Relapsed/Refractory Waldenstrom Macroglobulinemia - Episode 6
Steven P. Treon, MD, PhD:My personal experience with ibrutinib in the relapsed/refractory setting is that it really exceeded all expectations from the moment we were doing the clinical trial. I think it’s best to relate it in terms of patients’ own stories. I had a patient who was on the trial, and, because of his disease, became anemic. He was very tired and had to give up doing things around his house. One of the things that he gave up was shoveling snow. Why that would bring personal joy to somebody is beyond me, but it was something that he really lived forto be able to take care of his own home. It was something that he wanted to get back to doing.
So he started on the trial and received ibrutinib. When he came back to see us just a month later his blood counts were so much better. His energy was back and he went back to shoveling his own snow. To him, this was a personal accomplishment.
When we reflect on activity of drugs, we sometimes get lost in the translation of what drugs are doing. We get so trapped in response rates and progression-free survival that we really forget that we’re transforming patients’ lives.
This is really at the heart and soul of what we experienced when we were treating patients with ibrutinib. We were giving them new beginnings and were changing their lives dramatically. What was really exciting in the trial was that even the number of prior lines of therapy didn’t impact our responses. If the patient was refractory to their last therapy, which is usually a bad thing, they were benefitting just as much as somebody who had relapsed. This was a different drug from all of the other drugs that we were using. It spoke to the fact that we were targeting the essential mutation in Waldenström, which is theMYD88mutation.
One of the things that was really exciting once we discovered this mutation was trying to figure out its signaling. When we saw that BTK [Bruton tyrosine kinase] was at the heart and soul of howMYD88was able to transactivate its growth and survival signaling, we knew that we finally had the opportunity to use a targeted approach to treat this disease.
In commenting on the unmet needs for patients with Waldenström, I think BTK inhibitors and our ability to optimize their use in Waldenström represents an exciting challenge. Because of the targeted nature of BTK inhibitors, we know that these are going to become a very important mainstay of treatment for Waldenström patients. Being able to optimize BTK inhibitors in patients who haveCXCR4mutations is one of the challenges that we’re working on. There are CXCR4 antagonists that are being developed, and we have a clinical trial right now looking at one of these in combination with ibrutinib inCXCR4-mutated patients. I think we can expect to see more of these antagonists become part of the mainstay of treatment for patients with Waldenström. It’s also important to recognize that it’s not just about BTK inhibitors. There are other drugs that are also impacted byCXCR4mutations. And so, being able to leverage this knowledge will probably end up aiding us in our ability to help patients with these mutations across the board.
I’m also very excited about venetoclax. This is another very important drug. We’re seeing activity for this drug in patients who have seen prior treatment with ibrutinib and other BTK inhibitors. We also know from a lot of the basic science work done in laboratories that the combination of these 2 drugs can actually enhance the activity of a BTK inhibitor. For this reason, we’re very excited about an upcoming trial that will look at combining venetoclax with ibrutinib in patients with Waldenström.
One of the big challenges that remains is understanding how to best treat patients who do not have anMYD88mutation. This represents about 5% of patients with Waldenström. Because of the genomic landscape work that we have just published on, we know that many of these mutations occur under BTK in the signaling cascades. Many of them are actually mutations that we see in aggressive lymphoma. So it gives us some idea of why these tend to be more aggressively presenting cases. And so, being able to develop targeted therapies based on this knowledge is an unmet need that we’re working on.
Transcript edited for clarity.
A 42-Year-Old Male With Relapsed/Refractory Waldenström Macroglobulinemia