Hello and welcome to today’s VJHemOnc podcast. We are a global open access video journal bringing you the latest in hematology and hematological oncology. This month is Blood Cancer Awareness Month and in recognition we will be producing a special podcast series covering a variety of topics. Today’s episode focuses on pediatric acute myeloid and acute lymphoblastic leukemia. First, you will hear from Michele Redell, who shares insights into the Pediatric Acute Leukemia Screening Trial. This is a study to compile data on the rare condition of relapsed pediatric leukemia in order to better understand its pathogenesis and treatment.

Michele Redell

This came about through a series of conversations between leading pediatric leukemia investigators in this country involved in the Children’s Oncology Group and the leadership at the Leukemia and Lymphoma Society. So the COG investigators and the Leukemia and Lymphoma Society leadership agreed that there really is or has been not enough attention paid to children with leukemia. And so the PedAL screening protocol is really an effort to bring more… To bring more attention, to bring more systematic data collection and specimen collection so that we can continue to learn from these patients.

So the way that advances are made in clinical medicine is through clinical trials. Clinical trials are most informative when you have a lot of patients and you can do a randomized test where one group gets one treatment, another group gets another treatment, and then you can compare them head-to-head and learn which one is better. In pediatrics, leukemia is a very rare thing, and relapsed leukemia is fortunately even more rare. But that makes it really hard to do clinical trials because we just don’t have enough patients to do these ideal randomized studies. And so to try to fill that gap, to try to continue to learn from our patients, the screening protocol is building a big registry of these patients. So when a patient relapses, they enroll on the trial and we begin collecting data about them. We collect information about the patient themselves. We study their leukemia in a centralized way. So there’s a lab that will do that flow cytometry test and tell us about different potential targets for therapeutic studies. For AML patients, we’re doing another level of characterization of the leukemia, which is looking for genetic mutations and other abnormalities that help us learn more about the leukemia. And then just collecting a lot of data. So for ALL patients and AML patients, we want to know, you know, how long it was between the original diagnosis and their relapse and how did they do after relapse. For the AML patients, again, we’re gathering even more information about them because there just really is so little information about children after they relapse. So for the AML patients, we want to know how did their doctor at home treat them? How did that patient respond to that treatment? Were they able to get a bone marrow transplant? We know after relapse, bone marrow transplant is really the only way to cure the leukemia at that point. So really trying to understand just what are doctors doing in the country to treat children with relapsed leukemias. So that’s the registry part.

We’re also gathering samples. We have lots of really brilliant scientists around the country who are doing research in their labs. And these samples from relapse patients are so valuable for research like that to help us better understand leukemias and test the drugs that we’re trying to move forward into clinical trials. And then for clinical trials, there are some therapeutic studies, we call them sub-trials, that are associated with the screening protocol. So when a patient enrolls, they get their leukemia characterized, and then we can tell the doctor treating that patient if there are any trials that are associated with PedAL that their patient might qualify for.

Now you will hear from Mark Litzow, who speaks on a study comparing ALL B-cell samples from children versus adults in their response to various drugs.

Mark Litzow

So this is a study that came out of St. Jude’s Children’s Hospital, and they took ALL samples. B-cell ALL samples from children and adults, and they cultured them, and then they tested different chemotherapy drugs, and also inotuzumab, an immunotherapeutic agent, desatinib, tyrosine kinase inhibitor, and they looked at the differential response between children and adults and how they responded to the chemotherapy in this ex vivo or laboratory study. And they found that there was a difference in the responses in the children’s samples versus the adult samples for seven of the drugs. Now, six of them they could explain by the difference in the molecular subtypes. There’s a difference in the molecular subtyping. Children tend to have more favorable molecular subtypes compared to adults. And so they could explain in six of these seven drugs the difference based on their molecular subtype. One of them, 6-mercaptopurine, showed more benefit in children than in adults and kind of across all these different subtypes. So, it confirmed why children tend to have better outcomes with treatment of their ALL compared to adults. It may help inform us in the future about how we use these agents as well. But it was a very, very interesting study, the way it was designed and carried out.

Next, Christina Peters will speak on managing relapsed acute lymphoblastic leukemia in pediatrics and the importance of conditioning regimens in these patients, which is being assessed in the FORUM trial.

Christina Peters

So relapse in ALL is still a high-risk situation for children with acute lymphoblastic leukemia, but a lot of progress has been made over the last 20 years, I would say. And nowadays we can already very early in the treatment course identify patients who are at very high risk for relapse. Those might undergo nowadays not only allogeneic stem cell transplantation but also other cell therapies like for instance CAR-T cell therapy but for for instance, also NK cell therapy. And in the relapse situation, except for the very late isolated bone marrow relapses, allotransplant still has an important role to rescue patients after a relapse.

