Integration of RNA Sequencing, Whole Exome Sequencing, and Flow Cytometry Into Routine Diagnostic Workup of Pediatric Lymphomas.

The study was conducted to assess the feasibility of integrating state-of-the-art sequencing techniques and flow cytometry into diagnostic workup of pediatric lymphoma. RNA sequencing (RNAseq), whole exome sequencing, and flow cytometry were implemented into routine diagnostic workup of pediatric biopsies with lymphoma in the differential diagnosis. Within 1 year, biopsies from 110 children (122 specimens) were analyzed because of suspected malignant lymphoma. The experience with a standardized workflow combining histology and immunohistochemistry, flow cytometry, and next-generation sequencing technologies is reported. Flow cytometry was performed with fresh tissue in 83% (102/122) of specimens and allowed rapid diagnosis of T-cell and B-cell non-Hodgkin lymphomas. RNAseq was performed in all non-Hodgkin lymphoma biopsies and 42% (19/45) of Hodgkin lymphoma samples. RNAseq detected all but one of the translocations found by fluorescence in situ hybridization and PCR. RNAseq and whole exome sequencing identified additional genetic abnormalities not detected by conventional approaches. Finally, 3 cases are highlighted to exemplify how synergy between different diagnostic techniques and specialists can be achieved. This study demonstrates the feasibility and discusses the added value of integrating modern sequencing techniques and flow cytometry into a workflow for routine diagnostic workup of lymphoma. The inclusion of RNA and DNA sequencing not only supports diagnostics but also will lay the ground for the development of novel research-based treatment strategies for pediatric lymphoma patients.

Nivolumab plus Brentuximab vedotin +/- bendamustine combination therapy: a safe and effective treatment in pediatric recurrent and refractory classical Hodgkin lymphoma.

Introduction: Classical Hodgkin lymphoma (cHL) is the most common pediatric lymphoma. Approximately 10% of patients develop refractory or recurrent disease. These patients are treated with intensive chemotherapy followed by consolidation with radiotherapy or high-dose chemotherapy and autologous stem cell reinfusion. Although this treatment is effective, it comes at the cost of severe long-term adverse events, such as reduced fertility and an increased risk of secondary cancers. Recently, promising results of inducing remission with the immune checkpoint inhibitor nivolumab (targeting PD-1) and the anti-CD30 antibody-drug conjugate Brentuximab vedotin (BV) +/- bendamustine were published. Methods: Here we describe a cohort of 10 relapsed and refractory pediatric cHL patients treated with nivolumab + BV +/- bendamustine to induce remission prior to consolidation with standard treatment. Results and discussion: All patients achieved complete remission prior to consolidation treatment and are in ongoing complete remission with a median follow-up of 25 months (range: 12 to 42 months) after end-of-treatment. Only one adverse event of CTCAE grade 3 or higher due to nivolumab + BV was identified. Based on these results we conclude that immunotherapy with nivolumab + BV +/- bendamustine is an effective and safe treatment to induce remission in pediatric R/R cHL patients prior to standard consolidation treatment. We propose to evaluate this treatment further to study putative long-term toxicity and the possibility to reduce the intensity of consolidation treatment.

IgA antibody immunotherapy targeting GD2 is effective in preclinical neuroblastoma models.

