What is the role of rituximab in the treatment of advanced-stage diffuse large B-cell lymphoma (DLBCL)?

Updated: Aug 20, 2020
  • Author: Shipra Gandhi, MBBS; Chief Editor: Emmanuel C Besa, MD  more...
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Despite the clinical superiority of CHOEP-14 and ACVBP over CHOP-21 in patients with DLBCL, the parallel development and incorporation of rituximab into standard doses of CHOP-21 has challenged the clinical value of such toxic regimens in the post-rituximab era.

Based on results from clinical trials evaluating rituximab as monotherapy in aggressive lymphomas and the results reported by Czuczuman et al in patients with follicular lymphomas, [100] a phase II study evaluating the combination of rituximab and CHOP (R-CHOP) in aggressive B-cell lymphomas was conducted by Vose et al. [72] The overall response rate (ORR) to R-CHOP and rituximab was 94%, with 20 of 33 patients achieving a complete response (CR). At the time of the updated publication and after a median follow-up time of 63 months, the PFS rate was 82% and the OS rate was 88%.

The landmark study validating the addition of rituximab to CHOP chemotherapy was conducted by the GELA and presented by Coiffier et al. The GELA enrolled patients with newly diagnosed aggressive B-cell lymphomas who were older than 60 years and randomized them to receive either 8 cycles of either CHOP or R-CHOP at 21-day intervals. [101] The study included patients with stage I-IV DLBCL; 59% had 3 or more IPI score risk factors and 80% had Ann Arbor stage III or IV disease. The addition of rituximab to CHOP chemotherapy resulted in higher response rates than CHOP alone (76% vs 63%, respectively, P = 0.005). PFS and OS at the interim analysis (after 18-month follow-up) were significantly better in the R-CHOP arm (P < 0.001 and P = 0.007, respectively) when compared with CHOP.

A long-term analysis of the study after 5 years of follow up confirmed the efficacy of combining rituximab with systemic chemotherapy in terms of PFS (54% vs 30%; P < 0.0001) and OS (58% vs 45%; P = 0.0004). [101, 102]

The LNH-98.5 Study was updated after 10 years of follow up. [103] The 10-year PFS rate following therapy with R-CHOP or CHOP was 36.5% and 20%, respectively. Moreover, the 10-year OS rate was better in R-CHOP–treated DLBCL patients (43.5%) compared with patients treated with CHOP alone (27.6%). According to this study, the addition of rituximab to CHOP showed a clear benefit.

Another study conducted primarily in the United States was conducted to try to validate the results from the GELA study. Data from the Eastern Cooperative Oncology Group (ECOG) study 4944 in previously untreated elderly DLBCL patients randomized to R-CHOP versus CHOP and in responders to subsequent observation versus rituximab maintenance showed that the addition of rituximab to chemotherapy either during induction treatment or during maintenance improved the time to progression (TTP) compared with patients treated with CHOP chemotherapy alone. [104] Similar findings were found in younger patients with DLBCL with 0-1 IPI score risk factors, as described above.

Pfreundschuh et al reported a statistically significant benefit by adding rituximab to CHOP or CHOP-like chemotherapy in 824 patients with DLBCL in terms of PFS and OS. [92] After a follow-up period of 3 years, patients randomized to receive chemotherapy and rituximab had higher EFS (79% vs 59%, P < 0.0001) and had increased OS (93% vs 84%; P = 0.0001) than patients assigned to chemotherapy alone.

The benefit of adding rituximab to high-intermediate and high-risk DLBCL patients younger than 60 years has not been formally studied. The use of rituximab in combination with CHOP chemotherapy in this group of patients has been extrapolated from the results of the GELA and Mabthera International Trial (MInT) studies. While the addition of rituximab to standard doses of CHOP chemotherapy has improved the outcomes of patients with DLBCL, a significant number of patients do not to respond or relapse after initial responses, stressing the need to develop novel therapeutic strategies.

