Beatrice Ludwig-Kraus

Relapse after remission remains the primary cause of treatment failure in acute myeloid leukemia (AML), underscoring the need for strategies to eliminate residual leukemic cells. The bone marrow microenvironment, largely orchestrated by the CXCR4-CXCL12 axis, enables leukemia cell survival and chemoresistance by anchoring blasts in their protective bone marrow niche. Motixafortide, a selective CXCR4 antagonist, mobilizes leukemic cells and disrupts tumor-microenvironment interactions in preclinical models. In this randomized, double-blind, placebo-controlled phase II trial (NCT02502968; registered at ClinicalTrials.gov), 128 patients in first remission received high‑dose cytarabine (HiDAC) plus Motixafortide or placebo. Median relapse-free survival (RFS) did not substantially differ between groups: 10.3 months (95% CI, 8.0-12.0) for Motixafortide and 11.5 months (95% CI, 8.6-24.1) for placebo (log-rank p=0.98). But scMRD analysis, performed before consolidation, demonstrated heterogeneity of CXCR4 inhibition benefit: in the placebo group, higher CXCR4 expression was associated with increased relapse risk (p=0.02), whereas in the Motixafortide group, higher CXCR4 expression was linked to a reduced relapse rate (p=0.047). Exploratory analyses identified scMRD levels at which higher MRD burden was associated with inferior overall survival (OS). Taken together, combining functional MRD profiling with biomarker-driven patient selection, such as CXCR4 expression, may enable more precise and effective post-remission interventions in AML. This clinical trial is registered at EudraCT number: 2014-002702-21

Purpose: Evaluate long-term immunogenicity and its association with the number of vaccines and breakthrough infections in patients with hematologic malignancies compared to a healthy cohort. Methods: This study is an amendment of a multicenter study (DRKS00027372) which described the upsurge of anti-spike-IgGs on day 120 from a blunted day-35 response in patients with hematologic neoplasms. In this amendment, 191 individuals from the original study (patients with myeloid and lymphoid neoplasms and controls) were followed beyond month 12 after first SARS-CoV-2-vaccination. The long-term humoral and cellular responses and their correlation with the number of vaccines were studied. Results: After a median follow-up of 18 months, a median of three vaccinations (range 1–5) were given. Antibody levels did not correlate with the number of vaccinations (≤2 versus ≥3) (p = 0.3). With a median of 5274 U/mL anti-spike-IgGs, the inferior day-120 antibody response in patients with lymphoid neoplasms was no longer detected. Breakthrough SARS-CoV-2-infections, mostly mild, occurred in 67% of controls and 46% of patients. Patients with lymphoid neoplasms with two vaccinations did not have more infections compared to patients with more doses (p = 0.4). There was a significant decline in the spike-specific T-cell response for CovCD4⁺ and CovCD8⁺ (p < 0.001). On last assessment, 33% of individuals lost their day-120 CovCD4⁺-positive response (p < 0.001). There was no correlation between the number of vaccinations and cellular immune response in patients and controls (p = 0.3). Conclusions: In this study, breakthrough infections were high despite repeated boosting, which by itself does not lead to an upsurge in the cellular immune response in the majority of patients.

Preservation of function is an important goal during surgical management of cochleovestibular schwannomas. We here demonstrate the relief of vertigo and the preservation of function of all five vestibular receptors after removal of an intracochlear schwannoma with extension to the fundus of the internal auditory canal. A 61-year-old male with a five-year history of left-sided deafness, tinnitus, vertigo attacks, and an MRI consistent with an intracochlear schwannoma with limited extension through the modiolus to the fundus of the internal auditory canal (IAC) underwent transcanal, transcochlear total tumor removal and—due to a cerebrospinal fluid leak from the fundus of the IAC—revision surgery with lateral petrosectomy and blind sac closure of the external auditory canal. Despite complete removal of the cochlear partition of the inner ear (total cochlectomy), the patient’s vestibular receptors remained functional, and the vertigo symptoms disappeared. These results show that vestibular labyrinthine function may not only be preserved after partial or subtotal cochlectomy but also after complete cochlear removal. This further confirms the vestibular labyrinth’s robustness and encourages surgical management of transmodiolar schwannomas with limited extension to the fundus of the IAC.

In order to elucidate mechanisms for severe acute respiratory syndrome coronavirus 2 vaccination success in hematological neoplasia, we, herein, provide a comprehensive characterization of the spike-specific T-cell and serological immunity induced in 130 patients in comparison with 91 healthy controls. We studied 121 distinct T-cell subpopulations and the vaccination schemes as putative response predictors. In patients with lymphoid malignancies an insufficient immunoglobulin G (IgG) response was accompanied by a healthy CD4+ T-cell function. Compared with controls, a spike-specific CD4+ response was detectable in fewer patients with myeloid neoplasia whereas the seroconversion rate was normal. Vaccination-induced CD4+ responses were associated to CD8+ and IgG responses. Vector-based AZD1222 vaccine induced more frequently detectable specific CD4+ responses in study participants across all cohorts (96%; 27 of 28), whereas fully messenger RNA-based vaccination schemes resulted in measurable CD4+ cells in only 102 of 168 participants (61%; P < .0001). A similar benefit of vector-based vaccination was observed for the induction of spike-specific CD8+ T cells. Multivariable models confirmed vaccination schemes that incorporated at least 1 vector-based vaccination as key feature to mount both a spike-specific CD4+ response (odds ratio, 10.67) and CD8+ response (odds ratio, 6.56). Multivariable analyses identified a specific CD4+ response but not the vector-based immunization as beneficial for a strong, specific IgG titer. Our study reveals factors associated with a T-cell response in patients with hematological neoplasia and might pave the way toward tailored vaccination schemes for vaccinees with these diseases. The study was registered at the German Clinical Trials Register as #DRKS00027372.

