Is Dose-Dense Therapy Effective Against DLBCL in the Era of Rituximab?

If there is one disease for which patients have experienced a significant improvement in the cure rate over the past 10 years, it is diffuse large B-cell lymphoma (DLBCL). In their review article in this issue of ONCOLOGY, Nastoupil, Rose, and Flowers discuss the progress from the older chemotherapy regimen, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), to immuno-chemotherapy. The authors asked whether there is still debate surrounding dose intensity since the introduction of the monoclonal antibody rituximab (Rituxan [R]), which has improved the clinical outcomes of patients with DLBCL.

The focus of the review addressed the results of different dose-dense, dose-intense treatments such as CHOP given every 21 days vs every 14 days, the more intense ACVBP (Adriamycin [doxorubicin ], cyclophosphamide, vindesine, bleomycin, and prednisone), and DA-EPOCH (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) chemotherapies. The review questioned also whether there is still a role for consolidation with autologous stem cell transplantation (ASCT).

For several years, our group (Groupe d’Etude des Lymphomas de l’Adulte [GELA]) has contributed to this debate by studying a regimen (ACVBP) that was administered once every 2 weeks with an increasing dose intensity (mg/m²/week) according to the hypothesis by Hryniuk.[1] The scheduled dose intensity increases for the two main drugs, doxorubicin (× 2.2) and cyclophosphamide (× 2.4), was associated with increased survival in patients with DLBCL.[2] As noted, this regimen is very different from the regimens used in the US Intergroup study, in which there was no real increase in the dose intensities of these two drugs. In randomized studies based on head-to-head comparisons, we demonstrated that this regimen was superior to CHOP in several clinical situations,[3,4] but that acute toxicity would prevent its use in patients over the age of 65 years.[5]

In the rituximab era, a comparison between R-ACVBP and R-CHOP in 380 patients < 60 years, with an international prognostic index (IPI) of 1 resulted in a superior event-free survival and overall survival ([OS] 92% vs 80%, respectively),[6] with a greater efficacy in activated B-cell DLBCL. Mirroring the limited use of DA-EPOCH in Europe, this regimen was unfortunately not widely used outside of France and Belgium. The incorporation of vindesine (no longer widely available) was one of the main reasons for this trend, although it could have easily been substituted with another alkaloid. The main question is whether all young patients should be administered this intensive regimen when the results have been dramatically improved with only R-CHOP.

What are the options for young patients with a poor prognosis? We can agree that the role of high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) as a first line treatment has been unclear in the pre-rituximab era, due to the different selections of patients and procedures. Several conclusions can be drawn. First, the consolidation with ASCT should not be performed too early, but only after the patient has achieved a complete response or a good partial response. Second, the duration and the type of prior treatment play a role. Only patients with at least two adverse prognostic factors seem to benefit from it. However, given the improvement in the response rates with immunochemotherapy, fewer patients will relapse and be candidates for this therapy. Therefore, what results are available?

Two large phase II studies incorporating rituximab HDT and ASCT initially have been performed in DLBCL patients with at least two IPI factors.[7,8] In the GELA study involving 209 DLBCL patients, the 4-year progression-free survival (PFS) rate was 76%, and there was no difference between patients with two vs three IPI factors. Similar results have been observed in the Italian study by Tarella et al that included 112 patients.[8] Whether these results are superior to R-CHOP is still under debate. In their article, Nastoupil and colleagues discuss the results of the SWOG-led randomized Intergroup study in 370 patients. They suggest a higher rate of PFS at 2 years (69% vs 56%, respectively) with the addition of ASCT after complete remission vs CHOP alone. In Italy, the Italian Lymphoma Foundation (FIL) conducted a randomized study on 399 patients with at least two IPI factors, comparing different regimens with or without ASCT. The 2-year PFS was significantly improved to 70% with the addition of ASCT, compared with a rate of 59% with R-CHOP-14.[9] In both studies, however, there was no advantage in OS; possible cofounders of the OS data included ASCT at relapse in the standard arm.

Not all patients with adverse factors would require ASCT, and further selection criteria are warranted. One approach could be to use interim positron emission tomography (PET); salvage and consolidation with ASCT would only be used in PET-positive patients. The situation is still confusing regarding interim use of PET, and it is more complex than expected. If almost everybody agreed that a negative PET scan after 2 or 4 cycles is associated with a good outcome and a reduced chance of relapse, PET positivity would be defined more precisely than visual assessment. The difference in uptake between diagnosis and interim PET (delta SUV [standard uptake value]) to a certain threshold (below 66%) discriminates between patients with a high probability of relapse vs PET-negative patients.[10] Our group is working in that direction, and we have reported the first part of the study using PET evaluation.[10] In their review, Nastoupil, Rose, and Flowers discuss the experience of Stewart et al, showing that salvage and ASCT may overcome the expected poor outcome for the group of PET-positive patients. In addition, the randomized study of Milpied et al,[11] adjusting their previous study to interim PET, showed that for PET-negative patients, there is no difference between the immunochemotherapy arm vs consolidation with ASCT. Again, however, the addition of salvage followed by ASCT overcomes the expected poor outcome for PET-positive patients.

