Introduction/background: Development of neutralizing inhibitors against factor VIII (FVIII) is a major complication of haemophilia A treatment. Aim: The ongoing, international, open-label, uncontrolled, observational immune tolerance induction (ObsITI) study evaluates ITI, the standard of care in patients with inhibitors. Patients/methods: Forty-eight prospective patients in this interim analysis received a single plasmaderived, von Willebrand factor-stabilized, FVIII concentrate (pdFVIII/VWF) for ITI. According to recommended Bonn protocol, 'low responders' at ITI start (<5 BU) received 50-100 IU FVIII kg À1 daily, or every other day; 'high responders' (≥5 BU) received 100 IU FVIII kg À1 every 12 h. Results: Forty of 48 patients (83.3%), had at least one risk factor for poor ITI-prognosis at ITI start (i.e. age ≥7 years, >2 years since inhibitor diagnosis, inhibitor titre ≥10 BU at the start of ITI, or prior ITI failure). Nonetheless, 34 patients (70.8%) achieved complete success, 3 (6.3%) partial success, 1 (2.1%) partial response; ITI failed in 10 patients (20.8%), all with poor prognosis factors. All six low responders achieved complete success. ITI outcome was significantly associated with inhibitor titre level at ITI start (P = 0.0068), number of poor prognosis factors for ITI success (P = 0.0187), monthly bleeding rate during ITI (P = 0.0005) and peak inhibitor titre during ITI (P = 0.0007). Twenty-two of 35 high responder patients (62.9%) with ≥1 poor prognosis factor achieved complete success. Conclusion: Treatment with a single pdFVIII/VWF concentrate, mainly according to the Bonn protocol, resulted in a high ITI success rate in haemophilia A patients with inhibitors and poor prognosis for ITI success.

Peripheral T cell lymphomas (PTCL) are rare in children and adolescents, and data about outcome and treatment results are scarce. The present study is a joint, international, retrospective analysis of 143 reported cases of non-anaplastic PTCL in patients <19 years of age, with a focus on treatment and outcome features. One hundred forty-three patients, between 0.3 and 18.7 years old, diagnosed between 2000 and 2015 were included in the study. PTCL not otherwise specified was the largest subgroup, followed by extranodal NK/T cell lymphoma, hepatosplenic T cell lymphoma (HS TCL), and subcutaneous panniculitis-like T cell lymphoma (SP TCL). Probability of overall survival (pOS) at 5 years for the whole group was 0.56 ± 0.05, and probability of event-free survival was (pEFS) 0.45 ± 0.05. Patients with SP TCL had a good outcome with 5-year pOS of 0.78 ± 0.1 while patients with HS TCL were reported with 5-year pOS of only 0.13 ± 0.12. Twenty-five percent of the patients were reported to have a pre-existing condition, and this group had a dismal outcome with 5-year pOS of 0.29 ± 0.09. The distribution of non-anaplastic PTCL subtypes in pediatric and adolescent patients differs from what is reported in adult patients. Overall outcome depends on the subtype with some doing better than others. Pre-existing conditions are frequent and associated with poor outcomes. There is a clear need for subtype-based treatment recommendations for children and adolescents with PTCL.

C hildren and adolescents with pre-existing conditions such as DNA repair defects or other primary immunodeficiencies have an increased risk of non-Hodgkin lymphoma. However, largescale data on patients with non-Hodgkin lymphoma and their entire spectrum of pre-existing conditions are scarce. A retrospective multinational study was conducted by means of questionnaires sent out to the national study groups or centers, by the two largest consortia in childhood non-Hodgkin lymphoma, the European Intergroup for Childhood non-Hodgkin Lymphoma, and the international BerlinFrankfurt-Münster Study Group. The study identified 213 patients with non-Hodgkin lymphoma and a pre-existing condition. Four subcategories were established: a) cancer predisposition syndromes (n=124, 58%); b) primary immunodeficiencies not further specified (n=27, 13%); c) genetic diseases with no increased cancer risk (n=40, 19%); and d) non-classifiable conditions (n=22, 10%). Seventy-nine of 124 (64%) cancer predispositions were reported in groups with more than 20 patients: ataxia telangiectasia (n=32), Nijmegen breakage syndrome (n=26), constitutional mis-

