Our understanding of Hodgkin lymphoma (HL) molecular biology has been radically transformed over recent years due to the advent and the spreading of the new generation sequencing approaches. These ...advances offer new insights about genetic predisposition to HL in children and are currently being translated into promising and more selective drugs (brentuximab and checkpoint inhibitors) offering the perspective to reduce treatment-related toxicity. Thus, as more than 90% of pediatric patients are cured after the first line treatment, a major emphasis is placed on survivorship by reducing treatment intensity, in particular, the use of radiotherapy and chemotherapy associated with long-term toxicities. The purposes of this review are to summarize the recent advances performed in the field of molecular biology of HL, in particular the promising development of liquid biopsies. We also provide an update review of immunodeficiencies associated to HL in children recently identified. Finally, we report the recent studies supporting the efficacy of new targeted therapeutics in adult and pediatric cHL (anti-CD30 and anti-PD1).
Introduction
In order to describe relapsed B‐cell non‐Hodgkin lymphoma and mature acute leukemia in children/adolescents treated with the Lymphomes Malins B (LMB) regimen and their outcome in the ...rituximab era, relapses in the French LMB2001 study were reviewed.
Methods
Between February 2001 and December 2011, 33 patients out of 773 (4.3%) relapsed; 27 had Burkitt lymphoma and six large B‐cell histology. Median age at diagnosis was 10.1 years. One patient was initially treated in risk group A, 21 in group B, and 11 in group C.
Results
Median time to relapse after diagnosis was 4.5 months (range 2.4‐13.6). Thirty‐two patients received salvage therapy. Twenty‐seven received rituximab mainly in addition to high‐dose cytarabine and etoposide (n = 18) and/or ifosfamide, carboplatin, and etoposide (n = 7). First‐line salvage chemotherapy response rate was 66% with 47% being complete remission (CR). Twenty‐one patients received high‐dose chemotherapy (HDC) followed by autologous (n = 13) or allogeneic (n = 8) transplant. With a median follow‐up of 6.8 years, the 5‐year survival rate after relapse was 36.4% (95% confidence interval CI 22‐53%). Twelve patients were still alive; all but one (group A) received consolidation treatment. Achieving CR before consolidation was significantly associated with better survival, with a 5‐year survival rate of 75% (95% CI 46.8‐91.1%) for patients in CR before HDC, 33% (95% CI 9.7‐70%) for patients in partial remission, and 0% for nonresponders (P = .033).
Conclusion
Survival of children/adolescents with mature B‐cell lymphoma/leukemia remains poor after relapse with no apparent improvement with rituximab. Response rates to salvage chemo‐immunotherapies are insufficient and new drugs are urgently needed to improve disease control.
Background
Rebound thymic hyperplasia (RTH) is a common phenomenon caused by stress factors such as chemotherapy (CTX) or radiotherapy, with an incidence between 44% and 67.7% in pediatric lymphoma. ...Misinterpretation of RTH and thymic lymphoma relapse (LR) may lead to unnecessary diagnostic procedures including invasive biopsies or treatment intensification. The aim of this study was to identify parameters that differentiate between RTH and thymic LR in the anterior mediastinum.
Methods
After completion of CTX, we analyzed computed tomographies (CTs) and magnetic resonance images (MRIs) of 291 patients with classical Hodgkin lymphoma (CHL) and adequate imaging available from the European Network for Pediatric Hodgkin lymphoma C1 trial. In all patients with biopsy‐proven LR, an additional fluorodeoxyglucose (FDG)‐positron emission tomography (PET)‐CT was assessed. Structure and morphologic configuration in addition to calcifications and presence of multiple masses in the thymic region and signs of extrathymic LR were evaluated.
Results
After CTX, a significant volume increase of new or growing masses in the thymic space occurred in 133 of 291 patients. Without biopsy, only 98 patients could be identified as RTH or LR. No single finding related to thymic regrowth allowed differentiation between RTH and LR. However, the vast majority of cases with thymic LR presented with additional increasing tumor masses (33/34). All RTH patients (64/64) presented with isolated thymic growth.
Conclusion
Isolated thymic LR is very uncommon. CHL relapse should be suspected when increasing tumor masses are present in distant sites outside of the thymic area. Conversely, if regrowth of lymphoma in other sites can be excluded, isolated thymic mass after CTX likely represents RTH.
