What is the role of rituximab in the treatment of relapsed/refractory 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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As rituximab changed the treatment paradigm of patients with DLBCL, it has been postulated that the current subset of patients with refractory or relapsed DLBCL represent a different patient population than the one studied in pre-rituximab clinical trials. Several investigators are questioning if the response to second-line chemotherapy or if the value of HDC-ASCS in patients with relapsing or primary refractory DLBCL previously treated with R-CHOP has decreased compared with historical controls.

Martin et al, on behalf of the Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL/TAMO Cooperative Group), reported results from a retrospective analysis on the outcome of patients with DLBCL, evaluating the influence of rituximab on response rate to rituximab in combination with etoposide, methylprednisolone, cytarabine, and cisplatin (ESHAP) as salvage therapy. [120] Martin and colleagues studied 163 consecutive patients with relapsed/refractory DLBCL who received R-ESHAP as second-line therapy; 94 patients were previously treated with rituximab chemotherapy (R+ group) in the frontline setting and 69 patients received only chemotherapy alone (R- group).

Response rates were higher in patients who were not previously exposed to rituximab in a univariate analysis but not in a multivariate analysis. The OS and complete rates to R-ESHAP was 67% and 37% for DLBCL patients previously treated with rituximab-CHOP versus 81% and 56% for patients previously treated with CHOP (P =.045, P =.015), respectively. In addition, the PFS and OS rates at 3 years were significantly higher for the patients in the R- group (57% and 64%) compared with those patients in the R+ group (38% and 17%) (P < .0001, P =.0005). Of note, the same percentage of patients in both groups subsequently underwent HDC-ASCS.

In a multivariate analysis, prior exposure to rituximab was found to be a prognostic indicator of worse PFS and OS. [120] The results of this retrospective study suggest that DLBCL patients who relapse or do not respond to rituximab chemotherapy as first-line therapy have a more resistant type of disease and represent an emerging challenge for clinicians treating aggressive B-cell lymphomas. It also stresses the need to further study and define at the molecular level the mechanisms by which DLBCLs are developing resistance to chemoimmunotherapy.

On the other hand, it is uncertain whether rituximab can enhance the antitumor activity of systemic chemotherapy in the salvage setting or to what extent the use of HDC-ASCS improves the cure rates in previously R-CHOP–treated relapsed/refractory DLBCL. Two groups of investigators have shown improved response rates by adding rituximab to salvage regimens such as ifosfamide, carboplatin, and etoposide (ICE) or dexamethasone, high-dose cytarabine, and cisplatin (DHAP) compared with historical controls. [121, 122] However, the majority of the patients included in those clinical trials had not been previously exposed to rituximab in the frontline setting.

Groupe d'Etude des Lymphomes de l'Adulte (GELA) reported a subset analysis with long-term follow up of the 202 DLBCL patients who relapsed/progressed following frontline R-CHOP or CHOP chemotherapy in the context of the landmark study. All 202 patients underwent salvage chemotherapy, of which 31 received a rituximab-containing salvage regimen (22 and 9 previously treated with CHOP or R-CHOP, respectively). Patients treated with rituximab-containing salvage chemotherapy had a 2 years OS rate of 58%, as opposed to 24% for those treated with salvage chemotherapy alone (P =.00067). Of interest and while the numbers are small, the benefit of adding rituximab to the salvage regimen was statistically significant only for those DLBCL patients treated with CHOP chemotherapy in the frontline setting. [102]

While this observation is of interest, the sample size of those R-CHOP patients previously treated for relapsed/refractory DLBCL receiving rituximab-containing salvage chemotherapy was extremely small (9 patients), which should limit the significance of the conclusions derived from this study.

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