Select Excerpts from the Interview*

CD 2, Track 19

DR LOVE: Can you review the background of the Mabthera International trial (MInT) of patients with low-risk diffuse large B-cell lymphoma (DLBCL)?

DR PFREUNDSCHUH: In 2002, it was reported that the addition of rituximab to three-weekly CHOP significantly improved outcomes in elderly patients (Coiffier 2002). Based on that finding, we wondered whether this would also be the case in young patients at low risk. Because we thought it’s much more difficult to show an improvement in young patients at low risk, we calculated that we needed more than 800 patients to show a 10 percent difference in event-free survival.

To get these patients, it was clear that we would need an international effort, which requires compromise, so we were quite liberal with the selection of a CHOP-like regimen — doctors in each country could choose their own regimen. Our philosophy was that if rituximab really does something important, then it should work overall.

The first interim analysis showed such clear-cut differences in favor of the combination CHOP-like regimen with rituximab that the Data Safety Monitoring Board urged us to stop the trial when 50 patients were still under treatment (Pfreundschuh 2004a). The first analysis of the complete trial showed a highly significant advantage with respect to all endpoints including complete remission rates, event-free survival rates, freedom from treatment failure rates and overall survival. This was the most important message (Pfreundschuh 2004b; [4.1]).

The second most important message was that, in the area of combined CHOPlike chemotherapy with rituximab, we could distinguish two subgroups. After a multivariate analysis of risk factors in patients with a good prognosis (low risk and low intermediate risk according to the age-adjusted IPI), we could distinguish a very favorable subgroup that included patients with no risk factors and no bulky disease. They had an event-free survival of 90 percent that will be very difficult to improve upon. The less favorable subgroup — patients with one risk factor and/or bulky disease — had only a 77 percent event-free survival. This definitely needs further improvement.

CD 2, Track 20

DR LOVE: Can you discuss the comparison of CHOEP versus CHOP and the inf luence of adding rituximab to these regimens?

DR PFREUNDSCHUH: The trial demonstrated a significant advantage of CHOEP over CHOP (4.2). However, after the addition of rituximab, this advantage was neutralized. R-CHOP is as good as R-CHOEP, with respect to any subgroup, with respect to any endpoint. So the advantage is neutralized by the rituximab — and you could call rituximab, which has been shown to be a chemotherapy sensitizer — a chemotherapy equalizer.

I think everyone’s happy with that, because we are now using a one-day regimen as the standard in this population for six cycles. We don’t need eight cycles because the results are so good that we could not expect them to be improved upon. We don’t need CHOEP. The one-day CHOP regimen is as good as the three-day regimen, R-CHOEP, and it’s less toxic and much easier to handle.

CD 2, Track 21

DR LOVE: Can you talk about your research on dose-dense chemotherapy?

DR PFREUNDSCHUH: We had two trials, one in young patients with a good prognosis and the other in elderly patients (61 to 75 years of age), in which we compared CHOP with CHOEP, each given in the three-weekly and twoweekly intervals (Pfreundschuh 2004c; Pfreundschuh 2004d).

In the young patients, the CHOEP-14 improved overall survival, complete remission rates and event-free survival compared to the gold standard, CHOP- 21, but R-CHOP is clearly better than CHOEP-14, so that’s not a relevant discussion anymore.

In the elderly patients, CHOEP-14 — doubling the intensity, adding etoposide and reducing the interval to two weeks — was too toxic (4.3). We had therapy-associated deaths (eight percent) and treatment delays. The twoweekly regimen, CHOP-14, was significantly better compared to the threeweekly regimen, and mostly so in patients at high risk.

Select publications

* Conducted on May 16, 2005