Background
In the EuroNet Pediatric Hodgkin Lymphoma (EuroNet‐PHL) trials, decision on Waldeyer's ring (WR) involvement is usually based on clinical assessment, that is, physical examination and/or ...nasopharyngoscopy. However, clinical assessment only evaluates mucosal surface and is prone to interobserver variability. Modern cross‐sectional imaging technology may provide valuable information beyond mucosal surface, which may lead to a more accurate WR staging.
Patients, materials, and methods
The EuroNet‐PHL‐C1 trial recruited 2102 patients, of which 1752 underwent central review including reference reading of their cross‐sectional imaging data. In 14 of 1752 patients, WR was considered involved according to clinical assessment. In these 14 patients, the WR was re‐assessed by applying an imaging‐based algorithm considering information from 18F‐fluorodeoxyglucose positron emission tomography, contrast‐enhanced computed tomography, and/or magnetic resonance imaging. For verification purposes, the imaging‐based algorithm was applied to 100 consecutive patients whose WR was inconspicuous on clinical assessment.
Results
The imaging‐based algorithm confirmed WR involvement only in four of the 14 patients. Of the remaining 10 patients, four had retropharyngeal lymph node involvement and six an inconspicuous WR. Applying the imaging‐based algorithm to 100 consecutive patients with physiological appearance of their WR on clinical assessment, absence of WR involvement could be confirmed in 99. However, suspicion of WR involvement was raised in one patient.
Conclusions
The imaging‐based algorithm was feasible and easily applicable at initial staging of young patients with Hodgkin lymphoma. It increased the accuracy of WR staging, which may contribute to a more individualized treatment in the future.
Background
Optimal Phase‐II design to evaluate new therapies in refractory/relapsed Ewing sarcomas (ES) remains imperfectly defined.
Objectives
Recurrent/refractory ES phase‐I/II trials analysis to ...improve trials design.
Methods
Comprehensive review of therapeutic trials registered on five databases (who.int/trialsearch, clinicaltrials.gov, clinicaltrialsregister.eu, e‐cancer.fr, and umin.ac.jp) and/or published in PubMed/ASCO/ESMO websites, between 2005 and 2018, using the criterion: (Ewing sarcoma OR bone sarcoma OR sarcoma) AND (Phase‐I or Phase‐II).
Results
The 146 trials identified (77 phase‐I/II, 67 phase‐II, and 2 phase‐II/III) tested targeted (34%), chemo‐ (23%), immune therapies (19%), or combined therapies (24%). Twenty‐three trials were ES specific and 48 had a specific ES stratum. Usually multicentric (88%), few trials were international (30%). Inclusion criteria cover the recurrent ES age range for only 12% of trials and allowed only accrual of measurable diseases (RECIST criteria). Single‐arm design was the most frequent (88%) testing mainly single drugs (61%), only 5% were randomized. Primary efficacy outcome was response rate (RR=CR+PR; Complete+Partial response) (n = 116/146; 79%), rarely progression‐free or overall survival (16% PFS and 3% OS). H0 and H1 hypotheses were variable (3%–25% and 20%–50%, respectively). The 62 published trials enrolled 827 ES patients. RR was poor (10%; 15 CR=1.7%, 68 PR=8.3%). Stable disease was the best response for 186 patients (25%). Median PFS/OS was of 1.9 (range 1.3–14.7) and 7.6 months (5–30), respectively. Eleven (18%) published trials were considered positive, with median RR/PFS/OS of 15% (7%–30%), 4.5 (1.3–10), and 16.6 months (6.9–30), respectively.
Conclusion
This review supports the need to develop the international randomized phase‐II trials across all age ranges with PFS as primary endpoint.
Hundred and forty‐six phase‐II trials and 62 articles from 2005 to 2018 were analysed. Mostly multicentric, few trials were international (30%), only 5% were randomized. Results of 62 published trials enrolling 827 ES patients were disappointing. Combining chemotherapy with another agent is a promising strategy. International randomized trans‐age with PFS as primary endpoint could be promoted.
The objective of this guideline is to aid clinicians in making individual salvage treatment plans for pediatric and adolescent patients with first relapse or refractory (R/R) classical Hodgkin ...lymphoma (cHL). While salvage with standard dose chemotherapy followed by high dose chemotherapy and autologous stem cell transplant is often considered the standard of care in adult practice, pediatric practice adopts a more individualized risk stratified and response adapted approach to salvage treatment with greater use of non‐transplant salvage. Here, we present on behalf of the EuroNet Pediatric Hodgkin Lymphoma group, evidence and consensus‐based guidelines for standardized diagnostic, prognostic and response procedures to allocate children and adolescents with R/R cHL to stratified salvage treatments.
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