Blood

The phase 3 ECHELON-1 study demonstrated that brentuximab vedotin (A) with AVD (A+AVD) exhibited superior modified PFS versus ABVD for the frontline treatment of patients with stage III/IV classical Hodgkin lymphoma (cHL) (NCT01712490; 2011-005450-60). Maturing data from positron emission tomography (PET)-adapted trials highlight potential limitations of PET-adapted approaches, including toxicities with dose intensification and higher-than-expected relapse rates in PET2(-) patients. We present here an update of the ECHELON-1 study, including an exploratory analysis of 3-year PFS per investigator...

Prompt diagnostic work-up of suspected heparin-induced thrombocytopenia (HIT) is critical for guiding initial patient management. We assessed the performance of three immunoassays detecting anti-PF4/heparin-antibodies, derived a diagnostic algorithm with a short analytical turnaround-time (TAT) and prospectively validated it. Plasma samples were analysed by Zymutest-HIA-IgG, HemosIL-AcuStar-HIT-IgG and ID-H/PF4-PaGIA in retrospective (n=221) and prospective (n=305) derivation cohorts. We calculated likelihood ratios (LR) of result intervals and cut-off values with 100% negative (NPV) and positive (PPV) predictive value for a positive gold-standard functional assay (HIPA)...

Natural Killer Cell Deficiencies (NKDs) are an emerging phenotypic subtype of primary immune deficiency. NK cells provide a defense against virally infected cells using a variety of cytotoxic mechanisms, and patients who have defective NK cell development or function can present with atypical, recurrent or severe herpesviral infections. The current pipeline for investigating NKDs involves the acquisition and clinical assessment of patients with a suspected NKD followed by subsequent in silico, in vitro and in vivo laboratory research...

Activated PI3-kinase-δ syndrome (APDS) is a rare primary combined immunodeficiency caused by either dominant gain-of-function mutations in the PIK3CD gene encoding the catalytic subunit p110δ of phosphoinositide 3-kinase-δ (PI3K-δ) (referred to as type 1 APDS) or dominant loss-of-function mutations in the PIK3R1 gene encoding the p85α, p55α and p50α regulatory subunits (type 2 APDS). In types 1 and 2 APDS, the PI3K-δ hyperactivity resulting from the gene mutations leads to similar clinical presentations - characterized by increased susceptibility to bacterial and viral infections, and (to a lesser extent) by auto-immune manifestations...

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Primary immune deficiencies have been traditionally defined based on increased susceptibility to recurrent and/or severe infections. However, immune dysregulation, manifesting with autoimmunity or hyperinflammatory disease, has emerged as a common feature. This is especially the case in patients affected with combined immune deficiency (CID), a group of disorders caused by genetic defects that impair, but do not completely abolish T cell function. Hypomorphic mutations in the Recombination Activating Genes RAG1and RAG2represent the prototype of the broad spectrum of clinical and immunological phenotypes associated with CID...

Epstein-Barr virus (EBV) is an enigma - on one hand, it infects and persists in latent form in the vast majority of the global population, causing relatively benign disease in otherwise healthy individuals. On the other hand, EBV represents the first identified oncogenic virus, capable of causing at least 7 different types of malignancies, usually in immunocompromised individuals. Furthermore, some individuals with defined inborn errors of immunity exhibit extreme susceptibility to EBV-induced disease, developing severe and often fatal infectious mononucleosis, haemophagocytic lymphohistiocytosis, lymphoproliferative disease and/or EBV+ B-cell lymphoma...

Viral infections are common and are potentially life-threatening in patients with moderate to severe primary immunodeficiency disorders. Since T-cell immunity contributes to the control of many viral pathogens, adoptive immunotherapy with virus-specific T-cells has been a logical and effective way of combating severe viral disease in immunocompromised patients in multiple phase I and II clinical trials. Common viral targets include cytomegalovirus, Epstein-Barr virus, and adenovirus, though recent published studies have successfully targeted additional pathogens, including HHV6, BK virus and JC virus...

Using whole exome sequencing to examine the genetic causes of immune deficiency in 235 CVID patients seen in New York, 128 patients from Sweden, and 208 from Iran, revealed 73 known disease-causing genes associated with this heterogeneous immune defect. The patients at the time of study ranged from age 4 to age 90. Overall, for 31%, 36% and 54% of the patients in United States, Swedish or Iranian cohorts, mutations were identified. The multiplicity of genes identified reflects the complex requirements of B cell antigen signaling, activation, survival, migration, maturation and maintenance of antibody-secreting memory B cell populations to the plasma cell stage...

