Page 153 - Haematologica May 2022

DA-EPOCH-R in double expressor lymphoma
n=4 with extensive extranodal localization; stage II, n=23 (DEL, n=18; SH, n=6; DH/TH, n=3) were treated with DA-EPOCH-R and experienced an impressive 2-year PFS and OS of 92% and 95%, respectively. Interestingly, the majority of limited disease patients did not have TP53 mutation (mutated, n=2; wild-type, n=18; not tested, n=7). Only a handful of studies, mainly of retrospective nature, have been focused on the prognosis of single hit or DH/TH lymphomas with limited-stage disease. Torka and colleagues analyzed the outcome of 81 patients carrying MYC rearrangement, including 40 DH, who received the standard R-CHOP regimen or intensive chemotherapy.30 The authors did not find any statistical difference in PFS and OS across treatment strategies but in the subgroup of DH, the intensive therapy was associated with a higher CR rate.
Over the past years, the combination of CNS-IPI and biological factors has been considered the best way to estimate the CNS relapse risk. In a retrospective study of newly diagnosed DLBCL patients treated with R-CHOP, without any CNS systemic prophylaxis, Savage and col- leagues reported that the DEL/non-GCB subgroup had a significantly higher risk of CNS relapse as compared to the non-DEL/non-GCB subgroup (15% vs. 3%).31 In contrast, in the prospective Goya trial, COO and not MYC/BCL2 double expression impacted the risk of CNS relapse.32 More recently, the Nordic group has suggested the effica- cy of the early administration of HD-MTX in newly diag- nosed DLBCL at high risk of CNS relapse.33 Our study is the first in which the risk of CNS relapse has been evalu- ated following the administration of a DA-EPOCH-R reg- imen and HD-MTX in 66 of 122 (54%) patients. Our pop- ulation included 24% of patients with high-risk CNS-IPI. Despite the high-risk population analyzed, systemic CNS prophylaxis was associated with a very low cumulative incidence of CNS relapse (5%) and a significant advantage in PFS and OS. The advantage on the outcome can be influenced by other untested factors and should be con- firmed in a larger trial.
Xu-Monette et al.6 reported a 21% incidence of TP53 mutations in a large population of DLBCL patients treated with R-CHOP and demonstrated that TP53 disruption was associated to poor PFS and OS in both GCB and non-GCB subtypes. Following a better characterization of DLBCL beyond the COO, the frequency of this mutation was test- ed in DEL and did not result to be different from non DEL (25% vs. 22%, respectively). The role of genomic alter- ations, including TP53 mutations, has recently been inves- tigated in several studies by applying novel molecular tech-
niques.9 Interestingly, Meriranta et al. found a frequent association between TP53 alterations and MYC overex- pression or translocations and, in those with TP53 muta- tion, a worse outcome in DEL as compared to non-DEL was reported.34 Recently, Song et al. reported a poor prog- nosis in DLBCL carrying double-hit signature and TP53 inactivation.35 In our study, the prevalence of the TP53 mutation was in keeping with previous studies, and the PFS/OS following DA-EPOCH-R treatment in TP53-mutated patients remained significantly lower than that observed in non-mutated patients suggesting the fail- ure of intensive therapy to overcome the mutation adverse effect. The observed 2-year OS of 62% seems better when compared to the OS of 48% reported by Xu Monette6 with R-CHOP and of 27% described by Chiappella et al.36 fol- lowing intensified therapy. These are indirect comparisons requiring a clinical study to be validated.
The intensified treatment with DA-EPOCH-R was well tolerated considering that 56% of patients were older than 60 years. We observed a limited incidence of severe toxic- ities, with one death for pneumonia and two patients de- escalated to R-CHOP for repeated infections. Other observed adverse events were manageable and did not compromise the completion of the therapeutic program.
Our data are promising, but we have to consider some limitations including: i) the retrospective nature; ii) the absence of information about MYC translocation partners (IG vs. non-IG); iii) the determination of cell of origin per- formed according to the Hans algorithm and not by the nanostring technology; iv) the absence of a control series of non-DEL patients with a single rearrangement or with DH/TH genotype.
In conclusion, we show a good outcome for DA- EPOCH-R in combination with HD-MTX in DEL and DEL-SH lymphomas without TP53 mutations, but the lower survival of patients DEL-DH/TH subtype or DEL with TP53 mutations requires further clinical studies aimed at testing novel agents combined with chemotherapy.
Disclosures
No conflicts of interests to disclose.
Contributions
AD, AG designed research, analyzed data, and wrote the manuscript; FM, AT, AR, MB, AC, MP, LD, FR, FC and LF col- lected data; FB and RM performed statistical analyses; CC, CM and DR performed TP53 mutations; AC, DR, VM and FF per- formed histological diagnosis and FISH analysis; PC and CC-S supervised the study.
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