Pediatric Acute Lymphoblastic Leukemia

Susan R. Rheingold, MD

Where We Have Been, Where We Are Now

Recently, ONCOLOGY discussed therapy options, including chimeric antigen receptor (CAR)-T-cell therapies for pediatric acute lymphoblastic leukemia (ALL), with Susan R. Rheingold, MD. Dr. Rheingold is the Medical Director of the Oncology Outpatient Clinic and attending physician with the Cancer Center at Children’s Hospital of Philadelphia. She is also a Professor of Clinical Pediatrics at the Perelman School of Medicine in Philadelphia. Dr. Rheingold specializes in the care of children with hematologic malignancies.

Q: Could you talk about what has been the standard of care as far as initial therapies for pediatric patients diagnosed with ALL?

Dr. Rheingold: Over the past 5 to 6 decades, children’s hospitals and pediatric oncologists have created a uniform treatment plan for children and adolescents with ALL. When a child first presents to the hospital and there is concern that the child may have leukemia, what is initially looked at is the age of the child and the white blood cell (WBC) count at presentation. In children with very aggressive leukemia, the leukemia will spill out of the bone marrow where the cancer cells are being made and into the peripheral blood. This causes the child’s WBC count to go very high, sometimes upward of a million, which is well above the normal count of about 7,000 cells.

Using such data, children and adolescents are divided into two groups: those who might get away with basic chemotherapy and those (often including older children) who need a bit more chemotherapy to get to very similar cure rates. These groups are then broken down into what is called the National Cancer Institute (NCI) standard risk, or children younger than age 10 years who have WBC counts less than 50,000, and NCI high risk, or children who are age 10 years or older and have WBC counts over 50,000. That’s really just the starting point to determine the first 4 weeks of therapy. While the child is undergoing the therapy, a lot of background work goes on from which the oncologist and the hematopathologist are assessing the genetic abnormalities in the leukemia and how well the child is responding to the therapy. At the end of the first month of therapy, they do a very specialized test called the minimal residual disease (MDR) test. This test is looking for 1 in 100,000 leukemia cells still in the child’s bone marrow after just 28 days of therapy.

Oncologists take all that information to decide on the course of therapy. Currently in the United States, girls are treated for about 2¼ years. Boys are treated longer, 3 1/4 years, although we’re trying to modify that so boys and girls are treated equally. There are biologic reasons for why historically boys have been treated a little longer than girls. But this sets off a whole pattern of looking to see whether any genetic abnormalities might be targeted with a newer agent. So, we have clinical trials in which we are adding some new targeted therapies to our standard chemotherapy backbones. We also have clinical trials in which we are assessing different risk stratifications. This will determine the longer care and treatment plan for a newly diagnosed child.

Q: In 2017, CAR T-cell therapy (tisagenlecleucel) was approved for pediatric ALL patients for refractory disease or following relapse. Can you talk about when this immunotherapy is appropriate, patients are more likely to respond, and then in the context of other treatments that have been previously available for patients who have relapsed refractory disease?

Dr. Rheingold: When it was approved in August 2017, it was officially approved up to age 24 years and there was no lower age limit. It was also approved for patients with a second or greater relapse or patients who were refractory to therapy. The definition of refractory is essentially in the eye of the oncologist. Most, however, will say that children who never respond to their initial therapy and may have a positive MDR test months into their therapy or patients who have had a first relapse but don’t respond to relapse chemotherapy are universally considered refractory. So, that is where the US Food and Drug Administration (FDA) approval lies right now.

There are many ongoing clinical trials for both tisagenlecleucel and different versions of the CD19 CAR T-cell therapy at various centers to study whether we can give it earlier to patients who have very early first relapse (they relapse and the leukemia comes back while they are still getting initial therapy) or to patients who don’t respond to therapy in the first course of their treatment. For these children, we want to know if we can do better by getting CD19 CAR T-cell therapy to them earlier. Other groups that teams are looking at to see if the CAR T-cell therapy is appropriate are patients who just relapsed in their spinal fluid or around their brain, which the leukemia does about 20% of the time, and patients who can’t undergo a bone marrow transplant or in whom the toxicity of a transplant would be so significant that it could lead to a child’s morbidity or mortality. The latter would be very high risk and makes people prefer to try something like tisagenlecleucel therapy instead of a bone marrow transplant. Again, these are populations we are studying actively right now and for whom we are hoping to move up CAR T-cell therapy earlier in their treatment course.

Q: In the context of CAR T-cell therapy, which is an immunotherapy, do we have a better understanding now as to how to target and stimulate the immune system to fight pediatric ALL? Are there additional immunotherapies or other CD19 or other CAR T-cell targeted immunotherapies that are being tested for efficacy in ALL?

