Treatment and prognosis of pediatric non-Hodgkin lymphoma (NHL) have improved dramatically in the last 30 years. However, the St Jude NHL staging classification for pediatric NHL was developed more ...than 35 years ago. The most recent Lugano lymphoma staging classification focused on adult lymphoma. Furthermore, major limitations of the current pediatric NHL staging classification include lack of consideration of new distinct pediatric NHL histologic entities; absence of recognition of frequent skin, bone, kidney, ovarian, and other organ involvement; and lack of newer precise methods to detect bone marrow and CNS involvement, minimal disease quantification, and highly sensitive imaging technologies.
An international multidisciplinary expert panel convened in Frankfurt, Germany, in 2009 at the Third International Childhood, Adolescent and Young Adult NHL Symposium to develop a revised international pediatric NHL staging system (IPNHLSS), addressing limitations of the current pediatric NHL staging system and creating a revised classification. Evidence-based disease distribution and behavior were reviewed from multiple pediatric cooperative group NHL studies.
A revised IPNHLSS was developed incorporating new histologic entities, extranodal dissemination, improved diagnostic methods, and advanced imaging technology.
This revised IPNHLSS will facilitate more precise staging for children and adolescents with NHL and facilitate comparisons of efficacy across different treatment strategies, various institutions, multicenter trials, and cooperative groups by allowing for reproducible pediatric-based staging at diagnosis and relapse.
Non-Hodgkin lymphoma is the fourth most common malignancy in children, has an even higher incidence in adolescents, and is primarily represented by only a few histologic subtypes. Dramatic progress ...has been achieved, with survival rates exceeding 80%, in large part because of a better understanding of the biology of the different subtypes and national and international collaborations. Most patients with Burkitt lymphoma and diffuse large B-cell lymphoma are cured with short intensive pulse chemotherapy containing cyclophosphamide, cytarabine, and high-dose methotrexate. The benefit of the addition of rituximab has not been established except in the case of primary mediastinal B-cell lymphoma. Lymphoblastic lymphoma is treated with intensive, semi-continuous, longer leukemia-derived protocols. Relapses in B-cell and lymphoblastic lymphomas are rare and infrequently curable, even with intensive approaches. Event-free survival rates of approximately 75% have been achieved in anaplastic large-cell lymphomas with various regimens that generally include a short intensive B-like regimen. Immunity seems to play an important role in prognosis and needs further exploration to determine its therapeutic application. ALK inhibitor therapeutic approaches are currently under investigation. For all pediatric lymphomas, the intensity of induction/consolidation therapy correlates with acute toxicities, but because of low cumulative doses of anthracyclines and alkylating agents, minimal or no long-term toxicity is expected. Challenges that remain include defining the value of prognostic factors, such as early response on positron emission tomography/computed tomography and minimal disseminated and residual disease, using new biologic technologies to improve risk stratification, and developing innovative therapies, both in the first-line setting and for relapse.
Summary
We determined the risk factors associated with poor survival in children and adolescents with de novo mature B cell non‐Hodgkin lymphoma (B‐NHL) who had refractory or relapsed disease during ...or after the French‐American‐British mature lymphoma B (FAB/LMB) 96 multi‐agent chemotherapy. Among the 1 111 registered on study, 104 patients (9·4%) had refractory disease or disease relapse after first complete remission. Among these 104 patients, 28 (27%) patients had refractory disease and 76 (73%) had relapsed disease. The estimated 1‐ and 2‐year overall survival (OS) (95% confidence interval) was 31·5% (23·3–41·0%) and 22·3% (15·3–31·4%), respectively. Prognostic analysis of OS using a Cox multivariate model showed that factors independently associated with OS included lactate dehydrogenase ≥2 upper normal limit hazard ratio (HR) = 2·86 (1·57–5·2), P = 0·0006; time to failure (>6 months) HR = 0·59 (0·36–0·97), P = 0·038; and failure in bone marrow HR = 2·78 (1·65–4·68), P = 0·0001. New therapeutic strategies are required to significantly reduce refractory disease and disease relapse in patients with newly diagnosed mature B‐NHL and, more importantly, there is a critical need to develop novel retrieval approaches in patients with chemotherapy‐resistant disease.
