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WASHINGTON -- An FDA advisory committee today unanimously recommended approval of the CAR T-cell therapy tisagenlecleucel (CTL019) for pediatric and young-adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL).

The (ODAC) voted 10-0 in favor of approval after hearing reports from FDA staff and Novartis regarding the development, manufacturing, efficacy, and safety of CTL019, the first-ever CAR T-cell therapy submitted for FDA approval. The therapy consists of genetically modified antigen-specific autologous T cells programmed to target CD19, an antigen expressed by B-cells and tumors of B-cell origin.

As noted in the FDA staff report, the product's efficacy was not in question, but instead its short- and long-term safety. ODAC members expressed satisfaction with Novartis' plan to minimize risk, which includes limiting distribution of the therapy to selected centers experienced with CAR T-cell therapy (at least initially) and plans for extensive, long-term postmarketing surveillance.

"This is a very poor-risk population and represents a very great unmet need in the pediatric population," said Catherine M. Bollard, MD, of George Washington University here. "The clinical responses are remarkable, and I think Novartis has done a great job of putting together a plan for mitigating risk."

Brian Rini, MD, of the Cleveland Clinic, characterized the therapy as "potentially paradigm changing."

Despite unknowns surrounding the therapy, "it is hard to argue with the unprecedented clinical success we have seen in this population of patients who do not have other viable treatment options," added Grzegorz S. Nowakowski, MD, of the Mayo Clinic in Rochester, Minn.

ODAC chair Bruce Roth said the therapy is "clearly a high-risk approach for a disease that has very few alternative options that also are associated with toxicity. While I have some concerns about late toxicity, you have to be a long-term survivor to experience late toxicity, and I think that's what this drug gives us."

Principal supporting data for the application came from a phase II trial of children and young adults with relapsed/refractory ALL, given a single infusion of CTL019.

Overall, 52 of 63 evaluable patients had objective responses with CTL019, including patients whose disease proved resistant to multiple prior lines of therapy.

A safety analysis of 68 patients from the same phase II trial showed that potentially life-threatening grade 3/4 cytokine release syndrome (CRS) occurred in 32 patients, some of whom developed serious hemophagocytic lymphohistiocytosis (HLH) concurrently with CRS or after CRS resolution. No patient died of CRS.

Additionally, 30 patients developed neurologic adverse events of varying type and severity, ranging from encephalopathy, seizure, delirium, and hallucinations to muscular weakness and dysarthria.

The staff report also raised concern about the potential long-term safety of CTL019, specifically the potential to generate replication-competent retrovirus and the potential for insertional mutagenesis that could cause new malignancies. Those safety issues did not arise during the phase II trial, but the patients have relatively limited follow-up. As a result "postmarketing considerations for long-term safety monitoring may be necessary to address the potential safety concern."

Novartis officials acknowledged the adverse events associated with CAR T-cell therapy in general, including the potential for serious adverse events. They concluded that "the safety profile of tisagenlecleucel is well characterized, and toxicity is manageable in the hands of appropriately trained healthcare providers, although patients may require ICU-level care for the management of severe CRS." CTL019 demonstrated consistent safety across three separate clinical trials involving children and young adults with relapsed/refractory B-cell ALL, the officials added.

Novartis seeks approval of CTL019 for treatment of pediatric and young-adult patients with relapsed or refractory B-cell ALL. The FDA is not bound by the decisions of its advisory committees but follows the recommendations more often than not.

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