Mutational and transcriptional landscape of pediatric B-cell precursor lymphoblastic lymphoma.

ABSTRACT: Pediatric B-cell precursor (BCP) lymphoblastic malignancies are neoplasms with manifestation either in the bone marrow or blood (BCP acute lymphoblastic leukemia [BCP-ALL]) or are less common in extramedullary tissue (BCP lymphoblastic lymphoma [BCP-LBL]). Although both presentations are similar in morphology and immunophenotype, molecular studies have been virtually restricted to BCP-ALL so far. The lack of molecular studies on BCP-LBL is due to its rarity and restriction on small, mostly formalin-fixed paraffin-embedded (FFPE) tissues. Here, to our knowledge, we present the first comprehensive mutational and transcriptional analysis of what we consider the largest BCP-LBL cohort described to date (n = 97). Whole-exome sequencing indicated a mutational spectrum of BCP-LBL, strikingly similar to that found in BCP-ALL. However, epigenetic modifiers were more frequently mutated in BCP-LBL, whereas BCP-ALL was more frequently affected by mutation in genes involved in B-cell development. Integrating copy number alterations, somatic mutations, and gene expression by RNA sequencing revealed that virtually all molecular subtypes originally defined in BCP-ALL are present in BCP-LBL, with only 7% of lymphomas that were not assigned to a subtype. Similar to BCP-ALL, the most frequent subtypes of BCP-LBL were high hyperdiploidy and ETV6::RUNX1. Tyrosine kinase/cytokine receptor rearrangements were detected in 7% of BCP-LBL. These results indicate that genetic subtypes can be identified in BCP-LBL using next-generation sequencing, even in FFPE tissue, and may be relevant to guide treatment.

ATM germ line pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies.

ABSTRACT: Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene, predisposing children to hematological malignancies. We investigated their characteristics and outcomes to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21 (10%) with Hodgkin lymphoma and 8 (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% confidence interval [CI], 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (P = .76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI, 19.5-32.4). Germ line ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n = 110) were classified as having absent (n = 81) or residual (n = 29) ATM kinase activity. Four-year EFS was 39.4% (95% CI, 29-53.3) vs 78.7% (95% CI, 63.7-97.2), (P < .001), and TRM rates were 37.6% (95% CI, 26.4-48.7) vs 4.0% (95% CI, 0-11.8), (P = .017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR = 0.362, 95% CI, 0.16-0.82; P = .009) and increased TRM (hazard ratio [HR] = 14.11, 95% CI, 1.36-146.31; P = .029). Patients with A-T and leukemia/lymphoma may benefit from deescalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.

Decoding the molecular heterogeneity of pediatric monomorphic post-solid organ transplant lymphoproliferative disorders.

Posttransplant lymphoproliferative disorders (PTLDs) represent a broad spectrum of lymphoid proliferations, frequently associated with Epstein-Barr virus (EBV) infection. The molecular profile of pediatric monomorphic PTLDs (mPTLDs) has not been elucidated, and it is unknown whether they display similar genetic features as their counterpart in adult and immunocompetent (IMC) pediatric patients. In this study, we investigated 31 cases of pediatric mPTLD after solid organ transplantation, including 24 diffuse large B-cell lymphomas (DLBCLs), mostly classified as activated B cell, and 7 cases of Burkitt lymphoma (BL), 93% of which were EBV positive. We performed an integrated molecular approach, including fluorescence in situ hybridization, targeted gene sequencing, and copy number (CN) arrays. Overall, PTLD-BL carried mutations in MYC, ID3, DDX3X, ARID1A, or CCND3 resembling IMC-BL, higher mutational burden than PTLD-DLBCL, and lesser CN alterations than IMC-BL. PTLD-DLBCL showed a very heterogeneous genomic profile with fewer mutations and CN alterations than IMC-DLBCL. Epigenetic modifiers and genes of the Notch pathway were the most recurrently mutated in PTLD-DLBCL (both 28%). Mutations in cell cycle and Notch pathways correlated with a worse outcome. All 7 patients with PTLD-BL were alive after treatment with pediatric B-cell non-Hodgkin lymphoma protocols, whereas 54% of patients with DLBCL were cured with immunosuppression reduction, rituximab, and/or low-dose chemotherapy. These findings highlight the low complexity of pediatric PTLD-DLBCL, their good response to low-intensity treatment, and the shared pathogenesis between PTLD-BL and EBV-positive IMC-BL. We also suggest new potential parameters that could help in the diagnosis and the design of better therapeutic strategies for these patients.

