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Letters to the Editor
AB
Figure 2. Event-free survival and overall survival at 5 years for patients with primary mediastinal large B-cell lymphoma treated with the treatment regimen NHL-BFM 95, B-NHL-BFM 04 or DA-EPOCH-R. (A) Event-free survival (EFS) and (B) overall survival for patients with primary mediastinal large B-cell lymphoma (PMBCL) according to the type of treatment. EFS was significantly different between DA-EPOCH-R and B-non-Hodgkin lymphoma Berlin-Frankfurt-Münster (B-NHL-BFM) B04 (P=0.024) and DA-EPOCH-R and NHL-BFM 95 (N95) (P<0.001). The difference between 04 and N95 was not significant (P=0.142). DA-EPOCH- R: dose-adjusted chemo-immunotherapy etoposide, prednisone, cyclophosphamide, doxorubicin, and rituximab.
administered to all patients (only 39 of 46 (85%) of patients with available data).
In 15 pretreated patients, the median number of DA- EPOCH-R-courses was five, the median number of ITT was five, and the mean cumulative dose of doxorubicin was 260 mg/m2 BSA.
For treatment by DA-EPOCH-R, B04 and N95, esti- mates for EFS at 5 years were 84% (95% confidence interval [CI]: 72–91), 59% (95% CI: 39–74), and 39% (95% CI: 19–60), respectively (Figure 2). OS 90% (95% CI: 79–95), 72% (95% CI: 51–85) and 70% (95% CI: 45– 85), respectively (Figure 2). EFS and OS with DA-EPOCH-R were significant superior to treatment with B04 (P=0.016 for EFS, P=0.039 for OS) and N95 P<0.001 for EFS and P=0.026 for OS).
The observed EFS with DA-EPOCH-R was comparable to that of other trials ranging from 72% to 93%.4,6,7,10,11 To what extent rituximab alone contributed to the supe- rior outcome cannot be answered by our data. The addi- tion of rituximab to CHOP improved outcomes in adult patients with PMBCL.12 Recent preliminary data from the non-randomized, prospective IELSG37 trial suggest simi- lar efficacy for DA-EPOCH-R and R-CHOP14.13 The AEIOP reported 13 pediatric PMBCL patients treated with a modified MTX-based BFM-type backbone com- bined with rituximab resulting in an EFS of 84%.14 These data indicate that addition of rituximab contributed sub- stantially to the improved outcome.
Estimated EFS at 5 years for patients with LDH <500 U/L receiving PMBCL6, R3/R4, and R2 in B04/N95 were 67% (95% CI: 34–86), 67% (95% CI: 19–90), and 19% (95% CI: 1–54), respectively (Online Supplementary Figure S1A), with a significant difference between PMBCL6 and R2 (P=0.047). PMBCL7 was given to 16 patients with LDH ≥500 U/L in B04, R3/R4 in N95 to eight patients. The estimated EFS was 50% (95% CI: 25–71) and 33% (95% CI: 5–68), respectively (P=0.45, Online
Supplementary Figure S1B). The improvement with inten- sified B-NHL therapy in patients with LDH levels <500 U/L but not among those with LDH levels ≥500 U/L indi- cates a possible limit for further improvements by modi- fying standard B-NHL chemotherapy for PMBCL.
In patients treated by DA-EPOCH-R without pretreat- ment, EFS and OS at 5 years were 87% (95% CI: 74–93) and 91% (95% CI: 78–97), not significantly different from the outcome for 15 patients receiving DA-EPOCH- R after pretreatment (with an EFS and OS of 73% (95% CI: 44–89) and 86% (95% CI: 55–96), respectively (P=0.2 for EFS, P=0.54 for OS, Online Supplementary Figure S2). The heterogeneity in treatment with pretreatment in about 20% of patients is a limitation of our analysis, but likely reflects real-world diagnostic uncertainties, with a final diagnosis of PMBCL only made by central histopathological review in conjunction with the typical location.
There was no significant difference in EFS according to sex, initial LDH, extra-thoracic involvement, prednisone dose or the maximal dose-level reached in DA-EPOCH-R. Mean age was lower in patients experi- encing relapse (hazard ratio [HR]: 0.74, P=0.012), result- ing in an EFS of 90% (95% CI: 76–96) for 41 patients ≥16 years, compared with 73% (95% CI: 52–86) for 26 patients <16 years (P=0.07). The limited number of patients might explain that we could not identify risk fac- tors for treatment failure with DA-EPOCH-R except for younger age.
At relapse four of 11 (37%) patients treated by DA-EPOCH-R had parenchymal CNS involvement com- pared to zero of 22 after B04 chemotherapy (Gray´s test, P=0.08). Three of these patients had received only 60 mg/m2 prednisolone, two reached only dose level 1 or 2 and one received only one ITT for CNS prophylaxis. Further explanations for a possibly higher risk of CNS- relapse after DA-EPOCH-R include the use of prednisone
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