Medical Roundtable: Pediatric Non-Hodgkin Lymphoma (NHL) Classification Guidelines - International Pediatric NHL Staging System (IPNHLSS)

Moderator: Catherine Bollard, MD, FRACP, FRCPA¹

Discussants: Mitchell S. Cairo, MD²; Eric J. Lowe, MD³; Thomas G. Gross, MD, PhD⁴

Address for correspondence: Catherine Bollard, MD, FRACP, FRCPA, 111 Michigan Avenue, NW, 5th Floor Main, Suite 5225, Washington, DC 20010

E-mail: cbollard@cnmc.org 

Biographical sketch: From The George Washington University, School of Medicine and Health Sciences, Washington, DC1; Westchester Medical Center, New York Medical College, Valhalla, NY2; Children’s Hospital of the King’s Daughters, Norfolk, VA3; Center for Global Health at the National Cancer Institute, Rockville, MD

DR. BOLLARD: My name is Dr. Catherine Bollard. I'm Chief of the Division of Allergy and Immunology at Children's National Health System and the Chair of the NHL Committee of the Children's Oncology Group. I hope that today we can provide some clarity and give you some of our first-hand expertise and experience regarding some of the challenges and controversies of treating pediatric patients with non-Hodgkin lymphoma (NHL). Here with me are Drs. Mitchell Cairo, Chief of Pediatric Hematology/Oncology and Stem Cell Transplantation at New York Medical College in the Maria Fareri Children's Hospital, Westchester Medical Center; Eric Lowe, Division Director for Pediatric Hematology/Oncology at the Children's Hospital of the King's Daughters; and Thomas Gross, Deputy Director for Science at the Center for Global Health at the National Cancer Institute.

I'd like to start the questioning, firstly to Dr. Cairo, who recently published with a group of leaders in the pediatric lymphoma field, new staging and response classifications. Dr. Cairo, I’d like you to highlight how these are different from the current classifications, and what you see are the strengths and the limitations at this time.

DR. CAIRO: Thank you, Cath. The original staging classification was developed in the late 1970s by Dr. Murphy while she was at St. Jude's hospital, and either goes by the name the Murphy Staging Classification or the St. Jude's Classification. That classification I think was quite useful at that time when we recognized really only a couple subtypes of NHL, as well as the capabilities we had in those days both imaging as well as further molecular identification as well as trying to identify sites of spread. As some 35 years have evolved, new pathological entities have been identified, much more precise imaging techniques, new methods of detecting more evidence of minimal disease, and also identifying new organ sites of involvement, allowed the creation of a multidisciplinary international task force to look at how we could enhance the original observations by the St. Jude's group.

As Dr. Bollard pointed out, we eventually, over 9 years of evidence-based review, came up with an enhanced staging classification called the International Pediatric NHL Staging System (IPNHLSS).¹ In this new system we account for new histological subtypes, allow for different organ distributions, improve on the new imaging techniques to identify areas of involvement, and also to more molecularly identify extent of disease. I think the advantages are stated above. The disadvantage is that like all staging systems it's a breathing document. It will require international collaboration. As time evolves, this staging system will of course need to be updated as we gain new experience.

Briefly, in terms of the response classification that also came out of the same international multidisciplinary task force that was led by Dr. Sandlund at St. Jude's²; there had never been a response criteria that had been focused entirely in childhood and adolescent NHL. The previous response criteria had been developed by adult NHL investigators, and there was a need to develop the first response criteria for pediatric NHL because of different histologies, different sites of sanctuary disease, and now obviously enhanced imaging capabilities. That also now has been named the International Pediatric Non-Hodgkin Lymphoma Response Criteria (IPNHLRC)—hopefully for harmonizing a response across new studies, but also a breathing document that is going to be limited as we gain new knowledge into how we can better assess response as new techniques are developed.

DR. BOLLARD: I thank you very much for your detailed response. My next question is actually to Dr. Gross, who is currently chairing the international study for upfront diffuse large B-cell lymphoma and Burkitt lymphoma in pediatric young adults. I would like you to speak to a couple of issues, and you can put it in the context of the current randomized trial, looking at rituximab vs no rituximab for this disease. I think firstly it would be useful for you to speak to the implications of this new classification system as we go forward with choosing new therapeutic strategies for these patients, and in particular I'd like to focus on the newly diagnosed diffuse large B-cell lymphoma patients who are in that adolescent/young adult range.

I would also be interested in your opinion regarding how you would manage a patient who is 17 years old but is going to turn 18 tomorrow, and he comes to you with newly diagnosed diffuse large B-cell lymphoma. As you know, the adult oncologists treat diffuse large B-cell lymphoma different to Burkitt lymphoma, and in pediatrics we generally treat these diseases the same. Do you tell this patient that you will treat him today on a pediatric regimen, or do you tell him to go tomorrow, when he's 18, to be treated by an adult oncologist? I would like you to justify your answer please.

DR. GROSS: First to discuss the implications of the new staging as it applies to the current international trial. As Dr. Cairo pointed out, this was developed through a literature review and evidence based analyses, but like any new staging system, the value of staging is to provide us with information that can try to help us to identify patients to improve their outcome. Essentially, staging is to help direct therapy or provide prognosis for outcome, and the only way to do that is to test new systems or classifications in a prospective fashion. Indeed, that is what we are trying to do with this international effort.

This international effort, just as an aside, illustrates one of the challenges of all rare cancers, but particularly pediatrics. In pediatric mature B-cell NHL, both large-cell and Burkitt, we are now at a cure rate of about 90%. To make advances, we don't have enough patients seen in North America and Australia, and it requires international collaboration. This trial, to get 600 patients randomized, it will take 7 years with 14 countries participating—that is one of the challenges, certainly, we have with pediatric NHL. Also, we want to try to gain as much information as possible, not just to the effect of rituximab as Dr. Bollard said, but also to test other questions such as the role or the value in validating this new staging system.

