We report a case of severe, irreversible transverse myelitis following CD19-directed CAR-T cell therapy (axicabtagene ciloleucel) for refractory post-transplant lymphoproliferative disorder (PTLD) in a young female lung-transplant recipient. This case illustrates an emerging neurotoxic complication of CAR-T cell therapy and highlights convergent risk factors including demographics, tumor type and CAR construct. We discuss current evidence of CAR-T-associated myelopathy, its proposed inflammatory and immune-trafficking mechanisms, and the potential contribution of interleukins and chemokines such as IL-1, IL-6, IL-18, CCL-2 and CXCL10 signaling to spinal cord injury. We further address diagnostic challenges, and review current management strategies such as corticosteroids, IL-1 blockade, and IL-6 neutralization. This report underscores the need for heightened vigilance, early imaging, and systematic reporting to improve prevention and treatment of this rare but severe CAR-T-related neurotoxicity.

BACKGROUND:Chimeric antigen receptor (CAR) T-cell therapy is the standard of care for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, more than half of patients fail to achieve durable remission. Identifying predictive biomarkers within the CAR T-cell infusion product (IP) may guide strategies to improve clinical outcomes. PATIENTS AND METHODS:This single-center observational study, conducted at Lausanne University Hospital (CHUV), Switzerland, analyzed IPs from 13 patients with R/R DLBCL who underwent standard-of-care CAR T-cell therapy. A 39-marker mass cytometry panel was used to compare phenotypic and functional markers between long-term responders (R) and nonresponders (NR). Unsupervised and supervised analytic approaches were applied to IP data, and longitudinal peripheral blood samples were collected over 30 days after infusion to track CAR T-cell subpopulation dynamics. RESULTS:At a median follow-up of 13.5 months, median progression-free survival (PFS) was 13.3 months [95% confidence interval (CI) 9.7-24.3 months] in R (n = 8) versus 3.5 months (95% CI 0.5-5.4 months) in NR (n = 5) (hazard ratio 56.67, 95% CI 7.3-439.3, P = 0.0001). A CD3+CXCR3+CD7+ CAR T-cell subpopulation-found in both CD4+ and CD8+ compartments-was significantly enriched in R. These cells showed increased expression of perforin, granzyme B, and NKG2D (restricted to CD8+ cells). In contrast, NR had a higher frequency of CXCR3+CD7+LAG3+ CAR T-cells. Surface expression of CD3, CD7, CXCR3, and NKG2D were higher in R, whereas LAG3, Ki67, and CD71 were elevated in NR. A predictive cut-off ratio of CD3+CXCR3+CD7+LAG3+CAR+ T-cells <0.83 and CD3+CXCR3+CD7+NKG2D+CAR+ T-cells >1.034 yielded a predictive accuracy of 0.92. Serum CXCL9 and CXCL10 concentrations did not differ between groups. CONCLUSIONS:Enrichment of CD7+CXCR3+ CAR T-cells alongside elevated NKG2D expression in R, in contrast to higher LAG3 and CD71 in NR, emerged as potentially robust correlates of therapeutic outcome. Although derived from a small, hypothesis-generating cohort, these findings suggest that targeted analysis of IP composition may inform the development of biomarker-driven strategies to optimize CAR T-cell products and improve the likelihood of durable remission in R/R DLBCL.

