Rationale for Trial
Scheduling of Rituxan
Role of Rituxan and CHOP in Lower-Grade Lymphomas
Other Biological Therapies for Patients in Remission
Antibody Therapy for Patients not on Clinical Trials
Data from Phase II Trial
 

GREG BERK, MD: Hello, my name is Dr. Greg Berk of Cornell University Medical College. I am pleased to have Dr. Julie Vose, Clinical Professor of Medicine at the University of Nebraska Medical Center here today to discuss an overview of the recent CHOP Rituxan phase III clinical trial. Welcome, Dr. Vose.

JULIE VOSE, MD:  Thank you.

GREG BERK, MD:  Dr. Vose, can you start by giving us a little background of the rationale for this trial?

JULIE VOSE, MD:  Certainly. Patients with diffuse aggressive lymphoma, when treated with standard CHOP chemotherapy, typically have complete response rates, usually about 60 to 70 percent of patients. If we look at overall outcome, usually five-year survival is about 45 percent. Obviously that's good, but it's really not good enough. We're trying to look at ways to improve those outcomes, in particular in the high-risk patients.

This trial is based on some preliminary data, which I'll discuss a little bit later, that added Rituxan to the CHOP regimen. The preliminary data looked sort of exciting and so we've decided to take it on to a large randomized phase III trial to see if Rituxan could add anything to the CHOP regimen for high-risk patients with diffuse aggressive lymphoma.

GREG BERK, MD:  Thank you. The eligibility of patients for this trial, is this strictly dependent upon the presence of CD-20?

JULIE VOSE, MD:  The patients do have to have diffuse aggressive B cell lymphoma, so most of those patients would be diffuse large cell according to the WHO Classification. They do have to have CD-20 positivity, which almost all B cell aggressive lymphomas do. They have to have an International Prognostic Index greater than or equal to 2, which is low-intermediate on the non-age adjusted index, bulky stage II, III, or IV disease and then some other criteria that we typically use in protocols, such as no CNS lymphoma, no HIV-associated lymphoma, and no intercurrent illness.

GREG BERK, MD:  Right. Julie, this is a randomization between CHOP versus CHOP Rituxan.

JULIE VOSE, MD:  Correct. It's a one-to-one randomization. Patients receive six to eight cycles of CHOP versus six to eight cycles of Rituxan plus CHOP. The Rituxan is given as 375 mg/m2 on day one and the CHOP is given as standard doses starting on day three of each cycle.

GREG BERK, MD:  Can you discuss the rationale for that scheduling of the Rituxan that is concomitant therapy versus sequential?

JULIE VOSE, MD:  We did it that way in the phase II trial so that’s what we have piloted and have taken it forward in the phase III trial. The rationale behind that is somewhat based on some laboratory work that demonstrated that Rituxan can chemosensitize lymphoma cells to the effects of chemotherapy. Based on that initial information is why we chose this particular regimen to give it as a chemotherapy sensitization agent in addition to potentially an active treatment in itself.

GREG BERK, MD:  Can you give us a little background, Dr. Vose, on the role—not to diverge too much—but the role of Rituxan and CHOP in lower-grade lymphomas?  This is a little bit more established at this point.

JULIE VOSE, MD:  There has been a publication by Myron Czuczman looking at a slightly different regimen.  They gave Rituxan for two doses and then CHOP after that and interspersed the Rituxan and then two doses of Rituxan at the end.  That did show very good complete response rate and with a short amount of follow-up, patients are alive and free of disease in many of the cases.  So that is a little bit longer follow-up compared to what we have in the phase II trial with this regimen.  But as you know, patients with indolent lymphoma one really needs very long follow-up and obviously randomized trials to know if that’s any better than CHOP alone.

GREG BERK, MD:  Another issue that I'd like to bring up is you had obviously addressed the importance of improving the durability of what is pretty much very good responses to initial CHOP, but the problem with relapses and the essential treatment of minimal residual disease.  Aside from a patient going on a trial like this to determine if adding Rituxan is of benefit, are there any other—I know there isn't any established therapies for patients who have already achieved a complete remission on CHOP, but are there any other biological therapies that are being looked at once patients are in remission for consolidation with diffuse large cell lymphoma?

JULIE VOSE, MD:  There are some other clinical trials where Rituxan is used after CHOP chemotherapy, for example, in a trial that's been in the cooperative group. Patients receive randomization to CHOP versus CHOP plus Rituxan. Then they're randomized after that to Rituxan maintenance versus no maintenance. That's another area that's being looked into.

In addition, there has also been some trials looking at the radiolabeled antibodies following either CVP chemotherapy or CHOP chemotherapy or fludarabine chemotherapy for mostly indolent lymphomas. Then there are also some trials looking at interferon. Again, those are mostly for the indolent lymphomas and not so much for the aggressive lymphomas.

There are also some immunotherapy trials looking at vaccines post-CHOP chemotherapy for aggressive lymphomas. There is just a small phase II study with that going on right now.  Several small pilot trials, but nothing that's been established.

GREG BERK, MD:  It may become a little bit more confusing for the average practicing oncologists in the community when he may very well in the near future have a choice of different antibodies available. Like you said, Rituxan is already out there, but Bexxar may be right around the corner and some other radiolabeled antibodies as well. How is the practicing oncologists going to make a decision about which one he may use in this kind of setting for a patient who may not be eligible for clinical trial?

JULIE VOSE, MD:  To be honest, for patients with aggressive lymphomas, the role of these antibodies has not been well-established. I would say that I would not recommend these antibodies for patients with aggressive lymphoma off a clinical trial. I don't think that's appropriate at this time.

GREG BERK, MD:  Right. I didn't have any other questions, Julie, unless you wanted to make a few other comments specifically on the phase III trial.

JULIE VOSE, MD:  I think I might just give a little bit of data on the phase II trial with aggressive lymphoma that was the basis of this.

GREG BERK, MD:  Sure.

JULIE VOSE, MD:  That was 33 patients with diffuse aggressive lymphoma, received CHOP plus Rituxan as I outlined. This was done at five large referral centers. It was done several years ago so now we have at least two years minimum follow-up on all patients. At this time we have 29 out of the 33 patients who are alive and no evidence of progressive disease. It was very encouraging with that. That was what really took us forward to do the randomized trial.

The randomized trial is ongoing at a number of different centers. It's actually an international study. It has 210 patients per arm, so it is a very large study. I would really encourage everyone to participate in this trial.

GREG BERK, MD:  Is this a pharmaceutical-company-sponsored study or a cooperative group study?

JULIE VOSE, MD:  There are some cooperative group studies that are different. The study that we're talking about today is a Genentech sponsored study. Yes.

GREG BERK, MD:  I see. Lastly, in the phase II trials, did they have immunoblastic included in this or not?

JULIE VOSE, MD:  Yes. There would have been some. According to the Working Formulation Classification, there would have been some immunoblastic as well. Yes.

GREG BERK, MD:  But mantle cells were not included?

JULIE VOSE, MD:  Mantle cells were not included.

GREG BERK, MD:  I see. I don't mean to diverge too much from large cell. But many of us are using Rituxan in mantle cell lymphoma because of the significant risk associated with that pathologic subtype. Do you have any comments on that?

JULIE VOSE, MD:  Again, I think that the role is not well-established in clinical trials and I basically wouldn't treat a patient with that outside of a clinical trial.

GREG BERK, MD:  I see. Okay. I really very much appreciate your comments today, Dr. Vose. Once again, thank you very much.

JULIE VOSE, MD:  Thank you.
 

For more information about this clinical trial, please call 1-888-662-6728.