NGS May Play an Important Role in Helping Select Targeted Therapies in Extramedullary AML

Frequent targetable mutations in patients with extramedullary acute myeloid leukemia lends credence to the use of next-generation sequencing to determine the optimal targeted therapy approach.

Next-generation sequencing (NGS) could play a valuable role in selecting targeted therapies for patients with extramedullary acute myeloid leukemia (EM-AML) after investigators identified a high rate of targetable mutations in the population, according to a study published in Cancer.

In 19 patients who had available EM NGS data, 52% had at least 1 targetable mutation, with common variants including IDH1 (26%), MPM1 (21%), KMT2A-PTD (13%), IDH2 (11%), and FLT3 (6%). EM site NGS turned up a higher proportion of IDH1 mutations with NGS compared with non-EM site samples (26% vs 3%; P = .030).

A total of 58 patients with EM-AML were identified, 45 of whom were included in the clinical cohort of participating centers, including Moffitt Cancer Center (n = 19), Memorial Healthcare System (n = 12), and University of Miami (n = 14). Moreover, 13 patients had NGS data available that was obtained from a commercial laboratory. In those from the clinical cohort underwent all analyses, and the NGS cohort were added for frequencies of EM manifestations and mutations.

Thirty-one percent of patients had isolated EM-AML. EM disease was diagnosed in 40% of newly diagnosed patients and at relapsed in 60%. The median age was 62 years. Moreover, 56% of patients were male and 78% were White. Patients were distributed into favorable (29%), intermediate (33%), and adverse (38%) European Leukemia Network 2017 risk stratification prognostic groups. Patients with myeloid sarcoma had the most significant EM manifestation at 59% along with leukemia cutis in 33%.

Overall, the median overall survival (OS) was 18.2 months, with 19.1 months in those with newly diagnosed disease, and 11.6 months in those with relapsed/refractory disease. First-line intensive chemotherapy was administered in 58% of patients. OS did not change significantly based on bone marrow involvement or intensive induction chemotherapy use. The median OS was 21.9 months vs 18.2 months for those with isolated EM and concurrent medullary and EM, respectively (P = .17). Additionally, if patients had intensive induction chemotherapy, the OS was 18.2 months compared with 26.6 months for those who did not (P = .48).

NGS samples using EM tissue were taken from 40% of patients, 52% used bone marrow, and 8% used blood as the source of NGS testing. Of note, the most common mutations were NPM1 (25%), NRAS (23%), DNMT3A (21%), TET2 (15%), FLT3 (14%), IDH1 (13%), SRSF2 (13%), and IDH2 (10%). Thirty-three percent of samples tested that were non-EM and checked for KMT2A-PTD were found to have an alteration.

In patients with an IDH2 mutation, treatment with ivosidenib (Tibsovo) led to a complete response (CR) in 2 of 3 patients, and 1 patient treated enasidenib (Idhifa) had a CR. The median duration of response was 15 months, and the estimated median OS was 26.6 months in patients who responded to anti-IDH therapy. Another CR was noted in a patient treated with ivosidenib who was found to have isolated leukemia cutis during relapse following hematopoietic stem cell transplant. This patient continued treatment for 18 months with no EM recurrence or systemic relapse at study cut-off.


Ball S, Knepper TC, Deutsch YE, et al. Molecular annotation of extramedullary acute myeloid leukemia identifies high prevalence of targetable mutations. Cancer. Published online September 15, 2022. doi:10.1002/cncr.34459