{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T21:23:28Z","timestamp":1781731408664,"version":"3.54.5"},"reference-count":36,"publisher":"American Society of Hematology","issue":"3","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,7,18]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Patients with primary central nervous system lymphoma (PCNSL) are treated with high-dose methotrexate-based chemotherapy, which requires hospitalization and extensive expertise to manage related toxicity. The use of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could overcome these difficulties, but blood-brain barrier (BBB) penetration of related drugs is poor. Tumor necrosis factor-\u03b1 coupled with NGR (NGR-hTNF), a peptide targeting CD13+ vessels, induces endothelial permeabilization and improves tumor access of cytostatics. We tested the hypothesis that NGR-hTNF can break the BBB, thereby improving penetration and activity of R-CHOP in patients with relapsed\/refractory PCNSL (NCT03536039). Patients received six R-CHOP21 courses, alone at the first course and preceded by NGR-hTNF (0.8 \u03bcg\/m2) afterward. This trial included 2 phases: an \u201cexplorative phase\u201d addressing the effect of NGR-hTNF on drug pharmacokinetic parameters and on vessel permeability, assessed by dynamic contrast-enhanced magnetic resonance imaging and 99mTc-diethylene-triamine-pentacetic acid\u2013single-photon emission computed tomography, and the expression of CD13 on tumor tissue; and an \u201cexpansion phase\u201d with overall response rate as the primary end point, in which the 2-stage Simon Minimax design was used. At the first stage, if \u22654 responses were observed among 12 patients, the study accrual would have continued (sample size, 28). Herein, we report results of the explorative phase and the first-stage analysis (n = 12). CD13 was expressed in tumor vessels of all cases. NGR-hTNF selectively increased vascular permeability in tumoral\/peritumoral areas, without interfering with drug plasma\/cerebrospinal fluid concentrations. The NGR-hTNF\/R-CHOP combination was well tolerated: there were only 2 serious adverse events, and grade 4 toxicity was almost exclusively hematological, which were resolved without dose reductions or interruptions. NGR-hTNF\/R-CHOP was active, with 9 confirmed responses (75%; 95% confidence interval, 51-99), 8 of which were complete. In conclusion, NGR-hTNF\/R-CHOP was safe in these heavily pretreated patients. NGR-hTNF enhanced vascular permeability specifically in tumoral\/peritumoral areas, which resulted in fast and sustained responses.<\/jats:p>","DOI":"10.1182\/blood.2019000633","type":"journal-article","created":{"date-parts":[[2019,5,22]],"date-time":"2019-05-22T18:06:04Z","timestamp":1558548364000},"page":"252-262","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":49,"title":["R-CHOP preceded by blood-brain barrier permeabilization with engineered tumor necrosis factor-\u03b1 in primary CNS lymphoma"],"prefix":"10.1182","volume":"134","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9606-6124","authenticated-orcid":false,"given":"Andr\u00e9s J. M.","family":"Ferreri","sequence":"first","affiliation":[{"name":"Lymphoma Unit, Department of Onco-Hematology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0833-4761","authenticated-orcid":false,"given":"Teresa","family":"Calimeri","sequence":"additional","affiliation":[{"name":"Lymphoma Unit, Department of Onco-Hematology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5926-7517","authenticated-orcid":false,"given":"Gian Marco","family":"Conte","sequence":"additional","affiliation":[{"name":"Neuroradiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1512-6530","authenticated-orcid":false,"given":"Dario","family":"Cattaneo","sequence":"additional","affiliation":[{"name":"Unit of Clinical Pharmacology, Department of Laboratory Medicine, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Fallanca","sequence":"additional","affiliation":[{"name":"Nuclear Medicine Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurilio","family":"Ponzoni","sequence":"additional","affiliation":[{"name":"Universit\u00e0 Vita-Salute San Raffaele, Milan, Italy;"},{"name":"Pathology Unit,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eloise","family":"Scarano","sequence":"additional","affiliation":[{"name":"Datamanager and Study Coordinator Office, Lymphoma Unit,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7231-9569","authenticated-orcid":false,"given":"Flavio","family":"Curnis","sequence":"additional","affiliation":[{"name":"Division of Experimental Oncology, Tumor Biology and Vascular Targeting Unit, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Nonis","sequence":"additional","affiliation":[{"name":"Universit\u00e0 Vita-Salute San Raffaele, Milan, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Lopedote","sequence":"additional","affiliation":[{"name":"Universit\u00e0 