Secondary haematological dysplasia after CAR-T-cell therapy for acute lymphoblastic leukaemia in children.

The use of CAR-T is becoming more widespread in the treatment of haematological malignancies. In adults, secondary myelodysplastic syndromes (MDS) after CAR-T have been described. However, there are currently no data on the risk of MDS following CAR-T in children treated for acute lymphoblastic leukaemia (ALL). We studied all children treated with CAR-T cells at Hospital Sant Joan de Déu in Barcelona and those with persistent cytopenias were evaluated at the cytological, cytogenetic, and molecular levels to look for MDS. A total of 106 patients received CAR-T for ALL. Among 40 patients without early relapse or subsequent therapy after CAR-T, four fulfilled the WHO criteria for myelodysplasia. These four patients had received a haematopoietic stem cell transplantation (HSCT) prior to CAR-T and presented cytopenias with severe dysplastic changes in bone marrow after CAR-T. One patient had clonal MDS with high-risk cytogenetics arising from the host cells requiring a HSCT. Three patients had non-progressive dysplasia arising from the donor cells. Two are alive in complete remission with stable cytopenias and one succumbed to ALL relapse. This is the first description of post-CAR-T MDS and haematological dysplasia in children and highlights the need to monitor children with persistent post-CAR-T cytopenias.

Long-term sequelae and quality of life after childhood-onset craniopharyngioma: Results of a Spanish multicenter study.

PURPOSE: We aim to describe the characteristics of patients with childhood-onset craniopharyngioma and to analyze factors that impair quality of life (QoL) in this population. METHODS: Multicenter national study including patients treated between 2008 and 2022, from 2 to 25 years of age diagnosed with craniopharyngioma. QoL was assessed once during patient's follow-up by age-adapted versions of Pediatric Quality of Life Inventory (PedsQL) questionnaire. RESULTS: Sixty-six patients were included. Median age at diagnosis was 5 years (interquartile range [IQR]: 3-8), while median follow-up was 7.4 years (IQR: 2.8-9.7). Most craniopharyngioma were suprasellar (93.9%), and 59.7% had hypothalamic involvement (HI). All patients underwent surgery, 44.4% received radiotherapy, and 23.6% intracystic therapy. Most frequent long-term complications were visual deficit (72.7%) and endocrine impairment (94.5%). Patients exhibited hypothyroidism requiring hormone replacement (92.4%), hypocortisolism (80.3%), diabetes insipidus (86.4%), and/or growth hormone therapy (50%). When parents evaluated QoL, PedsQL median score was 53.8 points out of 100 (IQR: 41-71.6). Higher scores were noted when patients assessed their own QoL (median score 64.8 [IQR: 57.3-81.8]), observing statistically significant differences (p = .019). QoL was impaired by repeated surgeries (r = -.44; p = .014), HI (median score 51.5 [IQR: 39-63.8] vs. 76.4 [59-84.8]; p = .001), radiotherapy (median score 51.9 [IQR: 38.1-61.3] vs. 63.8 [IQR: 49-82.5]; p = .02) and longer follow-up (r = -.3; p = .01). CONCLUSION: In our study, most patients had significant comorbidities and low overall QoL scores, which was mainly affected by repeated surgery, radiation, and hypothalamic involvement. This reflects the need for further research and intensified studies of systemic therapy/alternate strategies to broaden the standard-of-care options, so that treatment-related sequalae can be avoided.

Distinct molecular profile of IRF4-rearranged large B-cell lymphoma.

