Diffuse Large B-Cell Lymphoma (DLBCL)


Yescarta® (axicabtagene ciloleucel) is one of the first autologous chimeric antigen receptor (CAR) T-cell therapies to use cells from a patient’s own immune system to target and fight cancer. This genetically modified immunotherapy is directed at antigen CD19, and each infusion of Yescarta contains a suspension of CAR-positive T cells that can recognize and eliminate CD19-expressing target cells.

Yescarta is for autologous use only, as it is prepared from the patient’s peripheral blood mononuclear cells, which are collected in a leukapheresis process. The drug is manufactured and distributed by Kite Pharma, a subsidiary of US-based biopharmaceutical company Gilead Sciences.1 The FDA first approved Yescarta on October 18, 2017.4 In March 2021, the FDA granted accelerated approval to Yescarta for the additional indication of adults with relapsed or refractory follicular lymphoma. In April 2022, the FDA granted its third indication to Yescarta.4,5

Indications

Yescarta is indicated for the treatment of adult patients with the following: 

  • Large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months after first-line chemoimmunotherapy
  • Relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma, after 2 or more regimens of systemic therapy.2
  • Relapsed or refractory follicular lymphoma after 2 or more lines of systemic therapy. Yescarta has received US Food and Drug Administration (FDA) accelerated approval for this indication on the basis of response rates.

Yescarta cannot be given to patients with primary central nervous system lymphoma.2

Mechanism of Action

Yescarta is a novel drug used in CAR-T therapy, in which a patient’s own T cells are genetically modified to recognize and attack lymphoma cells. Yescarta has an anti-CD19 extracellular domain that targets and binds to CD19 on the surface of normal and malignant B cells. After antigen binding, the CD28 and CD3-zeta costimulatory domains activate downstream signaling cascades that activate and promote the growth of T cells, causing them to become effector cells and release inflammatory cytokines and chemokines. The cells expressing CD19 are killed as a result of this chain of events.1,6,7 

Read more about DLBCL experimental therapies

Administration

A 3-day regimen of lymphodepletion is required for commencing treatment with Yescarta. This short round of chemotherapy preconditions the patient’s body to accept treatment.

The drug is for autologous use only and must be administered via intravenous infusion in a certified health care facility. Patients must be monitored daily at this facility for a week following the infusion for signs of cytokine release syndrome (CRS) and neurological toxicities. 2

A single infusion bag of Yescarta contains a suspension of CAR-positive T cells in approximately 68 mL. The dose of Yescarta is based on the number of CAR-positive viable T cells. The target dose is 2 x 106 CAR-positive viable T cells per kilogram of body weight, with a maximum dose of 2 x 108 CAR-positive viable T cells.2,3 

Read more about DLBCL treatment

Adverse Effects

The most common nonlaboratory adverse reactions to Yescarta, with an incidence >30%, are fever, cytokine release syndrome (CRS), fatigue, musculoskeletal pain, nausea, diarrhea, low blood pressure, encephalopathy, tachycardia, headache, febrile neutropenia, infection with unspecified pathogens, chills, and loss of appetite. The most common grade 3 to 4 laboratory abnormalities, with an incidence >30%, are lymphopenia, leukopenia, anemia, neutropenia, thrombocytopenia, and hypophosphatemia.2 

Warnings and Precautions

CRS in patients receiving Yescarta may include life-threatening events. Tocilizumab can be used to treat severe or life-threatening CRS with or without corticosteroids. Patients on Yescarta have also experienced neurologic toxicities, including fatal or life-threatening events, during or after the resolution of CRS and even without CRS. After Yescarta treatment, the patient should be monitored for the development of any neurologic side effects. Because of these potentials for CRS and neurotoxicity, Yescarta is to be administered only through the Yescarta and Tecartus Risk Evaluation and Mitigation Strategy (REMS) Program. Anyone with a current infection or inflammatory disease should not receive Yescarta. 