Background. CAR T-cell therapy is the standard of care for R/R DLBCL, but more than half of patients fail to achieve long-term remission. Identification of cellular biomarkers in CAR T-cell infusion products (IPs) that predict complete remission beyond six months may guide the development of strategies to improve outcomes. Methods. IPs from 13 R/R DLBCL patients were analyzed using a 39-marker mass cytometry panel, comparing cell populations between long-term responders (R) and non-responders (NR). Both unsupervised and supervised analyses were performed. Longitudinal blood samples were analyzed for 30 days to track CAR T-cell subpopulation dynamics. Results. At a median follow-up of 13.5 months, median progression-free survival (PFS) was 13.3 months (95% CI: 9.7-24.3) in R (n=8) versus 3.5 months (95% CI: 0.5-5.4) in NR (n=5). The HR for PFS was 56.67 (95% CI: 7.3-439.3; P=0.0001). A subset of CD3+CXCR3+CD7+ CAR T-cells found in both CD4+ and CD8+ populations was significantly enriched in R and expressed higher levels of perforin, granzyme B, and NKG2D (restricted to CD8+). NR had more CXCR3+CD7+LAG3+ CAR T-cells. CD3, CD7, CXCR3, and NKG2D cell surface levels were higher in R, whereas LAG3, Ki67, and CD71 were elevated in NR. A predictive cut-off ratio of CD3+CXCR3+CD7+LAG3+CAR+ T-cells <0.83 and CD3+CXCR3+CD7+NKG2D+CAR+ T-cells >1.034 yielded a predictive accuracy of 0.92. Serum CXCL9 and CXCL10 levels were not different between groups. Conclusions. Increased frequency of CAR T-cells expressing CD7, CXCR3 and NKG2D in R versus LAG3 and CD71 in NR emerged as strong correlates of therapeutic outcome. ### Competing Interest Statement MO received honoraria and speaker fees from Moderna, Roche and BMS. C.A. holds patents and provisional patent applications in the field of engineered T cell therapies. C.A. receives licensing fees and royalties from Immatics (through previous institution Baylor College of Medicine), participated in advisory boards for Kite/ Gilead, Janssen and Celgene/ BMS, received sponsored travel from Gilead (through current institution Lausanne University Hospital (CHUV). G.C. has received honoraria from Bristol-Myers Squibb. CHUV has received honoraria for advisory services provided by G.C. to Iovance and EVIR. G.C. has received royalties from the University of Pennsylvania for CAR T cell therapy licensed to Novartis and Tmunity Therapeutics. G.C. has received royalties from the Ludwig Institute for Cancer Research, UNIL and CHUV for NeoTIL intellectual property previously licensed to Tigen Pharma. G.C. is inventor in technologies related to T cell expansion and engineering for T cell therapy. RS participated in advisory boards for Janssen, Celgene/ BMS, AbbVie, Takeda and Incyte. ### Funding Statement This study did not receive any dedicated funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Cantonal Ethics Committee (CER-VD) of the Vaud Canton (Switzerland) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets supporting the results of this study are not publicly available. Requests for access to the dataset will be granted upon reasonable request to the principal investigator. Study data will be managed, stored, shared, and archived according to CHUV standard operating procedures to ensure the continued quality, integrity, and utility of the data.

Abstract Background Chemotherapy of acute myeloid leukaemia (AML) can cause a broad spectrum of cardiotoxic effects. Cardiac magnetic resonance (CMR) is key for the diagnosis of eosinophilic myocarditis (EM) defined by the presence of sub-endocardial necrosis and fibrosis. This case report describes the picture of severe triple-vessel ischaemia due to infiltration of eosinophilia without atherosclerotic coronary artery disease (CAD). Case summary A 57-year-old woman was diagnosed with AML requiring chemotherapy. Three days after initiation of chemotherapy, the patient presented with chest pain and new left ventricular (LV) dysfunction and hyper-eosinophilia. A CMR examination initially was compatible with severe triple-vessel ischaemia. Tissue characterization by CMR was not done due to severe dyspnoea promoting the differential diagnosis of triple-vessel CAD or chemotherapy-induced triple-vessel coronary spasm. However, invasive coronary angiography excluded obstructive CAD. Severe LV dysfunction and troponin elevation persisted arguing against coronary vasospasm. Chemotherapy induced a massive increase in blood eosinophils, and EM was considered as most likely diagnosis. Immunosuppressive treatment improved the patient’s status and a CMR later on confirmed the diagnosis of EM. Discussion Chemotherapy-induced massive eosinophilia can cause widespread coronary micro-vascular infiltration mimicking severe triple-vessel CAD. Early CMR did not evaluate tissue composition, and EM was not considered which delayed adequate treatment. A complete CMR assessment is key to establish the correct diagnosis.

In patients with relapsed/refractory Burkitt lymphoma (r/r BL), overall survival (OS) is poor, and effective therapies and evidence for the best therapy are lacking. The monoclonal antibody blinatumomab may represent a novel option. However, only limited data on the use of blinatumomab in r/r BL are so far available. This multi-center, retrospective case series investigated nine patients with r/r BL treated with blinatumomab. The safety of blinatumomab was assessed with respect to frequency and severity of adverse effects (AEs) infections, cytokine release syndrome (CRS) and neurotoxicity. Progression-free survival (PFS), OS and overall response rate (ORR) were analyzed to assess efficacy. No AEs > grade 2 occurred, and AEs were generally treatable and fully reversible. The best response to blinatumomab was complete remission in 3/9 patients and partial remission in 2/9, whilst 4/9 presented with progressive disease. Median PFS and OS were 2 and 6 months, respectively, ranging from 5 days to 32 months and 11 days to 32 months, respectively. Blinatumomab treatment was a successful bridging treatment to stem cell transplantation in 3/9 patients. The response to blinatumomab varied widely, and only one patient survived longer term, but activity in patients with r/r BL was evident in some patients, with its use being safe, warranting its prospective investigation.

