Molecular annotation of extramedullary acute myeloid leukemia identifies high prevalence of targetable mutations

Abstract

BACKGROUND: Genomic landscape of extramedullary acute myeloid leukemia (EM-AML), including myeloid sarcoma (MS) and leukemia cutis (LC), is not well characterized. The potential utility of next-generation sequencing (NGS) using EM tissue is not established. METHODS:In this multicenter retrospective study, clinical and NGS data were collected on patients with EM-AML. All statistical analyses were performed in SPSS Statistics (v 26). RESULTS: Our study included 58 patients with EM-AML. The median age at diagnosis was 62 years; 59% of patients had MS and 33% had LC. EM-AML was isolated (i.e., without blood or marrow involvement) in 31% and was first noted at relapse in 60% of patients. Median overall survival in our cohort was 18.2 months overall, with 19.1 months and 11.6 months in the newly diagnosed and the relapsed/refractory patients, respectively. At least one targetable or potentially targetable alteration was present in 52% of patients with EM-site NGS, with 26% IDH1, 21% NPM1, 11% IDH2, 6% FLT3, and 13% KMT2A-PTD. Mutations in IDH1 were significantly more prevalent on NGS from EM tissue than non-EM (blood or marrow) samples (26% vs. 3%; p = .030). Three of four patients treated with IDH inhibitors based on EM-site NGS experienced a complete response. CONCLUSIONS: Targetable mutations are frequent in EM-AML and EM-site NGS is warranted for selecting potential targeted therapies for patients with EM-AML..

A case of relapsed acute myeloid leukemia mimicking acute otomastoiditis

“…In line with this, a study by Ball et al. demonstrated a complete response in three out of four patients treated with IDH inhibitors based on on‐site next‐generation sequencing of the MS tumor 16 . Furthermore, significant discordance has been observed between the molecular profiles of the myeloid sarcoma tumors and concurrent bone marrow disease 16,23 .…”

“…4,16 For instance, patients with leukemia cutis showed a significantly inferior overall survival when compared to other sites of disease (median of 5.7 months vs. 21.9 months, respectively). 16 Interestingly, rare areas of involvement, including the bones, may be associated with better survival rates. 4 Current management of AML involves standard multi-agent chemotherapy with the possible addition of targeted therapy based on risk stratification and mutational profiling.…”

“…Finally, when present, extramedullary disease is generally considered a negative prognostic factor 2,14,15 . Specifically, the site and pattern of leukemic involvement appear to be important for patient outcomes 4,16 . For instance, patients with leukemia cutis showed a significantly inferior overall survival when compared to other sites of disease (median of 5.7 months vs. 21.9 months, respectively) 16 .…”

“…However, genetic events underlying extramedullary disease are still not well understood and remain controversial 15 . Potentially targetable mutations commonly encountered in AML have been associated with extramedullary disease in several recent next‐generation sequencing (NGS) studies 15,16 . In line with this, a study by Ball et al.…”

Acute Myeloid Leukemia with NPM1 Mutation and Disseminated Leukemia Cutis: Achievement of Molecular Complete Remission by Venetoclax/Azacitidine Combination in a Very Old Patient

“…Although successful response to azacitidine in an older AML patient with LC has been reported [5] and also very elderly individuals with AML may be suitable for hypomethylating agents [6], the prognosis remains dismal [3, 4]. Recently, longer overall survival and higher rates of remission have been reported in patients with AML ineligible for ICT after treatment with azacitidine plus venetoclax (AZA-VEN) compared to those treated with azacitidine alone [7] and an increasing number of specific agents are available for those presenting targetable mutations [8]. Therefore, this treatment combination currently represents the first option for AML patients unsuitable for ICT [4].…”