No abstract

We present 25-year experience with inhibitors in previously untreated patients (PUPs) with severe hemophilia A in Slovakia, where safe factor VIII (FVIII) concentrates have been used since 1990. A prospective study focused on inhibitor incidence in PUPs was established in 1997. Out of a total 61 PUPs born between January 1997 and October 2015, 59 were eligible for evaluation; 50 and 9 were treated with > 20 exposure days (ED) of plasma-derived FVIII (pdFVIII) and recombinant FVIII (rFVIII) products, respectively. In the entire group 13/59 (22%) PUPs developed inhibitors; i.e. 7/50 (14%) and 6/9 (67%) treated with pdFVIII and rFVIII, respectively. Univariate analysis of inhibitor risk factors in patient groups with and without inhibitors showed the rFVIII and serious/ recurrent infections within the first 50 EDs to be associated with inhibitor development (OR of 12.3 [95% CI 2.48-60.83; p ¼ 0.002] and 5.0; [95% CI 1.16-21.9; p ¼ 0.03), respectively]). Also, in multivariate Cox regression analysis, peak treatment ! 5 EDs reached statistical significance. The hazard ratio (HR) was 7.15 (95% CI 1.65-31.36) p ¼ 0.0086 for rFVIII and 4.38 (95% CI 1.02-18.67) p ¼ 0.046 for intensive treatment. Between 1993 and 2015, 21 immune tolerance inductions (ITIs) in 19 inhibitor patients were performed in the two largest hemophilia centers in Slovakia. In all but one ITI courses pdFVIII containing von Willebrand factor (FVIII/VWF) was used with preferred use of high-dose ITI (HD ITI) in high responders (HRs). Complete or partial success was achieved in 17/19 (89.5%) patients. Evaluating only the patients who already completed ITI, the success rate was even higher (15/16; 94%), including 7/7 low responders and

Despite poor survival, controversies remain in the treatment for refractory or relapsed pediatric non-Hodgkin lymphoma (r/r NHL). The current project aimed to collect international experience on the re-induction treatment of r/r NHL, hematopoietic stem cell transplantation (HSCT), risk factors associated with outcome, and to suggest treatment recommendations. Inclusion criteria were (i) refractory disease, disease progression or relapse of any NHL subtype except anaplastic large cell lymphoma, (ii) age < 18 years at initial diagnosis, (iii) diagnosis in/after January 2000. Data from 639 eligible patients were evaluable. The eight-year probability of overall survival was 34 ± 2% with highly significant differences according to NHL subtypes: 28 ± 3% for 254 Burkitt lymphoma/leukemia, 50 ± 6% for 98 diffuse large B-cell lymphomas, 57 ± 8% for 41 primary mediastinal large B-cell lymphomas, 27 ± 3% for 177 T-lymphoblastic lymphomas, 52 ± 10% for 34 precursor-B-cell lymphoblastic lymphomas and 30 ± 9% for 35 patients with rare NHL subtypes. Subtype-specific factors associated with survival and treatment recommendations are suggested. There were no survivors without HSCT, except in few very small subgroups. Conclusions: There is an urgent need to further improve survival in r/r NHL. The current study provides the largest real-world series, which underlines the role of HSCT and suggests treatment recommendations.

