Meta-Analysis of Complete Remission Rates Following First-Line Salvage Treatment after Anti-CD19 CAR-T Failure in Adult Patients with Relapsed and Refractory B-Cell Acute Lymphoblastic Leukemia

Introduction: Chimeric antigen receptor (CAR)-T cell therapy for B-cell acute lymphoblastic leukemia (B-ALL) has been associated with remission rates exceeding 70% in adult patients. Unfortunately, a subset of patients does not respond to CAR-T cells, and more than 50% of adults with remission experience B-ALL relapse within one year after the treatment, displaying a dismal prognosis. Given the relatively small number of adult patients with B-ALL treated with CAR-T cells, there is little evidence regarding the most optimal salvage therapy after CAR-T failure. No consensus regarding the most effective intervention has been established yet. Methods: The aim of the study was to perform a meta-analysis of response rates to first-line treatments after CAR-T failure to provide pooled estimates and suggest the most efficient regimens. The population of interest were patients aged 18 or older, treated for B-ALL, who did not achieve complete remission (CR) or relapsed after anti-CD19 CAR-T treatment without receiving consolidation therapy. Any treatment regimen administered as the first line for relapsing or refractory to CAR-T cells B-ALL was considered the intervention. CR rate was the study endpoint. PubMed MEDLINE, EMBASE, and CENTRAL were searched from the database inception to 15 July 2024 to identify studies suitable for the analysis. The meta-analysis was performed using a random-effects model to obtain pooled CR with 95% confidence intervals (CI) for each intervention group separately. The study was conducted according to the PRISMA statement, the protocol was registered at the PROSPERO register (CRD42024517420). All analyses were performed using R Statistical Software v4.3.1 with a meta package. Results: In the search process, 10 studies were identified meeting the inclusion criteria and providing appropriate data for the meta-analysis. The following salvage interventions were identified: retreatment with anti-CD19 CAR-T cells (n=4), anti-CD22 CAR-T cells (n=3), bispecific anti-CD19/CD22 CAR-T cells (n=1), blinatumomab (n=1), inotuzumab ozogamicin (n=1), allogeneic stem cell transplantation (alloSCT) in patients without CR (n=1). One study included two intervention cohorts. Only studies evaluating retreatment with anti-CD19 CAR-T and anti-CD22 CAR-T cells provided enough data for the meta-analysis. In both cases, patients had been evaluated for antigen status before the administration of the salvage regimen. Only individuals expressing CD19 or CD22 on leukemic cells were treated. Retreatment with anti-CD19 CAR-T cells yielded a pooled CR rate of 43% (95% CI: 12-76%). CR rates were reported in four prospective studies enrolling 27 patients in total. No significant heterogeneity was detected (I2 = 45%, p=0.14). Importantly, all studies reported infusion of non-commercial CAR-T cells both initially and as a salvage regimen (1 study examined murine CD19-specific region receptors, 1 study included humanized CD19 receptors), which may impede the extrapolation of the results to the general population of CAR-T recipients. Salvage administration of anti-CD22 CAR-T cells was reported in three prospective studies enrolling 28 patients in total. Pooled CR rate for anti-CD22 CAR-T cells was 78% (95% CI: 50-98%). The heterogeneity was not significant (I2 = 40%, p=0.19). Two studies enrolled patients treated previously with non-commercial CAR-T cells, whereas one study did not include specific information on the previous CAR-T. Conclusions: Data regarding salvage treatment regimens in B-ALL after CAR-T cell failure remains scarce in adult patients. To date, administration of either anti-CD19 or anti-CD22 CAR-T cells has been the most common choice, yielding CR rates of 43% (95% CI: 12-76%) and 78% (95% CI: 50-98%), respectively. As the choice of a given regimen depends on the antigen status, the obtained values should not be compared directly. Moreover, the CR rate in CAR-T cell therapy is associated with multiple factors such as the expression of target molecules or type of CAR-T product and previous regimens, which make the decision-making even more difficult. Considering the poor prognosis for the patients and data scarcity, reporting the results of the management after CAR-T cell therapy failure in B-ALL is of the utmost importance.