Pediatric large B-cell lymphomas (LBCLs) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse LBCLs (DLBCLs), not otherwise specified (NOS); 20 LBCL-IRF4 cases; and 12 cases of high-grade B-cell lymphoma (HGBCL), NOS in patients ≤25 years using an integrated approach, including targeted gene sequencing, copy-number arrays, and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B, and MYD88), losses of 17p13 and gains of chromosome 7, 11q12.3-q25, whereas DLBCL, NOS was predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (eg, SOCS1 and KMT2D), gains of 2p16/REL, and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma-related genes such as MYC, ID3, and DDX3X and homozygous deletions of 9p21/CDKN2A, whereas other cases were genetically closer to GCB DLBCL. Factors related to unfavorable outcome were age >18 years; activated B-cell (ABC) DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric and young adult LBCL, improve the classification of this group of tumors, and provide new parameters for risk stratification.

Diverse mutations and structural variations contribute to Notch signaling deregulation in paediatric T-cell lymphoblastic lymphoma.

BACKGROUND: T-cell lymphoblastic lymphoma (T-LBL) is an aggressive neoplasm closely related to T-cell acute lymphoblastic leukaemia (T-ALL). Despite their similarities, and contrary to T-ALL, studies on paediatric T-LBL are scarce and, therefore, its molecular landscape has not yet been fully elucidated. Thus, the aims of this study were to characterize the genetic and molecular heterogeneity of paediatric T-LBL and to evaluate novel molecular markers differentiating this entity from T-ALL. PROCEDURE: Thirty-three paediatric T-LBL patients were analyzed using an integrated approach, including targeted next-generation sequencing, RNA-sequencing transcriptome analysis and copy-number arrays. RESULTS: Copy number and mutational analyses allowed the detection of recurrent homozygous deletions of 9p/CDKN2A (78%), trisomy 20 (19%) and gains of 17q24-q25 (16%), as well as frequent mutations of NOTCH1 (62%), followed by the BCL11B (23%), WT1 (19%) and FBXW7, PHF6 and RPL10 genes (15%, respectively). This genetic profile did not differ from that described in T-ALL in terms of mutation incidence and global genomic complexity level, but unveiled virtually exclusive 17q25 gains and trisomy 20 in T-LBL. Additionally, we identified novel gene fusions in paediatric T-LBL, including NOTCH1-IKZF2, RNGTT-SNAP91 and DDX3X-MLLT10, the last being the only one previously described in T-ALL. Moreover, clinical correlations highlighted the presence of Notch pathway alterations as a factor related to favourable outcome. CONCLUSIONS: In summary, the genomic landscape of paediatric T-LBL is similar to that observed in T-ALL, and Notch signaling pathway deregulation remains the cornerstone in its pathogenesis, including not only mutations but fusion genes targeting NOTCH1.

Burkitt-like lymphoma with 11q aberration: a germinal center-derived lymphoma genetically unrelated to Burkitt lymphoma.

Burkitt-like lymphoma with 11q aberration is characterized by pathological features and gene expression profile resembling those of Burkitt lymphoma but lacks the MYC rearrangement and carries an 11q-arm aberration with proximal gains and telomeric losses. Whether this lymphoma is a distinct category or a particular variant of other recognized entities is controversial. To improve the understanding of Burkitt-like lymphoma with 11q aberration we performed an analysis of copy number alterations and targeted sequencing of a large panel of B-cell lymphoma-related genes in 11 cases. Most patients had localized nodal disease and a favorable outcome after therapy. Histologically, they were high grade B-cell lymphoma, not otherwise specified (8 cases), diffuse large B-cell lymphoma (2 cases) and only one was considered as atypical Burkitt lymphoma. All cases had a germinal center B-cell signature and phenotype with frequent LMO2 expression. The patients with Burkitt-like lymphoma with 11q aberration had frequent gains of 12q12-q21.1 and losses of 6q12.1-q21, and lacked common Burkitt lymphoma or diffuse large B-cell lymphoma alterations. Potential driver mutations were found in 27 genes, particularly involving BTG2, DDX3X, ETS1, EP300, and GNA13 However, ID3, TCF3, or CCND3 mutations were absent in all cases. These results suggest that Burkitt-like lymphoma with 11q aberration is a germinal center-derived lymphoma closer to high-grade B-cell lymphoma or diffuse large B-cell lymphoma than to Burkitt lymphoma.

