ALL: Cytogenetics and T-Cell Versus B-Cell Induction Strategies

Transcript:

Rachel E. Rau, MD: Ryan, what other cytogenetic abnormalities do you watch for or worry about in patients with newly diagnosed ALL [acute lymphoblastic leukemia]?

Ryan D. Cassaday, MD: There are certainly some that I keep an eye out for that I think do have important prognostic features, though I’ll admit that the likelihood that they independently would change my management is certainly less than the presence of the Philadelphia chromosome.

For example, high risk features that have borne out in terms of cytogenetic abnormalities, in adults at least, are things like complex karyotypes, hypodiploidy. Less well described in adults but certainly in pediatrics, is the intrachromosomal amplification of chromosome 21. It’s a relatively rare finding but is associated with relatively poor outcomes. So when I see these abnormalities in the cytogenetic reports that I get back, at least in my practice, I’m not typically changing anything about their treatment front, but I’ve certainly got my antenna up about keeping a really close eye on their response to therapy, maybe being a little bit more diligent in proactively thinking about stem cell transplantation. But for some of these abnormalities, my take on the data and my own clinical practice is if some of these higher risk features exist in the lucky subset of those who have a really good response to treatment and meet those milestones of early MRD [minimal residual disease] negativity and so forth, I’m usually still continuing on to chemotherapy and not referring them for transplant up front based solely on those abnormalities.

Rachel E. Rau, MD: Are there data to support that patients in those poor risk categories benefit from transplant?

Ryan D. Cassaday, MD: Not necessarily. I’m certainly familiar with some of the studies that just came out of the COG [Children's Oncology Group], and also St Jude Children’s Research Hospital, looking at the lack of benefit of transplant in patients with hypodiploid ALL. And I think that’s one thing I really struggle with personally, that allogeneic transplantation is a relatively blunt instrument. And oftentimes it’s relatively safe to jump to the conclusion that for a high-risk hematologic malignancy, transplant is what we should do. But the reality is for some of these subtypes we don’t really know that it’s going to be helpful. And I think studies like that help demonstrate that just because it’s a high-risk disease doesn’t necessarily mean a transplant is going to be a better option. But the reality is, particularly in adult patients with ALL, where salvaging these patients when they do relapse is a lot more challenging, we often will err on the side of overtreating, with the hope being that we’ll at least save a few of those relapses.

Jae Park, MD: But I think that’s really the trick question. We don’t have much data for the 4;11 translocation with hypodiploid patients. They’re usually MRD positive, but if they’re lucky enough to get early MRD-negative status, are they really high risk anymore? It used to be high risk before MRD was fully incorporated, before the era of the MRD-directed therapy.

So now with the better therapies that we have, it’s just like Philadelphia chromosome positive ALL where we used to be conducting transplants on more of these patients, but we really moved away from it because now we have better therapy. So I think these are the unanswered questions. There is a struggle when I say MRD negativity, should I be transplanting those patients? Younger patients, I agree, we tipped over to that a little bit. With the lack of data, I’m not quite convinced the transplant is really the answer for these patients. It will help most of the patients but, again, we really don’t have clear data, which makes it really challenging.

Ryan D. Cassaday, MD: I want to make sure that I double back and say, I omitted mentioning the 4;11 translocation or KMT2A [Lysine Methyltransferase 2A], formerly known as MLL rearranged disease. That is a challenging subset. That is actually a subgroup of patients where I typically am more inclined to recommend transplant up front, even for those who achieve early MRD negativity.

Mark R. Litzow, MD: I want to close this segment just by talking briefly about B-cell versus T-cell ALL. I think in the adult world, the main difference there is that based on the French randomized trial and a lot of historical data, we are incorporating rituximab [Rituxan] into induction therapy with our chemotherapy, particularly in patients who are CD20-positive. Although I always remember the pediatric study from Austria that showed they’re giving steroids upregulates CD20. So you can make an argument that everybody should get Rituxan. But we don’t tend to treat those patients otherwise much differently. And I wanted to have Rachel comment a little bit about your approach to B-cell versus T-cell ALL, because I think there are more differences in a pediatric world, as I understand it.

Rachel E. Rau, MD: Not so much. So in the Children’s Oncology Group we give our patients with T-cell ALL essentially the same backbone that we give our NCI [National Cancer Institute] high-risk B-cell ALL patients. Most other pediatric consortiums around the world actually enroll their T-cell and B-cell patients on the same trials and give them the same therapy with the more intensive induction and post induction therapies, so more in line with their higher risk B-cell ALL patients.

Very encouragingly though, we have been asking different questions in the Children’s Oncology Group for the last few iterations of clinical trials. And I think the nelarabine results from our AALL0434 trial were incredibly exciting. We’ve moved the patients with T-cell ALL into the realm of outcomes as our patients with B-cell ALL, which is quite remarkable. And so now we’re working on incorporating nelarabine as one of our standard chemotherapy agents for that particular disease. That being said, we know relapsed T-cell ALL is still almost impossible to cure; therefore, we’re looking for newer ways to prevent relapse in that population, so additional new agents are being considered to introduce them to the upfront population.

Transcript Edited for Clarity