Disease Course of Clinically Isolated Optic Neuritis.

BACKGROUND AND OBJECTIVES: Optic neuritis is the most common optic neuropathy in young adults and a frequent manifestation of multiple sclerosis. Its clinical course is pertinent to the design of visual pathway neuroprotection trials. METHODS: This is a secondary analysis of longitudinal data from the TONE trial, which included 103 patients from 12 German academic tertiary centers with acute unilateral optic neuritis as a clinically isolated syndrome and baseline high-contrast visual acuity <0.5 decimal. Patients were randomized to 1,000 mg methylprednisolone i.v./d plus either erythropoietin (33,000 IU/d) or placebo (saline solution) for 3 days. They were followed up at standardized intervals with a battery of tests including high-contrast visual acuity, low-contrast letter acuity, contrast sensitivity, visual fields, visual evoked potentials, and retinal optical coherence tomography. At 6 months, participants answered a standardized questionnaire on vision-related quality of life (NEI-VFQ 25). We describe the disease course with mixed-effects piecewise linear models and calculate structure-function correlations using Pearson r. Because erythropoietin had no effect on the visual system, we use pooled (treatment-agnostic) data. RESULTS: Patients experienced initial rapid and then decelerating improvements of visual function with thinning of inner and thickening of outer retinal layers. At 6 months, visual parameters were positively correlated with inner and negatively correlated with outer retinal thickness changes. Peripapillary retinal nerve fiber layer thinning predominantly occurred in sectors without previous swelling. At 6 months, macular ganglion cell and inner plexiform layer thinning was weakly correlated with the P100 peak time (r = -0.11) and moderately correlated with the amplitude of visual evoked potentials (r = 0.35). Only functional outcomes were at least moderately correlated with vision-related quality of life. DISCUSSION: The longitudinal data from this large study cohort may serve as a reference for the clinical course of acute optic neuritis. The pattern of correlation between visual evoked potentials and inner retinal thinning may argue that the latter is mostly due to ganglion cell loss, rather than dysfunction. Visual pathway neuroprotection trials with functional outcomes are needed to confirm that candidate drugs will benefit patients' vision-related quality of life. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov, NCT01962571.

The Joint Vasculitis Registry in German-speaking countries (GeVas): subgroup analysis of 266 AAV-patients.

OBJECTIVES: Prospective long-term observational data on the disease course of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) were missing in Germany to date. Therefore, the Joint Vasculitis Registry in German-speaking countries (GeVas) has been established to follow the course of patients with AAV. The aim of this study is to present baseline data of patients with newly diagnosed and relapsing AAV enrolled in the GeVas registry. METHODS: GeVas is a prospective, web-based, multicentre, clinician-driven registry for the documentation of organ manifestations, damage, long-term outcomes, and therapy regimens in various types of vasculitis. Recruitment started in June 2019. RESULTS: Between June 2019 and October 2022, 266 patients with AAV were included in the GeVas registry, hereof 173 (65%) with new-onset and 93 (35%) with relapsing AAV. One hundred and sixty-two (61%) patients were classified as granulomatosis with polyangiitis (GPA), 66 (25%) as microscopic polyangiitis (MPA), 36 (13%) as eosinophilic granulomatosis with polyangiitis (EGPA), and 2 (1%) as renal limited AAV. The median age was 59 years (51-70 years, IQR), 130 (51%) patients were female. Most patients were ANCA positive (177; 67%) and affected by general symptoms, pulmonary, ear nose throat (ENT), renal and neurological involvement. For induction of remission, the majority of patients received glucocorticoids (247, 93%) in combination with either rituximab (118, 45%) or cyclophosphamide (112, 42%). CONCLUSIONS: Demographic characteristics are comparable to those in other European countries. Differences were found regarding ANCA status, frequencies of organ manifestations, and therapeutic regimens. The GeVas registry will allow longitudinal observations and prospective outcome measures in AAV.

Visual Pathway Outcomes Based on Sample Size in Clinical Neuroprotection Research.

This cohort study calculates clinical trial sample sizes powered by visual pathway outcomes of acute optic neuritis in neuroprotection research.

