Page 181 - Haematologica Vol. 107 - September 2022

ARTICLE - Rituximab with LMB-chemotherapy regimen in PMLBL M.E. Dourthe et al.
These excellent results contrast with the results recently published with DA-EPOCH-R in 46 children and adoles- cents included in the international phase II Inter B-NHL- ritux 2010 study7 (Table 4). Although the characteristics of the patients included in this study do not differ from those of the phase II Inter B-NHL-ritux 2010, 12 disease-related events were observed in the phase II, 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 three (6.5%) parenchymal central nervous system relapses. All five disease-related events in the French LMB2001 study were local/mediastinal with no CNS relapses. Thus, CNS-directed therapy may be im- portant in PMLBL and explains why we recommended since 2008 LMB B/C-modified regimen with rituximab, with some intrathecal therapy but also HD MTX and high- dose cytarabine (AraC). Recently, a real-world study from the French LYSA group also reinforces the benefit of dose intense immuno-chemotherapy regimens in PMLBL17: pa- tients treated with R-ACVBP or R-CHOP14 achieved a better outcome than those treated with R-CHOP21 (pro- gression-free survival of 89.4% vs. 74.7%). R-ACVBP also included some CNS-directed therapies such as HD MTX and intrathecal in the majority of patients and CNS relapse rate was low (2.9%) in this series.
By contrast with the pediatric phase II Inter-B-NHL ritux 2010 trial, outstanding survival for adult patients with PMLBL has been reported with DA-EPOCH-R in a single- institution, non-randomized phase II study, of 51 patients with EFS of 93% (95% CI: 81-98) and OS of 97% (95% CI: 81-99).18 In the same way, a large multicenter retrospective analysis reported on the outcome of pediatric and adult patients treated with DA-EPOCH-R for PMLBL.19 Survivals were not statistically different between pediatric and adult patients for both EFS (81.0% vs. 87.4%, P=0.338) and OS (90.7% vs. 97.1%, P=0.170).
Clinically and pathologically, PMLBL disease in the pedi- atric population is indistinguishable from that seen in adult patients. Thus, the difference in outcome between
the two main DA-EPOCH-R studies is therefore hard to explain although the methodology of these studies is very different (i.e., international vs. single-institution). Other registry-based or retrospective studies of children and adolescents with PMLBL treated with DA-EPOCH-R have been also reported. The BFM NHL group reported their multicentric experience between 2004 and 2019 with modified DA-EPOCH-R (addition of at least one intrathecal triple therapy and a cumulative doxorubicin dose limit at 360 mg/m2) (n=67 patients) or intensified chemotherapy B-NHL BMF04 (n=29 patients) and compared it retrospec- tively to the treatment regimen in the B-NHL BMF95 trial (n=20 patients), both without rituximab.20 For patients treated with DA-EPOCH-R, the 5-year EFS and OS were 84% (95% CI: 72–91) and 90% (95% CI: 79–95), respect- ively. These results are intermediate between the out- standing results obtained in the phase II study in adult patients and the phase II Inter-B-NHL ritux 2010 in children (Table 4). However, despite the use of triple in- trathecal, at relapse four of 11 patients treated with DA- EPOCH-R had parenchymal CNS disease, strengthening the fact that it is necessary to improve CNS disease con- trol in this pathology.
Pediatric-type B-NHL regimens, such as LMB and others, have higher acute toxicity when compared with DA- EPOCH-R regimen. The DA-EPOCH-R phase II Inter-B-NHL ritux 2010 study in pediatric patients reported febrile neu- tropenia in 11% of courses and 46% of patients, infections grade ≥3 in 4% of courses and 17% of patients and sto- matitis grade ≥3 in 3% of courses and 15% of patients. Al- though we did not register toxicity in the prospective French LMB2001 trial (but no toxic death occurred), other LMB-based chemotherapy trials with rituximab reported febrile neutropenia, infection grade ≥3 and stomatitis grade ≥3, in 92.6%, 58.6%, and 79.6% of patients, respect- ively.21 However, management of long-term toxicity is also very important in this young population. The risks for sig- nificant long-term sequelae are relatively modest using
Table 4. Summary of R-DA-EPOCH studies and the LMB 2001 study.
Study
Regimen
Type of study
Population
N of patients
Median FU
N of events (CNS relapse)
EFS, % (95% CI)
OS, % (95% CI)
NCI18
DA-EPOCH-R
Phase 2, monocentric
Adults
51
5 years
3 (0)
93 (81-98)
97 (81-99)
BFM19
DA-EPOCH-R
Registry, multicentric
Child/ado
67
4 years
11 (4)
84 (72-91)
90 (79-95)
Inter B-NHL ritux 20107
DA-EPOCH-R
Phase 2, multicentric
Child/ado
46
5 years
14 (3)
70 (55-81)
85 (72-92)
LMB 2001
R-LMB
Registry, multicentric
Child/ado
21
6 years
1 (0)
95 (77-99)
100
LMB 2001
LMB
Registry, multicentric
Child/ado
21
10 years
4 (0)
81 (60-92)
90 (71-97)
Child/ado: children/adolescents; CI: confidence interval; EFS: event-free survival; FU: follow-up; OS: overall survival; DA-EPOCH-R: dose- adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab.
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