Bruce D. Cheson, MD

Disclosures

December 23, 2011

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Introduction

Hello. I am Bruce Cheson, Deputy Chief of Hematology/Oncology and head of Hematology at Georgetown University Hospital and the Lombardi Comprehensive Cancer Center in Washington, DC. I would like to welcome you to this edition of Medscape Oncology Insights, coming to you from the 2011 Annual Meeting of the American Society of Hematology, which is being held in what should be sunny San Diego, California, but we are having hail and thunderstorms at the present time.

Radioimmunotherapy: Most Effective, Least Used

Today I would like to talk about a subject that isn't talked about very much lately, and that is radioimmunotherapy. To my surprise, there was almost an entire session devoted to this modality of treatment, which I have often referred to as the most effective, yet least used treatment in lymphoma.

Radioimmunotherapy is a conjugate between a monoclonal antibody and a radioisotope, and there are 2 approved for clinical use in the United States. These are Y 90 ibritumomab tiuxetan and I-131 tositumomab. These agents have been around for quite a number of years, and we are still trying to find their places.

Most use of radioimmunotherapy has been in the relapse/refractory disease setting, where response rates in the range of 60%-80% have been reported in the pre-rituximab era, with a substantial number of complete remissions (and a complete remission can last for years). I have had a number of patients who have been in remission 5-8 years or longer. At this meeting, though, there is interest in maybe moving the drug upfront [as initial therapy]. Why do we want to do this? It would be more effective, and we might have less of a risk for the untoward effect of greatest concern, which is secondary malignancies, particularly acute myeloid leukemia and myelodysplastic syndrome.

Good Responses and Long Remissions

At this meeting we saw a few studies. We saw a study from Italy[1] and a study from Tim Illidge in England,[2] looking at single agent use of radioimmunotherapy. Tim Illidge was using a fractionated method of giving the drug, and the Italians used another method, but the response rates were more than 90%, and many of these were complete remissions. The follow-up periods were relatively short. Patients do relapse; about a third or more relapsed in the Italian study just by a couple of years, and it is still too early to comment on the others.

These findings support data published by Mark Kaminksi a number of years ago in The New England Journal of Medicine,[3] with the I-131 compound showing a 95% response rate. Most of these were complete remissions, some lasted 5-10 years and longer, and the toxicity was minimal. The antibody is given by infusion, and there is a little myelosuppression that tends to be 4-6 weeks later -- it takes a few weeks to come back, but that's it. The whole treatment takes a week or 8 days. These studies suggested that it is a potential upfront therapy.

A Radioimmunotherapy "Chaser"

The Southwest Oncology Group (SWOG) and the Cancer and Leukemia Group B (CALGB)[4] conducted a clinical trial looking at the "chaser" concept, where you give chemotherapy and you consolidate it with radioimmunotherapy. This was a large study in which patients received either 6 cycles of rituximab-cyclophosphamide-hydroxydaunomycin-oncovin-prednisone (R-CHOP) for their follicular or low-grade lymphoma (which is what all these studies relate to) and this was compared with 6 cycles of CHOP, followed by the I-131 tositumomab. The rationale for this study was some very encouraging phase 2 data from SWOG, and now our group (CALGB) joined them in this large phase 3 trial. We found that progression-free survival and overall survival were pretty much the same. Of course, this raises a number of questions. If they are the same, which one is preferable? We are used to R-CHOP, but chemotherapy followed by radioimmunotherapy is now a viable option. The study had some issues. It was designed more than a decade ago, so now we would probably give R-CHOP and some people would use rituximab maintenance, and the other arm which was CHOP followed by radioimmunotherapy but now would probably be CHOP-R followed by radioimmunotherapy. Would that be better than CHOP-R alone? We don't know.

Another study that has been published by Anton Hagenbeek and Franck Morchhauser and their colleagues, was the FIT trial, which looked at chemotherapy. This wasn't presented at the meeting, but it has been published.[5] Patients who responded to first-line induction treatment were randomly assigned to the Y 90 compound vs. observation. There was a significantly prolonged progression-free survival, comparing the radioimmunotherapy treated patients with the observation patients, but no survival benefit. Would we have gotten the same bang had we delayed the radioimmunotherapy until first relapse? We won’t know.

At this meeting there were some other relevant presentations. Nathan Fowler, my former fellow, currently at MD Anderson, looked at their data with the FMD (fludarabine, mitoxantrone, dexamethasone) regimen with follicular lymphoma, followed by radioimmunotherapy.[6] They had interesting results, but given the fact the FMD regimen by itself was associated with around a 5% risk for secondary malignancies, it remains to be seen whether adding radioimmunotherapy to that regimen (which pretty much no one uses anymore) will increase that problem. It is interesting because in the Mark Kaminski study that I mentioned above, the I-131 tositumomab by itself didn't seem to result in secondary leukemias and myelodysplasias, but in other studies, whenever you combine it with chemotherapy, whether it's fludarabine or cyclophosphamide, vincristine, and prednisone (CVP) you start to see increases in secondary malignancies.

Finally, there was a meta-analysis[7] which is relevant to this consolidation concept. In this meta-analysis they tried to compare the outcome with the radioimmunotherapy consolidation vs. rituximab maintenance strategies, and the suggestion was that there was no disadvantage to either way of doing business.

Barriers to Radioimmunotherapy Use

We are left here in a quandary as to how to best use radioimmunotherapy. It is a very good treatment for relapse/refractory disease and I use it occasionally, but there are a number of reasons why it doesn't seem to be used -- it is expensive, not everybody has access to it, the concerns for secondary malignancies, the availability of clinical trials, the availability of novel agents such as bendamustine and rituximab (which seems like it would be more effective), and the restricted eligibility criteria. So, it is available and it's a good option, but how do we move it up front? Will it ever be a standard drug alone? Will it take over in a consolidative role as people rehash Ollie Press' SWOG study? I don't know. It remains to be seen. We need to better scrutinize these data to determine whether radioimmunotherapy will play an important role in the initial treatment of patients with follicular and low-grade non-Hodgkin's lymphoma.

Conclusion

This is Bruce Cheson for Medscape Oncology reporting from the ASH 2011 meeting. Thank you for your attention, and I hope to be speaking with you again in the near future.

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