High-dose chemotherapy and autologous haematopoietic stem-cell transplantation in older, fit patients with primary diffuse large B-cell CNS lymphoma (MARTA): a single-arm, phase 2 trial.

BACKGROUND: Available treatments for older patients with primary diffuse large B-cell CNS lymphoma (PCNSL) offer progression-free survival of up to 16 months. We aimed to investigate an intensified treatment of high-dose chemotherapy and autologous haematopoietic stem-cell transplantation (HSCT) in older patients with PCNSL. METHODS: MARTA was a prospective, single-arm, phase 2 study done at 15 research hospitals in Germany. Patients aged 65 years or older with newly diagnosed, untreated PCNSL were enrolled if they had an Eastern Cooperative Oncology Group performance status of 0-2 and were fit for high-dose chemotherapy and autologous HSCT. Induction treatment consisted of two 21-day cycles of high-dose intravenous methotrexate 3·5 g/m2 (day 1), intravenous cytarabine 2 g/m2 twice daily (days 2 and 3), and intravenous rituximab 375 mg/m2 (days 0 and 4) followed by high-dose chemotherapy with intravenous rituximab 375 mg/m2 (day -8), intravenous busulfan 3·2 mg/kg (days -7 and -6), and intravenous thiotepa 5 mg/kg (days -5 and -4) plus autologous HSCT. The primary endpoint was progression-free survival at 12 months in all patients who met eligibility criteria and started treatment. The study was registered with the German clinical trial registry, DRKS00011932, and recruitment is complete. FINDINGS: Between Nov 28, 2017, and Sept 16, 2020, 54 patients started induction treatment and 51 were included in the full analysis set. Median age was 71 years (IQR 68-75); 27 (53%) patients were female and 24 (47%) were male. At a median follow-up of 23·0 months (IQR 16·8-37·4), 23 (45%) of 51 patients progressed, relapsed, or died. 12-month progression-free survival was 58·8% (80% CI 48·9-68·2; 95% CI 44·1-70·9). During induction treatment, the most common grade 3-5 toxicities were thrombocytopenia and leukopenia (each in 52 [96%] of 54 patients). During high-dose chemotherapy and autologous HSCT, the most common grade 3-5 toxicity was leukopenia (37 [100%] of 37 patients). Treatment-related deaths were reported in three (6%) of 54 patients, all due to infectious complications. INTERPRETATION: Although the primary efficacy threshold was not met, short induction followed by high-dose chemotherapy and autologous HSCT is active in selected older patients with PCNSL and could serve as a benchmark for comparative trials. FUNDING: Else Kröner-Fresenius Foundation, Riemser Pharma, and Medical Center-University of Freiburg.

Identification of clinical factors impacting outcome in patients undergoing autologous hematopoietic cell transplantation after BEAM and TEAM conditioning.

Organ dysfunction, including pulmonary function impairment, plays a key role in the choice of conditioning chemotherapy before autologous hematopoietic stem cell transplantation (auto-HSCT). Replacement of BCNU/carmustine as part of BEAM (BCNU/carmustine, etoposide, cytarabine, and melphalan) conditioning protocol by thiotepa (TEAM) reduces pulmonary toxicity while maintaining efficacy. We retrospectively analyzed the association of clinical characteristics, comorbidities, and organ function with outcomes after conditioning with BEAM or TEAM. Three hundred ninety-six patients undergoing auto-HSCT (n = 333 with BEAM; n = 63 with TEAM) at our institution between 2008 and 2021 were included in this study. In the multivariate analysis, CO-diffusion capacity corrected for hemoglobin (DLCOcSB) ≤ 60% of predicted, progressive disease (PD) before auto-HSCT, Karnofsky performance score (KPS) ≤ 80%, HCT-CI score ≥ 4, and cardiac disease before auto-HSCT were associated with decreased overall survival (OS) in patients treated with BEAM. In contrast, only PD before auto-HSCT was identified in patients treated with TEAM. Patients conditioned with BEAM and DLCOcSB ≤ 60% had higher non-relapse mortality, including pulmonary cause of death. In summary, we have identified clinical and pulmonary risk factors associated with worse outcomes in patients conditioned with BEAM compared to TEAM. Our data suggest TEAM conditioning as a valid alternative for patients with comorbidities, including pulmonary dysfunction and/or poorer performance scores, before auto-HSCT.

