FROM LANCET ONCOLOGY
High-dose chemotherapy with upfront autologous stem cell transplantation did not meaningfully improve survival at 5 years in a phase 3 trial of 399 patients under age 66 years with intermediate to high– or high-risk untreated diffuse large B-cell lymphoma.
Rates of treatment failure-free survival at 2 years were 71% for patients who received rituximab dose–dense chemotherapy followed by autologous stem cell transplantation (ASCT) and 62% for patients who received only the rituximab regimen (hazard ratio, 0.65; 95% confidence interval, 0.47-0.91; P = .01), Annalisa Chiappella, MD, of Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino (Italy) reported with her associates in Lancet Oncology.
This difference was “statistically significant but not clinically meaningful,” the researchers wrote. Five-year rates of overall survival were 78% and 77%, respectively. Also, intensifying the R-CHOP regimen failed to improve survival. “On the basis of these [final study] results, early consolidation with high-dose chemotherapy and autologous stem-cell transplantation cannot be recommended,” the researchers concluded. “R-CHOP should remain the standard treatment for diffuse large B-cell lymphoma in patients with poor prognosis.”
Patients with diffuse large B-cell lymphoma, whose age-adjusted International Prognostic Index (aa-IPI) scores are 2 or 3 (intermediate to high or high risk), have a poor prognosis despite standard treatment with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone). Given a historic lack of late-phase studies of this population, the researchers designed a multicenter, open-label, randomized phase 3 trial comparing rituximab dose–dense chemotherapy without ASCT with a shorter rituximab regimen followed by consolidation with R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus ASCT in untreated patients aged 18-65 years.
Rituximab-based chemotherapy consisted of 14-day cycles of either standard R-CHOP or an intensified R-CHOP–like regimen that increased the doses of cyclophosphamide (1200 mg/m2) and doxorubicin (70 mg/m2), the investigators noted (Lancet Oncol. 2017 Jun 28. doi: 10.1016/S1470-2045[17]30444-8 ).
In all, 96 patients were assigned to receive only standard R-CHOP (eight cycles), 100 patients were assigned to high-dose R-CHOP (six cycles), 103 patients were assigned to standard R-CHOP (four cycles) plus R-MAD (2 cycles) plus BEAM plus ASCT, and 96 patients were assigned to high-dose R-CHOP (four cycles) plus the same sequence of R-MAD, BEAM, and ASCT. A total of 325 (81%) patients completed treatment, and the median follow-up period was 72 months (interquartile range, 57 to 88 months). There was no evidence that treatment efficacy varied by age, sex, bone marrow involvement, or other histology results, but only the intermediate-high risk patients experienced a benefit in terms of failure-free survival.
Grade 3 or higher adverse hematologic events affected 183 (92%) ASCT recipients and 135 (68%) patients who received only R-CHOP or high-dose R-CHOP. Nonhematologic adverse events affected 45% and 16% of patients, respectively, and were mostly gastrointestinal in nature. Of recipients of ASCT, 12 stopped treatment because of infections, prolonged neutropenia, gastrointestinal symptoms, or cardiac abnormalities, and two patients who did not undergo ASCT stopped treatment because of infections or prolonged neutropenia. Three (13%) patients died from treatment-related causes, including eight patients in the transplantation groups and five of the other patients.
Previous studies have reported benefits from intensified R-CHOP–like regimens in diffuse large B-cell lymphoma, but these trials included low-risk patients.
“Our study enrolled only intermediate to high–risk or high-risk patients, and the findings do not support the hypothesis that increasing the dose of R-CHOP improves outcomes in patients with diffuse large B-cell lymphoma who are at high risk,” they wrote. “The addition of novel drugs, such as lenalidomide, ibrutinib, bortezomib, and others, to standard R-CHOP regimens has been reported in phase 1 or 2 studies with promising results in high-risk patients, leading to ongoing phase 3 randomized trials to assess the efficacy of these strategies. While awaiting the results of these randomized studies, the standard treatment in patients with diffuse large B-cell lymphoma at intermediate to high and high risk remains chemoimmunotherapy based on the standard R-CHOP regimen.”
Fondazione Italiana Linfomi funded the study. Dr. Chiappelli and several coinvestigators disclosed ties to Amgen, Celgene, Janssen, Nanostring, Pfizer, and other companies.