To talk about the controversy of treatment, certainly we know that there is a very different approach in pediatrics. For many years, we have treated diffuse large B-cell lymphoma just like Burkitt. This is a very important delineation when you're seen by a medical oncologist because the treatment for diffuse large B-cell lymphoma is outpatient therapy, ie rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP). Treatment for Burkitt is inpatient with high doses of methotrexate, but other higher doses of the same agents used to treat diffuse large B-cell lymphoma. The question is, do we really need to treat all the pediatric diffuse large B-cell lymphoma with these aggressive Burkitt regimens? I think one of the things that is encouraging to me as a pediatric oncologist is that we are beginning to learn that the biology is very different. Though the disease looks the same under the microscope or by flow cytometry, when you look at it genetically it's quite different. We know now that the younger the patient is with diffuse large B-cell lymphoma, even though it looks for all intents and purposes like the same disease as seen in adults, when you look at the genetics, many times, as high as 30% of the time, it will be genetically the same as a Burkitt lymphoma. I think when you're talking about young patients we can easily justify treating them both the same because the biology would suggest that a good number of patients would need Burkitt therapy to be cured.

Now, that changes over time, so that it appears that sometime in young adulthood, maybe somewhere between 25 and 35 years of age, you don't see the genetic disease that looks like diffuse large B-cell lymphoma, but is genetically Burkitt lymphoma. As for the 18-year-old patient that Dr. Bollard was posing to me, I've had several patients like this. I go through the pluses and minuses of the therapy, inpatient vs outpatient, but also the potential long-term side effects. The outpatient therapy has potentially more long-term side effects as far as potential infertility and potential heart damage. Every time I have given the choice to the family and the patient, the teenager has always chosen the outpatient therapy that you would get as an adult, and the parents always say they would rather have the inpatient therapy, and that spending a couple of days in the hospital to try to reduce the chance of long-term damage is their choice. It's a very interesting dynamic and I think sometimes the issues that go into choice of treatment are quite variable. My personal opinion is that hopefully in the future we will be able to have a better understanding of biology, so that when we see these patients, be they 18 or 25 years old, we're not looking at what it looks like under the microscope or who they see, and what they're used to giving, but the biology will determine which therapy is more likely to cure them. Right now we don't have that ability in most of the patients.

DR. BOLLARD: Thank you, Dr. Gross. Again, another very comprehensive answer to a difficult question. I'm actually going to push this back to Dr. Cairo and then impose the same soon to be 18-year-old patient to you. This time, he's coming to you with relapsed diffuse large B-cell lymphoma. What are you going to tell him? Are you going to treat him today on pediatric protocols, or will you wait until tomorrow when he could have access to adult protocols?

DR. CAIRO: I think the results are relatively similar, but, in part, the answer to the question is of course based on what their original therapy was. If the original therapy was the pediatric-inspired type of treatment, I think there's a world of experience of what are some of the best pediatric-inspired regimens to use for retrieval. If, however, the original therapy was an adult-inspired regimen, then I think the options are open because the disease may not be as resistant in that setting; therefore, one would want to consider all the adult type of retrieval regimens in that case, because that group of patients—at least in the adult experience—tend to have disease that may be more responsive because they're not as resistant to the higher dose and multi-agent therapy that a pediatric-inspired regimen would have given them had they been treated that way.

DR. BOLLARD: I was also trying to ask you to speak to the access that an 18-year-old might have to novel therapies that a 17-year-old might not. How do you address that issue?

DR. CAIRO: That's an excellent question. I think that for first relapse or first induction failure most of the retrieval regimens, the first line regimens, that are available, either pediatric inspired or adult inspired, probably don't require an investigational agent that an 18-year-old might have access to if he was being treated on an adult type of regimen. However, I would strongly encourage an 18-year-old who failed one retrieval regimen to consider experimental therapy. There I think the access to new agents—if you're 18 or over—are so much greater that I would encourage them to be treated on an adult retrieval regimen, where some of the newer agents may be investigational, are not available to a pediatric program.

DR. BOLLARD: Thank you very much, Dr. Cairo. I have one last question on the B-cell diseases before I move to Dr. Lowe, and the last question goes to Dr. Gross. Would you recommend that a patient with relapsed Burkitt lymphoma—now increasingly rare—be treated with salvage chemotherapy and then autologous transplant or allogeneic stem cell transplant?  

DR. GROSS: As the others on this discussion know, we performed an analysis from data in the Center for International Blood and Marrow Transplant Research (CIBMTR), and the problem is that Burkitt lymphoma tends to reoccur so rapidly after transplant. The median time to relapse is 3 months after transplant. We could not find a difference in the outcome between autografts and allografts because of its early reoccurrence. That said, my personal opinion is, since we know that Burkitt lymphoma is a hematologically spread disease, that I always prefer a donor source where I know they're not going to have tumor cells in them, which is an allogeneic donor. I always prefer an allogeneic donor, because I know it's tumor-free, but also it gives us an opportunity, if the disease will stay under control long enough, to potentially get an immune response against any residual tumor. For that reason, I recommend an allogeneic donor if it can be found readily.

DR. BOLLARD: Thank you very much, Dr. Gross. Now, on to Dr. Lowe, and Dr. Lowe's particular area of expertise is in anaplastic large cell lymphoma (ALCL) and T-cell diseases. I was wondering if you could explain to me the difference between T-cell lymphoblastic lymphoma and T-cell acute lymphoblastic leukemia (ALL), specifically since the World Health Organization (WHO) groups these two disease entities together as T-lymphoblastic leukemia/lymphoma. If you could clarify that classification that would be very helpful.

DR. LOWE: As you well know, many physicians believe that T-cell lymphoblastic leukemia and T-cell lymphoblastic lymphoma are very similar diseases, but they are not exactly the same disease although we sometimes treat them very similar. We know that T-cells do not mature in bone marrow but rather they are thymic driven cells. Because of this, there are distinct differences between the leukemia and lymphoma. For example, we know that the genetics between the two—although in limited samples—are not always the same, including in prognostic. Just one example, loss of heterozygosity at 6Q has been shown to be prognostically important in lymphoblastic lymphoma but not in T-cell ALL. I think the real challenge is to figure out what the differences are. I think we could argue that potentially, T-ALL is stage four T-cell lymphoblastic lymphoma.

