Long-term Sustained Remission Research Articles

Long-Term Clinical and Sustained REMIssion in Severe Eosinophilic Asthma Treated With Mepolizumab: The REMI-M Study

Biological therapies, such as mepolizumab, have transformed the treatment of severe eosinophilic asthma. While mepolizumab's short-term effectiveness is established, there is limited evidence on its ability to achieve long-term clinical remission. To evaluate the long-term effectiveness and safety of mepolizumab, explore its potential to induce clinical and sustained remission, and identify baseline factors associated with the likelihood of achieving remission over 24 months. The REMI-M is a retrospective, real-world, multicenter study that analyzed 303 severe eosinophilic asthma patients who received mepolizumab. Clinical, demographic, and safety data were collected at baseline, 3, 6, 12, and 24 months. The most commonly used definitions of clinical remission, which included no exacerbations, no oral corticosteroids (OCS) use, and good asthma control with or without assessment of lung function parameters, were assessed. Sustained remission was defined as reaching clinical remission at 12 months and maintaining it until the end of the 24-month period. Clinical remission rates ranged from 28.6% to 43.2% after 12 months and from 26.8% to 52.9% after 24 months, based on the different remission definitions. The proportion of patients achieving sustained remission varied between 14.6% to 29%. Factors associated with the likelihood of achieving clinical remission included the presence of aspirin-exacerbated respiratory disease, better lung function at baseline, male sex, absence of anxiety/depression, gastro-esophageal reflux disease, bronchiectasis, and reduced OCS consumption. Adverse events were infrequent. This study demonstrates the real-world effectiveness of mepolizumab in achieving clinical remission and sustained remission in severe eosinophilic asthma over 24 months. The identification of distinct factors associated with the likelihood of achieving clinical remission emphasizes the importance of comprehensive management of comorbidities and timely identification of patients who may benefit from biologics.

Long-term sustained clinical remission of peritoneal metastatic pancreatic ductal adenocarcinoma after sequential chemoradiation therapy: a case report

Patients with peritoneal metastatic pancreatic ductal adenocarcinoma (pmPDAC) with high-level serum carbohydrate antigens (CAs) always suffer extremely dismal prognosis, with a median survival of several months. Herein, we reported a case of pmPDAC with high serum CAs who had long-term clinical remission with normalization of CAs after chemoradiation. In November 2019, a 64-year-old male patient was admitted to our center with a solid mass measuring 2.8 × 2.5 × 2.0 cm in the body of the pancreas near the celiac trunk. Positron emission tomography-computed tomography (PET-CT) revealed an standardized uptake value max (SUVmax) of 4.2. The serum CA 242 level exceeded 150.0 U/mL (normal range: 0–20 U/mL), and CA 19-9 was elevated at 975.2 U/mL (normal range: 0–34 U/mL). During laparotomy, the tumor was found to encircle the celiac trunk over 180°, with several small peritoneal nodules in the lesser omental cavity. Pathological examination confirmed the diagnosis of pmPDAC. Next-generation sequencing revealed RAS G12V, EGFR mutation (-), low tumor mutation burden (TMB), and microsatellite stability (MSS). The patient underwent 6 cycles of the AG regimen (gemcitabine plus nab-paclitaxel), resulting in significant tumor shrinkage and a sharp decline in CAs. Partial remission was achieved. However, due to intolerant neurotoxicity, the AG regimen was discontinued. Subsequently, synchronous oral fluorouracil (S1) and radiation therapy were administered. Five months after radiation treatment, all CAs normalized. Oral S1 was continued for an additional 3 months. Eventually, all anti-cancer drugs were stopped. Computed tomography scans indicated that the tumor still surrounded the celiac trunk and common hepatic artery. After a thorough discussion, a wait-and-see strategy was adopted. Remarkably, 32 months after stopping anti-cancer medication, the patient remains in good health, with sustained normalization of CAs. At the last follow-up, he had lived for 50 months, and the normalization of the CAs was sustained for 36 months. Although he still suffers the risk of disease progression, it is a successful case of state-of-the-art chemoradiation for a dismal pmPDAC patient.

Sustained Remission Without Corticosteroids Among Patients With Pemphigus Who Had Rituximab as First-Line Therapy

