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Glucocorticoid-refractory (SR) chronic (c) graft-versus-host disease (GVHD) is a multisystem immunological disease and the leading cause of non-relapse mortality (NRM) in patients surviving longer than 2 years after allogeneic hematopoietic cell transplantation. Both ruxolitinib (RUX) and extracorporeal photopheresis (ECP) have shown activity for SR-cGVHD which motivated us to treat refractory cGHVD patients with the RUX–ECP combination. In this retrospective survey, 23 patients received RUX–ECP as salvage therapy for SR-cGVHD. The best response (CR or PR) at any time point during treatment was 74% (17/23) including 9% (2/23) CR and 65% (15/23) PR. The 24-months-survival was 75% (CI 56.0–94.1). Newly diagnosed cytopenia occurred in 22% (5/23) and CMV reactivation was observed in 26% (6/23) of the patients. Serum levels of soluble interleukin-2 receptor (sIL-2R) correlated with response. Our retrospective analysis shows that the RUX–ECP combination is safe and has activity in a fraction of patients with SR-cGVHD, which needs validation in a prospective trial.

Allogeneic hematopoietic cell transplantation (alloHCT) in older patients requires the weighing of risks and benefits for this potentially curative treatment while facing age-related limitations. Comprehensive geriatric and quality of life (EORTC QLQ C-30) assessements (CGA/QOL) in addition to disease-specific data were obtained in 108 consecutive patients (≥60 years) pre-HCT, at day +30, +100, and +180. Median follow-up of 106 patients alive at alloHCT was 43.5 months, median age 66 years (range 60–78). Eighty-six (81.2%) had advanced disease risk at HCT and 99 (91.7%) patients received reduced intensity conditioning (RIC). Median PFS was 13.4 months with 38.3% (95% CI: 28.6–47.4) alive and in remission at 2 years; median OS was 15.6 months with 43.9% (95% CI: 34.3–53.4) alive at 2 years. Prognostic factors for PFS were: age: HR 1.084 (95% CI: 1.032–1.137, p  = 0.0011); HCT-CI: HR 1.13 (95% CI: 1.001–1.274, p  = 0.048); for OS: age: HR 1.08 (95% CI: 1.031–1.139, p  = 0.0017), Karnofsky Index: HR 0.97 (95% CI: 0.954–0.996, p  = 0.02); EORTC QLQ C–30 fatigue: HR 1.09 (95% CI: 1.004–1.185, p  = 0.039); Up-and-Go: HR 3.26 (95% CI: 1.001–10.6, p  = 0.049). Follow-up assessments as time-dependent covariates were highly prognostic for OS and PFS. CGA/QOL confer additional prognostic utility in older alloHCT recipients.

Vessel wall imaging (VWI) using T1 dark blood MRI can depict inflammation of intracranial arteries in patients with cerebral vasculitis. Recently, 3D VWI sequences were introduced at 3 Tesla. We aimed to compare 2D and 3D VWI for detection of intracranial vessel wall enhancement (VWE) in patients suspected of cerebral vasculitis. 44 MRI scans of 39 patients were assessed that included bi-planar 2D T1 and whole-brain 3D T1 SPACE dark blood VWI pre and post contrast. Visibility and VWE were analyzed in 31 pre-specified intracranial artery segments. Additionally, leptomeningeal and parenchymal contrast enhancement was assessed. Overall, more arterial segments were visualized with 3D VWI (p<0.0001). Detection of VWE showed fair agreement between 2D and 3D VWI (κ = 0.583). On segmental level, more VWE was detected in intradural ICA by 2D VWI (p<0.001) and in VA V4 segment by 3D VWI (p<0.05). 3D VWI showed more leptomeningeal (p<0.05) and parenchymal (p<0.01) contrast enhancement. In patients with positive diagnosis of cerebral vasculitis, sensitivity was of 67% (2D and 3D VWI) and specificity was 44% (2D VWI) and 48% (3D VWI); more VWE was seen in arteries distal to VA and ICA compared to non-vasculitic patients. 2D and 3D VWI differed in the ability to detect VWE. Whole brain coverage with better evaluability of VAs and distal intracranial artery segments, and depiction of more parenchymal and leptomeningeal enhancement make 3D VWI more favorable. As VWE in arteries distal to VA and ICA may be used for discrimination of vasculitic and non-vasculitic patients, future increase in spatial resolution of 3D VWI sequences may be beneficial.

