DR. BOLLARD: Thank you very much, Dr. Lowe. I would also like you to discuss how ALCL differs between the pediatric and the adult populations, and how that dictates how you would treat those two patient populations.
DR. LOWE: So, ALCL really has a much shorter span in terms of its description pathologically. It was not described by itself until the mid 1980s. In the mid 1990s it started entering classification schemes. It wasn't until 2008 that the WHO separated out three distinct entities within ALCL. You have anaplastic lymphoma kinase (ALK)-positive ALCL, ALK-negative ALCL, and primary cutaneous ALCL. This is a great example where these three different entities have very different epidemiology, very different treatment strategies, and the fact that they are broken up has really helped move the field forward. For example, ALK-positive ALCL is really a disease of children, adolescents, and young adults. It's the most common ALCL by far in that age group. It's extremely rare to have an ALK-negative ALCL, and the pathological reason for the disease with ALK-positive ALCL is a translocation involving the ALK gene leads directly to oncogenesis.
Because of this, we have started to develop treatments that are designed to target this specific oncogenic driving translocation. This is in direct comparison to an ALK-negative ALCL, which is primarily a disease of older individuals, most commonly in their 50s and 60s. The outcome for this disease is consistently poorer than for ALK-positive disease. The treatment, while sometimes the same, is changing now that we have targets for the tyrosine kinase that is driving the ALK-positive ALCL. I think separating these two out has been a huge advantage in terms of figuring out what to do with pediatric ALCL because the 95 plus percent of ALCLs in pediatrics and young adults are ALK-positive.
Primary cutaneous ALCL is almost a completely different entity in and of itself, although it shares the same name. The primary cutaneous ALCLs are usually not treated on similar studies as the systemic forms of ALCL. The primary cutaneous form has different characteristics in terms of location, age, treatment, and natural course. The vast majority does not develop into systemic disease, and thus the treatment is very different. I think ALCL is a very good example where the different pathological entities have led to very different treatments based on what is driving the cancer.
DR. BOLLARD: Thanks, Dr. Lowe. I think that's very important to emphasize how ALK-positivity is more common in children than in adults, and the successes of crizotinib, even in phase 1 in pediatric patients with ALCL. My question now is given the success of this targeted agent in the relapse setting, even in phase 1, do you still see a role for allogeneic stem cell transplant for those patients who have relapsed after conventional therapy?
DR. LOWE: I do still see a role, but I'm not sure how much that role will shrink over time as we learn more and more about this disease. We know that there are very high risk patients that relapse or progress while receiving traditional chemotherapy. Those patients typically have achieved the best outcome with an allogeneic transplant. That said, I think crizotinib and other ALK inhibitors are changing the landscape of treatment for ALK-positive ALCL very fast. We know that some patients who are refractory to many other treatments go into remission with these drugs, and while I think that the role of allogeneic transplant is still there, I think that it may be changing over time. The other decision that I think will be difficult in terms of allogeneic transplant is for patients who receive ALK-inhibitors, like crizotinib, for initial treatment and then relapse. Many patients in that situation currently will end up having an allogenic transplant. However, one can argue that very much like chronic myeloid leukemia, these patients might be rescued without an allogeneic transplant using a second line ALK inhibitor. All of these things, obviously, we hope to know over time, but at this point in time are unknown.
DR. BOLLARD: Thank you very much. I'll take you out of the hot seat now. All of us talked about the concept of the importance of knowing the biology of what we're treating, and with the advent of novel targeted therapies, this concept of precision medicine is becoming increasingly important, ie, targeting the individual patient's tumor with the appropriate targeted agents for their tumor. This is maybe a question for Dr. Gross first, and then Dr. Cairo. What do you see are the challenges for being able to obtain the tissue from pediatric patients to perform these important and critical tests that will be needed as we move the field forward for the management of pediatric patients with NHL?
DR. GROSS: I think that the number one barrier is, as the technology improves to be able to make the essential diagnosis, we need less and less tissue for the pathologist. It becomes increasingly more of a challenge to obtain extra tissue because the standard of practice is to get just enough to make the diagnosis. Unless we can address this challenge, it's going to be extremely difficult.
DR. BOLLARD: Dr. Cairo, do you want to speak to that, since you recently completed a Children’s Oncology Group trial for Burkitt and diffuse large B-cell lymphoma?
DR. CAIRO: Thank you. I agree with Dr. Gross, and that particular trial, despite it being one of the primary objectives and also many of those patients actually had bone marrow involvement, which is the area that we access the easiest as the acute lymphoblastic leukemia colleagues have taught us. We still only were able to get 11 of some 90 patients entered on study, to have specimens sent. That being said, having just come back from the Fifth International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma, It appears that the Europeans have been much more successful in obtaining specimens for biology studies in particular, the future precision medicine-based trials. We should try to learn a little bit from our European colleagues, who seem to have a much higher percentage of getting specimens, and we need to make every effort, as Dr. Gross said of encouraging our colleagues, that this is as important as making the diagnosis. We face an uphill battle because of our high cure rate, the biology is often considered a second thought sometimes. Europeans are better than us at obtaining biological specimens and we need to compete to achieve the level that they have achieved in Europe.
DR. GROSS: It's almost a catch-22. We know from other diseases in pediatric oncology, but also in adult oncology, that once we are able to demonstrate that the biology will make a difference in the treatment and outcome of the patient, then we're able to get the tissue needed. I think a good example of that is neuroblastoma. However, we can't make those discoveries unless we get enough tissue to study. We're in this catch-22, we cannot demonstrate that the biology makes a difference, unless we will get the tissue for research.
DR. LOWE: I'd like to add one other point to this. I think the rarity of the diseases and the large number of centers that treat the patients also hinders obtaining pathological samples. Because pediatric NHL is a relatively rare disease, you can’t have a single champion for obtaining biology at one institution that can accomplish anything without many other institutions. It requires a large group effort which is more difficult than a single institution collecting colon cancer samples, for example, where you really only need one institution, one champion, one pathologist, and you have all the samples you need.