Kymriah (tisagenlecleucel) - 3 indications

Scroll down for more information on each condition:

• for the treatment of refractory B-cell precursor acute lymphoblastic leukemia; approved August 2017
• for the treatment of relapsed or refractory large B-cell lymphoma; approved May of 2018
• for the treatment of relapsed or refractory follicular lymphoma; approved May of 2022

General Information

Kymriah (tisagenlecleucel) is a CD19-directed genetically modified autologous T cell immunotherapy.

Kymriah is specifically indicated for:

• Patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.
• Adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.
• Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. 

Kymriah is supplied as a suspension for intravenous infusion. Scroll down for recommended dosing for each condition.

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. 

Indication 1 - for the treatment of refractory B-cell precursor acute lymphoblastic leukemia

approved August 2017

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). 

Indication 2 - for the treatment of relapsed or refractory large B-cell lymphoma

approved May of 2018

Dosing/Administration

Kymriah is provided as a single-dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive viable T cells. For adult patients administer 0.6 to 6.0 x 108 CAR-positive viable T cells.

Clinical Trial Results

The FDA approval of Kymriah in adult patients with r/r DLBCL is based on the pivotal phase II JULIET clinical trial, the first multi-center global registration study for Kymriah in adult patients with r/r DLBCL. JULIET enrolled patients from 27 sites in 10 countries across the US, Canada, Australia, Japan and Europe, including: Austria, France, Germany, Italy, Norway and the Netherlands. In the JULIET trial, patients were infused in the inpatient and outpatient setting. Kymriah showed an overall response rate (ORR) of 50%, with 32% of patients achieving a complete response (CR) and 18% achieving a partial response (PR) in 68 patients evaluated for efficacy. The median duration of response was not reached among these patients, indicating sustainability of response. 

In all patients infused with Kymriah (n=106), severe or life-threatening (grade 3/4) CRS, defined by the Penn Grading Scale -a rigorous scale for grading this reaction-, occurred in 23% of patients.

Indication 3 - for the treatment of relapsed or refractory follicular lymphoma

approved May of 2022 - approved under the FDA's accelerated approval program

Dosing/Administration

Kymriah is provided as a single-dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive viable T cells. For adult patients administer 0.6 to 6.0 x 108 CAR-positive viable T cells.

Clinical Trial Results

The FDA approval is based on data from the Phase II ELARA trial, a single-arm, open-label trial, in which 90 patients were evaluated for efficacy with a median follow-up of approximately 17 months. Eighty-six percent of patients treated with Kymriah achieved a response including 68% who experienced a complete response.  Prolonged durable response to treatment was demonstrated with an estimated 85% of patients who achieved a complete response still in response 12 months after initial response. Kymriah was shown to be effective in high-risk patients including those who were heavily pretreated or had refractory disease, POD24, bulky disease or those with high Follicular Lymphoma International Prognostic Index (FLIPI) scores.