ATLANTA – In young patients with high-risk diffuse large B-cell lymphoma, autologous stem cell transplantation can push the rate of progression-free survival beyond that achievable with rituximab and high-dose chemotherapy.
But transplants did not appear to confer an overall survival advantage for these patients in a study of 399 patients, Dr. Umberto Vitolo reported at the annual meeting of the American Society of Hematology.
More than a decade ago, rituximab transformed the treatment of diffuse large B-cell lymphoma (DLBCL), and called into question the role of intensified high-dose chemotherapy and transplantation as first-line therapy. But poorer outcomes for young patients with high-risk disease prompted Dr. Vitolo, of the University Hospital in Turin, Italy, and his colleagues to see whether treatment intensification after rituximab dose-dense chemotherapy, delivered at two different levels, could reduce risk in younger patients.
In a prospective phase III trial of the Italian Lymphoma Foundation, previously untreated adults aged 18-65 years (median age 49 years) with DLBCL and an age-adjusted IPI (International Prognostic Index) score of 2 or 3 were randomized to receive one of four regimens:
• Eight cycles of R-CHOP14 (rituximab-cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine), prednisone).
• Six cycles of R-MegaCHOP14 (CHOP with a higher dose of cyclophosphamide).
• Four cycles of R-CHOP14 plus R-HDC (rituximab–high-dose chemotherapy) followed by BEAM (BCNU, etoposide, cytarabine, and melphalan) and ASTC (autologous stem-cell transplant).
• Four cycles of R-MegaCHOP14 plus R-HDC followed by BEAM and ASCT.
At a median of 41 months’ follow-up, 3-year progression-free survival was 75% among patients treated with the most intensive regimen of rituximab and high-dose chemotherapy followed by autologous stem-cell transplant. Three-year progression-free survival was 58% for the patients who got rituximab dose-dense chemotherapy (hazard ratio [HR], 0.63; P = .008).
There was no difference in overall survival, he said. Dose intensification in the chemotherapy-only arms did not offer additional benefit, and increased toxicities.
In all, 75% of 199 patients assigned to the two ASCT arms completed the trial, compared with 88% of 200 patients assigned to the two rituximab dose-dense only arms.
An intention-to-treat analysis showed that the combined complete response and complete response unconfirmed (CR/CRu) rates were 69% for the R-MegaCHOP14/ASCT arm, 82% for R-CHOP/ASCT, 73% for R-MegaCHOP14 only, and 71% for R-CHOP14 only. The respective partial response rates were 3%, 3%, 8%, and 13%, and nonresponse rates were 24%, 13%, 16%, and 15%.
A progression-free survival advantage was seen for the ASCT arms compared with the no-transplant arms. There was no significant difference in progression-free survival benefit in the chemotherapy only arms (65% for R-CHOP14, and 64% for R-MegaCHOP14; P = .73).
In an exploratory analysis comparing the four study arms with R-CHOP14 as the reference arm, R-CHOP14/ASCT only was associated with a significant reduction in risk of progression-free survival (HR, 0.56; confidence interval, 0.35-0.91).
Among intermediate to high-risk (age-adjusted IPI2) patients, 3-year progression-free survival was 75% for those treated with ASCT and 65% for those treated with chemotherapy only (HR, 0.63; P = .031). Among high-risk patients (IPI3), the respective rates were 60% and 46%, but the difference was not significant.
Among patients with any response (CR/CRu and PR) after four courses of chemotherapy, those who went on to transplant had a 3-year progression-free survival of 73%, compared with 62% for those who did not get a transplant (P = .018).
In multivariate analysis, the only significant prognostic factors were transplant, age at randomization, and bone marrow positive disease after treatment, said Dr. Vitolo.
Grade 3 or 4 hematologic toxicities were higher among patients in the transplant arms but were generally manageable, Dr. Vitolo said. The incidence of grade 3 febrile neutropenia was 2% among all transplant recipients, compared with 0.3% for nonrecipients; grade 4 events occurred in 0.2% vs. 0.08%, respectively. All patients had G-CSF (granulocyte colony-stimulating factor) support.
There were six treatment-related deaths (3%) among transplanted patients and four (2%) treatment-related deaths in the chemotherapy-only arms.
The study was supported by a grant from Compagnia SanPaolo/FIRMS, Turin. Dr. Vitolo disclosed serving in an advisory capacity to Roche, the marketer of rituximab.