Protocol for a cross-sectional study: Effects of a Multiple Sclerosis Relapse Therapy with Methylprednisolone on Offspring Neurocognitive Development and Behaviour (MS-Children)

Introduction: Multiple Sclerosis (MS) is the most common neuroimmunological disease in women of childbearing age. Current MS therapy consists of immunomodulatory relapse prevention with disease-modifying therapies (DMTs) and acute relapse therapy with the synthetic glucocorticoid (GC) methylprednisolone (MP). As most DMTs are not approved for use during pregnancy, treatment is usually discontinued, increasing the risk for relapses. While MP therapy during pregnancy is considered relatively save for the foetus, it may be detrimental for later cognitive and neuropsychiatric function. The underlying mechanism is thought to be an epigenetically mediated desensitisation of GC receptors, the subsequent increase in stress sensitivity, and a GC-mediated impairment of brain development. The aim of this study is to investigate the associations of foetal MP exposure in the context of MS relapse therapy with later cognitive function, brain development, stress sensitivity, and behaviour. Methods and analysis: 80 children aged 8 to 18 years of mothers with MS will be recruited. 40 children, exposed to GC in utero will be compared to 40 children without foetal GC exposure. The intelligence quotient will serve as primary outcome. Secondary outcomes will include attention, motor development, emotional excitability, Attention-Deficit Hyperactivity Disorder-related symptoms, and behavioural difficulties. The Trier Social Stress Test will test stress sensitivity, EEG and MRI will assess functional and structural brain development. To determine underlying mechanisms, DNA methylation of the GC receptor gene and the H19/IGF2 locus and changes in the microbiome and the metabolome will be investigated. Primary and secondary outcomes will be analysed using linear regression models. Time-variant outcomes of the stress test will be analysed in two mixed linear models exploring overall activity and change from baseline. Ethics and dissemination: This study was approved by the participating institutions' ethics committees and results will be presented in accordance with the STROBE 2007 Statement. Trial registration: https://clinicaltrials.gov/ct2/show/NCT04832269?id=ZKSJ0130

Survival Following Relapse in Children with Acute Myeloid Leukemia: A Report from AML-BFM and COG

Post-relapse therapy remains critical for survival in children with acute myeloid leukemia (AML). We evaluated survival, response and prognostic variables following relapse in independent cooperative group studies conducted by COG and the population-based AML-BFM study group. BFM included 197 patients who relapsed after closure of the last I-BFM relapse trial until 2017, while COG included 852 patients who relapsed on the last Phase 3 trials (AAML0531, AAML1031). Overall survival at 5 years (OS) was 42 ± 4% (BFM) and 35 ± 2% (COG). Initial high-risk features (BFM 32 ± 6%, COG 26 ± 4%) and short time to relapse (BFM 29 ± 4%, COG 25 ± 2%) predicted diminished survival. In the BFM dataset, there was no difference in OS for patients who had a complete remission with full hematopoietic recovery (CR) following post-relapse re-induction compared to those with partial neutrophil and platelet recovery (CRp and CRi) only (52 ± 7% vs. 63 ± 10%, p = 0.39). Among 90 patients alive at last follow-up, 87 had received a post-relapse hematopoietic stem cell transplant (HSCT). OS for patients with post-relapse HSCT was 54 ± 4%. In conclusion, initial high-risk features and early relapse remain prognostic. Response assessment with full hematopoietic recovery following initial relapse therapy does not predict survival. These data indicate the need for post-relapse risk stratification in future studies of relapse therapies.