Long-term follow-up of patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation after primary induction failure.

Primary induction failure (PIF) in acute myeloid leukemia (AML) patients is associated with poor outcome, with allogeneic hematopoietic stem cell transplantation (HCT) being the sole curative therapeutic option. Here, we retrospectively evaluated long-term outcomes of 220 AML patients undergoing allogeneic HCT after PIF who never achieved remission, and identified clinical and molecular risk factors associated with treatment response and ultimate prognosis. In this high-risk population, disease-free survival was 25.2% after 5 years and 18.7% after 10 years, while overall survival rates were 29.8% and 21.6% after 5 and 10 years of HCT, respectively. 10-year non-relapse mortality was 32.5%, and 48.8% of patients showed disease relapse within 10 years after allogeneic HCT. Adverse molecular risk features determined at initial diagnosis, poor performance status at the time of allogeneic HCT, and long diagnosis-to-HCT intervals were associated with unfavorable prognosis. Collectively, our data suggests that immediate allogeneic HCT after PIF offers long-term survival and cure in a substantial subset of cases and that high-risk AML patients who never achieved complete response during induction might benefit from early donor search.

Comorbidity indices for prognostic evaluation in multiple myeloma: a comprehensive evaluation of the Revised Myeloma Comorbidity Index and other comorbidity indices with pro- and retrospective applications.

Not available.

Age-adjusted high-dose chemotherapy followed by autologous stem cell transplantation or conventional chemotherapy with R-MP as first-line treatment in elderly primary CNS lymphoma patients - the randomized phase III PRIMA-CNS trial.

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.

Phase II trial of hypomethylating agent combined with nivolumab for acute myeloid leukaemia relapse after allogeneic haematopoietic cell transplantation-Immune signature correlates with response.

Acute myeloid leukaemia (AML) relapse after allogeneic haematopoietic cell transplantation (allo-HCT) is often driven by immune-related mechanisms and associated with poor prognosis. Immune checkpoint inhibitors combined with hypomethylating agents (HMA) may restore or enhance the graft-versus-leukaemia effect. Still, data about using this combination regimen after allo-HCT are limited. We conducted a prospective, phase II, open-label, single-arm study in which we treated patients with haematological AML relapse after allo-HCT with HMA plus the anti-PD-1 antibody nivolumab. The response was correlated with DNA-, RNA- and protein-based single-cell technology assessments to identify biomarkers associated with therapeutic efficacy. Sixteen patients received a median number of 2 (range 1-7) nivolumab applications. The overall response rate (CR/PR) at day 42 was 25%, and another 25% of the patients achieved stable disease. The median overall survival was 15.6 months. High-parametric cytometry documented a higher frequency of activated (ICOS+ , HLA-DR+ ), low senescence (KLRG1- , CD57- ) CD8+ effector T cells in responders. We confirmed these findings in a preclinical model. Single-cell transcriptomics revealed a pro-inflammatory rewiring of the expression profile of T and myeloid cells in responders. In summary, the study indicates that the post-allo-HCT HMA/nivolumab combination induces anti-AML immune responses in selected patients and could be considered as a bridging approach to a second allo-HCT. Trial-registration: EudraCT-No. 2017-002194-18.

Treatment With Erythropoietin for Patients With Optic Neuritis: Long-term Follow-up.

