High-Dose Chemotherapy Plus Transplant Not Recommended for DLBCL

Patients with high-risk diffuse large B-cell lymphoma (DLBCL) had a reduced risk of treatment failure when assigned to an abbreviated course of rituximab-dose-dense chemotherapy plus high-dose cytarabine, mitoxantrone, and dexamethasone (R-MAD) plus carmustine, etoposide, cytarabine, and melphalan (BEAM) plus autologous stem cell transplantation compared with a full course of rituximab-dose-dense chemotherapy, according to a study published in Lancet Oncology. However, this treatment regimen did not result in an improvement in overall survival.

“On the basis of these results, early consolidation with high-dose chemotherapy and autologous stem cell transplantation cannot be recommended, and R-CHOP [rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone] should remain the standard treatment for DLBCL in patients with poor prognosis,” wrote Annalisa Chiappella, MD, of the department of hematology at Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino in Turin, Italy, and colleagues.

The study compared two different dose levels of R-CHOP: a full course of rituximab-dose-dense chemotherapy (no transplant group) compared with an abbreviated course of rituximab-dose-dense chemotherapy followed by consolidation with R-MAD and BEAM plus stem cell transplantation. The study included 399 patients age 18 to 65 years with untreated high-risk DLBCL. The patients were randomly assigned to one of four arms: R-CHOP delivered in a 14-day cycle (R-CHOP-14) for 8 cycles; high-dose R-CHOP-14 (R-MegaCHOP-14) for 6 cycles; R-CHOP-14 for 4 cycles followed by R-MAD plus BEAM and autologous stem-cell transplantation; or R-MegaCHOP-14 for 4 cycles followed by R-MAD plus BEAM and autologous stem cell transplantation. The primary endpoint was failure-free survival at 2 years.

With a median follow-up of 6 years, the 2-year failure-free survival rate for the whole population was 66%, the overall survival rate was 82%, and the progression-free survival rate was 69%. Patients assigned to transplant had significantly improved 2-year failure-free survival rates (71% vs 62%; hazard ratio [HR], 0.65; 95% CI, 0.47–0.91; P = .012) compared with patients who did not receive a transplant. However, there was no significant difference in 5-year overall survival between the transplant groups.

The researchers suggested several reasons why the difference in failure-free survival did not translate into a difference in overall survival as it has in other trials of DLBCL. First, this study did not include patients older than 65 years, suggesting that failure-free survival may not be a valid surrogate endpoint in this younger patient population. In addition, a difference in failure-free survival with transplant was only seen in patients with intermediate-high risk, which could have lowered the power of the comparison.

There was no significant difference in failure-free survival between patients who received R-CHOP-14 and R-MegaCHOP-14 (67% vs 66%). Based on this, the researchers wrote, “The findings do not support the hypothesis that increasing the dose of R-CHOP improves outcomes in patients with DLBCL who are at high risk.”

Grade 3 or worse hematologic events occurred in 92% of patients assigned to transplant and 68% of patients in the no-transplant group. The most common nonhematologic adverse event was gastrointestinal (25% of transplant patients vs 10% with no transplant).

“The addition of novel drugs such as lenalidomide, ibrutinib, bortezomib, and others to standard R-CHOP regimens has been reported in phase I or II studies with promising results in high-risk patients as well, leading to ongoing phase III randomized trials to assess the efficacy of these strategies,” the researchers noted. “While awaiting the results of these randomized studies, the standard treatment in patients with DLBCL at intermediate-high and high risk remains chemoimmunotherapy based on the standard R-CHOP regimen.”