I think that the WHO classifying the two diseases as one entity with T-lymphoblastic leukemia/lymphoma has hindered a little in the advancement of recognizing the differences in that many people assume that they're the same disease. When you look up from a pathological standpoint and you say, well, they're clearly the same disease because they're listed as a single entity, and when you look up treatment, you say, well they're treated very similar, so they must be the same disease. I think that does us a little disservice in trying to advance the field forward, because I think getting lymphoblastic lymphoma samples, which is challenging, is extremely important to determine the genetic drivers of this disease.

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.

DR. BOLLARD: Thank you, Dr. Lowe. I really thank you all for speaking in a very detailed way about the importance of obtaining tumor tissue to perform these critical biologic studies, because I do feel that's an important issue to overcome for the future care of our pediatric patients with NHL. I would like to discuss late effects in our survivors. As Dr. Gross said, survival rates for patients with B-cell lymphomas are generally outstanding. Dr. Gross, do you feel that late effects are not something the NHL group has to worry about now that we have obviated the need for radiation, or not? And what are your feelings about trying to minimize these late effects even further?

DR. GROSS: The good news is that over time, we have been able to come up with regimens that are highly effective but have reduced the agents we know have the highest risk of late effects—radiation being the primary one, but also anthracyclines we have been able to reduce in the vast majority of the patients, and to keep alkylating agents in the vast majority of the patients to a level that most patients do not have infertility. The long-term side effects are becoming pretty minimal, but the question is, how low do they have to be to be acceptable? The goal would be cure without any long-term effects. As I said before, certainly we have paid the price in short-term effects. Our regimens are inpatient, and they can have quite severe short-term side effects such as mucositis. We've made great advances but I think there's still room to go.

DR. CAIRO: I agree, of course, with my colleague Dr. Gross. Again, when we look at large series of chronic health care conditions, certainly children with treated NHL still comes up as one showing over 40% to 50% of patients having one or two serious chronic health care conditions. We know the data are a little antiquated, because they include patients who were treated with different regimens in the 1970s and all of the 1980s. However, I think our goal continues to be to identify the most effective treatment regimen, but with the least toxic long-term complications for our patients. That struggle is very difficult because of the very high success rate we have today, and to identify without hurting that high success rate less toxic therapies will require a collaborative, multidisciplinary, international effort to reach that goal.

DR. BOLLARD: Thank you very much Drs. Cairo and Gross. Dr. Lowe, did you have any closing remarks on the late effects issues for the T-cell mediated diseases in particular?

DR. LOWE: I would absolutely agree with Dr. Gross and Dr. Cairo that this is an important issue. I think we in pediatrics do a good job at following our patients for long-term side effects and creating guidelines for screening for these long-term side effects. That said, I think as we start to talk about better and better therapy and even more and more targeted therapy, what we don't know about some of these targeted therapies is their 15 and 20 year long-term side effects. We obviously hope that there aren't any, and that's why we are moving toward these drugs, but again, surveillance of those long-term side effects will be extremely important, especially when you're talking about medications for young children.

DR. BOLLARD: I'd like to thank you all very much for participating in this expert roundtable discussion today. I think the overarching points are that prognoses at the current time for newly diagnosed pediatric patients with NHL range from 70% to over 90% even for patients with disseminated disease. The challenges that we need to overcome are how we can optimize our up front treatment to prevent relapse in all, because I think we've all reiterated the fact that the outcomes for those few patients who do relapse remains extremely poor. I think there is still controversy about how to manage patients with relapsed disease, and how to temper our therapies against long-term side effects of our surviving patients. Finally, I think with the advent of novel targeted agents, it is incredibly important for the optimal management of our current and future patients that we are able to access tumor tissues and perform the critical biologic studies that are required to develop an effective precision medicine approach for pediatric patients with NHL. I would like to again thank Dr. Cairo, Dr. Gross, and Dr. Lowe for their excellent answers to my, at times, difficult and challenging questions and I would like to thank the organizers of this expert roundtable discussion. I hope that in the next decade that we will see even greater advances for the patient population that we treat. Thank you very much.

References

1. Rosolen RA, Perkins SL, Pinkerton CR, et al. Revised International Pediatric Non-Hodgkin Lymphoma Staging System. J Clin Oncol. 2015;33(18):2112–2118.

2. Sandlund JT, Guillerman RP, Perkins SL, et al. International Pediatric Non-Hodgkin Lymphoma Response Criteria. J Clin Oncol. 2015;33(18)2106-2111.

Moderator: Catherine Bollard, MD, FRACP, FRCPA¹

Discussants: Mitchell S. Cairo, MD²; Eric J. Lowe, MD³; Thomas G. Gross, MD, PhD⁴

Address for correspondence: Catherine Bollard, MD, FRACP, FRCPA, 111 Michigan Avenue, NW, 5th Floor Main, Suite 5225, Washington, DC 20010

E-mail: cbollard@cnmc.org 

Biographical sketch: From The George Washington University, School of Medicine and Health Sciences, Washington, DC1; Westchester Medical Center, New York Medical College, Valhalla, NY2; Children’s Hospital of the King’s Daughters, Norfolk, VA3; Center for Global Health at the National Cancer Institute, Rockville, MD

DR. BOLLARD: My name is Dr. Catherine Bollard. I'm Chief of the Division of Allergy and Immunology at Children's National Health System and the Chair of the NHL Committee of the Children's Oncology Group. I hope that today we can provide some clarity and give you some of our first-hand expertise and experience regarding some of the challenges and controversies of treating pediatric patients with non-Hodgkin lymphoma (NHL). Here with me are Drs. Mitchell Cairo, Chief of Pediatric Hematology/Oncology and Stem Cell Transplantation at New York Medical College in the Maria Fareri Children's Hospital, Westchester Medical Center; Eric Lowe, Division Director for Pediatric Hematology/Oncology at the Children's Hospital of the King's Daughters; and Thomas Gross, Deputy Director for Science at the Center for Global Health at the National Cancer Institute.

I'd like to start the questioning, firstly to Dr. Cairo, who recently published with a group of leaders in the pediatric lymphoma field, new staging and response classifications. Dr. Cairo, I’d like you to highlight how these are different from the current classifications, and what you see are the strengths and the limitations at this time.

