R-CHOP preceded by blood-brain barrier permeabilization with engineered tumor necrosis factor-a in primary CNS lymphoma

Andrés J.M. Ferreri, Teresa Calimeri, Gian Marco Conte, Dario Cattaneo, Federico Fallanca, Maurilio Ponzoni, Eloise Scarano, Flavio Curnis, Alessandro Nonis, Paolo Lopedote, Giovanni Citterio, Letterio S. Politi, Marco Foppoli, Stefania Girlanda, Marianna Sassone, Salvatore Perrone, Caterina Cecchetti, Fabio Ciceri, Claudio Bordignon, Angelo CortiNicoletta Anzalone

Research output: Contribution to journalArticle

Abstract

Patients with primary central nervous system lymphoma (PCNSL) are treated with highdose 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 contrastenhanced magnetic resonance imaging and 99mTc-diethylene-triamine-pentacetic acid-singlephotonemission 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 5 12). CD13 was expressed in tumor vessels of all cases. NGR-hTNF selectively increased vascular permeability in tumoral/peritumoral areas, without interferingwith drug plasma/cerebrospinal fluid concentrations. TheNGR-hTNF/R-CHOP combination was well tolerated: therewere only 2 serious adverse events, and grade 4 toxicitywas 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.

Original languageEnglish
Pages (from-to)252-262
Number of pages11
JournalBlood
Volume134
Issue number3
DOIs
Publication statusPublished - Jul 18 2019

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Ferreri, A. J. M., Calimeri, T., Conte, G. M., Cattaneo, D., Fallanca, F., Ponzoni, M., Scarano, E., Curnis, F., Nonis, A., Lopedote, P., Citterio, G., Politi, L. S., Foppoli, M., Girlanda, S., Sassone, M., Perrone, S., Cecchetti, C., Ciceri, F., Bordignon, C., ... Anzalone, N. (2019). R-CHOP preceded by blood-brain barrier permeabilization with engineered tumor necrosis factor-a in primary CNS lymphoma. Blood, 134(3), 252-262. https://doi.org/10.1182/blood.2019000633