Kooperativer Bibliotheksverbund

In: European Journal of Cancer, Elsevier BV, Vol. 82 ( 2017-09), p. 16-24

Type of Medium: Online Resource

ISSN: 0959-8049

URL: Article

DOI: 10.1016/j.ejca.2017.04.025

Language: English

Publisher: Elsevier BV

Publication Date: 2017

detail.hit.zdb_id: 1120460-6

detail.hit.zdb_id: 1468190-0

detail.hit.zdb_id: 82061-1

In: Blood, American Society of Hematology, Vol. 90, No. 2 ( 1997-07-15), p. 590-596

Abstract: Because of the recommendation to avoid the concomitant administration of growth factors and chemotherapy, there is only limited information on colony-stimulating factor (CSF ) therapy in acute lymphoblastic leukemia (ALL) induction protocols, in which cytotoxic drugs are administered in divided doses over a prolonged period of time, thus requiring a simultaneous administration of growth factors and chemotherapy. We conducted a prospective, randomized, controlled study to determine the safety and efficacy of granulocyte colony-stimulating factor (G-CSF; filgrastim) as an adjunct to phase I of induction chemotherapy for adult ALL. Patients (n = 53) were randomized to receive no growth factor or G-CSF (5 μg/kg/d subcutaneously) starting on day 2 of chemotherapy consisting of daunorubicin (45 mg/m2) and vincristine (1.5 mg/m2) on days 1, 8, 15, and 22; L-asparaginase (2500 U/m2) on days 1 through 14; and prednisone (60 mg/m2) on days 1 through 28. A total of 25 patients in the G-CSF group and 26 patients in the control arm fulfilled the inclusion criteria of the study. G-CSF markedly ameliorated neutropenia because the median proportion of days with neutropenia less than 1,000/μL was 29% in the G-CSF group as compared with 84% in the control arm (P 〈 .00005). The median time to reach absolute neutrophil counts (ANC) ≥ 1,000/μL was 16 days in G-CSF patients and 26 days in controls (P 〈 .001). More importantly, G-CSF significantly reduced the incidence of febrile neutropenia (12% v 42% in controls, P 〈 .05) and documented infections (40% v 77%, P 〈 .05). No significant differences were found with regard to requirements for red blood cell transfusions and platelet concentrates. A total of 24 of 25 (96%) patients in the G-CSF group and 20 of 25 (80%) evaluable control patients had complete remission after phase I of induction therapy. We conclude that G-CSF can be safely administered as an adjunct to induction therapy of ALL and is clinically beneficial by ameliorating neutropenia and reducing infectious complications.

Type of Medium: Online Resource

ISSN: 1528-0020 , 0006-4971

URL: Article

DOI: 10.1182/blood.V90.2.590.590_590_596

Language: English

Publisher: American Society of Hematology

Publication Date: 1997

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 90, No. 2 ( 1997-07-15), p. 590-596

Abstract: Because of the recommendation to avoid the concomitant administration of growth factors and chemotherapy, there is only limited information on colony-stimulating factor (CSF ) therapy in acute lymphoblastic leukemia (ALL) induction protocols, in which cytotoxic drugs are administered in divided doses over a prolonged period of time, thus requiring a simultaneous administration of growth factors and chemotherapy. We conducted a prospective, randomized, controlled study to determine the safety and efficacy of granulocyte colony-stimulating factor (G-CSF; filgrastim) as an adjunct to phase I of induction chemotherapy for adult ALL. Patients (n = 53) were randomized to receive no growth factor or G-CSF (5 μg/kg/d subcutaneously) starting on day 2 of chemotherapy consisting of daunorubicin (45 mg/m2) and vincristine (1.5 mg/m2) on days 1, 8, 15, and 22; L-asparaginase (2500 U/m2) on days 1 through 14; and prednisone (60 mg/m2) on days 1 through 28. A total of 25 patients in the G-CSF group and 26 patients in the control arm fulfilled the inclusion criteria of the study. G-CSF markedly ameliorated neutropenia because the median proportion of days with neutropenia less than 1,000/μL was 29% in the G-CSF group as compared with 84% in the control arm (P & lt; .00005). The median time to reach absolute neutrophil counts (ANC) ≥ 1,000/μL was 16 days in G-CSF patients and 26 days in controls (P & lt; .001). More importantly, G-CSF significantly reduced the incidence of febrile neutropenia (12% v 42% in controls, P & lt; .05) and documented infections (40% v 77%, P & lt; .05). No significant differences were found with regard to requirements for red blood cell transfusions and platelet concentrates. A total of 24 of 25 (96%) patients in the G-CSF group and 20 of 25 (80%) evaluable control patients had complete remission after phase I of induction therapy. We conclude that G-CSF can be safely administered as an adjunct to induction therapy of ALL and is clinically beneficial by ameliorating neutropenia and reducing infectious complications.