ImportanceThe Ritux 3 trial demonstrated the short-term efficacy and safety of first-line treatment with rituximab compared with a standard corticosteroid regimen in pemphigus. No data on the long-term follow-up of patients who received rituximab as first line are available.ObjectiveTo assess the long-term efficacy and safety of the Ritux 3 treatment regimen.Design, Setting, and ParticipantsThis 7-year follow-up study of the Ritux 3 trial included patients with pemphigus from 25 dermatology departments in France from January 1, 2010, to December 31, 2015.ExposurePatients were initially randomized in the rituximab plus prednisone group or prednisone-alone group.Main outcomes and measuresThe primary outcome was the 5- and 7-year disease-free survival (DFS) without corticosteroids, assessed by Kaplan-Meier curves. Secondary outcomes were occurrence of relapse, occurrence of severe adverse events (SAEs), and evolution of antidesmoglein (Dsg) antibody enzyme-linked immunosorbent assay values to predict long-term relapse.ResultsOf the 90 patients in the Ritux 3 trial, 83 were evaluated at the end of follow-up study visit (44 in the rituximab plus prednisone group; 39 in the prednisone-alone group) with a median (IQR) follow-up of 87.3 (79.1-97.5) months. Forty-three patients (93%) from the rituximab plus prednisone and 17 patients (39%) from the prednisone-alone group had achieved complete remission without corticosteroids at any time during the follow-up. Patients from the rituximab group had much longer 5- and 7-year DFS without corticosteroids than patients from the prednisone-alone group (76.7% and 72.1% vs 35.3% and 35.3%, respectively; P < .001), and had about half the relapses (42.2% vs 83.7%; P < .001). Patients who received rituximab as second-line treatment had shorter DFS than patients treated as first line (P = .007). Fewer SAEs were reported in the rituximab plus prednisone group compared with the prednisone-alone group, 31 vs 58 respectively, corresponding to 0.67 and 1.32 SAEs per patient, respectively (P = .003). The combination of anti-Dsg1 values of 20 or more IU/mL and/or anti-Dsg3 values of 48 or more IU/mL yielded 0.83 positive predictive value and 0.94 negative predictive value to predict long-term relapse.Conclusions and RelevanceIn this secondary analysis of the Ritux 3 trail, first-line treatment of patients with pemphigus with the Ritux 3 regimen was associated with long-term sustained complete remission without corticosteroid therapy without any additional maintenance infusion of rituximab.

Restoring immune tolerance in pemphigus vulgaris

Intravenous immunoglobulin (IVIg), a preparation of polyclonal serum IgG pooled from numerous blood donors, has been used for nearly three decades and is proving to be an efficient treatment for many autoimmune blistering diseases, including pemphigus vulgaris (PV). Despite its widespread use and therapeutic success, its mechanisms of action are not completely understood. Some of its anti-inflammatory and immunomodulatory actions have been studied. In this study, the authors present a twenty-year follow-up of 21 patients with clinical and immunopathological confirmed PV, treated with IVIg as monotherapy, according to an established published protocol. IVIg therapy produced long-term sustained, clinical, serological, and immunopathological remission. For 20 y, these patients received no drugs and experienced no disease. This observation suggests that there was the establishment of immune balance or restoration of immune regulation in these PV patients. Twelve (57%) patients experienced no relapse during follow-up. Six (29%) patients experienced a relapse due to acute stress or post-coronavirus infection and/or vaccination. Reinstitution of IVIg resulted in prompt sustained recovery. Three (14.2%) patients, in clinical and serological remission, died due to unrelated causes. No severe adverse effects from IVIg were documented in all 21 patients. The simultaneous or sequential anti-inflammatory and immunomodulatory effects of IVIg may have influenced the long-term clinical remission observed. This study provides a human prototype to examine the pathophysiology of autoimmunity and a model to study immune regulation and mechanisms that can facilitate restoring immune tolerance.

Exploring Predictive Biomarkers of Relapse in Ulcerative Colitis: A Proteomics Approach.

Risk stratification of subjects with a history of inflammatory bowel disease (IBD) into those likely to relapse and those who will remain quiescent continues to be a significant challenge. The aim of this study was to investigate whether certain proteomic signature profiles or biomarkers during remission are associated with future disease relapse in patients with ulcerative colitis (UC). Endoscopic rectal samples from patients with UC in clinical, endoscopic, and histological remission at index endoscopy were collected, as well as samplers from normal control individuals. The patients were stratified to early relapsers (ERs) if they developed clinical signs of UC flare within 6 months of index endoscopy or nonrelapsers (NRs) if there was no relapse after 36 months of follow-up. The pooled rectal samples from ERs, NRs, and control individuals were subjected to nano-liquid chromatography and tandem mass spectrometry as per standard iTRAQ (isobaric tags for relative and absolute quantitation) workflow methodology. Selected proteomics-yielded candidates were subjected to orthogonal validation via immunoblotting, in a biomarker discovery exercise. Sixty-one patients were included, of whom 8 had clinical relapse within 6 months from the index endoscopy, and 43 patients had no clinical symptoms of relapse within the 36-month follow-up period. Ten patients who had clinical signs of relapse between 6 and 36 months were excluded. Seventeen control individuals were also included. Soluble proteomics analyses between ERs, NRs, and control individuals revealed a series of upregulated and downregulated proteins. Following orthogonal validation, upregulated TRX (P = .001) and IGHA1 (P = .001) were observed in ERs relative to NRs. Several novel candidate tissue biomarkers have been identified in this study, which could discriminate patients with UC at risk of early relapse from those in long-term sustained remission. Our findings may pave the way for pre-emptive UC disease monitoring and therapeutic decision making.

