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Veno-occlusive disease (VOD) remains a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Prophylactic use of defibrotide (DF) might further reduce VOD rates but has no impact on the incidence of severe VOD or VOD-associated mortality. We investigated the cost-effectiveness of prophylactic DF according to the British Committee for Standards in Haematology/British Society for Blood and Marrow Transplantation guidelines in 348 children who underwent transplantation between 2001 and 2014 in our hospital, 138 of whom were at risk for VOD. The VOD incidence was 7.4% for the total cohort. Patients at risk had a higher incidence of VOD compared with patients without risk factors (15.2% versus 2.4%, P .0001). VOD occurred more often in patients after busulfan-based myeloablative conditioning than in patients after total body irradiation (11.2% versus 3.5%, P = .001). Donor types or the transplantation-related mortality (TRM) risk score did not correlate with VOD incidence. In 81% of patients who responded to therapeutic DF, VOD resolved completely. Overall VOD-associated mortality was .3% for the complete cohort, 3.7% for patients diagnosed with VOD, and 20% for patients with severe VOD. Neither the cumulative incidence of TRM (19% ± 8% versus 17% ± 2%, P = .706) nor the median length of hospitalization differed between patients with VOD and patients without. The median costs per HSCT in patients with VOD were about one-third higher than the overall median costs per transplantation at our institution. The calculated total costs of prophylactic DF treatment for 138 patients at risk was almost 6 times as high as the incremental costs for patients with VOD. We conclude that prophylactic DF for children at risk for VOD is not cost-effective with respect to TRM and length of hospital stay.

The impact of persistent mixed chimerism (MC) after haematopoietic stem cell transplantation (HSCT) remains unclarified. We investigated the incidence of MC in peripheral blood beyond day +50 after HSCT and its impact on rejection, chronic graft-versus-host disease (c-GvHD) and relapse in 161 children receiving allogeneic HSCT for haematological malignancies. The 1-year incidence of late MC was 26%. Spontaneous conversion to complete donor chimerism (CC) occurred in 43% of patients as compared to 62% after donor lymphocyte infusions. No graft rejection occurred. The 1-year incidence of c-GvHD was 20 ± 7% for MC, and 18 ± 4% for CC patients (P = 0·734). The 3-year cumulative incidence of relapse (CIR) according to chimerism status at days +50 and +100 was 22 ± 4% for CC patients vs. 22 ± 8% for MC patients (day +50; P = 0·935) and 21 ± 4% vs. 20 ± 7% (day +100; P = 0·907). Three-year CIRs in patients with persistent MC and patients with CC/limited MC were comparable (8 ± 7% vs. 19 ± 4%; P = 0·960). HSCT for acute leukaemia or myelodysplastic syndrome as secondary malignancies (hazard ratio (HR) 4·7; P = 0·008), for AML (HR 3·0; P = 0·02) and from mismatched donors (HR 3·1; P = 0·03) were independent factors associated with relapse. Our data suggest that late MC neither protects from c-GvHD nor does it reliably predict impending disease relapse.

Sickle cell disease (SCD) is still associated with substantial morbidity and reduced life expectancy. Disease-related mortality rises to 14% in adolescents and young adults. Overall and disease-free survival following haematopoietic stem cell transplantation (HSCT) is 90% and 95%, respectively. To reduce transplant-associated late effects, the feasibility of a highly immunosuppressive reduced-intensity conditioning (RIC) regimen was explored in children with SCD and a matched sibling donor. Eight patients (median age, 9 yr) and symptomatic SCD were included. The conditioning regimen consisted of fludarabine, melphalan and either thiotepa or total lymphoid irradiation plus antithymocyte globuline or alemtuzumab. The graft was bone marrow in seven and cord blood in one case. The conditioning regimen was well tolerated and no severe infectious complications occurred. All patients displayed mixed chimaerism on day +28. After a median follow-up of 4 yr, 3/8 patients have mixed leucocyte chimaerism and 8/8 patients have 100% donor erythropoiesis. HSCT from matched sibling donors following a RIC regimen was well tolerated and resulted in cure in all patients studied. If confirmed in larger patient cohorts, these observations will have important implications for the indications of HSCT in children with SCD.

Between 1990 and 2001, 68 patients with advanced Hodgkin's disease (HD) and 86 patients classified as low-/intermediate-grade B non-Hodgkin's lymphoma (NHL) were reported to the Austrian Stem Cell Transplantation Registry (ASCTR). Following autologous stem cell transplantation (SCT) for HD, overall survival was 56% [95% confidence interval (CI): 40-72%] with a disease-/progression-free survival of 49%, reaching a plateau at 5 years. Using multivariate Cox regression analysis BEAM conditioning (carmustine, cytarabine, etoposide and melphalan) was predictive for favourable outcome, better disease-/progression-free survival and a significantly lower risk for relapse. The cumulative incidence of relapse was 30%, even for patients in complete remission at time of SCT. The cumulative risk for developing a secondary malignancy increased continuously over time, achieving 20% at 7 years and 46% at 10 years with previous radiotherapy as the only risk factor in the multivariate analysis. Overall survival for NHL patients was 45% (95% CI: 26-64%) with a disease-/progression-free survival of 26% at 7 years. In the multivariate Cox regression analysis stage of disease at time of SCT was the most powerful parameter for overall survival, disease-/progression-free survival and relapse. Mantle cell lymphoma, greater than or equal to three lines of previous therapy, and a conditioning regimen other than BEAM were also predictive for death. The main reason for treatment failure was relapse (cumulative incidence 54-75%). Because of the high risk of relapse/progression in both disease categories and the additional high rate of second malignancies in HD patients, allogeneic stem cells should be considered a valuable alternative for selected patients. The efficacy of allotransplantation following reduced-intensity conditioning should be tested in randomised trials.