BACKGROUND: Immunotherapy targeting GD2 is very effective against high-risk neuroblastoma, though administration of anti-GD2 antibodies induces severe and dose-limiting neuropathic pain by binding GD2-expressing sensory neurons. Previously, the IgG1 ch14.18 (dinutuximab) antibody was reformatted into the IgA1 isotype, which abolishes neuropathic pain and induces efficient neutrophil-mediated antibody-dependent cellular cytotoxicity (ADCC) via activation of the Fc alpha receptor (FcαRI/CD89). METHODS: To generate an antibody suitable for clinical application, we engineered an IgA molecule (named IgA3.0 ch14.18) with increased stability, mutated glycosylation sites and substituted free (reactive) cysteines. The following mutations were introduced: N45.2G and P124R (CH1 domain), C92S, N120T, I121L and T122S (CH2 domain) and a deletion of the tail piece P131-Y148 (CH3 domain). IgA3.0 ch14.18 was evaluated in binding assays and in ADCC and antibody-dependent cellular phagocytosis (ADCP) assays with human, neuroblastoma patient and non-human primate effector cells. We performed mass spectrometry analysis of N-glycans and evaluated the impact of altered glycosylation in IgA3.0 ch14.18 on antibody half-life by performing pharmacokinetic (PK) studies in mice injected intravenously with 5 mg/kg antibody solution. A dose escalation study was performed to determine in vivo efficacy of IgA3.0 ch14.18 in an intraperitoneal mouse model using 9464D-GD2 neuroblastoma cells as well as in a subcutaneous human xenograft model using IMR32 neuroblastoma cells. Binding assays and PK studies were compared with one-way analysis of variance (ANOVA), ADCC and ADCP assays and in vivo tumor outgrowth with two-way ANOVA followed by Tukey's post-hoc test. RESULTS: ADCC and ADCP assays showed that particularly neutrophils and macrophages from healthy donors, non-human primates and patients with neuroblastoma are able to kill neuroblastoma tumor cells efficiently with IgA3.0 ch14.18. IgA3.0 ch14.18 contains a more favorable glycosylation pattern, corresponding to an increased antibody half-life in mice compared with IgA1 and IgA2. Furthermore, IgA3.0 ch14.18 penetrates neuroblastoma tumors in vivo and halts tumor outgrowth in both 9464D-GD2 and IMR32 long-term tumor models. CONCLUSIONS: IgA3.0 ch14.18 is a promising new therapy for neuroblastoma, showing (1) increased half-life compared to natural IgA antibodies, (2) increased protein stability enabling effortless production and purification, (3) potent CD89-mediated tumor killing in vitro by healthy subjects and patients with neuroblastoma and (4) antitumor efficacy in long-term mouse neuroblastoma models.

Characterization of human Fc alpha receptor transgenic mice: comparison of CD89 expression and antibody-dependent tumor killing between mouse strains.

Since mice do not express a homologue of the human Fc alpha receptor (FcαRI or CD89), a transgenic mouse model was generated in four different backgrounds (C57BL/6, BALB/c, SCID and NXG) expressing the FcαRI under the endogenous human promoter. In this study, we describe previously unknown characteristics of this model, such as the integration site of the FCAR gene, the CD89 expression pattern in healthy male and female mice and in tumor-bearing mice, expression of myeloid activation markers and FcγRs and IgA/CD89-mediated tumor killing capacity. In all mouse strains, CD89 expression is highest in neutrophils, intermediate on other myeloid cells such as eosinophils and DC subsets and inducible on, among others, monocytes, macrophages and Kupffer cells. CD89 expression levels are highest in BALB/c and SCID, lower in C57BL/6 and lowest in NXG mice. Additionally, CD89 expression on myeloid cells is increased in tumor-bearing mice across all mouse strains. Using Targeted Locus Amplification, we determined that the hCD89 transgene has integrated in chromosome 4. Furthermore, we established that wildtype and hCD89 transgenic mice have a similar composition and phenotype of immune cells. Finally, IgA-mediated killing of tumor cells is most potent with neutrophils from BALB/c and C57BL/6 and less with neutrophils from SCID and NXG mice. However, when effector cells from whole blood are used, SCID and BALB/c are most efficient, since these strains have a much higher number of neutrophils. Overall, hCD89 transgenic mice provide a very powerful model to test the efficacy of IgA immunotherapy against infectious diseases and cancer.

Improving outcomes of childhood and young adult non-Hodgkin lymphoma: 25 years of research and collaboration within the framework of the European Intergroup for Childhood Non-Hodgkin Lymphoma.

The European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL) was established 25 years ago with the goal to facilitate clinical trials and research collaborations in the field both within Europe and worldwide. Since its inception, much progress has been made whereby major improvements in outcomes have been achieved. In this Review, we describe the different diagnostic entities of non-Hodgkin lymphoma in children and young adults describing key features of each entity and outlining clinical achievements made in the context of the EICNHL framework. Furthermore, we provide an overview of advances in biopathology with an emphasis on the role of biological studies and how they have shaped available treatments. Finally, for each entity, we describe future goals, upcoming clinical trials, and highlight areas of research that require our focus going forward.

Machine Learning Logistic Regression Model for Early Decision Making in Referral of Children with Cervical Lymphadenopathy Suspected of Lymphoma.

