Clonal hematopoiesis is associated with risk of severe Covid-19

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15–2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15–3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22–3.30, p = 6×10−3) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15–2.13, p = 5×10−3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.

Prognostic Impact Of Baseline Immunologic Profile In Aggressive B-cell Non-Hodgkin’s Lymphomas

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Clonal hematopoiesis is associated with risk of severe Covid-19

ABSTRACTAcquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival.1–4 These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH.2,5,6 A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19.7,8 Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 515 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we found that CH was associated with severe Covid-19 outcomes (OR=1.9, 95%=1.2-2.9, p=0.01). We further explored the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH was significantly associated with risk of Clostridium Difficile (HR=2.0, 95% CI: 1.2-3.3, p=6×10−3) and Streptococcus/Enterococcus infections (HR=1.5, 95% CI=1.1-2.1, p=5×10−3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.

Tumor Molecular Profiling: Pediatric Results of the ProfiLER Study

PURPOSE The Program to Establish the Genetic and Immunologic Profile of Patient's Tumor for All Types of Advanced Cancer study (ClinicalTrials.gov identifier: NCT01774409 ) analyzed the genome of refractory cancers to identify a potential molecular-based recommended therapy (MBRT). The objectives of the pediatric substudy were to describe the incidence of genomic mutations, the MBRT, and the treatments undertaken with a molecular-targeted agent in a pediatric cohort. METHODS The tumor genome was analyzed within a 69-gene next-generation sequencing panel and an array comparative genomic hybridization assay. The results were evaluated by a multidisciplinary molecular board, and the targeted therapies were provided in the setting of a clinical trial or through compassionate use programs, when indicated. RESULTS Between November 2013 and June 2017, 50 patients younger than 19 years who were treated for a high-risk or relapsing tumor were included. Sarcomas (n = 24; 47%), CNS tumors (n = 14; 29%), and neuroblastomas (n = 5; 10%) were the most frequent tumor subtypes. Seven patients (14%) were excluded because no DNA could be recovered. Among the 43 remaining patients, 10 exhibited at least one targetable genomic alteration. Ultimately, four patients (8%) were treated with the recommended targeted therapy. CONCLUSION The results of this study confirm treatment with a targeted therapy for pediatric patients with cancer is still limited at present, as also is reported for adults.

Prognostic Impact of the Baseline Immunologic Profile in Patients with Aggressive B Non-Hodgkin Lymphomas