Sustained Remission and Decreased Severity of CAR T-Cell Related Adverse Events: A Pivotal Study Report of CNCT19 (inaticabtagene autoleucel) Treatment in Adult Patients with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia (R/R B-Cell ALL) in China

CNCT19 (inaticabtagene autoleucel) is an autologous CD19-specific chimeric antigen receptor (CAR) T-cell product. The patent protected CAR structure of CNCT19 contains a unique CD19 scFv, HI19a, which is different from commonly used FMC63. Together with using 4-1BB co-stimulatory domain in the CAR structure, CNCT19 is expected to reduce the severity of treatment-associated cytokine release syndrome (CRS) and neurologic toxicities (NT) while maintaining a stronger and longer durable anti-tumor effect.CNCT19 has been granted Breakthrough Therapy Designation by China National Medical Products Administration and Orphan Drug Designation by the U.S. FDA for the treatment of ALL.The trial of CNCT19 in adult Chinese patients with R/R B-cell ALL (NCT04684147) is a single-arm, open-label pivotal study conducted at 10 centers in China. The primary endpoint was the overall complete response rate (OCR) of complete response (CR) and CR with incomplete hematological recovery (CRi) within 3 months and at the end of Month 3 after CNCT19 infusion by central assessment.All 39 patients diagnosed with B-cell ALL were refractory and relapsed to multiple lines of prior therapy. Among the 39 patients 32 (82.1%) had reached MRD-negative OCR within 3 months after CNCT19 infusion, The median duration of response and OS have not been reached. 25 patients (64.1%) remained on CR (51.3%) or CRi (12.8%). at the end of Month 3 after CNCT19 infusion These patients had sustained long-term remission regardless of whether subsequent allo-HSCT treatment was done or not. The most common CNCT19-related adverse events (AEs) were CRS and NT and there were 4 cases of Grade ≥ 3 CRS (n=4, 10.3%) and 3 cases of Grade ≥ 3 NT (n=3, 7.7%). Following CNCT19 infusion, all the patients recovered. No death cases were reported due to CRS or NT.CNCT19 CAR-T cell therapy achieved a high rate of MRD-negative complete remission in adult patients with R/R B-cell ALL. Thus, with its distinct CAR structure containing a unique CD19 scFv (HI19a), CNCT19 provides effective treatment with potential long-term clinical benefits for adult patients with R/R B-cell ALL.

Long-Term Remissions in Patients with Peripheral T-Cell Lymphoma Following High-Dose Chemotherapy, Autologous Stem Cell Transplantation (ASCT) and Subsequent Radiotherapy

Purpose: The prognosis of patients with peripheral T-cell lymphoma and missing complete remission or relapsing before ASCT is assessed to be unfavourable. The aim of this study is to contribute data to the open question, whether additional radiotherapy improves the outcome. Patients and Methods: Forty-eight patients with peripheral T-cell-lymphoma were treated in our institution with high-dose therapy (usually BEAM protocol) and ASCT (age median 54 years, range 19-77). Twenty-five patients received ASCT in first treatment line, 13 in second line, 10 in third line (all refractory to 2nd-line salvage therapy). Seven of these 48 patients received radiotherapy (36-40 Gy, median 36) after ASCT. Results: Five-year overall survival (OS) and progression-free survival (PFS) after 1st-line ASCT and 2nd-line ASCT were 59% and 50%, respectively, and after 3rd-line ASCT significantly lower with 30% and 30%, respectively. Twenty-one patients achieved a sustained complete remission of 2.7 - 22.7 years (median 5.8). No patient relapsed after radiotherapy. Conclusion: Sustained long-term remissions can be achieved in patients with peripheral T-cell lymphoma following ASCT in first, second or third treatment line. Early irradiation after ASCT can possibly consolidate remission in localized residual or refractory disease.

Additive efficacy of a bispecific anti-TNF/IL-6 nanobody compound in translational models of rheumatoid arthritis.

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases affecting primarily the joints. Despite successful therapies including antibodies against tumor necrosis factor (TNF) and interleukin-6 (IL-6) receptor, only 20 to 30% of patients experience remission. We studied whether inhibiting both TNF and IL-6 would result in improved efficacy. Using backtranslation from single-cell RNA sequencing (scRNA-seq) data from individuals with RA, we hypothesized that TNF and IL-6 act synergistically on fibroblast-like synoviocytes (FLS) and T cells. Coculture of FLS from individuals with RA and T cells supported this hypothesis, revealing effects on both disease-driving pathways and biomarkers. Combining anti-TNF and anti-IL-6 antibodies in collagen-induced arthritis (CIA) mouse models resulted in sustained long-term remission, improved histology, and effects on bone remodeling pathways. These promising data initiated the development of an anti-TNF/IL-6 bispecific nanobody compound 1, with similar potencies against TNF and IL-6. We observed additive efficacy of compound 1 in a FLS/T cell coculture affecting arthritis and T helper 17 (TH17) pathways. This nanobody compound transcript signature inversely overlapped with described RA endotypes, indicating a potential efficacy in a broader patient population. In summary, we showed superiority of a bispecific anti-TNF/IL-6 nanobody compound or combination treatment over monospecific treatments in both in vitro and in vivo models. We anticipate improved efficacy in upcoming clinical studies.