While cervical lymphadenopathy is common in children, a decision model for detecting high-grade lymphoma is lacking. Previously reported individual lymphoma-predicting factors and multivariate models were not sufficiently discriminative for clinical application. To develop a diagnostic scoring tool, we collected data from all children with cervical lymphadenopathy referred to our national pediatric oncology center within 30 months (n = 182). Thirty-nine putative lymphoma-predictive factors were investigated. The outcome groups were classical Hodgkin lymphoma (cHL), nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), non-Hodgkin lymphoma (NHL), other malignancies, and a benign group. We integrated the best univariate predicting factors into a multivariate, machine learning model. Logistic regression allocated each variable a weighing factor. The model was tested in a different patient cohort (n = 60). We report a 12-factor diagnostic model with a sensitivity of 95% (95% CI 89-98%) and a specificity of 88% (95% CI 77-94%) for detecting cHL and NHL. Our 12-factor diagnostic scoring model is highly sensitive and specific in detecting high-grade lymphomas in children with cervical lymphadenopathy. It may enable fast referral to a pediatric oncologist in patients with high-grade lymphoma and may reduce the number of referrals and unnecessary invasive procedures in children with benign lymphadenopathy.

Thymus and activation-regulated chemokine (TARC) as treatment response marker for paediatric Hodgkin lymphoma: A pilot study.

Classical Hodgkin lymphoma (cHL) is characterised by malignant Hodgkin Reed-Sternberg cells located in an inflammatory microenvironment. Blood biomarkers result from active cross-talk between malignant and non-malignant cells. One promising biomarker in adult patients with cHL is thymus and activation-regulated chemokine (TARC). We investigated TARC as marker for interim and end-of-treatment response in paediatric cHL. In this multicentre prospective study, TARC levels were measured among 99 paediatric patients with cHL before each cycle of chemotherapy and were linked with interim and end-of-treatment remission status. TARC levels were measured by enzyme-linked immunosorbent assay. At diagnosis, TARC levels were elevated in 96% of patients. Plasma TARC levels declined significantly after one cycle of chemotherapy (p < 0.01 vs. baseline) but did not differ at interim assessment by positron emission tomography (p = 0.31). In contrast, median plasma TARC at end of treatment was significantly higher in three patients with progressive disease compared to those in complete remission (1.226 vs. 90 pg/ml; p < 0.001). We demonstrate that, in paediatric patients, plasma TARC is a valuable response marker at end-of-treatment, but not at interim analysis after the first two chemotherapy cycles. Further research is necessary to investigate TARC as marker for long-term progression free survival.

The Prognostic Value of Eight Immunohistochemical Markers Expressed in the Tumor Microenvironment and on Hodgkin Reed-Sternberg Cells in Pediatric Patients With Classical Hodgkin Lymphoma.

Immunohistochemical markers are associated with treatment outcome in adults with classical Hodgkin Lymphoma (cHL). Studies in children are scarce and inconsistent. We investigated in 67 children with cHL, whether the expression of CD15, CD30, PAX5, PD-1, PD-L1, CD68, CD163 and TARC at diagnosis is associated with disease free survival (DFS) and with interim remission status. Low CD15 and low TARC expression were associated with relapsed disease. Low expression of PD-L1 was associated with complete remission at interim PET-scan. Our data suggest a difference between pediatric and adult cHL. This underlines the importance of future research into specific prognostic factors in pediatric cHL, indispensable for improvement of treatment in this population.

Central venous catheter-associated complications in pediatric patients diagnosed with Hodgkin lymphoma: implications for catheter choice.

PURPOSE: The purpose of this study was to determine the most optimal central venous catheter (CVC) for pediatric patients with Hodgkin lymphoma (HL) in terms of complications. METHODS: A retrospective study including patients diagnosed with HL from 2015 to 2021 at the Princess Máxima Center was performed. Patients were followed from CVC insertion until removal or 06-2021, whichever came first. The primary outcome was the CVC-related complication incidence rate (IR) per 1000 CVC-days. Furthermore, the incidence rate ratio (IRR) was calculated by comparing complication IRs between peripherally inserted central catheters (PICC) and totally implantable venous access ports (TIVAP). Additionally, risk factors for central venous thrombosis (CVT) were identified. RESULTS: A total of 98 patients were included. The most frequently observed complications were local irritation/infections (18%; IR 0.93), malfunctions (15%; IR 0.88), and CVC-related CVTs (10%; IR 0.52). Single lumen PICCs were associated with a higher risk of complications (49% vs. 26%; IRR 5.12, CI95% 2.76-9.50), severe complications (19% vs. 7%; IRR 11.96, CI95% 2.68-53.42), and early removal (18% vs. 7%; IRR 9.96, CI95% 2.18-45.47). A single lumen PICC was identified as a risk factor for CVC-related CVT when compared to TIVAPs (12% vs. 7%, IRR 6.98, CI95% 1.45-33.57). CONCLUSION: The insertion of a TIVAP rather than a PICC should be recommended for pediatric patients with HL, especially in the presence of CVT-related risk factors. Future trials should evaluate the efficacy and safety of direct oral anticoagulants for the primary prevention of CVT in pediatric patients with a PICC and other CVT-related risk factors.

