Revised diagnostic criteria for myeloid neoplasms (MN) issued by the International Consensus Classification (ICC) and the World Health Organization (WHO) recommended major change pertaining to TP53-mutated (TP53mut) MN. However, these assertions have not been specifically examined in therapy-related myeloid neoplasm (t-MN), a subset enriched with TP53mut. We analyzed 488 t-MN patients for TP53mut. At least one TP53mut with variant allele frequency (VAF) ≥ 2% with or without loss of TP53 locus was noted in 182 (37.3%) patients and 88.2% of TP53mut t-MN had a VAF ≥10%. TP53mut t-MN with VAF ≥ 10% had a distinct clinical and biological profile compared to both TP53mut VAF < 10% and wild-type TP53 (TP53wt) cases. Notably, TP53mut VAF ≥ 10% had a significantly shorter survival compared to TP53wt (8.3 vs. 21.6 months; P < 0.001), while the survival of TP53mut VAF < 10% was comparable to TP53wt. Within TP53mut VAF ≥ 10% cohort, the inferior outcomes persisted irrespective of the single- or multi-hit status, co-mutation pattern, or treatments received. Finally, survival of TP53mut patients was poor across all the blast categories and MDS patients with >10% blasts had inferior survival compared to <5%. In summary, TP53mut VAF ≥10% signified a clinically and molecularly homogenous cohort regardless of the allelic status.

1527 Background: The epidermal growth factor receptor (EGFR) pathway is commonly deregulated in GBMs and its activity has been associated with treatment resistance in preclinical models. Accordingly, the Radiation Therapy Oncology Group (RTOG) recently conducted a Phase I/II study of Gefitinib, an EGFR tyrosine kinase inhibitor, in combination with radiotherapy for newly-diagnosed glioblastoma (GBM) patients. Methods: 178 GBM patients were entered on RTOG 0211 (Phase I: 31 patients and Phase II: 147 patients). The maximum tolerated dose (MTD) of Gefitinib was determined to be 500mg in non-EIACD patients, and the Phase II component of RTOG 0211 was continued at this dose level during radiation and as maintenance for 18 months afterward or until disease progression. Results: 119/147 patients completed treatment per protocol and/or with acceptable deviation. The median survival time for all patients in the study was 11.0 months. Progression-free survival was 5.1 months for all patients. When considering only patients who were treated per protocol, the median survival of RTOG 0211 patients was 11.5 months, compared to 11.0 months for historical controls treated in previous RTOG studies (p=0.14). RPA Class IV patients appeared to derive the greatest benefit from Gefitinib when combined with radiotherapy compared to historical controls, although not reaching statistical significance. Molecular and genetic profiling efforts are underway to determine which GBM patients derive greatest benefit from Gefitinib in the upfront setting, which will be reported at the time of the annual meeting. These include markers such as EGFRvIII and PTEN, which have been recently reported to be associated with response to anti-EGFR agents in the recurrent setting, and members of key signal transduction pathways regulated by EGFR. Conclusions: The observed survival advantage of newly-diagnosed GBM patients treated with Gefitinib in combination with radiotherapy compared to historical controls treated on previous RTOG studies does not reach statistical significance. Molecular and genetic profiling efforts are underway to identify subsets of GBM patients who might derive the greatest benefit from Gefitinib in the upfront setting. No significant financial relationships to disclose.