Adolescents (age 15 to 21 years) compared with younger children with mature B-cell non-Hodgkin's lymphoma (NHL) have been historically considered to have an inferior prognosis. We therefore analyzed ...the impact of age and other diagnostic factors on the risk of treatment failure in children and adolescents treated on the French-American-British Mature B-Cell Lymphoma 96 (FAB LMB 96) trial.
Patients were divided by risk: group A (limited), group B (intermediate), and group C (advanced), as previously described. Prognostic factors analyzed for event-free survival (EFS) included age (< 15 v ≥ 15 years), stage (I/II v III/IV), primary site, lactate dehydrogenase (LDH), bone marrow/CNS (BM/CNS) involvement, and histology (diffuse large B-cell lymphoma v mediastinal B-cell lymphoma v Burkitt lymphoma or Burkitt-like lymphoma).
The 3-year EFS for the whole cohort was 88% ± 1%. Age was not associated as a risk factor for increased treatment failure in either univariate analysis (P = .15) or multivariate analysis (P = .58). Increased LDH (≥ 2 × upper limit of normal ULN v < 2 × ULN), primary site, and BM-positive/CNS-positive disease were all independent risk factors associated with a significant increase in treatment failure rate (relative risk, 2.0; P < .001, P < .012, and P < .001, respectively).
LDH level at diagnosis, mediastinal disease, and combined BM-positive/CNS-positive involvement are independent risk factors in children with mature B-cell NHL. Future studies should be developed to identify specific therapeutic strategies (immunotherapy) to overcome these risk factors and to identify the biologic basis associated with these prognostic factors in children with mature B-cell NHL.
Summary
The main challenges in the treatment of T‐cell lymphoblastic lymphoma (T‐LBL) in children and adolescents are twofold: to increase survival rates in concert with reduction of acute and ...long‐term toxicities including the rate of secondary malignancies. The need for molecular and prognostic markers in T‐LBL is crucial to allow for systematic treatment optimization and may serve as targets for new treatment approaches.
Summary
Hereditary haemolytic anaemias are genetically and phenotypically heterogeneous disorders characterized by increased red cell destruction, with consequences ranging from innocuous to severe ...life‐threatening anaemia. Diagnostic laboratories endeavour to assist clinicians reach the exact patient diagnosis by using tests principally based on morphological and biochemical techniques. However, these routine studies may be inconclusive, particularly in newborn infants and when transfusions have recently been administered. Large numbers and size of the potentially involved genes also impose a practical challenge for molecular diagnosis using routine sequencing approaches. To overcome these diagnostic shortcomings, we have utilized next‐generation sequencing to provide a high‐throughput, highly sensitive assay. We developed a panel interrogating 28 genes encoding cytoskeletal proteins and enzymes with sequencing coverage of the coding regions, splice site junctions, deep intronic and regulatory regions. We then evaluated 19 samples, including infants with unexplained extreme hyperbilirubinaemia and patients with transfusion‐dependent haemolytic anaemia. Where possible, inheritance patterns of pathogenic mutations were determined by sequencing of immediate relatives. We conclude that this next‐generation sequencing panel could be a cost‐effective approach to molecular diagnosis of hereditary haemolytic anaemia, especially when the family history is uninformative or when routine laboratory testing fails to identify the causative haemolytic process.
Response criteria are well established for adult patients with non-Hodgkin lymphoma (NHL). A revised set of response criteria in adults with NHL was recently published. However, NHL in children and ...adolescents involves different histologies, primary sites of disease, patterns of metastatic spread, approaches to therapy, and responses to treatment compared with adult NHL. However, there are no standardized response criteria specific to pediatric NHL. Therefore, we developed international standardized methods for assessing response to therapy in children and adolescents with NHL.
An international multidisciplinary group of pediatric oncologists, pathologists, biologists, and radiologists convened during and after the Third and Fourth International Childhood, Adolescent and Young Adult NHL Symposia to review existing response and outcome data, develop methods for response evaluation that reflect incorporation of more sensitive technologies currently in use, and incorporate primary and metastatic sites of disease for the evaluation of therapeutic response in children and adolescents with NHL.
