Frequency of practice-changing findings identified by comprehensive genomic profiling in non-myeloid hematologic malignancies.

Abstract

3060 Background: Comprehensive genomic profiling (CGP) is increasingly used to guide management of myeloid and advanced solid malignancies, but its role in non-myeloid hematologic malignancies is less clear. Studies have found a high rate of potentially actionable variants by CGP in this population, but these do not always translate into clinical practice changes. We aimed to determine the rate at which variants found on CGP changed clinical practice. Methods: We retrospectively reviewed a cohort of 101 consecutive patients with non-myeloid hematologic malignancies at Duke, comprising a total of 105 samples that were sent for CGP by FoundationOne Heme (104) or HemeComplete (1) in 2014–2021. We identified variants of clinical significance and classified them by evidence level according to the AMP/ASCO/CAP 2017 guidelines (e.g., for therapies, level A: FDA-approved / in guidelines; B: expert consensus; C: clinical trial / FDA-approved in different tumor type; D: preclinical data). We further identified documented changes in clinical practice that occurred in direct response to CGP results. Results: Commonly cited reasons for CGP included guiding therapy selection (27), identifying resistance mutations (19), refining prognosis (14), and clarifying diagnosis (11). Of the 105 samples sent for sequencing, 92 (88%) yielded at least one pathogenic or likely pathogenic variant. CGP resulted after death in 12 patients and within 1 month of death in another 11 patients. Seventy-three out of 101 patients (72%) had at least one variant with therapy sensitizing, diagnostic, or prognostic significance (levels A–C) or associated with therapy resistance (levels A/D). While 61 patients (60%) had a therapy sensitizing variant, only 6 patients (10%) were offered a biomarker-directed therapy. In contrast, the presence of a resistance mutation led to discontinuation of current therapy or influenced future therapy selection in 9 of 13 patients (69%). The absence of a resistance mutation influenced choice of therapy in another 4 patients. Sequencing results also helped clarify a previously uncertain diagnosis in 4 patients and led to medical genetics referrals in 3 patients. Conclusions: Comprehensive genomic profiling of non-myeloid hematologic malignancies identified variants of clinical significance in 72% of patients and led to changes in practice in 22% of patients. CGP was often sent late in the clinical course. [Table: see text]