Anaplastic large cell lymphoma (ALCL) is the most common type of mature T-cell non-Hodgkin lymphoma in children/adolescents. ALCL is characterized by expression of CD30 in the neoplastic lymphoid ...cells with frequent expression of anaplastic lymphoma kinase (ALK), especially within the pediatric population. Despite multiple efforts to optimize the use of conventional chemotherapy, outcomes in children, adolescents, and adults with ALCL remain suboptimal. Thus, there is a need to improve survival for those with high-risk disease and decrease therapy exposures and toxicities for those with low-risk disease. Targeted therapies, such as the anti-CD30 antibody-drug conjugate, brentuximab vedotin, are new important therapeutic options. Phase I and II studies in adults with relapsed/refractory CD30
lymphomas, including ALCL, demonstrated the safety and efficacy of brentuximab vedotin, leading to FDA approval for relapsed/refractory ALCL in adults and successful incorporation into frontline therapies. Clinical trials in the pediatric population demonstrated similar results in those with relapsed/refractory ALCL. Incorporation of brentuximab vedotin into upfront therapy for children and adolescents with ALCL showed that this novel combination therapy has clinical advantages in comparison to conventional agents alone. Brentuximab vedotin is well-tolerated in both the pediatric and adult populations, even when used in combination with conventional agents. Brentuximab vedotin is an ideal agent to treat ALCL with excellent targeted activity and limited toxicity. Future studies are needed to identify how brentuximab vedotin should be utilized when combined with immunotherapy or other targeted agents (e.g., ALK inhibitors) in both the upfront and relapsed/refractory setting.
Background
Curative therapy places childhood cancer survivors at increased risk for second primary malignancies (SPMs). However, there have been few population‐based attempts to characterize ...differences between outcomes of SPMs in childhood cancer survivors and outcomes of first primary malignancies (FPMs).
Methods
Clinical and demographic information about childhood cancer survivors who developed SPMs and individuals with comparable FPMs was extracted from the Surveillance, Epidemiology, and End Results program. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox proportional hazards models comparing the overall survival (OS) of individuals with and without a history of childhood cancer. OS was evaluated both overall and for specific cancers diagnosed in 50 or more childhood cancer survivors. Models accounted for potential confounders, including sex, race, age, treatment decade, histology, and disease stage.
Results
Compared with individuals with FPMs (n = 1,332,203), childhood cancer survivors (n = 1409) with an SPM experienced poorer OS (HR, 1.86; 95% CI, 1.72‐2.02) after the study had accounted for cancer type, age, sex, race, and decade of diagnosis. A history of childhood cancer remained a poor prognostic factor for all specific cancers evaluated, including breast cancer (HR, 2.07; 95% CI, 1.63‐2.62), thyroid cancer (HR, 3.59; 95% CI, 2.08‐6.19), acute myeloid leukemia (HR, 2.38; 95% CI, 1.87‐3.05), brain cancer (HR, 2.09; 95% CI, 1.72‐2.55), melanoma (HR, 2.57; 95% CI, 1.55‐4.27), bone cancer (HR, 1.88; 95% CI, 1.37‐2.57), and soft‐tissue sarcoma (HR, 2.44; 95% CI, 1.78‐3.33).
Conclusions
Compared with individuals without a prior cancer diagnosis, survivors of childhood cancer with an SPM experienced inferior outcomes. Survival disparities were observed for the most frequent SPMs diagnosed in childhood cancer survivors.
Compared with individuals without a prior cancer diagnosis, survivors of childhood cancer with a second primary malignancy experience inferior outcomes. These disparities in overall survival are observed across cancer types, therapeutic exposures, and clinical factors.
The Pediatric Normal Tissue Effects in the Clinic (PENTEC) pulmonary task force reviewed dosimetric and clinical factors associated with radiation therapy (RT)-associated pulmonary toxicity in ...children.
Comprehensive search of PubMed (1965-2020) was conducted to assess available evidence and predictive models of RT-induced lung injury in pediatric cancer patients (<21 years old). Lung dose for radiation pneumonitis (RP) was obtained from dose-volume histogram (DVH) data. RP grade was obtained from standard criteria. Clinical pulmonary outcomes were evaluated using pulmonary function tests (PFTs), clinical assessment, and questionnaires.