Background The Revised- International Prognostic Index (R-IPI), the current standard prognostic tool for patients with diffuse large cell lymphoma (DLBCL), considers only patient and clinical disease characteristics. The role of host immune homeostasis as an independent prognostic indicator in different diseases including DLBCL is evolving. Rambaldi et al 2013, showed that the lymphocyte monocyte ratio (LMR) at diagnosis is a simple prognostic biomarker and independent of the R-IPI. Low level of immunoglobulin at diagnosis, in particular IgG, is associated with inferior survival in Hodgkin and Non Hodgkin lymphoma patients (NHL). In DLBCL patients who underwent autologous transplants, Brown et al 2004 documented 18 months relapse free survival of 44% if IgG levels at time of transplant are below 600 mg/dL and 63% if higher. To our knowledge, the prognostic impact of immunoglobulin levels at diagnosis in patients with aggressive B-NHL has not been investigated. Therefore, we aimed to evaluate the prognostic role of the immunologic profile in terms of the pretreatment levels LMR and of immunoglobulins in patients with aggressive B-NHL. Methods and results: We retrospectively patients diagnosed with aggressive B non-Hodgkin lymphoma (NHL) at both the European Institute of Oncology in Milan and the Mauriziano Hospital in Turin from April 2014 to October 2018. Patients with DLBCL, Burkitt, Mantle cell and follicular G3B lymphomas were eligible. All patients were treated with chemo-immunotherapy according to center guidelines and a written informed consent was obtained from all them. A total of 105 patients were included, with male predominance (60%), median age of 64.5 years (range 20-83) and ECOG score 0-1 in 66%. Stage III-IV disease was seen in 58%, extranodal involvement in 73%, bone marrow infiltration in 26%, bulky disease in 39% and high LDH in 66%. Median IgG level was 1003 (range 436-2236) and the median LMR was 2.4 (range 0.2-44.2). By univariate analysis older age, advanced stage, higher ECOG PS, 2 or more extranodal disease sites, poor R-IPI, higher LDH, low LMR ratio as well as low IgG level at diagnosis was associated with a worse 1-year PFS. LMR inferior or equal to 2.4 had 1-year PFS of 70%, compared to 90% if LMR was higher (p 0.025). Patients with IgG levels less than 1003 had 1-year PFS of 70% compared to 90% in higher IgG levels. The later, didn' t reach statistical significance, due to small number of patients, but remains clinically relevant. Interestingly, there was no correlation between the levels of IgG and the LMR. Therefore, we examined the impact of combining each to R-IPI groups. A low IgG at diagnosis worsen the PFS in patients with good or very good R-IPI with 1 year PFS 83% (95% CI 60-93%) compared 97% (95% CI 79%-100%) if IgG levels are higher. Interestingly, patients in the poor IPI risk group and high IgG levels ad 1-year PFS similar to the good risk group with low IgG levels (PFS 84%, 95% CI 57-94%). The worst PFS is seen in the group of patients with poor IPI score and low IgG, PFS 61%, (95% CI 40%-77%). Similar results were seen in case of LMR. We then examined a novel immunologic prognostic score system that includes the three factors: baselines IGg levels, LMR and the R-IPI Figure 1. Because IgG levels and LMR are independent we put the same weight on each factor as well as the R-IPI score. We gave 1 point to each factor R-IPI poor (1 point) + IgG low (1 point) + LMR low (1 point). The sum of the chosen points correlated with four risk groups: group 1 = 0 points, group =2 = 1 point, group 3= 2 points and group 4= 3 points. The 1 year PFS was 95% (95% CI 68%-99%), 94% (95% CI 77%-98%), 75% (95% CI 54%-87%), 52% (95% CI 27%-73%), respectively. Conclusion: To our knowledge, this study is the first to report the prognostic implications of pretreatment levels of immunoglobulin IgG within the immunologic profile of patients with aggressive B-NHL. Our results suggests that IgG level at diagnosis is a clinically important prognostic factor. With the proposed immunologic score, patients are reclassified into four sub-groups with 3 significantly different 1-year PFS of 95% 75%, 50% in patients with no or one poor risk factor, 2 factors or 3 factors, respectively. This study confirms that the addition of baseline immunologic profile to R-IPI in patients with aggressive B-NHL optimizes their prognostic stratification and better identify patients who are at risk of poor outcome compared to the R-IPI alone. Disclosures Saglio: BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Jansen: Consultancy; Celgene: Consultancy.

Primary antiphospholipid syndrome in children: experience from two tertiary centres in South India

Background: Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by the presence of episodes of vascular thrombosis, recurrent fetal loss and other clinical features in the presence of antiphospholipid antibodies. The aim of the study was to analyze the clinical manifestations and immunologic profile of children presenting with APS.Methods: Authors did a retrospective case record study of patients admitted with thrombotic events between September 2013 and August 2018 and identified patients with positive antiphospholipid antibodies. Children who had clinical features of active lupus were not included.Results: The clinical and immunologic profile of 7 pediatric patients presenting with APS over 5 years from 2013 to 2018 were analysed. Symptoms secondary to vascular thrombosis were limb swelling, stroke, gangrene of toes and Budd Chiari syndrome.Conclusions:APS though rare should be considered in the differential diagnosis of children presenting with thrombotic events. They need long term anticoagulants to prevent further episodes.

The Role of Regulatory T Cells in the Regulation of Upper Airway Inflammation

Allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyps (CRSwNP) are inflammatory diseases of the upper airway, with a similar immunologic profile, characterized by aberrant and persistent type 2 inflammation. One cell population that has been identified as altered in both disease types is regulatory T cell (Treg). Tregs have the capacity to modulate T-effector function and suppress inflammatory cytokine production in a broad range of cell types. Given the ability of Tregs to control inflammation, the role of Tregs in respiratory diseases has attracted much attention. As discussed in this article, alterations in the Treg numbers and function, or both, have been identified in AR and CRSwNP, although much of the data is conflicting. Here, we explored what is known and, in many cases, unknown about the mechanisms by which Tregs differentiate and function, and how these functions can be controlled in the mucosal microenvironment. By gaining a greater understanding of these processes, it may be possible to harness the natural immunosuppressive activity of Tregs to ameliorate the chronic inflammation associated with AR and CRSwNP.