The FORUM trial for omitting radiation under majority age has shown that the conditioning regimen, besides the remission status, impacts on the outcome of the patients. Because what we have demonstrated over the last eight years is that total body irradiation in combination with etoposide is superior to so-called chemo conditioning regimen, which consisted in our prospective randomized trial of a combination of fludarabine, thiotepa, and either busulfan or treosulfan. The second important issue is it is better to have a suitable sibling or unrelated donor because here the outcome results are much better compared to a haploidentical donor transplant in relapsed ALL. So F1 stands for FORUM, FORUM-emitting radiation under majority age. And it is the biggest prospective trial ever performed in children and adolescents with acute lymphoblastic leukemia. So that means that we have in the meantime recruited nearly 1,800 patients in 38 countries on five continents and in more than 120 centers. So this is real-world data, and we are proud to present also here our results on this ongoing trial. It will stop recruitment next year, and we will continue to collaborate with all our partners and set up an F2 trial, which has new questions. We try to reduce the total body irradiation dose and compare it prospectively between 12 and 8 gray. And the second important randomization will include patients with graft-versus-host disease who should receive ruxolitinib in the early treatment of acute graft-versus-host disease equal or more than grade 2. And then we have another, I think, important approach, and that is that we want to collaborate with our partners from the adult centers and include also young adults with an upper age limit to 45 years. So I think this fantastic collaboration beyond all political borders is a really achievement also for our patients.

Christina Peters now goes on to discuss the optimisation of bridging therapy to CAR-T in children and young adults with acute lymphoblastic leukaemia and barriers that remain in treating paediatric patients with CAR-T therapies.

Christina Peters

Bridging before treatment with CAR T-cells is an important component to get rid of overt leukemia burden before giving the patient CAR T-cells in the time frame between aphoresis and CAR T-cell therapy. And in the beginning, when we started our treatment approaches and procedures with CAR we had the impression that patients have to get rid of all leukemic cells. And of course, in some situations, that was associated with toxicity, but also with infection. And in the meantime, we came together and published a white paper, what is important for these patients waiting for their CAR T-cell product. And in some situations, you might have the possibility as a treating physician to give only mild chemotherapy or wait. In other situations, we need more complex treatment options, for instance, chemo-conditioning combinations. But also here we have to consider that we need collaboration because in this tricky situation, sometimes we have to be very careful for these vulnerable patients with deciding what therapy is the best option. Although we had collected a lot of data, it is still not an evidence-based approach and hopefully we will learn in the future more on the age-specific but also stage-depending results to find the best bridging therapy for those patients.

Unfortunately, at the moment, the pharmaceutical licensed product is only eligible for patients with resistant or relapsed leukemia, which brings us in certain circumstances to a situation where the T-cells which were collected are quite exhausted because the patient is short after an allogenic stem cell transplantation or received a lot of chemotherapy. So to get hopefully in the future better approaches where we can apply CAR T-cell therapy earlier in the treatment phase would be really an important step forward. At the moment, we treat patients with CAR T-cells, especially children with ALL, only in advanced stages of disease. CAR T-cells are well tolerable in most of the patients with a very low treatment-related mortality, but also for the efficacy, we see a certain amount of relapses And then a second or a first allogenic stem cell transplantation is still indicated to rescue these patients.

Finally, we go back to Michelle Riddell, who speaks on the challenges that remain in the treatment of pediatric acute myeloid leukemia, highlighting chemotherapy resistance as the main challenge and the challenges of using CAR T-cell therapies in AML.

Michele Redell

You know, in my mind, the main problem or the main challenge with AML, AML is my particular focus and interest, is chemotherapy resistance, right? So right now, maybe 50 to 60 percent of children who are diagnosed with AML will be cured. The other 40 percent, almost all of them will actually get into remission. But then six months later, a year later, two years later, the leukemia comes back. It’s the same leukemia. But it has often, we think, acquired the ability to survive chemotherapy. And so what we’re really trying to understand is how does that happen? And what are those changes or what are those processes that the leukemia cells can develop or enhance so that they can survive the chemotherapy once they grow back? Because now they have been they’ve proven themselves able to survive chemotherapy. It’s often really hard to get those patients back into remission. And so what we want to understand is what are those processes? Are there different vulnerabilities? Are there different targets biologically that we could develop drugs for that maybe we already have drugs for that we can use in the right way to eradicate that leukemia forever, right?

In ALL, one of the really hot therapies that we have right now is immunotherapy, right? We have antibodies that can help the immune system eradicate the leukemia. We have engineered T-cells. We call them CAR T-cells. It stands for chimeric antigen receptor T-cells. Those have really transformed the way that we treat relapsed ALL. So there’s a lot of interest in trying to build a strategy like that for AML. But there are challenges to that that don’t really apply to ALL. So there aren’t a lot of targets that really distinguish a malignant AML cell from a normal myeloid cell. And so there’s a lot of concern about toxicity. And also, these immunotherapies require the immune system to be at least somewhat functional. And in AML patients, oftentimes their immune system just really can’t participate, can’t help make those immunotherapy strategies successful. So I think that’s where a lot of the field is right now, is to try to figure out how to make these immunotherapies more successful in AML patients. There are lots of smart people working on that. So I think that’s a really exciting field right now. So many challenges make it seem overwhelming, but I have confidence that these brilliant people working on it are going to figure it out.

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