Time to CAR T-cell Therapy May Impact Outcomes for Patients With Relapsed/Refractory Large B-cell Lymphoma in New CIBMTR Analysis

CAR T-cell

The effects of the period between leukapheresis and infusion (“vein-to-vein” time) for Yescarta® (axicabtagene ciloleucel) in adult patients with relapsed or refractory (R/R) large B-cell lymphoma were examined in one of the biggest real-world investigations of patients who underwent CAR T-cell treatment (LBCL). Shorter vein-to-vein times were linked to better outcomes in patients receiving Yescarta treatment, according to the research, which was controlled for important prognostic markers. At the American Society of Hematology (ASH) Annual Meeting & Exposition 2022, data were presented on December 11.

“These real-world data further clarify the positive impact that shorter vein-to-vein time can have on patient outcomes”, “Additional studies must be conducted to further understand the impact of vein-to-vein time on treatment outcomes in the context of other prognostic features such as requirement for bridging therapy and tumor burden. It is important for both community oncologists seeking a CAR T consult and cell therapists to understand the potential impact of lost time when seeking the best possible CAR T result for their patients.”

Frederick L. Locke, MD, Chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center

Yescarta has demonstrated lower median vein-to-vein wait times between leukapheresis and infusion in the pivotal clinical trials of the three commercially available CAR T-cell treatments for LBCL.

“As the leader in cell therapy, it’s important that we understand all of the factors that can contribute to the best possible outcomes for patients”, “We’re continuing to invest in technical advances to reduce times even further. I am hopeful studies like this will prompt improvements in the health care delivery system to reduce lost time for patients leading up to apheresis.”

Chris McDonald, SVP, Global Head of Technical Operations, Kite

Using the Center for International Blood and Marrow Transplant Research (CIBMTR) Research Database, the post-marketing registry of commercial patients prescribed Yescarta, this new real-world use analysis evaluated Yescarta patients between October 2017 and August 2020. The overall median vein-to-vein time for Yescarta was 27 days among all patients in the analysis (n=1,383 treated across 78 U.S. authorised treatment centres), including apheresis, both pre- and post-manufacturing transport, manufacturing time, hospital scheduling and readiness, including patient pre-conditioning prior to receiving their CAR T treatment. From the beginning of cell enrichment until harvest, Kite’s manufacturing time for Yescarta in the US is a median of seven days, with an overall 16-day turnaround time (Leukapheresis to Product Release).

The same analysis showed that a better complete response (CR) rate and overall survival were related to shorter vein-to-vein times (OS). Patients with a vein-to-vein time of less than 28 days or between 28 and 39 days had CR rates of 60% or 61%, respectively, with a median follow-up of 24.2 months, whereas patients with a vein-to-vein time of 40 days or more had a CR rate of 50%. Patients with a vein-to-vein time of up to 39 days experienced a 53% OS rate at 24 months, compared to 38% for patients with a vein-to-vein time of 40 days or longer.

Regardless of vein-to-vein duration, similar incidences of Grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS), Grade 3 cytokine release syndrome (CRS), and persistent neutropenia were seen. Patients’ risk of thrombocytopenia was lower in those with shorter vein-to-vein times. Patients with a vein-to-vein duration of fewer than 28 days may have a higher incidence of ICANS of any grade, but regardless of vein-to-vein time, the majority of cases were cured by 21 days after commencement.

CAR T-cell therapies are one-time procedures created from a patient’s own T-cells, which are white blood cells. Leukapheresis is used to remove the cells, which are then transferred to Kite’s specialised manufacturing facilities where a Chimeric Antigen Receptor is added (CAR). The cells are thoroughly examined, stored, packed, and shipped back to the hospital to be reinfused back into the patient after an individual therapy has been developed for them. Over 300 authorised treatment facilities worldwide, including 117 of the top cancer hospitals in the U.S., have treated over 11,000 patients using Kite’s CAR T-cell therapy.

About LBCL

LBCL is the most prevalent non-Hodgkin lymphoma type both internationally and in the United States (NHL). Each year, LBCL is diagnosed in more than 18,000 people in the US. Second-line therapy is required for about 30–40% of LBCL patients because the disease will either relapse (come back) or become refractory (not respond) to first-line therapy.

What Yescarta is

Please review the complete US prescribing information, which includes the medication guide and BOXED WARNING.