BACKGROUND AND OBJECTIVE: Erythropoietin (EPO) is a candidate neuroprotective drug. We assessed its long-term safety and efficacy as an adjunct to methylprednisolone in patients with optic neuritis and focused on conversions to multiple sclerosis (MS). METHODS: The TONE trial randomized 108 patients with acute optic neuritis but without previously known MS to either 33,000 IU EPO or placebo in conjunction with 1,000 mg methylprednisolone daily for 3 days. After reaching the primary end point at 6 months, we conducted an open-label follow-up 2 years after randomization. RESULTS: The follow-up was attended by 83 of 103 initially analyzed patients (81%). There were no previously unreported adverse events. The adjusted treatment difference of peripapillary retinal nerve fiber layer atrophy in relation to the fellow eye at baseline was 1.27 µm (95% CI -6.45 to 8.98, p = 0.74). The adjusted treatment difference in low-contrast letter acuity was 2.87 on the 2.5% Sloan chart score (95% CI -7.92 to 13.65). Vision-related quality of life was similar in both treatment arms (National Eye Institute Visual Functioning Questionnaire median score [IQR]: 94.0 [88.0 to 96.9] in the EPO and 93.4 [89.5 to 97.4] in the placebo group). The rate of multiple sclerosis-free survival was 38% in the placebo and 53% in the EPO group (hazard ratio: 1.67, 95% CI 0.96 to 2.88, p = 0.068). DISCUSSION: In line with the results at 6 months, we found neither structural nor functional benefits in the visual system of patients with optic neuritis as a clinically isolated syndrome, 2 years after EPO administration. Although there were fewer early conversions to MS in the EPO group, the difference across the 2-year window was not statistically significant. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with acute optic neuritis, EPO as an adjunct to methylprednisolone is well tolerated and does not improve long-term visual outcomes. TRIAL REGISTRATION INFORMATION: The trial was preregistered before commencement at clinicaltrials.gov (NCT01962571).

Low-dose AtropIne for Myopia Control in Children (AIM): protocol for a randomised, controlled, double-blind, multicentre, clinical trial with two parallel arms.

INTRODUCTION: Myopia is a major cause of degenerative eye disease and increases the risk of secondary visual impairment. Mitigating its progression therefore has great potential of clinically relevant benefit as shown by using highly diluted atropine eye drops in children of Asian origin. However, limited evidence is available regarding the efficacy and safety of low-dose atropine therapy in non-Asian populations. Hence, the Low-dose AtropIne for Myopia Control in Children (AIM) study will test the efficacy and safety of 0.02% atropine vs placebo in a German population. METHODS AND ANALYSIS: AIM is a national, multicentre, prospective, randomised, placebo-controlled, double-blind trial with two parallel arms. The primary objective is to assess the efficacy of atropine 0.02% eyedrops for myopia control in children of Caucasian origin. The primary outcome is the change in cycloplegic refraction after 1 year of treatment (D/year). Secondary and tertiary outcome measures comprise the change in axial length (mm/year) in children treated with 0.02% atropine compared with placebo, the myopic progression of participants treated with 0.01% compared with 0.02% atropine (D/year and mm/year), and the safety profile of both 0.02% and 0.01% atropine. Furthermore, the myopic progression 1 year after cessation of therapy with 0.02% atropine will be evaluated. Inclusion criteria are an age of 8-12 years and myopia of -1 D to -6 D with an estimated annual myopia progression of ≥0.5 D. After randomisation, patients will receive either atropine 0.02% (arm A) or placebo eye drops (arm B) in the first year of treatment. In the second year, they will continue to receive atropine 0.02% (arm A) or switch to atropine 0.01% (arm B). In the third year, they will switch to placebo (arm A) or continue with atropine 0.01% (arm B). To achieve a statistical power of 80%, the calculated sample size is 300. The trial has started in October 2021 with a planned recruitment period of 18 months. ETHICS AND DISSEMINATION: AIM has been approved by the Central Ethics Committee of the University Medical Center Freiburg (21-1106), local ethics committees of each participating centre and the German Federal Institute for Drugs and Medical Devices (61-3910-4044659). It complies with the Declaration of Helsinki, local laws and ICH-GCP. Results and underlying data from this trial will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT03865160.

Does the Pathologic Fracture Predict Severe Paralysis in Patients with Metastatic Epidural Spinal Cord Compression (MESCC)?-A Retrospective, Single-Center Cohort Analysis.

