R‐CHOP PRECEDED BY ENGINEERED TUMOR NECROSIS FACTOR (TNF) IN RELAPSED OR REFRACTORY PRIMARY DIFFUSE LARGE B‐CELL LYMPHOMA OF THE CNS (rPCNSL): FINAL RESULTS OF THE INGRID TRIAL

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Background: Patients (pts) with PCNSL are usually treated with high-dose methotrexate-based combinations that are not currently used in other DLBCL and require hospitalization and extensive expertise to manage toxicity. The use of R-CHOP could overcome these difficulties, but CNS availability of related drugs is poor. TNF induces blood-brain barrier (BBB) permeabilization and enhances CNS access of anticancer drugs. Coupling TNF with NGR, a peptide that targets CD13+ tumor vessels, improves its biological effects. Thus, we tested the hypothesis that this conjugate (NGR-hTNF) can break the BBB, thereby improving CNS access and activity of R-CHOP in pts with rPCNSL enrolled in a phase II trial (NCT03536039). Herein, we report results of activity, safety and BBB permeabilization. Methods: HIV-neg adults with PCNSL failed after methotrexate-based chemo and measurable disease were enrolled and treated with 6 courses of R-CHOP21 preceded by NGR-hTNF (0.8 μg/m2). Overall response rate (ORR) was the primary endpoint. The two-stage Simon Minimax design was used; sample size estimated to demonstrate an improvement from 30% ORR to 50% was 28 pts. NGR-hTNF/RCHOP would be declared active if ≥12 responses were recorded. Secondary endpoints regarded changes induced by NGR-hTNF in vessel permeability, assessed by Dynamic Contrast Enhanced MRI (DCE-MRI) and 99mTc-DTPA-SPECT, and in anticancer drug levels in CSF and plasma, and CD13 expression on diagnostic tumor samples. Results: 28 pts (median age 58 yo, range 26-78; 14 males) were enrolled; 21 (75%) pts had intermediate-high IELSG score. Pts were heavily pretreated: 25 had received ASCT, WBRT or both; 15 had refractory disease. NGR-hTNF/RCHOP was active: the predetermined activity threshold (≥12 responses) was achieved, with confirmed tumor response in 21 pts (75%; 95%CI= 59-91), which was complete in 11. At a median follow-up of 12 (4-20) months, 8 pts remain relapse free and 9 are alive. Treatment was well tolerated; toxicities were quickly solved without dose reductions or interruptions. G4 toxicities were neutropenia (44% of courses), thrombocytopenia (20%), anemia (2%), and FN (1%). 15 SAE were recorded in 13 pts: seizures (3), DVT (2), infections (5), syncope (2), constipation, FN, and LVEF reduction. There were 7 g1-2 TNF infusion reactions. DCE-MRI and SPECT studies showed an increase of vascular permeability after NGR-hTNF infusion in tumor and perilesional areas. Specificity of this effect was suggested also by CD13 expression in all tumor samples, and by absence of changes in CSF/plasma drug levels after NGR-hTNF infusion. Conclusions: NGR-hTNF/RCHOP is active and safe in pts with rPCNSL. CD13, the target of TNF, was expressed in tumor tissue and, consistently, NGR-hTNF enhanced vascular permeability specifically in tumor and perilesional areas. This innovative approach deserves to be addressed as first-line treatment in PCNSL pts. Keywords: primary CNS lymphoma (PCNSL) R-CHOP

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