Thrombocytopenia is a serious issue for all patients with classical Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) because it causes severe and life-threatening bleeding. ...Lentiviral gene therapy (GT) for WAS has shown promising results in terms of immune reconstitution. However, despite the reduced severity and frequency of bleeding events, platelet counts remain low in GT-treated patients.
We carefully investigated platelet defects in terms of phenotype and function in untreated patients with WAS and assessed the effect of GT treatment on platelet dysfunction.
We analyzed a cohort of 20 patients with WAS/XLT, 15 of them receiving GT. Platelet phenotype and function were analyzed by using electron microscopy, flow cytometry, and an aggregation assay. Platelet protein composition was assessed before and after GT by means of proteomic profile analysis.
We show that platelets from untreated patients with WAS have reduced size, abnormal ultrastructure, and a hyperactivated phenotype at steady state, whereas activation and aggregation responses to agonists are decreased. GT restores platelet size and function early after treatment and reduces the hyperactivated phenotype proportionally to WAS protein expression and length of follow-up.
Our study highlights the coexistence of morphologic and multiple functional defects in platelets lacking WAS protein and demonstrates that GT normalizes the platelet proteomic profile with consequent restoration of platelet ultrastructure and phenotype, which might explain the observed reduction of bleeding episodes after GT. These results are instrumental also from the perspective of a future clinical trial in patients with XLT only presenting with microthrombocytopenia.
Summary
Recent multi‐stage genome‐wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) that are robustly associated with chronic lymphocytic leukaemia (CLL) risk. ...Given that most of these SNPs map to non‐coding regions of the genome, it suggests that the functional basis of many GWAS signals will be through differential gene expression. By referencing publically accessible expression quantitative trait loci (eQTL) data on lymphoblastoid cells lines (LCLs) we have globally demonstrated an association between GWAS P‐values and eQTLs, consistent with much of the variation in CLL risk being defined by variants impacting on gene expression. To explore using eQTL data to select GWAS SNPs for replication, we genotyped rs2072135 (GWAS P‐value = 0·0024, eQTL P‐value = 1·510−19) in five independent case‐control series totalling 1968 cases and 3538 controls. While not attaining statistical significance (combined P‐value = 1 × 10−4), rs2072135 defines a promising risk locus for CLL. Incorporating eQTL information offers an attractive strategy for selecting SNPs from GWAS for validation.
Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34
cell gene therapy (GT) following busulfan reduced-intensity ...conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34
cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4-15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34
cells infused and younger age at GT affected positively the plateau of CD3
transduced cells, lymphocytes and CD4
CD45RA
naive T cells, whereas the cell dose positively influenced the final plateau of CD15
transduced cells. These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT03478670 .
Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional ...loci with similar effect sizes, we conducted a meta-analysis of two GWA studies, comprising 13,315 individuals genotyped for 38,710 common tagging SNPs. We undertook replication testing in up to eight independent case-control series comprising 27,418 subjects. We identified four previously unreported CRC risk loci at 14q22.2 (rs4444235, BMP4; P = 8.1 x 10(-10)), 16q22.1 (rs9929218, CDH1; P = 1.2 x 10(-8)), 19q13.1 (rs10411210, RHPN2; P = 4.6 x 10(-9)) and 20p12.3 (rs961253; P = 2.0 x 10(-10)). These findings underscore the value of large sample series for discovery and follow-up of genetic variants contributing to the etiology of CRC.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
To identify new risk variants for chronic lymphocytic leukemia (CLL), we conducted a genome-wide association study of 299,983 tagging SNPs, with validation in four additional series totaling 2,503 ...cases and 5,789 controls. We identified four new risk loci for CLL at 2q37.3 (rs757978, FARP2; odds ratio (OR) = 1.39; P = 2.11 × 10−9), 8q24.21 (rs2456449; OR = 1.26; P = 7.84 × 10−10), 15q21.3 (rs7169431; OR = 1.36; P = 4.74 × 10−7) and 16q24.1 (rs305061; OR = 1.22; P = 3.60 × 10−7). We also found evidence for risk loci at 15q25.2 (rs783540, CPEB1; OR = 1.18; P = 3.67 × 10−6) and 18q21.1 (rs1036935; OR = 1.22; P = 2.28 × 10−6). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We conducted a genome-wide association study of 299,983 tagging SNPs for chronic lymphocytic leukemia (CLL) and performed validation in two additional series totaling 1,529 cases and 3,115 controls. ...We identified six previously unreported CLL risk loci at 2q13 (rs17483466; P = 2.36 × 10−10), 2q37.1 (rs13397985, SP140; P = 5.40 × 10−10), 6p25.3 (rs872071, IRF4; P = 1.91 × 10−20), 11q24.1 (rs735665; P = 3.78 × 10−12), 15q23 (rs7176508; P = 4.54 × 10−12) and 19q13.32 (rs11083846, PRKD2; P = 3.96 × 10−9). These data provide the first evidence for the existence of common, low-penetrance susceptibility to a hematological malignancy and new insights into disease causation in CLL.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Introduction: In the CLL11 study, obinutuzumab (G) plus chlorambucil (Clb; G-Clb) significantly improved outcomes relative to rituximab plus Clb and Clb alone in previously untreated patients (pts) ...with chronic lymphocytic leukemia (CLL) and comorbidities, but was associated with an increased incidence and severity of infusion-related reactions (IRRs), cytopenias and treatment discontinuations (Goede et al. N Engl J Med 2014; Goede et al. EHA 2018). IRRs have been associated with the release of pro-inflammatory cytokines, including interleukin-6 (IL-6; Freeman et al. Blood 2015). Tocilizumab (TCZ) is a monoclonal antibody that blocks downstream signaling by IL-6. It has regulatory approval (FDA/EMA) for the treatment of chimeric antigen receptor T-cell induced cytokine release syndrome, and could potentially be used to limit the IRRs associated with G administration. GALACTA was a randomized, double-blind, Phase Ib trial in previously untreated pts with CLL and co-morbidities (NCT02336048). Its primary objective was to determine the safety and tolerability of TCZ prior to G-Clb. Secondary endpoints included pharmacokinetics and pharmacodynamics of TCZ in this population, and impact on the efficacy of the G-CIb combination.
