By Yuliya Linhares, MD
How can Liso-Cell (Lisocabtagene Maraleucel) help patients with RR large B-cell lymphoma? Today I'm going to be talking about the outreach study. So outreach study is the phase 2 prospective study evaluating the safety and efficacy of treatment with chimeric antigen receptor T-cell therapy Lisocabtagene Maraleucel (Liso-cel).
Liso-cel (Liscobtagene Maraleucel) in patients with third line or later relapse or refractory large B-cell lymphoma across outpatient and inpatient setting at community or non university sites in the United States. So we know that we can give CAR T-cell (therapy) safely at the academic centers, but what about community centers or non-university sites?
So in this study, the sites that were included had to have bone marrow transplant and phase 1 capability. Patients were considered to be monitored as outpatients if Liso-cel (Liscobtagene Maraleucel) was admin administered in the outpatient facility or in the inpatient facility, but then patients were discharged the same day.
The patients had to be closely monitored for outpatient monitoring. Patients had to live within one hour of their CAR T-cell center, and were monitored daily for the first week, either via phone or physical visits, and subsequently, they were monitored every 2 weeks.
The caregivers were educated on specific CAR T-cell (therapy) toxicities, such as infections, cytokine release syndrome, and neurological events. And the caregiver had to stay with the patient to be able to transport the patient to the CAR T-cell center within one hour.
So overall, let's talk about our patient population, patients were hospitalized at first sign of cytokine release syndrome on neurotoxicity, or the first sign of infection. Overall, 82 patients were treated on the trial, and these were relaxer refractory diffuses large B-cell lymphoma patients who were receiving CAR-T cells (therapy) as a third line of higher therapy.
The median age of this patients was mid 60s, so our typical patients had overall high disease burden. There were small differences between the patients that ended up staying outpatient versus inpatient. Patients who received treatment in the outpatient setting tended to have a higher percentage of transformed lymphomas While there were slightly more patients with high grade B-cell lymphoma in patients who were hospitalized and hospitalization for CAR T-cell (therapy) treatment and observation was actually a discretion of the treating physician. So possibly high tumor burden or other preexisting risk factors socioeconomic situation could prompt the investigator to hospitalize the patient for envision observation. Otherwise the patient characteristics were similar in the patients who were hospitalized and in the patients who were monitored in the outpatient setting. Overall, 57 patients were monitored in the outpatient setting, and 25 patients were treated in the inpatient setting.
Now we'll talk about the adverse events. Overall, most common grade 3 or higher adverse event was cytopenia and most cytopenias were grade 3 or 4, only about half of all patients experienced any grade cytokine release syndrome on neurological events and incidences of cytokine release syndrome and neurological events were similar in outpatients and in patients.
Remarkably, there was no grade 5 cytokine release syndrome, and there were no grade 5 neurological events. Only 40% of patients experienced cytokine release, pa syndrome, and all CRS was grade 1 0 2. 29% of patients reported neurological events with only 10% of patients having grade 3 or 4 events.
Tocilizumab use and corticosteroid use was low. 12% of inpatients received tocilizumab in overall population, only 5% of patients received tocilizumab, 18% of patients received both tocilizumab and steroids in regards to infections. 11% of patients developed grade 3 or high infections, and 33% of patients had prolonged cytopenias, which lasted at day 29 and beyond. Remarkably, 25% of patients who were observed in the outpatient setting were never hospitalized, and most patients who were admitted 72 hours after CAR T-cell infusion.
Outpatients stay was shorter in patients that were planned to be MA monitored as outpatient patients who were planned to be monitored as outpatient. On average were admitted for 6 days versus 15 days. For patients who were admitted for CAR T-cell Observation, ICU, admissions and stays were low. Only 2% of patients who were monitored in the outpatient setting, initially were transferred to ICU and 8% of patients who were monitored on the inpatient basis were transferred to a ICU.
So now we'll talk about responses to Liso-cel (Liscobtagene Maraleucel) overall response rate was 82% for patients who were observed in the outpatient setting, and 76% for patients who were observed in the inpatient setting with overall response rate of 80% complete remission rate was 58% in the outpatient group and 44% in the inpatient group with 54% CRA total responses were durable with median duration of response of nearly 15 months in the total population. Median progression-free survival was nearly 6 months and in the outpatient cohort, the median progression-free survival was 6 months versus 4 months in inpatient without significant difference, median overall survival was not reached in total population or in the outpatient subgroup, and was 22 months in inpatients.
The highlights of this study are the following. 25% of patients who were planned to be observed in the outpatient basis were hospitalized. There was no grade 5 cytokine release syndrome or neurotoxicity. CRS was only grade 1 or 2 with only 40% of patients experiencing CRS, and overall Tocilizumab use was low at 5%.
Overall response rates were high at 80% with CR rate of 54% in total population. Median duration of response was nearly 15 months and was not reached in the inpatient subgroup. Median progression-free survival was nearly 6 months median overall survival was not reached in total population and in patients who were planned to be observed on an outpatient basis, and was 22 months in the patients who were observed in the inpatient setting. Overall, the results of this trial were consistent with the results of TRANSCEND trial.
In addition, health related quality of life was measured with patient reported outcome tools on the outreach trial. Health related quality of life was measured with patient reported outcome tools on the outreach trial. In the overall patient population treatment with Liso-cel (Liscobtagene Maraleucel) as third line and higher therapy in patients with relapsed of refractory large B-cell lymphoma led to improved or maintained symptoms, specifically role functioning.
Fatigue and pain were improved with CAR-T cells treatment. Overall health related quality of life was improved as well as functioning. This is consistent with findings from previous CAR T-cell trials. In summary, it is important to report and follow health related quality of life in patients treated with CAR T-cell therapies.
