Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with Nuclear factor kappa B (NF-κB). The role of BTK in primary CNS lymphoma (PCNSL) is unknown. We performed a Phase 1 clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS Lymphoma. Clinical responses to ibrutinib occurred in 10/13 (77%) PCNSL patients, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of Caspase Recruitment Domain Family Member 11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-Cell Antigen Receptor-associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with Phosphatidylinositol 3-kinase (PI3K)/mTOR activation markers. Inhibition of the PI3K-isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells.

• We conducted a phase-2 study in newly diagnosed PCNSL utilizing R-MPV and HDC with ASCT.• Excellent disease control and OS (2-year PFS: 79%) were observed, with an acceptable toxicity profile and minimal neurotoxicity.High-dose methotrexate-based chemotherapy is the mainstay of treatment of primary central nervous system lymphoma (PCNSL), but relapses remain frequent. High-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) may provide an alternative to address chemoresistance and overcome the blood-brain barrier. In this single-center phase-2 study, newly diagnosed PCNSL patients received 5 to 7 cycles of chemotherapy with rituximab, methotrexate (3.5 g/m 2 ), procarbazine, and vincristine (R-MPV). Those with a complete or partial response proceeded with consolidation HDC with thiotepa, cyclophosphamide, and busulfan, followed by ASCT and no radiotherapy. Primary end point was 1-year progression-free survival (PFS), N 5 32. Median age was 57, and median Karnofsky performance status 80. Following R-MPV, objective response rate was 97%, and 26 (81%) patients proceeded with HDC-ASCT. Among all patients, median PFS and overall survival (OS) were not reached (median follow-up: 45 months). Two-year PFS was 79% (95% confidence interval [CI], 58-90), with no events observed beyond 2 years. Two-year OS was 81% (95% CI, 63-91). In transplanted patients, 2-year PFS and OS were 81%. There were 3 treatment-related deaths. Prospective neuropsychological evaluations suggested relatively stable cognitive functions posttransplant. In conclusion, this treatment was associated with excellent disease control and survival, an acceptable toxicity profile, and no evidence of neurotoxicity thus far. This trial was registered at www.clinicaltrials.gov as NCT00596154. (Blood. 2015;125(9):1403-1410 IntroductionMore than 90% of patients with primary central nervous system lymphoma (PCNSL) display a diffuse large B-cell lymphoma (DLBCL) phenotypic subtype, but standard DLBCL regimens such as cyclophosphamide, doxorubicin, vincristine and prednisone and variations are ineffective in this disease.1,2 This has been explained by poor penetration of these agents across the blood-brain barrier (BBB), a problem that has been partially addressed with the development of high-dose methotrexate-based regimens (HD-MTX) that result in therapeutic central nervous system (CNS) and cerebrospinal fluid (CSF) levels after rapid infusions of 1.5 to 8 g/m 2 . 3-5 Such high methotrexate doses are made possible with the concomitant use of leucovorin, which prevents bone marrow and systemic organ damage, while limiting rescue of lymphoma cells in the CNS because it has poor BBB penetration. This clever strategy, used with or without wholebrain radiotherapy (WBRT), has resulted in remarkable survival improvements, with recent studies reporting median overall survival (OS) of 31 to 79 months, 6-13 as compared with 12 months observed with WBRT alone.14 In spite of these improvements, early and late relapses remain frequent, and the majority of pa...

Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.

Sunitinib is active in recurrent atypical/malignant meningioma patients. A randomized trial should be performed.