Perspective from Ryan D. Cassaday, MD
August 30, 2017
5 min read

FDA approves Kymriah as first chimeric antigen receptor T-cell therapy

Perspective from Ryan D. Cassaday, MD
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Stephan A. Grupp
Kenneth C. Anderson

The FDA today approved tisagenlecleucel T-suspension for the treatment of children and young adults with B-cell acute lymphoblastic leukemia.

Tisagenlecleucel T-suspension (Kymriah, Novartis) — the first chimeric antigen receptor (CAR) T-cell therapy approved in the United States — is indicated for patients aged up to 25 years with refractory B-cell precursor ALL, as well as those whose disease is in second or later relapse.

Tisagenlecleucel is the first CAR T-cell therapy to demonstrate early, deep and durable remission in this patient population, and it likely will become the new standard of care, according to Stephan A. Grupp, MD, PhD, Yetta Deitch Novotny professor of pediatrics at Perelman School of Medicine at University of Pennsylvania and director of the Cancer Immunotherapy Frontier Program at Children’s Hospital of Philadelphia.

“This is a group of patients for whom current treatments don’t do anything,” Grupp told HemOnc Today. “They have very little long-term prospect of remaining in remission and almost no potential for cure. … This is a group with a very high unmet medical need.”

Novartis and University of Pennsylvania entered into a global collaboration in 2012 to research, develop and commercialize CAR T-cell therapies for the treatment of cancers.

Patients with relapsed or refractory B-cell precursor ALL often undergo several treatments, including chemotherapy, radiation, targeted therapy or stem cell transplant. However, prognosis remains poor, as more than 90% of patients die within 5 years.

Tisagenlecleucel — a novel immunocellular therapy formerly known as CTL019 — is comprised of genetically modified T cells that target CD19, an antigen expressed on the surface of B cells.

The FDA based tisagenlecleucel’s approval on results of the open-label, single-arm phase 2 ELIANA trial, conducted at 25 centers in the United States, Canada, Europe, Australia and Japan.

Sixty-eight patients were infused with tisagenlecleucel, and 63 were evaluable for efficacy.

Fifty-two patients (83%) achieved complete remission or complete remission with incomplete blood count within 3 months of infusion. Median duration of remission had not been reached (95% CI, 7.5 months to not estimable).


Researchers detected no minimal residual disease among responding patients.

“We have been very impressed by how well this approach works for this patient population,” Grupp, lead investigator of the ELIANA trial, told HemOnc Today. “Short term, it works very well to get patients into remission. We’re also starting to see long-term efficacy.

“The first patient we treated 5 years ago remains in remission, and the event-free survival for patients who respond is around 60% at 1 year,” Grupp added. “There are a lot of patients who are getting long-term disease control, and we hope there is actually some permanence to their disease control from this one-time therapy.”

Forty-nine percent of patients in the ELIANA trial experienced grade 3 or grade 4 cytokine release syndrome, caused by an overreactive immune response.

The FDA today also announced the approval of tocilizumab (Actemra, Genentech) — an anti-human interleukin-6 receptor antibody administered via IV injection — for the treatment of CAR T-cell therapy-induced severe or life-threatening cytokine release syndrome in patients aged 2 years or older.

“Cytokine release syndrome is a significant toxicity,” Grupp said. “Those T cells are growing very rapidly, and they produce a lot of inflammatory proteins. However, we have learned a lot about how to deal with cytokine release syndrome, and also how to predict it. We started using tocilizumab in our patients about 5 years ago, and that has really saved the field of active cell therapy.”

Eighteen percent of patients in the ELIANA trial experienced grade 3 or grade 4 neurologic events within 8 weeks of treatment. The most common neurologic events included headache (37%), encephalopathy (34%), delirium (21%), anxiety (13%) and tremor (9%).

Adverse reactions that occurred in more than 20% of patients included cytokine release syndrome, hypogammaglobulinemia, infections, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury and delirium.

Due to the potential of fatal or life-threatening side effects, the FDA approved a Risk Evaluation and Mitigation Strategy for tisagenlecleucel to help educate clinicians about the risks associated with treatment.


The approval of tisagenlecleucel “marks an important shift” in the treatment paradigm for hematologic malignancies, according to ASH President Kenneth C. Anderson, MD, director of Lebow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute.

“We now have proof that it is possible to eradicate cancer by harnessing the power of a patient’s own immune system,” Anderson said in a society-issued press release. “This is a potentially curative therapy in patients whose leukemia is unresponsive to other treatments and represents the latest milestone in the shift away from chemotherapy toward precision medicine. …

“While the importance of CAR-T cannot be overstated, this approval only pertains to a small population of children,” Anderson added. “More research is needed to make this therapy more effective for a broader population, to reduce the severe side effects that patients experience during treatment, and ultimately to find a broader application beyond blood cancers. Continued research will also lead to improved manufacturing of large numbers of cells, which is necessary to make this therapy accessible to more patients.”

Novartis expects to make additional filings with the FDA and European regulatory authorities later this year, including an application for use of tisagenlecleucel for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma. – by Mark Leiser

For more information:

Stephan A. Grupp, MD, PhD, can be reached at

Disclosure: Grupp reports research support from Novartis.