TP53 DNA binding domain mutational status and rituximab-based treatment are independent prognostic factors for pediatric Burkitt lymphoma patients stratification.

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Cost-effectiveness analysis alongside the inter-B-NHL ritux 2010 trial: rituximab in children and adolescents with B cell non-Hodgkin's lymphoma.

OBJECTIVES: The randomized controlled trial Inter-B-NHL ritux 2010 showed overall survival (OS) benefit and event-free survival (EFS) benefit with the addition of rituximab to standard Lymphomes Malins B (LMB) chemotherapy in children and adolescents with high-risk, mature B cell non-Hodgkin's lymphoma. Our aim was to assess the cost-effectiveness of rituximab-chemotherapy versus chemotherapy alone in the French setting. METHODS: We used a decision-analytic semi-Markov model with four health states and 1-month cycles. Resource use was prospectively collected in the Inter-B-NHL ritux 2010 trial (NCT01516580). Transition probabilities were assessed from patient-level data from the trial (n = 328). In the base case analysis, direct medical costs from the French National Insurance Scheme and life-years (LYs) were computed in both arms over a 3-year time horizon. Incremental net monetary benefit and cost-effectiveness acceptability curve were computed through a probabilistic sensitivity analysis. Deterministic sensitivity analysis and several sensitivity analyses on key assumptions were also conducted, including one exploratory analysis with quality-adjusted life years as the health outcome. RESULTS: OS and EFS benefits shown in the Inter-B-NHL ritux 2010 trial translated into the model by rituximab-chemotherapy being the most effective and also the least expensive strategy over the chemotherapy strategy. The mean difference in LYs between arms was 0.13 [95% CI 0.02; 0.25], and the mean cost difference € - 3 710 [95% CI € - 17,877; € 10,525] in favor of rituximab-chemotherapy group. For a € 50,000 per LY willingness-to-pay threshold, the probability of the rituximab-chemotherapy strategy being cost-effective was 91.1%. All sensitivity analyses confirmed these findings. CONCLUSION: Adding rituximab to LMB chemotherapy in children and adolescents with high-risk mature B-cell non-Hodgkin's lymphoma is highly cost-effective in France. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01516580.

Large B-cell lymphoma with IRF4 rearrangement: a multi-centric study with focus on potential misleading phenotypes.

Large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) is a rare lymphoid neoplasm, usually occurring in the pediatric/young-adult age. Despite this, subsets of cases occur in elderly patients and express CD5, possibly entering the differential diagnosis with adult aggressive lymphomas, such as blastoid/pleomorphic mantle cell lymphoma (MCL-B/P). To better characterize the clinical-pathological features and differential diagnosis of LBCL-IRF4, we conducted a multi-centric study on 12 cases, focusing on CD5, Cyclin D1, and SOX11 expression. While most cases had typical presentation, adult-to-elderly age at diagnosis and unusual anatomic locations were reported in 3/12 (25.0%) and 2/12 (16.7%) patients, respectively. Histologically, CD5 was positive in 4/12 (33.3%) cases, Cyclin D1 was invariably negative, and SOX11 was weakly/partially expressed in 1/12 (8.3%) case. In conclusion, LBCL-IRF4 can have unconventional clinical presentations that may challenge its recognition. Although CD5 is frequently expressed, negativity for Cyclin D1 and SOX11 contributes to the differential diagnosis with MCL-B/P.

MiR-146a-5p enrichment in small-extracellular vesicles of relapsed pediatric ALCL patients promotes macrophages infiltration and differentiation.

Anaplastic large cell lymphoma (ALCL) is a CD30-positive lymphoma accounting for 20% of all pediatric T-cell lymphomas. Current first line treatment can cure most of ALCL patients but 10-30% of them are resistant or relapse. In this context, liquid biopsy has the potential to help clinicians in disease screening and treatment response monitoring. Small-RNA-sequencing analysis performed on plasma small-extracellular vesicles (s-EVs) from 20 pediatric anaplastic lymphoma kinase positive (ALK + ) ALCL patients at diagnosis revealed a specific miRNAs cargo in relapsed patients compared to non-relapsed, with seven miRNAs enriched in s-EVs of relapsed patients. MiR-146a-5p and miR-378a-3p showed a negative prognostic impact both in univariate and multivariate analysis, possibly representing, together with let-7 g-5p, a miRNA panel for the early identification of high-risk patients. Among them, miR-146a-5p is known to modulate tumor supporting-M2 macrophages differentiation, but the role of these cells in pediatric ALK + ALCL is still unknown. To elucidate the role of miR-146a-5p and M2 macrophages in pediatric ALCL disease, THP-1-derived macrophages were treated with s-EVs from ALK + ALCL cell lines, showing increased miR-146a-5p intracellular expression, migrating capability and M2-markers CD163 and Arginase-1 upregulation. In turn, conditioned media from M2 macrophages or miR-146a-5p-transfected THP-1 increased ALCL cells' aggressive features and were enriched in interleukin-8. Overall, these data suggest a role of miR-146a-5p in promoting macrophage infiltration and M2-like polarization in ALCL. Our findings incite further investigation on the role of M2 macrophages in ALCL aggressiveness and dissemination, also considering the novel treatment options targeting tumor associated macrophages.

