Antibody therapies for lymphoma in children

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

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. Furthermore, we aim 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.

Background

Description of the condition

Lymphomas are the third most common malignancy of childhood. They often present as painless masses, accompanied by signs and symptoms resulting from local compression, as well as systemic signs and symptoms, such as fever and weight loss (Young 2000). They comprise non-Hodgkin lymphoma, Hodgkin lymphoma and post-transplantation lymphoproliferative disease. Approximately 7% of all childhood malignancies are accounted for by non-Hodgkin lymphoma (Gross 2007). Non-Hodgkin lymphoma is more common in children older than 10 years, with a peak incidence between 15 and 19 years of age (Bickert 2002).

In paediatric non-Hodgkin lymphoma there are four major subtypes that account for about 90% of childhood non-Hodgkin lymphoma: Burkitt lymphoma, diffuse large B-cell lymphoma, precursor T- and B-cell lymphoblastic lymphoma, and anaplastic large cell lymphoma (Gross 2007; Miles 2007; Jaglowski 2009).

Burkitt lymphoma accounts for about 40% of non-Hodgkin lymphoma in children and is rare in adults (Gross 2007; Miles 2012). Current treatment with combined chemotherapy, including methotrexate, doxorubicin, cyclophosphamide, prednisolone and vincristine results in cure rates over 90% in limited disease (Miles 2007; Miles 2012), and five-year event free survival of 85-90% in advanced stage disease (Miles 2012). Cure rates for endemic Burkitt lymphoma in developing countries are usually significantly lower (<50%) due to limited resources (Hesseling 2013).

Diffuse large B-cell lymphoma make up for 10% of all childhood non-Hodgkin lymphoma (Gross 2007). Standard chemotherapy results in cure rates of over 90% in limited disease (Miles 2007).

T- and B-cell lymphoblastic lymphomas account for approximately 30% of non-Hodgkin lymphoma in children and young adults (Cairo 2005; Gross 2007; Miles 2012). Lymphoblastic lymphoma originate from immature or precursor lymphoid cells, similar to acute lymphatic leukaemia. The similarity between lymphoblastic lymphoma and acute lymphatic leukaemia results in similar chemotherapy strategies. Current cure rates are 80-85% (Miles 2007).

Anaplastic large cell lymphoma, is an, in over 90%, CD30-positive T-cell lymphoma and is responsible for 10-15% of paediatric non-Hodgkin lymphoma (Cairo 2005; Gross 2007). Initial response to the intensive and short chemotherapy regimens is over 80%, however relapse is a significant clinical problem and occurs in 25-30% of the patients within two years (Brugieres 2009; Miles 2007).

Hodgkin lymphoma accounts for 30% of the lymphomas diagnosed in children. Hodgkin lymphoma is divided in classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma. Using current multi-agent chemotherapy regimens cure rates excess 90% (Bickert 2002; Daw 2011) for early stage and 80% for advanced stage disease. In early stage disease relapse rates are about 10%, in advanced stage disease relapse occurs even in 25% of the patients.

Post-transplantation lymphoproliferative disease is one of the immunodeficiency-associated lymphoproliferative disorders. It occurs after solid organ or hematopoietic stem cell transplantation and is associated with Epstein-Barr virus infection and T-lymphocyte depletion (Sandrini 2010). The first step in treatment is reduction of immune suppression. Anti-CD20 antibodies (e.g. rituximab), chemotherapy and radiotherapy are other treatment options. There is no consensus treatment, however treatment with rituximab plays a crucial role.

Description of the intervention

In most paediatric cancers, the cure rates are high. This is the result of constant improvement of multi-agent chemotherapy. However, in the past years a plateau has been reached. Modulation of conventional therapy is unlikely to significantly improve outcome any further (Capitini 2010; Rossig 2011). In addition, long-term adverse side effects of current therapies are significant including reduced fertility and development of secondary malignancies (Capitini 2010; Rossig 2011).

Furthermore, recurrent non-Hodgkin lymphoma and Hodgkin lymphoma in children are still difficult to treat. In recurrent Hodgkin lymphoma the initial response to therapy is 65%; however, the five-year survival rate is only 26%. For non-Hodgkin lymphoma these numbers are even lower, with an initial response of 42% and a five-year survival rate of 23% (Bickert 2002).

Development of new better targeted therapeutic agents is therefore needed to overcome long-term toxicity and to further improve cure rates. Targeted therapy using monoclonal antibodies is one of these new, very promising approaches.

The most successful example of antibody-based cancer immunotherapy is rituximab. Rituximab is a chimeric antibody directed against the CD20 antigen (Cioc 2008; van Meerten 2011). CD20 is mainly found on pre-B and mature B-lymphocytes (Castillo 2008), and is expressed in almost all cases of Burkitt lymphoma and diffuse large B-cell lymphoma (Miles 2007). Rituximab has been used since 1996 in adult follicular lymphoma. It improves the overall response rate and overall survival (Schulz 2007; van Meerten 2011) and is now the standard component of first-line therapy in adults (van Meerten 2011). Since the success of rituximab, several other monoclonal antibodies against CD20 have been developed. Ofatumumab, veltuzumab, ocrelizumab and aftuzumab are examples of these new generation anti-CD20 antibodies (van Meerten 2011).

How the intervention might work

Monoclonal antibodies are immunoglobulins that recognise specific antigens expressed on the surface of target cells (van Meerten 2011). During the past decade they have been successfully applied as cancer therapy in adults (Scott 2012; Weiner 2010). Anti-tumour effects are due to four major mechanisms. These comprise complement-dependent cytotoxicity resulting in membrane damage and osmotic lysis and activation of antibody dependent cellular cytotoxicity via NK-cell-mediated cytolysis (Grupp 2008). Furthermore, antibody-coated cells are recognised by antigen-presenting cells, e.g. macrophages and dendritic cells, inducing phagocytosis with consequent lysosomal degradation and antigen presentation (Janeway 2001). The latter enables induction of adaptive anti-cancer T-cell immunity. Finally, direct anti-tumour effects can occur by blocking growth factor receptors necessary for tumour cell survival (Grupp 2008). Conjugation of antibodies to cytotoxic drugs or radionuclides can further increase their efficacy (Grupp 2008; Weiner 2010).

Why it is important to do this review

In adult patients, monoclonal antibody cancer therapy has shown very promising results (Capitini 2010). The prototypic antibody rituximab received approval from the U.S. Food and Drug Administration (FDA) for treatment of relapsed or refractory low-grade or follicular B-non-Hodgkin lymphoma in adults in 1997. However, none of the therapeutic antibodies available for adult cancer patients have been approved for treatment of paediatric cancers (MacDonald 2010; Meyer-Wentrup 2013).

Many differences between adult and paediatric oncology need to be taken into account when a successful adult therapy is considered for paediatric patients: Firstly, lymphoma biology differs between adult and childhood lymphoma (Deffenbacher 2012; Meinhardt 2010; Murphy 1980; Rossig 2011). Second, the spectrum of childhood malignancies varies greatly from that in adults (Rossig 2011). Furthermore, cure rates are much higher in childhood than in adult cancer (Meinhardt 2010; Rossig 2011). Smaller numbers of paediatric cancer patients and superior therapy outcome make it more difficult to include patients in phase II/III trials (Rossig 2011). Taken together this makes extrapolating treatment results of antibody-based lymphoma therapy in adults to paediatric lymphoma patients difficult. This review therefore aims to summarise and assess the available data on antibody-based therapy of lymphoma in children.

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. Furthermore, we aim 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.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) and controlled clinical trials about the use of antibody therapy in childhood lymphoma treatment.

