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Addition of Rituximab Does Not Improve Outcome in Aggressive B-Cell Lymphoma With Skeletal Involvement, but Radiotherapy Benefit Found

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Key Points

  • On multivariate analysis, the addition of rituximab to chemotherapy did not improve event-free survival or overall survival in patients with diffuse large B-cell lymphoma and skeletal involvement.
  • In the MInT and RICOVER-60 trials, the addition of rituximab to CHOP significantly improved event-free survival and overall survival in patients without skeletal involvement but not in those with skeletal involvement.
  • Radiotherapy to affected sites was associated with significantly improved event-free survival in patients with skeletal involvement.

In a retrospective analysis of German High-Grade Non-Hodgkin Lymphoma Study Group trials reported in Journal of Clinical Oncology, Gerhard Held, MD, of Saarland University Medical School in Homburg, and colleagues assessed the impact of rituximab (Rituxan) and radiotherapy on outcome in patients with aggressive B-cell lymphoma and skeletal involvement. The analysis showed that the addition of rituximab to chemotherapy did not improve outcome and suggested that radiotherapy was associated with improved outcome.

Study Details

The analysis included nine consecutive German High-Grade Non-Hodgkin Lymphoma Study Group studies in which patients with diffuse large B-cell lymphoma received CHOP- (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHEOP (CHOP and etoposide)-like regimens with or without rituximab. Event-free survival and overall survival were assessed in patients with vs without skeletal involvement and in those who did or did not receive rituximab. Analyses were also performed in populations of the two largest trials comparing CHOP regimens with and without rituximab, the MabThera International Trial (MInT), which was conducted in young patients with good prognoses, and the Rituximab With CHOP Over 60 Years (RICOVER-60) Study.

Analysis in Entire Population

Of the total of 3,840 patients, 2,814 patients (73.3%) were treated without and 1,026 patients (26.7%) were treated with rituximab, and 292 (7.6%) had skeletal involvement. Of the 292 patients with skeletal involvement, 61 (20.9%) were treated with and 231 (79.1%) without rituximab. The frequency of skeletal involvement was higher in patients not receiving rituximab than in those receiving rituximab (8.2% vs 5.9%). Median time of observation was 41 months in the entire group and 44 months in patients with skeletal involvement.

Among the 2,814 patients treated without rituximab, there was no significant difference between 231 patients with and 2,583 patients without skeletal involvement in 3-year event-free survival (55% vs 59%, P = .341) or overall survival (69% vs 75%, P = .070). Among the 1,026 patients treated with rituximab, the 61 patients with skeletal involvement had significantly worse 3-year event-free survival than the 965 patients without skeletal involvement (57% vs 72%, P = .002) and borderline worse 3-year overall survival (74% vs 82%, P= .055).

Since skeletal involvement was associated with adverse International Prognostic Index (IPI) prognostic factors, a multivariable analysis was performed adjusting for IPI risk factors. In this analysis, hazard ratios for event-free survival in patients with skeletal involvement were 0.9 (P =.173) in patients not receiving rituximab vs 1.4 (P=.131) in those receiving rituximab. Hazard ratios for overall survival were 0.9 (P = .328) vs 1.0 (P = .945).  

Outcomes in MInT and RICOVER-60 Trials

In the combined MInT and RICOVER-60 studies, 1,013 patient received CHOP with and 1,022 without rituximab. In multivariable analysis adjusting for IPI prognostic factors, hazard ratios for event-free survival in patients with skeletal involvement were 0.8 (P = .181) in those not receiving rituximab vs 1.5 (P = .048) in those receiving rituximab, and hazard ratios for overall survival were 0.7 (P = .083) vs 1.1 (P = .828).

In multivariate analysis of the individual MInT (51 patients with and 772 without skeletal involvement) and RICOVER-60 trials (86 patients with and 1,136 without skeletal involvement), the addition of rituximab to CHOP improved event-free survival (HR in MInT = 0.4, P < .001;  HR in RICOVER-60 = 0.6, P < .001) and overall survival (HR in MInT = 0.4, P < .001; HR in  RICOVER-60 = 0.7, P = .002) in patients without skeletal involvement. CHOP plus rituximab did not improve event-free survival (HR in MInT = 1.4, P = .444; HR in RICOVER-60 = 0.8, P = .449) or overall survival (HR in MInT = 0.6, P = .449; HR in RICOVER-60 = 1.0, P = .935) in those with skeletal involvement.

Radiotherapy Analysis

The analysis of the effect of radiotherapy was restricted to 161 patients with skeletal involvement who achieved a complete or partial response after the end of immunochemotherapy, because patients achieving less than a partial response went off protocol to receive salvage chemotherapy. Compared with 29 patients not receiving radiotherapy to sites of skeletal involvement, the 133 who received radiotherapy had significantly better 3-year event-free survival (75% vs 36%, P < .001) and nonsignificantly better 3-year overall survival (86% vs 71%, P = .064).

Since patients who did not receive radiotherapy had worse prognostic factors than those who received radiotherapy, a multivariable analysis adjusting for IPI risk factors and bulky disease was performed. In this analysis, radiotherapy was still associated with significantly better event-free survival (HR = 0.3; = .001) and nonsignificantly better overall survival (HR = 0.5, = .111). Radiotherapy appeared to have a beneficial effect in both limited and advanced disease stages; hazard ratios were 0.4 (P = .146) for event-free survival and 1.2 (P = .864) for overall survival among 78 patients with stage I or II disease and 0.3 (P = .001) for event-free survival and 0.4 (P = .059) for overall survival among 83 patients with stage III or IV disease.

The investigators concluded: “Rituximab failed to improve the outcome of patients with diffuse large B-cell lymphoma with skeletal involvement, although our data suggest a beneficial effect of radiotherapy to sites of skeletal involvement. Whether radiotherapy to sites of skeletal involvement can be spared in cases with a negative positron emission tomography after immunochemotherapy should be addressed in appropriately designed prospective trials.”

Dr. Held and Samira Zeynalova, PhD, of Leipzig University, contributed equally to the study, and Michael Pfreundschuh, MD, of Saarland University Medical School is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by Deutsche Krebshilfe.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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