Purpose: Lower-grade gliomas (LGGs) are malignant tumors in young adults. Current therapy is associated with short-and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1/IDH2).Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes. Experimental Design:We conducted a multicenter, open-label, phase I, dose escalation study of vorasidenib in 93 patients with mutant IDH1/2 (mIDH1/2) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154.Results: Vorasidenib showed a favorable safety profile in the glioma cohort. Doselimiting toxicities of elevated transaminases occurred at doses >100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG (RANO-LGG) in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2-40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients.Research.

Between 11 and 37% of extranodal marginal zone lymphoma (EMZL) patients present with disease involvement in multiple mucosal sites (MMS). We analyzed 405 EMZL patients seen between 1995 and 2017: 265 (65.4%) patients presented with stage I disease, 49 of 309 (15.8%) patients with bone marrow involvement, and 35 of 328 (10.7%) patients with monoclonal gammopathy (MG). Forty-three (10.6%) patients had MMS presentation, which was more frequently seen in patients aged >60 years (55.8%). Five (17.9%) of 28 MMS patients had MG. MMS patients commonly exhibited the International Prognostic Index (IPI) >2 (79.1%), Follicular Lymphoma International Prognostic Index (FLIPI) >2 (39.5%), and Mucosa-Associated Lymphoid Tissue Lymphoma International Prognostic Index (MALT-IPI) 2-3 (60.5%). Both MMS presentation and MG were associated with shorter survival univariately. In multivariable Cox regression models, shorter progression-free survival (PFS) and overall survival (OS) were observed in patients with MMS (hazard ratio [HR] = 3.08 and 2.92, respectively), age ≥60 years (HR = 1.52 and 2.45, respectively), and in patients who failed to attain a complete remission following initial therapy (HR = 3.27 and 2.13, respectively). Elevated lactate dehydrogenase was associated with shorter PFS (HR = 1.92), while anemia (HR = 2.46) was associated with shortened OS. MALT-IPI ≥2 (HR = 2.47 and 4.75), FLIPI >2 (HR = 1.65 and 2.09), and IPI >2 (HR = 2.09 and 1.73) were associated with shorter PFS and OS, respectively. Higher grade transformation (HGT) occurred in 11 (25.6%) MMS patients with a 5-year cumulative incidence of 13.2% (95% CI 4.7-26.1%). EMZL patients with MMS presentation represent a novel clinical subset associated with shorter PFS, OS, and higher incidence of HGT that needs novel therapeutic approaches.

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Glioblastoma is the most common and aggressive primary brain tumor. Despite standard multimodality therapy, median overall survival remains poor with a 5-year survival rate of approximately 5% in most studies (range 4.7–13.0%). Strong interest in targeting IDH mutations has led to a variety of studies in both hematologic malignancies and solid tumors and to the approval of IDH inhibitors such as ivosidenib, an IDH1 inhibitor, in hematologic malignancies. Here, we present the first case study of a patient with a recurrent IDH1-mutant glioblastoma who experienced improved seizure control and radiographic stable disease for more than 4 years while treated with ivosidenib. Such findings support the further development of IDH inhibitors as single agents and/or in combination for the treatment of IDH-mutant glioma.

PURPOSE Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas. PATIENTS AND METHODS Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy. RESULTS Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events. CONCLUSION GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

Primary vitreoretinal lymphoma (PVRL) is a subset of primary CNS lymphoma that presents as isolated ocular disease without brain involvement. Although ocular radiotherapy (RT) is an effective treatment for PVRL, the optimal treatment is uncertain. PVRL may later involve the brain in 56%-85% of patients. We report on 12 PVRL patients treated with a combination of bilateral RT and a systemic chemotherapy (CT) regimen containing high-dose methotrexate (M). Ten received RT (30-40 Gy) followed by CT, one received RT, and one was treated with intravitreal M; all achieved a complete response (CR). Three patients had tumor recurrence in the brain and received CT and one patient relapsed in the eye with a second recurrence in the brain. Three patients achieved CR-2 remain alive and one died of dementia. One died from recurrent CNS disease. With a median follow of 68 months (range, 17-154 months), median progression-free and overall survival have not been reached. Bilateral RT followed by M-based CT is an effective treatment for reducing CNS progression and prolonging survival.

Extranodal marginal zone lymphoma (EMZL) is a heterogeneous disease with a subset of patients exhibiting a more aggressive course. We previously reported that EMZL with multiple mucosal sites (MMS) at diagnosis is characterized by shorter survival.To better recognize patients with different patterns of progression-free survival (PFS) we developed and validated a new prognostic index primarily based on patient's disease characteristics. We derived the "Revised mucosa-associated lymphoid tissue International Prognostic Index" (Revised MALT-IPI) in a large data set (n = 397) by identifying candidate variables that showed highest prognostic association with PFS.The revised MALT-IPI was validated in two independent cohorts, from the University of Iowa/Mayo Clinic (n = 297) and from IELSG-19 study (n = 400). A stepwise Cox regression analysis yielded a model including four independent predictors of shorter PFS. Revised MALT-IPI has scores ranging from 0 to 5, calculated as a sum of one point for each of the following-age >60 years, elevated LDH, and stage III-IV; and two points for MMS. In the training cohort, the Revised MALT-IPI defined four risk groups: low risk (score 0, reference group), low-medium risk (score 1, HR = 1.85, p = .008), medium-high risk (score 2, HR = 3.84, p < .0001), and high risk (score 3+, HR = 8.48, p < .0001). Performance of the Revised MALT-IPI was similar in external Juan Pablo Alderuccio and Isildinha M. Reis contributed equally to this work.