Conor Killmurray

Data from a prospective in vivo assessment suggest that good chimeric antigen receptor (CAR) T-cell expansion on day 10 (C10) after infusion could be an early biomarker to help predict response and survival in patients with B-cell lymphoma. The data were presented at the virtual 48th Annual EBMT meeting.

“No biomarker can predict [CAR T-cell therapy] outcomes 

 on an individual patient level,” explained Martina Pennisi, MD, attending physician, Fondazione IRCCS Istituto Nazionale Tumori in Milan, Italy, in a virtual presentation of the study results. “Therefore, their use in clinical practice is currently limited. So, our aim was to evaluate whether CAR T-cell monitoring in peripheral blood could predict a treatment response in real life.”

Treatment using the CAR T-cell therapies tisagenlecleucel (tisa-cel; Kymriah) and axicabtagene ciloleucel (axi-cel; Yescarta) is becoming a stand of care for patients with lymphoma, investigators noted; however, markers for response are not well characterized. They added that although clinical features–poor performance score, high systemic inflammatory state, tumor burden, lactate dehydrogenase–may be associated with lower efficacy, according to previous studies, higher axi-cel peak concentrations have also been associated with better response rates at 30 days and had a longer progression-free survival (PFS).

“However, response and survival do not appear to be influenced by patients' characteristics in other reports and the role of CAR-T expansion in peripheral blood (PB) has never been prospectively investigated in a real-life setting,” investigators wrote in the abstract of the findings.

Therefore, a single-center prospective study looked at 53 patients with diffuse large B-cell lymphoma (n = 28), transformed follicular lymphoma (n = 15), primary mediastinal large B-cell lymphoma (n = 8), or high-grade B-cell lymphoma (n = 9), who received either tisa-cel (n = 26) or axi-cel (n = 27). Investigators aimed to correlate 

 expansion kinetics with lymphoma response from both CAR T-cell therapies, as well as to evaluate survival and adverse events (AEs).

The majority of patients had an ECOG performance score of 0 (81%) and stage III to IV disease (77%), and 42% of patients reporting having received 3 or more prior lines of therapy.

Samples of PB were collected on days 5, 7, 10, 14, 21, and 28 after CAR T-cell infusion, and then monthly until disease progression or 1 year after infusion. Flow cytometry was then used to assess the sample and find viable cells for study to determine the peak of the CAR T-cell treatment.

After 90 days, overall response rates in the axi-cel and tisa-cel groups were 59% (n = 16) and 58% (n = 15), respectively, including complete response rates of 48% (n = 13) and 58% (n = 15).

Researchers found that the kinetics of both therapies were similar by looking at the median time to peak expansion of T-cells (Tmax), which was 10 days for patients in both the tisa-cel and axi-cel arm. Investigators also calculated the median maximum concentration of CAR T cells in treated patients and at day 10 (C10) this number was at 25 cells (range, 12-82), while the overall median maximum of CAR T cells was at 54 (range, 25-104).

Area under the curve from day 0 to day 30 was calculated to be 123 (range, 55-248), and researchers found no significant difference in these areas when comparing the treatment arms. Moreover, researchers found that the area under the curve and maximum T cells at 10 days were strongly correlated (correlation score, 0.88; 95% CI, 0.79-0.92, 

 = .001), which showed that patients peaking at 10 days was a promising result.

“After considering other variables that could be associated with response, only C10 was associated with a significant, good response (

 = .038) at day 90,” said Pennisi. “We then looked at patients that were considered responders at day 90 and we looked at the association of all kinetic parameters of expansion of CAR T cells, and we found that responders had significantly higher parameters compared to non-responders.”

Safety on these therapies was still manageable, with immune effector cell-associated neurotoxicity syndrome observed in only 5 patients, all of which were grade 1. Overall, 13 patients experienced grade of 2 or higher cytokine release syndrome, including 6 patients in the axi-cel arm and 7 in the tisa-cel arm. To treat these AEs 24 patients were given tocilizumab (13 in the axi-cel arm and 11 in the tisa-cel arm) and 17 were treated with steroids.