Mini photopheresis for refractory chronic graft-versus-host disease in children and adolescents.

BACKGROUND: Extracorporeal photopheresis (ECP) has been established to treat graft-versus-host disease. Our mini ECP technique (mini-ECP) allows for treatment of patients with GVHD and contraindications for classical ECP or low body weight. The safety and efficacy of applying ECP for the long-term treatment of chronic GVHD (cGVHD) have not been described. STUDY DESIGN AND METHODS: A retrospective analysis of mini-ECP treatments for children and adolescents with cGVHD was performed. Mini-ECP with 100 to 200 mL of whole blood was used to treat 14 patients. The median age at the start of treatment was 7 years (range, 1-17 years), and median body weight was 20 kg (range, 8-53 kg). A total of 703 mini-ECP treatments was performed. The median number of treatments per patient was 35 (range, 8-129), and median treatment duration was 11 months (range, 1.4-28.5 months). RESULTS: Mini-ECP was well tolerated. Four adverse events occurred in three patients, and two of them were related to the ECP procedure. Complete or partial responses were observed in 10 patients. Steroids were discontinued in seven patients and tapered in three others. Responses were seen in the skin, mouth, gastrointestinal tract, and eyes. CONCLUSION: Mini-ECP represents a less invasive ECP alternative for low-body-weight patients with cGVHD and contraindications for apheresis.

Evolution of the Innovative Therapies for Children With Cancer Consortium Trial Portfolio for Drug Development for Children With Cancer.

PURPOSE: The aim of the Innovative Therapies for Children with Cancer (ITCC) consortium is to improve access to novel therapies for children and adolescents with cancer. The evolution of the ITCC clinical trial portfolio since 2003 was reviewed. METHODS: All ITCC-labeled phase I/II trials opened between January 1, 2003 and February 3, 2018 were analyzed in two periods (2003-2010 and 2011-2018), and data were extracted from the ITCC database, regulatory agencies' registries, and publications. RESULTS: Sixty-one trials (62% industry-sponsored) enrolled 3,198 patients. The number of trials in the second period increased by almost 300% (16 v 45). All biomarker-driven trials (n = 14) were conducted in the second period. The use of rolling six and model-based designs increased (1 of 9, 11% v 21 of 31, 68%), and that of 3 + 3 designs decreased (5 of 9, 55% v 5 of 31, 16%; P = .014). The proportion of studies evaluating chemotherapeutics only decreased (5 of 16, 31% v 4 of 45, 9%), the proportion of single-agent targeted therapies did not change (9 of 16, 56.2% v 24 of 45, 53.3%), the proportion of combination targeted therapies trials increased (2 of 16, 12%, v 17 of 45, 38%), the proportion of randomized phase II trials increased (1 of 7, 14% v 8 of 14, 57%). More trials were part of a pediatric investigation plan in the second period (4 of 16, 25% v 21 of 45, 46%). The median time for Ethics Committees' approvals was 1.7 times longer for academic compared with industry-sponsored trials. CONCLUSION: This study reports a shift in the paradigm of early drug development for childhood cancers, with more biologically relevant targets evaluated in biomarker-driven trials or in combination with other therapies and with more model-based or randomized designs and a greater focus on fulfilling regulatory requirements. Improvement of trial setup and recruitment could increase the number of patients benefiting from novel agents.

Haploidentical versus Cord Blood Transplantation in Pediatric AML. A Retrospective Outcome Analysis on Behalf of the Pediatric Subcommittee of GETH (Grupo Español de Trasplante Hematopoyético).