Dr. Rheingold: There are several different CAR T-cell constructs, some of them going against the same CD19 protein that’s almost universally expressed on the outside of pediatric ALL, or pediatric B-cell ALL. There are also what we would call second-generation or humanized versions. Newer versions exist that are trying to stimulate the immune response even further, and CAR-T-cell therapies are in clinical trials targeting other proteins on the outside of leukemia cells. Here at the Children’s Hospital of Philadelphia and at the NCI, there is a CAR targeted to CD22, another protein on the outside of B-cell ALL that again is almost universally expressed.

Some centers in the United States right now have adult trials in which they are infusing both CAR CD19 and CAR CD22 simultaneously or they have engineered a CAR that can bind to both CD19 and CD22 simultaneously. Soon, we will be moving down to the pediatric population with the goal to prevent relapse of the child’s leukemia with a leukemia that no longer expresses the protein that the initial CAR T-cell therapy was trying to attack. Leukemia cells can get “smart” and downregulate the CD19 protein on the outside of their cells so that they’re invisible to the CAR T-cells floating around in the patient’s blood and bone marrow. We refer to these as CD19-negative relapses and thus the need for approaches like CD22-targeted therapy. There are also other targets that are actively being investigated. Hopefully in the next couple of years, we will have some targeted to very specific subtypes of protein. A gene called KMT2A seen frequently in infant ALL is of great interest in trying to target some of the abnormalities associated with that particular protein in other types of leukemia such as acute myeloid leukemia.

Q: Are there other types of therapies being investigated for pediatric B-cell ALL that you could highlight?

Dr. Rheingold: The Children’s Oncology Group currently has a national trial open at over 200 pediatric oncology centers where they’re studying a different means of attacking the CD19 protein with a drug called blinatumomab that is a bispecific antibody. It has one linker that attacks to the CD19 on the B-cell ALL, but as it is bispecific, it has a second linker that attacks to the patient’s T cells floating around in their body. So, with blinatumomab you don’t have to take the T cells out of the child. You can use the T cells that are in the child at the time the drug is actively infusing. The Children’s Oncology Group is studying whether adding that to our traditional relapse chemotherapy is better than just the relapse chemotherapy alone. Early data have shown that the blinatumomab infusions are less toxic than comparable cycles of intensive chemotherapy, but as the study is still accruing we don’t know if adding it in will improve outcomes. Blinatumomab itself was approved on the basis of early phase 1 and phase 2 clinical trials in pediatrics for children with second or greater relapse. It is very actively being used for patients who had relapsed both on that study and then off the study.

A different drug currently being studied in a phase 2 trial is inotuzumab, which is an antibody CD22 attached to a poison packet of calicheamicin. This is FDA-approved in adults, and we pediatric oncologists are actively trying to study it in pediatric and young adult patients as monotherapy. Preliminary data is promising based on some compassionate use reports that have been published. The Europeans as well are studying inotuzumab, which is given once a week for 3 weeks in pediatric patients.

Both of these drugs we hope to move forward in newly diagnosed patients in the next generation of the Children’s Oncology Group trials. This would mean that some children would get standard chemotherapy and some would get standard chemotherapy with blocks of these immunotherapies, either blinatumomab or inotuzumab, added in to their chemotherapy to see if we could increase cure rates and to make sure that when these are added into the regular chemotherapy, we don’t have increased toxicity.

Q: Finally, overall on the biology of pediatric B-cell ALL or its treatments, what are the big questions that you and your colleagues are addressing or would like to address as far as improving outcomes for children with this disease?

Dr. Rheingold: Immunotherapy is great at targeting B-cell ALL. We are not targeting T-cell ALL as well. When you collect the T cells, it’s very hard to get them to kill themselves when you reinfuse them into a patient. So, we are looking and trying to create immunotherapy that would work for T-cell ALL relapses as well as the current armamentarium of immunotherapy that works for B-cell ALL relapses.

The other area we have not discussed is precision medicine or targeted therapy. There are some genetic subtypes of leukemia that we have come to realize will be very responsive to drugs targeted to their genetic abnormality. The classic example of this is Philadelphia chromosome-positive ALL. In this case, there was a translocation and the very first targeted cancer therapy was designed to bind and eradicate the abnormal protein that was being made when the translocation occurred in the leukemia cells. That drug imatinib has now been proven through the Children’s Oncology Group to increase cure rates significantly. Pediatric patients were cured 30% to 40% of the time with bone marrow transplants. By adding a single oral drug the patients took daily to a chemotherapy backbone, now upward of 70% to 80% of children are cured.

Other subtypes of leukemia that people have discovered are now called Philadelphia-like ALL. These respond to the same drug, and we are studying whether those subgroups also do better when we use tyrosine kinase inhibitors in combination with standard chemotherapy. So ruxolitinib, dasatinib, and imatinib are all being studied on top of chemotherapy backbones.

