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Letters to the Editor
Figure 1. Patient allocation and treatment assignment. Patients with diagnosis of primary mediastinal large B-cell lymphoma (PMBCL) were identified from 3 trials. Two patients received treatment not according to protocol and were excluded from the analysis. One patient from the non-Hodgkin lymphoma Berlin- Frankfurt-Münster (NHL-BFM) Registry 2012 (REG12) received treatment according to the NHL-BFM 95 treatment strategy (R2).
dose limit at 360 mg/m2 of body-surface area (BSA). A first analysis by our group of 15 patients treated with DA-EPOCH-R showed an EFS and OS of 92±8% after 2 years.5 A retrospective analysis of 156 adults and children with PMBCL treated with DA-EPOCH-R reports an EFS of 86% at 3 years.6 However, in the prospective Intergroup trial testing DA-EPOCH-R, the 2-year EFS of children and adolescents with PMBCL was 72%, not dif- ferent from the historical control.7
We analyzed children and adolescents with PMBCL confirmed by central histopathological review, excluding mediastinal grey zone lymphoma, enrolled in the B04 trial (German clinical trial registry: DRKS00009436) or the NHL-BFM Registry 2012 between 2004 and 2019 to i) assess the efficacy of intensified B-NHL-BFM chemotherapy (n=29 patients) and modified DA-EPOCH-R (n=67 patients), ii) compare it retrospec- tively to the treatment regimen in the NHL-BFM 95 trial (N95, n=20 patients) and iii) identify risk factors for treat- ment failure with DA-EPOCH-R.
Treatment details for N95, B04 and DA-EPOCH-R are summarized in the Online Supplementary Table S1. N95 treatment was stratified by lactate dehydrogenase (LDH) and stage to risk groups R2–R4, as previously reported.8 In B04, treatment was intensified by adding two courses: patients with LDH <500 U/L received six (PMBCL6), those with LDH ≥500 U/L seven (PMBCL7) 5-day courses of chemotherapy including high-dose methotrexate infused over 24 hours (h) and ITT. Outside the protocol, three patients received one or two doses of rituximab and one patient received initial emergency-mediastinal radio- therapy. One patient each after B04 and DA-EPOCH-R received radiotherapy for a persisting mediastinal mass. From September 2010, DA-EPOCH-R was recommended with the described modifications. Erroneously, 60 mg/m2 prednisone was used instead of 120 mg/m2 as protocol- specified for 26 patients.
The primary endpoint was the EFS at 5 years, defined as time from diagnosis to death, relapse, progressive dis- ease, or secondary malignancy, estimated using the
Kaplan-Meier method. OS was defined as time from diagnosis to death. Survival and competing risk compar- isons were performed by log-rank analysis and Gray´s test.9 Data were updated as of January 3, 2021.
For this analysis, 116 of 118 registered patients were included (Figure 1). Their median age was 16.2 years, 53% were female. Patient characteristics are summarized in Table 1.
Fifteen patients in the trial N95 and 15 patients treated by DA-EPOCH-R enrolled in B04 have been reported previously.2,5,8
Of 20 patients treated according to N95, six patients with LDH levels at diagnosis ≥500 U/L received the intended treatment (R3/R4). Of 14 patients with LDH <500 U/L, eight received the protocol-intended treatment with four courses (R2) and six were treated more inten- sively (R3/R4). B04 therapy was used for 29 patients, of whom 12 with LDH <500 U/L were scheduled for six courses, one for seven. All 16 patients with LDH ≥500 U/L received the intended treatment with seven courses.
Among 67 patients treated by DA-EPOCH-R, 15 received pretreatment other than one dose of rituximab or a BFM-type prephase (B04 chemotherapy in 13 patients - 1 course A24 in 2, 1 course AA24 in 10 patients, 2 courses AA24 and BB24 in 1 patient, 2 courses of OEPA and one course of R-CHOEP in 1 patient each). Fifty-two patients without pretreatment received six (n=50) or eight (n=2) courses of DA-EPOCH-R. The mean cumulative doxorubicin dose was 310 mg/m2 of BSA (range, 200–415 mg/m2). The median number of ITT was 2.5 (range, 0–8) in 50 patients with available data. The maximal dose levels reached were 1, 2, 3, 4, and 5 in 5 (10%), 6 (12%), 17 (34%), 17 (34%) and 5 (10%) patients, respectively, and unknown in two patients.
The levels reached were slightly lower than reported by Dunleavy and colleagues.4 Dose decisions were at the discretion of the treating physicians, and reasons for non- escalation might include concerns for sequelae, overesti- mation of hematological toxicity due to frequent blood counts for dose decisions, or the fact that G-CSF was not
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