The use of high-dose chemotherapy and autologous hematopoietic blood or marrow transplantation for high-risk aggressive non-Hodgkin lymphoma has been extensively evaluated over the past few decades. This treatment was originally used only for patients with relapsed aggressive lymphoma. However, as the patients who were at higher risk for relapse could more easily be identified by clinical features and the technique became safer, it was used in some trials earlier in the course of the disease for higher-risk patients according to the International Prognostic Index (IPI).¹

Prior to the addition of rituximab (Rituxan) to standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), several trials demonstrated an improvement when early transplantation was performed in first remission.^2,3 However, there were also conflicting trials that did not demonstrate a benefit for early transplantation in this patient population.^4,5 A meta-analysis of these earlier randomized trials demonstrated similar overall survival among patients undergoing upfront autologous stem cell transplantation.⁶

Evolving Trial Design

In a study reported by Stiff et al,⁷ reviewed in this issue of The ASCO Post, 370 patients with aggressive non-Hodgkin lymphoma were entered into a trial starting in 1999 and ending accrual in 2007. During this time period, the classification of the non-Hodgkin lymphomas was modified from the Working Formulation to the World Health Organization classification. In addition, over the time frame of the study, rituximab plus CHOP (R-CHOP) was found to be superior to CHOP alone for the treatment of CD20-positive aggressive lymphomas.⁸ Therefore, after about one-third of the patients were entered, the induction therapy was changed to R-CHOP for this study.

Patients entered on the trial were those with high or high-intermediate IPI risk. The patients who obtained a complete or partial response to the R-CHOP or CHOP induction therapy were randomly assigned to a consolidation autologous stem cell transplant in first remission or to complete the induction therapy, after which they could receive a stem cell transplant at the time of relapse.

Study Considerations

The first lesson from this study is that a third of the patients entering the study did not go on to the randomization due to early progression of their aggressive lymphoma or other issues. Despite the improved outcome with R-CHOP, there are still a number of high-intermediate or high IPI risk patients who don’t get a remission with the induction regimen or relapse soon after R-CHOP.

Overall, the 2-year progression-free survival was higher in the early transplant group compared to the R-CHOP group (69% vs 55%, P = .005). However, the estimated 2-year overall survival was not different between the groups—74% in the transplant group and 71% in the standard group (P = .30).

In the subset of high-intermediate IPI patients, there was no difference in progression-free or overall survival (P = .32). However in the subset of high IPI patients, the effect was significant with a 2-year progression-free survival in the transplant group of 75% compared to only 41% in the standard therapy group (P = .001). The overall survival rate was also significantly higher for the high IPI patients who underwent transplant—82% vs 64% for the standard therapy patients (P = .01).

Next Steps

This study is an important step forward in defining the use of high-dose chemotherapy and stem cell transplantation for patients who will benefit the most from transplant in the R-CHOP induction era. Although other recent trials have given us an expected baseline for transplantation in relapsed aggressive lymphoma, contemporary trials in the R-CHOP era that define the role of early transplantation in high-risk patients have been missing.

The next step will be further identification of high-risk populations with specific genetic abnormalities, such as the “double-hit” or “triple-hit” lymphomas, and the role of early transplantation or alternative therapies in these genetic subsets. As our understanding of the cell of origin and activated pathways in the different types of lymphomas improves, the use of more targeted therapies may evolve.

Based upon the study by Stiff et al,⁷ and pending further information on which specific genetic subtypes of aggressive lymphomas can benefit from early transplantation, this treatment should be considered for transplant-eligible patients with aggressive lymphoma who present with a high-risk IPI. ■

Dr. Vose is the Neumann M. and Mildred E. Harris Professor and Chief of the Division of Hematology/Oncology at the University of Nebraska Medical Center, Omaha.

Disclosure: Dr. Vose reported no potential conflicts of interest.

References

1. International Non-Hodgkin’s Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin lymphoma. N Engl J Med 329:987-994, 1993.

2. Haioun C, Lepage E, Gisselbrecht C, et al: Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin’s lymphoma: Final analysis of the prospective LNH87-2 protocol—a Groupe d’Etude des Lymphomes de l’Adulte study. J Clin Oncol 18:3025-3030, 2000.

3. Freedman AS, Takvorian T, Neuberg D, et al: Autologous bone marrow transplantation in poor-prognosis intermediate-grade and high-grade B-cell non-Hodgkin’s lymphoma in first remission: A pilot study. J Clin Oncol 11:931-936, 1993.

4. Gisselbrecht C, Lepage E, Molina T, et al: Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 20:2472-2479, 2002.

5. Martelli M, Gherlinzoni R, De Renzo A, et al: Early autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin’s lymphoma: An Italian multicenter randomized trial. J Clin Oncol 21:1255-1262, 2003.

6. Greb A, Bohlius J, Trelle S, et al: High-dose chemotherapy with autologous stem cell support in first-line treatment of aggressive non-Hodgkin lymphoma—results of a comprehensive meta-analysis. Cancer Treat Rev 33:338-346, 2007.

7. Stiff PJ, Unger JM, Cook JR, et al: Autologous transplantation as consolidation for aggressive non-Hodgkin’s lymphoma. N Engl J Med 369:1681-1690, 2013.

8. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002.