DR. CAIRO: Thank you, Cath. The original staging classification was developed in the late 1970s by Dr. Murphy while she was at St. Jude's hospital, and either goes by the name the Murphy Staging Classification or the St. Jude's Classification. That classification I think was quite useful at that time when we recognized really only a couple subtypes of NHL, as well as the capabilities we had in those days both imaging as well as further molecular identification as well as trying to identify sites of spread. As some 35 years have evolved, new pathological entities have been identified, much more precise imaging techniques, new methods of detecting more evidence of minimal disease, and also identifying new organ sites of involvement, allowed the creation of a multidisciplinary international task force to look at how we could enhance the original observations by the St. Jude's group.

As Dr. Bollard pointed out, we eventually, over 9 years of evidence-based review, came up with an enhanced staging classification called the International Pediatric NHL Staging System (IPNHLSS).¹ In this new system we account for new histological subtypes, allow for different organ distributions, improve on the new imaging techniques to identify areas of involvement, and also to more molecularly identify extent of disease. I think the advantages are stated above. The disadvantage is that like all staging systems it's a breathing document. It will require international collaboration. As time evolves, this staging system will of course need to be updated as we gain new experience.

Briefly, in terms of the response classification that also came out of the same international multidisciplinary task force that was led by Dr. Sandlund at St. Jude's²; there had never been a response criteria that had been focused entirely in childhood and adolescent NHL. The previous response criteria had been developed by adult NHL investigators, and there was a need to develop the first response criteria for pediatric NHL because of different histologies, different sites of sanctuary disease, and now obviously enhanced imaging capabilities. That also now has been named the International Pediatric Non-Hodgkin Lymphoma Response Criteria (IPNHLRC)—hopefully for harmonizing a response across new studies, but also a breathing document that is going to be limited as we gain new knowledge into how we can better assess response as new techniques are developed.

DR. BOLLARD: I thank you very much for your detailed response. My next question is actually to Dr. Gross, who is currently chairing the international study for upfront diffuse large B-cell lymphoma and Burkitt lymphoma in pediatric young adults. I would like you to speak to a couple of issues, and you can put it in the context of the current randomized trial, looking at rituximab vs no rituximab for this disease. I think firstly it would be useful for you to speak to the implications of this new classification system as we go forward with choosing new therapeutic strategies for these patients, and in particular I'd like to focus on the newly diagnosed diffuse large B-cell lymphoma patients who are in that adolescent/young adult range.

I would also be interested in your opinion regarding how you would manage a patient who is 17 years old but is going to turn 18 tomorrow, and he comes to you with newly diagnosed diffuse large B-cell lymphoma. As you know, the adult oncologists treat diffuse large B-cell lymphoma different to Burkitt lymphoma, and in pediatrics we generally treat these diseases the same. Do you tell this patient that you will treat him today on a pediatric regimen, or do you tell him to go tomorrow, when he's 18, to be treated by an adult oncologist? I would like you to justify your answer please.

DR. GROSS: First to discuss the implications of the new staging as it applies to the current international trial. As Dr. Cairo pointed out, this was developed through a literature review and evidence based analyses, but like any new staging system, the value of staging is to provide us with information that can try to help us to identify patients to improve their outcome. Essentially, staging is to help direct therapy or provide prognosis for outcome, and the only way to do that is to test new systems or classifications in a prospective fashion. Indeed, that is what we are trying to do with this international effort.

This international effort, just as an aside, illustrates one of the challenges of all rare cancers, but particularly pediatrics. In pediatric mature B-cell NHL, both large-cell and Burkitt, we are now at a cure rate of about 90%. To make advances, we don't have enough patients seen in North America and Australia, and it requires international collaboration. This trial, to get 600 patients randomized, it will take 7 years with 14 countries participating—that is one of the challenges, certainly, we have with pediatric NHL. Also, we want to try to gain as much information as possible, not just to the effect of rituximab as Dr. Bollard said, but also to test other questions such as the role or the value in validating this new staging system.

To talk about the controversy of treatment, certainly we know that there is a very different approach in pediatrics. For many years, we have treated diffuse large B-cell lymphoma just like Burkitt. This is a very important delineation when you're seen by a medical oncologist because the treatment for diffuse large B-cell lymphoma is outpatient therapy, ie rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP). Treatment for Burkitt is inpatient with high doses of methotrexate, but other higher doses of the same agents used to treat diffuse large B-cell lymphoma. The question is, do we really need to treat all the pediatric diffuse large B-cell lymphoma with these aggressive Burkitt regimens? I think one of the things that is encouraging to me as a pediatric oncologist is that we are beginning to learn that the biology is very different. Though the disease looks the same under the microscope or by flow cytometry, when you look at it genetically it's quite different. We know now that the younger the patient is with diffuse large B-cell lymphoma, even though it looks for all intents and purposes like the same disease as seen in adults, when you look at the genetics, many times, as high as 30% of the time, it will be genetically the same as a Burkitt lymphoma. I think when you're talking about young patients we can easily justify treating them both the same because the biology would suggest that a good number of patients would need Burkitt therapy to be cured.

Now, that changes over time, so that it appears that sometime in young adulthood, maybe somewhere between 25 and 35 years of age, you don't see the genetic disease that looks like diffuse large B-cell lymphoma, but is genetically Burkitt lymphoma. As for the 18-year-old patient that Dr. Bollard was posing to me, I've had several patients like this. I go through the pluses and minuses of the therapy, inpatient vs outpatient, but also the potential long-term side effects. The outpatient therapy has potentially more long-term side effects as far as potential infertility and potential heart damage. Every time I have given the choice to the family and the patient, the teenager has always chosen the outpatient therapy that you would get as an adult, and the parents always say they would rather have the inpatient therapy, and that spending a couple of days in the hospital to try to reduce the chance of long-term damage is their choice. It's a very interesting dynamic and I think sometimes the issues that go into choice of treatment are quite variable. My personal opinion is that hopefully in the future we will be able to have a better understanding of biology, so that when we see these patients, be they 18 or 25 years old, we're not looking at what it looks like under the microscope or who they see, and what they're used to giving, but the biology will determine which therapy is more likely to cure them. Right now we don't have that ability in most of the patients.