Currently, there is uncertainty about the predictive factors for metastatic epidural spinal cord compression (MESCC) and consecutive symptomatology in tumor patients. Prognostic algorithms for identifying patients at risk for paralysis are missing. The influence of the pathologic fracture on the patient's symptoms is widely discussed in the literature and we hypothesize that pathologic fractures contribute to spinal cord compression and are therefore predictive of severe paralysis. We tested this hypothesis in 136 patients who underwent surgery for spinal metastases. The most common primary cancers were prostate (24.3%, n = 33), breast (11.0%, n = 15), lung (10.3%, n = 14), and cancer of unknown primary (10.3%, n = 14). MESCC primarily affected the thoracic (77.2%, n = 105), followed by the lumbar (13.2%, n = 18) and cervical (9.6%, n = 13) spine. Pathologic fractures occurred in 63.2% (n = 86) of patients, mainly in osteolytic metastases. On the American spinal injury association (ASIA) impairment scale (AIS), 63.2% (n = 86) of patients exhibited AIS grade D and 36.8% (n = 50) AIS grade C-A preoperatively. The presence of a pathologic fracture alone did not predict severe paralysis (AIS C-A, p = 0.583). However, the duration of sensorimotor impairments, patient age, spinal instability neoplastic score (SINS), and the epidural spinal cord compression (ESCC) grade together predicted severe paralysis (p = 0.006) as did the ESCC grade 3 alone (p = 0.028). This is in contrast to previous studies that stated no correlation between the degree of spinal cord compression and the severity of neurologic impairments. Furthermore, the high percentage of pathologic fractures found in this study is above previously reported incidences. The risk factors identified can help to predict the development of paralysis and assist in the improvement of follow-up algorithms and the timing of therapeutic interventions.

Potent high-avidity neutralizing antibodies and T cell responses after COVID-19 vaccination in individuals with B cell lymphoma and multiple myeloma.

Individuals with hematologic malignancies are at increased risk for severe coronavirus disease 2019 (COVID-19), yet profound analyses of COVID-19 vaccine-induced immunity are scarce. Here we present an observational study with expanded methodological analysis of a longitudinal, primarily BNT162b2 mRNA-vaccinated cohort of 60 infection-naive individuals with B cell lymphomas and multiple myeloma. We show that many of these individuals, despite markedly lower anti-spike IgG titers, rapidly develop potent infection neutralization capacities against several severe acute respiratory syndrome coronavirus 2 variants of concern (VoCs). The observed increased neutralization capacity per anti-spike antibody unit was paralleled by an early step increase in antibody avidity between the second and third vaccination. All individuals with hematologic malignancies, including those depleted of B cells and individuals with multiple myeloma, exhibited a robust T cell response to peptides derived from the spike protein of VoCs Delta and Omicron (BA.1). Consistently, breakthrough infections were mainly of mild to moderate severity. We conclude that COVID-19 vaccination can induce broad antiviral immunity including ultrapotent neutralizing antibodies with high avidity in different hematologic malignancies.

Multidisciplinary tumor board analysis: validation study of a central tool in tumor centers.

The established standard to ensure state-of-the-art cancer treatment is through multidisciplinary tumor boards (TBs), although resource- and time-intensive. In this validation study, the multiple myeloma (MM)-TB was reexamined, aiming to validate our previous (2012-2014) results, now using the TB data from March 2020 to February 2021. We assessed MM-TB protocols, physicians' documentation, patient, disease, remission status, progression-free survival (PFS), and overall survival (OS) as left-truncated survival times. Moreover, TB-adherence, level of evidence according to grade criteria, time requirements, study inclusion rates, and referral satisfaction were determined. Within a 1-year period, 312 discussed patients were documented in 439 TB protocols. Patient and disease characteristics were typical for comprehensive cancer centers. The percentages of patients discussed at initial diagnosis (ID), with disease recurrence or in need of interdisciplinary advice, were 39%, 28%, and 33%, respectively. Reasons for the MM-TB presentation were therapeutic challenges in 80% or staging/ID-defining questions in 20%. The numbers of presentations were mostly one in 73%, two in 20%, and three or more in 7%. The TB adherence rate was 93%. Reasons for non-adherence were related to patients' decisions or challenging inclusion criteria for clinical trials. Additionally, we demonstrate that with the initiation of TBs, that the number of interdisciplinarily discussed patients increased, that TB-questions involve advice on the best treatment, and that levels of compliance and evidence can be as high as ≥ 90%. Advantages of TBs are that they may also improve patients', referrers', and physicians' satisfaction, inclusion into clinical trials, and advance interdisciplinary projects, thereby encouraging cancer specialists to engage in them.