Type of Medium: Online Resource

ISSN: 1528-0020 , 0006-4971

URL: Article

DOI: 10.1182/blood.V90.2.590

Language: English

Publisher: American Society of Hematology

Publication Date: 1997

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2515-2515

Abstract: Background In the Phase III trial (AML-001; NCT01074047) that assessed azacitidine (AZA) vs conventional care regimens (CCR; intensive chemotherapy, low-dose cytarabine or best supportive care as preselected by the treating physician) in older patients (≥65 years) with newly diagnosed acute myeloid leukemia (AML) and 〉 30% bone marrow (BM) blasts, AZA was associated with a clinically meaningful improvement in overall survival (OS) vs CCR.1Patient registry data, if performed with adequate quality control, can complement and be of additional value to data generated in clinical trials. The Austrian Azacitidine Registry (AAR; NCT01595295) was initiated to gain a comprehensive view of the use, safety and efficacy of AZA in patients with AML in a 'real world' clinical practice setting.2,3 No formal exclusion criteria existed, as the aim was to include all AML patients treated with AZA, irrespective of age, comorbidities, and/or previous lines of treatment.2,3 Aims and methods The aim of this analysis was to assess the efficacy and safety of 1st -line AZA in patients with AML who were included in the AAR and who fulfilled the BM blast percentage and white blood cell (WBC) count entry criteria of the AML-001 trial (BM blasts 〉 30% and WBC 〈 15G/L). Outcomes of the subgroups of patients with poor-risk cytogenetics and with AML and myelodysplasia-related changes (AML-MRC) who received 1st -line AZA were also evaluated. Results A total of 95 patients were identified that fulfilled the BM blast percentage and WBC count entry criteria of the AML-001 trial (data cut-off June 19 2015). Apart from a higher proportion of AML-MRC and a lower proportion of AML-not otherwise specified (AML-NOS) within the AAR, baseline characteristics were comparable to those observed in AML-001 (i.e. age, BM blast percentage, gender, therapy-related AML, prior myelodysplastic syndrome (MDS), Eastern Cooperative Oncology Group Performance Status (ECOG PS), cytogenetic risk, transfusion dependence, hemoglobin level, WBC count, absolute neutrophil count, and platelet (PLT) count; Figure 1). Patient status at data cut-off, reasons for AZA discontinuation and treatment characteristics were also similar: median number of AZA cycles was 5 (1-51) and 6 (1-28) for the AAR and AML-001 trial, respectively (Figure 1). Patient outcome in terms of overall response according to International Working Group criteria4 (31.5 vs 29.0%), red blood cell (42.1 vs 38.5%) and PLT transfusion independence (34.5 vs 40.6%) did not differ significantly between the AAR and the AML-001 trial. Furthermore, median OS was highly concordant between the AAR and AML-001 overall (10.8 vs 10.4 months; Figure 2A) as well as for various patient subgroups: 12.2 vs 12.7 months for