DR. BOLLARD: Thank you, Dr. Gross. Again, another very comprehensive answer to a difficult question. I'm actually going to push this back to Dr. Cairo and then impose the same soon to be 18-year-old patient to you. This time, he's coming to you with relapsed diffuse large B-cell lymphoma. What are you going to tell him? Are you going to treat him today on pediatric protocols, or will you wait until tomorrow when he could have access to adult protocols?

DR. CAIRO: I think the results are relatively similar, but, in part, the answer to the question is of course based on what their original therapy was. If the original therapy was the pediatric-inspired type of treatment, I think there's a world of experience of what are some of the best pediatric-inspired regimens to use for retrieval. If, however, the original therapy was an adult-inspired regimen, then I think the options are open because the disease may not be as resistant in that setting; therefore, one would want to consider all the adult type of retrieval regimens in that case, because that group of patients—at least in the adult experience—tend to have disease that may be more responsive because they're not as resistant to the higher dose and multi-agent therapy that a pediatric-inspired regimen would have given them had they been treated that way.

DR. BOLLARD: I was also trying to ask you to speak to the access that an 18-year-old might have to novel therapies that a 17-year-old might not. How do you address that issue?

DR. CAIRO: That's an excellent question. I think that for first relapse or first induction failure most of the retrieval regimens, the first line regimens, that are available, either pediatric inspired or adult inspired, probably don't require an investigational agent that an 18-year-old might have access to if he was being treated on an adult type of regimen. However, I would strongly encourage an 18-year-old who failed one retrieval regimen to consider experimental therapy. There I think the access to new agents—if you're 18 or over—are so much greater that I would encourage them to be treated on an adult retrieval regimen, where some of the newer agents may be investigational, are not available to a pediatric program.

DR. BOLLARD: Thank you very much, Dr. Cairo. I have one last question on the B-cell diseases before I move to Dr. Lowe, and the last question goes to Dr. Gross. Would you recommend that a patient with relapsed Burkitt lymphoma—now increasingly rare—be treated with salvage chemotherapy and then autologous transplant or allogeneic stem cell transplant?  

DR. GROSS: As the others on this discussion know, we performed an analysis from data in the Center for International Blood and Marrow Transplant Research (CIBMTR), and the problem is that Burkitt lymphoma tends to reoccur so rapidly after transplant. The median time to relapse is 3 months after transplant. We could not find a difference in the outcome between autografts and allografts because of its early reoccurrence. That said, my personal opinion is, since we know that Burkitt lymphoma is a hematologically spread disease, that I always prefer a donor source where I know they're not going to have tumor cells in them, which is an allogeneic donor. I always prefer an allogeneic donor, because I know it's tumor-free, but also it gives us an opportunity, if the disease will stay under control long enough, to potentially get an immune response against any residual tumor. For that reason, I recommend an allogeneic donor if it can be found readily.

DR. BOLLARD: Thank you very much, Dr. Gross. Now, on to Dr. Lowe, and Dr. Lowe's particular area of expertise is in anaplastic large cell lymphoma (ALCL) and T-cell diseases. I was wondering if you could explain to me the difference between T-cell lymphoblastic lymphoma and T-cell acute lymphoblastic leukemia (ALL), specifically since the World Health Organization (WHO) groups these two disease entities together as T-lymphoblastic leukemia/lymphoma. If you could clarify that classification that would be very helpful.

DR. LOWE: As you well know, many physicians believe that T-cell lymphoblastic leukemia and T-cell lymphoblastic lymphoma are very similar diseases, but they are not exactly the same disease although we sometimes treat them very similar. We know that T-cells do not mature in bone marrow but rather they are thymic driven cells. Because of this, there are distinct differences between the leukemia and lymphoma. For example, we know that the genetics between the two—although in limited samples—are not always the same, including in prognostic. Just one example, loss of heterozygosity at 6Q has been shown to be prognostically important in lymphoblastic lymphoma but not in T-cell ALL. I think the real challenge is to figure out what the differences are. I think we could argue that potentially, T-ALL is stage four T-cell lymphoblastic lymphoma.

I think that the WHO classifying the two diseases as one entity with T-lymphoblastic leukemia/lymphoma has hindered a little in the advancement of recognizing the differences in that many people assume that they're the same disease. When you look up from a pathological standpoint and you say, well, they're clearly the same disease because they're listed as a single entity, and when you look up treatment, you say, well they're treated very similar, so they must be the same disease. I think that does us a little disservice in trying to advance the field forward, because I think getting lymphoblastic lymphoma samples, which is challenging, is extremely important to determine the genetic drivers of this disease.

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.

DR. BOLLARD: Thank you, Dr. Lowe. I really thank you all for speaking in a very detailed way about the importance of obtaining tumor tissue to perform these critical biologic studies, because I do feel that's an important issue to overcome for the future care of our pediatric patients with NHL. I would like to discuss late effects in our survivors. As Dr. Gross said, survival rates for patients with B-cell lymphomas are generally outstanding. Dr. Gross, do you feel that late effects are not something the NHL group has to worry about now that we have obviated the need for radiation, or not? And what are your feelings about trying to minimize these late effects even further?

DR. GROSS: The good news is that over time, we have been able to come up with regimens that are highly effective but have reduced the agents we know have the highest risk of late effects—radiation being the primary one, but also anthracyclines we have been able to reduce in the vast majority of the patients, and to keep alkylating agents in the vast majority of the patients to a level that most patients do not have infertility. The long-term side effects are becoming pretty minimal, but the question is, how low do they have to be to be acceptable? The goal would be cure without any long-term effects. As I said before, certainly we have paid the price in short-term effects. Our regimens are inpatient, and they can have quite severe short-term side effects such as mucositis. We've made great advances but I think there's still room to go.

DR. CAIRO: I agree, of course, with my colleague Dr. Gross. Again, when we look at large series of chronic health care conditions, certainly children with treated NHL still comes up as one showing over 40% to 50% of patients having one or two serious chronic health care conditions. We know the data are a little antiquated, because they include patients who were treated with different regimens in the 1970s and all of the 1980s. However, I think our goal continues to be to identify the most effective treatment regimen, but with the least toxic long-term complications for our patients. That struggle is very difficult because of the very high success rate we have today, and to identify without hurting that high success rate less toxic therapies will require a collaborative, multidisciplinary, international effort to reach that goal.