Types of participants

Children under the age of 18 years old at the time of diagnosis, with newly diagnosed, relapsed or refractory Hodgkin lymphoma (classic Hodgkin lymphoma, nodular lymphocyte predominant Hodgkin lymphoma (also called nodular paragranuloma), or lymphoproliferative disease (Epstein-Barr virus-lymphoma and post-transplantation lymphoproliferative disease) or non-Hodgkin lymphoma (Burkitt lymphoma, T-cell lymphoma (anaplastic large cell lymphoma), B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, Burkitt-like lymphoma). We will only include a study, which also included non-eligible patients, if information for the subgroup of eligible patients is available.

Types of interventions

We want to compare the treatment results of antibody therapy with the results of standard therapy (in most cases chemotherapy). The adult experience has shown antibodies are usually added to standard chemotherapy regimens instead of being given as a single agent. Our analysis will therefore also include studies in which standard chemotherapy is compared to standard plus antibody therapy.

We will include the following antibody (related) therapies used to treat childhood lymphoma, regardless of dosage, intensity, frequency, duration:

  • rituximab;

  • brentuximab vedotin;

  • blinatumomab;

  • epratuzumab;

  • veltuzumab;

  • ofatumumab;

  • epratuzumab;

  • ibritumomab;

  • tositumomab;

  • alemtuzumab;

  • galiximab;

  • dacetuzumab;

  • apolizumab;

  • anti-CD27;

  • mogamulizumab;

  • visilizumab;

  • otelixizumab;

  • muromonab-CD3;

  • thymocyte antibody.

Types of outcome measures

Outcome measures are part of the study inclusion eligibility criteria, and thus we will include studies if at least one of our outcomes of interest is measured. We will contact the authors of any other study that did not report relevant outcomes in order to ascertain if outcomes were not measured rather than not reported.

Primary outcomes
  1. Remission (partial, complete), relapse rate, event-free and overall survival and adverse effects for each lymphoma type and treatment option separately

  2. Adverse effects of antibody therapy mentioned in the included studies, such as: Immunosuppression (febrile neutropenia or use of antibiotics or infection), prolonged B-cell depletion (> 6 months), progressive multifocal leukoencephalopathy, infusion reactions, skin changes, pulmonary toxicity, renal failure (due to acute cell lysis), hepatotoxicity, cardiac toxicity, seizures

Defining remission and relapse is difficult in paediatric lymphoma. Study protocols for different lymphoma subtypes use different definitions. We will therefore report the definitions for remission and relapse applied by the individual studies and interpret the treatment results in view of these definitions.

We will report all adverse effects, including those scored by using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (NCI 2010), the World Health Organization (WHO) criteria for toxicity of treatment or any other scoring system.

Secondary outcomes

Our secondary outcome measure is quality of life.

Search methods for identification of studies

We will not impose language restrictions and we will update our literature searches every two years.

Electronic searches

We will search the following electronic databases:

The strategies are designed by one author (VMZ) with help of a librarian, and the search will be run by the same author.

Searching other resources

We will screening references of the included studies and reviews, and also contact experts in the field to retrieve potentially remaining articles. We will search conference proceedings abstracts of the International Society of Paediatric Oncology (SIOP), the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) for studies during the last five years (from 2009-2013). Furthermore, we will also search the WHO International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/) portal and ClinicalTrials.gov (http://clinicaltrials.gov/) for ongoing trials. The search strategies are illustrated in Appendix 4 and Appendix 5, respectively. One author (VMZ) will run the searches of the ongoing trials databases

Data collection and analysis

Selection of studies

After removing duplicates, two independent authors (VMZ, FMW) will screen the titles and abstract against our inclusion and exclusion criteria. Disagreement will be resolved by discussion and by seeking the opinion of a third author (SCG). Thereafter, the two authors (VMZ, FMW) will retrieve the full-text of each potentially relevant article for further assessment. Disagreement will be resolved by discussion and reviewing of the articles by the third author (SCG).

We will include a flow chart of the search and selection results in this review, and we will clearly state details of the reasons for exclusion of any study considered for the review.

Data extraction and management

Two authors will extract data independently (VMZ, FMW), using a specially-developed data extraction form. When disagreement occurs a third author (SCG) will also perform the data extraction and disagreement will be resolved by discussion between all three authors. The data extraction sheet will be pilot tested with relevant articles. Information will be collected on participants (baseline characteristics including mean age, gender distribution, diagnosis (inclusive stage and primary localisation, and number of blasts in bone marrow)), treatment details (type of treatment, duration and doses), and outcome (including mean follow-up duration). For each study the different types of lymphoma and different treatment regimes per lymphoma type will be reported separately.

Furthermore, information about the studies will be collected: number of patients included, loss to follow-up, country, author, paper, year of publication, study design, quality of the study, funding source details and the declaration of interests.

Assessment of risk of bias in included studies

Two authors (VMZ,FMW) will independently assess the risk of bias of each included study against the following key criteria.

  • Selection bias: random sequence generation, allocation concealment.

  • Performance bias: blinding of participants, blinding of personnel, other potential threats to validity for each outcome separately.

  • Detection bias: blinding of outcome assessors for each outcome separately, other potential threats to validity for each outcome separately.

  • Attrition bias: incomplete outcome data for each outcome separately.

  • Reporting bias: selective outcome reporting; to prevent this we will contact the authors in case of missing data.

This is in accordance with methods recommended by the Cochrane Collaboration and the Cochrane Childhood Cancer Group (Higgins 2011; Kremer 2012). We will use the following judgements: "low risk of bias", "high risk of bias", or "unclear risk of bias" (either lack of information or uncertainty over the potential for bias). We will present the results in the 'Characteristics of included studies' tables (Higgins 2011). If necessary, we will consult a third author (SCG) to resolve disagreements.

Regardless of the outcome of the assessment of risk of bias, we will use all studies in the analyses. However, we will take into account the risk of bias in included studies when we interpret the review's results.

Measures of treatment effect

When possible, we will express the treatment effect for dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs). We will assess survival as time to event data (hazard ratios, HRs). We will use Parmar's method if HRs have not been explicitly presented in the study (Parmar 1998). We will express the treatment effect for continuous outcomes as mean differences (MDs) with 95% CIs. Where continuous outcomes are measured using different scales, we will use standardised mean differences (SMDs) with 95% CIs instead.

Dealing with missing data

When data is missing with regard to study selection, data extraction and/or risk of bias assessment, we will contact the trial authors, and keep track of response numbers.

Assessment of heterogeneity

Two authors (VMZ, FMW) will assess clinical heterogeneity across the included studies, and meta-analysis will only be conducted when both authors agree that study participants, treatment and outcomes are sufficiently similar. However, clinical heterogeneity is expected, as we are interested in different antibody therapies in various lymphomas. Therefore, we will perform subgroup analyses to identify sources of heterogeneity (Subgroup analysis and investigation of heterogeneity).

We will assess statistical heterogeneity by visually assessing the extent of overlap in 95% CIs in the forest plots and using the I2 statistic. When I2 > 50% we will consider that there is substantial heterogeneity.

Assessment of reporting biases

In addition to the evaluation of reporting bias as described in the Assessment of risk of bias in included studies section, we will assess reporting bias by constructing a funnel plot when there is a sufficient number (at least 10) of included studies in a meta-analysis. When there are fewer studies, the power of the tests is too low to distinguish chance from real asymmetry (Higgins 2011).

Data synthesis

We will analyse data of clinically and statistically homogeneous studies using the Cochrane Collaboration's statistical software, Review Manager 2014. We will conduct meta-analyses using the Mantel-Haenszel method for dichotomous outcomes and the inverse variance method for continuous outcomes. We will use the random-effects analytical model.