Human invariant natural killer T cells (iNKTs) are a rare innate-like lymphocyte population that recognize glycolipids presented on CD1d. Studies in mice have shown that these cells are heterogenous and capable of enacting diverse functions, and the composition of iNKT subsets can alter disease outcomes. In contrast, far less is known about how heterogeneity in human iNKTs relates to disease. To address this, we use a high-dimensional, data-driven approach to devise a framework to parse human iNKT heterogeneity...

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Several studies suggest that harnessing Natural Killer (NK) cell reactivity mediated through Killer cell Immunoglobulin-like Receptors (KIR) could reduce the risk of relapse after allogeneic Hematopoietic Cell Transplantation (HCT). Based on one promising model, information on KIR2DS1 and KIR3DL1 and their cognate ligands can be used to classify donors as KIR-advantageous or disadvantageous. This study was aimed at externally validating this model in unrelated donor HCT. The impact of the predictor on Overall Survival (OS) and relapse incidence was tested in a Cox regression model adjusted for patient age, a modified disease risk index, performance status, donor age, HLA-match, sex-match, CMV-match, conditioning intensity, type of T-cell depletion and graft type...

Major histocompatibility complex (MHC) class II deficiency is a rare but life-threatening primary combined immunodeficiency. Hematopoietic cell transplantation (HCT) remains the only curative treatment for this condition, but transplant survival in published series was poor. We analysed the outcome of 25 such patients undergoing first HCT at our centre between 1995 and 2018. Median age at diagnosis was 6.5 months (range, birth to 7.5 years). Median age at transplant was 21.4 months (range, 0.1-7.8 years). Donors were matched family donors (MFD) (n=6), unrelated donors (UD) (n=12) and haploidentical donors (HID) (n=7)...

The BCL-2 inhibitor venetoclax combined with hypomethylating agents or low-dose cytarabine represents an important new therapy for older or unfit patients with acute myeloid leukemia (AML). We analyzed 81 patients receiving these venetoclax-based combinations to identify molecular correlates of durable remission, response followed by relapse (adaptive resistance) or refractory disease (primary resistance). High response rates and durable remissions were typically associated with NPM1 or IDH2 mutations (mut), with prolonged molecular remissions prevalent for NPM1mut...

Follicular lymphoma B cells undergo continuous somatic hypermutation (SHM) of their immunoglobulin variable region genes, generating a heterogeneous tumour population. SHM introduces DNA sequences encoding N-glycosylation sites Asparagine-X-Serine/Threonine (N-gly sites) within the V-region that are rarely found in normal B cell counterparts. Unique attached oligomannoses activate B cell receptor signalling pathways following engagement with calcium-dependent lectins expressed by tissue macrophages. This novel interaction appears critical for tumour growth and survival...

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Mutations in the epigenetic regulators DNMT3A and IDH1/2 co-occur in patients with acute myeloid leukemia and lymphoma. Here, we demonstrate that these two epigenetic mutations cooperate to induce leukemia. Leukemia-initiating cells from Dnmt3a-/- mice that express an IDH2 neomorphic mutant have a megakaryocyte-erythroid progenitor-like immunophenotype, activate a stem-cell-like gene signature, and repress differentiated-progenitor genes. We observe there is an epigenomic dysregulation with the gain of repressive H3K9 trimethylation and loss of H3K9 acetylation in diseased mouse bone marrow stem and progenitor cells (HSPC)...

Overactivated complement is a high-risk feature in HSCT recipients with transplant associated thrombotic microangiopathy (TA-TMA), and untreated patients have dismal outcomes. We present our experience of 64 pediatric HSCT recipients with high risk TA-TMA and multi-organ injury treated with the complement blocker eculizumab. We demonstrate significant improvement in 1y post-HSCT survival to 66% in treated patients from our previously reported untreated cohort with same high-risk TA-TMA features that had 1y post-HSCT survival of 16...

Relapse remains the most common cause of treatment failure for patients with acute myeloid leukaemia (AML) who undergo allogeneic stem cell transplantation (alloSCT) and carries a grave prognosis. Multiple studies have identified the presence of measurable residual disease (MRD) assessed by flow cytometry (FCM) prior to alloSCT as a strong predictor of relapse, but it is not clear how these findings apply to patients who test positive in molecular MRD assays which have far greater sensitivity. We analysed pre-transplant blood and bone marrow samples by reverse-transcription polymerase chain reaction (RT-qPCR) in 107 patients with NPM1 mutant AML enrolled in the UK National Cancer Research Institute (NCRI) AML17 study...

No abstract text is available yet for this article.