A Rare Case Presentation of Erythema Annulare Centrifugum-Like Acute Psoriasis

We report a case of erythema annulare centrifugum-like psoriasis occurring in a 44-year-old female. The patient presented with annular erythematous plaques with trailing collarette scales affecting the elbows and antecubital fossae, which are consistent with a clinical diagnosis of erythema annulare centrifugum (EAC). Given the presence of classical clinical features of EAC, this case was notable due to biopsy findings, which revealed classic histologic changes of psoriasis. This finding supports the diagnosis of erythema annulare centrifugum-like psoriasis and represents a rare presentation of acute psoriasis. Treatment with topical mometasone led to rapid and sustained long-term remission.

Should dexamethasone alone or in combination be the initial steroid for adult ITP: Still a relevant question.

Corticosteroids are used in first-line treatment in newly diagnosed immune thrombocytopenia. The goal of treatment is primarily to decrease autoantibody-mediated platelet clearance. Ideally initial treatment would not just increase the platelet count but also provide a long-term sustained remission. While many clinicians use prednisone (PDN) as their first choice of corticosteroid, others prefer dexamethasone. The controversy is the subject of debates. Short courses of higher-dose corticosteroids were first reported by the Andersen study in 1994. The study posited high-dose dexamethasone as a 'cure' for all ITP patients. Later, studies addressed the number of dexamethasone cycles, indications to repeat cycles and timing between cycles, with varied long-term results. The results with dexamethasone were compared to PDN in some studies: the four-day cycles of dexamethasone work faster in increasing platelet counts and appear to reduce the occurrence of severe adverse events. Therefore, it is probably a better option for patients with low platelet counts and bleeding diathesis; however, curative superiority, the initial reason to administer it, compared to PDN is not well demonstrated. Across the studies, treatment with high-dose dexamethasone seems to be safer, with lower incidence of all adverse events compared to PDN, which might be a reflection of shorter treatment duration and possibly also lower cumulative steroid dose. Dexamethasone in combination with rituximab in first-line treatment produced higher response rates with better long-term results compared to high-dose dexamethasone alone and is a particularly good option in younger women.

P347 Vedolizumab as first line biologic therapy in elderly patients with contraindications against anti-TNF therapy - A real-world nationwide cohort of patients with inflammatory bowel diseases

Abstract Background Data regarding the efficacy and safety of vedolizumab as the first line of biologic therapy for elderly patients with ulcerative colitis (UC) and Crohn’s disease (CD) or patients with contraindications against anti-tumor necrosis factor antagonists (anti-TNFs) are scarce. Therefore, we aimed to investigate the short and long-term efficacy and safety of vedolizumab in patients with bio-naïve UC and CD stratified according to age. Methods A Danish nationwide cohort study was conducted between November 2014 and November 2019, including all bio-naïve patients receiving vedolizumab. The primary outcomes were clinical remission, steroid-free clinical remission, and sustained clinical remission defined as clinical remission at week 14 through week 52. Elderly patients were defined as patients aged 60 years or older at initiation of vedolizumab. Results The study included 56 patients (UC: 31 (55.4%), CD: 25 (44.6%)) with 15 (60.0%) and nine (47.4%) elderly patients with UC and CD, respectively. Elderly patients with UC and CD experienced higher rates of early response, remission, and steroid-free clinical remission, which, however, did not reach statistical significance (Figures 1 and 2). However, elderly patients with CD had similar long-term response as compared with younger patients. In the overall study population, lack of remission at week 52 was associated with female gender (p=0.01) in UC and ileal CD (p=0.03). Discontinuation due to primary non-response occurred in 20.0% and 5.3%, while rates of secondary loss of response were 12.0% and 5.3% after 26 weeks and 52 weeks, respectively. Only one UC patient, who developed a serious infection, experienced a serious adverse event during treatment with vedolizumab. However, mild adverse events were experienced by 35.5% and 8.0% of patients with UC and CD, respectively. As shown in Table 1, elderly patients experienced adverse events similar to the corresponding younger patients. Conclusion Vedolizumab is effective for induction of short and long-term sustained clinical remission in bio-naïve elderly and younger UC and CD patients with contraindications to anti-TNFs.

"I'm a Survivor": Perceptions of Chronic Disease and Survivorship Among Individuals in Long-Term Remission from Opioid Use Disorder.

BackgroundWhile opioid use disorder (OUD) is prevalent, little is known about what patients with OUD in sustained remission think about the chronic disease model of OUD and their perspectives of the cause, course, and ongoing treatment needs of their OUD.ObjectiveTo (1) examine patient perceptions of the chronic disease model of addiction and disease identity and (2) use an explanatory model framework to explore how these perceptions inform ongoing treatment needs and help maintain abstinence.DesignQualitative study of a cross-sectional cohort of patients with OUD in long-term sustained remission currently receiving methadone or buprenorphine. Participants completed a single in-depth, semi-structured individual interview.ParticipantsTwenty adults were recruited from two opioid treatment programs and two office-based opioid treatment programs in Baltimore, MD. Half of the participants were Black, had a median (IQR) age of 46.5 (43–52) years and the median (IQR) time since the last non-prescribed opioid was 12 (8–15) years.ApproachHybrid deductive-inductive thematic analysis of the transcribed interviews.Key ResultsSome participants described a chronic OUD disease identity where they continue to live with OUD. Participants who maintain an OUD identity describe inherent traits or predetermination of developing OUD. Maintaining a disease identity helps them remain vigilant against returning to drug use. Others described a post-OUD/survivor identity where they no longer felt they had OUD, but the experience remains. Each perspective informed attitudes about continued treatment with methadone or buprenorphine and strategies to remain in remission.ConclusionsThe identity that people with OUD in sustained remission maintain was the lens through which they viewed other aspects of their OUD including cause and ongoing treatment needs. An alternative, post-OUD/survivorship model emerged or was accepted by participants who did not identify as currently having OUD. Understanding patient perspectives of OUD identity might improve patient-centered care and improve outcomes.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-021-06925-z.