In these times of COVID-19 pandemic, concern has been raised about the potential effects of SARS-CoV-2 infection on immunocompromised patients, particularly on those receiving B-cell depleting agents and having therefore a severely depressed humoral response. Convalescent plasma can be a therapeutic option for these patients. Understanding the underlying mechanisms of convalescent plasma is crucial to optimize such therapeutic approach. Here, we describe a COVID-19 patient who was deeply immunosuppressed following rituximab (anti-CD20 monoclonal antibody) and concomitant chemotherapy for chronic lymphoid leukemia. His long-term severe T and B cell lymphopenia allowed to evaluate the treatment effects of convalescent plasma. Therapeutic outcome was monitored at the clinical, biological and radiological level. Moreover, anti-SARS-CoV-2 antibody titers (IgM, IgG and IgA) and neutralizing activity were assessed over time before and after plasma transfusions, alongside to SARS-CoV-2 RNA quantification and virus isolation from the upper respiratory tract. Already after the first cycle of plasma transfusion, the patient experienced rapid improvement of pneumonia, inflammation and blood cell counts, which may be related to the immunomodulatory properties of plasma. Subsequently, the cumulative increase in anti-SARS-CoV-2 neutralizing antibodies due to the three additional plasma transfusions was associated with progressive and finally complete viral clearance, resulting in full clinical recovery. In this case-report, administration of convalescent plasma revealed a stepwise effect with an initial and rapid anti-inflammatory activity followed by the progressive SARS-CoV-2 clearance. These data have potential implications for a more extended use of convalescent plasma and future monoclonal antibodies in the treatment of immunosuppressed COVID-19 patients.

Abstract Convalescent plasma to treat coronavirus disease 2019 (COVID-19) is currently the focus of numerous clinical trials worldwide, but the criteria of treatment efficacy remain largely unknown. Here, we describe a severely immunosuppressed patient following rituximab and chemotherapy for chronic lymphoid leukemia, who became infected by SARS-CoV-2. His prolonged viral disease was successfully cured after four cycles of convalescent plasma. Its immunomodulatory properties led to the rapid improvement of inflammation, pneumonia and blood cell counts, already after the first cycle. Importantly, the cumulative increase in anti-SARS-CoV-2 neutralizing antibodies following each plasma transfusion was associated to progressive viral clearance, resulting in clinical recovery from infection. Our data provide insight into the different modes of action of plasma components. Understanding the underlying mechanisms will help to optimize the treatment of COVID-19 patients.

High cut-off dialysis, increasingly used in multiple myeloma patients, is susceptible to influence anticancer drug elimination. We report about lenalidomide disposition in a patient on high cut-off dialysis for renal failure secondary to myeloma cast nephropathy.

A 62-year-old man complaining of neck pain was found to have a mass in the left carotid region. He was on treatment for hypertension but had no symptoms suggestive of catecholamine excess. Urinary dopamine values were near or above the upper reference limit in 2 samples (Table 1). Free and total plasma methoxytyramine, plasma dopamine, …

Applying knowledge acquired from recent medical studies to patient care poses a daily challenge to physicians. Chief residents from the Department of Internal Medicine at the University Hospital of Lausanne carried out a review of some of the issues they considered important. The conclusions of these various publications may have a significant impact on the daily practice of hospital-based internal medicine. Modern medicine based on scientific studies is a reminder that in spite of the essential importance of clinical experience, it is crucial to confront it with the results of relevant publications from the medical literature.

Internists must regularly adjust their patients care according to recent relevant publications. The chief residents from the Department of Internal Medicine of a university hospital present some major themes of internal medicine treated during the year 2009. Emphasis will be placed primarily on changes in the daily hospital practice induced by these recent studies. This variety of topics illustrates both the broad spectrum of the current internal medicine, and the many uncertainties associated with modern medical practice based on evidence.