Acute lymphoblastic leukemia is the most common form of cancer in children. The 10-year event-free survival ranged from 77 to 85% after having achieved complete remission rates of 93% or higher. The main cause of treatment failure is relapse arising from outgrowth of residual leukemic cells that are refractory to therapy. An intense effort has been made to develop methods to determine the degree of minimal residual leukemia cells present in patients considered to be in morphological remission. Because of the strong correlation between minimal residual disease (MRD) levels and risk of relapse, monitoring of MRD provides unique information regarding treatment response. The MRD monitoring based on real-time quantitative PCR detection of patient-specific immunoglobulin and T-cell receptor (Ig/TCR) gene rearrangements is currently considered to be the most reliable tool for MRD-based diagnosis in ALL. Because the significance of MRD monitoring has been strongly supported by several studies and because it has been implemented in the latest protocols, there has been a significant effort to develop MRD monitoring in the Slovak Republic since 2005. Between October 2006 and December 2009, 50 children with ALL who were treated at three Slovak centers were included in the RQ PCR MRD pilot project. A total of 40 patients with BCP-ALL ( B cell precursor ALL) and 4 patients with T ALL were analyzed for Ig/TCR rearrangement. We identified 106 different rearrangements in the 44 ALL patients analyzed. Based on MRD stratification, we identified 26 patients who were stratified into the HRG ( high risk group) (n = 3; 11.5%), IRG ( intermediate risk group) (n = 14; 54%) and SRG ) standard risk group) (n = 9; 34.5%). Morphology-based risk stratification allows the identification of most HRG patients identified also by MRD-based stratification, but fails to discriminate the IRG assigned to therapy reduction. Patients in the SRG and the IRG could profit from MRD-based risk assignment. Key words: pediatric acute lymphoblastic leukemia, minimal residual disease, immunoglobulin and T cell receptor gene rearrangements -stories of clinical oncology [1,2]. In 2000, the treatment results of childhood ALL trials performed in the early 1990s by major study groups were uniformly presented. The 10-year event-free survival ranged from 77 to 85% after having achieved complete remission rates of 93% or higher [3,4,5,6]. The main cause of treatment failure, which occurs in approximately 20% of patients, is relapse arising from outgrowth of residual leukemic cells that are refractory to therapy.Over the last 2-3 decades, an intense effort has been made to develop methods to determine the degree of residual leukemia Neoplasma 57, 6, 2010 Acute lymphoblastic leukemia (ALL) is the most common form of cancer in children, accounting for approximately 25% of all childhood cancers and about 80% of childhood leukemia. The treatment of childhood ALL is one of the true success Abbreviations: D33P -MRD positivity at day 33; D33N -MRD negativity at day 33; D78P -M...

Treatment of childhood acute lymphoblastic leukemia (ALL) according to the 1st Slovak protocol started in the Slovak Republic in 1971 in eight pediatric departments. Gradually, two other protocols were written, and 496 children were treated with these three protocols from 1971 to 1992. Since 1992, all children have been treated in three pediatric oncological departments. From 1992 to 1996, protocols for standard and high-risk ALL were developed that were used for 111 children in Bratislava, while the centres in Banska Bystrica and Košice had started to use BFM protocols. Since 1997, all patients with ALL have been treated according to ALL BFM 95, and since 2002, they have been included in the ALL IC BFM 2002 study. We evaluated treatment results in the standard arm of ALL BFM 95 and compared it with previous Slovak protocols. Rates of complete remission increased from 90.6% in the fi rst Slovak protocol to 97.1% in BFM 95; EFS and OS increased from 0.46 and 0.50 to 0.67 and 0.72, respectively. Relapse rates decreased from 42% to 20.5%. EFS was signifi cantly worse in children with leukocyte counts >100 × 10 9 /l and in the HR group in comparison to standard-and medium-risk groups. OS was also signifi cantly worse in T-cell ALL than in B-cell ALL. Death rates in the 1st complete remission decreased gradually in the Slovak protocols from 10.4% to 1.8%, but were high in BFM 95 (10.8%) due to more intensive therapy and initial unsatisfactory experiences with BFM protocols. All parameters improved in the ALL IC BFM 2002 study.