Vita-Salute San Raffaele, Milan, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Citterio","sequence":"additional","affiliation":[{"name":"Lymphoma Unit, Department of Onco-Hematology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6190-6688","authenticated-orcid":false,"given":"Letterio S.","family":"Politi","sequence":"additional","affiliation":[{"name":"Neuroradiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Foppoli","sequence":"additional","affiliation":[{"name":"Lymphoma Unit, Department of Onco-Hematology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Girlanda","sequence":"additional","affiliation":[{"name":"Hematology and BMT Unit, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Sassone","sequence":"additional","affiliation":[{"name":"Lymphoma Unit, Department of Onco-Hematology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8196-0481","authenticated-orcid":false,"given":"Salvatore","family":"Perrone","sequence":"additional","affiliation":[{"name":"Lymphoma Unit, Department of Onco-Hematology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3461-4049","authenticated-orcid":false,"given":"Caterina","family":"Cecchetti","sequence":"additional","affiliation":[{"name":"Lymphoma Unit, Department of Onco-Hematology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Ciceri","sequence":"additional","affiliation":[{"name":"Universit\u00e0 Vita-Salute San Raffaele, Milan, Italy;"},{"name":"Hematology and BMT Unit, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Bordignon","sequence":"additional","affiliation":[{"name":"MolMed SpA, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0893-6191","authenticated-orcid":false,"given":"Angelo","family":"Corti","sequence":"additional","affiliation":[{"name":"Universit\u00e0 Vita-Salute San Raffaele, Milan, Italy;"},{"name":"Division of Experimental Oncology, Tumor Biology and Vascular Targeting Unit, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4249-2723","authenticated-orcid":false,"given":"Nicoletta","family":"Anzalone","sequence":"additional","affiliation":[{"name":"Neuroradiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy;"},{"name":"Universit\u00e0 Vita-Salute San Raffaele, Milan, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2020021108430359700_B1","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1182\/asheducation-2016.1.379","article-title":"Primary central nervous system lymphoma","volume":"2016","author":"Batchelor","year":"2016","journal-title":"Hematology Am Soc Hematol Educ Program"},{"issue":"12","key":"2020021108430359700_B2","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1038\/leu.2011.169","article-title":"Modern concepts in the biology, diagnosis, differential diagnosis and treatment of primary central nervous system lymphoma","volume":"25","author":"Deckert","year":"2011","journal-title":"Leukemia"},{"key":"2020021108430359700_B3","volume-title":"WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues","author":"Kluin","year":"2017"},{"key":"2020021108430359700_B4","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1182\/asheducation-2017.1.565","article-title":"Therapy of primary CNS lymphoma: role of intensity, radiation, and novel agents","volume":"2017","author":"Ferreri","year":"2017","journal-title":"Hematology Am Soc Hematol Educ Program"},{"issue":"6","key":"2020021108430359700_B5","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1002\/1097-0142(20000915)89:6<1359::AID-CNCR21>3.0.CO;2-9","article-title":"A medical research council randomized trial in patients with primary cerebral non-Hodgkin lymphoma: cerebral radiotherapy with and without cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy","volume":"89","author":"Mead","year":"2000","journal-title":"Cancer"},{"issue":"7","key":"2020021108430359700_B6","doi-asserted-by":"crossref","first-page":"e322","DOI":"10.1016\/S1470-2045(15)00076-5","article-title":"Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology","volume":"16","author":"Hoang-Xuan","year":"2015","journal-title":"Lancet Oncol"},{"issue":"21","key":"2020021108430359700_B7","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1093\/jnci\/djt276","article-title":"Selective permeabilization of the blood-brain barrier at sites of metastasis","volume":"105","author":"Connell","year":"2013","journal-title":"J Natl Cancer Inst"},{"issue":"6","key":"2020021108430359700_B8","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s40259-013-0048-z","article-title":"Peptide-mediated targeting of cytokines to tumor vasculature: the NGR-hTNF example","volume":"27","author":"Corti","year":"2013","journal-title":"BioDrugs"},{"issue":"1","key":"2020021108430359700_B9","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1369\/jhc.2010.956644","article-title":"Enhanced expression of CD13 in vessels of inflammatory