EWSR1-WT1 Target Genes and Therapeutic Options Identified in a Novel DSRCT In Vitro Model.

Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive soft tissue sarcoma with a lack of effective treatment options and a poor prognosis. DSRCT is characterized by a chromosomal translocation, resulting in the EWSR1-WT1 gene fusion. The molecular mechanisms driving DSRCT are poorly understood, and a paucity of preclinical models hampers DSRCT research. Here, we establish a novel primary patient-derived DSRCT in vitro model, recapitulating the original tumor. We find that EWSR1-WT1 expression affects cell shape and cell survival, and we identify downstream target genes of the EWSR1-WT1 fusion. Additionally, this preclinical in vitro model allows for medium-throughput drug screening. We discover sensitivity to several drugs, including compounds targeting RTKs. MERTK, which has been described as a therapeutic target for several malignancies, correlates with EWSR1-WT1 expression. Inhibition of MERTK with the small-molecule inhibitor UNC2025 results in reduced proliferation of DSRCT cells in vitro, suggesting MERTK as a therapeutic target in DSRCT. This study underscores the usefulness of preclinical in vitro models for studying molecular mechanisms and potential therapeutic options.

Anti-GD2 IgA kills tumors by neutrophils without antibody-associated pain in the preclinical treatment of high-risk neuroblastoma.

BACKGROUND: The addition of monoclonal antibody therapy against GD2 to the treatment of high-risk neuroblastoma led to improved responses in patients. Nevertheless, administration of GD2 antibodies against neuroblastoma is associated with therapy-limiting neuropathic pain. This severe pain is evoked at least partially through complement activation on GD2-expressing sensory neurons. METHODS: To reduce pain while maintaining antitumor activity, we have reformatted the approved GD2 antibody ch14.18 into the IgA1 isotype. This novel reformatted IgA is unable to activate the complement system but efficiently activates leukocytes through the FcαRI (CD89). RESULTS: IgA GD2 did not activate the complement system in vitro nor induced pain in mice. Importantly, neutrophil-mediated killing of neuroblastoma cells is enhanced with IgA in comparison to IgG, resulting in efficient tumoricidal capacity of the antibody in vitro and in vivo. CONCLUSIONS: Our results indicate that employing IgA GD2 as a novel isotype has two major benefits: it halts antibody-induced excruciating pain and improves neutrophil-mediated lysis of neuroblastoma. Thus, we postulate that patients with high-risk neuroblastoma would strongly benefit from IgA GD2 therapy.

Biology and Clinical Applicability of Plasma Thymus and Activation-Regulated Chemokine (TARC) in Classical Hodgkin Lymphoma.

Thymus and activation-regulated chemokine (TARC) is produced by different cell types and is highly expressed in the thymus. It plays an important role in T cell development, trafficking and activation of mature T cells after binding to its receptor C-C chemokine receptor type 4 (CCR4) and consecutive signal transducer and activator of transcription 6 (STAT6) activation. Importantly, TARC is also produced by malignant Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). In cHL, HRS cells survive and proliferate due to the micro-environment consisting primarily of type 2 T helper (Th2) cells. TARC-mediated signaling initiates a positive feedback loop that is crucial for the interaction between HRS and T cells. The clinical applicability of TARC is diverse. It is useful as diagnostic biomarker in both children and adults with cHL and in other Th2-driven diseases. In adult cHL patients, TARC is also a biomarker for treatment response and prognosis. Finally, blocking TARC signaling and thus inhibiting pathological Th2 cell recruitment could be a therapeutic strategy in cHL. In this review, we summarize the biological functions of TARC and focus on its role in cHL pathogenesis and as a biomarker for cHL and other diseases. We conclude by giving an outlook on putative therapeutic applications of antagonists and inhibitors of TARC-mediated signaling.

Single-cell atlas of developing murine adrenal gland reveals relation of Schwann cell precursor signature to neuroblastoma phenotype.