“We believe that C10 can represent an early biomarker to predict response and survival 

 on an individual patient level. However, further studies on larger populations are warranted to validate our results,” Pennisi concluded.

Pennisi M, Monfrini C, Aragona V, et al. Real-life experience with commercial CAR-T cells for lymphoma patients: early expansion kinetic predicts disease response and survival. Presented at: EBMT 48th Annual Meeting; March 19-23, 2022; Virtual. Abstract OS13-07.

Articles

Research presented at the EBMT meeting suggests cell expansion may be a good biomarker of both response and outcomes. 

CAR T-Cell Expansion Indicative of Response in B-cell Lymphoma

This content originally appeared on our sister site, 

The CD19-directed chimeric antigen receptor (CAR) T-cell therapy ARI-0001has demonstrated efficacy in relapsed or refractory (R/R) high-risk

(CLL) and Richter transformation, according to a recent analysis of a small study.

Data from the analysis were presented at the EBMT- EHA 4th European CAR T-Cell Meeting, February 10-12, 2022, by Valentín Ortiz-Maldonado, MD, of the Department of Hematology at the Hospital Clínic de Barcelona, Spain. Investigators found that 2 patients with Richter transformation experienced a CD19-negative relapse in their lymph nodes 2.1 months and 3 months after cell infusion, respectively, at a median follow-up of 5.6 months (range, 1.2-45.3). The 2-year overall survival rate was 62.5% (95% CI, 32%-100%) from the ARI-0001 cell infu- sion and 51.4% (95% CI, 24%-100%) overall.

“Regarding specific toxicities, almost 90% of patients didn’t [experience] any major grade of CRS, but [there] were mild [cases of] CRS of grade 1 to 2,” Ortiz-Maldonado said during his presentation. “On the other hand, there [were] no cases of ICANS [immune effector cell-associated neurotoxicity syndrome] or related mortality.”

ARI-0001 is constructed of an anti-CD19 single-chain variable fragment with a CD8 hinge and 2 signaling domains: 4-1BB and CD3z. Investigators analyzed 9 patients treated in the CART19-BE-01 trial (NCT03144583) or through a compassionate use program. 

First Patient Dosed in T-Cell Malignancy CAR T-Cell Therapy Trial

Median age was 58 years (range, 47-74) of 9 evaluable patients, 33% of which were female. Patients had a median of 5 prior lines of therapy (range, 2-9), including ibrutinib (Imbruvica) in 100%, venetoclax (Venclexta) in 55%, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in 55%, and allogeneic stem cell transplant in 22%. Six of the patients had Richter transformation and 8 had extra- medullary disease. Six patients had high- to very high-risk CLL, with 6 having 

 alterations and 3 having complex karyotype.

Responses, by International Workshop on CLL criteria, were observed in 7 patients, with 6 complete responses. One patient had a response lasting more than 51 months. All 6 patients with Richter transformation responded. Measurable residual disease–negative complete response was documented in the peripheral blood and bone marrow of all patients analyzed.

Patients were given 90 mg/m2 fludarabine each day plus 900 mg/m2 of cyclophosphamide on days 6, 5, and 4 prior to ARI-0001 cell infusion. This was then followed by a dose of 1 × 106 CAR T-cells/kg for patients with CLL. Patients with Richter transformation were given a dose of 5 × 106 CAR T-cells/kg as a single infusion on day 0 or split up by 10%, 30%, and 60% on 3 days separated by 24 hours each.

All 11 patients that underwent apheresis alive at the time of infusion had successful CAR T-cell production. Infusion is pending for 2 patients.

All of the infused patients experienced absolute B-cell aplasia (ABCA), with active ABCA ongoing up to 4.2 years. Median peak ARI- 0001 cell expansion reached 5.7 copies/ng. Measurable CAR T cells were seen as far as 2.5 years.

The therapy was well-tolerated, although cytokine release syndrome (CRS) did occur in 89% of patients, 11% of these events were grade 3 or higher. The median time to CRS was 1 day (range, 0-3) and the median duration of CRS was 5 days (range, 1-17). Four patients required tocilizumab (Actemra) and 2 required steroids for CRS.

