Dose-Adjusted Etoposide, Doxorubicin, and Cyclophosphamide With Vincristine and Prednisone Plus Rituximab Therapy in Children and Adolescents With Primary Mediastinal B-Cell Lymphoma: A Multicenter Phase II Trial

Burke, G A Amos; Minard‐Colin, Véronique; Aupérin, Anne; Alexander, Sarah; Pillon, Marta; Delgado, Rafaël; Zsíros, József; Uyttebroeck, Anne; Dartigues, Peggy; Miles, Rodney R.; Kazanowska, Bernarda; Chiang, Alan Kwok Shing; Haouy, Stèphanie; Bollard, Catherine M.; Csóka, Monika; Wheatley, Keith; Barkauskas, Donald A.; Adamson, Peter C.; Vassal, Gilles; Patte, Catherine; Gross, Thomas G.

doi:10.1200/jco.21.00920

Cited by 20 publications

(33 citation statements)

References 16 publications

(32 reference statements)

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“…These excellent results contrast with the results recently published with DA-EPOCH-R in 46 children and adolescents included in the international phase 2 Inter B-NHL-ritux 2010 study 7 (Table 4). Although the characteristics of the patients included in this study do not differ from those of the phase 2 Inter B-NHL-ritux 2010, 12 disease-related events were observed in the phase 2, with 4-year EFS and OS of 69.6% (95%CI 55.2%-80.9%) and 84.8% (95%CI 71.8%-92.4%), respectively, and 3 (6.5%) parenchymal central nervous system relapses.…”

Section: Discussioncontrasting

confidence: 96%

“… 21 However, management of long-term toxicity is also very important in this young population. The risks for significant long-term sequelae are relatively modest using LMB chemotherapy backbone 22 and the total cumulative dose of doxorubicin is limited and of 240 mg/m 2 with the LMB B/C-modified combination (favorably compared with the DA-EPOCH-R in the Inter-B-NHL ritux 2010 study where 72% of patients received ≥300 mg/m 2 doxorubicin and 24% ≥350 mg/m 2 ) 7 .…”

Section: Discussionmentioning

confidence: 99%

“…In children and adolescents, the first prospective international Phase 2 study of DA-EPOCH-R regimen 7 failed to reproduce the outstanding survival reported with this regimen in some adults studies. Treatment strategies originally designed for Burkitt lymphoma are successfully used for children with diffuse large B-cell lymphoma (DLBCL) 8,9 but patients with PMLBL presented more aggressive disease and specific approaches were needed 10,11 .…”

Section: Introductionmentioning

confidence: 99%

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Rituximab in addition to LMB-based chemotherapy regimen in children and adolescents with primary mediastinal large B-cell lymphoma: results of the French LMB2001 prospective study

et al. 2022

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Primary Mediastinal large B-cell Lymphoma (PMLBL) is a rare entity predominantly affecting adolescents and young adults. Recently, an international phase 2 trial in pediatric patients using dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R) failed to reproduce excellent survival reported in some adult studies. The optimal therapy regimen needs to be determined in this disease. French prospective LMB2001 trial included all patients < 18 years with mature B-cell lymphoma treated in French centers. For patients with PMLBL, treatment included 4 to 8 courses of Lymphomes Malins B (LMB)-based chemotherapy without radiotherapy. From 2008, rituximab was added before each chemotherapy course. From 09/2001 to 03/2012, 42 patients with PMLBL were registered. The median age was 15 years (range 8-18). 21 patients were treated by chemotherapy plus rituximab. The median follow-up was 7.1 years (Interquartile range, 5.8-11.1). Five-year event-free (EFS) and overall survival (OS) were 88.1% (95%Confidence Interval (CI), 75.0%-94.8%) and 95.2% (95%CI, 84.0%-98.7%) for the whole population. The 5-year EFS was 81.0% (95%CI, 60.0%-92.3%) and 95.2% (95%CI, 77.3%-99.2%) (HR=0.24 (95%CI 0.03-2.2)) and 5-year OS was 90.5% (95%CI, 71.1%-97.3%) and 100% for patients treated without and with rituximab, respectively. Only 1/21 patients treated with rituximab and LMB-based chemotherapy had local early treatment failure but achieved prolonged complete remission with second-line chemotherapy and radiotherapy. Intensive LMB-based chemotherapy with rituximab achieved excellent survival in children/adolescents with PMLBL. Further international prospective studies are required to confirm these results in this population.

