Impact of a 40-Gene Targeted Panel Test on Physician Decision Making for Patients With Acute Myeloid Leukemia

Abstract

PURPOSE Physicians treating hematologic malignancies increasingly order targeted sequencing panels to interrogate recurrently mutated genes. The precise impact of these panels on clinical decision making is not well understood. METHODS Here, we report our institutional experience with a targeted 40-gene panel (MyeloSeq) that is used to generate a report for both genetic variants and variant allele frequencies for the treating physician (the limit of mutation detection is approximately one AML cell in 50). RESULTS In total, 346 sequencing reports were generated for 325 patients with suspected hematologic malignancies over an 8-month period (August 2018 to April 2019). To determine the influence of genomic data on clinical care for patients with acute myeloid leukemia (AML), we analyzed 122 consecutive reports from 109 patients diagnosed with AML and surveyed the treating physicians with a standardized questionnaire. The panel was ordered most commonly at diagnosis (61.5%), but was also used to assess response to therapy (22.9%) and to detect suspected relapse (15.6%). The panel was ordered at multiple timepoints during the disease course for 11% of patients. Physicians self-reported that 50 of 114 sequencing reports (44%) influenced clinical care decisions in 44 individual patients. Influences were often nuanced and extended beyond identifying actionable genetic variants with US Food and Drug Administration–approved drugs. CONCLUSION This study provides insights into how physicians are currently using multigene panels capable of detecting relatively rare AML cells. The most influential way to integrate these tools into clinical practice will be to perform prospective clinical trials that assess patient outcomes in response to genomically driven interventions.

Hematopoietic cell transplantation donor-derived memory-like NK cells functionally persist after transfer into patients with leukemia

“…We performed deep [median 2538× coverage; variant allele fraction (VAF) limit of detection 0.06% or more stringent per mutation] error-corrected NGS of 40 genes recurrently mutated in AML ( 17 ) using baseline study screening PB samples to evaluate somatic mutations present pretreatment (fig. S2, A and B).…”

“…All patients underwent metaphase karyotyping and FISH for cytogenetic assessments plus targeted genotyping per institutional standard of care at the time of enrollment. Retrospective mutational assessment was performed using HaloPlex high-sensitivity (HS) amplicon sequencing (Agilent) targeting 40 genes mutated in AML ( 17 ). Genomic DNA (gDNA) was isolated from PBMCs using the DNeasy Blood & Tissue Kit (Qiagen, #69506) per the manufacturer’s protocols.…”

Clinical whole-genome sequencing identifies NSD3 as the correct fusion partner of NUP98 in a patient with acute myeloid leukemia and t(8;11)(p11.2;p15): a case report

“…Notably, this observation may have particular relevance in cases of AML or MDS when FISH is consistent with the presence of an FGFR1 rearrangement, which may in fact be an NSD3 rearrangement. More broadly, the application of genome sequencing may result in a more complete understanding of genetic underpinnings of each patient's disease, and thus allow clinicians the opportunity to more accurately risk stratify and tailor treatment strategies [10].…”

“…In addition to structural and copy number variations, both MyeloSeq (Methods S2) [10] and ChromoSeq assays (i.e., next generation targeted and wholegenome sequencing, respectively) also identi ed two premature stop codons in WT1 and STAG2 (Table 1); two genes with known implications in AML [11,12]. Both were classi ed as variants of uncertain clinical signi cance following standard guidelines provided by Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists [13].…”

Distinct clonal identities of B-ALLs arising after lenolidomide therapy for multiple myeloma

“…The targeted panel sequencing was performed as previously described. 30 Briefly, amplicon capture-based enrichment with unique molecular identifiers were employed. Variants were identified using a sequencing and annotation pipeline and reports were generated for physician review.…”