Three patients died during the trial, with 1 patient having died from their disease while waiting for infusion that was delayed due to the COVID-19 pandemic. One patient who responded to the treatment with stable disease progressed to diffuse large B-cell lymphoma and died after a CD19 relapse in 7 months, and another who had a partial response to treatment later progressed to plasmablastic lymphoma and died after 3.7 months. The patient with the highest CRS grade of 3 was alive and free of disease 4.2 months after treatment, and the lon- gest outcome was 45.4 months. Seven patients continued to be followed at the time of data cutoff.

Comparatively, Ortiz-Maldonado said that complete response rates for patients with R/R CLL treated with CD19-directed CAR T cells were between 19% and 45%. Overall response rates were between 19% and 82%.

“[In conclusion, our data seem] to be in line with other outcomes from academic or industry teams for a small cohort of [patients with] CLL. Our long tails [of the survival curves] have been able to show long-term remission in CLL, and further research in standalone therapy [is warranted],” Ortiz-Maldonado concluded.

Ortiz-Maldonado V, Frigola G, Español-Rego M, et al. ARI-0001 CART19 cells in patients with relapsed/refractory chronic lymphocytic leukaemia and Richter’s transformation. Presented at: EMBT-EHA 4th European CAR T-Cell Meeting; February 10-12, 2022; virtual. Abstract BA03-6

Seven patients from the trial continued to be followed-up as of the data cut-off date.

CAR T-Cell Therapy Promising in R/R Chronic Lymphocytic Leukemia

Financial barriers to care, such as payer approvals and complicated administrative processes, continue to challenge patients with cancer despite progress made with chimeric antigen receptor (CAR)-T cell therapies, according to research from Cardinal Health Specialty Solutions.

Investigators surveyed over 300 oncologists from the United States between February and April 2021 and found that 60% believe that CAR T-cell therapy costs are either “reasonable” or “not inappropriate” compared to 39% of patients in a previous study from 2017. Moreover, 91% of oncologists referred at least 1 patient to CAR T-cell therapy over the past year which was up by 54% in 2017 and 71% in 2019.

"The innovative science behind cell therapies like CAR T is transforming the long-term outlook for many cancer patients,” said Heidi Hunter, president of Cardinal Health Specialty Solutions, in a press release. “Our latest research shows that, despite some barriers to access, oncologists are embracing these new therapies and are optimistic about their continued use in the future of oncology care.”

In the previous study from Cardinal Health in 2019, researchers had concluded that there was a need to improve administrative processes and address costs of therapy to make sure patients referred to CAR T-cell therapy were given it in a timely manner.2 While these obstacles remain, more patients are being referred to CAR T-cell therapy than in 2019. In February 2019 46% of surveyed physicians said they had not referred any patients for CAR-T cell therapy dropping to 29% of surveyed physicians in November of 2019.

Referrals for CAR T-cell therapy in the oncology setting heavily relies on community oncologists referring patients to larger academic institutions that make up the majority of approved centers for administration of CAR T-cell therapy. This led researchers from Cardinal Health to survey oncologists from geographically diverse locations across the United States. In the 2019 study, researchers saw a significant interest in utilizing the therapy and that over time there was more awareness of data showing success in the utilization of these treatments.

Since the first approval of CAR T-cell therapy for patients with cancer, interest in the use of CAR T cells have only grown with further approvals for 

axicabtagene ciloleucel (axi-cel; Yescarta) in the treatment of adult patients with relapsed or refractory follicular lymphoma

multiple myeloma on idecabtagene vicleucel

 (ide-cel; formerly bb2121; Abecma). Moreover, these newly approved therapies are starting to become available at major cancer centers like the 

However, similar to the 2021 study, physicians still cited administrative and financial challenges as the largest barrier to referring patients to CAR T-cell therapy with 73% of respondents in 2019 saying they prescribed bridging chemotherapy to a patient referred for CAR T-cell therapy due to a delay in obtaining the treatment from the manufacturer. Moreover, 65% reported that the patient’s condition had deteriorated before

“The key takeaways for CAR T centers is to invest in streamlining the intake process and enhance communications regarding clinical decisions, patient progress, and clear follow-up instructions to the referring community hematologist/oncologist. The manufacturers can assist with rapid review and certification of CAR T centers,” researchers wrote at the time.

