Evolving Treatment Landscape of BTK Inhibitors in B-Cell Malignancies - Episode 1
Steven P. Treon, MD, PhD: To diagnose Waldenström macroglobulinemia, it’s important to do a number of things. These are all specified very nicely in the NCCN [National Comprehensive Cancer Network] criteria, but you do need to do a bone marrow biopsy. This will allow one to be able to look at the morphology of the bone marrow to determine if a lymphoplasmacytic cell infiltrate is present. It also allows for the opportunity to do molecular diagnostic testing for both the MYD88 mutation as well as CXCR4. We know that both of these mutations are very important determinants of disease presentation and can help us also predict which therapeutics should be considered in the treatment of Waldenström.
In addition to that, we would want blood testing to be done. You’d want to be able to determine that there’s a monoclonal IgM protein. You’d want to be able to look at the serum IgM level, because this also could be very important in managing the patient given the concerns around hyperviscosity. You’d want to know what the CBC [complete blood count] looks like. You’d want to be able to get a prognostic marker like a beta-2 microglobulin level. And we would also, as part of the work-up, consider doing CT [computed tomography] scans of the abdomen, chest, and pelvis to determine whether extramedullary disease is present. We see that in about 20% of cases, even at time of diagnosis.
It’s very important when you look at the bone marrow biopsy of the patient to do molecular diagnostic testing, and MYD88 testing is essential. It helps us in being able to make the diagnosis of Waldenström, and it’s important for the clinicians to keep in mind. There are other things that can overlap that look very similar to Waldenström. Take for instance, IgM myeloma. We recently saw a very nice publication alluding to the fact that in MYD88 wild-type patients, in those who don’t have the MYD88 mutation, many times IgM myeloma cases were lumped in. They can have very similar disease features. And it’s really important to be able to separate those patients out because, of course, they’re managed very, very differently. So MYD88 testing is very important.
Also, CXCR4 testing. It’s a very important marker, in terms of understanding disease presentation. Those patients who have the mutation, particularly those who have the nonsense variant, that’s where part of the protein becomes truncated, usually present with high IgM levels and even symptomatic hyperviscosity. But also, CXCR4 is giving us a window into therapeutics that we ought to be considering for these patients, including the use of BTK [Bruton tyrosine kinase] inhibitors.
Imaging tests can be considered for Waldenström patients. One should consider them at the time of diagnosis to be able to understand if extramedullary disease is present but also at time of relapse, where it’s much more common to have extramedullary disease. We also have numerous cases of disease outside of lymph nodes, including the pleural space. So that would be done on a need-to-understand basis, when you have patients presenting with a particular symptomatology.
We also consider PET [positron emission tomography] scans in the management of Waldenström patients when we start suspecting transformation. So if you have a particular area that shows exaggerated tumor cell growth, like lymph nodes that are out of bounds in a particular regional area, it’s important to consider a PET scan to be able to rule out transformation, because those patients invariably will be treated very differently.
When you look at the diagnostic criteria for Waldenström, we take into account the MYD88 status, particularly when we start considering prognosis. Those patients who have the MYD88 mutation appear to do better. They have longer survival. In fact, the survival has changed tremendously given many new therapeutics, including BTK inhibitors that have been introduced. Over 18 years is now the median overall survival when one looks at the MYD88-mutated population, and that’s seen in about 95% to 97% of all patients.
Now this was a mutation that we discovered in our laboratory, thanks to whole genome sequencing. And about 95% of all the patients will have the L265P variant. This is where a leucine is actually substituted by a proline.
And whenever you see that, you’ve got to suspect that there’s going to be important structural changes to the molecule itself. So you can pick this up by using allele-specific PCR [polymerase chain reaction]. This is usually what’s done in most molecular laboratories. But a small percentage of patients will also have non-L265P-mediated variance. If you are working this patient up, and you find that the patient is wild-type, meaning that you don’t see the MYD88 mutation but have a strong suspicion for Waldenström, you’ve got to consider also these other variants that may be present. Because if you have a MYD88 mutation, it not only has important prognostic connotation but also helps you with therapeutics. BTK inhibitors, in particular, are good for those patients who have a MYD88 mutation.
We test for CXCR4 because it’s very important to be able to work this into the use of therapeutics and also to give you at least some idea of how those therapeutics ought to be used. For instance, with CXCR4 mutations we know that time to response with BTK inhibitors is going to be lagging. So if you have somebody who needs an immediate response, somebody with, let’s say, symptomatic hyperviscosity who you need to get their IgM done, you may consider an alternative therapeutic if somebody has a CXCR4 mutation and you’re looking to have a fast response.
We also know from the iNNOVATE data that was just updated at ASH [the American Society of Hematology Annual Meeting & Exposition] that the addition of rituximab may be particularly beneficial to that population of patients who are CXCR4 mutated. In fact, we see a much quicker time to major response. So understanding the underlying CXCR4 mutation status is very important.
We also now are recognizing more and more that TP53 mutations may also be important. This is seen in a small population of all Waldenström patients—maybe about 2% to 5% of all patients based on what we know so far—but these are usually patients that have more aggressive disease and seem to benefit with BTK inhibitors. So it’s important for one to be able to also consider TP53 testing when it’s available.
Transcript Edited for Clarity