We will not perform meta-analyses if a high level of statistical heterogeneity is found (I2 ≥ 75%). In case of a high level of heterogeneity or when there are insufficient data for meta-analyses, we will present a narrative synthesis. We will analyse time to event data by the generic inverse variance function of Review Manager 2014 to combine logs of the HRs. We will perform our analyses according to the guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

If a trial has multiple intervention groups, we will assess the data separately for each type of intervention and compare with those of the control group (conventional therapy).

Two authors (VMZ, FMW) will independently devise a 'Summary of findings' table. The table includes a summary of the results (the overall survival rate, event-free survival rate, overall remission rate, relapse rate, adverse effects and quality of life) and numbers of participants and studies addressing these outcomes; a depiction of the quality of the body of evidence; comments; and footnotes. We will assess quality of the body of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework, which combines considerations of risk of bias, directness, heterogeneity, precision and publication bias (Higgins 2011).

Subgroup analysis and investigation of heterogeneity

We will analyse the following subgroups:

  • lymphoma type;

  • newly diagnosed vs. relapsed/refractory lymphoma (to investigate if there is a difference in outcome when the antibody therapy is used as a first line treatment or if it is only appropriate in relapsed/refractory lymphoma);

  • dosage regimes (high vs. low) and frequency of doses (this analysis aims to identify if there is a difference in outcome when an other treatment regime is used);

  • therapy combinations e.g. with radiotherapy vs. without; with surgery vs. without; different types of chemotherapy to investigate if there is an optimal treatment to which antibody therapy could be added.

Sensitivity analysis

We will conduct sensitivity analyses to assess the effect of risk of bias in the included studies, comparing all studies with studies rated as low risk of bias for each assessed item.

Acknowledgements

The editorial base of the Cochrane Childhood Cancer Group is funded by Stichting Kinderen Kankervrij (KiKa).

Appendices

Appendix 1. Search strategy for CENTRAL (via the "Advanced search" page)

1. For children we will use:
(child:ti,ab OR children:ti,ab OR childhood:ti,ab OR pediatric:ti,ab OR pediatrics:ti,ab OR paediatric:ti,ab OR paediatrics:ti,ab OR newborn:ti,ab OR new-born:ti,ab OR neonate:ti,ab OR neonates:ti,ab OR infant:ti,ab OR baby:ti,ab OR toddler:ti,ab OR toddlers:ti,ab OR youngster:ti,ab OR adolescence:ti,ab OR adolescent:ti,ab OR teenage:ti,ab OR teenager:ti,ab OR puberty:ti,ab OR Schoolchild:ti,ab OR “School child”:ti,ab OR Boy:ti,ab OR Boys:ti,ab OR Boyhood:ti,ab OR girl:ti,ab OR girls:ti,ab OR girlhood:ti,ab OR youth:ti,ab OR youths:ti,ab OR teen:ti,ab OR teens:ti,ab OR preschool:ti,ab OR “preschool child”:ti,ab OR suckling:ti,ab OR sucklings:ti,ab OR juvenile:ti,ab OR juveniles:ti,ab)

2. For lymphoma we will use:
Lymphoma:ti,ab OR Lymphomas:ti,ab OR Hodgkin:ti,ab OR Hodgkin’s:ti,ab OR Hodgkins:ti,ab OR Non-hodgkin:ti,ab OR Non-hodgkin’s:ti,ab OR Non-hodgkins:ti,ab OR “Non Hodgkin”:ti,ab OR “Non hodgkin’s”:ti,ab OR “Non hodgkins”:ti,ab OR Nonhodgkin:ti,ab OR Nonhodgkin’s:ti,ab OR Nonhodgkins:ti,ab OR HD:ti,ab OR HL:ti,ab OR NHL:ti,ab OR NHD:ti,ab OR Burkitt:ti,ab OR Burkitt’s:ti,ab OR Burkitts:ti,ab OR “Malignant Lymphogranuloma”:ti,ab OR “Malignant Lymphogranulomas”:ti,ab OR “Malignant lymphogranulomatosis”:ti,ab OR “Lymphogranuloma maligne”:ti,ab OR “Lymphogranuloma malignum”:ti,ab OR Lymphogranulomatosis:ti,ab OR “Malignant Granuloma”:ti,ab OR “Malignant Granulomas”:ti,ab OR “Malignant granulomatosis”:ti,ab OR “Reed hodgkin disease”:ti,ab OR “Reed sternberg disease”:ti,ab OR “Classic HL”:ti,ab OR “Classical HL”:ti,ab OR “Classic HD”:ti,ab OR “Classical HD”:ti,ab OR “NLP HD”:ti,ab OR “NLPHD”:ti,ab OR “NLP HL”:ti,ab OR NLPHL:ti,ab OR “LP HL”:ti,ab OR “LPHL”:ti,ab OR “Nodular paragranuloma”:ti,ab OR “Nodular paragranulomas”:ti,ab OR BL:ti,ab OR BLL:ti,ab OR ALCL:ti,ab OR DLBCL:ti,ab OR “Giant follicular lymphosarcoma”:ti,ab OR “Giant follicular lymphosarcomas”:ti,ab OR “Giant follicle lymphosarcoma”:ti,ab OR “Giant follicle lymphosarcomas”:ti,ab OR “Giant follicular blastoma”:ti,ab OR “Giant follicular blastomas”:ti,ab OR “Giant follicle blastoma”:ti,ab OR “Giant follicle blastomas”:ti,ab OR “Giant follicular lymphoblastoma”:ti,ab OR “Giant follicular lymphoblastomas”:ti,ab OR “Giant follicle lymphoblastoma”:ti,ab OR “Giant follicle lymphoblastomas”:ti,ab OR “Brill-Symmers Disease”:ti,ab OR “Brill Symmers Disease”:ti,ab OR “Lymphoproliferative disease”:ti,ab OR “Lymphoproliferative disorder”:ti,ab OR “Lymphoproliferative disorders”:ti,ab OR “Lymphoproliferative syndrome”:ti,ab OR “Lymphoproliferative syndromes”:ti,ab OR Lymphoreticulosis:ti,ab OR “Immunoproliferative disease”:ti,ab OR “Immune proliferative disease”:ti,ab OR “Immunoproliferative disorder”:ti,ab OR “Immunoproliferative disorders”:ti,ab OR “Immune proliferative disorder”:ti,ab OR “Immune proliferative disorders”:ti,ab OR “Lymphomatoid Granulomatosis”:ti,ab OR “Post-transplant lymphoproliferative disease”:ti,ab OR “Posttransplant lymphoproliferative disease”:ti,ab OR “Post-transplant lymphoproliferative disorder”:ti,ab OR “Post-transplant lymphoproliferative disorders”:ti,ab OR “Posttransplant lymphoproliferative disorder”:ti,ab OR “Posttransplant lymphoproliferative disorders”:ti,ab OR PTLD:ti,ab OR ((“Lymph node”:ti,ab OR “Lymph nodes”:ti,ab OR Lymphocytic:ti,ab OR Lymphoid:ti,ab) AND (tumor:ti,ab OR tumors:ti,ab OR tumour:ti,ab OR tumours:ti,ab OR malignancy:ti,ab OR malignancies:ti,ab OR Malignant:ti,ab OR Neoplasm:ti,ab OR Neoplasms:ti,ab OR leukemia:ti,ab OR leukemias:ti,ab))

