TY - JOUR
T1 - R-CHOP preceded by blood-brain barrier permeabilization with engineered tumor necrosis factor-a in primary CNS lymphoma
AU - Ferreri, Andrés J.M.
AU - Calimeri, Teresa
AU - Conte, Gian Marco
AU - Cattaneo, Dario
AU - Fallanca, Federico
AU - Ponzoni, Maurilio
AU - Scarano, Eloise
AU - Curnis, Flavio
AU - Nonis, Alessandro
AU - Lopedote, Paolo
AU - Citterio, Giovanni
AU - Politi, Letterio S.
AU - Foppoli, Marco
AU - Girlanda, Stefania
AU - Sassone, Marianna
AU - Perrone, Salvatore
AU - Cecchetti, Caterina
AU - Ciceri, Fabio
AU - Bordignon, Claudio
AU - Corti, Angelo
AU - Anzalone, Nicoletta
PY - 2019/7/18
Y1 - 2019/7/18
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.2019000633
DO - 10.1182/blood.2019000633
M3 - Article
C2 - 31118164
AN - SCOPUS:85070114482
VL - 134
SP - 252
EP - 262
JO - Blood
JF - Blood
SN - 0006-4971
IS - 3
ER -