CD19-directed chimeric antigen receptor (CAR) T cells have evolved as new standard-of-care (SOC) treatment in patients with relapsed/refractory large B-cell lymphoma (LBCL). Here, we report the first German real-world data on SOC CAR-T cell therapies with the aim to explore risk factors associated with outcome. Patients who received SOC axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for LBCL and were registered with the German Registry for Stem Cell Transplantation (DRST) were eligible. Main outcomes analyzed were toxicities, response, overall survival (OS), and progression-free survival (PFS). We report 356 patients who received axi-cel (n=173) or tisa-cel (n=183) between November 2018 and April 2021 at 21 German centers. Whereas the axi-cel and tisa-cel cohorts were comparable for age, sex, LDH, IPI, and pretreatment, the tisa-cel group comprised significantly more patients with poor performance status, ineligibility for ZUMA-1, and need for bridging, respectively. With a median follow-up alive of 11 months, Kaplan-Meier estimates of OS, PFS, and non-relapse mortality (NRM) 12 months after dosing were 52%, 30%, and 6%, respectively. While NRM was largely driven by infections subsequent to prolonged neutropenia and/or severe neurotoxicity and significantly higher with axi-cel, significant risk factors for PFS on multivariate analysis included bridging failure, elevated LDH, age, and tisa-cel use. In conclusion, this study suggests that important outcome determinants of CD19-directed CAR-T cell treatment of LBCL in the real-world setting are bridging success, CAR-T product selection, LDH, and the absence of prolonged neutropenia and/or severe neurotoxicity. These findings may have implications for designing risk-adapted CAR-T cell therapy strategies.

Malignant gliomas are the most common and lethal primary intracranial tumors. To date, no reliable biomarkers for the detection and risk stratification of gliomas have been identified. Recently, we demonstrated significant levels of microRNAs (miRNAs) to be present in cerebrospinal fluid (CSF) samples from patients with primary CNS lymphoma. Because of the involvement of miRNA in carcinogenesis, miRNAs in CSF may serve as unique biomarkers for minimally invasive diagnosis of glioma. The objective of this pilot study was to identify differentially expressed microRNAs in CSF samples from patients with glioma as potential novel glioma biomarkers. With use of a candidate approach of miRNA quantification by reverse-transcriptase polymerase chain reaction (qRT-PCR), miRNAs with significant levels in CSF samples from patients with gliomas were identified. MiR-15b and miR-21 were differentially expressed in CSF samples from patients with gliomas, compared to control subjects with various neurologic disorders, including patients with primary CNS lymphoma and carcinomatous brain metastases. Receiver-operating characteristic analysis of miR-15b level revealed an area under the curve of 0.96 in discriminating patients with glioma from patients without glioma. Moreover, inclusion of miR-15b and miR-21 in combined expression analyses resulted in an increased diagnostic accuracy with 90% sensitivity and 100% specificity to distinguish patients with glioma from control subjects and patients with primary CNS lymphoma. In conclusion, the results of this pilot study demonstrate that miR-15b and miR-21 are markers for gliomas, which can be assessed in the CSF by means of qRT-PCR. Accordingly, miRNAs in the CSF have the potential to serve as novel biomarkers for the detection of gliomas.

We performed serial measurable residual disease (MRD) monitoring in bone marrow (BM) and peripheral blood (PB) samples of 155 intensively treated patients with RUNX1-RUNX1T1-positive AML using an RT-qPCR-based assay with a sensitivity of up to 10^-6. We assessed both reduction of RUNX1-RUNX1T1 transcript levels and achievement of MRD negativity (MRD^neg) for impact on prognosis. Achievement of MR^2.5 (>2.5 log reduction) after treatment cycle 1 and achievement of MR^3.0 after treatment cycle 2 were significantly associated with a reduced risk of relapse (P=0.034 and P=0.028, respectively). After completion of therapy, achievement of MRD^neg in both, BM and PB, was an independent favorable prognostic factor for cumulative incidence of relapse (4-year CIR BM: 17% vs 36%, P=0.021; PB: 23% vs 55%; P=0.001) and overall survival (4-year OS rate BM: 93% vs 70%, P=0.007; PB: 87% vs 47%; P<0.0001). Finally, during follow-up serial RT-qPCR analyses allowed prediction of relapse in 77% of patients exceeding a cut-off value of 150 RUNX1-RUNX1T1 transcript levels in BM, and in 84% of patients exceeding a value of 50 RUNX1-RUNX1T1 transcript levels in PB. KIT mutation was a significant factor predicting for lower CR rate and inferior outcome, but its prognostic impact was outweighed by RUNX1-RUNX1T1 transcript levels during treatment. Virtually all relapses occurred within one year after end of treatment with a very short latency from molecular to morphologic relapse, necessitating MRD assessment at short intervals during this time period. Based on our data we here propose a refined practical guideline for MRD assessment in RUNX1-RUNX1T1-positive AML. Key Points MRD assessment in t(8;21) AML allows identifications of patients at high relapse risk at defined time points during treatment and follow-up. MRD^neg at EOT is the most valuable favorable factor for relapse risk and OS, and serial MRD analyses define cut-offs predicting relapse.

Treatment with autologous chimeric antigen receptor (CAR) T cells has emerged as a highly effective approach in neuroimmunological disorders such as myasthenia gravis. We report a case of successful anti-CD19 CAR T cell use in treatment-refractory stiff-person syndrome (SPS). To investigate clinical and immunological effects of anti-CD19 CAR T cell use in treatment-refractory SPS, a 69-y-old female with a 9-y history of treatment-refractory SPS with deteriorating episodes of stiffness received an infusion of autologous anti-CD19 CAR T cells (KYV-101) and was monitored clinically and immunologically for more than 6 mo. CAR T cell infusion resulted in reduced leg stiffness, drastic improvement in gait, walking speed increase over 100%, and daily walking distance improvement from less than 50 m to over 6 km within 3 mo. GABAergic medication (benzodiazepines) was reduced by 40%. KYV-101 CAR T cells were well tolerated with only low-grade cytokine release syndrome. This report of successful use of anti-CD19 CAR T cells in treatment-refractory SPS supports continued exploration of this approach in SPS and other B cell–related autoimmune disorders.

Myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) are autoimmune disorders affecting neuromuscular transmission. Their combined occurrence is rare, and treatment remains challenging. Two women diagnosed with concomitant MG/LEMS experienced severe, increasing disease activity despite multiple immunotherapies. Anti-CD19 chimeric antigen receptor (CAR) T cells have shown promise for treating autoimmune diseases. This report details the safe application of anti-CD19 CAR T cells for treating concomitant MG/LEMS. After CAR T cell therapy, both patients experienced rapid clinical recovery and regained full mobility. Deep B cell depletion and normalization of acetylcholine receptor and voltage-gated calcium channel N-type autoantibody levels paralleled major neurological responses. Within 2 months, both patients returned to everyday life, from wheelchair dependency to bicycling and mountain hiking, and remain stable at 6 and 4 months post-CAR T cell infusion, respectively. This report highlights the potential for anti-CD19 CAR T cells to achieve profound clinical effects in the treatment of neuroimmunological diseases.