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Anwer: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; In-Cyte: Speakers Bureau.

Background

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Introduction:

Introduction:

Introduction:Graft versus host disease (GvHD) is the most common and debilitating complication of allogeneic hematopoietic cell transplantation (HCT). Among the two clinically significant forms, moderate-severe chronic GvHD (cGvHD) is more difficult to treat than grade 2-4 acute GvHD (aGvHD). Chronic GvHD rarely shows a sustained complete response to immunosuppressive drugs and non-responders either die or suffer long-term. However, if an early and accurate prediction of ensuing cGvHD is posiible, then the high risk patients can be identified and treated preemptively.In the present investigation, we retrospectively analyzed the transcriptome of immunity related genes at one month post-transplant with the aim to identify a potential early and accurate predictor of clinically significant cGvHD.

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Background:

Background:

Background:Treatment of Chronic lymphocytic leukemia (CLL) depends on stage of disease, age, functional status, comorbidities and presence of cytogenetic abnormalities such as (del17p mutation). Ibrutinib was initially approved in CLL given its better response in del17p patients as compared to the standard chemo immunotherapy. Since initial approval, Ibrutinib has also been evaluated in del17p negative CLL patients. Aim of our study is to discuss the efficacy of ibrutinib based regimen in CLL.

Background

Background- Acute myeloid leukemia (AML) in elderly patients (>65 years) is associated with poor prognosis with median overall survival (mOS) of 6 months. Hypomethylating agents (Azacytidine (Aza) and Decitabine) are used in elderly patients who are not candidates for intensive chemotherapy. Aza has resulted in complete remission/complete remission with incomplete hematologic recovery (CR/CRi) of 18-27.8% and mOS of 10.4-24.5 months. Decitabine resulted in CR/CRi of 18-47% and mOS of 7.7-8 months. We conducted a systemic review to assess survival benefit of novel combination drug regimens (CDR) involving hypomethylating agent (HMA) in elderly patients with newly diagnosed AML.

Introduction:

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Background:

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BACKGROUND:Recipientsof allogeneic HCT remain vulnerable to a heightened risk of reactivation of otherwise latent viral infections owing to a compromised immune system early after transplantation. Uncontrolled reactivation of Epstein-Barr virus (EBV) leading to post-transplant lymphoproliferative disorder (PTLD) is one of such major complications after T-cell depleted HCT. Recovering within weeks after transplantation and being first in line of defense against viral infections, natural killer (NK) cells are deemed important in the immunopathogenesis of EBV complications. Their role however remains elusive. NK cell responses are regulated by a series of activating and inhibitory cell surface receptors, central to which are the Killer Immunoglobulin-like Receptors (KIR). Through these receptors NK cells discriminate healthy cells from 'altered' self-cells by scaling the perturbations in HLA expression after viral transformation of the target cell. Here, we set out to determine whether and how KIR gene and motifs' content of HCT donors and/or recipients influences the development of PTLD after allo-HCT.

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Introduction:

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for malignant and non-malignant hematological disorders. Unfortunately, complications of HCT, primarily graft versus host disease (GVHD) and relapse of the underlying disease are substantial. In Alberta, all HCTs are performed with antithymocyte globulin conditioning and >95% of these use HLA matched donors. However, in spite of that approximately 35% Albertan HCT recipients die or suffer long-term from GVHD while another 20% die due to disease relapse. Unfortunately, strategies/treatments aiming to control GVHD in most cases lead to increase in the rate of disease relapse and infections. In the recent years, the natural killer (NK) cell genetic system has garnered substantial research interest as an immunogenetic system that significantly influences HCT outcomes. The complexity of NK cell function is modulated by a series of activating and inhibitory cell surface receptors known as the Killer Immunoglobulin-like Receptors (KIR). Here we set out to determine the influence of KIR matching between HCT donor and recipient pairs on allogenic HCT complications.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for malignant and non-malignant hematological disorders. Unfortunately, complications of HCT, primarily graft versus host disease (GVHD) and relapse of the underlying disease are substantial. In Alberta, all HCTs are performed with antithymocyte globulin conditioning and >95% of these use HLA matched donors. However, in spite of that approximately 35% Albertan HCT recipients die or suffer long-term from GVHD while another 20% die due to disease relapse. Unfortunately, strategies/treatments aiming to control GVHD in most cases lead to increase in the rate of disease relapse and infections. In the recent years, the natural killer (NK) cell genetic system has garnered substantial research interest as an immunogenetic system that significantly influences HCT outcomes. The complexity of NK cell function is modulated by a series of activating and inhibitory cell surface receptors known as the Killer Immunoglobulin-like Receptors (KIR). Here we set out to determine the influence of KIR matching between HCT donor and recipient pairs on allogenic HCT complications.Hypothesizing that donor-recipient KIR gene/profile mismatch would affect the allo-HCT outcomes, we genotyped 92 (discovery cohort) and 111 (validation cohort) allo-HCT pairs by Luminex-based rSSO method. The KIR genotypes were classified into AA and Bx genotypes on the basis of KIR gene constitution of the individual. Donor (D) and recipients (R) were ‘matched' for KIR genotypes when both carried either AA (two copies of group A haplotypes) or B/x (at least one copy of group B haplotype) genotypes. Effect of KIR matching on significant GVHD (described as grade 2-4 acute GVHD or chronic GVHD needing systemic therapy) as well as disease relapse was analyzed using binomial regression and Kaplan-Meier statistics.As observed in both the discovery and validation cohorts, a significant protection against GVHD was conferred upon when both the donor and recipient were matched for the KIR genotypes (HR=2.224; p=0.01) without any effect on disease relapse (HR=1.098; p=0.934) (figure1).In spite of D-R matching for major immunogenetic determinants like HLA, complications of allogeneic HCT are significant. Since GVHD represents a flip side to graft-vs-leukemia (GVL) reaction, strategies to decrease GVHD in most cases have resulted in increased relapse. Matching donor and recipients for KIR genotypes can offer a significant protection against GVHD without increasing the risk of disease relapse.No relevant conflicts of interest to declare.