YESCARTA is a genetically altered autologous T cell immunotherapy that targets CD19 and is recommended for the treatment of:

Adult patients with first-line chemoimmunotherapy-refractory large B-cell lymphoma or relapses within a year of first-line chemoimmunotherapy.

Adult patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, or DLBCL resulting from follicular lymphoma who have relapsed or are resistant to two or more courses of systemic therapy.

Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.

Adult patients having two or more courses of systemic therapy for resistant or relapsed follicular lymphoma (FL). Based on the response rate, this indication is granted under rapid approval. Continued approval for this indication might be conditioned on the confirmatory trial’s clinical benefit being confirmed and described (s).

Important safety information for the U.S.


  • Patients receiving YESCARTA experienced Cytokine Release Syndrome (CRS), including deadly or life-threatening events. Patients with current infections or inflammatory conditions should not be given YESCARTA. Tocilizumab or tocilizumab combined with corticosteroids are used to treat severe or life-threatening CRS.
  • Patients receiving YESCARTA experienced neurologic toxicities, including fatal or life-threatening events, whether they occurred concurrently with CRS or after CRS clearance. After receiving YESCARTA medication, keep an eye out for neurotoxicities. As required, give corticosteroids or supportive care.
  • The YESCARTA and TECARTUS REMS Program is the only restricted programme that offers YESCARTA as part of a Risk Evaluation and Mitigation Strategy (REMS).

Cytokine Release Syndrome (CRS) (CRS)

There were CRS, including deadly or life-threatening ones. 90% (379/422) of patients with non-Hodgkin lymphoma (NHL) experienced CRS, with Grade 3 occurring in 9% of cases. 93% (256/276) of patients with large B-cell lymphoma (LBCL) experienced CRS, with Grade 3 CRS occurring in 9% of cases. Four LBCL patients who passed away after taking YESCARTA had active CRS episodes at the time of their deaths. For patients with LBCL in ZUMA-1, the median duration of CRS was 7 days, and the median time to onset was 2 days after infusion (range: 1-12 days) (range: 2-58 days). The median time from infusion until the development of CRS was 3 days for patients with LBCL in ZUMA-7 (range: 1–10 days), and the median duration was 7 days (range: 2-43 days).

In ZUMA-5, 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) experienced CRS, with 8% developing Grade 3 CRS. One of the iNHL patients who passed away after taking YESCARTA had a CRS event that was still going on at the time of death. For individuals with iNHL, the median time from the onset of CRS was 4 days (range: 1–20 days), and the median duration was 6 days (range: 1–27 days).

Fever (85%), hypotension (40%), tachycardia (32%), chills (22%), hypoxia (20%), headache (15%), and weariness (12%) were the main symptoms of CRS ( 10%) across all patients. Heart arrhythmias, such as atrial fibrillation and ventricular tachycardia, renal failure, cardiac failure, respiratory failure, cardiac arrest, capillary leak syndrome, multi-organ failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome are serious events that may be linked to CRS.

In two additional cohorts of LBCL patients in ZUMA-1, the effects of tocilizumab and/or corticosteroids on the prevalence and severity of CRS were evaluated. Tocilizumab and/or corticosteroids were given to patients with continuous Grade 1 episodes in 93% (38/41) of those cases; 2% (1/41) of those cases had Grade 3 CRS; no patients had Grade 4 or 5 events. The median start of CRS was 2 days, with a range of 1 to 8 days, and the typical illness duration was 7 days (range: 2-16 days). A cohort of 39 patients received prophylactic corticosteroid medication for three days starting on the day of YESCARTA infusion.

31 of the 39 individuals (or 79%) who had CRS were treated with tocilizumab and/or therapeutic dosages of corticosteroids; no one had CRS that progressed to Grade 3 throughout this time. The median time for the development of CRS was 5 days, and the median time for the condition to last was 4 days (range: 1-10 days). The risks and advantages of preventive corticosteroids should be weighed against the patient’s pre-existing comorbidities, the possibility of Grade 4 and extended neurologic toxicities, and the lack of a known mechanistic explanation.