More than 2,400 abstracts were identified; 460 articles had detailed treatment and toxicity data; and 11 articles with both detailed DVH and toxicity data were formally reviewed. Pooled cohorts treated during 1999 to 2016 included 277 and 507 patients age 0.04 to 22.7 years who were evaluable for acute and late RP analysis, respectively. After partial lung RT, there were 0.4% acute and 2.8% late grade 2, 0.4% acute and 0.8% late grade 3, and no grade 4 to 5 RP. RP risk after partial thoracic RT with mean lung dose (MLD) <14 Gy and total lung V
<30% is low. Clinical and self-reported pulmonary outcomes data included 8,628 patients treated during 1970 to 2013, age 0 to 21.9 years. At a median 2.9- to 21.9-year follow-up, patients were often asymptomatic; abnormal PFTs were common and severity correlated with lung dose. At ≥10-year follow-up, multi-institutional studies suggested associations between total or ipsilateral lung doses >10 Gy and pulmonary complications and deaths. After whole lung irradiation (WLI), pulmonary toxicity is higher; no dose response relationship was identified. Bleomycin and other chemotherapeutics at current dose regimens do not contribute substantially to adverse pulmonary outcomes after partial lung irradiation but increase risk with WLI.
After partial lung RT, acute pulmonary toxicity is uncommon; grade 2 to 3 RP incidences are <1%. Late toxicities, including subclinical/asymptomatic impaired pulmonary function, are more common (<4%). Incidence and severity appear to increase over time. Upon review of available literature, there appears to be low risk of pulmonary complications in children with MLD < 14 Gy and V
<30% using standard fractionated RT to partial lung volumes. A lack of robust data limit guidance on lung dose/volume constraints, highlighting the need for additional work to define factors associated with RT-induced lung injury.
Summary
Over 50% of patients with systemic LCH are not cured with front‐line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with ...clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long‐term efficacy, late toxicities, relative cost and patient‐reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.
We present 2 diagnostically challenging cases of pediatric/adolescent relapsed/refractory aggressive mature B-cell non-Hodgkin lymphoma (B-NHL) within the spectrum of Burkitt lymphoma and diffuse ...large B-cell lymphoma and illustrate the different therapeutic regimens that are employed for pediatric and adult cancer centers. Both cases displayed varying-sized lymphoma cells with occasional single prominent nucleoli and heterogeneous BCL2 expression. Cytogenetics revealed complex karyotypes with t(8:14)(q24.2;q32) and
rearrangement by FISH. Next generation sequencing revealed deleterious
and
mutations. We concluded that both could be diagnosed as "DLBCL-NOS with
rearrangement" using the current pathologic classifications, 2022 International Consensus Classification (ICC) and World Health Organization Classifications of Haematolymphoid Tumors (WHO-HAEM5). This report illustrates diagnostic challenges and treatment dilemmas that may be encountered, particularly for adolescent and young adults (AYA).
Pediatric nonmalignant lymphoproliferative disorders (PLPDs) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be ...life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD.
The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes.
PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant Epstein-Barr virus (EBV) infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing.
Whole exome sequencing identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, P = .03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs 90%; P = .002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients.
PLPD defines children at high risk for mortality, and whole exome sequencing informs clinical risks and therapeutic opportunities for this diagnosis.
Telomere biology disorders predispose affected individuals to specific malignancies and organ fibrosis in tissues sensitive to telomere length (TL) shortening, especially after exposure to ...chemotherapy and radiation. We report a case of a 17‐year‐old female with Hodgkin lymphoma who developed severe chemotherapy‐related toxicities. She was subsequently found to have peripheral blood lymphocyte TL < 1st percentile and a pathogenic variant in TERT inherited from her father. This case demonstrates that early genetic evaluation of patients who experience greater than expected therapy‐related toxicities may be warranted to help guide further decisions regarding therapy, imaging modalities, and lifelong cancer prevention surveillance.
Hodgkin lymphoma (HL) histopathology is characterized by rare malignant Reed-Sternberg cells among an inflammatory infiltrate. We hypothesized that characteristics of inflammation in pediatric HL ...lesions would be reflected by the levels of inflammatory cytokines or chemokines in pre-therapy plasma of children with HL. The study objectives were to better define the inflammatory pre-therapy plasma proteome and identify plasma biomarkers associated with extent of disease and clinical outcomes in pediatric HL. Pre-therapy plasma samples were obtained from pediatric subjects with newly diagnosed HL and healthy pediatric controls. Plasma concentrations of 135 cytokines/chemokines were measured with the Luminex platform. Associations between protein concentration and disease characteristics were determined using multivariate permutation tests with false discovery control. Fifty-six subjects with HL (mean age: 13 years, range 3-18) and 47 controls were analyzed. The cytokine/chemokine profiles of subjects with HL were distinct from controls, and unique cytokines/chemokines were associated with high-risk disease (IL-10, TNF-α, IFN-γ, IL-8) and slow early response (CCL13, IFN-λ1, IL-8). TNFSF10 was significantly elevated among those who ultimately relapsed and was significantly associated with worse event-free survival. These biomarkers could be incorporated into biologically based risk stratification to optimize outcomes and minimize toxicities in pediatric HL.
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