Using the current adult NHL response criteria as a starting point, international pediatric NHL response criteria were developed incorporating both contemporary diagnostic imaging and pathology techniques, including novel molecular and flow cytometric technologies used for the determination of minimal residual disease.
Use of the international pediatric NHL response criteria in children and adolescents receiving therapy for NHL incorporates data obtained from new and more sensitive technologies that are now being widely used for disease evaluation, providing a standardized means for reporting treatment response.
The prognosis for higher risk childhood B-cell non-Hodgkin lymphoma has improved over the past 20 years but the optimal intensity of treatment has yet to be determined. Children 21 years old or ...younger with newly diagnosed B-cell non-Hodgkin lymphoma/B-cell acute lymphoblastic leukemia (B-NHL/B-ALL) with higher risk factors (bone marrow BM with or without CNS involvement) were randomized to standard intensity French-American-British/Lymphoma Malignancy B (FAB/LMB) therapy or reduced intensity (reduced cytarabine plus etoposide and deletion of 3 maintenance courses M2, M3, M4). All patients with CNS disease had additional high-dose methotrexate (8 g/m2) plus extra intrathecal therapy. Fifty-one percent had BM involvement, 20% had CNS involvement, and 29% had BM and CNS involvement. One hundred ninety patients were randomized. The probabilities of 4-year event-free survival (EFS) and survival (S) were 79% ± 2.7% and 82% ± 2.6%, respectively. In patients in remission after 3 cycles who were randomized to standard versus reduced-intensity therapy, the 4-year EFS after randomization was 90% ± 3.1% versus 80% ± 4.2% (one-sided P = .064) and S was 93% ± 2.7% versus 83% ± 4.0% (one-sided P = .032). Patients with either combined BM/CNS disease at diagnosis or poor response to cyclophosphamide, Oncovin vincristine, prednisone (COP) reduction therapy had a significantly inferior EFS and S (P < .001). Standard-intensity FAB/LMB therapy is recommended for children with high-risk B-NHL (B-ALL with or without CNS involvement).
The Children's Oncology Group (COG) protocol AALL0434 evaluated the safety and efficacy of multi-agent chemotherapy with Capizzi-based methotrexate/pegaspargase (C-MTX) in patients with newly ...diagnosed pediatric T-cell lymphoblastic lymphoma (T-LL) and gained preliminary data using nelarabine in high-risk patients.
The trial enrolled 299 patients, age 1-31 years. High-risk (HR) patients had ≥ 1% minimal detectable disease (MDD) in the bone marrow at diagnosis or received prior steroid treatment. Induction failure was defined as failure to achieve a partial response (PR) by the end of the 4-week induction. All patients received the augmented Berlin-Frankfurt-Muenster (ABFM) C-MTX regimen. HR patients were randomly assigned to receive or not receive 6 5-day courses of nelarabine incorporated into ABFM. Patients with induction failure were nonrandomly assigned to ABFM C-MTX plus nelarabine. No patients received prophylactic cranial radiation; however, patients with CNS3 disease (CSF WBC ≥ 5/μL with blasts or cranial nerve palsies, brain/eye involvement, or hypothalamic syndrome) were ineligible.
At end-induction, 98.8% of evaluable participants had at least a PR. The 4-year event-free survival (EFS) and overall survival (OS) were 84.7% ± 2.3% and 89.0% ± 2.0%. The 4-year disease-free survival (DFS) from end-induction was 85.9% ± 2.6%. There was no difference in DFS observed between the HR and standard-risk groups (
= .29) or by treatment regimen (
= .55). Disease stage, tumor response, and MDD at diagnosis did not demonstrate thresholds that resulted in differences in EFS. Nelarabine did not show an advantage for HR patients. CNS relapse occurred in only 4 patients.
COG AALL0434 produced excellent outcomes in one of the largest trials ever conducted for patients with newly diagnosed T-LL. The COG ABFM regimen with C-MTX provided excellent EFS and OS without cranial radiation.
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