Mechanism of Action

Kymriah (tisagenlecleucel) is a CD19-directed genetically modified autologous T cell immunotherapy which involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells. The CAR is comprised of a murine single-chain antibody fragment which recognizes CD19 and is fused to intracellular signaling domains from 4-1BB (CD137) and CD3 zeta. The CD3 zeta component is critical for initiating T-cell activation and antitumor activity, while 4-1BB enhances the expansion and persistence of Kymriah. Upon binding to CD19-expressing cells, the CAR transmits a signal to promote T-cell expansion, activation, target cell elimination, and persistence of the Kymriah cells

Side Effects

Adverse effects associated with the use of Kymriah may include, but are not limited to, the following:

Cytokine release syndrome

Hypogammaglobulinemia

Infections-pathogen unspecified

Pyrexia

Decreased appetite

Headache

Encephalopathy

Bleeding episodes

Tachycardia

Nausea

Diarrhea

Vomiting

Viral infectious disorders

Hypoxia

Fatigue

Acute kidney injury

Delirium

The Kymriah label comes with the following Boxed Warning:

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Kymriah. Do not administer Kymriah to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab.

Neurological toxicities, which may be severe or life-threatening, can occur following treatment with Kymriah, including concurrently with CRS. Monitor for neurological events after treatment with Kymriah. Provide supportive care as needed.

Kymriah is available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the Kymriah REMS.

Dosing/Administration

Kymriah is supplied as a suspension for intravenous infusion. Prior to infusion: premedicate with acetaminophen and an H1-antihistamine and confirm the availability of tocilizumab in the event of a CRS reaction. Dosing is based on the number of chimeric antigen receptor (CAR) positive viable T-cells. For patients 50 kg or less, administer 0.2 to 5.0 x 10(6) CAR-positive viable T- cells per kg body weight intravenously. For patients above 50 kg, administer 0.1 to 2.5 x 10(8) total CAR-positive viable T-cells (non-weight based) intravenously.

Clinical Trial Results

The FDA approval of Kymriah was based on an open-label, multicenter single-arm trial in pediatric and young adults with R/R B-cell precursor ALL. In total, 88 subjects were enrolled and 63 were evaluable for efficacy. Treatment consisted of lymphodepleting chemotherapy (fludarabine 30 mg/m2 daily for four days and cyclophosphamide 500 mg/m2 daily for two days), followed by a single dose of Kymriah. Of the 22 patients who had a WBC count < 1000/µL, 20 received lymphodepleting chemotherapy prior to Kymriah while two received Kymriah infusion without lymphodepleting chemotherapy. Fifty-three patients received bridging chemotherapy between time of enrollment and lymphodepleting chemotherapy. The efficacy of Kymriah was established on the basis of complete remission (CR) within three months after infusion, the duration of CR, and proportion of patients with CR and minimal residual disease (MRD) < 0.01 percent by flow cytometry (MRD-negative). Among the 63 infused patients, 52 (83 percent) achieved CR/CRi, all of which were MRD-negative. With a median follow-up of 4.8 months from response, the median duration of CR/CRi was not reached (range: 1.2 to 14.1+ months). Median time to onset of CR/CRi was 29 days with onset of CR/CRi between 26 and 31 days for 50/52 (96 percent) responders. The stem cell transplantation rate among those who achieved CR/CRi was 12 percent (6/52).