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Building upon a study published in The Lancet Neurology showing the feasibility of transiently expressed B-cell maturation antigen (BCMA)-targeted RNA chimeric antigen receptor (CAR) T-cell therapy in patients with myasthenia gravis,1 we report a case that indicates that a different CAR T-cell approach that targets CD19 with a stably expressed CAR, delivered following a conventional lymphodepleting regimen, might be safe and effective in the treatment of severe and refractory myasthenia gravis. Previous treatment attempts, including thymectomy (in April, 2022, performed at another academic centre), acetylcholinesterase inhibitors (initiated in 2012 at our institution), and B-cell-depleting antibodies (rituximab, administered in April and October, 2021, at our institution) did not stabilise the disease course, which was class V according to the Myasthenia Gravis Foundation of America criteria (defined as intubation, with or without mechanical ventilation, except when used during routine postoperative management).3 Moreover, a proteasome inhibitor (bortezomib, administered in May and November, 2022), immunosuppressive drugs (mycophenolate mofetil, administered for 21 months preceding the CAR T-cell infusion), and immunoglobulin therapy (initiated in October, 2021) had proven futile in providing long-term relief (appendix p 4). The serological findings were paralleled by the patient's improved muscle strength and fatigue over the first 2 months after CD19 CAR T infusion, evidenced by the steady increase in the time that the patient could hold out her arm horizontally, her enhanced walking ability without any supportive devices, and the reduction of the clinical multiparameter Besinger disease activity and the Quantitative Myasthenia Gravis scores3,8 (figure).

JAK2-V617F-positive chronic myeloproliferative neoplasia (CMN) commonly displays dysfunction of integrins and adhesion molecules expressed on platelets, erythrocytes, and leukocytes. However, the mechanism by which the 2 major leukocyte integrin chains, β1 and β2, may contribute to CMN pathophysiology remained unclear. β1 (α4β1; VLA-4) and β2 (αLβ2; LFA-1) integrins are essential regulators for attachment of leukocytes to endothelial cells. We here showed enhanced adhesion of granulocytes from mice with JAK2-V617F knockin (JAK2+/VF mice) to vascular cell adhesion molecule 1- (VCAM1-) and intercellular adhesion molecule 1-coated (ICAM1-coated) surfaces. Soluble VCAM1 and ICAM1 ligand binding assays revealed increased affinity of β1 and β2 integrins for their respective ligands. For β1 integrins, this correlated with a structural change from the low- to the high-affinity conformation induced by JAK2-V617F. JAK2-V617F triggered constitutive activation of the integrin inside-out signaling molecule Rap1, resulting in translocation toward the cell membrane. Employing a venous thrombosis model, we demonstrated that neutralizing anti-VLA-4 and anti-β2 integrin antibodies suppress pathologic thrombosis as observed in JAK2+/VF mice. In addition, aberrant homing of JAK2+/VF leukocytes to the spleen was inhibited by neutralizing anti-β2 antibodies and by pharmacologic inhibition of Rap1. Thus, our findings identified cross-talk between JAK2-V617F and integrin activation promoting pathologic thrombosis and abnormal trafficking of leukocytes to the spleen.