Background This pilot trial aimed to investigate whether modified short-term fasting (mSTF) reduces the incidence of chemotherapy-induced toxicities and whether an initial ketogenic diet (KD) as fasting supportive diet reduces fasting-related discomfort and improves the compliance. Methods In this controlled cross-over trial, gynaecologic cancer patients undergoing chemotherapy with a minimum of 4 cycles fasted for 96 h during half of their chemotherapy cycles and consumed a normocaloric diet during the other chemotherapy cycles. The caloric intake during mSTF was restricted to 25% of each patient’s daily requirement. In addition, half of the patients should eat a 6-day normocaloric KD prior to each mSTF period to investigate a KD’s hunger-suppression effect. Chemotherapy-induced toxicities, fasting-related discomfort, body composition, quality of life, laboratory values, and compliance were assessed at each chemotherapy. Results Thirty patients aged 30–74 years (median 54 years) completed the study. During mSTF the frequency and severity score of stomatitis [− 0.16 ± 0.06; 95% CI -0.28 - (− 0.03); P  = 0.013], headaches [− 1.80 ± 0.55; 95% CI -2.89 – (− 0.71); P  = 0.002], weakness [− 1.99 ± 0.87; 95% CI -3.72 – (− 0.26); P  = 0.024] and the total toxicities’ score were significantly reduced [− 10.36 ± 4.44; 95% CI -19.22 - (− 1.50); P  = 0.023]. We also observed significantly fewer chemotherapy postponements post-mSTF, reflecting improved tolerance of chemotherapy [− 0.80 ± 0.37; 95% CI -1.53 – (− 0.06); P  = 0.034]. A significant reduction in mean body weight by − 0.79 ± 1.47 kg during mSTF was not compensated and remained until study’s conclusion ( P  < 0.005). On average, Insulin [− 169.4 ± 44.1; 95% CI -257.1 – (− 81.8); P  < 0.001] and Insulin-like growth factor 1 levels [− 33.3 ± 5.4; 95% CI -44.1 – (− 22.5); P  < 0.001] dropped significantly during fasting. The KD as a fasting supportive diet neither reduced fasting-related discomfort nor improved compliance of our fasting regimen. Conclusion MSTF is safe and feasible in gynaecologic cancer patients. Our results indicate that mSTF during chemotherapy can reduce chemotherapy-induced toxicities and enhance the tolerance of chemotherapy. Larger clinical trials are required to recommend mSTF for cancer patients. Trial registration germanctr.de: DRKS00011610 , registered 30 January, 2017.

Acute graft-versus-host disease (GVHD) can affect the central nervous system (CNS). The role of microglia in CNS-GVHD remains undefined. In agreement with microglia activation, we found that profound morphological changes and MHC-II and CD80 upregulation occurred upon GVHD induction. RNA sequencing-based analysis of purified microglia obtained from mice with CNS-GVHD revealed TNF upregulation. Selective TNF gene deletion in microglia of Cx3cr1creER Tnffl/- mice reduced MHC-II expression and decreased CNS T cell infiltrates and VCAM-1+ endothelial cells. GVHD increased microglia TGF-β-activated kinase-1 (TAK1) activation and NF-κB/p38 MAPK signaling. Selective Tak1 deletion in microglia using Cx3cr1creER Tak1fl/fl mice resulted in reduced TNF production and microglial MHC-II and improved neurocognitive activity. Pharmacological TAK1 inhibition reduced TNF production and MHC-II expression by microglia, Th1 and Th17 T cell infiltrates, and VCAM-1+ endothelial cells and improved neurocognitive activity, without blocking graft-versus-leukemia effects. Consistent with these findings in mice, we observed increased activation and TNF production of microglia in the CNS of GVHD patients. In summary, we prove a role for microglia in CNS-GVHD, identify the TAK1/TNF/MHC-II axis as a mediator of CNS-GVHD, and provide a TAK1 inhibitor-based approach against GVHD-induced neurotoxicity.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is potentially curative for acute myeloid leukemia (AML). The inherent graft-versus-leukemia activity (GvL) may be optimized by donor lymphocyte infusions (DLI). Here we present our single-center experience of DLI use patterns and effectiveness, based on 342 consecutive adult patients receiving a first allo-HSCT for AML between 2009 and 2017. The median age at transplantation was 57 years (range 19–79), and the pre-transplant status was active disease in 58% and complete remission (CR) in 42% of cases. In a combined landmark analysis, patients in CR on day +30 and alive on day +100 were included. In this cohort (n=292), 93 patients received cryopreserved aliquots of peripheral blood-derived grafts for DLI (32%) and median survival was 55.7 months (2-year/5-year probability: 62%/49%). Median survival for patients receiving a first dose of DLI “preemptively,” in the absence of relapse and guided by risk marker monitoring (preDLI; n=42), or only after hematological relapse (relDLI; n=51) was 40.9 months (2-year/5-year: 64%/43%) vs 10.4 months (2-year/5-year: 26%/10%), respectively. Survival was inferior when preDLI was initiated at a time of genetic risk marker detection vs mixed chimerism or clinical risk only. Time to first-dose preDLI vs time to first-dose relDLI was similar, suggesting that early warning and intrinsically lower dynamics of AML recurrence may contribute to effectiveness of preDLI-modified GvL activity. Future refinements of the preemptive DLI concept will benefit from collaborative efforts to diagnose measurable residual disease more reliably across the heterogeneous genomic spectrum of AML.