3. For antibody therapy we will use:
antibody:ti,ab OR antibodies:ti,ab OR mAb:ti,ab OR Immunotherapy:ti,ab OR "Immune therapy":ti,ab OR "Immunoglobulin therapy":ti,ab OR "Immunological therapy":ti,ab OR "Immunological treatment":ti,ab OR "Cancer immunotherapy":ti,ab OR "Tumor immunotherapy":ti,ab OR Immunoglobulin:ti,ab OR Immunoglobulins:ti,ab OR Rituximab:ti,ab OR "Anti-CD20":ti,ab OR Mabthera:ti,ab OR Rituxan:ti,ab OR reditux:ti,ab OR rituxin:ti,ab OR "IDEC-C2B8":ti,ab OR "Brentuximab vedotin":ti,ab OR Adcetris:ti,ab OR "anti-CD30":ti,ab OR "cAC10-vcMMAE":ti,ab OR "SGN-35":ti,ab OR "SGN35":ti,ab OR "SGN 35":ti,ab OR "Anti-CD19":ti,ab OR "MDX 1342":ti,ab OR "MDX-1342":ti,ab OR "Anti-MDX 1342":ti,ab OR "Anti-MDX1342":ti,ab OR "Anti-MDX-1342":ti,ab OR blinatumomab:ti,ab OR "medi 538":ti,ab OR medi538:ti,ab OR "mt 103":ti,ab OR mt103:ti,ab OR epratuzumab:ti,ab OR "anti-CD22":ti,ab OR "hLL2 agent":ti,ab OR LymphoCide:ti,ab OR "immu 1903":ti,ab OR immu1903:ti,ab OR "immu-1903":ti,ab OR veltuzumab:ti,ab OR "anti-CD20 IgG":ti,ab OR "ha 20":ti,ab OR ha20:ti,ab OR "ha-20":ti,ab OR "immu 106":ti,ab OR immu106:ti,ab OR "immu-106":ti,ab OR Ofatumumab:ti,ab OR Arzerra:ti,ab OR “HuMax-CD20”:ti,ab OR "HuMax CD20":ti,ab OR HuMaxCD20:ti,ab OR "humac CD20":ti,ab OR "gsk 1841157":ti,ab OR gsk1841157:ti,ab OR epratuzumab:ti,ab OR "epratuzumab y 90":ti,ab OR "epratuzumab yttrium y 90":ti,ab OR "epratuzumab tetraxetan yttrium y 90":ti,ab OR "epratuzumab Iodine-131":ti,ab OR "90Y-labeled ibritumomab tiuxetan":ti,ab OR "Ibritumomab tiuxetan":ti,ab OR Ibritumomab:ti,ab OR "yttrium-90-ibritumomab tiuxetan":ti,ab OR Zevalin:ti,ab OR "in-111 zevalin":ti,ab OR "y-90 zevalin":ti,ab OR zevaline:ti,ab OR "idec 129":ti,ab OR "idec y2b8":ti,ab OR idec129:ti,ab OR Tositumomab:ti,ab OR "Tositumomab I 131":ti,ab OR "tositumomab iodine-131":ti,ab OR "iodine-131 tositumomab":ti,ab OR "iodine-131-tositumomab":ti,ab OR "131I-labeled tositumomab":ti,ab OR "Tositumomab-I131":ti,ab OR Bexxar:ti,ab OR "bexxar dosimetric":ti,ab OR "bexxar i 131 dosimetric":ti,ab OR "131I anti-B1":ti,ab OR Alemtuzumab:ti,ab OR Campath:ti,ab OR MabCampath:ti,ab OR "Campath-1H":ti,ab OR Lemtrada:ti,ab OR "Campath 1G":ti,ab OR "Campath-1G":ti,ab OR "Campath-1-G":ti,ab OR Campath1G:ti,ab OR "Campath 1M":ti,ab OR "Campath-1M":ti,ab OR "Campath-1-M":ti,ab OR Campath1M:ti,ab OR Campath1H:ti,ab OR "Campath 1H":ti,ab OR "Campath-1H":ti,ab OR "Campath-1-H":ti,ab OR "Campath 1":ti,ab OR "Anti-CD52":ti,ab OR "ldp 103":ti,ab OR ldp103:ti,ab OR galiximab:ti,ab OR "Anti-CD80":ti,ab OR "anti-B7-1 mAb":ti,ab OR "P-16C10":ti,ab OR "IDEC-114":ti,ab OR "idec 114":ti,ab OR idec114:ti,ab OR dacetuzumab:ti,ab OR "anti-CD40":ti,ab OR "SGN 40":ti,ab OR "SGN40 cpd":ti,ab OR "SGN-40":ti,ab OR SGN40:ti,ab OR "hu S2C6":ti,ab OR Apolizumab:ti,ab OR "Hu1D 10":ti,ab OR Hu1D10:ti,ab OR Remitogen:ti,ab OR "anti-CD27 ":ti,ab OR "anti-CCR4":ti,ab OR mogamulizumab:ti,ab OR "AMG 761":ti,ab OR AMG761:ti,ab OR "AMG-761":ti,ab OR "KW 0761":ti,ab OR KW0761:ti,ab OR "KW-0761":ti,ab OR "km 8761":ti,ab OR km8761:ti,ab OR "anti-CD3":ti,ab OR "OKT-3":ti,ab OR OKT3:ti,ab OR "OKT 3":ti,ab OR visilizumab:ti,ab OR "hu m 291":ti,ab OR "hu m291":ti,ab OR "hum 291":ti,ab OR hum291:ti,ab OR nuvion:ti,ab OR "SMART anti-CD3":ti,ab OR Nuvion:ti,ab OR Otelixizumab:ti,ab OR "gsk 2136525":ti,ab OR "gsk2136525 ":ti,ab OR "trx 4":ti,ab OR trx4:ti,ab OR "Muromonab-CD3":ti,ab OR "muromonab-cd3":ti,ab OR orthoclone:ti,ab OR "anti-thymocyte immunoglobulin":ti,ab OR "antithymocyte immunoglobulin":ti,ab OR "antithymocytic immunoglobulin":ti,ab OR "thymocyte antiserum":ti,ab OR "thymocyte isoantiserum":ti,ab OR "thymocyte serum":ti,ab OR "thymocyte isoantibody":ti,ab OR "anti thymocyte antiserum":ti,ab OR "antithymocyte antiserum":ti,ab OR "anti thymocyte serum ":ti,ab OR "antithymocyte serum":ti,ab OR "antithymic serum":ti,ab OR "antithymocytic serum":ti,ab OR "antithymus serum":ti,ab OR "anti thymocyte globulin":ti,ab OR "antithymocyte globulin":ti,ab OR "anti thymocytic globulin":ti,ab OR "antithymocytic globulin":ti,ab OR atg:ti,ab OR atgam:ti,ab OR thymoglobulin:ti,ab OR thymoglobuline:ti,ab OR "thymus antiserum":ti,ab

Final search 1 AND 2 AND 3

ti,ab = title, abstract

Appendix 2. Search strategy for PubMed

1. For children we will use:
(child[MeSH] OR paediatrics[MeSH] OR infant[MeSH] OR adolescent[MeSH] OR “preschool child”[MeSH] OR child[tiab] OR children[tiab] OR childhood[tiab] OR pediatric[tiab] OR pediatrics[tiab] OR paediatric[tiab] OR paediatrics[tiab] OR newborn[tiab] OR new-born[tiab] OR neonate[tiab] OR neonates[tiab] OR infant[tiab] OR baby[tiab] OR toddler[tiab] OR toddlers[tiab] OR youngster[tiab] OR adolescence[tiab] OR adolescent[tiab] OR teenage[tiab] OR teenager[tiab] OR puberty[tiab] OR Schoolchild[tiab] OR “School child”[tiab] OR Boy[tiab] OR Boys[tiab] OR Boyhood[tiab] OR girl[tiab] OR girls[tiab] OR girlhood[tiab] OR youth[tiab] OR youths[tiab] OR teen[tiab] OR teens[tiab] OR preschool[tiab] OR “preschool child”[tiab] OR suckling[tiab] OR sucklings[tiab] OR juvenile[tiab] OR juveniles[tiab])