Anti-relapse therapy of endometriosis: possible variations

Research aim: to determine the clinical efficacy and safety of bioavailable curcumin Longimin® in the complex anti-relapse therapy of patients with extragenital endometriosis after surgery.Materials and methods. Study involved 45 women with a mean age of 29.3 ± 3.6 years with a diagnosis of extragenital endometriosis. After surgical treatment of this disease all patients were prescribed dienogest 2 mg/day for 6 months with anti-relapse purpose. After that, 22 patients did not receive drug treatment (group 1) and other 23 women started a six-month course of 400 mg bioavailable curcumin (group 2).Results. After 12 months of observation 3 cases (13.6%) of newly formed foci of endometriosis were found among patients of group 1, two of which were multi-endometriomas, and the third was retrocervical heterotopia. There were no signs of recurrence in the group of sequential use of dienogest and bioavailable curcumin. In addition, 6 months after completion of hormonal treatment the number of women with chronic pelvic pain in group 1 was increased and average score on a visual analogue scale (VAS) was increased by 80% (p ≤0.05). It was accompanied by a stable moderately high level of anxiety throughout the observation period. At the same time the number of women who complained of intermenstrual pain in group 2 decreased from 15 to 13, and the average VAS score decreased by 13% (p ≥0.05) during the treatment period. Patients in group 2 noted an improvement in emotional control during treatment, which resulted in the average score decrease on the scale of personal and situational anxiety of the Spielberg-Hanin's questionnaire (25% and 30% respectively, p ≤0.05).Conclusions. The nature of the endometriosis development and progression is multipathogenetic. Blocking only its hormonal link, especially in cases of extragenital forms, may not be sufficient to stop the pathological process and prevent recurrence in the long term. Оbtained results of sequential course of dienogest and bioavailable curcumin Longimin® with anti-relapse purpose showed the wider clinical effectiveness of this therapy, which is probably based on additional inhibition of systemic inflammation, proliferation, stroma and psychogenic component of disease.

Impact of Novel Therapies on CD4-T-Cell-Numbers and Infectious Complications in Patients with Relapsed/Refractory Multiple Myeloma

Introduction: Despite improvements in the prognosis of multiple myeloma (MM), most patients ultimately relapse and undergo multiple lines of therapy. Due to the immunocompromising effects of virtually all anti-myeloma agents as well as the disease itself, infections are a frequent complication during therapy and the most important cause of mortality in patients with MM. Establishment of clear predictors of infectious complications, especially under therapy with novel agents, is therefore of major clinical importance to identify patients at risk and to guide anti-infective prophylaxis. Methods: In this prospective, observational cohort study we examined the development of CD4+ T-cell numbers during anti-myeloma therapies which were based on the novel agents daratumumab, carfilzomib, elotuzumab, or pomalidomide and their impact on infectious complications in 96 patients with relapsed/refractory MM (median prior lines of therapy: 2 [1-13], median age: 70 years of age [42-90]). Data on infectious events including CTC-AE severity grading, antimicrobial prophylaxis strategies and vaccination status was collected before start of therapy, after 3 months and after 6 months of therapy. Flow cytometry was used to identify T-cell subsets at all three timepoints. Results: Before start of therapy, 25 patients (26%) had CD4+ cell counts < 200/µl, 75 patients (78%) had CD4+ cell counts < 500/µl. In a multivariate linear regression model the number of previous lines of therapy had a significant negative impact on CD4+-cell numbers at start of relapse therapy (p=0.03), whereas age and active therapy within in the last 6 months did not. With regard to relapse therapy, both pomalidomide and carfilzomib led to a significant reduction in CD4+ cell count after 3 months of therapy (p=0.03 and p= 0.04, resp.) in a multivariate linear regression model. This effect was not noticeable in treatments based on daratumumab. In a multivariate logistic regression analysis with regard to the occurrence of infections ≥ CTC II° within the first 3 cycles of therapy, CD4+ cell count at start of relapse therapy was the only predictor with borderline statistical significance (p=0.06). Conclusions: A significant proportion of patients with relapsed refractory MM show a severe reduction of CD4+ T-cells already at start of relapse therapy, especially after multiple lines of therapy. CD4+ cell count at start of relapse therapy might indicate an increased risk of infectious complications. Additional studies with a larger number of patients are warranted to further elucidate the impact of CD4+ cell count at start of relapse therapy as a predictor of infectious complications in MM and whether it might serve to better identify patients at risk of infectious complications and steer antimicrobial prophylaxis strategies. Disclosures John: Proteona: Research Funding. Mueller-Tidow:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Research Funding; Jose-Carreras-Siftung: Research Funding; Bayer AG: Research Funding; BiolineRx: Research Funding; Wilhelm-Sander-Stiftung: Research Funding; BMBF: Research Funding; Deutsche Krebshilfe: Research Funding; Janssen-Cilag Gmbh: Membership on an entity's Board of Directors or advisory committees; Deutsche Forschungsgemeinschaft: Research Funding. Jordan:priME Oncology: Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Voluntis: Membership on an entity's Board of Directors or advisory committees; Pomme-med: Speakers Bureau; Hexal: Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dome: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; medupdate: Speakers Bureau; Helsinn: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tesaro: Membership on an entity's Board of Directors or advisory committees; ClinSolResearch: Membership on an entity's Board of Directors or advisory committees; Riemser: Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Kreussler: Membership on an entity's Board of Directors or advisory committees; art-tempi: Speakers Bureau. Goldschmidt:Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Novartis: Honoraria, Research Funding; Mundipharma GmbH: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Molecular Partners: Research Funding; Merck Sharp and Dohme (MSD): Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; GlaxoSmithKline (GSK): Honoraria; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding. Raab:Heidelberg Pharma: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Extramedullary Relapse after Chemotherapy-Only Conditioning in Latin-Americans with Acute Leukemia: A Common Problem

Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for acute leukemia (AL) with the potential to achieve long-term remission. Nevertheless, relapse remains the main cause of mortality after allo-HSCT. Isolated extramedullary relapse (iEMR) is defined as the presence of clonal blasts in tissues other than the medullary compartment, in the absence of bone marrow relapse (BMR) and with full donor chimerism. Reports on its prevalence and risk factors are rare and its implications on prognosis and treatment continue to be an area of active study. Our aim was to describe the rates, clinical characteristics, and outcomes of patients with iEMR in the post-allo-HSCT setting. Methods Retrospective multicenter study that included patients ≥15-years-old diagnosed with AL who underwent allo-HSCT with chemotherapy-only conditioning regimens between 1999-2019. Patients referred to participating centers after HSCT and those with incomplete medical records were excluded. The Kaplan-Meier method was used to construct survival curves, differences between groups were analyzed using the log-rank test, and a standard Cox-regression was carried out for multivariate analysis. Results One hundred twenty-four patients were included with a median follow-up of 12 months (1-158) after allo-HSCT. The most common AL phenotype was lymphoblastic (ALL) in 66.1% (n=82). High-risk cytogenetics were present in 23.9% (n= 28). Twenty-three patients (18.5%) had a history of extramedullary disease (EMD) prior to allo-HSCT, CNS being the most common site in 52.2% (n=12). Additional baseline characteristics are presented in Table 1. Median overall survival (OS) for the cohort was 15 months (1-158). Factors related to decreased OS on univariate analysis are shown in Table 2. Independent risk factors for mortality were: belonging to the non-AYA group (HR 4.7,95%CI 1.6-13.3; p=0.004), grade III-IV acute GVHD (HR 3.9, 95%CI 1.6-9.8; p=0.003), and absence of chronic GHVD (HR 10.3, 95%CI 3.4-30.9; p<0.001). Sixty-seven patients (54%) relapsed after allo-HSCT with a median time to relapse of 13 months (1-158). Of these, 19 (28.4%) had EM involvement, of which 16 (23.9%) had iEMR. All cases of iEMR occurred in patients with ALL. The most commonly involved EM sites were CNS in 47.3% (n=9), skin in 26.3% (n=5), and breast in 15.8% (n=3). Of patients with post-allo-HSCT CNS relapse, 85.7% (n=6) had prior history of pre-HSCT CNS EMD. Post-relapse therapy was administered to 76.1% (n=51), including a second allo-HSCT in 25.5% (n=13), the remaining patients transitioned to palliative care. Median relapse free survival (RFS) was 13 months (1-124). Factors demonstrating a protective role are described in Table 2. On multivariate analysis, early disease stage at time of HSCT (HR 0.35, 95% CI 0.18-0.71; p=0.003) and the development of chronic GVHD (HR 0.29, 95% CI 0.15-0.54; p<0.001) had a positive impact on RFS. The median OS after relapse was 4 months (2.6-5.3). Factors related to increased survival on univariate analysis are described in Table 2 and in Figure 1. On multivariate analysis, an iEMR (HR 0.13, 95% CI 0.026-0.67; p= 0.015), as compared to a relapse with a medullary component, and a complete remission after post-relapse therapy (HR 0.095, 95%CI 0.039-0.233; p<0.001) positively impacted OS. Conclusion Isolated EMR was highly prevalent in our population as compared to historical cohorts. This reflects differences in Latin American AL epidemiologic distribution, with high representation of ALL, and our limited access to conditioning regimens based on total body irradiation. Patients that had an iEMR and achieved treatment response had improved survival outcomes which may reflect a more indolent biology allowing the clinician time to implement therapy intensification interventions. Additionally, in our setting, escalation of pre-HSTC therapy to achieve deeper responses and tailoring HSCT, in combination with post-HSCT CNS prophylaxis, are potential strategies that should be pursued further. Disclosures No relevant conflicts of interest to declare.

