Children with Down syndrome carry an elevated risk of developing acute lymphoblastic leukemia (ALL). Along with increased incidence of the disease, these children experience higher frequency of toxicity with chemotherapy and generally have poorer outcomes.
Diagnosis of B-ALL at 4 and relapse at 15
Steven, 21, who has Down syndrome, was diagnosed with B-ALL when he was 4 years old. He was successfully treated in his hometown of Toronto, Canada, using standard chemotherapy. Nearly 11 years later, in December 2015, his mother, Theresa, noticed petechiae. “I experienced a sinking feeling that this could be leukemia again,” says Theresa — and it was. A relapse of B-ALL was confirmed within hours and Steven was immediately admitted to the local children’s hospital.
Theresa describes Steven's pediatric oncologist as “a fierce advocate for Steven and all patients who have Down syndrome. His quest is to have CAR [chimeric antigen receptor] T-cell therapy become the first course of treatment for leukemia patients who have Down syndrome.”
CAR T-cell therapy for children with Down syndrome and B-ALL
The CD19-directed CAR T-cell therapy known as Kymriah® (tisagenlecleucel, formerly CTL019) received U.S. Food and Drug Administration approval in August 2017 for children and young adults up to age 25 with B-ALL that is refractory or in second or greater relapse, based on the extraordinary success of studies led by Children’s Hospital of Philadelphia (CHOP) in collaboration with University of Pennsylvania and Novartis. The therapy reprograms the patient’s own T cells to locate and kill B cells that have the protein CD19 on their surface.
At the time of Steven’s relapse, he was not eligible for a multi-institutional trial of CTL019, which was soon to open at his home institution because this was his first relapse. Worried about poor outcomes of relapse therapy in patients with Down syndrome, Steven’s oncologist contacted the Cancer Immunotherapy Program at CHOP and was told Steven might be eligible to enroll in a clinical trial led by Shannon Maude, MD, PhD, that is evaluating an alternative, humanized CD19 CAR-T product, referred to as huCART19 or CTL119. Steven’s T cells were collected in his Canadian hospital, and he was started on a modified chemotherapy regimen to control the leukemia while reducing intensity in an attempt to minimize toxicity.
Weeks later, in January 2016, Steven and his family came to CHOP for the consent meeting required of each potential cell therapy recipient. After an evaluation, Steven was enrolled in the trial.
Steven returned to Canada and received chemotherapy for several weeks while his T cells went through the manufacturing process to reprogram them to locate and eliminate the cancerous B cells.
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He returned to CHOP in March 2016 and received the CAR T-cell therapy. Considering that the family had been hopefully anticipating this game-changing therapy for three months, Theresa found it remarkable that the infusion was so fast and simple. “It was uneventful,” she reports. “We were surprised by how quickly the procedure took place — only a few minutes.”
Four days later, Steven developed a fever — a common side effect — and was admitted to CHOP. High, persistent fever is a hallmark of the most common side effect after CD19 CAR T-cell therapy, cytokine release syndrome (CRS). Generally, CRS severity correlates with high disease burden. He remained inpatient for 6 days and was out for only about an hour when he was re-admitted following a seizure.
Neurotoxicity occurs in approximately 40% of patients, who might experience delirium, confusion and aphasia that can last several days. More rarely, some patients experience seizures. Unlike CRS, the reason for this reaction is not fully understood, but recent research conducted at CHOP and other institutions suggests the involvement of several cytokines. Steven received anti-seizure medications with no further seizures, and he was discharged after 2 days.
Now, more than a year-and-a-half after the therapy, Steven is thriving. “He is living a very active and fulfilling life, and is feeling and looking completely healthy,” reports Theresa.
The Cancer Immunotherapy Program at CHOP is developing a clinical trial of CAR T-cell therapy for children with Down syndrome and B-ALL in first relapse.