In the most recent survey researchers asked oncologists about the impact of COVID-19 on oncology and their perceptions of the oncology landscape moving forward. Two-thirds of participants reported delays in routine screenings due to the pandemic, but 89% said they will continue using telemedicine even after the end of the pandemic. However, about 4 in 10 oncologists said it was difficult to perform under a value-based care model in pandemic conditions and only 1 in 4 participants believed the current technologies support success in value-based care

1. Oncologists have grown more comfortable with CAR-T therapy, research finds. News release. Cardinal Health. June 3, 2021. Accessed June 3, 2021. https://prn.to/3cj4I8a
2. Gajra A, Jeune-Smith Y, Kish J, et al. Perceptions of community hematologists/oncologists on barriers to chimeric antigen receptor T-cell therapy for the treatment of diffuse large B-cell lymphoma.

Surveyed oncologists supported the use of CAR T-cell therapy at higher rates than previous years.

Financial Barriers Remain Despite Increased CAR T-Cell Referrals

Data on the use of chimeric antigen receptor (CAR) T-cell therapies in the real-world setting show that axicabtagene ciloleucel (axi-cel; Yescarta) and tisagenlecleucel (tisa-cel; Kymriah) have mostly been used to treat patients with diffuse large b-cell lymphoma (DLBCL) in the outpatient setting with results suggesting earlier use may be possible in certain cases, according to an analysis presented at the virtual European Hematology Association Annual Meeting.

Looking at a total of 93 patients with DLBCL, 58% (n = 54) received axi-cel and 42% (n = 39) received tisa-cel, the majority of which (59%) received either CAR T-Cell therapy in the outpatient setting, compared to 40% in inpatient care. In a median follow up of 6.3 months, 45% of patients received either 2 or more lines of systemic therapy prior to receiving tisa-cel or axi-cel, while 17% received their systemic therapy after the CAR T-cell therapy. Tisa-cel or axi-cel was initiated at a median of 12.9 months following the initial diagnosis of DLBCL.

Commercial insurance was the primary payer during the time of therapy on either tisa-cel or axi-cel for 83% of patients with DLBCL, followed by 12% on Medicare, 3.2% on Medicaid, and 1 patient was unknown. Following CAR T-cell therapy, 82.8% did not receive therapy, 10.8% had 1 therapy after CAR T-cell therapy, and 6.5% had 2 therapies following either tisa-cel or axi-cel. For patients given systemic therapy following CAR T-cell therapy, a majority received rituximab (Rituxan) followed by, ibrutinib (Calquence), lenalidomide (Revlimid), nivolumab (Opdivo), and pembrolizumab (Keytruda). Researchers found a median of 4.4 months between CAR T-cell therapy and the next line of therapy.

Patients with at least 1 claim for either axi-cel or tisa-cel and were diagnosed with DLBCL were identified from the US claims database Symphony Integrated Dataverse (IDV) that houses 280 million active unique patients which represent 73% of specialty prescriptions, 58% of medical claims, and 30% of hospital claims. Nine patients were excluded due to having insufficient data, but initially 114 patients were identified to have been treated with either axi-cel or tisa-cel treatment, 21 of which were diagnosed with acute lymphoblastic leukemia (ALL).

Axi-cel and tisa-cel have been on the US market following their approval for treatment in patients with large b-cell lymphoma in 2017 and 2018 respectively. Data was looked at between 2018 to 2020, with the majority of patients initiated on CAR T-cell therapy in 2020 (41%).

“Despite short follow-up, 1 in 6 patients appear to have relapsed disease based on need for

additional systemic therapy,” the researchers concluded. “Further research is warranted to understand real-world clinical outcomes among patients treated with CAR T therapy outside the trial setting.”

Klink A, Savill K, Liassou D, et al. Real-World Treatment with CAR T-Cell Therapy of United States (US) Patients with Large B Cell Lymphoma (LBCL). Presented at: European Hematology Association 2021 Virtual Congress; June 9-19, 2021; virtual. Abstract EP737.

