Mark R. Litzow, MD: Ryan or Bijal, could you comment about T-cell ALL, some of the subcategories there, and your sense of the initial assessment of those patients?

Ryan D. Cassaday, MD: I think there are certainly some molecular factors that are perhaps involved in prognosticating with T-cell ALL. The French group has looked at this and has identified a 4-gene panel that involves either the presence or absence of mutations of these different genes. It’s a little cumbersome from a clinical perspective, because not a lot of labs are able to routinely test for these. So, it’s not clear to me how routinely it can be used in clinical practice, but it may be something where as our technologies improve, these could be utilized further. Unlike the Ph-like story—which is definitely an evolving and interesting one, but it is really more a phenomenon of B-cell ALL—we’re still a little bit behind the curve in terms of understanding some of the really important biologic risk factors in T-cell ALL, I think.

Bijal D. Shah, MD: Yes, I’d agree. I will push back a little. I do think it’s along the same lines as B-cell ALL to try and pick up on those NOTCH, RAS, and PTEN mutations. I do think that it was the GMALL (German Multicenter ALL Working Group) experience that demonstrated that opposed to MRD alone, while it does predict for the risk of relapse, if you include this genetic risk assessment you get a broader sense of who’s likely to fare poorly. And so, we do try to build both MRD and genomics into the risk stratification for all the reasons I mentioned before.

Taking a step back, anecdotally, what we see is a lot of these mutations tend to accumulate in this early T-cell precursor subgroup. We tend to see particularly RAS mutations in that category of patients. Early T-cell ALL thus far has been defined by flow cytometry. And so, we’re looking principally for a CD4, CD8-negative population with a dim CD5 and the presence of these myeloid antigens like CD33 and CD34. This has been the tool that we use. We, again, are going to approach the early T-cell precursor patients with the same sort of very close observation that I would say we would do for a Ph-like patient. This is the patient who I may be more apt to get an MRD estimate for early, but also repeated, for example, after consolidation.

Aaron C. Logan, MD, PhD: It’s probably worth noting that like B-cell ALL, this is a scenario where the immunophenotype up front can be particularly useful if you identify the early climbing precursor phenotype, although there are some controversial data about how prognostic that it is. I think in COG studies that has been used in the past as one of the branch points for different types of therapy. In the adult medicine world, we have not implemented different therapies, but I would agree with closer monitoring for MRD because they may have a higher likelihood of failure.

Bijal D. Shah, MD: And slower clearance of MRD as well.

Mark R. Litzow, MD: It’s interesting that some of those patients can have a FLT3 mutation. They can have some features that would suggest some myeloid characteristics, so I think it is a challenging group. What is our sense, Aaron, in those patients—the early thymic precursor patients—as to whether they have a poorer prognosis or not? I think there has been some controversy about that.

Aaron C. Logan, MD, PhD: There has been some controversy. I think my read of the literature is that there are enough studies that have called into question whether this immunophenotype carries a high risk that I’m worried about it. I’m worried about the lack of clearance of MRD, which, as we’re going to talk about, is probably one of our major goals with therapy for ALL. And so, as a transplanter, I need to make a decision: Am I going to transplant this patient or not? One of the major criterion that I’m going to use is whether they achieve MRD negativity by some of the milestones that we talk about. I think that the ETP patients are at higher risk of failing those milestones. And so, while as a transplanter I get every patient potentially ready for a transplant, I’m certainly looking really hard for a donor for an ETP patient, just in case.

Transcript Edited for Clarity