P0399RELAPSE TREATMENT WITH LOW DOSE OF STEROIDS IN STEROID-SENSITIVE MINIMAL CHANGE DISEASE

Background and Aims Treatment of Minimal change disease (MCD) consists of high dose of steroids (HDS) for several weeks implying significant drug toxicity. On the other hand, renal relapses of steroid-sensitive MCD sometimes respond to lower doses of steroids. Method The objective of the study was to analyze weather low dose for steroids (LDS) is effective for treatment MCD relapses among frequently-relapsing steroid-sensitive patients. Since 2019, new relapses of steroid-sensitive patients with MCD within the Nephrology Department of Hospital Ramón y Cajal were treated with LDS. Cumulative dose of steroids, time to remission and time free of relapse were compared between relapse episodes treated with LDS and previous relapses among same patients treated with HDS. Results Twenty-six relapses among six steroid-sensitive MCD patients were analyzed. 15 relapses were treated with LDS and compared with 11 previous relapses among same patients treated with HDS. Mean dose of prednisone for initial treatment of the relapse was 0.89 ± 0.1 mg/kg in patients treated with HDS and 0.45 ± 0.1 mg/kg in patients treated with LDS. Mean cumulative dose of prednisone among patients treated with LDS and HSD were 1998.1 ± 1418 mg and 5611.7 ± 2326 mg, respectively. (p=0.001). Mean cumulative dose of prednisone adjusted by body weight among patients treated with LDS and HSD were 23.43 ± 14.27 mg/kg and 68.93 ± 27.05 mg/kg, respectively. (p=0.019). There was no difference in duration of treatment among HDS and LSD groups (163.45 ± 86.43 vs 138.80 ± 108.80, respectively; p = 0.525). All patients achieved complete remission after steroid therapy in both LSD and HSD groups. Mean time to remission was 18.7 days among HSD relapses and 18.4 days among the LSD relapses (p = 0.9). Time free of relapse after therapy among HDS and LDS treated relapses was 9.1 ± 5.3 months and 5.5 ± 3.5 months, respectively (p = 0.1). Conclusion Among steroid-sensitive MCD patients, relapse therapy with low dose of steroids (0.5 mg/kg) seems to be effective and allows minimization of steroid cumulative dose and drug toxicity.