Real-world data regarding the use of tisagenlecleucel and axicabtagene ciloleucel CAR T-cell therapy are reported at 2021 EHA. 

Data Collected in Patients With DLBCL Reveal Real-World Trends for Use of Axi-Cel and Tisa-Cel

In the first few years of their availability in the United States, axicabtagene ciloleucel (axi-cel; Yescarta) and tisagenlecleucel (tisa-cel; Kymriah) have been used to mostly treat patients with diffuse large b-cell lymphoma (DLBCL) in the outpatient setting who are receiving the CAR T-cell therapies prior to failure on 2 prior lines of therapy, according to findings from a real world study presented at the virtual European Hematology Association Annual Meeting.

“Despite short follow-up, 1 in 6 patients appear to have relapsed disease based on need for additional systemic therapy,” the researchers concluded. “Further research is warranted to understand real-world clinical outcomes among patients treated with CAR T therapy outside the trial setting.”

Axicabtagene ciloleucel and tisagenlecleucel have been used mostly to treat patients with diffuse large B-cell lymphoma in the outpatient setting. 

Real-World Data Highlight Utility of CAR T-cell Therapies in DLBCL

ALLO-501, an allogeneic CAR T-cell therapy, paired with ALLO-647, a monoclonal antibody, yielded high response rates and a manageable safety profile in patients with relapsed/refractory diffuse large B-cell or follicular lymphoma, according to a first-in-human study presented at the 2020 ASCO Virtual Scientific Program. 

The 2 treatments were used sequentially in the open-label, phase I ALPHA study that occurred at 6 U.S. sites, demonstrating an overall response rate (ORR) of 63%, including a 37% complete response rate in 19 evaluable, previously treated adults.

Researchers believe that allogeneic CAR T therapy, made from healthy donor T cells, can provide the benefits of autologous CAR T therapy while increasing patient access, the study’s lead author, Sattva S. Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston, explained. He added that providing an off-the-shelf version of CAR T-cell therapy makes it available to patients more quickly, including on occasions when repeat dosing is necessary.

ALL0-501 is a genetically modified anti-CD19 CAR T-cell product in which the protein TCR alpha is disrupted to reduce the risk of graft-versus-host disease (GvHD). To support the effectiveness of the 2-pronged approach, the protein CD52 has been knocked out in ALLO-501 so that its partner therapy, the anti-CD52 monoclonal antibody ALLO-647, can be used successfully in lymphodepletion.

ALPHA’s primary endpoint was the safety and dose-limiting toxicity of ALL0-647 followed by ALLO-501. A secondary endpoint was ORR.

Eligible participants had advanced disease, an ECOG status of 0 or 1 and had been treated with at least 2 previous lines of therapy. Prior treatment with an anti-CD20 monoclonal antibody or with autologous CAR T therapy was permitted, as long as the patient’s tumor remained CD19-positive.

A total of 22 patients, whose median age was 63 years, were treated. Approximately two-thirds had diffuse large B-cell lymphoma and the rest had follicular lymphoma. Approximately half had high-risk disease. Their median number of previous treatments was 4.

Patients underwent lymphodepletion that included fludarabine, cyclophosphamide and ALLO-647; 3 regimens of varying doses were tested, which included ALLO-647 doses of 39 mg and 90 mg. This was followed by infusion of ALLO-501 at CAR-T cell doses of 40 million, 120 million, or 360 million, Neelapu said.

All the medication in the trial was made from the T cells of a single healthy donor, he said.

At a median follow-up of 3.8 months, 63% of patients (n = 12) demonstrated a response to treatment (95% CI, 38%-84%), including 37% (n = 7) who had complete responses (95% CI, 16%-62%). Most patients experienced tumor shrinkage, Neelapu said. The median time until response was 1 month, and 9 patients continue to respond. One patient achieved a complete response after a second infusion of ALLO-501, Neelapu reported.

He noted that 10 of 16 patients evaluated to date showed evidence of CAR-T cell expansion, which was associated with better response.