Patients should also be monitored during and after the infusion for hypersensitivity reactions and signs and symptoms of infection, as severe and fatal infections have occurred after a Yescarta infusion. If noted, treatment should be adjusted accordingly. It’s required to monitor a patient’s complete blood cell count, as prolonged grade 3 or higher cytopenias have been noted following Yescarta infusion. Hypogammaglobulinemia may develop with this therapy, so it’s important to monitor and consider the use of immunoglobulin replacement therapy, if required. Secondary malignancies may also occur. In such cases, Kite Pharma should be contacted immediately. Patients should be advised not to drive or operate heavy machinery and not to engage in other potentially dangerous work for a minimum of 8 weeks following the administration of Yescarta.2 

Get full prescribing information for Yescarta at MPR

Safety and Efficacy in Trials

The initial FDA approval of Yescarta was based on results from ZUMA-1 (NCT02348216), a single-arm, open-label, multicenter pivotal trial that evaluated the efficacy of a single infusion of Yescarta in adult patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. In ZUMA-1, Yescarta achieved an objective response rate of 72%, with a median time to response of 0.9 months.1,6 In overall survival data following a single infusion of Yescarta updated after 3 years (median follow-up of 39.1 months), approximately half of patients with refractory large B-cell lymphoma in the ZUMA-1 pivotal phase 2 cohorts were alive, and the median overall survival was 25.8 months. Preliminary results of the safety management study (cohort 4) of ZUMA-1 indicate that early steroid interventions can decrease the incidence of CRS and neurologic events seen with Yescarta without affecting the high response rates in patients with relapsed or refractory large B-cell lymphoma.8,9

ZUMA-5 (NCT03105336) is a single-arm, multicenter phase 2 clinical trial that led to accelerated approval of this drug for the treatment of follicular lymphoma.6

ZUMA-7 (NCT03391466) is a randomized, open-label, multicenter study that compared Yescarta to the current standard of care (SOC) second-line therapy, defined as a platinum-based salvage combination chemotherapy regimen followed by high-dose therapy and autologous stem cell transplant in those who respond to salvage chemotherapy. This study was conducted in adult patients with relapsed or refractory diffuse large B-cell lymphoma. In ZUMA-7, 359 patients were randomized to receive a single infusion of Yescarta or current SOC second-line therapy. The primary efficacy measure was event-free survival (EFS) as evaluated by an independent review committee. The patients treated with Yescarta demonstrated a clinically and statistically significant improvement in EFS in comparison with those who received SOC. In addition, 40.5% of the patients treated with Yescarta were alive at 2 years without disease progression or a requirement for additional cancer treatment, vs 16.3% of those managed with SOC. The estimated median EFS was 8.3 months with Yescarta and 2.0 months with SOC.6,10 

Read more about DLBCL prognosis

References

  1. Yescarta (axicabtagene ciloleucel) for the treatment of large B-cell lymphoma. Clinical Trials Arena. March 25, 2019. Accessed August 22, 2022. 
  2. YESCARTA® (axicabtagene ciloleucel) suspension for intravenous infusion. Highlights of prescribing information. Kite Pharma; 2022. Accessed August 22, 2022.
  3. Yescarta. RxList. Updated June 28, 2021. Accessed August 22, 2022. 
  4. FDA Approves Yescarta. News release. Drugs.com; October 18, 2017. 
  5. Yescarta receives U.S. FDA approval as first CAR T-cell therapy for initial treatment of relapsed or refractory large B-cell Lymphoma (LBCL). News release. Drugs.com; April 1, 2022.
  6. Yescarta (axicabtagene ciloleucel). wcg CenterWatch. Accessed August 22, 2022.
  7. Yescarta immunotherapy: engineered to identify and attack target cells. Kite Pharma; 2022. Accessed August 22, 2022.
  8. Kite announces new Yescarta® data from ZUMA-1. News release. Business Wire; June 3, 2019. 
  9. Kite’s Yescarta yields positive results in ZUMA-1 trial in refractory large B-cell lymphoma. News release. Pharmaceutical Business Review; December 2019.
  10. FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. News release. U.S. Food and Drug Administration; April 1, 2022.

Reviewed by Kyle Habet, MD, on 8/26/2022.

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