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CAR T-Cell Therapy Approval Starts New Path in Childhood Leukemia

Angelica Welch
Published: Thursday, Nov 16, 2017

In addition to CAR T-cell therapy, there are also some interesting antibody-based immunotherapies for patients with acute leukemias. The CD19 x CD3 bispecific T cell engager antibody blinatumomab (Blincyto) and the CD22-targeting antibody-drug conjugate inotuzumab ozogamicin (Besponsa) were recently FDA-approved for adults with relapsed B-ALL. Blinatumomab and inotuzumab are actively being studied in children with relapsed B-ALL via current Children’s Oncology Group (COG) trials. In AML, earlier efforts focused on targeting CD33 with the antibody-drug conjugate gemtuzumab ozogamicin (Mylotarg), which was also recently FDA approved for adults with AML. Mylotarg has also been extensively tested in children with AML via a COG trial.

I am also particularly interested in a new CD123-targeting dual-antigen retargeting antibody, flotetuzumab, that is demonstrating interesting early activity in a phase 1 trial with adults with relapsed/refractory AML. We are actively developing a phase 1 COG trial of flotetuzumab for children with relapsed AML. It is certainly an exciting time in the leukemia field with many promising new targeted immunotherapies.

Are there any current trials in pediatric leukemia that look promising?

Another major area of investigation is testing kinase inhibitors in specific genetic subsets of childhood B-ALL that have activated oncogenic kinase signaling. The recent identification of the Philadelphia chromosome-like (Ph-like) subset of ALL has led to two active trials through the COG, as well as similar studies at St. Jude Children’s Research Hospital, looking at the addition of kinase inhibitors to chemotherapy backbones. The COG trial AALL1131 is studying the efficacy of dasatinib (Sprycel) in children with Ph-like ALL and ABL class mutations, and the COG trial AALL1521 is investigating the addition of ruxolitinib (Jakafi) in Ph-like ALL with JAK pathway mutations.

There has also been a lot of buzz about FLT3 mutations in adult AML. The FLT3 inhibitor midostaurin (Rydapt) was FDA-approved this past year, and exciting early phase clinical trial data have been presented regarding more selective FLT3 inhibitor treatment of adults with relapsed AML. The COG is also planning to study these next-generation selective FLT3 inhibitors in children with FLT3-mutant AML, both in the relapsed and newly diagnosed settings.

You mentioned some targets and agents used in adult leukemia. In what ways does this treatment translate to pediatrics, if at all?

Globally, drug development in children has been terribly slow, because often a drug must be tested extensively in adult patients before we might have access to it in pediatrics. The approval of CD19 CAR T cells first in children with B-ALL is thus a major success in terms of efficacy, as well as getting something approved first in pediatrics.

I will also caution that children often tolerate anti-cancer agents much differently—and often better than adults—so it is critically important to assess toxicity and efficacy of new drugs specifically in a pediatric population. Children often have fewer medical comorbidities, and we are often able to drive the dose of a medication higher in children than adults safely and tolerably. It is also very important to include our adolescents and young adults, who have a foot in both the pediatric and adult worlds, in trials of new agents to determine their unique toxicity and activity profiles

While the biology of pediatric and adult leukemias certainly can differ, we have a lot to learn from each other across the age spectrum. Many of the successes in treatment of childhood ALL have now been translated to the care of adults with ALL. Conversely, there are many exciting new drugs for adults with genetic subsets AML that we also hope to be able to study in children.

What advice would you give community oncologists and other specialists that manage children with hematologic malignancies?

First and foremost, a deep molecular characteristic of a patient's leukemia is incredibly informative. Now that we have new technologies like next-generation sequencing, we can profile a child’s leukemia at a very sophisticated level to identify the mutations or alterations that might drive the leukemia and be amenable to targeted therapies.

We also know that how patients respond to the first month of chemotherapy is incredibly important and prognostic. This is what we call measurement of minimal residual disease assessments, which is usually done in North America by flow cytometry and in Europe by polymerase chain reaction (PCR)-based testing.

New and very sensitive next-generation PCR-based techniques are now available, so we will likely learn a lot more in the coming years about the prognostic impact of the depth of patients’ molecular responses with treatmetn.


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Online CME Activities
TitleExpiration DateCME Credits
Oncology Briefings™: Overcoming Chronic Iron Overload in Pediatric AML and MDSJun 30, 20181.0
Oncology Briefings™: Updates in Rare Hematology: Advancing Care and Improving Outcomes for Patients with Aplastic AnemiaAug 31, 20181.0
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