We fully agree with the conclusions of the authors who believe, based on the two randomized studies comparing R-CHOP-14 and R-CHOP-21, that there is no need to propose R-CHOP-14 as a standard of care in the elderly. We are waiting for the results of the comparison between DA-EPOCH-R and R-CHOP-21, which will determine the gene profile of DLBCL. Those data will indicate how the biologic risk stratification subtypes should be used for future studies, with a focus on the activated B cell (ABC) subtype. The different types of responses have been seen in DLBCL subtypes with RDHAP (rituximab, dexamethasone, Ara-C [cytarabine], and cisplatin) in a salvage setting,[12] and it has been reported that mostly regimens including lenalidomide (Revlimid)[13] or bortezomib (Velcade)[14] may be active in the ABC subtype. We also agree that dose-dense or dose-intense treatments have not provided the expected therapeutic breakthroughs. In select young patients, however, R-ACVBP or consolidation with ASCT should be considered. Finally, we are all awaiting technological progress to translate into clinical practice the development of targeted therapy to cure more DLBCL. The authors should be acknowledged for their work as well as their clear and precise discussion.

Financial Disclosure:Dr. Gisselbrecht is a principal investigator for Roche.

References:

REFERENCES

1. Hryniuk WM. The importance of dose intensity in the outcome of chemotherapy. Important Adv Oncol. 1988;121-41.

2. Lepage E, Gisselbrecht C, Haioun C, et al. Prognostic significance of received relative dose intensity in non-Hodgkin’s lymphoma patients: application to LNH-87 protocol. The GELA. (Groupe d’Etude des Lymphomes de l’Adulte). Ann Oncol. 1993;4:651-6.

3. Tilly H, Mounier N, Lederlin P, et al. Randomized comparison of ACVBP and m-BACOD in the treatment of patients with low-risk aggressive lymphoma: the LNH87-1 study. Groupe d’Etudes des Lymphomes de l’Adulte. J Clin Oncol. 2000;18:1309-15.

4. Reyes F, Lepage E, Ganem G, et al. ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med. 2005;352:1197-205.

5. Tilly H, Lepage E, Coiffier B, et al. Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood. 2003;102:4284-9.

6. Recher C, Coiffier B, Haioun C, et al. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011;378:1858-67.

7. Fitoussi O, Belhadj K, Mounier N, et al. Survival impact of rituximab combined with ACVBP and upfront consolidation autotransplantation in high-risk diffuse large B-cell lymphoma for GELA. Haematologica. 2011;96:1136-43.

8. Tarella C, Zanni M, Di Nicola M, et al. Prolonged survival in poor-risk diffuse large B-cell lymphoma following front-line treatment with rituximab-supplemented, early-intensified chemotherapy with multiple autologous hematopoietic stem cell support: a multicenter study by GITIL (Gruppo Italiano Terapie Innovative nei Linfomi). Leukemia. 2007;21:1802-11.

9. Vitolo U, Chiappella A, Brusamolino E, et al. A randomized multicentre phase III study for first line treatment of young patients with high risk (aa-IPI 2–3) diffuse large B-cell lymphoma (DLBCL): rituximab (R) plus dose-dense chemotherapy CHOP14/MegaCHOP14 with or without intensified high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). Results of DLCL04 trial of Italian Lymphoma Foundation (FIL). Ann Oncol. 2011;22(Suppl 4):abstr 072.

10. Casasnovas RO, Meignan M, Berriolo-Riedinger A, et al. SUVmax reduction improves early prognosis value of interim positron emission tomography scans in diffuse large B-cell lymphoma. Blood. 2011;118:37-43.

11. Milpied NJ, Legouill S, Lamy T, et al. No benefit of first-line rituximab (R)- high-dose therapy (R-HDT) over R-CHOP14 for young adults with diffuse large B-cell lymphoma. Preliminary results of the GOELAMS 075 prospective multicentre randomized trial. Blood. 2010;116:abstr 685.

12. Thieblemont C, Briere J, Mounier N, et al. The germinal center/activated B-cell subclassification has a prognostic impact for response to salvage therapy in relapsed/refractory diffuse large B-cell lymphoma: a bio-CORAL study. J Clin Oncol. 2011;29:4079-87.

13. Hernandez-Ilizaliturri FJ, Deeb G, et al. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype. Cancer. 2011;117:5058-66.

14. Dunleavy K, Pittaluga S, Czuczman MS, et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood. 2009;113:6069-76.