Rivaroxaban Compared with Standard Anticoagulants for the Treatment of Acute Venous Thromboembolism in Children: a Randomised, Controlled, Phase 3 Trial

Background: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. Methods: In a multicentre, parallel-group, open-label, randomised study, children (aged 0–17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. Findings: From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87–95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29–35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0·40, 95% CI 0·11–1·41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0·012). Major or clinically relevant non-major bleeding in participants who received ≥1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1·58, 95% CI 0·51–6·27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. Interpretation: In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. Funding: Bayer AG and Janssen Research & Development. © 2020 Elsevier Ltd

Immunophenotypic features of bone marrow tumor cell in Burkitt lymphoma/leukemia: B-lineage acute lymphoblastic leukemia diagnostics opportunities

Bone marrow tumor blasts immunophenotyping is an essential part of Burkitt lymphoma/leukemia (BL) and B-cell precursor acute lymphoblastic leukemia (BCP-ALL) differential diagnostics. Nevertheless immunoglobulin heavy and light chains detection on the cell surface could meet several biological and methodological pitfals. Thus the aim of the present study was development of additional BL immunophenotypic criteria. Leukemic blasts antigen profile in 21 BL cases and 84 children with BCP-ALL was compared in a retrospective way. Antigen expression patterns in BL and BCP-ALL were significantly different. It was shown that even in cases with weak immunoglobulin M expression these two tumor types could be distinguished well by complex immunophenotype analysis. In present study all cases of CD34-negative B-lineage ALL without myeloid coexpression and with high CD20-positive cells proportion belonged to BL

SECONDARY SOLID TUMORS IN CHILDREN AFTER ALLOGENEIC HEMATOPOIETIC STEM CELLS TRANSPLANTATION: CASE REPORTS AND LITERATURE REVIEW

Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective approach to cure numerous malignant and nonmalignant diseases. This method is more available now, respectively the number of survivors – recipients of HSCT increases every year. Among long-term complications of HSCT secondary solid cancers are one of the most life-threatening. We discuss different types of secondary solid tumours after HSCT and describe international recommendations of their screening and diagnostic. Several case reports from the single center could illustrate these serious late effects

Treatment of B-cells non-Hodgkin lymphomas with combined immunochemotherapy: ability to treatment optimization

The results of two consecutive multicenter clinical trials enrolled 241 patient with childhood mature B-cells non-Hodgkin lymphomas/leukemia are presented. Patients received treatment according B-NHL 2004mab protocol (n = 83) and B-NHL 2010M (n = 158) with combined immunochemotherapy (ICT) in Russian and Belarus pediatric clinics from 2004 to 2015 years. Primary patients with different mature B-NHL (Burkitt lymphoma/leukemia, diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma (DLBCL and PMBCL)) aged from 2 to 18 years are included in the studies.Protocol B-NHL 2004mab for treatment of children and adolescents with B-NHL/B-AL, stage III and IV, includes a combination of chemotherapy (PCT) and rituximab – an antibody against the B-cells receptor CD20. PCT courses similar to those in the B-NHL BFM90 protocol (group III) with the exception of methotrexate dose in induction courses, reduced to 1 g/m2 /24 h in order to reduce toxicity. Rituximab (Mabthera, 375 mg/m2 /h) used for the first time in the treatment of children and adolescents with B-NHL. Of the 83 patients included, clinical remission was achieved in 77 (92.8 %). With a median follow time of 51.6 months, remission continued in 23 (85.2 %) patients with B-AL, in 32 (88.9 %) patients with LB and 19 (95.0 %) patients – with DLBCL. With median follow time of 65.2 months, event-free and overall survival was 84 ± 6 and 82 ± 8 %, respectively.Based on previous experience in order to further optimize B-NHL treatment, new protocol B-NHL 2010M with effect-adapted therapy and improvement of stratification risk group criteria was proposed. Overall survival in patients of 1st and 2nd risk groups with full implementation of diagnosis and treatment is approaching 100 %. In interim analysis of 3rd risk group patients, pOS was 88 ± 3 %. The incidence of induction death (infections, metabolic complications) remains within 2.7 % (n = 4); refractory cases (n = 2; 1.3 %) and relapses (n = 4; 2.7 %) developed after 2–4 months of remission, were observed only in patients with Burkitt lymphoma/leukemia. In this cases 2nd line therapy and auto-HSCT is not allowed to achieve remission. All PMBCL and DLBCL patients were achieved remission, but in 50 % of cases only after second line, radio- and cell therapy.The authors conclude that a combined immunochemotherapy of B-NHL in children and adolescents, including the target drug (rituximab) and 5-day courses of cytostatic therapy, highly effective, despite a reduce induction intensity. Therapy for the analyzed protocol requires qualitative dynamic efficacy monitoring and timely correction of therapy. In order to solve a refractory problem and further reduce the toxicity, necessary to continue research using fundamental discoveries in recent years

HETEROGENEITY OF CHILDHOOD B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (EGIL SUBTYPE BIV)

Introduction. Surface immunoglobulin expression is a main immunophenotypic criteria of mature subtype of B-lineage acute lymphoblastic leukemia. Although the majority of such cases represents Burkitt leukemia/lymphoma, it was shown for several times that membrane IgM could be detected in the absence of other mature lymphomas signs.The aim of the study was to evaluate heterogeneity of childhood acute lymphoblastic leukemia (ALL) with surface IgM expression and to assess correspondence of BIV EGIL ALL subtype with Burkitt lymphoma (BL) bone marrow dissemination.Materials and methods. Immunophenotypic, cytomorfologic and genetic data of 54 BIV-ALL cases were analyzed.Results. Among the studied patients 39 had BL, while others belonged to B-cell precursor ALL (BCP-ALL). All BL patients and none of BCP-ALL patients carried C-MYC rearrangement while in BCP-ALL group in 8 cases and in any BL cases KMT2A rearrangements were found. None of BCP-ALL children had L3 morphology according to FAB classification.Conclusions. B-lineage ALL with surface IgM expression is rather heterogeneous group of cases including typical BL and rare cases of BCP-ALL even with KMT2A-rearrangements. Combination of all available diagnostic technologies will allow precise split of these two different disease and select the appropriate treatment scheme

Rare cases of laboratory tests discrepancies in diagnostics of pediatric Burkitt lymphoma/leukemia

Introduction. The main features of bone marrow blasts cells in Burkitt lymphoma/leukemia (BL) are L3 morphology, mature immunophenotype of blasts with surface IgM expression, and presence of typical MYC gene rearrangements.The aim of the study was to show discrepancy examples in laboratory signs of BL.Patients and methods. 10 patients (8 boys and 2 girls) aged 1 to 18 years were included in the present study. The inclusion criterion was the identification of discrepancies between flow cytometric, morphological and cytogenetic data.Results. In 2 cases there were no rearrangements of the MYC gene. In 2 patients, the L2 morphological variant went against the presence of typical MYC gene rearrangements. In one case, undifferentiated blasts cells were described by morphology together with presence of surface IgM, and atypical genetics. In 8 patients, there was no expression of surface IgM. Of these, patients with absence of cytomorphological data cytometric and genetic data were controversial.Сonclusion. The cases presented in this study and the cases described in the literature demonstrate the importance of an attentive and comprehensive approach in evaluating the results of laboratory tests in the diagnosis of BL