Women with a history of VTE, thrombophilia or both are at increased risk for VTE during pregnancy, but the optimal management strategy, and the need for thromboprophylaxis is not well defined in clinical guidelines because of limited trial data. The EThIG (Efficacy of Thromboprophylaxis as an Intervention during Gravidity) is a multicenter trial that prospectively enrolled 810 pregnant women at risk of VTE. Women were assigned to one of 3 management strategies: Low risk group I (including women with prior secondary VTE, or asymptomatic thrombophilia) with “watchful waiting” management, and dalteparin prophylaxis postpartum (50–100 IU/kg), or earlier if additional risk factors occurred; high risk group II (e.g. idiopathic VTE or symptomatic thrombophilia) receiving 50–100 IU/kg dalteparin; and very high-risk group III (e.g. acute VTE, prior long-term OAC, symptomatic AT-deficiency or antiphospholipid syndrome), receiving 100–200 IU/kg dalteparin. Primary efficacy outcome measure was symptomatic VTE, main safety outcome measures were haemorrhages, osteoporosis, thromboctopenia and pregnancy outcome. Results (mean ± SD / 95% CI): 810 women (age 30.8±5.4 years, weight 73.6±16.1kg) were enrolled, 28 % in group I, 58 % in II and 14% in III, including 66 women with acute VTE. 60.1% had prior VTE, 75.4% had thrombophilia (42.1 % FV-Leiden, 2.1 % homozygous, 9.5 % FII G20210A, 4.1% PC-, 1 % AT-deficiency; 17.4 % APS). 35.8 % had previous miscarriage, still birth or physical malformation. Comorbid conditions included lupus erythematosus, liver transplantation, ventricular septum defect, paraplegia, hepatitis C, nephrotic syndrome, asthma, chronic haemolytic anaemia, thalassaemia, osteoporosis and thrombocytopaenia. Median treatment initiation was at 17.0 weeks, at 24.0 weeks in group I, 14.5 weeks in group II and 16.0 weeks for group III. Mean daily dose was 66.2 ± 22.5 IU per kg (group I), 76.8 ± 24.1 IU per kg (group II) and 120.0 ± 49.1 IU per kg (group III). Objectively confirmed, symptomatic VTE occurred in 5 of 810 women (0.6%;0.2–1.5%). The rate of serious bleeding was 3.0% (1.9–4.4%), 0.9% (0.3–1.8%) occurred in the antepartum period, 2.1% (1.3–3.4%) peri-partum;1.1% (0.5–2.2%) was possibly heparin-related. There was no evidence of heparin-induced thrombocytopenia, and one case of osteoporosis (fracture of the saccygous bone during delivery). There were 94.4% successful pregnancies, 40 foetuses (4.9%; 3.6–6.7%) were lost due to miscarriage, 7 due to elective termination. Risk-stratified heparin prophylaxis was associated with a low incidence of symptomatic venous thromboembolism and few clinically important adverse events. Antepartum heparin prophylaxis is warranted in pregnant women with prior idiopathic thrombosis or symptomatic thrombophilia.

Women with a history of VTE, thrombophilia or both are at increased risk for VTE during pregnancy, but the optimal management strategy, and the need for thromboprophylaxis is not well defined in clinical guidelines because of limited trial data. The EThIG (Efficacy of Thromboprophylaxis as an Intervention during Gravidity) is a multicenter trial that prospectively enrolled 810 pregnant women at risk of VTE. Women were assigned to one of 3 management strategies: Low risk group I (including women with prior secondary VTE, or asymptomatic thrombophilia) with “watchful waiting” management, and dalteparin prophylaxis postpartum (50–100 IU/kg), or earlier if additional risk factors occurred; high risk group II (e.g. idiopathic VTE or symptomatic thrombophilia) receiving 50–100 IU/kg dalteparin; and very high-risk group III (e.g. acute VTE, prior long-term OAC, symptomatic AT-deficiency or antiphospholipid syndrome), receiving 100–200 IU/kg dalteparin. Primary efficacy outcome measure was symptomatic VTE, main safety outcome measures were haemorrhages, osteoporosis, thromboctopenia and pregnancy outcome.