Venetoclax, Rituxan, and Bendamustine in Follicular Lymphoma

For this post, I'm doing a couple of things. I want to give another quick report on an ASCO Part 2 session, and I also want to report on some Follicular Lymphoma research. They are connected.

The ASCO part 2 session is called "Rise of the Combinations in Targeted Therapies." This session didn't have anything to do with Follicular Lymphoma, but it did talk about a general topic that is important to FL: combination therapies. This is the practice of using several different treatments instead of just one. Ideally, combinations work better than single agents. An example might be Rituxan in Follicular Lymphoma. As good as Rituxan might be on its own for some patients (like me), when it is combined with chemo like CHOP, it makes the chemo work even better. 2 + 2 = 5. 

Because of this, it seems like every new treatment goes through a trial on its own, but also goes through a bunch of combination trials. That not all of them work, but sometimes the combinations do a great job. (Like R-squared.)

The ASCO session was, frankly, a Cancer Nerd's dream. It got very heavily into the reasons why some combinations work and some don't. I won't get into the specifics because 1) none of it had to do with Follicular Lymphoma, and 2) I didn't understand a bunch of it. But even not understanding some of the details, the point was clear. Newer "targeted" treatments (as the title says) focus on pathways. For a cancer cell to grow and live, it needs to follow a certain path, with genes controlling enzymes that turn things off and on. By identifying the pathway, researchers can develop treatments that shut things off that are supposed to be on, and shut things on that are supposed to be off. It disrupts the pathway and keeps the cancer cell from growing and living.

The problem is, cancer cells are smart, and when a path is shut off, they can find a way around it. That's why combinations can work. If the new pathway is identified, then a second treatment can be given that shuts off (or on) the new set of switches that the cancer cell is relying on. A successful combination can shut off all those paths and keep the cancer cell from growing.

There's more to it than that, as I said, but that's essentially how it works. Imagine a city where construction projects keep closing off streets that you need to go down. Eventually, you just park your car and walk. (The car is cancer, in case you didn't follow that.)

One problem with combinations, though, is the potential side effects. While each individual treatment cuts off a pathway, it also does some damage, and with more than one treatment, that damage can add up. There's always a balance. That's why clinical trials test both how well a treatment works, and how safe it is. 

Which brings us to the new research on Follicular Lymphoma. It's an article from the journal Blood called "Venetoclax-Rituximab ± Bendamustine vs Bendamustine-Rituximab in Relapsed/Refractory Follicular Lymphoma: CONTRALTO." It's a report on a clinical trial called CONTRALTO that compares three combinations: Bendamustine + Rituxan (a very common chemotherapy combo), Venetoclax + Rituxan, and Venetoclax + Rituxan + Bendamustine.

Venetoclax is an inhibitor. It targets a protein called BCL-2, or B Cell Lymphoma-2. This protein prevents some cells from dying, and in some blood cancers, it can make some chemotherapies less effective. It is already used in Chronic Lymphocytic Leukemia, another slow-growing blood cancer. Seems like a good candidate for FL.

The results were mixed. Patients who received Venetoclax + Rituxan (there were 52 of them) had a Complete Response Rate of 17%. Patients in the Venetoclax + BR group (51 of them) had a 75% CR. Patients in the BR group (again, 51 of them) had a 69% CR rate.

However, while the treatment was more effective, the toxicity was much higher for the V+BR groups than the other two groups. almost 94% of patients had fairly severe side effects (versus 52% in the V + R group and 60% in the B + R group). More patients had to stop taking the V + BR group because of side effects than in the other two groups. 

The researchers think that playing with the BR dosing might help reduce side effects. They were encouraged, though, by the Venetoclax + Rituxan combo, and think it's worth studying more.

I thought this was a pretty timely example of both the positives and negatives of combination therapies. The triple combo was much more effect than the double combos, but also less safe.

And it's a good illustration of why it's so complicated to develop new treatments. That V + B + R combo seems great in theory: take an effective immunochemotherapy combination and add something that might make the chemo more effective. Alas, triple the treatments meant triple the potential side effects. 

My guess is that combos aren't going away any time soon. And as more clinical trials explore those combos, researchers will know more about how they work. So even failures can bring something worthwhile.