Objective Body composition assessment derived from cross-sectional imaging has shown promising results as a prognostic biomarker in several tumor entities. Our aim was to analyze the role of low skeletal muscle mass (LSMM) and fat areas for prognosis of dose-limiting toxicity (DLT) and treatment response in patients with primary central nervous system lymphoma (PCNSL). Methods Overall, 61 patients (29 female patients, 47.5%) with a mean age of 63.8 ± 12.2 years, range 23–81 years, were identified in the data base between 2012 and 2020 with sufficient clinical and imaging data. Body composition assessment, comprising LSMM and visceral and subcutaneous fat areas, was performed on one axial slice on L3-height derived from staging computed tomography (CT) images. DLT was assessed during chemotherapy in clinical routine. Objective response rate (ORR) was measured on following magnetic resonance images of the head accordingly to the Cheson criteria. Results Twenty-eight patients had DLT (45.9%). Regression analysis revealed that LSMM was associated with objective response, OR = 5.19 (95% CI 1.35–19.94, p  = 0.02) (univariable regression), and OR = 4.23 (95% CI 1.03- 17.38, p  = 0.046) (multivariable regression). None of the body composition parameters could predict DLT. Patients with normal visceral to subcutaneous ratio (VSR) could be treated with more chemotherapy cycles compared to patients with high VSR (mean, 4.25 vs 2.94, p  = 0.03). Patients with ORR had higher muscle density values compared to patients with stable and/or progressive disease (34.46 ± vs 28.18 ± HU, p  = 0.02). Conclusions LSMM is strongly associated with objective response in patients with PCNSL. Body composition parameters cannot predict DLT. Clinical relevance statement Low skeletal muscle mass on computed tomography (CT) is an independent prognostic factor of poor treatment response in central nervous system lymphoma. Analysis of the skeletal musculature on staging CT should be implemented into the clinical routine in this tumor entity. Key Points • Low skeletal muscle mass is strongly associated with the objective response rate . • No body composition parameters could predict dose-limiting toxicity .

The annualised incidence of primary immune thrombocytopenia is approximately 3·3 cases per 100 000 people among adults. 1 Despite several treatment options, including approved thrombopoietin receptor agonists and commonly used antibody-reducing approaches—such as B-cell depletion with the anti-CD20 monoclonal antibody rituximab, BTK inhibitors, SYK inhibitors, corticosteroids, and splenectomy—a subset of patients develop refractory immune thrombocytopenia. 2 For these individuals, who are estimated to comprise less than 10% of the total immune thrombocytopenia population, conventional therapies do not achieve durable platelet recovery, resulting in life-threatening bleeding episodes and substantially impaired quality of life. In April, 2024, after a case review by an independent interdisciplinary committee, the hospital board, and the hospital's legal department, the patient gave written informed consent to receive autologous CD19 CAR T-cell therapy as an individualised treatment under German law, which allows the use of unlicensed therapies ( appendix p 1). Within the reconstituting B cell compartment, we observed predominantly CD21 + CD27 – naive cells, with low to absent (switched or non-switched) CD21 + CD27 + memory B cells and CD38 + CD20 – plasmablasts ( figure D), which is also consistent with previous data in patients with autoimmune diseases receiving CAR T cells. 3,9 To avoid withdrawal effects after stopping thrombopoietin receptor agonist, romiplostim treatment, which had been interrupted since day –9, was resumed on day 16 after infusion. Pathogenic autoantibodies against glycoprotein IIb/IIIa were no longer detectable after day 42 ( appendix p 8). [...]the patient's chronic fatigue had resolved 3 months after treatment, and he was planning to return to work in December, 2024.

Body composition assessment has shown promising results as a prognostic biomarker as depicted by cross-sectional imaging of several tumor entities including lymphomas. The present study sought to elucidate the prognostic relevance of subcutaneous and visceral fat tissue (SAT and VAT) in patients with primary central nervous system lymphoma (PCNSL). Overall, 74 patients (36 female patients, 46.7%) with a mean age of 64.2±12.8 years (range=23-81 years) were identified in the database with sufficient clinical and imaging data and included into this retrospective study. Fat area assessment was performed on one axial slide on L3-height derived from staging computed tomography (CT) images. Subcutaneous, visceral, and intramuscular adipose tissues (SAT, VAT, IMAT) were estimated. Also, density of SAT, VAT, and IMAT were estimated. Finally, the ratio VAT/SAT (VSR) was calculated. Overall and progression-free survival (OS and PFS) were used as study end points. In the observation period, overall, 47 patients (63.5%) died. Mean OS was 33.8±45.4 months and mean PFS was 26.6±42.7 months. The mean VAT value was 162±99.5 cm , the mean SAT was 202.4±103.3 cm , the mean VSR was 0.92±0.69. The hazard ratios (HRs) for overall survival were 0.87 for high VAT, 1.52 for SAT, and 0.73 for VSR in univariable analysis. For PFS it was 0.24 for VAT, 1.11 for SAT, and 1.07 for VSR. No values achieved statistical significance. Similar results were shown in Kaplan-Meier analysis for OS and PFS, respectively. Parameters of adipose tissue are not associated with OS and PFS in patients with PCNSL.