An objective assessment in newly diagnosed multiple myeloma to avoid treatment complications and strengthen therapy adherence.

In heterogeneous multiple myeloma (MM) patients treatment decisions are challenging. The hypothesis was that adaptation of treatment intensity (dose reduction [DR] vs. none) according to an objective risk score (revised-myeloma comorbidity index [R-MCI]) rather than physician judgement alone may improve therapy efficacy and avoid toxicities. We performed this study in 250 consecutive MM patients who underwent a prospective fitness assessment at our center, after having received induction protocols based on physicians' judgement. DR, serious adverse events (SAE), response, progression-free survival (PFS) and overall survival (OS) were compared in fitness (fit, intermediate-fit, frail), age (<60, ≥70 years [y]) and therapy intensity subgroups at baseline and follow-up. Fit and <60 y patients were mostly treated with full intensity, whereas frail and ≥70 y patients usually received DR. Hematological and non-hematological SAE were more frequently seen in frail versus ≥70 y patients. Dose adaptations were mainly necessary in frail patients. OS and PFS were similar in fit and intermediate-fit but significantly worse in frail patients (P=0.0245/P<0.0001), whereas in age-based subgroups, OS and PFS differences did not reach significance (P=0.1362/P=0.0569). Non-hematological SAE were another negative predictor for impaired OS and PFS (P=0.0054/P=0.0021). In the follow-up performed at a median of 11 months after the first fitness assessment, the R-MCI improved or remained stable in 90% versus deteriorated in only 10% of patients. In conclusion, separation by R-MCI/frailty-defined subgroups was superior to age-based subgroups and can be used to improve tailored treatment. Fitter patients benefit from intensive therapies, whereas frail patients bear a need for initial DR.

Exercise during Hemodialysis in Patients with Chronic Kidney Failure.

Exercise during Hemodialysis in Patients with Chronic Kidney FailureThe authors report on a trial of an exercise intervention provided during dialysis sessions for patients with chronic renal failure. They found that the intervention is safe and improves physical function.

Cellular and Humoral SARS-CoV-2 Vaccination Responses in 192 Adult Recipients of Allogeneic Hematopoietic Cell Transplantation.

To determine factors influencing the vaccination response against SARS-CoV-2 is of importance in recipients of allogeneic hematopoietic cell transplantation (allo-HCT) as they display an increased mortality after SARS-CoV-2 infection, an increased risk of extended viral persistence and reduced vaccination response. Real-life data on anti-SARS-CoV-2-S1-IgG titers (n = 192) and IFN-γ release (n = 110) of allo-HCT recipients were obtained using commercially available, validated assays after vaccination with either mRNA (Comirnaty™, Pfizer-BioNTech™, NY, US and Mainz, Germany or Spikevax™, Moderna™, Cambridge, Massachusetts, US) or vector-based vaccines (Vaxzevria™,AstraZeneca™, Cambridge, UK or Janssen COVID-19 vaccine™Johnson/Johnson, New Brunswick, New Jersey, US), or after a heterologous protocol (vector/mRNA). Humoral response (78% response rate) was influenced by age, time after transplantation, the usage of antithymocyte globulin (ATG) and ongoing immunosuppression, specifically corticosteroids. High counts of B cells during the vaccination period correlated with a humoral response. Only half (55%) of participants showed a cellular vaccination response. It depended on age, time after transplantation, ongoing immunosuppression with ciclosporin A, chronic graft-versus-host disease (cGvHD) and vaccination type, with vector-based protocols favoring a response. Cellular response failure correlated with a higher CD8+ count and activated/HLA-DR+ T cells one year after transplantation. Our data provide the basis to assess both humoral and cellular responses after SARS-CoV2 vaccination in daily practice, thereby opening up the possibility to identify patients at risk.

