Does Chemotherapy Still Have a Role in the Treatment of FL?

Transcript 

I'm Bruce Cheson from Georgetown University Hospital, the Lombardi Comprehensive Cancer Center. I'm here today to talk to you about why we don't do chemotherapy anymore in the treatment of follicular lymphoma.

To do that, you need to reflect on the history of chemotherapy. Where did it come from? It came from World War I, World War II, when the Germans were dumping mustard gas on the Allied forces. What happened were horrendous complications on the soldiers, but serendipitously they found that they developed lymphocytopenia, shrinkage of lymph nodes and spleen.

To make lemonade out of lemons, Goodman and Gilman, Dameshek and Wintrobe, famous hematologists and biochemists of the day, took the mustard gas and developed a safer variant of it, nitrogen mustard injected into to lymphoma patients, and saw responses.

They were short, but it was the first evidence that you could actually treat somebody with a systemic agent and have their cancer respond.

These alkylating agents that we use today and are the backbone for many chemotherapy regimens are the derivatives of mustard gas with all the intended consequences of secondary malignancies, bone marrow suppression, etc.

Back several decades ago, this little drug called rituximab came along. It gave us the opportunity to start developing non-chemotherapeutic strategies. Back in 2004, we investigators in what was then the Cancer and Leukemia Group B started developing biological doublets.

We took rituximab and then we added an anti-CD80 called galiximab. Put it together. Got response rates in 80% to 90% of previously untreated follicular lymphoma patients. Some of these are durable to this day.

Our next study in previously untreated patients was rituximab and epratuzumab, an anti-CD22. We found the same thing, responses 80% to 90% of patients. Many of them durable.

We then were looking for another partner. This time we came upon lenalidomide, the second-generation immunomodulatory agent. We developed what we call R², this rituximab lenalidomide, or R².

We first tested it in previously treated patients with follicular lymphoma, relapsed patients, and compared it to lenalidomide alone and found a markedly improved response rate, complete response rate, and twice the event free survival.

We then moved this regimen up front as did a former fellow of mine, Nathan Fowler. We used R ² in previously untreated patients. We got response rates in excess of 90%, the vast majority complete remissions. These were very durable.

Now, 2 randomized trials have solidified the role of non-chemotherapy. There's the AUGMENT study of R² versus rituximab in relapsed/refractory follicular lymphoma.

That was so positive that it was granted FDA approval in that context. Then, the front line was the RELEVANCE trial, which was R² versus R chemotherapy, in which it's the most positive negative trial that we did.

It's negative because it was designed, unfortunately, as a superiority trial, but what came out was that R² and R-chemo had the same response rate, complete response rate, durable response at 30 months, progression free and overall survival, but with less toxicity in the R² arm.

Non-chemo regimens can be just as effective as chemo regimens. If you look at the plethora of drugs in development now, there isn't a single chemotherapy drug that is being developed and brought up through the ranks.

There are all these drugs targeting the cell surface, mnemonic funnel antibodies, by specifics, antibody drug conjugates, drugs that target the inner workings of the cell, the various pathways, BTK, Bi3K, BCL-2 inhibitors, and drugs that are affecting the microenvironment, the milieu. These are the immunomodulatory drugs, the checkpoint inhibitors.

Now, our role is to better understand the lymphoma so that we can put these drugs together in an intelligent manner and further improve the outcome of our patients using drugs that are not the derivatives of nasty mustard gas.

Thank you.