Abstract Patients (pts) with polycythemia vera (PV) suffer from pruritus, night sweats, and other symptoms, as well as from thromboembolic complications and progression to post-PV myelofibrosis. Ruxolitinib (RUX) is approved for second-line therapy in high-risk PV pts with hydroxyurea intolerance or resistance. The RuxoBEAT trial (NCT02577926, registered on October 1, 2015, at clinicaltrials.gov) is a multicenter, open-label, two-arm phase-IIb trial with a target population of 380 pts with PV or ET, randomized to receive RUX or best available therapy. This pre-specified futility analysis assesses the early clinical benefit and tolerability of RUX in previously untreated PV pts (6-week cytoreduction was allowed). Twenty-eight patients were randomly assigned to receive RUX. Compared to baseline, after 6 months of treatment, there was a significant reduction of median hematocrit (46 to 41%), the median number of phlebotomies per year (4.0 to 0), and median patient-reported pruritus scores (2 to 1), and a trend for reduced night sweat scores (1.5 to 0). JAK2V617F allele burden, as part of the scientific research program, also significantly decreased. One hundred nine adverse events (AEs) occurred in 24/28 patients (all grade 1 to 3), and no pt permanently discontinued treatment because of AEs. Thus, treatment with ruxolitinib in untreated PV pts is feasible, well-tolerated, and efficient regarding the above-mentioned endpoints.

Purpose Treatment recommendations for patients with polycythemia vera (PV) are well established. Most multicenter trials investigating novel therapeutic strategies for PV are developed and conducted at university hospitals and specialized academic centers. The majority of patients in Germany, however, are treated in an outpatient (ambulatory) setting. The aim of this study was to evaluate the ‘real-life’ situation in a cohort of 1467 patients by analyzing data from a survey conducted at private practices and primary care centers. Methods Eligible private practices and primary care centers treating patients with MPN were recruited to participate in a paper–pencil-based survey conducted from March 2015 until March 2016 in Germany. Hematologists were asked to report from patient charts. Descriptive analyses were conducted to assess for outcomes examined by reported prognostic risk scores, symptom scores and clinical response criteria. Results In total, 34 centers participated in our retrospective survey and provided data on 1476 patients. Most patients were of older age (66.7 % older than 66 years of age), which was the main risk factor according to the criteria published by Tefferi and colleagues. Molecular status at diagnosis was not evaluated in 23 % of patients. Low rates of constitutional symptoms were reported in this physician-based survey with concentration problems, fatigue and itching being the main PV-related symptoms. Phlebotomy and hydroxyurea were the main cytoreductive measures for hematocrit control. The majority of patients were responsive (67.8 %) and tolerant (77.3 %) to hydroxyurea therapy. Interferon and JAK inhibitor therapy were used in <10 % of patients, respectively. Overall, leukocytosis, thrombocytosis and hematocrit could be effectively controlled by any therapy applied. Lack of efficacy was reported on reduction of constitutional symptoms and splenomegaly. Conclusions The patient population investigated was older than participants in published large multicenter trials. The majority of patients were categorized as ‘high risk.’ Age was the main risk factor. Molecular status was unavailable in the majority of patients diagnosed prior to 2008. The physician-based survey reported on significantly lower rates of constitutional symptoms than patient-based surveys in the literature. Consistent with previously published reports, hydroxyurea is the main agent used for PV therapy in an outpatient setting resulting in efficient control of hematopoietic parameters. Constitutional symptoms and splenomegaly, however, may not be reduced efficiently, which could be improved by the use of JAK inhibitor treatment for high-risk patients in the future.

Background Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL). Methods Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 10 6 and 50 × 10 6 CARTs/m 2 . Leukapheresis, manufacturing and administration of CARTs were performed in-house. Results For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response. Conclusion In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www.clinicaltrials.gov as NCT03676504.