To further study the role of dose-dense chemotherapy in DLBCL in the post-rituximab era, the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) evaluated the benefit of adding rituximab to CHOP-14 in elderly patients with DLBCL. Pfreundschuh et al reported the results of the rituximab with CHOP over age 60 years (RICOVER-60) trial. [105]

In this study, 1222 elderly patients (aged 61-80 years) were randomized to receive either 6 or 8 cycles of CHOP-14 with or without rituximab. Involved-field radiation therapy (IF-XRT) was planned for extranodal or bulky sites. The results of this study demonstrated that the addition of rituximab to systemic chemotherapy improved the EFS and OS in DLBCL patients and that 6 cycles of chemotherapy were as effective as 8 cycles. After a 3-year period of follow-up, the EFS rates were as follows:

  • CHOP-14 for 6 cycles: 47.2% 
  • CHOP-14 for 8 cycles: 53%
  • R-CHOP-14 for 6 cycles: 66.5%
  • R-CHOP-14 for 8 cycles: 63.1% 

In addition, OS after 3 years of follow up was 67% and 66% in patients treated with 6 or 8 cycles of CHOP-14, in contrast to 78.1% and 72.5% for those patients treated with 6 or 8 cycles of R-CHOP-14, respectively. Of the 4 regimens assessed in this study, 6 cycles of R-CHOP-14 was found to be the preferred treatment for elderly patients, with which other approaches should be compared.

A topic of debate continues to be whether R-CHOP-14 is superior to R-CHOP-21. A quick glance to the data presented by the GELA or the RICOVER-60 trial could suggest that R-CHOP-14 appears to yield higher PFS and OS rates at 3-year follow-up. However, it is important to note that the DLBCL patients enrolled in both studies are different. The GELA study included more patients with DLBCL (84% vs 78%) stage I/II (20% vs 55%) and/or high-intermediate/high-risk IPI score categories (59% vs 39%) than the RICOVER-60 study. A randomized study by the GELA group comparing R-CHOP-21 to R-CHOP-14 in patients with DLBCL failed to demonstrate any clinical benefit from using R-CHOP-14 over R-CHOP-21. [106]

Additional clinical trials have explored the combination of rituximab with other chemotherapy regimens. Wilson et al, from the National Cancer Institute, studied dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone (DA-EPOCH) in combination with rituximab (DA-EPOCH-R) in previously untreated DLBCL. [107] In this regimen, the doses of etoposide, vincristine, cyclophosphamide, and doxorubicin are adjusted with each cycle to achieve an absolute neutrophil count nadir of 500 cells/µL. The study enrolled 72 consecutive patients with untreated DLBCL who were aged at least 18 years and had stage II or higher disease. Patients received 6-8 cycles of DA-EPOCH-R. Involved-field radiation therapy (IFRT) was not permitted. Correlative studies were performed to address biomarkers of disease response by immunohistochemistry (IHC). At 5 years, PFS and OS were 79% and 80%, respectively. [107, 108]

In a randomized Alliance/Cancer and Leukemia Group B (CALGB) phase III study comparing R-CHOP-21 with DA-EPOCH-R in previously untreated DLBCL, DA-EPOCH-R was more toxic and did not improve PFS or OS compared with R-CHOP.  The authors concluded that, "The more favorable results with R-CHOP compared with historical controls suggest a potential patient selection bias and may preclude generalizability of results to specific risk subgroups." [109]

The following four alternative strategies currently have been or are being evaluated in clinical studies, with promising activity in DLBCL patients [110, 111, 112, 113, 114, 115] :

  1. Dose-dense rituximab (ie, 12 doses of rituximab delivered concomitantly with 6 cycles of CHOP-14)
  2. Targeting of the ubiquitous proteasome with bortezomib as a means to potentiate the antitumor activity of chemoimmunotherapy
  3. The use of rituximab maintenance in the relapsed/refractory setting (CORAL study)
  4. The use of high dose-chemotherapy and autologous stem cell support (HDC-ASCS) in first remission, especially for those patients with high- risk disease

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