and neoplastic tissues","volume":"59","author":"Di Matteo","year":"2011","journal-title":"J Histochem Cytochem"},{"issue":"11","key":"2020021108430359700_B10","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1038\/81183","article-title":"Enhancement of tumor necrosis factor alpha antitumor immunotherapeutic properties by targeted delivery to aminopeptidase N (CD13)","volume":"18","author":"Curnis","year":"2000","journal-title":"Nat Biotechnol"},{"issue":"3","key":"2020021108430359700_B11","first-page":"867","article-title":"Differential binding of drugs containing the NGR motif to CD13 isoforms in tumor vessels, epithelia, and myeloid cells","volume":"62","author":"Curnis","year":"2002","journal-title":"Cancer Res"},{"issue":"4","key":"2020021108430359700_B12","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1172\/JCI0215223","article-title":"Improving chemotherapeutic drug penetration in tumors by vascular targeting and barrier alteration","volume":"110","author":"Curnis","year":"2002","journal-title":"J Clin Invest"},{"issue":"1","key":"2020021108430359700_B13","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s10637-005-4540-2","article-title":"Effects of the tumor vasculature targeting agent NGR-TNF on the tumor microenvironment in murine lymphomas","volume":"24","author":"van Laarhoven","year":"2006","journal-title":"Invest New Drugs"},{"issue":"1","key":"2020021108430359700_B14","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1158\/1078-0432.CCR-05-1147","article-title":"Synergistic antitumor activity of cisplatin, paclitaxel, and gemcitabine with tumor vasculature-targeted tumor necrosis factor-alpha","volume":"12","author":"Sacchi","year":"2006","journal-title":"Clin Cancer Res"},{"issue":"6","key":"2020021108430359700_B15","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/S1470-2045(18)30193-1","article-title":"NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial","volume":"19","author":"Gregorc","year":"2018","journal-title":"Lancet Oncol"},{"key":"2020021108430359700_B16","first-page":"240","article-title":"WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues","author":"Kluin","year":"2008"},{"issue":"2","key":"2020021108430359700_B17","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1200\/JCO.2003.09.139","article-title":"Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience","volume":"21","author":"Ferreri","year":"2003","journal-title":"J Clin Oncol"},{"issue":"3","key":"2020021108430359700_B18","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/S1053-4296(03)00031-6","article-title":"CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment","volume":"13","author":"Trotti","year":"2003","journal-title":"Semin Radiat Oncol"},{"issue":"22","key":"2020021108430359700_B19","doi-asserted-by":"crossref","first-page":"5034","DOI":"10.1200\/JCO.2005.13.524","article-title":"Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma","volume":"23","author":"Abrey","year":"2005","journal-title":"J Clin Oncol"},{"issue":"3","key":"2020021108430359700_B20","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1148\/radiol.2017170362","article-title":"Brain gliomas: multicenter standardized assessment of dynamic contrast-enhanced and dynamic susceptibility contrast MR images","volume":"287","author":"Anzalone","year":"2018","journal-title":"Radiology"},{"issue":"1-2","key":"2020021108430359700_B21","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.jchromb.2007.02.033","article-title":"Simultaneous analysis of cyclophosphamide, doxorubicin and doxorubicinol by liquid chromatography coupled to tandem mass spectrometry","volume":"852","author":"DiFrancesco","year":"2007","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci"},{"issue":"6","key":"2020021108430359700_B22","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/sj.bjc.6603660","article-title":"Temozolomide as salvage treatment in primary brain lymphomas","volume":"96","author":"Reni","year":"2007","journal-title":"Br J Cancer"},{"issue":"3","key":"2020021108430359700_B23","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1002\/hon.2037","article-title":"Salvage chemoimmunotherapy with rituximab, ifosfamide and etoposide (R-IE regimen) in patients with primary CNS lymphoma relapsed or refractory to high-dose methotrexate-based chemotherapy","volume":"31","author":"Mappa","year":"2013","journal-title":"Hematol Oncol"},{"issue":"6","key":"2020021108430359700_B24","doi-asserted-by":"crossref","first-page":"826","DOI":"10.4161\/mabs.26008","article-title":"Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics","volume":"5","author":"Golay","year":"2013","journal-title":"MAbs"},{"issue":"6","key":"2020021108430359700_B25","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.4049\/jimmunol.1101877","article-title":"Targeting TNF-\u03b1 to neoangiogenic vessels enhances lymphocyte infiltration in