2. For lymphoma we will use:
Lymphoma[MeSH] OR “Lymphoproliferative disorders”[MeSH] OR Lymphoma[tiab] OR Lymphomas[tiab] OR Hodgkin[tiab] OR Hodgkin’s[tiab] OR Hodgkins[tiab] OR Non-hodgkin[tiab] OR Non-hodgkin’s[tiab] OR Non-hodgkins[tiab] OR “Non Hodgkin”[tiab] OR “Non hodgkin’s”[tiab] OR “Non hodgkins”[tiab] OR Nonhodgkin[tiab] OR Nonhodgkin’s[tiab] OR Nonhodgkins[tiab] OR HD[tiab] OR HL[tiab] OR NHL[tiab] OR NHD[tiab] OR Burkitt[tiab] OR Burkitt’s[tiab] OR Burkitts[tiab] OR “Malignant Lymphogranuloma”[tiab] OR “Malignant Lymphogranulomas”[tiab] OR “Malignant lymphogranulomatosis”[tiab] OR “Lymphogranuloma maligne”[tiab] OR “Lymphogranuloma malignum”[tiab] OR Lymphogranulomatosis[tiab] OR “Malignant Granuloma”[tiab] OR “Malignant Granulomas”[tiab] OR “Malignant granulomatosis”[tiab] OR “Reed hodgkin disease”[tiab] OR “Reed sternberg disease”[tiab] OR “Classic HL”[tiab] OR “Classical HL”[tiab] OR “Classic HD”[tiab] OR “Classical HD”[tiab] OR “NLP HD”[tiab] OR “NLPHD”[tiab] OR “NLP HL”[tiab] OR NLPHL[tiab] OR “LP HL”[tiab] OR “LPHL”[tiab] OR “Nodular paragranuloma”[tiab] OR “Nodular paragranulomas”[tiab] OR BL[tiab] OR BLL[tiab] OR ALCL[tiab] OR DLBCL[tiab] OR “Giant follicular lymphosarcoma”[tiab] OR “Giant follicular lymphosarcomas”[tiab] OR “Giant follicle lymphosarcoma”[tiab] OR “Giant follicle lymphosarcomas”[tiab] OR “Giant follicular blastoma”[tiab] OR “Giant follicular blastomas”[tiab] OR “Giant follicle blastoma”[tiab] OR “Giant follicle blastomas”[tiab] OR “Giant follicular lymphoblastoma”[tiab] OR “Giant follicular lymphoblastomas”[tiab] OR “Giant follicle lymphoblastoma”[tiab] OR “Giant follicle lymphoblastomas”[tiab] OR “Brill-Symmers Disease”[tiab] OR “Brill Symmers Disease”[tiab] OR “Lymphoproliferative disease”[tiab] OR “Lymphoproliferative disorder”[tiab] OR “Lymphoproliferative disorders”[tiab] OR “Lymphoproliferative syndrome”[tiab] OR “Lymphoproliferative syndromes”[tiab] OR Lymphoreticulosis[tiab] OR “Immunoproliferative disease”[tiab] OR “Immune proliferative disease”[tiab] OR “Immunoproliferative disorder”[tiab] OR “Immunoproliferative disorders”[tiab] OR “Immune proliferative disorder”[tiab] OR “Immune proliferative disorders”[tiab] OR “Lymphomatoid Granulomatosis”[tiab] OR “Post-transplant lymphoproliferative disease”[tiab] OR “Posttransplant lymphoproliferative disease”[tiab] OR “Post-transplant lymphoproliferative disorder”[tiab] OR “Post-transplant lymphoproliferative disorders”[tiab] OR “Posttransplant lymphoproliferative disorder”[tiab] OR “Posttransplant lymphoproliferative disorders”[tiab] OR PTLD[tiab] OR ((“Lymph node”[tiab] OR “Lymph nodes”[tiab] OR Lymphocytic[tiab] OR Lymphoid[tiab]) AND (tumor[tiab] OR tumors[tiab] OR tumour[tiab] OR tumours[tiab] OR malignancy[tiab] OR malignancies[tiab] OR Malignant[tiab] OR Neoplasm[tiab] OR Neoplasms[tiab] OR leukemia[tiab] OR leukemias[tiab]))