As results of frontline and relapse protocols for children with acute lymphoblastic leukaemia (ALL) are improving over time, there is a strong need for prospective haematopietic stem cell transplantation (SCT) trials, ensuring well standardized procedures for all relevant components which are potentially responsible for heterogeneity in post-SCT outcome. Therefore, in 2003 the Berlin-Frankfurt-Münster (BFM)-Study Group initiated a prospective international multicenter trial (ALL-SCT-BFM 2003). Main goals are the standardization and harmonisation of the SCT procedure and the question, if nowadays SCT from a matched sibling donor (MSD) is equivalent to SCT from a very well matched donor (MD). Further, we want to determine the efficacy of a SCT from HLA-mismatched donors (MMD) compared to SCT from MD/MSD as well as the incidence of acute and chronic graft versus host disease (GvHD) after SCT. Between September 2003 and June 2007, 381 patients (185 in CR1, 196 in CR2 or after subsequent relapse) were recruited by 27 participating SCT centers in Austria, Germany and Switzerland. Indications for SCT were poor response to induction treatment, either detected by morphology on day 33 or by minimal residual disease load measured after 11 weeks of treatment, cytogenetic aberrations [t(9;22), t(4;11)], early bone marrow relapses of ALL, or any subsequent ALL relapse. 76 patients had an indication for a MSD, 131 patients for a MD, and 174 patients for a MMD. Compliance with HLA-typing procedures according to the trial guidelines (high resolution typing of HLA A, B, C, DRB1 and DQB1) improved over time: 54% in 2004, 83% in 2005, 90% in 2006, and so far 100% in 2007. Unmanipulated bone marrow was used in 73% of MSD- and MD-SCT as recommended by the protocol. The recommended conditioning regimens (TBI+VP16 for MSD, TBI+VP16+ATG for MD, and TBI+Flu+VP16+ATG for MMD; in children younger than 2 years, TBI was substituted by BU+Cy) were used in 80% of all patients. GvHD prophylaxis (cyclosporine A for MSD, and cyclosporine A plus “short methotrexate” for MD) was given in 83% of all patients according to the trial guidelines. In most cases, deviations were due to clinical reasons. As the trial ALL-SCT-BFM 2003 is ongoing till 2009, interim results regarding outcome will not be presented. Nevertheless, treatment-related mortality is still very low (7%) and has improved over time since the very early beginning. Final results will be a very stable basis for subsequent ALL-SCT trials, focussing on controlled modifications and interventions in those patients being at highest risk for relapse subsequent to SCT.

Viral infections remain a major cause for transplant related mortality. The introduction of PCR-based assays permits rapid, specific and highly sensitive detection of various viral infections prior to clinical symptoms and thus facilitates preemtive treatment strategies. However a broad routine screening by PCR during the early post-transplant period is cost-intensive. Clinical benefit of broad vs restriced viral screening by PCR was evaluated in total of 98 consecutive pediatric SCT-patients(pts). The first 56 consecutive pts underwent broad viral screening including CMV, ADV, EBV, HSV, VZV, HHV6, HHV7, HHV8, PVB19, RSV, BKV, Enterovirus, Influenza A and B, and Parainfluenza 1–3. PCR-screening was performed twice weekly until day +28 and once weekly until day +100 in peripheral blood (PB), stool, urine and mouth wash. A total of 15675 samples were analyzed. HSV-IgG positive pts. received prophylactic acyclovir. All pts. received preemptive treatment for CMV viremia (gancyclovir) and ADV viremia (cidofovir). Pts with EBV-viremia exceeding 103 copies per ml PB received gancyclovir. In pts. undergoing the broad screening 50/56 pts were positive for at least one virus. The overall incidence of viremia was 61%. HHV6 was detectable in 66% (39% in PB), HHV7 in 16% (11% in PB), CMV in 36% (all in PB, in 23% additionally positive in other sites), EBV in 39% (35% in PB), ADV in 27% (5% in PB), BKV in 13% (all in urine) and PVB19 in one pts. Although the first detection of a viral infection occured before day +120 in all children, PCR positivity persisted throughout the first year post-transplant in many cases. There was no significant difference in the incidence of overall viral infection, viremia or multiple viremia between pts. with T-cell depleted grafts and those with unmanipulated grafts. However T-cell depletion was associated with significantly more lethal viral infections (32% vs 6%, p=0,0127). There was no significant difference in the incidence of viral infections, viremia and lethal viral disease between pts receiving myeloablative conditioning and those receiving reduced intensity conditioning. Isolated HHV6 or HHV7 viremia was not associated with any clinical symptoms and there was no difference concerning the incidence of CMV viremia, lethal viral disease or TRM between pts with and without HHV6 viremia. Of the 20 pts with CMV viremia, 6 pts had lethal CMV disease. 10% of the patients with EBV viremia were symptomatic, the disease being lethal in one case. The three pts who developed ADV viremia had previously been ADV positive in stool. All three pts died from disseminated ADV disease despite treatment with cidofovir. All pts with BKV positive urine had hemorrhagic cystitis. On the basis of these results, the viral screening for the subsequent 42 pts PCR screening was restricted to ADV, CMV and EBV in PB, ADV in stool and BKV in urine once weekly until day +28 and every two weeks thereafter, reducing the cost of the viral screening to 13%. For the patients undergoing restricted screening there was no difference concerning the incidence of CMV, EBV, ADV viremia and the incidence of lethal viral disease (18% vs 14%). We conclude that broad and cost intensive PCR screening for viral infections is of no clinical benefit.