Background Primary central nervous system lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL) confined to the central nervous system (CNS) with rising incidence among patients > 65 years. Although elderly patients are able to tolerate aggressive systemic chemotherapy, previous studies have demonstrated inferior outcomes for patients who present with a poor performance status (PS) and older age. Usually, intensive treatment approaches including high-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) are only offered to patients younger than 65–70 years of age. Methods This is an open-label, multicentric, non-randomized, single arm phase II trial. We will recruit 51 immuno-competent patients with newly diagnosed PCNSL from 12 German centers. The objective is to investigate the efficacy of age-adapted induction treatment followed by HDT-ASCT. All enrolled patients will undergo induction chemotherapy consisting of 2 cycles of rituximab 375 mg/m 2 /d (days 0 & 4), methotrexate 3.5 g/m 2 (d1), and cytarabine 2 × 2 g/m 2 /d (d2–3) every 21 days. After 2 cycles of induction chemotherapy, patients achieving at least stable disease will undergo HDT-ASCT with busulfan 3.2 mg/kg/d (days − 7-(− 6)) and thiotepa 5 mg/kg/d (days − 5-(− 4)) followed by autologous stem cell transplantation. The primary endpoint of this study is 1-year progression-free survival (PFS). Secondary endpoints include PFS, overall survival, treatment response and treatment-related morbidities. Minimal follow-up after treatment completion is 12 months. Discussion Current treatment options for PCNSL have improved over the last years, resulting in the potential to achieve durable remission or cure in patients < 70 years. Age alone may not be the only criterion to select patients for this effective treatment approach and probably many elderly patients are undertreated just because of advanced age. There have been no multicentre trials investigating this curative treatment concept in elderly and fit PCNSL patients so far. We aim to answer whether HDT-ASCT is feasible and effective in fit patients > 65 years with newly-diagnosed PCNSL. Trial registration German clinical trials registry DRKS00011932 registered 18 August 2017.

Background Graft-versus-Host Disease (GvHD) causes significant morbidity and mortality in patients after allogeneic stem cell transplantation. Donor T-cells cause inflammation and tissue damage in GvHD target organs such as liver, gut and skin. Cytokine receptor associated kinases JAK1 and JAK2 are critical for inflammatory cytokine response in GvHD. Ruxolitinib is a small molecule inhibitor of JAK1 and JAK2. Preliminary data indicated substantial clinical activity in patients with steroid-refractory (SR) acute and chronic GvHD. Methods The RIG-study is an investigator-initiated open-label, multicenter, prospective randomized controlled two-arm phase 2 study, comparing the efficacy of ruxolitinib and best available treatment (BAT) versus BAT in steroid-refractory acute GvHD (SR-aGvHD). Patients with acute skin, intestinal or liver GvHD > grade 1 and failure of previous treatment are eligible. The trial aims to include 160 patients who will be randomized in a 1:1 ratio and stratified by GvHD grade (≤ grade 3 versus grade 4) and number of previous immunosuppressive treatments (≤ 3 versus ≥4). The primary endpoint is the overall response rate at day 28, defined as: Improvement of at least one stage in the severity of acute GvHD in one organ without deterioration in any other organ, or disappearance of any GvHD signs from all organs without requirement for new systemic immunosuppressive treatment. Secondary objectives include time to response, overall survival, event-free survival, non-relapse mortality (NRM), failure-free survival, graft failure rates, quality of life and changes in serum levels of pro-inflammatory cytokines and GvHD-related biomarkers. Discussion This randomized prospective trial will provide further evidence if the retrospectively collected data demonstrating activity of ruxolitinib for SR-aGvHD can be reproduced. A major advantage of ruxolitinib might be the limited and predictable toxicity profile compared to other immunosuppressive therapies that mainly includes viral reactivation and cytopenias. This trial will establish candidate biomarkers to predict and monitor responses to ruxolitinib. As a next step ruxolitinib might be tested upfront against steroids or in a preemptive manner to prevent GvHD to occur. Trial registration NCT02396628 (registration date 17.07.2015); DRKS00007939 (registration date 26.03.2015).

