Tisagenlecleucel is a chimeric antigen receptor T cell (CAR-T) therapy that has been licensed by the FDA. According to new research published in Blood Advances, young people who got higher doses of CAR-T therapy lived longer than those who got lower doses.

Tisagenlecleucel has been a welcome treatment option for young patients with B-cell acute lymphoblastic leukemia (B-ALL) whose illness does not respond to chemotherapy or recurs after a past response since it was approved as the first gene therapy to be made available in the United States in 2017.

The wide dosing range permitted for the medication, however, can be a challenge for physicians who occasionally must choose between using a higher or lower dose with scant data to support these choices. Based on actual data, this new study provides the first insights into ideal dosing.

“In the past,” says Liora Schultz, MD, a pediatric oncologist at Stanford Children’s Health | Lucile Packard Children’s Hospital and the study’s lead author, “we did not have data to guide clinical decisions around commercial CAR T-cell dosing and didn’t know if higher doses would affect toxicity and compromise outcomes, or support enhanced anti-leukemia effect.” 

As it supports the use of increased dosing when accessible within the approved tisagenlecleucel dose range, the study “has direct clinical applicability.”

The most prevalent cancer in children is ALL, and the most prevalent subtype of ALL is B-ALL. Chemotherapy is frequently effective in treating it, although about 20% of patients—or one out of every five—either do not respond to treatment or later relapse.

CAR T-cell therapy is a form of immunotherapy in which a patient’s T cells—immune cells in the body that fight infection—are taken out, genetically altered in a lab to help them recognize cancer cells, and then injected back into the patient’s bloodstream, where they find and kill cancer cells.

For young patients with relapsed or resistant B-ALL, this therapy is increasingly being used as an addition to or an alternative to stem cell transplantation.

For individuals weighing 50 kilograms or less, tisagenlecleucel is approved at a dose range of 0.2 to 5 million CAR T cells/kg, or 10 to 250 million CAR T cells for those over 50 kilograms.

According to the initial number of T cells collected and the rate at which the changed cells multiply in the lab, the actual number of CAR T cells produced for each patient varies significantly.

Any quantity of CAR T cells that falls within the acceptable range is regarded as a safe dose, but if more than the required number of cells are available, physicians may choose to utilize a larger or lower quantity.

Tisagenlecleucel clinical trials produced dose recommendations that led to the therapy’s approval, but real-world data is helpful to fine-tune dosing and guide decision-making when there are several possibilities.

In the trial, 185 patients aged 26 or younger who received tisagenlecleucel for relapsed or refractory B-ALL were examined for rates of overall survival, event-free survival, and relapse-free survival at one year.

They discovered that, in comparison to patients who received a dose at the lower end (between zero and 1.3 million cells/kg), patients who received a dose at the higher end of the permitted range (between 2.4 and 5.1 million cells/kg) had significantly higher survival rates according to all three measures.

86 percent of patients in the highest dose group were still alive at one year, as opposed to 59 percent in the lowest dose group. Higher doses did not appear to increase toxicity or raise any safety issues, according to the study’s findings.

The results imply that delivering tisagenlecleucel doses at the higher end of the recommended range may aid in achieving a more long-lasting and effective response without increasing the risk of harm. 

“A lot of effort is focused on complex engineering and development of next-generation CAR-T therapies,” adds Dr. Schultz. “This study aims to explore if clinical manipulations using our current approved construct, tisagenlecleucel, can achieve even incremental advances in the field.”

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