Alternative Treatment Options Emerging for Relapsed Pediatric Patients With ALL

Susan R. Rheingold, MD

The September 2017 FDA approval of tisagenlecleucel (Kymriah), the chimeric antigen receptor (CAR) T-cell therapy, has already made a significant impact on pediatric patients with acute lymphoblastic leukemia (ALL).

Additionally, inotuzumab ozogamicin (Mylotarg) and blinatumomab (Blincyto) have proven successful alternative options for younger patients, as well. There are currently ongoing trials recruiting patients through the Children’s Oncology Group that are investigating the response of these drugs in relapsed or refractory B-cell ALL.

“There are many great trials for patients with relapsed ALL,” said Susan R. Rheingold, MD. “Children and infants with relapsed ALL should go on these trials to get access to these new drugs. It is important to encourage families to participate.”

OncLive: What is the role of CAR T-cell therapy in pediatric ALL?

Are there any other regimens in the pipeline that are showing a similar impact?

In an interview with OncLive, Rheingold, medical director of the Oncology Outpatient Clinic, physician with the Cancer Center at Children’s Hospital of Philadelphia, discusses the impact of CAR T-cell therapy on patients with ALL and options for patients who relapse on treatment.Rheingold: CAR T-cell therapy is not yet approved for upfront treatment. However, for relapsed disease, it has made a significant change in the number of children it will put back into remission and ultimately cure. It is probably the most promising new cancer therapy in a long time for any type of cancer. However, it is not a frontline therapy for newly diagnosed children; therefore, it will not be replacing frontline chemotherapy just yet.It is better to have relapsed ALL now rather than 10 years ago, because there is a whole class of immunotherapy drugs that are altering the treatment paradigm.

This includes inotuzumab ozogamicin, which targets a different protein on the outside of CD22. There is also blinatumomab, which targets the same protein as the CAR T-cell therapy, but T cells are not needed.

We are learning more about genetic evaluation of this leukemia and we are finding other targets that might already have approved drugs in lung cancer or colorectal cancer. We are attempting to learn about those drugs to move them into the pediatric treatment landscape.

Which ongoing trials are you anticipating the results of?

Targeted therapy and immunotherapy is giving us a much bigger armamentarium for patients with relapsed ALL. The CAR T trials are still ongoing. They will begin to look at some specific populations to give this treatment earlier, such as infants with ALL and patients with Down syndrome.

The inotuzumab ozogamicin trial is the first pediatric trial in the United States that is open and enrolling through the Children’s Oncology Group right now. The first relapsed disease trial through the Children’s Oncology Group is studying blinatumomab. The study is looking at blinatumomab replacing blocks of chemotherapy as it is less toxic.

Currently, what are the most pressing unmet needs for pediatric patients with ALL?

Those are some trials for targeted therapy, but there are many ongoing trials looking at different types of pediatric cancer. Since all trials will have a cohort of patients with ALL or acute myeloid leukemia, the investigators of the trials are interested in seeing what will lead to a better response or we can target something specifically.For ALL, we need more treatments for patients under 1 year old, who mostly have a specific subtype of cancer that is difficult to treat. These patients have a 50% outcome and the younger the patient, the worse the outcome. If a patient is less than 3 months old, they have less than a 20% survival rate.

There is a group of patients with relapsed ALL where CAR T-cell therapy does not work. CAR T-cell therapy, inotuzumab, and blinatumomab attack B-cell ALL, which makes patients with the T-cell ALL difficult to treat. We can cure 90% of those patients, but if they relapse after initial therapy, it is a challenge. T-cell ALL and infant ALL are 2 very challenging subtypes.

What advice do you have for physicians who are treating pediatric patients with ALL?

Within B-cell ALL, there is the Philadelphia chromosome (Ph)-like ALL. This is where we are starting to use the new targeted agents. We are finding genetic abnormalities that may be targetable. If we can target them and add that drug to chemotherapy, we can most likely do the same for Ph-positive ALL. By adding a treatment to chemotherapy, it could radically change the number of patients who are cured.Many times, the parent does a lot of the research and comes back to the oncologist with trials that they found online for their children with relapsed ALL. Parents should not have to do that. There are many great trials for patients with relapsed ALL. Children and infants with relapsed ALL should go on these trials to get access to these new drugs. It is important to encourage families to participate.

Unfortunately, it can be overwhelming for a family to travel to a big city or a bigger center that can provide one of these trials. It is not practical for these large studies to be at smaller centers due to many reasons, such as administration details. It can be a challenge to get these patients onto newer trials that investigate the genome of the leukemia to see what other targets might exist to expand these trials further. If the patients have a specific target that has a drug in another cancer type, it could be added to chemotherapy at the time of relapse.

Is there any other information that is worth mentioning?

Families are the biggest advocates for their child. For example, there is always a family member who has some form of medical knowledge and takes the time to look up trials online. That family member can call the center and then the center can call the family to discuss the child entering the trial. Doctors should be working to get these patients on trials to hopefully find them a newer drug before the child is terribly ill and is too sick to receive them.Considering CAR T-cell therapy, families need to get their child to the center to collect T cells early. They can be stored if they are not needed but sometimes, after chemotherapy, it is hard to collect the T cells. You do not want to collect them when the patient is first diagnosed, but, if they relapse, it should be considered.