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I would say that I'm most frequently asked, which patients should be referred for CAR T-cell therapy? And the response is that really any patient that has relapsed or refractory large B-cell lymphoma may be a CAR T-cell candidate at this point. We can't really consider age as a hard limit.
As a matter of fact, Liso-cel (Liscobtagene Maraleucel) is approved for patients with a relapsed refractory large B-cell lymphoma who are not candidates for stem cell transplant. Maybe due to age, maybe due to organ function, and we may be able to administer CAR T-cells to patients over 70 and even 80 years old. So it's really the functional status, the socioeconomic status, meaning caregiver support and the organ function that matter.
Additionally the question is when should we refer patients? To CAR T-cell Center, and I would say as soon as you suspect that the patient may need CAR T-cell therapy. So usually I recommend referrals as soon as relapse to refractory disease is detected or suspected. Sometimes we work on patients simultaneously.
For CAR T-cell therapy as well as for stem cell transplant. Relapse refracture large B-cell lymphoma patients who go in complete remission with salvage therapy most likely will be candidates for autologous stem cell transplant consolidation versus patients with relapse refractory disease will be candidates for CAR T-cell therapy.
Additionally, now CAR T-cells are approved for patients with refractory disease after the first line (therapy) of systemic therapy. Or patients who relapse early after the first line of systemic therapy. So patients who relapse within 12 months of initial therapy, so a lot of times those patients have high burden disease, in the sick the disease pace is high. So it's again, important for us to see this patients early because there's always a delay between the referral and actual CAR T-cell infusion. We have to go through insurance approvals, we have to evaluate the patient, we have to collect CAR T-cell we have to collect T-cells.
In order to manufacture chimeric antigen receptor T-cells. So there are many potential delays. So I would like to see our patients early and the early we see them the more possible it is for us to actually get those patients to CAR T-cell infusion. Additionally collaboration between.
The treating physician and CAR T-cell (therapy) physician (healthcare professionals) is crucial because it's important to discuss what kind of bridging therapies should be used. For example, bind ma bind mastin may affect the quality of T-cell collection as well as the quality of chimeric antigen receptor T-cell function, so we prefer not to use it. And there are many other special situations and we may talk about targeted therapies that are preferred to not be used as a bridge versus cytotoxic therapies and so forth.
I'm very hopeful that with this data demonstrating that administering CAR T-cells, in this case specifically Lido cell is feasible and safe in community and non university (hospital) centers, that we're going to have more centers offering and administering this therapy. Unfortunately, many patients who are candidates for CAR T-cells are not referred for this treatment or never get to this treatment due to distance to CAR T-cell center due to financial concerns. So with higher availability of this treatment, we're going to be able to save more lives.
So there are just so much going on in CAR T-cell (therapy) research and we are very excited about CAR T-cells targeting various antigens besides CD 19, which can overcome resistance. Two CAR T-cells CD 19 targeted CAR T-cells. Their are cart being developed. They have, that have dual targets or have built in off switches in case of toxicity.
Additionally we are looking at utilizing CAR T-cells as. Lymphoma treatments in an earlier and earlier lines of therapy. So for example, utilizing Liso-cel (Liscobtagene Maraleucel) as well as other carts in the second line, or even for high risk aggressive lymphomas in the first line. Additional of course we're looking at CAR T-cell (therapy) combinations with other, biological compounds such as, for example, there's an ongoing trial of acalabrutinib, which is a BTK inhibitor combined with Liso-cel in relapse aggressive B-cell lymphomas with hope to improve the efficacy.
For my colleagues, I would like to say that the key takeaway is that we should really think very carefully about each and every relapse refractory, diffuse, like B-cell patient, and think of Everyone who has refractory disease is a potential CAR T-cell (therapy) candidate. We see that at least with Liso-cel (Liscobtagene Maraleucel), as in our study, the rates of severe complications are low.
For example cytokine release syndrome. Was mostly mild at grade 1/2 and was only in 40% of patients. And there was no grade five or high neurotoxicity. Therefore, when we counsel our patients we can talk about potentially curative therapy that is going to be feasible in in a vast majority of patients with relapse or refractory disease.
So I would like to say that early referral of potential CAR T-cell candidates to the CAR T-cell transplant Center is crucial for their survival and Car T-Cell physicians are always very happy and welcome collaboration with community oncologists. So we hope to see more patients at our center and offer this therapy to more patients.
Yuliya Linhares, M.D., a medical oncologist and clinical researcher, has been appointed Chief of the Lymphoma Service at the Miami Cancer Institute at Baptist Health South Florida, the sole member of the Memorial Sloan Kettering Cancer Alliance in the state. Dr. Linhares is an expert in both autologous and allogeneic stem cell transplantation, and specializes in the comprehensive treatment of lymphoma. She also has unique experience with bloodless chemotherapy and stem cell transplantation, which is essential for patients whose religious beliefs prohibit blood transfusions.
Dr. Linhares is triple board-certified in internal medicine, hematology, and medical oncology by the American Board of Internal Medicine. She graduated with honor from the University of North Carolina School of Medicine in Chapel Hill, North Carolina, where she got her medical degree. She finished her internal medicine residency and hematology-oncology fellowship at the University of California, Los Angeles. Dr. Linhares treated patients in the Blood and Marrow Transplant Program at Cedars-Sinai Medical Center in Los Angeles before joining Miami Cancer Institute.
At UCLA School of Medicine, Dr. Linhares has considerable experience instructing medical students, residents, and oncology fellows. She acts as an editorial reviewer for major peer-reviewed scientific journals, is frequently published in several medical journals, and gives invited speeches at academic conferences. Dr. Linhares belongs to both the American Society of Hematology and the American Society for Blood and Marrow Transplantation.