Neuroblastoma is the most common extracranial solid tumor and accounts for ∼10% of pediatric cancer-related deaths. The exact cell of origin has yet to be elucidated, but it is generally accepted that neuroblastoma derives from the neural crest and should thus be considered an embryonal malignancy. About 50% of primary neuroblastoma tumors arise in the adrenal gland. Here, we present an atlas of the developing mouse adrenal gland at a single-cell level. Five main cell cluster groups (medulla, cortex, endothelial, stroma, and immune) make up the mouse adrenal gland during fetal development. The medulla group, which is of neural crest origin, is further divided into seven clusters. Of interest is the Schwann cell precursor ("SCP") and the "neuroblast" cluster, a highly cycling cluster that shares markers with sympathoblasts. The signature of the medullary SCP cluster differentiates neuroblastoma patients based on disease phenotype: The SCP signature score anticorrelates with ALK and MYCN expression, two indicators of poor prognosis. Furthermore, a high SCP signature score is associated with better overall survival rates. This study provides an insight into the developing adrenal gland and introduces the SCP gene signature as being of interest for further research in understanding neuroblastoma phenotype.

Upcoming immunotherapeutic combinations for B-cell lymphoma.

After initial introduction for B-cell lymphomas as adjuvant therapies to established cancer treatments, immune checkpoint inhibitors and other immunotherapies are now integrated in mainstream regimens, both in adult and pediatric patients. We here provide an overview of the current status of combination therapies for B-cell lymphoma, by in-depth analysis of combination therapy trials registered between 2015-2020. Our analysis provides new insight into the rapid evolution in lymphoma treatment, as propelled by new additions to the treatment arsenal. We conclude with prospects on upcoming clinical trials which will likely use systematic testing approaches of more combinations of established chemotherapy regimens with new agents, as well as new combinations of immunotherapy and targeted therapy. Future trials will be set up as basket or umbrella-type trials to facilitate the evaluation of new drugs targeting specific genetic changes in the tumor or associated immune microenvironment. As such, lymphoma patients will benefit by receiving more tailored treatment that is based on synergistic effects of chemotherapy combined with new agents targeting specific aspects of tumor biology and the immune system.

Improved survival for adolescents and young adults with Hodgkin lymphoma and continued high survival for children in the Netherlands: a population-based study during 1990-2015.

Population-based studies that assess long-term patterns of incidence, major aspects of treatment and survival are virtually lacking for Hodgkin lymphoma (HL) at a younger age. This study assessed the progress made for young patients with HL (<25 years at diagnosis) in the Netherlands during 1990-2015. Patient and tumour characteristics were extracted from the population-based Netherlands Cancer Registry. Time trends in incidence and mortality rates were evaluated with average annual percentage change (AAPC) analyses. Stage at diagnosis, initial treatments and site of treatment were studied in relation to observed overall survival (OS). A total of 2619 patients with HL were diagnosed between 1990 and 2015. Incidence rates increased for 18-24-year-old patients (AAPC + 1%, P = 0·01) only. Treatment regimens changed into less radiotherapy and more 'chemotherapy only', different for age group and stage. Patients aged 15-17 years were increasingly treated at a paediatric oncology centre. The 5-year OS for children was already high in the early 1990s (93%). For patients aged 15-17 and 18-24 years the 5-year OS improved from 84% and 90% in 1990-1994 to 96% and 97% in 2010-2015, respectively. Survival for patients aged 15-17 years was not affected by site of treatment. Our present data demonstrate that significant progress in HL treatment has been made in the Netherlands since 1990.

Plasma thymus and activation-regulated chemokine (TARC) as diagnostic marker in pediatric Hodgkin lymphoma.

Pediatric classical Hodgkin's lymphoma (cHL) is characterized by Hodgkin Reed-Sternberg cells located in an inflammatory microenvironment. Blood biomarkers result from active crosstalk between these cells. One promising biomarker in adult cHL patients is "thymus-and-activation-regulated chemokine" (TARC). The objectives of this study were to define normal TARC values in non-cHL children and to investigate and correlate pretherapy TARC as diagnostic marker in pediatric cHL. In this multicenter prospective study, plasma and serum samples were collected of newly diagnosed cHL patients before start of treatment (n = 49), and from randomly selected non-cHL patients (n = 81). TARC levels were measured by enzyme-linked immunosorbent assay. The non-cHL patients had a median plasma TARC value of 71 pg/mL (range: 18-762), compared to 14 619 pg/mL (range: 380-73 174) in cHL patients (P < .001). TARC values had a high discriminatory power (AUC = .999; 95% confidence interval, .998-1). A TARC cutoff level of 942 pg/mL maximized the sum of sensitivity (97.9%) and specificity (100%). TARC plasma levels were associated with age, treatment level, bulky disease, B-symptoms, and erythrocyte sedimentation rate. TARC was found to be a highly specific and sensitive diagnostic marker for pediatric cHL. This noninvasive marker could be of great value as screening test in the work-up for pediatric patients with lymphadenopathy.