Sustained Remission in Patients With Rheumatoid Arthritis Receiving Triple Therapy Compared to Biologic Therapy: A Swedish Nationwide Register Study.

To compare the real-life effectiveness of biologic therapy (a biologic disease-modifying antirheumatic drug plus methotrexate [MTX]) versus triple therapy (MTX plus sulfasalazine plus hydroxychloroquine/chloroquine) for sustained remission of rheumatoid arthritis (RA). RA patients who were registered in the nationwide Swedish Rheumatology Quality Register between 2000 and 2012 and were receiving biologic or triple therapy as a first treatment strategy after MTX monotherapy were included. Sustained remission was defined as a Disease Activity Score in 28 joints (DAS28) of <2.6 for ≥6 months (short-term sustained remission) or for ≥24 months (long-term sustained remission). Treatment groups were compared during treatment, at 1 year, and at 2 years for 1) all patients starting therapy and 2) patients continuing to receive therapy, using propensity score-adjusted regression analyses. In addition, survival analyses were used to compare treatment groups at any time during follow-up irrespective of therapy retention. A total of 1,502 patients were included (1,155 receiving biologic therapy and 347 receiving triple therapy). For patients starting therapy, the adjusted odds ratios (ORs) of achieving short-term and long-term remission, respectively, at 1 year after start of biologic therapy versus triple therapy were 1.79 (95% confidence interval [95% CI] 1.18-2.71) and 1.86 (95% CI 1.00-3.48). At 2 years, the ORs were 1.92 (95% CI 1.21-3.06) and 1.62 (95% CI 0.94-2.79), respectively. For patients continuing to receive therapy, corresponding results at 1 year were 1.12 (95% CI 0.72-1.75) and 1.1 (95% CI 0.59-2.16); at 2 years, 0.85 (95% CI 0.49-1.47) and 0.76 (95% CI 0.41-1.39). Hazard ratios for short-term and long-term sustained remission at any time during follow-up were 1.15 (95% CI 0.91-1.46) and 1.09 (95% CI 0.77-1.54), respectively. Among patients starting biologic or triple therapy, biologic therapy was more effective for remaining on therapy and achieving sustained remission. However, similar probabilities were found for achieving sustained remission among patients remaining on therapy and at any time during follow-up irrespective of therapy retention. Although the likelihood of reaching sustained remission is higher with biologic therapy, for certain RA patients triple therapy may still be an alternative to biologic therapy without hampering future chances of obtaining sustained remission.

A Case of Recurrence/Refractory Mediastinal Hodgkin&amp;apos;s Lymphoma Relapsed After Allogeneic Hematopoietic Stem Cell Transplantation: Immunotherapy Brings Hope

Hodgkin lymphoma (HL), is a B-cell lymphoma. HL is a common hematological malignancy, mostly seen in young and middle-aged people. According to NCCN guidelines, common treatment options include ABVD, BEACOPP, StandfordV, etc. Most HL have a good prognosis and even can be cured. However, some Refractory / Recurrent (R/R) HL, continue to progress during treatment or even relapse after the completion of a complete chemotherapy course 3 months. At this time, the best treatment for R/R HL is high-dose chemotherapy / Autologous Hematopoietic Stem Cell Transplantation (HDC/HSCT). This paper reports a case of Recurrence/Refractory (R/R) mediastinal Hodgkin's lymphoma that relapsed after Allogeneic Hematopoietic Stem Cell Transplantation. After receiving a variety of treatments, including chemotherapy, radiotherapy, autologous hematopoietic stem cell transplantation and so on, no long-term sustained remission was achieved. Traditional chemotherapy regimen has not brought ideal therapeutic effect to patients, but the rapid development of immunotherapy in recent years has brought new hope to patients. Finally sustained remission was achieved under the treatment of Brentuximab Vedotin combined with PD-1 inhibitor. This paper combined with the literature reports and discussed the clinical characteristics, treatment process and related experience and thinking methods of immunotherapy related to PD-1 inhibitors in this refractory and easy-to-relapse case. To provide more clinical data for the application of immunotherapy in R/R HL.