patients with AML-MRC (Figure 2B); 14.6 vs 14.1 months for patients with normal cytogenetics; 13.1 vs 13.0 months for patients with intermediate-risk cytogenetics; and 7.2 vs 6.4 months for patients with high-risk cytogenetics (Figure 2C). After 1 year, 47.4% of patients were still alive in the AAR cohort compared with 46.5% in the AML-001 trial (p=0.924). Event-free survival was 5.5 (range: 0-35.3) vs 6.7 (range: 5-8.8) months in the AAR and AML-001 trial, respectively. The 30-day (8.4 vs 6.6%; p=0.642) and 60-day (15.5 vs 16.2%; p=0.903) mortality rates were comparable. The incidence of febrile neutropenia (24.2 vs 28.0%) and Grade 3-4 treatment-emergent (TE) neutropenia were similar between the AAR and AML-001; however, higher rates of TE thrombocytopenia (47.4 vs 15.7%; p=0.023) and anemia (31.6 vs 26.3%; p 〈 0.001) were observed in the AAR. Conclusion These data confirm the safety and efficacy of AZA in a patient-population for whom this drug has not yet been approved, i.e. AML with more than 30% BM blasts and without leukocytosis. These data therefore complement prospective clinical trial data and support the role of well-designed and in-depth clinical registries. References 1. Dombret H, et al. Blood 2015;126:291-9 2. Pleyer L, et al. J Hematol Oncol 2013;6:32 3. Pleyer L, et al. Ann Hematol 2014;93:1825-38 4. Cheson BD, et al. J Clin Oncol 2003;21:4642-9 Disclosures Pleyer: Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AOP Orphan Pharmaceuticals: Honoraria. Off Label Use: Vidaza (azacitidine) is indicated for the treatment of adult AML patients who are not eligible for hematopoietic stem cell transplantation with 20-30% blasts and multi-lineage dysplasia, according to WHO classification. This cohort also includes AML patients with 〉 30% bone marrow blasts.. Burgstaller:Novartis: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Research Funding; Mundipharma: Honoraria. Girschikofsky:Mundipharma: Consultancy, Honoraria; Pfizer: Honoraria, Research Funding. Sill:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Thaler:AOP Orphan: Research Funding. Halter:Medical University Innsbruck: Employment. Zebisch:Celgene: Honoraria. Pichler:Celgene: Honoraria. Pfeilstöcker:Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Autzinger:Wilhelminenspital: Employment. Lang:Celgene: Consultancy. Geissler:Celgene: Membership on an entity's Board of Directors or advisory committees. Geissler:Klinikum Klagenfurt: Employment. Sperr:Ariad: Consultancy; Celgene: Consultancy. Hojas:LKH Fürstenfeld: Employment. Greil:Astra-Zeneca: Honoraria; Ratiopharm: Research Funding; GSK: Research Funding; Sanofi Aventis: Honoraria; Pfizer: Honoraria, Research Funding; Eisai: Honoraria; AOP Orphan: Research Funding; Novartis: Honoraria; Celgene: Consultancy; Merck: Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; Roche, Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Janssen-Cilag: Honoraria; Boehringer-Ingelheim: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.2515.2515