DR. BOLLARD: Thank you very much Drs. Cairo and Gross. Dr. Lowe, did you have any closing remarks on the late effects issues for the T-cell mediated diseases in particular?

DR. LOWE: I would absolutely agree with Dr. Gross and Dr. Cairo that this is an important issue. I think we in pediatrics do a good job at following our patients for long-term side effects and creating guidelines for screening for these long-term side effects. That said, I think as we start to talk about better and better therapy and even more and more targeted therapy, what we don't know about some of these targeted therapies is their 15 and 20 year long-term side effects. We obviously hope that there aren't any, and that's why we are moving toward these drugs, but again, surveillance of those long-term side effects will be extremely important, especially when you're talking about medications for young children.

DR. BOLLARD: I'd like to thank you all very much for participating in this expert roundtable discussion today. I think the overarching points are that prognoses at the current time for newly diagnosed pediatric patients with NHL range from 70% to over 90% even for patients with disseminated disease. The challenges that we need to overcome are how we can optimize our up front treatment to prevent relapse in all, because I think we've all reiterated the fact that the outcomes for those few patients who do relapse remains extremely poor. I think there is still controversy about how to manage patients with relapsed disease, and how to temper our therapies against long-term side effects of our surviving patients. Finally, I think with the advent of novel targeted agents, it is incredibly important for the optimal management of our current and future patients that we are able to access tumor tissues and perform the critical biologic studies that are required to develop an effective precision medicine approach for pediatric patients with NHL. I would like to again thank Dr. Cairo, Dr. Gross, and Dr. Lowe for their excellent answers to my, at times, difficult and challenging questions and I would like to thank the organizers of this expert roundtable discussion. I hope that in the next decade that we will see even greater advances for the patient population that we treat. Thank you very much.

References

1. Rosolen RA, Perkins SL, Pinkerton CR, et al. Revised International Pediatric Non-Hodgkin Lymphoma Staging System. J Clin Oncol. 2015;33(18):2112–2118.

2. Sandlund JT, Guillerman RP, Perkins SL, et al. International Pediatric Non-Hodgkin Lymphoma Response Criteria. J Clin Oncol. 2015;33(18)2106-2111.

Moderator: Catherine Bollard, MD, FRACP, FRCPA¹

Discussants: Mitchell S. Cairo, MD²; Eric J. Lowe, MD³; Thomas G. Gross, MD, PhD⁴

Address for correspondence: Catherine Bollard, MD, FRACP, FRCPA, 111 Michigan Avenue, NW, 5th Floor Main, Suite 5225, Washington, DC 20010

E-mail: cbollard@cnmc.org 

Biographical sketch: From The George Washington University, School of Medicine and Health Sciences, Washington, DC1; Westchester Medical Center, New York Medical College, Valhalla, NY2; Children’s Hospital of the King’s Daughters, Norfolk, VA3; Center for Global Health at the National Cancer Institute, Rockville, MD

DR. BOLLARD: My name is Dr. Catherine Bollard. I'm Chief of the Division of Allergy and Immunology at Children's National Health System and the Chair of the NHL Committee of the Children's Oncology Group. I hope that today we can provide some clarity and give you some of our first-hand expertise and experience regarding some of the challenges and controversies of treating pediatric patients with non-Hodgkin lymphoma (NHL). Here with me are Drs. Mitchell Cairo, Chief of Pediatric Hematology/Oncology and Stem Cell Transplantation at New York Medical College in the Maria Fareri Children's Hospital, Westchester Medical Center; Eric Lowe, Division Director for Pediatric Hematology/Oncology at the Children's Hospital of the King's Daughters; and Thomas Gross, Deputy Director for Science at the Center for Global Health at the National Cancer Institute.

I'd like to start the questioning, firstly to Dr. Cairo, who recently published with a group of leaders in the pediatric lymphoma field, new staging and response classifications. Dr. Cairo, I’d like you to highlight how these are different from the current classifications, and what you see are the strengths and the limitations at this time.

DR. CAIRO: Thank you, Cath. The original staging classification was developed in the late 1970s by Dr. Murphy while she was at St. Jude's hospital, and either goes by the name the Murphy Staging Classification or the St. Jude's Classification. That classification I think was quite useful at that time when we recognized really only a couple subtypes of NHL, as well as the capabilities we had in those days both imaging as well as further molecular identification as well as trying to identify sites of spread. As some 35 years have evolved, new pathological entities have been identified, much more precise imaging techniques, new methods of detecting more evidence of minimal disease, and also identifying new organ sites of involvement, allowed the creation of a multidisciplinary international task force to look at how we could enhance the original observations by the St. Jude's group.

As Dr. Bollard pointed out, we eventually, over 9 years of evidence-based review, came up with an enhanced staging classification called the International Pediatric NHL Staging System (IPNHLSS).¹ In this new system we account for new histological subtypes, allow for different organ distributions, improve on the new imaging techniques to identify areas of involvement, and also to more molecularly identify extent of disease. I think the advantages are stated above. The disadvantage is that like all staging systems it's a breathing document. It will require international collaboration. As time evolves, this staging system will of course need to be updated as we gain new experience.

Briefly, in terms of the response classification that also came out of the same international multidisciplinary task force that was led by Dr. Sandlund at St. Jude's²; there had never been a response criteria that had been focused entirely in childhood and adolescent NHL. The previous response criteria had been developed by adult NHL investigators, and there was a need to develop the first response criteria for pediatric NHL because of different histologies, different sites of sanctuary disease, and now obviously enhanced imaging capabilities. That also now has been named the International Pediatric Non-Hodgkin Lymphoma Response Criteria (IPNHLRC)—hopefully for harmonizing a response across new studies, but also a breathing document that is going to be limited as we gain new knowledge into how we can better assess response as new techniques are developed.

DR. BOLLARD: I thank you very much for your detailed response. My next question is actually to Dr. Gross, who is currently chairing the international study for upfront diffuse large B-cell lymphoma and Burkitt lymphoma in pediatric young adults. I would like you to speak to a couple of issues, and you can put it in the context of the current randomized trial, looking at rituximab vs no rituximab for this disease. I think firstly it would be useful for you to speak to the implications of this new classification system as we go forward with choosing new therapeutic strategies for these patients, and in particular I'd like to focus on the newly diagnosed diffuse large B-cell lymphoma patients who are in that adolescent/young adult range.

