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

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.

• Authors: 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 Corti, Nicoletta Anzalone
• Journal: Blood (Blood) Vol. 134 Issue 3 Pg. 252-262 (07 18 2019) ISSN: 1528-0020 [Electronic] United States
• PMID: 31118164 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 by The American Society of Hematology.

Chemical References

• Biomarkers
• R-CHOP protocol
• Recombinant Fusion Proteins
• Tumor Necrosis Factor-alpha
• tumor necrosis factor-alpha, CNGRC fusion protein, human
• Rituximab
• Vincristine
• Doxorubicin
• Cyclophosphamide
• CD13 Antigens
• Prednisone

Topics

• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Biomarkers
• Blood-Brain Barrier (diagnostic imaging, drug effects)
• CD13 Antigens (metabolism)
• Cell Membrane Permeability
• Central Nervous System Neoplasms (diagnosis, drug therapy, metabolism, mortality)
• Cyclophosphamide (adverse effects, therapeutic use)
• Doxorubicin (adverse effects, therapeutic use)
• Female
• Humans
• Immunohistochemistry
• Lymphoma, Non-Hodgkin (diagnosis, drug therapy, metabolism, mortality)
• Male
• Neuroimaging (methods)
• Prednisone (adverse effects, therapeutic use)
• Recombinant Fusion Proteins (administration & dosage, pharmacokinetics)
• Research Design
• Rituximab (adverse effects, therapeutic use)
• Tomography, Emission-Computed, Single-Photon
• Treatment Outcome
• Tumor Necrosis Factor-alpha (administration & dosage, pharmacokinetics)
• Vincristine (adverse effects, therapeutic use)