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 3742-3742

Abstract: Background Current response criteria for AML were established for and validated in younger patients (pts) fit for and treated with intensive chemotherapy (IC) in an era before hypomethylating agents (HMA) were available. According to these criteria: 1 Achievement of morphologic complete response (CR; defined as bone marrow blasts [BMB] 〈 5%, absolute neutrophil count 〉 1.0G/L, platelets ≥100G/L and red blood cell transfusion independence) is a prerequisite for cure, and is deemed the sole outcome associated with improved overall survival (OS)1 2 Pts without morphologic CR are considered non-responders1 3 Morphologic leukemia free state (MLFS; defined as 〈 5% BMB, irrespective of cytopenias) is considered inferior to CR 4 Hematologic improvement (HI) without BMB clearance is considered treatment failure1,2 However, evidence is accumulating that these definitions may not be applicable to older AML pts treated with HMA. For example, achievement of CR with HMA may not be necessary for clinical benefit and prolonged OS.3-5 We have previously shown that older AML pts achieving HI according to myelodysplastic syndrome (MDS) criteria6 have clinical benefit from extended azacitidine (AZA) treatment.3,4 In addition, treatment goals and modalities differ for HMA vs IC. Thus, the question arises whether current response criteria remain valid for older AML pts unfit for IC. Aims and methods To define new response criteria, including the 1st criteria for assessment of HI, for older AML pts unfit for IC with the intention of keeping them as simple to implement as possible. Human errors in response assessment according to these proposed criteria were excluded by the development of algorithms for automated computational calculation from data entered into the eCRF. We next assessed the supplementary value of HI in addition to BMB reduction, as well as the value of HI irrespective of BMB reduction, with regards to predicting treatment outcomes. Results In total, 193 AML pts receiving AZA 1st line were included in this analysis. Baseline and treatment characteristics were mostly comparable to those of AML pts included in a recent phase 3 clinical trial (Fig 1).7 Overall, 5 categories of HI and hematologic progression were defined, using: erythrocytes (E), platelets (P), neutrophils (N), peripheral blood blasts, and elevated white blood cells (Fig 2). We based our definitions on IWG 2006 MDS criteria and adapted these for the more aggressive disease biology and kinetics of AML, and treatment goals and modalities of HMA. Our data indicate that: 1 AML pts achieving HI (irrespective of BMB reduction) had significantly longer OS than those without HI (16.1 vs 6.0 mo, p 〈 0.001; Fig 3A) 2 OS was prolonged irrespective of the cell lineage in which HI occurred (17.1, 17.5 and 18.0 mo for pts with HI-N, HI-E or HI-P, respectively) 3 OS correlated with the number of cell lineages/types in which HI was achieved (6.0 vs 14.4 vs 19.7 mo [p 〈 0.001] for HI in 0 vs 1-2 vs 〉 2 lineages/types; Fig 3B) 4 Pts with MLFS did not have worse OS than pts with CR (Fig 3C) 5 Definition of response according to our proposed criteria resulted in clinically meaningful separation of 3 response types with significant differences in median OS: 23.0 (CR or MLFS) vs 13.5 (HI and not CR or MLFS) vs 4.4 mo (non-responders) (p 〈 0.001; Fig 3D) Conclusions While achievement of CR according to IWG 2003 criteria1 remains the primary goal for AML pts treated with IC, we guardedly introduce new response criteria for pts unfit for IC treated with non-curative treatment such as HMA. Applying these criteria to our large real world cohort, we show that pts achieving HI in the absence of BMB clearance (considered non-responders using current criteria)1, had a significant survival benefit from continued AZA treatment compared to pts with no HI. We conclude that these patients should be considered as responders and kept on treatment, and hypothesize that achievement of HI could be used as a surrogate parameter for response in pts unable or unwilling to undergo BM biopsy for response assessment. This proposal requires concerted validation efforts and we hope that our data stimulate cooperations. References 1 Cheson BD JCO 2003;21:4642 2 Lopez G Blood 2001;98:329;abs 1388 3 Pleyer L J Hematol Oncol 2013;6:32 4 Pleyer L Ann Hematol 2014;93:1825 5 Schuh AC Haematologica 2015;100:abs P575 6 Cheson BD Blood 2006;108:419 7 Dombret H Blood 2015;126:291 Disclosures Pleyer: AOP Orphan Pharmaceuticals: Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Off Label Use: Vidaza (azacitidine) is indicated for the treatment of adult AML patients who are not eligible for hematopoietic stem cell transplantation with 20-30% blasts and multi-lineage dysplasia, according to WHO classification. This cohort also includes AML patients with 〉 30% bone marrow blasts.. Burgstaller:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Mundipharma: Honoraria; AOP Orphan Pharmaceuticals: Honoraria, Research Funding. Girschikofsky:Pfizer: Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria. Sill:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Thaler:AOP Orphan: Research Funding. Halter:Medical University Innsbruck: Employment. Zebisch:Celgene: Honoraria. Pichler:Celgene: Honoraria. Pfeilstöcker:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Autzinger:Wilhelminenspital: Employment. Lang:Celgene: Consultancy. Geissler:Celgene: Membership on an entity's Board of Directors or advisory committees. Geissler:Klinikum Klagenfurt: Employment. Sperr:Celgene: Consultancy; Ariad: Consultancy. Hojas:LKH Fürstenfeld: Employment. Greil:Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Astra-Zeneca: Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; Ratiopharm: Research Funding; GSK: Research Funding; Sanofi Aventis: Honoraria; Novartis: Honoraria; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria; AOP Orphan: Research Funding; Roche, Celgene: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.3742.3742