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Section: Discussioncontrasting

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rituximab in addition to LMB-based chemotherapy regimen in children and adolescents with primary mediastinal large B-cell lymphoma: results of the French LMB2001 prospective study

et al. 2022

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“…In a 2019 study by Giulino-Roth et al [ 78 ] of adult and pediatric patients with PMLBCL, patients who received DA-EPOCH-R had a 3-year EFS rate of nearly 86% and an OS rate of 95%; however, more children than adults developed thrombosis (46% vs. 23%, respectively). In contrast, a more recent phase 2 trial by Burke et al [ 79 ] involving only pediatric (<18 years old) patients with PMLBCL demonstrated that treatment with DA-EPOCH-R did not confer better EFS or OS (70% and 85%, respectively) compared to control treatment which had similar rates. This international study also compared its results with historical survival rates from the FAB/LMB 96 study.…”

Section: Conventional Treatment Of Nhl In Children and Adolescentsmentioning

confidence: 90%

Management of Aggressive Non-Hodgkin Lymphomas in the Pediatric, Adolescent, and Young Adult Population: An Adult vs. Pediatric Perspective

Sheikh

Elgehiny²,

Ragoonanan

et al. 2022

Cancers

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Non-Hodgkin lymphoma (NHL) is a broad entity which comprises a number of different types of lymphomatous malignancies. In the pediatric and adolescent population, the type and prognosis of NHL varies by age and gender. In comparison to adults, pediatric and adolescent patients generally have better outcomes following treatment for primary NHL. However, relapsed/refractory (R/R) disease is associated with poorer outcomes in many types of NHL such as diffuse large B cell lymphoma and Burkitt lymphoma. Newer therapies have been approved in the use of primary NHL in the pediatric and adolescent population such as Rituximab and other therapies such as chimeric antigen receptor T-cell (CAR T-cell) therapy are under investigation for the treatment of R/R NHL. In this review, we feature the characteristics, diagnosis, and treatments of the most common NHLs in the pediatric and adolescent population and also highlight the differences that exist between pediatric and adult disease. We then detail the areas of treatment advances such as immunotherapy with CAR T-cells, brentuximab vedotin, and blinatumomab as well as cell cycle inhibitors and describe areas where further research is needed. The aim of this review is to juxtapose established research regarding pediatric and adolescent NHL with recent advancements as well as highlight treatment gaps where more investigation is needed.

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“…We have discussed this in our Discussion and suggested that DA-EPOCH without rituximab may be less effective than the historical pediatric regimens. 2…”

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Reply to R. Lakhotia et al

Burke

Minard‐Colin

Aupérin

et al. 2022

JCO

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We thank Lakhotia et al 1 for their interest in our article. 2 Their opening comment that dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R) did not improve event-free survival (EFS) compared with historical controls treated with rituximab plus pediatric chemotherapy regimens is unfortunately incorrect as the historical controls for our study were all treated without rituximab. We have discussed this in our Discussion and suggested that DA-EPOCH without rituximab may be less effective than the historical pediatric regimens. 2 Lakhotia et al 1 raised the important point of dose intensity as a determinant of outcome in lymphoma and hypothesized that our finding of errors in dose escalation in at least one course in 29% of patients led to the observed lack of improvement with DA-EPOCH-R. Although this is certainly a plausible hypothesis, we do not think this is applicable for two main reasons. First, appropriately designed randomized trials are required to determine the impact of dose intensity on outcome for patients treated for non-Hodgkin lymphoma, 3 and to our knowledge, there has not been such a study for DA-EPOCH-R in primary mediastinal large B-cell lymphoma (PMLBL). Second, delivered dose intensity and its impact on outcome of DA-EPOCH-R have not been reported to date in any other study to our knowledge and so we do not agree that it is reasonable to suppose that the failures to escalate in at least one dose that we have reported contributed to the performance of DA-EPOCH that we observed. In addition, the EFS of patients correctly escalated in our study was 76.7% (95% CI, 59.1 to 88.2) which was inferior to that expected based on the National Cancer Institute (NCI) study, suggesting that factors other than dose intensity account for the poorer performance of DA-EPOCH-R in the pediatric setting.

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Dose-Adjusted Etoposide, Doxorubicin, and Cyclophosphamide With Vincristine and Prednisone Plus Rituximab Therapy in Children and Adolescents With Primary Mediastinal B-Cell Lymphoma: A Multicenter Phase II Trial

Cited by 20 publications

References 16 publications

Rituximab in addition to LMB-based chemotherapy regimen in children and adolescents with primary mediastinal large B-cell lymphoma: results of the French LMB2001 prospective study

Rituximab in addition to LMB-based chemotherapy regimen in children and adolescents with primary mediastinal large B-cell lymphoma: results of the French LMB2001 prospective study

Management of Aggressive Non-Hodgkin Lymphomas in the Pediatric, Adolescent, and Young Adult Population: An Adult vs. Pediatric Perspective

Reply to R. Lakhotia et al

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