Current practices of follow-up programs for childhood cancer survivors in Italy.

INTRODUCTION: Quality of life in childhood cancer survivors is largely affected by survivorship care and transition from treatment to long-term follow-up (LTFU). Referring to evidence-based recommendations, we wanted to evaluate LTFU care for survivors through a survey among the Italian Association for Pediatric Hematology-Oncology (AIEOP) centers. The project aimed to evaluate the availability of services in Italy, investigate strengths and weaknesses, analyze improvements of awareness in the field, and identify the gaps that need to be addressed by different centers. METHODS: Together with the family representatives, on behalf of AIEOP's Late Effects Working Group, we developed a questionnaire on assisting childhood cancer survivors. All AIEOP centers received one questionnaire including information on local health system organizations; LTFU for childhood cancer survivors; services for adult survivors of childhood cancer; information provided to survivors/caregivers and care plan delivery. RESULTS: Forty-eight AIEOP centers were contacted and 42 replied, with a response rate of 87.5%. The majority of respondents confirmed their interest in assisting patients with a survivorship care plan (95.2%), regardless of a clinic or dedicated staff. DISCUSSION: This is the first overview of LTFU in Italy, which provides detailed results at national levels, prompting consideration of improvements in the last decade. Although there is a high level of interest in survivorship care, many centers lack resources to implement such programs. The identification of these challenges is useful for planning future strategies.

Pediatric gray zone lymphoma according to the 2022 WHO classification: An Italian cohort study.

BACKGROUND: The 2022 World Health Organization (WHO) classification redefines the concept of gray zone lymphoma (GZL), restricting it in practice to cases of mediastinal/thymic origin (mediastinal gray zone lymphoma, MGZL) with overlapping features between primary mediastinal B-cell lymphoma (PMBCL) and classical Hodgkin lymphoma (CHL). Cases with histological characteristics of GZL but occurring without mediastinal involvement are better classified as diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS), with few exceptions. PROCEDURE: We collected clinical and pathological data about all Italian pediatric patients diagnosed with GZL over a 20-year period. RESULTS: We identified only four cases of bona fide MGZL. All patients were adolescent and presented with a mediastinal disease, always associated with other nodal involvement. B symptoms and increased levels of both erythrocyte sedimentation rate (ESR) and lactate dehydrogenase (LDH) were observed. Only two patients achieved a first complete remission, suggesting a more aggressive clinical behavior than either PMBCL or CHL. CONCLUSION: Prospective studies evaluating prognostic factors and establishing the most effective first-line therapy for MGZL are highly needed.

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.

Refractory Anaplastic Large Cell Lymphoma Rescued by the Combination of the Second-Generation ALK Inhibitor Brigatinib, High-dose Chemotherapy and Allogeneic Stem Cell Transplantation: A Case Report and Review of the Literature.

The treatment of pediatric patients with refractory or relapsed anaplastic large cell lymphoma (ALCL) is still a major challenge. In addition to conventional chemotherapy and stem cell transplantation, new therapeutic options such as anti-CD30 drugs and anaplastic lymphoma kinase (ALK) inhibitors have been recently introduced in this setting. Among ALK inhibitors, only the first-generation molecule crizotinib is approved for pediatric use, while second-generation molecules, such as brigatinib, are still under investigation. Here we report the case of a 13-year-old boy diagnosed with stage IV ALCL, refractory to first-line conventional chemotherapy and second-line therapy with the anti CD30 antibody-drug conjugate brentuximab-vedotin, who finally achieved remission after a combination of conventional high-dose chemotherapy and the second-generation ALK inhibitor brigatinib. The latter was chosen for its ability to penetrate through the blood-brain barrier, due to the persistent involvement of the patient's cerebral nervous system. The remission was then consolidated with an allogeneic hematopoietic stem cell transplantation (HSCT) from an unrelated donor using myeloablative conditioning with total body irradiation. At 24 months after HSCT, the patient is in complete remission, alive and well. An updated review regarding the use of ALK inhibitors in ALCL patients is provided.