The ABACHAI clinical trial protocol: Safety and efficacy of abatacept (s.c.) in patients with CTLA-4 insufficiency or LRBA deficiency: A non controlled phase 2 clinical trial.

Background: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) insufficiency and lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency are both complex immune dysregulation syndromes with an underlying regulatory T cell dysfunction due to the lack of CTLA-4 protein. As anticipated, the clinical phenotypes of CTLA-4 insufficiency and LRBA deficiency are similar. Main manifestations include hypogammaglobulinemia, lymphoproliferation, autoimmune cytopenia, immune-mediated respiratory, gastrointestinal, neurological, and skin involvement, which can be severe and disabling. The rationale of this clinical trial is to improve clinical outcomes of affected patients by substituting the deficient CTLA-4 by administration of CTLA4-Ig (abatacept) as a causative personalized treatment. Objectives: Our objective is to assess the safety and efficacy of abatacept for patients with CTLA-4 insufficiency or LRBA deficiency. The study will also investigate how treatment with abatacept affects the patients' quality of life. Methods: /Design: ABACHAI is a phase IIa prospective, non-randomized, open-label, single arm multi-center trial. Altogether 20 adult patients will be treated with abatacept 125 mg s.c. on a weekly basis for 12 months, including (1) patients already pretreated with abatacept, and (2) patients not pretreated, starting with abatacept therapy at the baseline study visit. For the evaluation of drug safety infection control during the trial, for efficacy, the CHAI-Morbidity Score will be used. Trial registration: The trial is registered in the German Clinical Trials Register (Deutsches Register Klinischer Studien, DRKS) with the identity number DRKS00017736, registered: 6 July 2020, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00017736.

Optimizing MATRix as remission induction in PCNSL: de-escalated induction treatment in newly diagnosed primary CNS lymphoma.

BACKGROUND: Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (PCNSL) is a rare disorder with an increasing incidence over the past decades. High-level evidence has been reported for the MATRix regimen (high-dose methotrexate (HD-MTX), high-dose AraC (HD-AraC), thiotepa and rituximab) followed by high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) supporting this approach to be considered a standard therapy in newly diagnosed PCNSL patients ≤ 70 years. However, early treatment-related toxicities (predominantly infectious complications), occurring in up to 28% per MATRix cycle, diminish its therapeutic success. Furthermore, sensitivity to first-line treatment is an independent prognostic factor for improved overall survival (OS) in PCNSL. Thus, patients achieving early partial remission (PR) after 2 cycles of MATRix might be over-treated with 4 cycles, in the context of consolidation HCT-ASCT. METHODS: This is an open-label, multicentre, randomized phase III trial with two parallel arms. 326 immunocompetent patients with newly diagnosed PCNSL will be recruited from 37 German, 1 Austrian and 12 UK sites. Additional IELSG (International Extranodal Lymphoma Study Group) sites are planned. The objective is to demonstrate superiority of a de-escalated and optimised remission induction treatment strategy, followed by HCT-ASCT. Randomization (1:1) will be performed after completion of all screening procedures. Patients in Arm A (control treatment) will receive 4 cycles of MATRix. Patients in Arm B (experimental treatment) will receive a pre-phase (R/HD-MTX), followed by 2 cycles of MATRix. Patients in both arms achieving PR or better will proceed to HCT-ASCT (BCNU, thiotepa). The primary endpoint of the study is event-free-survival (EFS), defined as time from randomization to premature end of treatment due to any reason, lymphoma progression or death whichever occurs first. Secondary endpoints include OS, progression free survival (PFS), toxicity, neurocognitive impairment and quality of life. Minimal follow-up is 24 months. DISCUSSION: Current treatment options for PCNSL in patients ≤ 70 years have improved remarkably over recent years. However, the potential efficacy benefits are offset by an increased incidence of short-term toxicities which can impact on treatment delivery and hence on survival outcomes. In patients ≤ 70 years with newly diagnosed PCNSL addressing the need to reduce treatment-related toxicity by de-escalating and optimising the induction phase of treatment, is a potentially attractive treatment strategy. TRIAL REGISTRATION: German clinical trials registry DRKS00022768 registered June 10th, 2021.