I would also be interested in your opinion regarding how you would manage a patient who is 17 years old but is going to turn 18 tomorrow, and he comes to you with newly diagnosed diffuse large B-cell lymphoma. As you know, the adult oncologists treat diffuse large B-cell lymphoma different to Burkitt lymphoma, and in pediatrics we generally treat these diseases the same. Do you tell this patient that you will treat him today on a pediatric regimen, or do you tell him to go tomorrow, when he's 18, to be treated by an adult oncologist? I would like you to justify your answer please.

DR. GROSS: First to discuss the implications of the new staging as it applies to the current international trial. As Dr. Cairo pointed out, this was developed through a literature review and evidence based analyses, but like any new staging system, the value of staging is to provide us with information that can try to help us to identify patients to improve their outcome. Essentially, staging is to help direct therapy or provide prognosis for outcome, and the only way to do that is to test new systems or classifications in a prospective fashion. Indeed, that is what we are trying to do with this international effort.

This international effort, just as an aside, illustrates one of the challenges of all rare cancers, but particularly pediatrics. In pediatric mature B-cell NHL, both large-cell and Burkitt, we are now at a cure rate of about 90%. To make advances, we don't have enough patients seen in North America and Australia, and it requires international collaboration. This trial, to get 600 patients randomized, it will take 7 years with 14 countries participating—that is one of the challenges, certainly, we have with pediatric NHL. Also, we want to try to gain as much information as possible, not just to the effect of rituximab as Dr. Bollard said, but also to test other questions such as the role or the value in validating this new staging system.

To talk about the controversy of treatment, certainly we know that there is a very different approach in pediatrics. For many years, we have treated diffuse large B-cell lymphoma just like Burkitt. This is a very important delineation when you're seen by a medical oncologist because the treatment for diffuse large B-cell lymphoma is outpatient therapy, ie rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP). Treatment for Burkitt is inpatient with high doses of methotrexate, but other higher doses of the same agents used to treat diffuse large B-cell lymphoma. The question is, do we really need to treat all the pediatric diffuse large B-cell lymphoma with these aggressive Burkitt regimens? I think one of the things that is encouraging to me as a pediatric oncologist is that we are beginning to learn that the biology is very different. Though the disease looks the same under the microscope or by flow cytometry, when you look at it genetically it's quite different. We know now that the younger the patient is with diffuse large B-cell lymphoma, even though it looks for all intents and purposes like the same disease as seen in adults, when you look at the genetics, many times, as high as 30% of the time, it will be genetically the same as a Burkitt lymphoma. I think when you're talking about young patients we can easily justify treating them both the same because the biology would suggest that a good number of patients would need Burkitt therapy to be cured.

Now, that changes over time, so that it appears that sometime in young adulthood, maybe somewhere between 25 and 35 years of age, you don't see the genetic disease that looks like diffuse large B-cell lymphoma, but is genetically Burkitt lymphoma. As for the 18-year-old patient that Dr. Bollard was posing to me, I've had several patients like this. I go through the pluses and minuses of the therapy, inpatient vs outpatient, but also the potential long-term side effects. The outpatient therapy has potentially more long-term side effects as far as potential infertility and potential heart damage. Every time I have given the choice to the family and the patient, the teenager has always chosen the outpatient therapy that you would get as an adult, and the parents always say they would rather have the inpatient therapy, and that spending a couple of days in the hospital to try to reduce the chance of long-term damage is their choice. It's a very interesting dynamic and I think sometimes the issues that go into choice of treatment are quite variable. My personal opinion is that hopefully in the future we will be able to have a better understanding of biology, so that when we see these patients, be they 18 or 25 years old, we're not looking at what it looks like under the microscope or who they see, and what they're used to giving, but the biology will determine which therapy is more likely to cure them. Right now we don't have that ability in most of the patients.

DR. BOLLARD: Thank you, Dr. Gross. Again, another very comprehensive answer to a difficult question. I'm actually going to push this back to Dr. Cairo and then impose the same soon to be 18-year-old patient to you. This time, he's coming to you with relapsed diffuse large B-cell lymphoma. What are you going to tell him? Are you going to treat him today on pediatric protocols, or will you wait until tomorrow when he could have access to adult protocols?

DR. CAIRO: I think the results are relatively similar, but, in part, the answer to the question is of course based on what their original therapy was. If the original therapy was the pediatric-inspired type of treatment, I think there's a world of experience of what are some of the best pediatric-inspired regimens to use for retrieval. If, however, the original therapy was an adult-inspired regimen, then I think the options are open because the disease may not be as resistant in that setting; therefore, one would want to consider all the adult type of retrieval regimens in that case, because that group of patients—at least in the adult experience—tend to have disease that may be more responsive because they're not as resistant to the higher dose and multi-agent therapy that a pediatric-inspired regimen would have given them had they been treated that way.

DR. BOLLARD: I was also trying to ask you to speak to the access that an 18-year-old might have to novel therapies that a 17-year-old might not. How do you address that issue?

DR. CAIRO: That's an excellent question. I think that for first relapse or first induction failure most of the retrieval regimens, the first line regimens, that are available, either pediatric inspired or adult inspired, probably don't require an investigational agent that an 18-year-old might have access to if he was being treated on an adult type of regimen. However, I would strongly encourage an 18-year-old who failed one retrieval regimen to consider experimental therapy. There I think the access to new agents—if you're 18 or over—are so much greater that I would encourage them to be treated on an adult retrieval regimen, where some of the newer agents may be investigational, are not available to a pediatric program.

DR. BOLLARD: Thank you very much, Dr. Cairo. I have one last question on the B-cell diseases before I move to Dr. Lowe, and the last question goes to Dr. Gross. Would you recommend that a patient with relapsed Burkitt lymphoma—now increasingly rare—be treated with salvage chemotherapy and then autologous transplant or allogeneic stem cell transplant?  

