Rituximab plus high-dose chemotherapy (MegaCHOEP) or conventional chemotherapy (CHOEP-14) in young, high-risk patients with aggressive B-cell lymphoma: 10-year follow-up of a randomised, open-label, phase 3 trial
Mené en Allemagne sur 275 patients atteints d'un lymphome agressif à cellules B à haut risque de récidive (âge : 18-60 ans), cet essai de phase III compare l'efficacité sur le long terme, du point de vue de la survie sans événement, et la toxicité d'une chimiothérapie conventionnelle (cyclosphosphamide, doxorubicine, vincristine, étoposide et prednisolone avec du rituximab) et d'un traitement de première ligne combinant chimiothérapie à hautes doses et rituximab suivi par une greffe autologue de cellules souches hématopoïétiques (durée médiane de suivi : 9,3 ans)
Résumé en anglais
Background : R-MegaCHOEP was the first phase 3 study comparing high-dose chemotherapy plus rituximab followed by autologous haematopoietic stem-cell transplantation (HSCT) with conventional chemotherapy plus rituximab in first-line therapy for patients aged 60 years or younger with high-risk aggressive B-cell lymphoma. Little is known about the long-term outcomes of these patients. We aimed to evaluate the long-term efficacy and safety of conventional chemotherapy versus high-dose chemotherapy after 10 years of follow-up in the R-MegaCHOEPtrial.
Methods : In this open-label, randomised, phase 3 trial done across 61 centres in Germany, patients aged 18–60 years with newly diagnosed, high-risk (age-adjusted International PrognosticIndex [IPI] 2 or 3) aggressive B-cell lymphoma were randomly assigned (1:1, usingPocock minimisation) to eight cycles of conventional chemotherapy (cyclosphosphamide,doxorubicin, vincristine, etoposide, and prednisolone) plus rituximab (R-CHOEP-14)or four cycles of high-dose chemotherapy plus rituximab followed by autologous HSCT(R-MegaCHOEP). The trial was unmasked. Patients were stratified by age-adjusted IPIfactors, presence of bulky disease (tumour mass ≥7·5 cm diameter), and treatment centre.The primary endpoint was event-free survival, analysed here 10 years after randomisation.10-year overall survival, progression-free survival, conditional survival, relapsepatterns, secondary malignancies, and molecular characteristics were also analysed.All analyses were done on the intention-to-treat population. This trial is registeredwith ClinicalTrials.gov, NCT00129090.
Findings : Between March 3, 2003, and April 7, 2009, 275 patients were randomly assigned to R-CHOEP-14(n=136) or R-MegaCHOEP (n=139). 130 patients in the R-CHOEP-14 group and 132 patientsin the R-MegaCHOEP group were included in the intention-to-treat population. Aftera median follow-up of 9·3 years (IQR 5·1–11·1), 10-year event-free survival was 51%(95% CI 42–61) in the R-MegaCHOEP group and 57% (47–67) in the R-CHOEP-14 group (adjustedhazard ratio [HR] 1·3 [95% CI 0·9–1·8], p=0·23). 10-year progression-free survivalwas 59% (50–68) in the R-MegaCHOEP group and 60% (51–70) in the R-CHOEP-14 group (adjustedHR 1·1 [0·7–1·7], p=0·64). 10-year overall survival was 66% (57–76) in the R-MegaCHOEPgroup and 72% (63–81) in the R-CHOEP-14 group (adjusted HR 1·3 [0·8–2·1], p=0·26).Relapse occurred in 30 (16% [95% CI 11–22]) of 190 patients who had complete remissionor unconfirmed complete remission; 17 (17%) of 100 patients in the R-CHOEP-14 groupand 13 (14%) of 90 patients in the R-MegaCHOEP group. Seven (23%) of 30 patients hadlow-grade histology at relapse and had better outcomes compared with patients whorelapsed with aggressive histologies. Lymphoma affected the CNS in 18 (28%) of 64patients with treatment failure. 22 secondary malignancies were reported in the intention-to-treatpopulation; in 12 (9%) of 127 patients in the R-CHOEP-14 group and ten (8%) of 126patients in the R-MegaCHOEP group.
Interpretation : Event-free survival and overall survival were similar between groups after 10 yearsof follow-up; outcomes were not improved in the R-MegaCHOEP group by high-dose chemotherapy and autologous HSCT. Patients who relapsed with aggressive histology showed a highincidence of CNS involvement and poor prognosis. For these patients, novel therapiesare greatly warranted.