That being said, the number of newer targeted agents that are being approved for all types of adult cancers that might work on pediatric leukemia pathways is tremendous. So, we have to figure out the toxicity of these drugs alone and in combination, and how exactly to get them into the appropriate patients who are showing the genetic susceptibility in their specific type of leukemia. It’s an exciting time to be a pediatric leukemia specialist, but we have a lot of work ahead of us to see how much more targeted therapy and immunotherapy we can add to chemotherapy and then begin to study how we can reduce chemotherapy so children don’t have the same amount of long-term effects they have had historically.

Key Question

Is it clear from the studies that have been done whether there are patients who are more likely to respond? Also, can you talk about whether the CAR T-cell therapy is still being done at specific centers that have experience with this treatment?

Dr. Rheingold: The only pediatric centers in the United States right now that are participating in CAR T-cell therapy trials are centers with expertise in bone marrow transplant, meaning they have accreditation to collect normal T cells from patients with leukemia through a process called apheresis and they have the ability to give stem-cell infusions. These centers received a lot of the accreditation they need because they are actively doing bone marrow transplants. Other centers are learning how to collect, and we will probably have more centers that have the capability of doing this in the future. Currently, most of the trials are going on in about 40 centers across the United States, but I think that will increase to upward of 60 to 80 centers at which patients will be able to receive CAR T-cell therapy in the next couple of years. There are also more centers that can collect the T cells but don’t actually have experience with infusing them. As long as these centers collect them in the standards required, the patient’s T cells can be frozen and shipped across the country very safely and then either manufactured in a clinical trial site or by the manufacturer of tisagenlecleucel if it’s that product.

What is great about CAR T-cell therapy is it seems that all patients, ages, and genetic subtypes respond. Upward of 90% of patients who actually receive the infusion go into complete remission. We really have not identified any subgroup that does not seem to do as well. Bigger and bigger numbers will allow us to begin to break down genetic subgroups over the next couple of years to see if there is any difference, but the experience right now is as long as it’s a B-cell ALL and it expresses the CD19 protein, most patients have a very good, if not excellent chance of going into complete remission with tisagenlecleucel therapy.

Key Question

Is it clear from the studies that have been done whether there are patients who are more likely to respond? Also, can you talk about whether the CAR T-cell therapy is still being done at specific centers that have experience with this treatment?

Dr. Rheingold: The only pediatric centers in the United States right now that are participating in CAR T-cell therapy trials are centers with expertise in bone marrow transplant, meaning they have accreditation to collect normal T cells from patients with leukemia through a process called apheresis and they have the ability to give stem-cell infusions. These centers received a lot of the accreditation they need because they are actively doing bone marrow transplants. Other centers are learning how to collect, and we will probably have more centers that have the capability of doing this in the future. Currently, most of the trials are going on in about 40 centers across the United States, but I think that will increase to upward of 60 to 80 centers at which patients will be able to receive CAR T-cell therapy in the next couple of years. There are also more centers that can collect the T cells but don’t actually have experience with infusing them. As long as these centers collect them in the standards required, the patient’s T cells can be frozen and shipped across the country very safely and then either manufactured in a clinical trial site or by the manufacturer of tisagenlecleucel if it’s that product.

What is great about CAR T-cell therapy is it seems that all patients, ages, and genetic subtypes respond. Upward of 90% of patients who actually receive the infusion go into complete remission. We really have not identified any subgroup that does not seem to do as well. Bigger and bigger numbers will allow us to begin to break down genetic subgroups over the next couple of years to see if there is any difference, but the experience right now is as long as it’s a B-cell ALL and it expresses the CD19 protein, most patients have a very good, if not excellent chance of going into complete remission with tisagenlecleucel therapy.

Financial Disclosure:Dr. Rheingold received a research grant from Pfizer.

PERSPECTIVE

At the Forefront of Development

Pat Brown, MD

The cure rate for pediatric ALL in the U.S. has risen from 0% in the 1960s to nearly 90% today. This is among the most profound medical success stories in history. A critical contributor to this progress, and progress made in childhood cancer generally, is the comprehensive, collaborative research network that includes the vast majority of hospitals and physicians that treat children, adolescents and young adults with cancer. The improved outcomes in pediatric ALL have been due to a number of factors, including optimizing combinations of chemotherapy, improving supportive care to minimize severe side effects, and incorporating novel diagnostic technologies to guide more personalized, risk-stratified treatment. In addition, pediatric ALL is at the forefront of the development of novel treatments that harness our own immune systems to kill cancer, including chimeric antigen receptor (CAR) T-cells, bispecific T-cell engaging antibodies (BiTEs) and antibody-drug conjugates (ADCs).

Financial Disclosure:Dr. Brown has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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