Purpose: To assess humoral responses longitudinally and cellular immunogenicity following SARS-CoV-2-vaccination in patients with hematologic and oncologic malignancies receiving checkpoint-inhibitors. Methods: This prospective multicenter trial of the East-German-Study-Group-for-Hematology-and-Oncology, enrolled 398 adults in a two (patients; n = 262) to one (controls; n = 136) ratio. Pre-vaccination, day 35 (d35), and day 120 (d120) blood samples were analyzed for anti-spike antibodies and d120 IL-2⁺IFNγ⁺TNFα⁺-CD4⁺- and CD8⁺-cells. Laboratories were blinded for patients and controls. Results: Patients belonged to the myeloid (n = 131), lymphoid (n = 104), and checkpoint-inhibitor (n = 17) cohorts. While d35 seroconversion was higher in controls (98%) compared to patients (68%) (p < 0.001), d120 seroconversion improved across all patient cohorts [checkpoint-inhibitors (81% to 100%), myeloid (82% to 97%), lymphoid (48% to 66%)]. CD4⁺- and CovCD8⁺-cells in the lymphoid (71%/31%) and control (74%/42%) cohorts were comparable but fewer in the myeloid cohort (53%, p = 0.003 /24%, p = 0.03). In patients with hematologic malignancies, no correlation between d120 humoral and cellular responses was found. A sizeable fraction of lymphoid patients demonstrated T-cell responses without detectable spike-specific-IgGs. Conclusions: Evidence of vaccine-elicited humoral and/or cellular immunogenicity in most patients is provided. Both humoral and cellular responses are crucial to determine which patients will generate/maintain immunity. The findings have implications on public health policy regarding recommendations for SARS-CoV-2 booster doses.

Background: Nucleocapsid gene-positive, envelope gene-negative (N2+/E-) SARS CoV-2 PCR results obtained with the Cepheid Xpert Xpress SARS-CV-2 assay are an infrequent and difficult to interpret phenomenon. Objectives: Assess the validity of the N2+/E- cases with an indirect approach by analysing their occurrence in relation to overall positive PCR rates and absolute number of PCR tests. Study design: We analysed the rate N2+/E- results obtained with the Xpert Xpress SARS-CoV-2 assay from 24909 nasopharyngeal swaps, collected from June 2021 to July 2022 in a large hospital population in Germany. Additionally, 3022 samples were analysed with Xpert Xpress CoV-2 plus assay in August/September 2022. Results: Monthly positive rates obtained with the Xpert Xpress SARS-CoV-2 were 0.3% to 17.5% and the number of N2+/E- cases varied from one to 40 per month (total n = 198). The incidence of monthly N2+/E- cases closely followed the overall frequency of positive tests (p < 0.001), while there was no correlation with the monthly number of PCR test (p = 0.37). For the Xpert Xpress CoV-2 plus test, 12.6% of the positive PCR results were double negative with only one of the three target genes being amplified. Conclusion: The observed distribution of N2+/E- cases implicates, that they are not merely artefacts, but rather represent samples with a very low viral load. This phenomenon will persist with the Xpert Xpress SARS-CoV-2 plus assay, which also produced more than 10% results where only one target gene replicated with a very high Ct value.

Objectives: Characterization of an in vitro diagnostic zinc assay (LT‐SYS) on a Roche cobas c502 analyzer and evaluation of the influence of pre‐analytic factors on zinc concentration measurements.Design and methods: Imprecision, bias, linearity, limit of blank (LoB), and limit of detection (LoD) were established and method comparisons were performed based on the respective CLSI guidelines. The influence of time elapsed until analysis, the usage of a pneumatic tube delivery system (PTDS) and of special trace element sample tubes was evaluated as well.Results: Estimates of imprecision ranged from 0.9% to 5.0% and bias was low with 1.3% and 1.5% deviation from target value. Linearity was met for the measuring range of 1.15‐34.7 μmol/L (7.51‐226.9 μg/dL), LoB and LoD were 0.17 μmol/L (1.11 μg/dL) and 0.73 μmol/L (4.77 μg/dL) respectively. The method comparison revealed an average deviation of 8.44% (y=0.542+1.036x). Plasma samples had 7.3% higher zinc values than serum samples on the average. Zinc values of uncentrifuged serum and plasma samples increased 20% in 8 hours, while after centrifugation no significant increase could be detected. Usage of PTDS increased zinc values by 17% and usage of trace element sample tubes showed no advantage over normal ones.Conclusions: The LT‐SYS zinc assay showed a fully acceptable performance with good degrees of imprecision and bias, no deviation from linearity and both a very low LoB and LoD. Samples for zinc analysis should be centrifuged timely and transport over PTDS should be avoided.