A Multicentre Randomised Trial of First Line Treatment Pathways for Newly Diagnosed Immune Thrombocytopenia: Standard Steroid Treatment Versus Combined Steroid and Mycophenolate. the Flight Trial

BACKGROUND Immune thrombocytopenia (ITP) is a rare autoimmune condition associated with bleeding risk and fatigue. Current first line ITP treatment is with high dose corticosteroids but frequent side effects, heterogeneous responses and high relapse rates are significant problems, with only 20% remaining in sustained long-term remission. In the UK, mycophenolate (MMF) is frequently used as second line treatment, with retrospective data in ITP suggesting efficacy in 50-80% of patients with good tolerability, although responses are often delayed. The FLIGHT trial aimed to test the hypothesis that MMF combined with corticosteroid is a more effective first line ITP treatment than current standard of care, corticosteroid alone. METHODS In this multicentre, UK based, open label, randomised controlled trial, we randomly assigned 120 patients with ITP requiring first line treatment, to corticosteroid alone (standard care) versus combined corticosteroid and MMF (1:1 ratio). Patients &amp;gt;16 years old, with baseline platelet count &amp;lt;30 x109/L requiring first line treatment were eligible. Exclusions included HIV, Common Variable Immunodeficiency (CVID), pregnancy, breast feeding or an unwillingness to follow contraception advice if assigned to MMF. Dosing of corticosteroid followed international consensus guidance (either dexamethasone pulses or prednisolone initial daily dose of 1mg/kg then taper) and dosing of MMF included a strategy to taper and stop 6 months after starting treatment. The primary efficacy outcome was time from randomisation to treatment failure, defined as platelets &amp;lt;30x109/L and a clinical need for second line treatment (included refractory and relapsed ITP). Secondary outcomes included side effects, bleeding events, and patient reported outcomes (PROM) measured at baseline, 2, 4, 6 and 12 months, by validated questionnaires (SF36v2 (Your health &amp; wellbeing): Quality of life (QoL), FACIT-Fatigue (v4): Fatigue, FACT-Th6 (v4): Bleeding and ICECAP-A v2: QoL) RESULTS Of the 120 ITP patients consented, recruited and randomised (52.4% male, mean age 54 years, range 17-87), mean baseline platelet count was 7 x109/L and mean follow up was for 18 months (maximum follow up 24 months, minimum follow up of 12 months). Patient demographics and baseline values are shown in table 1. Significantly fewer treatment failures occurred in patients randomised to MMF as shown in figure 1 (22% [n=13 of 59] vs 44% [n=27 of 61], aHR=0.41 [0.21, 0.80], p=0.0064, and when secondary ITP patients were excluded, aHR 0.37 [0.19, 0.71] p=0.0029). There were similar rates between the groups of significant adverse events, bleeding events, rescue treatments, hospital admissions and treatment side effects including infection (n=14 in each group), neutropenia (4 patients in corticosteroid group), and gastrointestinal side effects (table 2). However, some aspects of quality of life (QoL) were worse in those patients assigned to the MMF group including physical role, physical function and fatigue. CONCLUSIONS This is the first randomised trial using MMF to treat ITP, demonstrating good efficacy and tolerability, even with the inclusion of elderly patients (27.5% were &amp;gt;70 years, 15.8% &amp;gt;75 years). Therefore, MMF may be considered an effective, well tolerated first line treatment option, alongside a short course of steroids, for some patients with ITP, approximately halving the risk of refractory or relapsed ITP. At final follow up, 56% of patients treated with corticosteroid alone had not required 2nd line treatment, which is higher than previous reports. It is unclear why some aspects of QoL were worse in the MMF group. This is an important reminder that disease response and patient experience may not correlate and emphasises the importance of including PROM outcomes within trials. For ITP, to date, PROMs have only been systematically evaluated in the TPO-RA randomised controlled trials. The FLIGHT trial received ethical approval from NRES Committee South West and is registered, (EudraCT Number: 2017-001171-23. ClinicalTrials.gov number: NCT03156452). This abstract presents independent research funded by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfPB) Programme (Grant Reference Number PB-PG-0815-20016). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Mycophenolate is unlicensed for ITP treatment

Progress in the therapy of myasthenia gravis: getting closer to effective targeted immunotherapies

To provide an update on immunomodulating and immunosuppressive therapies in myasthenia gravis and highlight newly approved, or pending approval, therapies with new biologics. Preoperative IVIg is not needed to prevent myasthenic crisis in stable myasthenia gravis patients scheduled for surgery under general anesthesia, based on controlled data. Rituximab, if initiated early in new-onset myasthenia gravis, can lead to faster and more sustained remission even without immunotherapies in 35% of patients at 2 years. Biomarkers determining the timing for follow-up infusions in Rituximab-responding AChR-positive patients are discussed. Most patients with MuSK-positive myasthenia gravis treated with Rituximab have sustained long-term remission with persistent reduction of IgG4 anti-MuSK antibodies. Eculizumb in the extension REGAIN study showed sustained long-term pharmacological remissions and reduced exacerbations. Three new biologic agents showed promising results in phase-II controlled myasthenia gravis trials: Zilucoplan, a subcutaneous macrocyclic peptide inhibiting complement C5; Efgartigimod, an IgG1-derived Fc fragment binding to neonatal FcRn receptor; and Rozanolixizumab, a high-affinity anti-FcRn monoclonal antibody. Finally, the safety of ongoing myasthenia gravis immunotherapies during COVID19 pandemic is discussed. New biologics against B cells, complement and FcRn receptor, are bringing us closer to successful targeted immunotherapies in the chronic management of myasthenia gravis promising an exciting future for antibody-mediated neurological diseases.

