Page 109 - Haematologica May 2022

CAR-T for elderly patients with DLBCL
P=0.048). Age, sex, ECOG PS, administration of bridging therapy and the occurrence of CRS had no impact on CR rate.
At 3, 6, and 12 months, the projected PFS was 51%, 39%, and 32%, respectively in the elderly group, and approached 67%, 54%, and 54%, respectively in the younger group). Median PFS was 3.6 (95% CI: 1.6-5.6) months in the elderly patients, while not reached in the younger group of patients (P=0.209), Figure 2. Multivariate regression model identified prior autologous HCT (hazard ratio [HR]: 0.208, 95% CI: 0.05-0.87, P=0.032) and a CR state 1 month post CAR-T cell therapy (HR: -0.076, 95% CI: 0.025-0.23, P<0.001) to be asso- ciated with better PFS, while both high LDH prior infusion of CAR-T cells (HR: -2.7, 95% CI: 1.1-6.7, P=0.03) and non-ger- minal center B-cell immunophenotype (HR: 2.29, 95% CI: 0.98-5.4, P=0.057) were associated with shorter PFS. Age and ECOG PS had no impact on PFS.
At 3, 6, and 12 months, projected OS was 84%, 74%, and 69%, respectively in the elderly group, 87%, 76%, and 53% in the younger group. Median OS was not reached in both groups (P=0.792), Figure 3. Multivariate regression model for OS identified a CR state 1 month post CAR-T cell therapy (HR: 0.017, 95% CI: 0.003-0.11, P<0.001) to be associated with increased OS, while both receiving bridging therapy and high LDH prior to CAR-T cell nfusion (HR: 5.6, 95% CI: 0.99-32.3, P=0.05 and HR: 4.9, 95% CI: 1.5-16.1, P=0.008, respectively) were associated with shorter OS. Age and ECOG PS had no impact on OS.
Discussion
This study explored the characteristics and outcome of all consecutive patients, 70 years or older, referred for CAR-T cells during the study period, and matched these patients with younger individuals, based on PS and LDH prior to admission for infusion. We showed that both tox- icity and efficacy are similar in elderly compared to the younger patients.
Despite the improvement in outcomes of elderly DLBCL patients over the last two decades, the prognosis remains disappointing, with 2-year event-free survival of 57%.16 Unfortunately, response rates achieved with second line salvage therapy in these non-transplant eligibility patients are generally dismal and most patients die of their disease in less than a year.17,18 Therefore, CAR-T cell therapy, pro- viding the only curative option for these elderly patients, should be strongly considered.
At present, many countries employ very restrictive crite- ria for selecting patients to CAR-T cell therapy, considering CAR-T cell therapy as a "highly toxic" treatment.15,19,20 According to their policies, patients that present with sig- nificant comorbidities (i.e., <45% EF, PS>1, chronic renal disease etc.) are ineligible for CAR-T cell therapy. Thus, a substantial proportion of elderly patients, "fulfilling these criteria", would be ineligible for CAR-T cell therapy. Indeed, the French group excluded 41% of all referred DLBCL patients due to employment of these restrictive standards. As such, the median age of CAR-T cell therapy patients in some centers in Europe is lower than 60 years, indicating that the majority of elderly DLBCL patients that experienced disease relapse and required CAR-T cell ther- apy, were not considered for this life saving treatment.20,21
According to our data, almost all (96%) elderly patients that were referred to CAR-T cell therapy, were found to be
eligible and underwent successful apheresis. although ana- lyzed in only a portion of the patients in the elderly group," lymphocyte fitness", reflected by T-cell subsets and exhaustion markers, was non-inferior in elderly compared with younger patients, and translated into comparable CAR-T cell products with no increase in production failure and similar expansion of CAR-T cells. These results are analogous to those reported in the ZUMA-1 trial.8
Despite the fact that two thirds of our patients had a poor PS and almost half entered CAR-T cell therapy with increased LDH levels (reflecting highly proliferative dis- ease), 84% were eventually transfused. This transfusion rate is not inferior to that reported in other real life series, including highly selective CAR-T cell programs, emphasiz- ing the importance of logistical factors and decreasing the time from enrollment to infusion.14,20
Acute treatment related toxicities, including CRS and ICANS, were mainly grades 1-2, with no differences between the cohorts as previously proposed by others.10 The relatively low incidence of high grade ICANS in both young and elderly patients, might reflect the predominant employment of tisagenlecleucel in our cohort of patients. In contrast, studies focusing on early toxicity of axicabta- gene, have generally reported higher rates of high grades ICANS, especially in older aged patients.8,22 Of note, prior cerebral vascular disease nor dementia were found to be associated with increased risk for ICANS in our cohort of patients.
Long-term toxicity was not higher in elderly versus younger patients. Interestingly, a substantial number of patients developed reactivation of CMV, and rarely, HHV6, with no need for active intervention in the majority, and with no infection-related sequels. This manifestation has not been reported yet and we continue to perform routine surveillance monitoring to further investigate post CAR-T cell therapy virus reactivation. The risk for significant hypogammaglobulinemia and persistent cytopenia were not higher in the aged patient and were in line with those reported in prior real-life series.6-8
An important finding of our study is the dual effect of CAR-T cell therapy on patients’ quality of life, during admission and after returning home. During hospitaliza- tion, patients reported on increase disability, aggravation in cancer/treatment-related symptoms and worsening emo- tional distress. Considering that patients are usually hospi- talized for 3-4 weeks, direct intervention during that period, employing intensive physical and emotional rehabilitation programs may help alleviating symptoms. Thereafter, those patients who respond to CAR-T cell therapy may expect to gain a long-term clinically meaningful improvements in daily functioning.23 Indeed, in our cohort of patients, all symptoms improved after several months, and patients reported a significant progress in their quality of life.
Despite the poor features of our elderly cohort of patients (poor PS in 66%, high LDH in approximately 40%, progressive disease and ≥3 prior lines in almost half), the CR rate was 46.3%, similar to the CR rate reported in the Juliet study and in other real-world series.6,8,10 CR rate was affected by LDH level only, and was not adversely affected by age, supporting prior smaller unmatched stud- ies, that reported similar overall and complete response rates in elderly versus younger patients.8 PFS in these elderly patients was also not statistically shorter than in their younger counterparts and was similar to that reported in the Juliet study.6 In line with previous reports, cell of origin
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