Before administering YESCARTA, make sure that 2 doses of tocilizumab are available. Patients should be observed for CRS symptoms and signs at least once a day for 7 days in the accredited healthcare facility and then every other day for 4 weeks after that. In the event that CRS symptoms or signs manifest at any time, advise patients to seek emergency medical assistance. At the first indication of CRS, start receiving supportive care, tocilizumab, or, if necessary, tocilizumab and corticosteroids.


Neurologic toxicities (including immune effector cell-associated neurotoxicity syndrome) that were fatal or life-threatening occurred. Neurologic toxicities occurred in 78% (330/422) of all patients with NHL receiving YESCARTA, including ≥ Grade 3 in 25%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL in ZUMA-1, including ≥ Grade 3 in 31% and in 74% (124/168) of patients in ZUMA-7 including ≥ Grade 3 in 25%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL in ZUMA-1. The median time to onset for neurologic toxicity was 5 days (range: 1-133 days) and the median duration was 15 days in patients with LBCL in ZUMA-7. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including ≥ Grade 3 in 21%. The median time to onset was 6 days (range: 1-79 days) and the median duration was 16 days. Ninety-eight percent of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of YESCARTA infusion. Neurologic toxicities occurred within the first 7 days of infusion for 87% of affected patients with LBCL and 74% of affected patients with iNHL.

The most common neurologic toxicities (≥ 10%) in all patients combined included encephalopathy (50%), headache (43%), tremor (29%), dizziness (21%), aphasia (17%), delirium (15%), and insomnia (10%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including aphasia, leukoencephalopathy, dysarthria, lethargy, and seizures occurred. Fatal and serious cases of cerebral edema and encephalopathy, including late-onset encephalopathy, have occurred.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41), and 20% (8/41) had Grade 3 neurologic toxicities; no patients experienced a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Of those patients, 85% (33/39) developed neurologic toxicities, 8% (3/39) developed Grade 3, and 5% (2/39) developed Grade 4 neurologic toxicities. The median time to onset of neurologic toxicities was 6 days (range: 1-274 days) with a median duration of 12 days (range: 1-107 days). Prophylactic corticosteroids for management of CRS and neurologic toxicities may result in a higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset of and decrease the duration of CRS.

Monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.


Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program called the YESCARTA and TECARTUS REMS Program which requires that: Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after YESCARTA infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer YESCARTA are trained in the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).


Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of YESCARTA.


Severe or life-threatening infections occurred. Infections (all grades) occurred in 45% of patients with NHL; ≥ Grade 3 infections occurred in 17% of patients, including ≥ Grade 3 infections with an unspecified pathogen in 12%, bacterial infections in 5%, viral infections in 3%, and fungal infections in 1%. YESCARTA should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 36% of all patients with NHL and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.

In immunosuppressed patients, including those who have received YESCARTA, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells, including YESCARTA. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.


Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion. ≥ Grade 3 cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 39% of all patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%). Monitor blood counts after infusion.


There can be hypogammaglobulinemia and B-cell aplasia. In 14% of all NHL patients, hypogammaglobulinemia was identified as an adverse response. Following therapy, keep an eye on your immunoglobulin levels and take infection preventative measures, antibiotic prophylaxis, and immunoglobulin replacement as needed. The safety of receiving live viral vaccinations before, during, or after YESCARTA treatment has not been investigated. Live virus vaccination is not advised for at least 6 weeks before lymphodepleting chemotherapy begins, during YESCARTA treatment, and until the immune system has recovered after treatment.


There could be a relapse of primary cancer. Always keep an eye out for subsequent cancers. If one does, call Kite at 1-844-454-KITE (5483) to get information on how to get patient samples for testing.


In the eight weeks following YESCARTA infusion, patients run the risk of having changed or diminished consciousness or coordination due to the possibility of neurologic events, such as altered mental state or seizures. Tell patients to avoid using heavy or potentially harmful machinery and participating in dangerous jobs or activities during this initial period.


The most common non-laboratory adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-7 included fever, CRS, fatigue, hypotension, encephalopathy, tachycardia, diarrhea, headache, musculoskeletal pain, nausea, febrile neutropenia, chills, cough, infection with an unspecified pathogen, dizziness, tremor, decreased appetite, edema, hypoxia, abdominal pain, aphasia, constipation, and vomiting.

The most common adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-1 included CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections with an unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.

The most common non-laboratory adverse reactions (incidence ≥ 20%) in patients with iNHL in ZUMA-5 included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with an unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.

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