Methods: Previously untreated CLL pts who were unsuitable for more intensive therapy (CIRS score >6 or creatinine clearance <70mL/min) were randomized 2:1 to receive a single IV infusion of TCZ 8mg/kg or placebo (PLB) prior to G on day (D) 1 of cycle (C) 1 of G-Clb. Pts were stratified prior to randomization by absolute lymphocyte count (ALC; >50x109/L) and mean fluorescence intensity of CD20 on CLL-gated cells. G-CIb was administered as: G 1000mg IV on D1/D2 (100mg/900mg), D8 and D15 of C1, and D1 of C2-6; Clb 0.5mg/kg PO on D1 and D15 of C1-6. Prior to the first G dose in C1, standard premedication (antipyretic, antihistamine, corticosteroids) was administered in addition to TCZ or PLB. IRR was defined as any adverse event (AE) occurring during or within 24 hours of G infusion and judged by the investigator as related to G.
Results: A total of 38 pts were enrolled between June 26, 2015 and Jan 22, 2018; 25 were randomized to TCZ and 13 to PLB. Median age was 74 years (range 54-87), 63% were male, 95% had ECOG PS 0-1, and 95% had Binet stage B/C disease. Baseline characteristics were well balanced, with the exception of more males in the TCZ arm (72%) than the PLB arm (46%). Despite a similar proportion of baseline ALC ≤50 versus >50x109/L in the two treatment arms, more pts in the TCZ arm had levels which were >100x109/L (15% in PLB vs 28% in TCZ). At the time of analysis, 25 pts had completed all 6 cycles, 6 remained on treatment, and 7 had discontinued.
IRRs occurred in 18/25 (72%) pts in the TCZ arm and 10/13 (77%) in the PLB arm. Grade ≥3 IRRs occurred in 11/25 (44%) pts in the TCZ arm and 4/13 (31%) pts in the PLB arm. Four pts discontinued treatment due to IRRs: 3 (12%) in the TCZ arm and 1 (8%) in the PLB arm. Similar to previous reports, cytokine levels peaked on D1 after 100mg G had been administered. Serum amyloid A (Figure 1) and C-reactive protein (CRP) (Figure 2) were sub-optimally reduced in the TCZ arm. Of the 19 pts with measurable TCZ levels, no marked differences in exposure were seen based on IRR intensity. However, TCZ exposure was lower on average than in rheumatoid arthritis pts of equivalent weight treated with the same dose (mean Cmax 154 vs 193µg/mL), and TCZ-treated pts that developed IRRs had comparatively less suppression of CRP than those who did not.
Conclusions: Preliminary results suggest that use of a single 8mg/kg dose of TCZ prior to the first dose of G was feasible, but did not appear to prevent IRRs in this pt population. The study was primarily designed to assess the safety of the combination, and was underpowered to detect meaningful differences between groups in IRR severity. TCZ-treated pts who developed IRRs had higher baseline risk than those who did not, and the TCZ dose may have been insufficient, resulting in the lack of efficacy. Whether inhibition of this pro-survival cytokine enhances the cytotoxic potential of the regimen is not yet determined; updated results will be presented at the meeting.
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Freeman:Seattle Genetics: Honoraria; Abbvie: Honoraria. Böttcher:Celgene: Research Funding; Genentech: Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. De la Serna:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gobbi:Novartis: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Janssen: Consultancy; Pfister: Membership on an entity's Board of Directors or advisory committees. Di Bernardo:Roche: Employment. Mallalieu:Roche: Employment, Equity Ownership. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Knapp:Roche: Employment. Gribben:Janssen: Honoraria, Research Funding; Abbvie: Honoraria; Acerta Pharma: Honoraria, Research Funding; TG Therapeutics: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Medical Research Council: Research Funding; Novartis: Honoraria; Kite: Honoraria; Cancer Research UK: Research Funding; Pharmacyclics: Honoraria; Unum: Equity Ownership; Roche: Honoraria; Wellcome Trust: Research Funding; NIH: Research Funding.
To comprehensively evaluate the impact of recently identified colorectal cancer (CRC) variants at 1q41, 3q26.2, 8q23.3, 8q24.21, 10p14, 11q23.1, 12q13.13, 14q22.2, 15q13.3, 16q22.1, 18q21.1, ...19q13.11, 20p12.3, and 20q13.33 on risk and CRC phenotype, the authors analyzed 8,878 cases and 6,051 controls from the United Kingdom ascertained in 1999-2007. The impact of variants on the familial CRC risk was enumerated from age-, sex-, and calendar-specific CRC rates in the 50,924 first-degree relatives of cases. Each of the 14 susceptibility loci independently influences CRC with the risk increasing with increasing number of risk alleles carried (per allele odds ratio = 1.13; P = 2.99 × 10−58) and, for those within the upper quintile, there is a 2.3-fold increased risk. In first-degree relatives of cases with ≤17, 18-21, and ≥22 risk alleles, standardized incidence ratios were 1.76, 2.08, and 2.25, respectively. Although the discriminatory attributes of the 14 CRC susceptibility loci for individual risk prediction are poor (area under the curve = 0.58), they may allow subgroups of the population at different CRC risks to be distinguished.
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