Haploidentical stem cell transplantation (Haplo-SCT) and cord blood transplantation (CBT) are both effective alternative treatments in patients suffering from acute myeloid leukemia (AML) and lacking a matched HLA donor. In the last years, many centers have abandoned CBT procedures mostly due to concern about poorer immune recovery compared with Haplo-SCT. We conducted a retrospective multicenter study comparing the outcomes using both alternative approaches in AML. A total of 122 transplants (86 Haplo-SCTs and 36 CBTs) from 12 Spanish centers were collected from 2007 to 2021. Median age at hematopoietic stem cell transplantation (HSCT) was 7 years (0.4-20). Thirty-nine patients (31.9%) showed positive minimal residual disease (MRD) at HSCT and a previous HSCT was performed in 37 patients (30.3%). The median infused cellularity was 14.4 × 106/kg CD34+ cells (6.0-22.07) for Haplo-SCT and 4.74 × 105/kg CD34+ cells (0.8-9.4) for CBT. Median time to neutrophil engraftment was 14 days (7-44) for Haplo-SCT and 17 days (8-29) for CBT (P = .03). The median time to platelet engraftment was 14 days (6-70) for Haplo-SCT and 43 days (10-151) for CBT (P < .001). Graft rejection was observed in 13 Haplo-SCTs (15%) and in 6 CBTs (16%). The cumulative incidence of acute graft versus host disease (GvHD) grades II-IV was 54% and 51% for Haplo-SCT and CBT, respectively (P = .50). The cumulative incidence of severe acute GvHD (grades III-IV) was 22% for Haplo-SCT and 25% for CBT (P = .90). There was a tendency to a higher risk of chronic GvHD in the Haplo-SCT group being the cumulative incidence of 30% for Haplo-SCT and 12% for CBT (P = .09). The cumulative incidence of relapse was 28% and 20% for Haplo-SCT and CBT, respectively (P = .60). We did not observe statistically significant differences in outcome measures between Haplo-SCT and CBT procedures: 5-year overall survival (OS) was 64% versus 57% (P = .50), 5-year disease-free survival (DFS) 58% versus 57% (P = .80), GvHD-free and relapse-free survival (GFRFS) 41% versus 54% (P = .30), and cumulative incidence of transplant-related mortality (TRM) 14% versus 15% (P = .80), respectively. In the multivariate analysis, MRD positivity and a disease status >CR1 at the time of HSCT were significantly associated with poorer outcomes (P < .05). In conclusion, our study supports that both haploidentical and cord blood transplantation show comparable outcomes in pediatric AML patients. We obtained comparable survival rates, although CBT showed a trend to lower rates of chronic GvHD and higher GFRFS, demonstrating that it should still be considered a valuable option, particularly for pediatric patients.

MYC-rearranged mature B-cell lymphomas in children and young adults are molecularly Burkitt Lymphoma.

Aggressive B-cell non-Hodgkin lymphomas (NHL) in children, adolescents, and young adults (CAYA) include Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and a subset of high-grade tumors with features intermediate between these entities whose genetic and molecular profiles have not been completely elucidated. In this study, we have characterized 37 aggressive B-NHL in CAYA, 33 with high-grade morphology, and 4 DLBCL with MYC rearrangement (MYC-R), using targeted next-generation sequencing and the aggressive lymphoma gene expression germinal center B-cell-like (GCB), activated B-cell-like (ABC), and dark zone signatures (DZsig). Twenty-two tumors had MYC-R without BCL2 breaks, and two MYC-non-R cases had BCL6 translocations. MYC-R cases, including DLBCL, carried BL-related mutations and copy number alterations. Conversely, MYC-non-R lymphomas had alterations in the B-cell receptor signaling/NF-κB pathway (71%). DZsig was expressed in 12/13 of MYC-R tumors but only in 2/10 of MYC-non-R GCB tumors (P < 0.001). The 3-year event-free survival (EFS) of the whole cohort was 79.6%. TP53 and KMT2C mutations conferred inferior outcome (3-year EFS P < 0.05). Overall, MYC-R lymphomas in CAYA have a molecular profile similar to BL regardless of their high-grade or DLBCL morphology, whereas MYC-non-R has more heterogeneous genetic alterations closer to that of DLBCL.

Safety and outcome of children, adolescents and young adults participating in phase I/II clinical oncology trials: a 9-year center experience.