DR. GROSS: As the others on this discussion know, we performed an analysis from data in the Center for International Blood and Marrow Transplant Research (CIBMTR), and the problem is that Burkitt lymphoma tends to reoccur so rapidly after transplant. The median time to relapse is 3 months after transplant. We could not find a difference in the outcome between autografts and allografts because of its early reoccurrence. That said, my personal opinion is, since we know that Burkitt lymphoma is a hematologically spread disease, that I always prefer a donor source where I know they're not going to have tumor cells in them, which is an allogeneic donor. I always prefer an allogeneic donor, because I know it's tumor-free, but also it gives us an opportunity, if the disease will stay under control long enough, to potentially get an immune response against any residual tumor. For that reason, I recommend an allogeneic donor if it can be found readily.

DR. BOLLARD: Thank you very much, Dr. Gross. Now, on to Dr. Lowe, and Dr. Lowe's particular area of expertise is in anaplastic large cell lymphoma (ALCL) and T-cell diseases. I was wondering if you could explain to me the difference between T-cell lymphoblastic lymphoma and T-cell acute lymphoblastic leukemia (ALL), specifically since the World Health Organization (WHO) groups these two disease entities together as T-lymphoblastic leukemia/lymphoma. If you could clarify that classification that would be very helpful.

DR. LOWE: As you well know, many physicians believe that T-cell lymphoblastic leukemia and T-cell lymphoblastic lymphoma are very similar diseases, but they are not exactly the same disease although we sometimes treat them very similar. We know that T-cells do not mature in bone marrow but rather they are thymic driven cells. Because of this, there are distinct differences between the leukemia and lymphoma. For example, we know that the genetics between the two—although in limited samples—are not always the same, including in prognostic. Just one example, loss of heterozygosity at 6Q has been shown to be prognostically important in lymphoblastic lymphoma but not in T-cell ALL. I think the real challenge is to figure out what the differences are. I think we could argue that potentially, T-ALL is stage four T-cell lymphoblastic lymphoma.

I think that the WHO classifying the two diseases as one entity with T-lymphoblastic leukemia/lymphoma has hindered a little in the advancement of recognizing the differences in that many people assume that they're the same disease. When you look up from a pathological standpoint and you say, well, they're clearly the same disease because they're listed as a single entity, and when you look up treatment, you say, well they're treated very similar, so they must be the same disease. I think that does us a little disservice in trying to advance the field forward, because I think getting lymphoblastic lymphoma samples, which is challenging, is extremely important to determine the genetic drivers of this disease.

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.

DR. BOLLARD: Thank you, Dr. Lowe. I really thank you all for speaking in a very detailed way about the importance of obtaining tumor tissue to perform these critical biologic studies, because I do feel that's an important issue to overcome for the future care of our pediatric patients with NHL. I would like to discuss late effects in our survivors. As Dr. Gross said, survival rates for patients with B-cell lymphomas are generally outstanding. Dr. Gross, do you feel that late effects are not something the NHL group has to worry about now that we have obviated the need for radiation, or not? And what are your feelings about trying to minimize these late effects even further?

DR. GROSS: The good news is that over time, we have been able to come up with regimens that are highly effective but have reduced the agents we know have the highest risk of late effects—radiation being the primary one, but also anthracyclines we have been able to reduce in the vast majority of the patients, and to keep alkylating agents in the vast majority of the patients to a level that most patients do not have infertility. The long-term side effects are becoming pretty minimal, but the question is, how low do they have to be to be acceptable? The goal would be cure without any long-term effects. As I said before, certainly we have paid the price in short-term effects. Our regimens are inpatient, and they can have quite severe short-term side effects such as mucositis. We've made great advances but I think there's still room to go.

DR. CAIRO: I agree, of course, with my colleague Dr. Gross. Again, when we look at large series of chronic health care conditions, certainly children with treated NHL still comes up as one showing over 40% to 50% of patients having one or two serious chronic health care conditions. We know the data are a little antiquated, because they include patients who were treated with different regimens in the 1970s and all of the 1980s. However, I think our goal continues to be to identify the most effective treatment regimen, but with the least toxic long-term complications for our patients. That struggle is very difficult because of the very high success rate we have today, and to identify without hurting that high success rate less toxic therapies will require a collaborative, multidisciplinary, international effort to reach that goal.

DR. BOLLARD: Thank you very much Drs. Cairo and Gross. Dr. Lowe, did you have any closing remarks on the late effects issues for the T-cell mediated diseases in particular?

DR. LOWE: I would absolutely agree with Dr. Gross and Dr. Cairo that this is an important issue. I think we in pediatrics do a good job at following our patients for long-term side effects and creating guidelines for screening for these long-term side effects. That said, I think as we start to talk about better and better therapy and even more and more targeted therapy, what we don't know about some of these targeted therapies is their 15 and 20 year long-term side effects. We obviously hope that there aren't any, and that's why we are moving toward these drugs, but again, surveillance of those long-term side effects will be extremely important, especially when you're talking about medications for young children.

DR. BOLLARD: I'd like to thank you all very much for participating in this expert roundtable discussion today. I think the overarching points are that prognoses at the current time for newly diagnosed pediatric patients with NHL range from 70% to over 90% even for patients with disseminated disease. The challenges that we need to overcome are how we can optimize our up front treatment to prevent relapse in all, because I think we've all reiterated the fact that the outcomes for those few patients who do relapse remains extremely poor. I think there is still controversy about how to manage patients with relapsed disease, and how to temper our therapies against long-term side effects of our surviving patients. Finally, I think with the advent of novel targeted agents, it is incredibly important for the optimal management of our current and future patients that we are able to access tumor tissues and perform the critical biologic studies that are required to develop an effective precision medicine approach for pediatric patients with NHL. I would like to again thank Dr. Cairo, Dr. Gross, and Dr. Lowe for their excellent answers to my, at times, difficult and challenging questions and I would like to thank the organizers of this expert roundtable discussion. I hope that in the next decade that we will see even greater advances for the patient population that we treat. Thank you very much.

References

1. Rosolen RA, Perkins SL, Pinkerton CR, et al. Revised International Pediatric Non-Hodgkin Lymphoma Staging System. J Clin Oncol. 2015;33(18):2112–2118.

2. Sandlund JT, Guillerman RP, Perkins SL, et al. International Pediatric Non-Hodgkin Lymphoma Response Criteria. J Clin Oncol. 2015;33(18)2106-2111.