Increased risk of hematologic malignancies in primary immunodeficiency disorders: opportunities for immunotherapy.

Primary immunodeficiency disorders (PIDs) convey increased susceptibility to infections and sometimes to malignancies, particularly lymphomas. Such cancer development can be contributed by immune impairments resulting in weakened immunological surveillance against (pre)malignant cells and oncogenic viruses. Molecular defects in PID-patients are therefore being clarified, identifying new targets for innovative immunotherapy. Particularly pediatric cancers are being scrutinized, where over one-third of cancer-related deaths are accounted for by leukemia and lymphomas. Here we review how immunopathogenic mechanisms of several PIDs might associate with lymphoma development. We furthermore delineate existing immunotherapy strategies in adults for potential therapeutic application in childhood leukemia and lymphomas.

Expression and clinical association of programmed cell death-1, programmed death-ligand-1 and CD8+ lymphocytes in primary sarcomas is subtype dependent.

In order to explore the potential of immune checkpoint blockade in sarcoma, we investigated expression and clinical relevance of programmed cell death-1 (PD-1), programmed death ligand-1 (PD-L1) and CD8 in tumors of 208 sarcoma patients. Primary untreated osteosarcoma (n = 46), Ewing sarcoma (n = 32), alveolar rhabdomyosarcoma (n = 20), embryonal rhabdomyosarcoma (n = 77), synovial sarcoma (n = 22) and desmoplastic small round cell tumors (DSRCT) (n = 11) were examined immunohistochemically. PD-L1 expression was predominantly detected in alveolar and embryonal rhabdomyosarcomas (15% and 16%, respectively). In the alveolar subtype PD-L1 expression was associated with better overall, event-free and metastases-free survival. PD-1 expression on lymphocytes was predominantly seen in synovial sarcomas (18%). High levels of CD8+ lymphocytes were predominantly detected in osteosarcomas (35%) and associated with worse event-free survival in synovial sarcomas. Ewing sarcoma and DSRCTs showed PD-1 on tumor cells instead of on tumor infiltrating lymphocytes. Overall, expression and clinical associations were found to be subtype dependent. For the first time PD-1 expression on Ewing sarcoma (19%) and DSRCT (82%) tumor cells was described.

Antibody therapies for lymphoma in children.

BACKGROUND: Lymphomas are the third most common malignancy in childhood. Cure rates are high but have reached a plateau. Therefore new treatment modalities should be developed. Antibody therapy is a successful new treatment option in adult lymphoma. However, none of the therapeutic antibodies available for adults with cancer have been approved for treatment of paediatric lymphoma. OBJECTIVES: To assess the efficacy of antibody therapy for childhood lymphoma in terms of survival, response and relapse rates, compared with therapy not including antibody treatment. To assess quality of life and the occurrence of adverse effects caused by antibody therapy treatment in children compared with therapy not including antibody treatment. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2014, Issue 10), MEDLINE in PubMed (from 1945 to October 2014), EMBASE in EMBASE.com (from 1980 to October 2014) and reference lists of relevant articles. Furthermore, we searched conference proceedings abstracts of SIOP, ASCO and ASH for studies from 2009 to 2013), and the World Health Organization (WHO) ICTRP portal and ClinicalTrials.gov for ongoing trials. SELECTION CRITERIA: Randomised controlled trials and controlled clinical trials comparing conventional therapy with antibody therapy in children with lymphoma. DATA COLLECTION AND ANALYSIS: Two authors independently performed the study selection. MAIN RESULTS: We found no studies meeting the inclusion criteria of the review. AUTHORS' CONCLUSIONS: At this moment, it is not possible to draw evidence-based conclusions regarding clinical practice. Phase I and II studies show a positive effect of using antibody therapy in childhood lymphoma. Further research is needed to evaluate and implement antibody therapy for paediatric lymphoma.