R-CHOP preceded by blood-brain barrier permeabilization with engineered tumor necrosis factor-α in primary CNS lymphoma
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Le résumé fourni par la source
Abstract 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-α 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 μg/m2) afterward. This trial included 2 phases: an “explorative phase” 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–single-photon emission computed tomography, and the expression of CD13 on tumor tissue; and an “expansion phase” with overall response rate as the primary end point, in which the 2-stage Simon Minimax design was used. At the first stage, if ≥4 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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- R-CHOP preceded by blood-brain barrier permeabilization with engineered tumor necrosis factor-α in primary CNS lymphoma
- Date Crossref
- 18/07/2019
- Éditeur
- American Society of Hematology
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Vita-Salute San Raffaele University pays non établi dans la noticeUniversité ou école supérieure
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Istituti di Ricovero e Cura a Carattere Scientifico pays non établi dans la noticeÉtablissement de santé
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Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele pays non établi dans la noticeÉtablissement de santé
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ASST Fatebenefratelli Sacco Unit of Clinical Pharmacology pays non établi dans la noticeÉtablissement de santé
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Target (United States) pays non établi dans la noticeEntreprise
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MolMed (Italy) pays non établi dans la noticeEntreprise
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Lymphoma Unit pays non établi dans la noticeInstitution
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IRCCS San Raffaele Scientific Institute Neuroradiology Unit pays non établi dans la noticeStructure de recherche
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Pathology Unit pays non établi dans la noticeInstitution
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Università Vita-Salute San Raffaele pays non établi dans la noticeInstitution
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Datamanager and Study Coordinator Office pays non établi dans la noticeInstitution
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Division of Experimental Oncology pays non établi dans la noticeInstitution
Vita-Salute San Raffaele University, Istituti di Ricovero e Cura a Carattere Scientifico et Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.