3. For antibody therapy we will use:
Antibodies[MeSH] OR Immunotherapy[MeSH] OR “I-131 anti-B1 antibody”[MeSH] OR Rituximab[MeSH] OR “cAC10-vcMMAE”[MeSH] OR “MDX-1342” [MeSH] OR epratuzumab[MeSH] OR veltuzumab[MeSH] OR epratuzumab[MeSH] OR Ofatumumab[MeSH] OR Ibritumomab tiuxetan[MeSH] OR Alemtuzumab[MeSH] OR galiximab[MeSH] OR dacetuzumab[MeSH] OR Apolizumab[MeSH] OR mogamulizumab[MeSH] OR visilizumab[MeSH] OR Otelixizumab[MeSH] OR antibody[tiab] OR antibodies[tiab] OR mAb[tiab] OR Immunotherapy[tiab] OR "Immune therapy"[tiab] OR "Immunoglobulin therapy"[tiab] OR "Immunological therapy"[tiab] OR "Immunological treatment"[tiab] OR "Cancer immunotherapy"[tiab] OR "Tumor immunotherapy"[tiab] OR Immunoglobulin[tiab] OR Immunoglobulins[tiab] OR Rituximab[tiab] OR "Anti-CD20"[tiab] OR Mabthera[tiab] OR Rituxan[tiab] OR reditux[tiab] OR rituxin[tiab] OR "IDEC-C2B8"[tiab] OR "Brentuximab vedotin"[tiab] OR Adcetris[tiab] OR "anti-CD30"[tiab] OR "cAC10-vcMMAE"[tiab] OR "SGN-35"[tiab] OR "SGN35"[tiab] OR "SGN 35"[tiab] OR "Anti-CD19"[tiab] OR "MDX 1342"[tiab] OR "MDX-1342"[tiab] OR "Anti-MDX 1342"[tiab] OR "Anti-MDX1342"[tiab] OR "Anti-MDX-1342"[tiab] OR blinatumomab[tiab] OR "medi 538"[tiab] OR medi538[tiab] OR "mt 103"[tiab] OR mt103[tiab] OR epratuzumab[tiab] OR "anti-CD22"[tiab] OR "hLL2 agent"[tiab] OR LymphoCide[tiab] OR "immu 1903"[tiab] OR immu1903[tiab] OR "immu-1903"[tiab] OR veltuzumab[tiab] OR "anti-CD20 IgG"[tiab] OR "ha 20"[tiab] OR ha20[tiab] OR "ha-20"[tiab] OR "immu 106"[tiab] OR immu106[tiab] OR "immu-106"[tiab] OR Ofatumumab[tiab] OR Arzerra[tiab] OR “HuMax-CD20"[tiab] OR "HuMax CD20"[tiab] OR HuMaxCD20 [tiab] OR "humac CD20"[tiab] OR "gsk 1841157"[tiab] OR gsk1841157[tiab] OR epratuzumab[tiab] OR "epratuzumab y 90"[tiab] OR "epratuzumab yttrium y 90"[tiab] OR "epratuzumab tetraxetan yttrium y 90"[tiab] OR "epratuzumab Iodine-131"[tiab] OR "90Y-labeled ibritumomab tiuxetan"[tiab] OR "Ibritumomab tiuxetan"[tiab] OR Ibritumomab[tiab] OR "yttrium-90-ibritumomab tiuxetan"[tiab] OR Zevalin[tiab] OR "in-111 zevalin"[tiab] OR "y-90 zevalin"[tiab] OR zevaline[tiab] OR "idec 129"[tiab] OR "idec y2b8"[tiab] OR idec129[tiab] OR Tositumomab[tiab] OR "Tositumomab I 131"[tiab] OR "tositumomab iodine-131"[tiab] OR "iodine-131 tositumomab"[tiab] OR "iodine-131-tositumomab"[tiab] OR "131I-labeled tositumomab"[tiab] OR "Tositumomab-I131"[tiab] OR Bexxar[tiab] OR "bexxar dosimetric"[tiab] OR "bexxar i 131 dosimetric"[tiab] OR "131I anti-B1"[tiab] OR Alemtuzumab[tiab] OR Campath[tiab] OR MabCampath[tiab] OR "Campath-1H"[tiab] OR Lemtrada[tiab] OR "Campath 1G"[tiab] OR "Campath-1G"[tiab] OR "Campath-1-G"[tiab] OR Campath1G[tiab] OR "Campath 1M"[tiab] OR "Campath-1M"[tiab] OR "Campath-1-M"[tiab] OR Campath1M[tiab] OR Campath1H[tiab] OR "Campath 1H"[tiab] OR "Campath-1H"[tiab] OR "Campath-1-H"[tiab] OR "Campath 1"[tiab] OR "Anti-CD52"[tiab] OR "ldp 103"[tiab] OR ldp103[tiab] OR galiximab[tiab] OR "Anti-CD80"[tiab] OR "anti-B7-1 mAb"[tiab] OR "P-16C10"[tiab] OR "IDEC-114"[tiab] OR "idec 114"[tiab] OR idec114[tiab] OR dacetuzumab[tiab] OR "anti-CD40"[tiab] OR "SGN 40"[tiab] OR "SGN40 cpd"[tiab] OR "SGN-40"[tiab] OR SGN40[tiab] OR "hu S2C6"[tiab] OR Apolizumab[tiab] OR "Hu1D 10"[tiab] OR Hu1D10[tiab] OR Remitogen[tiab] OR "anti-CD27 "[tiab] OR "anti-CCR4"[tiab] OR mogamulizumab[tiab] OR "AMG 761"[tiab] OR AMG761[tiab] OR "AMG-761"[tiab] OR "KW 0761"[tiab] OR KW0761[tiab] OR "KW-0761"[tiab] OR "km 8761"[tiab] OR km8761[tiab] OR "anti-CD3"[tiab] OR "OKT-3"[tiab] OR OKT3[tiab] OR "OKT 3"[tiab] OR visilizumab[tiab] OR "hu m 291"[tiab] OR "hu m291"[tiab] OR "hum 291"[tiab] OR hum291[tiab] OR nuvion[tiab] OR "SMART anti-CD3"[tiab] OR Nuvion[tiab] OR Otelixizumab[tiab] OR "gsk 2136525"[tiab] OR "gsk2136525 "[tiab] OR "trx 4"[tiab] OR trx4[tiab] OR "Muromonab-CD3"[tiab] OR "muromonab-cd3"[tiab] OR orthoclone[tiab] OR "anti-thymocyte immunoglobulin"[tiab] OR "antithymocyte immunoglobulin"[tiab] OR "antithymocytic immunoglobulin"[tiab] OR "thymocyte antiserum"[tiab] OR "thymocyte isoantiserum"[tiab] OR "thymocyte serum"[tiab] OR "thymocyte isoantibody"[tiab] OR "anti thymocyte antiserum"[tiab] OR "antithymocyte antiserum"[tiab] OR "anti thymocyte serum "[tiab] OR "antithymocyte serum"[tiab] OR "antithymic serum"[tiab] OR "antithymocytic serum"[tiab] OR "antithymus serum"[tiab] OR "anti thymocyte globulin"[tiab] OR "antithymocyte globulin"[tiab] OR "anti thymocytic globulin"[tiab] OR "antithymocytic globulin"[tiab] OR atg[tiab] OR atgam[tiab] OR thymoglobulin[tiab] OR thymoglobuline[tiab] OR "thymus antiserum"[tiab]

Final search 1 AND 2 AND 3

tiab = title, abstract

Appendix 3. Search strategy for EMBASE (EMBASE.com)

1. For children we will use:
child/exp OR pediatrics/exp OR infant/exp OR adolescent/exp OR ‘preschool child’/exp OR Adolescence/exp OR Toddler/exp OR Newborn/exp OR Childhood/exp OR juvenile/exp OR girl/exp OR Boy/exp OR School child/exp OR child:ab,ti OR children:ab,ti OR childhood:ab,ti OR pediatric:ab,ti OR pediatrics:ab,ti OR paediatric:ab,ti OR paediatrics:ab,ti OR newborn:ab,ti OR new-born:ab,ti OR neonate:ab,ti OR neonates:ab,ti OR infant:ab,ti OR baby:ab,ti OR toddler:ab,ti OR toddlers:ab,ti OR youngster:ab,ti OR adolescence:ab,ti OR adolescent:ab,ti OR teenage:ab,ti OR teenager:ab,ti OR puberty:ab,ti OR Schoolchild:ab,ti OR ‘School child’:ab,ti OR Boy:ab,ti OR Boys:ab,ti OR Boyhood:ab,ti OR girl:ab,ti OR girls:ab,ti OR girlhood:ab,ti OR youth:ab,ti OR youths:ab,ti OR teen:ab,ti OR teens:ab,ti OR preschool:ab,ti OR ‘preschool child’:ab,ti OR suckling:ab,ti OR sucklings:ab,ti OR juvenile:ab,ti OR juveniles:ab,ti