Introduction: Enrolling children with cancer in early phase trials is crucial to access innovative treatments, contributing to advancing pediatric oncology research and providing tailored therapeutic options. Our objective is to analyze the impact of these trials on patient outcomes and safety, and to examine the evolution and feasibility of trials in pediatric cancer over the past decade. Methods: All patients recruited in pediatric anticancer phase I/II clinical trials from January 2014 to December 2022 were included. Clinical records and trial protocols were analyzed. Results: A total of 215 patients (median age 11.2 years, range 1-29.5) were included in 52 trials (258 inclusions). Patients with extracranial solid tumors (67%), central nervous system (CNS) tumors (24%), and leukemia (9%) were included. The most common investigational drugs were small molecules (28.3%) and antibodies (20.5%). Serious adverse events were experienced by 41% of patients, 4.4% discontinued treatment because of toxicity and two had toxic deaths. Median event-free survival was 3.7 months (95%CI: 2.8-4.5), longer in phase II trials than in phase I (2 vs. 6.3 months; p ≤ 0.001). Median overall survival was 12 months (95%CI: 9-15), higher in target-specific vs. non-target-specific trials (14 vs. 6 months; p ≤ 0.001). Discussion: A significant and increasing number of patients have been included in early clinical trials, suggesting that both oncologists and families consider it valuable to be referred to specialized Units to access new therapies. Moreover, our data suggests that participation in early clinical trials, although not without potential toxicities, might have a positive impact on individual outcomes.

ECLIM-SEHOP: how to develop a platform to conduct academic trials for childhood cancer.

INTRODUCTION: ECLIM-SEHOP platform was created in 2017. Its main objective is to establish the infrastructure to allow Spanish participation into international academic collaborative clinical trials, observational studies, and registries in pediatric oncology. The aim of this manuscript is to describe the activity conducted by ECLIM-SEHOP since its creation. METHODS: The platform's database was queried to provide an overview of the studies integrally and partially supported by the organization. Data on trial recruitment and set-up/conduct metrics since its creation until November 2023 were extracted. RESULTS: ECLIM-SEHOP has supported 47 studies: 29 clinical trials and 18 observational studies/registries that have recruited a total of 5250 patients. Integral support has been given to 25 studies: 16 trials recruiting 584 patients and nine observational studies/registries recruiting 278 patients. The trials include front-line studies for leukemia, lymphoma, brain and solid extracranial tumors, and other key transversal topics such as off-label use of targeted therapies and survivorship. The mean time from regulatory authority submission to first patient recruited was 12.2 months and from first international site open to first Spanish site open was 31.3 months. DISCUSSION: ECLIM-SEHOP platform has remarkably improved the availability and accessibility of international academic clinical trials and has facilitated the centralization of resources in childhood cancer treatment. Despite the progressive improvement on clinical trial set-up metrics, timings should still be improved. The program has contributed to leveling survival rates in Spain with those of other European countries that presented major differences in the past.

Effect of rituximab on immune status in children with mature B-cell non-Hodgkin lymphoma: a prespecified secondary analysis of the Inter-B-NHL Ritux 2010 trial.