Higher accuracy of surgical over core needle biopsy for the diagnosis of lymphoproliferative disorders.

INTRODUCTION: The diagnosis of lymphoproliferative disorders (LPDs) is based on histological evaluation of representative tissue samples. Despite surgical excision biopsies (SEBs) are reference procedures for such diagnoses, lymph node core needle biopsies (LNCBs) are increasingly performed. The diagnostic yield of LNCB is, however, debated and few studies have compared the reproducibility of LNCB and SEB findings. METHODS: To address the diagnostic value of LNCB and SEB, the present study considered a retrospective series of 43 paired LNCB/SEB samples. After histological revision, concordance rates between matched LNCB/SEB samples were evaluated, assuming SEB as gold standard procedure. The actionability of LNCB and SEB-based diagnoses (i.e., relevance for planning further medical interventions) was also assessed. RESULTS: Overall, LNCB provided actionable diagnoses in 39/43 (90.7%) cases, but a consistent subset of them (7/39 [17.9%]) turned out to be wrong at SEB. The cumulative diagnostic inaccuracy of LNCB (i.e., inadequate samples plus wrong diagnoses) was 25.6% and the mean diagnostic delay in such cases was 54.2 days. CONCLUSIONS: Although limited by selection biases due to its retrospective nature, this study highlights the intrinsic limitations of LNCB for the diagnosis of LPDs. SEB remains the gold standard procedure and should be performed in all suitable cases.

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.

[18F]FDG PET-MR in the Evaluation and Follow-Up of Incidental Bone Ischemic Lesions in a Mono-Center Cohort of Pediatric Patients Affected by Hodgkin's Lymphoma.

Hodgkin's lymphoma (HL) is one of the neoplasms with the best prognosis in children, adolescents and young adults, but sufferers are burdened by the possibility of developing adverse effects such as Bone Ischemic Lesions (BILs) which are lesions of the bone caused by the loss of/reduction in blood flow. The main goal of this retrospective study was to evaluate the role of [18F]FDG-PET-MR in the early detection of BILs in a single-center cohort of uniformly treated pediatric HL patients. BILs were assessed through PET-MR images as the appearance of medullary lesion surrounded by a serpiginous, tortuous border. From 2017 to 2022, 10/53 (18.9%) HL patients developed BILs which were mostly (8/10 patients) multifocal. Overall, 30 lesions were identified in the 10 asymptomatic patients, all with the above-mentioned features at MR and with very low [18F]FDG uptake. BILs were incidentally detected during HL therapy (n = 6) and follow-up (n = 4), especially in the long bones (66.7%). No factors correlated with the occurrence of BIL were identified. No patients developed complications. PET-MR is a sensitive combined-imaging technique for detecting BILs that are asymptomatic and self-limiting micro-ischemic lesions. BILs can be monitored by clinical follow-up alone both during and after therapy.

Autoimmune Lymphoproliferative Syndrome (ALPS) Disease and ALPS Phenotype: Are They Two Distinct Entities?

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder of lymphocyte homeostasis classically due to mutation of FAS, FASL, and CASP10 genes (ALPS-FAS/CASP10). Despite recent progress, about one-third of ALPS patients does not carry classical mutations and still remains gene orphan (ALPS-U, undetermined genetic defects). The aims of the present study were to compare the clinical and immunological features of ALPS-FAS/CASP10 versus those of ALPS-U affected subjects and to deepen the genetic characteristics of this latter group. Demographical, anamnestic, biochemical data were retrieved from medical record of 46 ALPS subjects. An enlarged panel of genes (next-generation sequencing) was applied to the ALPS-U group. ALPS-U subjects showed a more complex phenotype if compared to ALPS-FAS/CASP10 group, characterized by multiorgan involvement (P = 0.001) and positivity of autoimmune markers (P = 0.02). Multilineage cytopenia was present in both groups without differences with the exception of lymphocytopenia and autoimmune neutropenia that were more frequent in ALPS-U than in the ALPS-FAS/CASP10 group (P = 0.01 and P = 0.04). First- and second-line treatments were able to control the symptoms in 100% of the ALPS-FAS/CASP10 patients, while 63% of ALPS-U needed >2 lines of treatment and remission in some cases was obtained only after target therapy. In the ALPS-U group, we found in 14 of 28 (50%) patients 19 variants; of these, 4 of 19 (21%) were known as pathogenic and 8 of 19 (42%) as likely pathogenic. A characteristic flow cytometry panel including CD3CD4-CD8-+TCRαß+, CD3+CD25+/CD3HLADR+, TCR αß+ B220+, and CD19+CD27+ identified the ALPS-FAS/CASP10 group. ALPS-U seems to represent a distinct entity from ALPS-FAS/CASP10; this is relevant for management and tailored treatments whenever available.