2 For lymphoma we will use:
Lymphoma/exp OR ‘Lymphoproliferative disease’/exp OR Lymphoma:ab,ti OR Lymphomas:ab,ti OR Hodgkin:ab,ti OR ‘Hodgkin/s’:ab,ti OR Hodgkins:ab,ti OR Non-hodgkin:ab,ti OR ‘Non-hodgkin/s’:ab,ti OR Non-hodgkins:ab,ti OR ‘Non hodgkin’:ab,ti OR ‘Non hodgkin/s’:ab,ti OR ‘Non hodgkins’:ab,ti OR Nonhodgkin:ab,ti OR ‘Nonhodgkin/s’:ab,ti OR Nonhodgkins:ab,ti OR HD:ab,ti OR HL:ab,ti OR NHL:ab,ti OR NHD:ab,ti OR Burkitt:ab,ti OR ‘Burkitt/s’:ab,ti OR Burkitts:ab,ti OR ‘Malignant Lymphogranuloma’:ab,ti OR ‘Malignant Lymphogranulomas’:ab,ti OR ‘Malignant lymphogranulomatosis’:ab,ti OR ‘Lymphogranuloma maligne’:ab,ti OR ‘Lymphogranuloma malignum’:ab,ti OR Lymphogranulomatosis:ab,ti OR ‘Malignant Granuloma’:ab,ti OR ‘Malignant Granulomas’:ab,ti OR ‘Malignant granulomatosis’:ab,ti OR ‘Reed hodgkin disease’:ab,ti OR ‘Reed sternberg disease’:ab,ti OR ‘Classic HL’:ab,ti OR ‘Classical HL’:ab,ti OR ‘Classic HD’:ab,ti OR ‘Classical HD’:ab,ti OR ‘NLP HD’:ab,ti OR ‘NLPHD’:ab,ti OR ‘NLP HL’:ab,ti OR NLPHL:ab,ti OR ‘LP HL’:ab,ti OR ‘LPHL’:ab,ti OR ‘Nodular paragranuloma’:ab,ti OR ‘Nodular paragranulomas’:ab,ti OR BL:ab,ti OR BLL:ab,ti OR ALCL:ab,ti OR DLBCL:ab,ti OR ‘Giant follicular lymphosarcoma’:ab,ti OR ‘Giant follicular lymphosarcomas’:ab,ti OR ‘Giant follicle lymphosarcoma’:ab,ti OR ‘Giant follicle lymphosarcomas’:ab,ti OR ‘Giant follicular blastoma’:ab,ti OR ‘Giant follicular blastomas’:ab,ti OR ‘Giant follicle blastoma’:ab,ti OR ‘Giant follicle blastomas’:ab,ti OR ‘Giant follicular lymphoblastoma’:ab,ti OR ‘Giant follicular lymphoblastomas’:ab,ti OR ‘Giant follicle lymphoblastoma’:ab,ti OR ‘Giant follicle lymphoblastomas’:ab,ti OR ‘Brill-Symmers Disease’:ab,ti OR ‘Brill Symmers Disease’:ab,ti OR ‘Lymphoproliferative disease’:ab,ti OR ‘Lymphoproliferative disorder’:ab,ti OR ‘Lymphoproliferative disorders’:ab,ti OR ‘Lymphoproliferative syndrome’:ab,ti OR ‘Lymphoproliferative syndromes’:ab,ti OR Lymphoreticulosis:ab,ti OR ‘Immunoproliferative disease’:ab,ti OR ‘Immune proliferative disease’:ab,ti OR ‘Immunoproliferative disorder’:ab,ti OR ‘Immunoproliferative disorders’:ab,ti OR ‘Immune proliferative disorder’:ab,ti OR ‘Immune proliferative disorders’:ab,ti OR ‘Lymphomatoid Granulomatosis’:ab,ti OR ‘Post-transplant lymphoproliferative disease’:ab,ti OR ‘Posttransplant lymphoproliferative disease’:ab,ti OR ‘Post-transplant lymphoproliferative disorder’:ab,ti OR ‘Post-transplant lymphoproliferative disorders’:ab,ti OR ‘Posttransplant lymphoproliferative disorder’:ab,ti OR ‘Posttransplant lymphoproliferative disorders’:ab,ti OR PTLD:ab,ti OR ((‘Lymph node’:ab,ti OR ‘Lymph nodes’:ab,ti OR Lymphocytic:ab,ti OR Lymphoid:ab,ti) AND (tumor:ab,ti OR tumors:ab,ti OR tumour:ab,ti OR tumours:ab,ti OR malignancy:ab,ti OR malignancies:ab,ti OR Malignant:ab,ti OR Neoplasm:ab,ti OR Neoplasms:ab,ti OR leukemia:ab,ti OR leukemias:ab,ti))

3. For antibody therapy we will use:
Antibody/exp OR Immunotherapy/exp OR antibody:ab,ti OR antibodies:ab,ti OR mAb:ab,ti OR Immunotherapy:ab,ti OR ‘Immune therapy’:ab,ti OR ‘Immunoglobulin therapy’:ab,ti OR ‘Immunological therapy’:ab,ti OR ‘Immunological treatment’:ab,ti OR ‘Cancer immunotherapy’:ab,ti OR ‘Tumor immunotherapy’:ab,ti OR Immunoglobulin:ab,ti OR Immunoglobulins:ab,ti OR Rituximab:ab,ti OR ‘Anti-CD20’:ab,ti OR Mabthera:ab,ti OR Rituxan:ab,ti OR reditux:ab,ti OR rituxin:ab,ti OR ‘IDEC-C2B8’:ab,ti OR ‘Brentuximab vedotin’:ab,ti OR Adcetris:ab,ti OR ‘anti-CD30’:ab,ti OR ‘cAC10-vcMMAE’:ab,ti OR ‘SGN-35’:ab,ti OR ‘SGN35’:ab,ti OR ‘SGN 35’:ab,ti OR ‘Anti-CD19’:ab,ti OR ‘MDX 1342’:ab,ti OR ‘MDX-1342’:ab,ti OR ‘Anti-MDX 1342’:ab,ti OR ‘Anti-MDX1342’:ab,ti OR ‘Anti-MDX-1342’:ab,ti OR blinatumomab:ab,ti OR ‘medi 538’:ab,ti OR medi538:ab,ti OR ‘mt 103’:ab,ti OR mt103:ab,ti OR epratuzumab:ab,ti OR ‘anti-CD22’:ab,ti OR ‘hLL2 agent’:ab,ti OR LymphoCide:ab,ti OR ‘immu 1903’:ab,ti OR immu1903:ab,ti OR ‘immu-1903’:ab,ti OR veltuzumab:ab,ti OR ‘anti-CD20 IgG’:ab,ti OR ‘ha 20’:ab,ti OR ha20:ab,ti OR ‘ha-20’:ab,ti OR ‘immu 106’:ab,ti OR immu106:ab,ti OR ‘immu-106’:ab,ti OR Ofatumumab:ab,ti OR Arzerra:ab,ti OR ‘HuMax-CD20’:ab,ti OR ‘HuMax CD20’:ab,ti OR HuMaxCD20:ab,ti OR ‘humac CD20’:ab,ti OR ‘gsk 1841157’:ab,ti OR gsk1841157:ab,ti OR epratuzumab:ab,ti OR ‘epratuzumab y 90’:ab,ti OR ‘epratuzumab yttrium y 90’:ab,ti OR ‘epratuzumab tetraxetan yttrium y 90’:ab,ti OR ‘epratuzumab Iodine-131’:ab,ti OR ‘90Y-labeled ibritumomab tiuxetan’:ab,ti OR ‘Ibritumomab tiuxetan’:ab,ti OR Ibritumomab:ab,ti OR ‘yttrium-90-ibritumomab tiuxetan’:ab,ti OR Zevalin:ab,ti OR ‘in-111 zevalin’:ab,ti OR ‘y-90 zevalin’:ab,ti OR zevaline:ab,ti OR ‘idec 129’:ab,ti OR ‘idec y2b8’:ab,ti OR idec129:ab,ti OR Tositumomab:ab,ti OR ‘Tositumomab I 131’:ab,ti OR ‘tositumomab iodine-131’:ab,ti OR ‘iodine-131 tositumomab’:ab,ti OR ‘iodine-131-tositumomab’:ab,ti OR ‘131I-labeled tositumomab’:ab,ti OR ‘Tositumomab-I131’:ab,ti OR Bexxar:ab,ti OR ‘bexxar dosimetric’:ab,ti OR ‘bexxar i 131 dosimetric’:ab,ti OR ‘131I anti-B1’:ab,ti OR Alemtuzumab:ab,ti OR Campath:ab,ti OR MabCampath:ab,ti OR ‘Campath-1H’:ab,ti OR Lemtrada:ab,ti OR ‘Campath 1G’:ab,ti OR ‘Campath-1G’:ab,ti OR ‘Campath-1-G’:ab,ti OR Campath1G:ab,ti OR ‘Campath 1M’:ab,ti OR ‘Campath-1M’:ab,ti OR ‘Campath-1-M’:ab,ti OR Campath1M:ab,ti OR Campath1H:ab,ti OR ‘Campath 1H’:ab,ti OR ‘Campath-1H’:ab,ti OR ‘Campath-1-H’:ab,ti OR ‘Campath 1’:ab,ti OR ‘Anti-CD52’:ab,ti OR ‘ldp 103’:ab,ti OR ldp103:ab,ti OR galiximab:ab,ti OR ‘Anti-CD80’:ab,ti OR ‘anti-B7-1 mAb’:ab,ti OR ‘P-16C10’:ab,ti OR ‘IDEC-114’:ab,ti OR ‘idec 114’:ab,ti OR idec114:ab,ti OR dacetuzumab:ab,ti OR ‘anti-CD40’:ab,ti OR ‘SGN 40’:ab,ti OR ‘SGN40 cpd’:ab,ti OR ‘SGN-40’:ab,ti OR SGN40:ab,ti OR ‘hu S2C6’:ab,ti OR Apolizumab:ab,ti OR ‘Hu1D 10’:ab,ti OR Hu1D10:ab,ti OR Remitogen:ab,ti OR ‘anti-CD27 ‘:ab,ti OR ‘anti-CCR4’:ab,ti OR mogamulizumab:ab,ti OR ‘AMG 761’:ab,ti OR AMG761:ab,ti OR ‘AMG-761’:ab,ti OR ‘KW 0761’:ab,ti OR KW0761:ab,ti OR ‘KW-0761’:ab,ti OR ‘km 8761’:ab,ti OR km8761:ab,ti OR ‘anti-CD3’:ab,ti OR ‘OKT-3’:ab,ti OR OKT3:ab,ti OR ‘OKT 3’:ab,ti OR visilizumab:ab,ti OR ‘hu m 291’:ab,ti OR ‘hu m291’:ab,ti OR ‘hum 291’:ab,ti OR hum291:ab,ti OR nuvion:ab,ti OR ‘SMART anti-CD3’:ab,ti OR Nuvion:ab,ti OR Otelixizumab:ab,ti OR ‘gsk 2136525’:ab,ti OR ‘gsk2136525 ‘:ab,ti OR ‘trx 4’:ab,ti OR trx4:ab,ti OR ‘Muromonab-CD3’:ab,ti OR ‘muromonab-cd3’:ab,ti OR orthoclone:ab,ti OR ‘anti-thymocyte immunoglobulin’:ab,ti OR ‘antithymocyte immunoglobulin’:ab,ti OR ‘antithymocytic immunoglobulin’:ab,ti OR ‘thymocyte antiserum’:ab,ti OR ‘thymocyte isoantiserum’:ab,ti OR ‘thymocyte serum’:ab,ti OR ‘thymocyte isoantibody’:ab,ti OR ‘anti thymocyte antiserum’:ab,ti OR ‘antithymocyte antiserum’:ab,ti OR ‘anti thymocyte serum ‘:ab,ti OR ‘antithymocyte serum’:ab,ti OR ‘antithymic serum’:ab,ti OR ‘antithymocytic serum’:ab,ti OR ‘antithymus serum’:ab,ti OR ‘anti thymocyte globulin’:ab,ti OR ‘antithymocyte globulin’:ab,ti OR ‘anti thymocytic globulin’:ab,ti OR ‘antithymocytic globulin’:ab,ti OR atg:ab,ti OR atgam:ab,ti OR thymoglobulin:ab,ti OR thymoglobuline:ab,ti OR ‘thymus antiserum’:ab,ti