BACKGROUND: Survival of children and adolescents with high-risk, mature B-cell non-Hodgkin lymphoma is improved by the addition of rituximab to chemotherapy. The effect of rituximab on immune reconstitution after therapy has not been well described. Herein, we evaluate the immune effects of the addition of rituximab to intensive chemotherapy, a prespecified secondary aim of the Inter-B-NHL Ritux 2010 trial. METHODS: The Inter-B-NHL Ritux 2010 trial was an international, open-label, randomised, phase 3 trial in children (age 6 months to 18 years) with high-risk, mature B-cell non-Hodgkin lymphoma, comparing chemotherapy alone or chemotherapy with rituximab. Measures of immune status were completed at baseline, 1 month from the end of treatment, and 1 year from the start of therapy, and yearly thereafter until normalised. For this secondary analysis, we report on the proportions of patients with low lymphocyte counts and immunoglobulin concentrations at these timepoints with total lymphocyte count, B-cell count, and IgG concentration as the main endpoints. Other endpoints of interest included exposure to immunoglobulin replacement therapy and vaccine serologies. The population assessed for immune endpoints was the eligible per-protocol population with at least one immune parameter at one timepoint. Comparisons of immune status were made between the randomised treatment groups. Safety in the post-therapy period was assessed in the population eligible for the immunity study who were followed up at least 3 months after the end of treatment and without cancer-related events. The Inter-B-NHL Ritux 2010 study was registered with ClinicalTrials.gov, NCT01516580; status completed, with analyses of secondary aims ongoing. FINDINGS: From Dec 19, 2011, to June 13, 2017, 421 patients (344 [82%] boys and 77 [18%] girls; mean age was 8·8 years [SD 4·1]) were enrolled and had immune data at baseline during follow-up, or both. The study population included randomly assigned patients (n=289) and a non-randomised cohort enrolled after the planned interim analysis (n=132). At baseline, 99 (34%) of 290 patients with available data (excluding patients with bone marrow disease with peripheral blast cells) had lymphopenia, and 178 (48%) of 368 had hypogammaglobulinemia. 1 month from the end of therapy, patients who received chemotherapy with rituximab were more likely than those who received chemotherapy alone to have lymphopenia (86 [81%] of 106 vs 53 (60%) of 89, odds ratio [OR] 2·92 [95% CI 1·53-5·57], p=0·0011), B-cell lymphopenia (72 [96%] of 75 vs 36 [64%] of 56, OR 13·33 [3·71-47·84], p<0·0001), and hypogammaglobulinemia (67 [71%] of 95 vs 37 [47%] of 79, OR 2·72 [1·45-5·07], p=0·0017). Differences remained at 1 year for hypogammaglobulinemia only (52 [55%] of 94 vs 16 [25%] of 63, OR 3·64 [1·81-7·31], p=0·0003). Patients in the chemotherapy with rituximab group were more likely than those in the chemotherapy group to receive immunoglobulin replacement (26 [16%] 164 vs nine [7%] of 158, hazard ratio [HR] 2·63 [95% CI 1·23-5·62], p=0·010), mainly due to low immunoglobulin concentration. In the combined treatment groups, including non-randomly assigned patients, the proportion of patients who had loss of protective serologies to a vaccine preventable infection varied from four (9%) of 47 for polio to 21 (42%) of 50 for Streptococcus pneumoniae (pneumococcus). One patient (chemotherapy with rituximab group) had a life-threatening infectious event of polymicrobial bacterial sepsis reported 2 months after the final chemotherapy administration. INTERPRETATION: Children with high-risk mature B-cell non-Hodgkin lymphoma receiving chemotherapy with rituximab were at risk of prolonged hypogammaglobulinemia, although severe infections were rare. Strategies for immunoglobulin replacement and revaccination are needed. FUNDING: Clinical Research Hospital Program of the French Ministry of Health, Cancer Research UK, National Institute for Health Research Clinical Research Network in England, Children's Cancer Foundation Hong Kong, US National Cancer Institute, F Hoffmann-La Roche.

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.

Pediatric Precursor B-Cell Lymphoblastic Malignancies: From Extramedullary to Medullary Involvement.

B-cell lymphoblastic lymphoma (BCP-LBL) and B-cell acute lymphoblastic leukemia (BCP-ALL) are the malignant counterparts of immature B-cells. BCP-ALL is the most common hematological malignancy in childhood, while BCP-LBL accounts for only 1% of all hematological malignancies in children. Therefore, BCP-ALL has been well studied and treatment protocols have changed over the last decades, whereas treatment for BCP-LBL has stayed roughly the same. Clinical characteristics of 364 pediatric patients with precursor B-cell malignancies were studied, consisting of BCP-LBL (n = 210) and BCP-ALL (n = 154) patients. Our results indicate that based on the clinical presentation of disease, B-cell malignancies probably represent a spectrum ranging from complete isolated medullary disease to apparent complete extramedullary disease. Hepatosplenomegaly and peripheral blood involvement are the most important discriminators, as both seen in 80% and 95% of the BCP-ALL patients and in 2% of the BCP-LBL patients, respectively. In addition, we show that the overall survival rates in this cohort differ significantly between BCP-LBL and BCP-ALL patients aged 1−18 years (p = 0.0080), and that the outcome for infants (0−1 years) with BCP-LBL is significantly decreased compared to BCP-LBL patients of all other pediatric ages (p < 0.0001).