Cardiopulmonary performance reflects how well different organ systems interact. It is inter alia influenced by body composition, determines patients’ quality of life and can also predict mortality. However, it is not yet used for risk prediction prior to allogeneic hematopoietic cell transplantations (alloHCT). Thus, we aimed to examine the predictive power of peak oxygen consumption (VO2peak) as a representative of cardiopulmonary performance and that of body composition before alloHCT to determine overall survival (OS) and non-relapse mortality (NRM) 2 years after transplantation. We also compared it with the predictive power of four commonly-used risk scores: revised Pretransplant Assessment of Mortality (rPAM), Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI), revised Disease Risk Index (rDRI), European Society for Blood and Marrow Transplantation (EBMT). Fifty-nine patients performed a cardiopulmonary exercise test and body composition assessments before alloHCT and were observed for 2 years. Sixteen patients died. VO2peak and most risk scores assessed pre-transplant revealed no association with OS or NRM. Body composition parameters only within univariable analyses. But higher rDRI and the male sex, were associated with shorter OS and higher NRM. We thus propose that the current risk assessments be reconsidered. The predictive value of VO2peak and body composition need further clarification, however.

Background Older primary central nervous system lymphoma (PCNSL) patients have an inferior prognosis compared to younger patients because available evidence on best treatment is scarce and treatment delivery is challenging due to comorbidities and reduced performance status. High-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) after high-dose methotrexate (MTX)-based immuno-chemotherapy has become an increasingly used treatment approach in eligible elderly PCNSL patients with promising feasibility and efficacy, but has not been compared with conventional chemotherapy approaches. In addition, eligibility for HCT-ASCT in elderly PCNSL is not well defined. Geriatric assessment (GA) may be helpful in selecting patients for the best individual treatment choice, but no standardized GA exists to date. A randomized controlled trial, incorporating a GA and comparing age-adapted HCT-ASCT treatment with conventional chemotherapy is needed. Methods This open-label, multicenter, randomized phase III trial with two parallel arms will recruit 310 patients with newly diagnosed PCNSL > 65 years of age in 40 centers in Germany and Austria. The primary objective is to demonstrate that intensified chemotherapy followed by consolidating HCT-ASCT is superior to conventional chemotherapy with rituximab, MTX, procarbazine (R-MP) followed by maintenance with procarbazine in terms of progression free survival (PFS). Secondary endpoints include overall survival (OS), event free survival (EFS), (neuro-)toxicity and quality of life (QoL). GA will be conducted at specific time points during the course of the study. All patients will be treated with a pre-phase rituximab-MTX (R-MTX) cycle followed by re-assessment of transplant eligibility. Patients judged transplant eligible will be randomized (1:1). Patients in arm A will be treated with 3 cycles of R-MP followed by maintenance therapy with procarbazine for 6 months. Patients in arm B will be treated with 2 cycles of MARTA (R-MTX/AraC) followed by busulfan- and thiotepa-based HCT-ASCT. Discussion The best treatment strategy for elderly PCNSL patients remains unknown. Treatments range from palliative to curative but more toxic therapies, and there is no standardized measure to select patients for the right treatment. This randomized controlled trial will create evidence for the best treatment strategy with the focus on developing a standardized GA to help define eligibility for an intensive treatment approach. Trial registration German clinical trials registry DRKS00024085 registered March 29, 2023.