Final search 1 AND 2 AND 3

ab,ti = abstract, title ; / = Emtree term

Appendix 4. Search strategy for the WHO ICTRP search portal (via the "Advanced search" page)

The following strategy will be used to search WHO ICTRP:

In Condition: (leukemia OR lymphoma)

In Intervention: antibody search up to 250 characters:

1. antibody OR antibodies OR mAb OR immunotherapy OR immune therapy OR immunological therapy OR immunological treatment OR immunoglobulin OR immunoglobulins OR rituximab OR anti-CD20 OR mabthera OR rituxan OR reditux OR rituxin OR IDEC-C2B8

2. brentuximab vedotin OR adcetris OR anti-CD30 OR cAC10-vcMMAE OR SGN 35 OR Anti-CD19 OR MDX 1342 OR blinatumomab OR medi 538 OR mt 103 OR epratuzumab OR anti-CD22 OR hLL2 agent OR lymphoCide OR immu 1903 OR veltuzumab OR anti-CD20 IgG OR ha 20

3. immu 106 OR ofatumumab OR Arzerra OR HuMax CD20 OR humac CD20 OR gsk 1841157 OR epratuzumab OR ibritumomab OR zevalin OR zevaline OR idec 129 OR idec y2b8 OR tositumomab OR bexxar OR bexxar i 131 dosimetric OR 131I anti-B1 OR alemtuzumab OR campath

4. MabCampath OR Lemtrada OR Anti-CD52 OR ldp 103 OR galiximab OR Anti-CD80 OR anti-B7-1 mAb OR P-16C10 OR IDEC-114 OR idec 114 OR dacetuzumab OR anti-CD40 OR SGN 40 OR hu S2C6 OR apolizumab OR Hu1D 10 OR remitogen OR anti-CD27 OR anti-CCR4

5. mogamulizumab OR AMG 761 OR KW 0761 OR km 8761 OR anti-CD3 OR OKT 3 OR visilizumab OR hu m 291 OR hum 291 OR nuvion OR SMART anti-CD3 OR otelixizumab OR gsk 2136525 OR trx 4 OR muromonab-CD3 OR orthoclone OR antithymocyte immunoglobulin

6. antithymocytic immunoglobulin OR thymocyte antiserum OR thymocyte isoantibody OR antithymocyte antiserum OR antithymocyte serum OR antithymic serum OR antithymocytic serum

7. antithymus serum OR antithymocyte globulin OR antithymocytic globulin OR atg OR atgam OR thymoglobulin OR thymoglobuline OR thymus antiserum

Tick off: Search for Clinical trials in Children.

Appendix 5. Search strategy for Clinicaltrial.gov (via the "Advanced search" page)

In Condition: (leukemia OR lymphoma)

In Intervention: antibody search up to 250 characters:

1. antibody OR antibodies OR mAb OR immunotherapy OR immune therapy OR immunological therapy OR immunological treatment OR immunoglobulin OR immunoglobulins OR rituximab OR anti-CD20 OR mabthera OR rituxan OR reditux OR rituxin OR IDEC-C2B8

2. brentuximab vedotin OR adcetris OR anti-CD30 OR cAC10-vcMMAE OR SGN 35 OR anti-CD19 OR MDX 1342 OR blinatumomab OR medi 538 OR mt 103 OR epratuzumab OR anti-CD22 OR hLL2 agent OR LymphoCide OR immu 1903 OR veltuzumab

3. anti-CD20 IgG OR ha 20 OR immu 106 OR ofatumumab OR arzerra OR HuMax CD20 OR humac CD20 OR gsk 1841157 OR epratuzumab OR ibritumomab OR zevalin OR zevaline OR idec 129 OR idec y2b8 OR tositumomab OR bexxar OR bexxar i 131 dosimetric

4. 131I anti-B1 OR alemtuzumab OR campath OR MabCampath OR lemtrada OR anti-CD52 OR ldp 103 OR galiximab OR anti-CD80 OR anti-B7-1 mAb OR P-16C10 OR IDEC-114 OR idec 114 OR dacetuzumab OR anti-CD40 OR SGN 40 OR hu S2C6

5. apolizumab OR Hu1D 10 OR remitogen OR anti-CD27 OR anti-CCR4 OR mogamulizumab OR AMG 761 OR KW 0761 OR km 8761 OR anti-CD3 OR OKT 3 OR visilizumab OR hu m 291 OR hum 291 OR nuvion OR SMART anti-CD3 OR otelixizumab

6. gsk 2136525 OR trx 4 OR muromonab-CD3 OR orthoclone OR antithymocyte immunoglobulin OR antithymocytic immunoglobulin OR thymocyte antiserum OR thymocyte isoantibody OR antithymocyte antiserum OR antithymocyte serum

7. antithymic serum OR antithymocytic serum OR antithymus serum OR antithymocyte globulin OR antithymocytic globulin OR atg OR atgam OR thymoglobulin OR thymoglobuline OR thymus antiserum

Tick off with Additional Criteria, Age Group: Child (birth-17)

Declarations of interest

The authors declare that there are no conflicts of interest.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • KWF, Netherlands.

    Friederike Meyer-Wentrup is a KWF-research fellow. Her salary and research expenses are paid for by the KWF.

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