No dose-limiting toxicity or GvHD was observed in any of the patients treated. The most common adverse events of grade 3 or higher were neutropenia (55.6%), leukopenia (33.3%), and anemia (22.2%). Seven patients developed cytokine release syndrome, 2 of them at grade 1, 4 at grade 2 and 1 at grade 3, all reversible without steroids or tocilizumab (Actemra), according to the researchers. About half the patients had infusion reactions, most grade 2 or lower. Eleven infections reported were grade 3 and lower, mostly asymptomatic and diagnosed during weekly monitoring, Neelapu said. Finally, 1 patient developed a grade 1 neurotoxicity that resolved without treatment.

Neelapu said the safety of the 2 drugs appears comparable to that of autologous CAR T products currently approved for use.

Researchers noted that higher doses of ALLO-647 could have a potential association with deeper responses, as a larger proportion of patients on the greater dose saw a complete response. Follow-up is ongoing as researchers seek to enroll more patients to test for further response. 

Neelapu SS, Munoz J, Locke FL, et. al. First-in-human data of ALLO-501 and ALLO-647 in relapsed/refractory large B-cell or follicular lymphoma: ALPHA study. Presented at: 2020 ASCO Virtual Scientific Program; May 29, 2020. Abstract 8002.  

The allogeneic CAR-T cell therapy ALLO-501, paired with the monoclonal antibody ALLO-647, demonstrated clinical responses and manageable toxicity in patients with pretreated large B-cell and follicular lymphomas in the Phase I ALPHA trial.

Off-the-Shelf CAR T-Cell Therapy Shows Promise in Relapsed/Refractory B-Cell Lymphomas

The allogeneic chimeric antigen receptor (CAR)-T cell therapy ALLO-501, paired with the monoclonal antibody ALLO-647, has clinical activity and a manageable safety profile in patients with relapsed/refractory large B-cell or follicular lymphoma. The first-in-human findings were presented during the virtual scientific program of the American Society of Clinical Oncology (ASCO) 2020 Annual Meeting.

The two treatments were used sequentially in the open-label, phase I ALPHA study that occurred at six U.S. sites, demonstrating an overall response rate of 63%, including a 37% complete response rate, in 19 evaluable, previously treated adults in this population.

Researchers believe that allogeneic CAR-T therapy, made from healthy donor T cells, can provide the benefits of autologous CAR T therapy while increasing patient access, the study’s lead author, Sattva S. Neelapu, MD, of The University of Texas MD Anderson Cancer Center in Houston, explained May 29. He said that providing an off-the-shelf version of CAR-T cell therapy makes it available to patients more quickly, including on occasions when repeat dosing is necessary.

ALL0-501 is a genetically modified anti-CD19 CAR-T cell product in which the protein TCR alpha is disrupted to reduce the risk of graft-versus-host disease (GvHD). To support the effectiveness of the two-pronged approach, the protein CD52 has been knocked out in ALLO-501 so that its partner therapy, the anti-CD52 monoclonal antibody ALLO-647, can be used successfully in lymphodepletion.

ALPHA’s primary endpoint was the safety and dose-limiting toxicity of ALL0-647 followed by ALLO-501. A secondary endpoint was overall response rate.

Eligible participants had advanced disease, an ECOG status of 0 or 1 and had been treated with at least two previous lines of therapy. Prior treatment with an anti-CD20 monoclonal antibody or with autologous CAR-T therapy was permitted, as long as the patient’s tumor remained CD19-positive.

Patients underwent lymphodepletion that included fludarabine, cyclophosphamide and ALLO-647; three regimens of varying doses were tested, which included ALLO-647 doses of 39 mg and 90 mg. This was followed by infusion of ALLO-501 at CAR-T cell doses of 40 million, 120 million or 360 million, Neelapu said.

At a median follow-up of 3.8 months, 63% of patients (n=12) demonstrated a response to treatment (95% CI, 38%-84%), including 37% (n=7) who had complete responses (95% CI, 16%-62%). Most patients experienced tumor shrinkage, Neelapu said. The median time until response was 1 month, and 9 patients continue to respond. One patient achieved a complete response after a second infusion of ALLO-501, Neelapu reported.

Neelapu said the safety of the two drugs appears comparable to that of autologous CAR-T products currently approved for use.