Hypogammaglobulinemia in Children After Hematopoietic Stem Cell Transplantation and Rituximab Treatment: Relevance of B Cell Subsets.

Rituximab (RTX) is widely employed to treat Epstein-Barr virus reactivation in children undergoing Hematopoietic Cell Transplantation (HCT). The resulting loss of B cells may cause persistent hypogammaglobulinemia. This retrospective cross-sectional study aims to identify flow cytometry biomarkers associated with persistent hypogammaglobulinemia in patients receiving RTX after HCT. We analyzed 5 patients (cases group) requiring immunoglobulin substitution due to low level of IgG (IgG <5 g/L) detected after RTX treatment and 5 patients (controls group) not requiring long-term immunoglobulin (Ig) substitution. We investigated the B cell reconstitution, and in patients group we observed a significantly lower count in B total, IgD+CD27+ marginal B cells and IgD-CD27+ switched-memory B cells, after a median of 5 years from HCT, compared with the control group. Despite the importance limits of our study and the heterogeneity of our data (age of included patients, time of evaluation, interval between RTX dose and assessment) we conclude that RTX given early after HCT might cause a deranged B cell maturation, contributing to the delation in B cell recovery following HCT, and switched memory and marginal zone B cell counts could be a promising biomarker to identify patients requiring long-term Ig substitution.

Quantitative Plasma Proteomics to Identify Candidate Biomarkers of Relapse in Pediatric/Adolescent Hodgkin Lymphoma.

Classical pediatric Hodgkin Lymphoma (HL) is a rare malignancy. Therapeutic regimens for its management may be optimized by establishing treatment response early on. The aim of this study was to identify plasma protein biomarkers enabling the prediction of relapse in pediatric/adolescent HL patients treated under the pediatric EuroNet-PHL-C2 trial. We used untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics at the time of diagnosis­before any therapy­as semiquantitative method to profile plasma proteins specifically associated with relapse in 42 children with nodular sclerosing HL. In both the exploratory and the validation cohorts, six proteins (apolipoprotein E, C4b-binding protein α chain, clusterin, fibrinogen γ chain, prothrombin, and vitronectin) were more abundant in the plasma of patients whose HL relapsed (|fold change| ≥ 1.2, p < 0.05, Student's t-test). Predicting protein function with the Gene Ontology classification model, the proteins were included in four biological processes (p < 0.01). Using immunoblotting and Luminex assays, we validated two of these candidate biomarkers­C4b-binding protein α chain and clusterin­linked to innate immune response function (GO:0045087). This study identified C4b-binding protein α chain and clusterin as candidate early plasma biomarkers of HL relapse, and important for the purpose of shedding light on the molecular scenario associated with immune response in patients treated under the EuroNet-PHL-C2 trial.

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).

Phosphoproteomic Analysis Reveals a Different Proteomic Profile in Pediatric Patients With T-Cell Lymphoblastic Lymphoma or T-Cell Acute Lymphoblastic Leukemia.

T-cell lymphoblastic lymphoma (T-LBL) and lymphoblastic leukemia (T-ALL) arise from the transformation of precursor T-cells sharing common morphological and immunophenotypic features. Despite this, T-LBL and T-ALL show different genomic/transcriptomic profiles and whether they represent two distinct disease entities or variant manifestations of the same disease is still a matter of debate. In this work, we performed a Reverse Phase Protein Array study on T-LBL and T-ALL samples and demonstrated that they are characterized by a different phosphoproteomic profile. Indeed, T-LBLs showed the hyperactivation of FAK/ERK1/2 and AKT/mTOR pathways, whereas JAK/STAT pathway was significantly hyperphosphorylated in T-ALLs. Moreover, since the only criteria for discriminating T-LBL from T-ALL is blasts' infiltration below 25% in the bone marrow and lymphoma patients can present with a percentage of blasts close to this cut-off, a biomarker that could help distinguishing the two diseases would be of great help for the clinical diagnosis and treatment decision. Pursuing this aim, we identified a proteomic signature of six proteins whose expression/activation was able to discriminate stage IV T-LBL from T-ALL. Moreover, we demonstrated that AKT hyperphosphorylation alone was able to distinguish stage IV T-LBL from both T-ALL and stage III T-LBL. Concluding, these data demonstrate that T-ALL and T-LBL bear different phosphoproteomic profiles, further sustaining the hypothesis of the two disease as different entities and paving the way for the identification of new biomarkers able to distinguish stage IV T-LBL from T-ALL disease, so far based only on BM involvement criteria.