Transcriptome Profiling of Immune Response to Dendritic/AML Fusion Vaccine

Introduction In a clinical trial of patients vaccinated after chemotherapy-induced remission with patient-derived AML cells fused with autologous dendritic cells (DC/AML fusions) we demonstrated durable AML-specific immunity. 71% of patients sustained long-term remission from AML at 55-91 months (responders) while those who experienced relapse had recurrence at 2-26 months (non-responders). Objectives We performed genomic analysis of the marrow microenvironment to identify factors associated with durable remission after vaccination. Methods RNA sequencing was done using banked formalin-fixed paraffin embedded (FFPE) marrow at serial time points. Ingenuity Pathways IPA 9.0 was used to define pathways and upstream regulators. To characterize the cellular components, single cell RNA-seq was performed on fresh frozen aspirates with cell cluster annotation performed by Single Cell Wizard software and peripheral blood was used for TCR clonal diversity by NGS. Results Heatmaps depict significant (p-value ≤0.01 and fold change ≥2) differential gene expression both pre- and post-vaccination in responders compared to non-responders. Prior to vaccination there was inhibition of TGF-β in responders. Notable upregulated pathways in responders after vaccination (p value Conclusion In a cohort of AML patients treated with DC/AML fusions, we found distinct gene signatures amongst patients with long term remisison vs those with early relapse. The transcriptomes indicate a microenvironment in which TGF-β-mediated immunosuppression is inhibited after chemotherapy and in which interleukins, B cell and macrophage signaling are activated are associated with vaccine response, and have potential for combinatorial therapeutic strategies. T cell costimulation and activation are key components of response with NK cells and DC activation playing a supporting role. A durable oligoclonal T cell expansion suggests vaccine is capable of enhancing the T cell repertroie which could provide a unique opportunity to identify target antigens by TCR-epitope pairing.

Long-Term Clinical and Molecular Remissions in Patients with Mantle Cell Lymphoma (MCL) Following High-Dose Therapy (HDT) and Autologous Stem Cell Transplantation (ASCT)

Background:Long-term clinical and molecular remissions in patients with MCL following HDT and ASCT have been evaluated in only a few studies. Results are especially limited for remission duration over 5 years. So the curability of this disease remains an open question. Patients and methods:Altogether 61 patients with MCL were treated in our institution with ASCT from 1998 to April 2019 (50 1st-line ASCT, ten 2nd-line ASCT, one 3rd-line ASCT). The data were collected retrospectively in 29 and prospectively in 32 patients who participated in two clinical trials: the 1st-line therapy trials of the German Low Grade Lymphoma Study Group (GLSG, principal investigator W. Hiddemann [Dreyling M, Blood 2005] and the European Mantle Cell Lymphoma Network [Hermine O, Lancet 2016], respectively. The diagnosis was regularly approved by the reference pathology of the GLSG (W.K.). The induction therapy before 1st-line ASCT consisted of 6 courses CHOP (n=11), mostly combined with rituximab and followed by Dexa-BEAM, and 6 alternating courses of R-CHOP and R-DHAP (n=39), respectively. For the salvage treatment patients usually received three to four courses of the DHAP protocol or the ESHAP protocol, since 2001 also combined with rituximab.Stem cell apheresis was carried out in the Blood Transfusion Service following these protocols in remission. High-dose protocols: 1) total body irradiation with cyclophosphamide or melphalan and cytarabin (n=32) or 2) BEAM (n=29). Patients with partial remission after ASCT received a radiotherapy (RT) with 30-36 Gy in the field of persisting lymphoma, if possible (n=4). Since 09/2016 patients received a maintenance therapy with rituximab after ASCT (every 2 months, planned for 3 years, n=14). Further details are described in an earlier publication of our first 36 patients (Metzner B, Ann Hematol 2013). Response assessment was performed by careful clinical examination and by ultrasound, chest x-ray and partly CT at regular 3 - 12 monthly time points. In the case of long-term remission (≥ 5 years; n = 18), peripheral blood was regularly tested twice a year for minimal residual disease (MRD) by quantitative t(11;14) or allel specific IGH RQ-PCR and/or IGH-consensus PCR.Calculations were done using IBM SPSS Statistics Version 25. Data were analysed as of 01 July 2019. Results:With a median follow-up of 5 years (range 0.1-20) 10-year overall survival, progression-free survival (PFS) and freedom from progression (FFP) after 1st-line ASCT were 54%, 46% and 52%, respectively, after 2nd-line ASCT 42%, 20%and 20%, with a significant difference for PFS (p=0.045) and FFP (p=0.014) between 1st-line and 2nd-line cohort.Further prognostic factors (like sex, age, MIPI, bone marrow involvement, remission grade at ASCT: CR vs. PR, type of HDT: TBI vs. BEAM…) seemed to be without relevance (considering the small subgroups). Only one clinical relapse occurred after 5 years following ASCT in 1stor 2ndremission, respectively (one patient 6 years after 1st-line ASCT and another patient 7 years after 2nd-line ASCT and subsequent radiotherapy). So far, 18 patients experienced long-term remissions of at least 5 years (median 9 years, from 5 to 16 years). Fifteen of 17 tested patients were MRD negative at last follow-up, the two MRD positive patients (positive at a low level below the quantitative measuring range) had no clinical signs of relapse at last follow-up. None of these 18 patients had received rituximab maintenance therapy. None showed clinical criteria of "smoldering mantle cell lymphoma" at induction therapy. Treatment-related mortality at 100 days after ASCT was 1.6% (pneumonitis following TBI). One patient developed a secondary invasive malignancy in remission after ASCT (acute myeloid leukemia 4 years following TBI). Conclusion: Sustained long-term clinical and molecular remissions up to 16 years can be achieved following ASCT (without rituximab maintenance therapy), indicating the potential curative impact of 1st-line ASCT in MCL. The 2nd-line ASCT was obviously less effective. Disclosures Dreyling: Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Acerta: Other: scientific advisory board; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding.