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Acta Radiologica, SAGE Publications, Vol. 36, No. 3 ( 1995-05), p. 243-247

Abstract: The purpose of this study was to evaluate MR angiography (MRA) and color Doppler sonography as noninvasive screening methods in suspected renovascular hypertension. Fifty-five consecutive patients with arterial hypertension were examined prospectively using high resolution 3-D TOF MRA and color Doppler sonography. Intraarterial angiography was the standard of reference. Stenoses of 60% or more were regarded as significant. MR angiograms were evaluated by 3 independent observers who studied 110 main renal arteries. All 8 significant stenoses and 2 occlusions were correctly classified with MRA while one 60% stenosis was underestimated by color Doppler sonography. Mild stenoses were overestimated by MRA in 4 and by color Doppler sonography in 6 cases. A drawback of both methods was the large number of not evaluable arteries (6 in MRA, 11 in color Doppler sonography). These arteries were regarded as pathologic because stenosis could not be excluded. Due to this fact specificities of MRA and color Doppler sonography were 90% and 85% respectively. Accessory vessels were detected in 47% (8/17) by MRA and in 0% (0/17) by color Doppler sonography.

Type of Medium: Online Resource

ISSN: 0284-1851 , 1600-0455

URL: Article

DOI: 10.1177/028418519503600306

Language: English

Publisher: SAGE Publications

Publication Date: 1995

detail.hit.zdb_id: 2024579-8

In: Clinical and Experimental Immunology, Oxford University Press (OUP), Vol. 147, No. 1 ( 2006-11-27), p. 106-111

Abstract: Kawasaki disease is an acute febrile syndrome in infancy, characterized by vasculitis of medium-sized arteries. Without treatment the disease can lead to coronary artery lesions (CAL) in approximately 25% of the children. Therapy consists of intravenous immunoglobulins (IVIG), leading to a decrease of complications to 5–16%. Little is known about the working mechanisms of IVIG. In this study we evaluated the involvement of Fcγ receptors (FcγRs) in Kawasaki disease by the determination of the frequency of known single nucleotide polymorphisms (SNPs) in the genes coding for the FcγRs and compared this with frequencies in a cohort of healthy controls. There was no difference in the distribution of the functionally relevant genotypes for FcγRIIa-131H/R, FcγRIIb-232I/T, FcγRIIIa-158 V/F and FcγRIIIb-NA1/NA2 between the patient group and the healthy controls. Furthermore, there were no polymorphisms linked to the disease severity as indicated by the absence or development of CAL during the disease. Altered transcription or expression of FcγR on specific cell types of the immune system may still play a role in susceptibility and treatment success, but at a level different from the functional SNPs in FcγR genes tested in this study.

Type of Medium: Online Resource

ISSN: 1365-2249 , 0009-9104

URL: Article

DOI: 10.1111/j.1365-2249.2006.03266.x

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2006

detail.hit.zdb_id: 2020024-9

In: Gastrointestinal Endoscopy, Elsevier BV, Vol. 81, No. 5 ( 2015-05), p. AB310-AB311

