Mark R. Litzow, MD: Rachel, can you tell us a little bit about maintenance therapy and what the current approaches are with that sometimes neglected component of therapy, what the current pediatric approaches are?

Rachel E. Rau, MD: The maintenance chemotherapy regimen that was employed by the vast majority of pediatric consortiums is a combination of 6-mercaptopurine [6-MP] and oral methotrexate. In the Children’s Oncology Group, we’ve also incorporated pulses of monthly vincristine and five-day courses of a corticosteroid. However, given that the Europeans don’t incorporate much, if any, pulses of vincristine and steroid, the Children’s Oncology Group [COG] recently studied if we could reduce the frequency with which we give those pulses. AALL0932 went from Q4 week pulses of vincristine and steroids to Q12 week pulses of vincristine and steroids and found that the outcomes were equivalent.

We have moved from every four-week pulses of vincristine and steroids on the backbone of 6-MP and methotrexate, to every 12 weeks. I think that’s a move in the right direction as well, taking out elements of therapy where while they’re relatively well tolerated, we see a fair amount of osteonecrosis secondary to steroids, hypertension, hyperglycemia, and long-term issues with obesity. I think it’s great that we can remove some of those elements that we’ve now demonstrated really don’t have a positive effect on outcome.

Mark R. Litzow, MD: Ryan, what’s your approach to maintenance therapy?

Ryan D. Cassaday, MD: Essentially the same. Most adult ALL [acute lymphoblastic leukemia] regimens, to my knowledge, have used a similar, if not identical, approach. POMP is sort of the classic four-drug acronym: prednisone, vincristine, methotrexate, mercaptopurine. One thing that I’ve borrowed to a certain extent from the pediatric experience is I certainly try to dose adjust the methotrexate and mercaptopurine, often up if I can, to try to maintain a certain level of mild cytopenias. I think the pediatricians have done a nice job studying that and showing some data to suggest that the chance of staying in remission with a strategy like that is better. It’s not necessarily a one-size-fits-all approach. That said, in my experience, it’s not uncommon for the patients to have dose reductions particularly early on, because they’re still recovering from all the myelosuppressive effects, particularly if it’s hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone], for example, and their blood counts take a while to recover. We start on mercaptopurine or methotrexate and they develop significant neutropenia. It sometimes takes a few months to get that sorted out, but once they’ve recovered, I try every month or so to reassess what their doses are and try to push them up a little bit. I sometimes joke with my patients that the perfect CBC [complete blood count] for a patient on POMP is a neutrophil count of about 1200/μL and a platelet count of about 120 x 10⁹/L.

Rachel E. Rau, MD: Yes, we aim for 500/μL to 1500/μL on the ANC [absolute neutrophil count] with our 6-MP dosing. Are you routinely screening for NUDT15 [nudix hydrolase 15] and TPMT [thiopurine S-methyltransferase] genotype?

Ryan D. Cassaday, MD: I’m not, because in my experience, I’ve seen a number of patients who are very susceptible to the effects of mercaptopurine, independent of those mutations. I find that screening doesn’t necessarily pick out all the patients who I’m going to run into trouble with. My approach is, I usually end up starting a little on the low end anyway, just because a lot of patients are still recovering from the effects of the more intense phase of their therapy, and then I let their blood counts be the guide.

Mark R. Litzow, MD: Rachel, you talked a little bit about late effects, and you and your colleagues have been very good about studying some late effects of this therapy and in trying to reduce it in patients where you can do that without compromising efficacy. Can you talk a little bit about what you in pediatrics are doing in terms of addressing late effects and tracking them?

Rachel E. Rau, MD: I think it’s been a good movement forward in the field that people are now paying attention to what happens to patients after we treat them. I think one of the big outcomes from that is a reduction of the use of cranial radiation for many of our patients. Even when I was in training, we were irradiating almost every patient with T-cell ALL, even some of those without CNS [central nervous system] disease at diagnosis. I think based on our experience, but more so experience from around the world, that’s probably not necessary in the vast majority of patients and obviously has a huge detrimental impact on the patient moving forward, patients who we’re very likely to cure. A few points reduction in your IQ isn’t the extent of it.

We know that they have higher rates of depression, lower rates of employment, lower rates of college attendance, higher anxiety, and other major quality of life impacting events that can probably be mitigated, at least to a degree, by the elimination of cranial radiation. Certainly, our replacement of intrathecal chemotherapy, while effective, probably has some toxicity of its own that we haven’t fully appreciated in the long-term setting. But I think we’ll learn more about that as we’ve removed more and more of the cranial radiation. Other long-term adverse effects are cardiovascular, so identifying patients who may not need that induction anthracycline has been an important step forward. Then cutting out steroids where we can prevents the obesity that also contributes to the cardiovascular disease that we see in our long-term survivors. While not my area of expertise, there are people who have studied this very intently, and I think now that we’re getting patients who are 20- to 30-year survivors of this disease, we’re learning a ton about the problems that they face later in life.

Mark R. Litzow, MD: Yes.

Jae Park, MD: AVN, avascular necrosis, I think is particularly challenging if you look at the number of patients, especially affecting more males than women there too. These are guys in their 30s and 40s, and these particular patients are in the prime of their lives, they’re very active. And then all of a sudden they experience AVN and are unfortunately dealing with how they can’t golf or do other things, they need a joint replacement. So I think these are challenging patients. I’m actually looking forward to the day that maintenance therapy could be shorter, and I’m actually glad to hear about some of the COG’s effort, trying to take some of the low-risk patients and reduce the length of the vincristine or the steroids for these patients. Then with these newer therapies, and of course some of the cellular therapies, hopefully we can move away from the maintenance altogether maybe someday. I think it’s a big issue that we sometimes don’t really think about.

Mark R. Litzow, MD: Yes, I have a 22-year-old patient who just had to have both his hips replaced. It’s a very common scenario.

Ryan D. Cassaday, MD: I would say in my experience, as much as I think it’s helped to incorporate some of the pediatric-inspired regimens in these adult patients, the thing that I’m seeing more of than anything else really is the avascular necrosis. I’d say I see a lot more of that in the patients who get those therapies, because they are so heavy-handed with the steroids in particular.

Jae Park, MD: We do check the vitamin D now. We do everything that we can to try to prevent AVN. It takes a village really to take care of these types of patients, particularly adolescent and young adult groups. I think there is a lot going on in their lives there too. And the compliance with the maintenance therapy is just as important to make sure they get a cure. It’s doable, but it takes some effort and we have to think about them and try to not forget about this bone health just hopefully to minimize this complication.

Mark R. Litzow, MD: There’s a whole field emerging of adolescent and young adult oncology that bridges pediatrics and the adult world. It’s been very exciting to see changes in that area.

Transcript Edited for Clarity