulties over selection bias since most patients lack a suitable sibling donor, and importantly, that a very long follow-up is needed to assess results of a second course of chemotherapy.On the other hand, it has been stated th...

Tumor necrosis factor (TNF-alpha) has been implicated as a principal mediator in the pathogenesis of septic shock. TNF-alpha was measured by immunoradiometric assay in serum samples from 23 full-term infants with sepsis (15 with severe infection and 8 with septic shock) and in 20 healthy full-term newborns. Serum TNF-alpha levels were significantly higher in the group with sepsis, at the time of admission to the neonatal intensive care unit, than in the healthy neonates. The highest TNF levels were found in those newborns with septic shock, particularly in those who died. Although the method is far too slow for any clinical routine work, our results suggest that the presence of elevated serum TNF-alpha levels could be considered a sensitive and specific test for predicting septic shock and its clinical outcome.

Of 100 bone marrow transplant recipients, 30 (30%) received a CD4(+) lymphocyte-depleted graft (1x10(6) CD8(+) T lymphocytes/kg of body weight). Replication of Epstein-Barr virus (EBV) was observed in 40 patients (40%). The use of a CD4(+) lymphocyte-depleted graft was the only independent risk factor for replication of EBV (relative risk, 11.5; 95% confidence interval, 5.8-22.8; P<.0001). Nevertheless, EBV load in those patients was not higher than in the rest of patients, and the low EBV load prevented the development of lymphoproliferative disease. These results suggest that the presence of CD8(+) T lymphocytes in the bone marrow graft can control EBV load, thereby reducing the risk of developing lymphoproliferative disease.

Invasive fungal disease (IFD) causes significant morbidity and mortality among children undergoing allo-SCT. In this prospective pilot study, we analyze voriconazole as primary antifungal prophylaxis. From October 2004 to July 2010, 56 children o18 years of age were enrolled in this study. Patients received voriconazole doses of 5 mg/ kg per 12 h (n ¼ 23) or 7 mg/kg per 12 h (n ¼ 33), with a limiting dose of 200 mg/12 h, from day À1 to day þ 75 or later in patients with active acute GVHD. Patients were followed up for IFD for 6 months. In this series, 37 (66.1%) patients successfully completed treatment (85.7% during neutropenic period) without empirical or preemptive antifungal therapy, adverse effects or IFD. Nine (16.1%) children needed preemptive (n ¼ 2) or empirical (n ¼ 7) antifungal therapy, and one (1.8%) of them developed a fatal probable IFD during the study period. A total of 10 (17.8%) children developed adverse effects related to voriconazole prophylaxis, leading to definitive withdrawal on median day 26.5 (in 7 patients after granulocytic recovery). The most frequent adverse effect was persistent elevation of hepatic enzymes in seven (12.5%) children. There were no differences between doses of 5 and 7 mg/kg per 12 h. Our results suggest that voriconazole can be safely used as primary antifungal prophylaxis in children undergoing allo-SCT.