Select Excerpts from the Interview

CD 1, Track 2

DR LOVE: Would you provide an overview of research in dose-dense chemotherapy for lymphoma?

DR MOSKOWITZ: We have been administering dose-dense chemotherapy to patients with untreated diffuse large B-cell lymphoma, peripheral T-cell lymphoma or aplastic large cell lymphoma since 1993. Initially, we administered induction therapy with 60 mg/m² of doxorubicin and 1.4 mg/m² of vincristine, not capped (1.1). We repeated the imaging studies, and patients who had an excellent response received consolidation therapy with high-dose cyclophosphamide every two weeks times three — very similar to the dosedense treatment with AC in breast cancer.

The long-term follow-up was published last year in the Annals of Oncology (Portlock 2004). In general, we were not enamored with the high-dose cyclophosphamide component, and at that time we were doing gallium scanning. Patients who still had gallium-avid disease after the doxorubicin-based chemotherapy rarely went into remission with cyclophosphamide.

Therefore, we developed a new strategy utilizing CHOP administered every 14 days. It was not an uncommon treatment program — it was also being studied in a German lymphoma study group. In general, we administered standard-dose CHOP every two weeks, and again we did not cap the vincristine dose. We administered growth factors, usually on days six through 10, and we found that the regimen was well tolerated.

The patients were a mixed population, but the long-term event-free survival was more than 60 percent. The regimen took only 12 weeks to administer, and at that time — in the pre-rituximab era — we considered using accelerated chemotherapy for all patients with diffuse large B-cell lymphoma.

DR LOVE: How was it tolerated in older patients?

DR MOSKOWITZ: We didn’t recommend it for older patients. However, in a landmark paper published in Blood last year (Pfreundschuh 2004), the German lymphoma study group reported that CHOP-14 administered for six cycles is the standard treatment, at least in Germany, for older patients with diffuse large B-cell lymphoma. It turned out to be the winner compared to CHOP every 21 days or CHOP with etoposide. So it’s well tolerated in the older patient population.

CD 1, Track 3-4

DR LOVE: When do you believe patients with lymphoma experience the maximum benefit from dose-dense chemotherapy?

DR MOSKOWITZ: We believe that if you can get the chemotherapy in on time at full dose, patients will probably derive the maximal benefit early on in their treatment. The definition of maximal benefit has been in a state of flux.

We are conducting a study at Memorial Sloan-Kettering right now that incorporates rituximab-based treatment, dose-dense chemotherapy, and ifosfamide/carboplatin/etoposide (ICE) chemotherapy in the up-front setting. In order to be eligible, a patient must have at least one risk factor in the age-adjusted International Prognostic Index: advanced stage disease, elevated LDH or a poor performance status.

With that background, we chose an induction regimen of R-CHOP administered every 14 days. We previously piloted that regimen and published those findings this year in Leukemia and Lymphoma (Halaas 2005). No difference appeared between the side-effect profiles of R-CHOP every 14 days and R-CHOP every 21 days. Once again, in a mixed population of patients, long-term event-free survival approached 80 percent with diffuse large B-cell lymphoma.

Thus far, our study has accrued approximately 60 patients. The primary endpoint was to bring ICE — which is currently the most common secondline regimen used in the United States — up front. We’ve administered it to almost 700 patients with aggressive lymphoma and Hodgkin’s lymphoma, and we believe it’s ready for prime time. So the standard treatment arm in this particular study receives R-CHOP-14 for four cycles followed by three cycles of ICE consolidation. In order to receive that treatment, a patient’s PET scan must be negative after R-CHOP-14 has been administered four times.

DR LOVE: What do we know about follow-up on patients from your study?

DR MOSKOWITZ: Of the first 60 patients, we had one patient who progressed on R-CHOP-14, so we have 59 patients left. Of the 59 remaining patients, 40 had a negative PET scan after the R-CHOP-14. Of those 40 patients, 36 patients remain progression-free. Only four patients who had a positive interim restaging PET scan progressed.

It’s interesting that the positive predictive value of an interim restaging PET scan at this time is poor — it’s in the 30 percent range. That means it makes no sense to change your treatment based on this interim restaging PET scan.

The other thing that’s interesting with this dose-dense treatment is that diffuse large B-cell lymphoma turns out to be more than one disease. The best way of thinking about it is that B-cell lymphoma derives from a certain cell within the lymph node — we call that the cell of origin. To simplify, B-cell lymphoma derives from either a germinal center B cell or a nongerminal center B cell. Among patients who receive CHOP chemotherapy for de novo diffuse large B-cell lymphoma, there’s evidence in the literature that those whose cell of origin is of the germinal center do much better than those whose cell of origin is of the nongerminal center (Hans 2004).

However, in this particular study, dose-dense, aggressive chemotherapy can overcome the prognostic significance of the cell of origin, so patients with nongerminal center-derived, diffuse large B-cell lymphoma have experienced exactly the same benefits as patients whose cell of origin arose from the germinal center.

Right now, the follow-up in the study is short — it’s only 18 months — but the event-free survival is 87 percent. It’s a 100-patient study, and we’re on patient 65. I am reluctant to present the data until we have accrued nearly all of the patients. Considering the accrual trend, I suspect the data will be presented during ASH 2006.

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