Type of Medium: Online Resource

ISSN: 0016-5107

URL: Article

DOI: 10.1016/j.gie.2015.03.472

Language: English

Publisher: Elsevier BV

Publication Date: 2015

detail.hit.zdb_id: 2006253-9

In: The Journal of Pathology, Wiley, Vol. 257, No. 5 ( 2022-08), p. 687-696

Abstract: Giant cell tumour of bone (GCTB) comprises the eponymous osteoclastic multinucleated giant cells eliciting bone lysis, an H3F3A ‐mutated neoplastic mononucleated fibroblast‐like cell population, and H3F3A wild‐type mononucleated stromal cells. In this study, we characterised four new cell lines from GCTB. Furthermore, we compared the genome‐wide DNA methylation profile of 13 such tumours and three further cell lines with giant cell‐rich lesions comprising three H3F3B ‐mutated chondroblastomas, three USP6‐ rearranged aneurysmal bone cysts, three non‐ossifying fibromas, two hyperparathyroidism‐associated brown tumours as well as mesenchymal stem cells, osteoblasts, and osteoclasts. In an unsupervised analysis, we delineated GCTB and chondroblastomas from the other analysed tumour entities. Using comparative methylation analysis, we demonstrated that the methylation pattern of the cell lines approximately equals that of H3F3A ‐mutated stromal cells in tissue. These patterns more resemble that of osteoblasts than that of mesenchymal stem cells, which argues for the osteoblast as the cell of origin of giant cell tumours of bone. Using enrichment analysis, we detected distinct hypermethylated clusters containing histone and collagen genes as well as target genes of the tumour suppressor p53. We found that the promotor regions of CDKN1A , CDKN2A , and IGFBP3 are methylated more strongly in GCTB than in the other giant cell‐containing lesions, mesenchymal stem cells, osteoblasts, and osteoclasts ( p   〈  0.001). This hypermethylation correlates with the lower gene expression at the mRNA level for these three genes in the cell lines, the lack of p16 and p21 in these cell lines, and the lower expression of p16 and p21 in GCTB. Overall, our analysis reveals characteristic DNA methylation patterns of giant cell tumours of bone and chondroblastomas and shows that cell lines of giant cell tumours of bone are a valid model for further analysis of H3F3A ‐mutated tumour cells. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Type of Medium: Online Resource

ISSN: 0022-3417 , 1096-9896

URL: Issue

URL: Article

DOI: 10.1002/path.v257.5

DOI: 10.1002/path.5925

Language: English

Publisher: Wiley

Publication Date: 2022

detail.hit.zdb_id: 1475280-3

In: European Journal of Immunology, Wiley, Vol. 48, No. 2 ( 2018-02), p. 344-354

Abstract: The efficacy of cancer therapeutic antibodies varies considerably among patients. Anti‐cancer antibodies act through different mechanisms, including antibody‐dependent cellular cytotoxicity (ADCC) triggered via Fcγ receptors (FcγR). This phagocyte ADCC can be promoted by interference with CD47‐SIRPα interactions, but the magnitude of this enhancement also varies among individuals. Both FcγR and SIRPα display considerable genetic variation, and we investigated whether this explains some of the variability in ADCC. Because of linkage disequilibrium between FcγR variants the interpretation of previous reports suggesting a potential link between FcγR polymorphisms and ADCC has been troublesome. We performed an integrated genetic analysis that enables stratification. ADCC by activated human neutrophils towards Trastuzumab‐coated breast cancer cells was predominantly dependent on FcγRIIa. Neutrophils from individuals with the FcγRIIa‐131H polymorphic variant displayed significantly higher killing capacity relative to those with FcγRIIa‐131R. Furthermore, ADCC was consistently enhanced by targeting CD47‐SIRPα interactions, and there were no significant functional differences between the two most prevalent SIRPα polymorphic variants. Thus, neutrophil ADCC capacity is directly related to the FcγRIIa polymorphism, and targeting CD47‐SIRPα interactions enhances ADCC independently of FcγR and SIRPα genotype, thereby further suggesting that CD47‐SIRPα interference might be a generic strategy for potentiating the efficacy of antibody therapy in cancer.

Type of Medium: Online Resource

ISSN: 0014-2980 , 1521-4141

URL: Issue

URL: Article

DOI: 10.1002/eji.v48.2

DOI: 10.1002/eji.201747215

Language: English

Publisher: Wiley

Publication Date: 2018

detail.hit.zdb_id: 1491907-2