tumors and increases the therapeutic potential of immunotherapy","volume":"188","author":"Calcinotto","year":"2012","journal-title":"J Immunol"},{"issue":"25","key":"2020021108430359700_B26","doi-asserted-by":"crossref","first-page":"18542","DOI":"10.1016\/S0021-9258(17)46661-0","article-title":"Ligand passing: the 75-kDa tumor necrosis factor (TNF) receptor recruits TNF for signaling by the 55-kDa TNF receptor","volume":"268","author":"Tartaglia","year":"1993","journal-title":"J Biol Chem"},{"issue":"4","key":"2020021108430359700_B27","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1158\/1078-0432.CCR-09-1621","article-title":"Phase I clinical and magnetic resonance imaging study of the vascular agent NGR-hTNF in patients with advanced cancers (European Organization for Research and Treatment of Cancer Study 16041)","volume":"16","author":"van Laarhoven","year":"2010","journal-title":"Clin Cancer Res"},{"issue":"15","key":"2020021108430359700_B28","doi-asserted-by":"crossref","first-page":"2604","DOI":"10.1200\/JCO.2009.27.3649","article-title":"Phase II study of asparagine-glycine-arginine-human tumor necrosis factor alpha, a selective vascular targeting agent, in previously treated patients with malignant pleural mesothelioma","volume":"28","author":"Gregorc","year":"2010","journal-title":"J Clin Oncol"},{"issue":"2","key":"2020021108430359700_B29","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/sj.bjc.6605162","article-title":"Phase Ib study of NGR-hTNF, a selective vascular targeting agent, administered at low doses in combination with doxorubicin to patients with advanced solid tumours","volume":"101","author":"Gregorc","year":"2009","journal-title":"Br J Cancer"},{"issue":"3","key":"2020021108430359700_B30","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/S0360-3016(98)00450-7","article-title":"Primary central nervous system non-Hodgkin\u2019s lymphoma (PCNSL): survival advantages with combined initial therapy? A final report of the North Central Cancer Treatment Group (NCCTG) Study 86-72-52","volume":"43","author":"O\u2019Neill","year":"1999","journal-title":"Int J Radiat Oncol Biol Phys"},{"issue":"2","key":"2020021108430359700_B31","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.ijrobp.2010.06.002","article-title":"CHOD\/BVAM chemotherapy and whole-brain radiotherapy for newly diagnosed primary central nervous system lymphoma","volume":"81","author":"Laack","year":"2011","journal-title":"Int J Radiat Oncol Biol Phys"},{"issue":"2","key":"2020021108430359700_B32","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1200\/JCO.1996.14.2.556","article-title":"Preirradiation chemotherapy with cyclophosphamide, doxorubicin, vincristine, and dexamethasone for primary CNS lymphomas: initial report of radiation therapy oncology group protocol 88-06","volume":"14","author":"Schultz","year":"1996","journal-title":"J Clin Oncol"},{"issue":"17","key":"2020021108430359700_B33","doi-asserted-by":"crossref","first-page":"3986","DOI":"10.1158\/1078-0432.CCR-14-2116","article-title":"Genome-wide analysis uncovers novel recurrent alterations in primary central nervous system lymphomas","volume":"21","author":"Braggio","year":"2015","journal-title":"Clin Cancer Res"},{"issue":"3","key":"2020021108430359700_B34","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/leu.2014.264","article-title":"The mutational pattern of primary lymphoma of the central nervous system determined by whole-exome sequencing","volume":"29","author":"Vater","year":"2015","journal-title":"Leukemia"},{"issue":"7","key":"2020021108430359700_B35","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1182\/blood-2015-10-673236","article-title":"Targetable genetic features of primary testicular and primary central nervous system lymphomas","volume":"127","author":"Chapuy","year":"2016","journal-title":"Blood"},{"issue":"20","key":"2020021108430359700_B36","doi-asserted-by":"crossref","first-page":"2766","DOI":"10.1200\/JCO.2010.31.4187","article-title":"First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximab-CHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial","volume":"29","author":"Vitolo","year":"2011","journal-title":"J Clin Oncol"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/134\/3\/252\/1557662\/bloodbld2019000633.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/134\/3\/252\/1557662\/bloodbld2019000633.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,18]],"date-time":"2022-09-18T12:20:42Z","timestamp":1663503642000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/134\/3\/252\/260716\/RCHOP-preceded-by-bloodbrain-barrier"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,18]]},"references-count":36,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2019,7,18]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2019000633","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,18]]}}}