Tumor Mutation Burden and Driver Mutations: Further Insight into the Genomic Landscape of Pediatric Brain Tumors

To investigate the relationship between tumor mutation burden (TMB) and driver mutations and their role as predictive biomarkers to guide targeted therapy in pediatric brain tumors. Higher TMB has been found to relate to lower incidence of driver mutations, but this relationship has not been studied in pediatric brain tumors. To characterize the association between TMB and known driver mutations, comprehensive genomic profiling (CGP) was performed on 723 pediatric (≤21 years) brain tumor samples using DNA extracted from 40 microns of formalin-fixed paraffin-embedded tissue. CGP utilized hybridization-captured, adaptor ligation-based libraries sequenced to a mean coverage depth of >500X for up to 315 cancer-related genes. TMB was calculated as mutations per megabase and categorized as low (0-6), intermediate (6-20), or high (20+). Analysis included 80 clinically relevant driver mutations; genomic alterations known to confer a selective growth advantage. Of 723 brain tumors, TMB was low in 91.8%, intermediate in 6.1%, and high in 2.1%. When excluding tumor suppressor genes (TSGs), there was a decreased incidence of driver mutations in high TMB tumors (p<0.001). Additionally, BRAF alterations were not identified in high TMB tumors, but were enriched in low TMB tumors (p<0.01). H3F3A alterations were associated with a higher TMB despite not having any incidence in high TMB tumors; they were enriched in intermediate TMB tumors. When including TSGs, however, 93% of tumors in the high TMB cohort harbored a driver mutation; 70% and 63% in the intermediate and low TMB cohorts, respectively (p<0.05). There is an association between high TMB and incidence of TSG alterations (p<10-10), especially TP53 alterations (p<10-13). Of the 15 tumors with high TMB, 14 were high grade gliomas (HGG) and had alterations in TP53; the one high TMB tumor that was not a HGG also did not have a TP53 mutation. Three biallelic mismatch repair mutations identified were MSH2, MSH6, and PMS2; they were associated with a higher TMB (p<0.01). This is the first study to compare TMB with incidence of driver mutations in pediatric brain tumors and demonstrates that the relationship may depend on the type of driver mutation present. Patients with high TMB have the potential to respond to immunotherapy, with long-term sustained remission as TMB is associated with a higher level of neoantigens and an increased immunogenicity. Future studies should focus on identifying optimal treatment strategies for these subsets of patients, including using immunotherapy with radiotherapy, as preclinical data suggests the combination may be more effective. Characterizing pediatric brain tumors by TMB and driver mutations may represent a rapid method of risk stratification and potentially predict clinical response to immunotherapy with or without adjuvant radiation and chemotherapy.

Innovative Education and Engagement Tools for Rheumatology and Immunology Public Engagement with Augmented Reality.

Rheumatoid arthritis (RA) affects around 1% of the population, which places a heavy burden on society and has severe consequences for the individuals affected. The early diagnosis and implementation of disease-modifying anti-rheumatic drugs significantly increase the chance of achieving long-term sustained remission. Therefore, raising awareness of RA amongst the general public is important in order to decrease the time of diagnosis of the disease. Augmented reality (AR) can be tremendously valuable in a teaching and learning context, as the coexistence of real and virtual objects aids learners in understanding abstract ideas and complicated spatial relationships. It has also been suggested that it raises motivation in users through interactivity and novelty. In this chapter we explore the use AR in public engagement, and detail the design, development and evaluation of a blended learning experience utilising AR. A set of informative printed posters was produced, enhanced by an accompanying interactive AR application. The main user testing was conducted with 27 participants at a science outreach event at the Glasgow Science Centre. Findings report mean positive attitudes regarding all aspects of the study, highlighting the potential of AR for public engagement with topics such as RA.