Page 104 - Haematologica May 2022

R. Ram et al.
for selected patients both allogeneic and autologous hematopoietic cell transplantations are curative therapeutic options, for elderly patients who are non-transplant eligible options are limited, and those who fail to respond/relapse following first line therapy, die of the disease.3,4
The introduction of chimeric antigen receptor T (CAR-T) cell therapy, providing long-term remission in 30-40% of patients,5,6 appears to be the most powerful, if not the only potentially curative therapy for these relapsed/refractory (R/R) elderly DLBCL patients.
Nevertheless, elderly patients (>65-70 years old) are often considered ineligible for CAR-T cell therapy; having a rela- tively poor performance status (PS) and concomitant comorbidities, making them more susceptible for treat- ment-related adverse events , particularly cytokine release syndrome (CRS) and immune effector cell-associated neu- rotoxicity syndrome (ICANS).7
A recent analysis, evaluating the outcome of young versus elderly patients (age >65 years, n=27), included in the ZUMA-1 trial after fulfilling the inclusion criteria (e.g., Eastern Cooperative Oncology Group performace status [ECOG PS]= 0-1, left ventricular ejection fraction [LVEF] >50%), reported similar rates of CRS, complete remission (CR) and long-term remissions in both age groups. However, the incidence of ICANS grade 3, was higher in elderly patients.8 In addition, encouraging response rates were also reported in several small retrospective studies, though toxicity profile remained debatable.9-11
Hence, we aimed to retrospectively analyze the real- world data of the efficacy and toxicity profile of a non- selective population of elderly DLBCL patients treated with CAR-T cell therapy, compared with matched younger patients. In addition, we focused on both clinical parame- ters and quality of life domains, as well as on T-cell subpop- ulations and fitness of elderly patients, compared to younger counterparts.
Methods
Since April 2019 tisagenlecleucel has been commercially avail- able in Israel, while axicabtagene ciloleucel has been available since April 2020. The national infrastructure of eligibility for CAR- T cell therapy does not require a centralized committee to approve the treatment. Each center has been approved by the relevant phar- maceutical companies, the MOH, and in some cases by JACIE for the infusion of CAR-T cells. Among all three accredited centers in Israel, we retrospectively searched the DLBCL CAR-T surveillance database for all patients referred for CD19-directed CAR-T. The study was performed in accordance with the Declaration of Helsinki and was approved by the institutional ethics committee.
For referral and eligibility, lymphopheresis, bridging therapy, and preparative regimen and supportive care sections see the Online Supplementary Appendix.
Definitions of endpoints
Microbiological and clinical documented infections (MDI and CDI, respectively) were defined according to the European Conference on Infections in Leukemia (ECIL) guidelines12 and organ dysfunction was defined as either congestive heart failure, acute kidney injury, or atrial fibrillation. Adverse events were grad- ed according to the National Cancer Institute Common Toxicity Criteria Version 5.0.
Patients were monitored daily for the occurrence of CRS and ICANS. Grading and treatment followed the American Society
for Transplantation and Cellular Therapy (ASTCT) and European Society for Blood and Marrow Transplantation (EBMT) recommendations.7,13 Briefly, tocilizumab was given in the context of fluid-resistant hypotension grade 2 CRS or low saturation and steroids were started in cases of tocilizumab- refractory CRS or ICANS grade 2 or higher. Disease status was evaluated by Positron emission tomography/computed tomog- raphy (PET-CT) scan, performed within 7 days prior to admis- sion for CAR-T cell therapy, and on day 30 and 90 post CAR-T cell infusion. Following white blood cell count recovery, patients carried out a weekly full blood count, and monthly cytomegalo virus (CMV) and Kaposi's sarcoma-associated herpes virus 6 (HHV6), and immunoglobulins status for the first year. The cell therapy coordinator nurse assessed quality of life prior to, 30 days after and 90 days after infusion using the EORTC QLQ- C30 (version 3) questionnaires (including the following domains – disability assessment, cancer/toxicity-associated symptoms, emotional symptoms, overall health self-assessment, and overall quality of life self-assessment).
For evaluation of pretreatment T-cell compartment and assess- ment of CAR-T cell product and persistency see the Online Supplementary Appendix.
Statisticalanalysis
All consecutive patients ≥70 years (study cohort) were matched with patients younger than 70 years (control group). Patients were identified from a surveillance database of the participating centers. Matching was performed according to ECOG PS at screening (0-1 vs. 2-3) and lactose dehydrogenase (LDH) blood levels prior the infusion of CAR-T cell product (high vs. normal). Selection of these two parameters was based on previous real-word data, published by two different groups, confirming these parameters to predict patient's outcome.14,15
Continuous variables were described as the mean, median, stan- dard deviation and range of number observations, as applicable. Categorical data were described with contingency tables including frequency and percent. Comparison between the different base- line domains of the study cohort and counterpart control cohort was performed using wither Pearson Chi-Square or non-paramet- ric Student t-test, as appropriate. One-way ANOVA test with F cal- culation was performed to compare the quality-of-life question- naire domains between base line, 30 days and 3 months values.
A linear regression was performed for the association between baseline characteristics and response to CAR-T cell infusion. Cox proportional-hazards model was performed to identify parameters associated with progression-free survival (PFS) or overall survival (OS). Status of disease at 1 month post CAR-T cell therapy was analyzed as a time-dependent covariate. A two-sided P-value of <0.05 was considered as statistically significant.
Results
Between April 2019 and October 2020, 49 patients, ≥70 years of age were screened for eligibility in three CAR-T cell therapy centers in Israel. Two patients were ineligible for CAR-T cell collection (ECOG=4, n=1; active hepatitis B virus infection, n=1). Forty-seven patients (96%) were eligible and all underwent successful apheresis. Median time from referral to apheresis was 11 days (range, 1-71 days), with no difference in time to apheresis between elderly and younger cohorts (mean days from referral to apheresis 18.8 vs. 15.4, respectively, P=0.453). In six patients (12.7%), CAR-T manufactured cell product was not eventually infused (out of specification and termina-
1112
haematologica | 2022; 107(5)