Ozer, Byram H.

Abstract Background Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the DNA methylation signature of classical PXA but with a wider histologic spectrum, including overlap with glioblastoma (GBM). Methods To clarify the histologic and molecular scope of mcPXA and characterize its clinical behavior, a cohort of 469 tumor samples from 458 patients matching to mcPXA by the DKFZ classifier (v12.6 score ≥0.85) was interrogated. Results Patient median age was 23 years (range 1-73 years) with a female predominance (259 female/199 male). CDKN2A/B homozygous deletion was observed in 406 of 469 (87%) samples. In samples tested for BRAF p.V600E mutations (n = 279), 240 (86%) harbored the mutation. A chr7+/chr10− pattern was observed in 103 of 469 (22%) samples. Among samples tested for TERT promoter mutations (n = 143), 32 (22%) harbored the mutation. Progression-free and overall survival of patients with mcPXA were comparable to patients with methylation class IDH-mutant astrocytoma, low grade, but a GBM-like subset (ie, cases with a pre-methylation working diagnosis of GBM) showed shorter survival. Histologic features of high grade, including palisading necrosis and microvascular proliferation, were prognostic in mcPXA. Compared to patients with BRAF p.V600E-altered GBM, patients with mcPXA were younger and had a lower frequency of TERT promoter mutations. Conclusion Tumors in mcPXA share molecular characteristics with histologically defined PXA, and high-grade histologic features can help predict their clinical behavior. The use of an epigenetic classification of PXA reveals that this group of tumors is more common than previously appreciated and warrants in-depth study to identify efficacious therapeutic options.

Abstract BACKGROUND Preclinical studies have demonstrated that IDH1-mutant (IDHmt) gliomas harbor a BRCAness phenotype with a defect in homologous recombination that confers PARP inhibitor sensitivity. METHODS The phase II component of ABTC 1801 examined the efficacy of the combination of pamiparib (BeiGene BGB-290) with low dose metronomic temozolomide in recurrent IDHmt grade 2 and 3 gliomas. In this two-stage design, Arm A enrolled patients who had failed two lines and Arm B a single line of alkylator therapy. Pamiparib and temozolomide doses based on phase I results was 60 mg BID and 20 mg daily. Primary endpoint was objective response rate (ORR). RESULTS 39 patients (Arm A 15, Arm B 24) enrolled in the phase II. Median age was 45 (range: 25-69), 56% male, and median KPS 90. 72% of tumors were MGMT methylated. There were no confirmed responses in Arm A and one in Arm B; neither arm met the threshold for additional accrual. One-third of subjects discontinued treatment for reasons other than progressive disease. Estimated median PFS was 5.8 months in Arm A and 11.3 months in Arm B. Seven subjects (Arm A 3, Arm B 4) developed DLT during treatment. Grade 3+ toxicity was principally hematologic; 9 patients had grade 3 anemia, 7 grade 3 and 3 grade 4 neutropenia, and 3 grade 3 thrombocytopenia. In enhancing and non-enhancing tumors from 8 surgical arm patients, median unbound drug tumor/plasma ratios were 0.98 and 0.92, respectively; and median unbound pamiparib tumor concentrations were 209 and 188 nmol/L (or nmol/kg), respectively, which were >20-fold the in vitro IC50 for PARP inhibition. CONCLUSIONS While pamiparib appeared to achieve sufficient pharmacologically active concentrations in both enhancing and non-enhancing tumors, combination with temozolomide did not produce a meaningful ORR in IDHmt recurrent gliomas. Cumulative hematologic toxicity was substantial.