Disease Course and Treatment Patterns of Acute Myeloid Leukemia with FLT3 Mutations and Myeloid Sarcoma Reveal High Efficacy of Gilteritinib: A Multicentric Retrospective Study
Authors: Angotzi Francesco , Borlenghi Erika , Sartor Chiara , Giannini Maria Benedetta , Marconi Giovanni , Tamellini Edoardo , Turrini Mauro , Loscocco Federica , Audisio Ernesta , Federico Vincenzo , Vetro Calogero , Visentin Andrea , Gurrieri Carmela , Trentin Livio , Ferrara Felicetto , Lessi Federica 
Published: December 2024

Introduction
The proliferation of acute myeloid leukemia (AML) blasts in extramedullary tissues, termed myeloid sarcoma (MS), is observed in 2 - 10% of all patients with AML, and has a controversial prognostic impact. Since patients with MS are excluded from clinical trials and previous studies were conducted before the advent of targeted therapies for AML, little is known about the clinical course of patients with MS with targetable mutations such FMS-like tyrosine kinase 3 (FLT3), which are present in ~25% of patients and have been associated with a higher risk of developing MS.
Methods
We conducted a multicentric retrospective study across 9 Italian institutions including patients diagnosed with FLT3-mutated AML and histologically confirmed MS presenting concurrently with AML either at diagnosis or at disease relapse. Relevant information was extracted from health records. Variables were summarized by descriptive statistics and survival and univariate analyses performed according to the Kaplan Meier method and Cox proportional-hazards model.
Results
A total of 24 patients were included in the study, 13 (54%) females and 11 (46%) males, with a median age of 62 years (range: 30 - 81). MS presented at the time of AML diagnosis in 13 (54%) and at disease relapse after the first line of therapy in 11 (46%). Nineteen (79%) patients were FLT3-ITD and 5 (21%) a FLT3-TKD mutated, concurrent NPM1 mutations were identified in 16 (67%) and IDH 1/2 mutations in 4/14 (29%) patients tested. Four (17%) patients were classified as favorable, 18 (75%) as intermediate and 2 (8%) as adverse risk according to the 2022 ELN risk classification. The most common sites of MS localization were the skin in 14 (58%), and the central nervous system (CNS) in 9 (38%). Other localizations (one patient each) where the lower gastrointestinal (GI) tract, upper GI tract, ovary, mammary gland, muscle, and soft tissues. Only 3 (13%) patients had multiple concomitant MS localizations. At the first occurrence, MS was treated with chemotherapy (CT) in 10 (42%), CT + midostaurin in 4 (17%), gilteritinib in 8 (33%), and venetoclax + decitabine or upfront allogenic stem cell transplantation (allo-SCT) in 1 (4%) patient each. A total of 16 (68%) patients achieved a CR with complete regression of all MS, 3 (13%) a PR, whereas 5 (21%) were refractory. Among those achieving a CR, 8/16 (50%) eventually relapsed, but only 4/8 (50%) with recurring MS. Of the 8 patients who did not achieve a CR, 6 (75%) received further therapy: 3 with gilteritinib, 2 with venetoclax + azacitidine and 1 with chemotherapy.
With a median follow-up of 30.3 months, the median overall survival (OS) was 11.1 months (95% CI: 10.3 - NR) from the time of MS presentation. There was no difference in survival between patients presenting with MS at the time of AML diagnosis vs. those who developed MS at first relapse (median OS 11.1 vs. 10.7 months respectively; p = 0.5). Variables significantly associated with OS were CNS (HR: 3.4; 95% CI: 1.1 - 11.2; p = 0.04) or skin involvement (HR: 0.27; 95% CI: 0.1 - 0.9) and proceeding to alloSCT (HR: 0.10; 95%CI: 0.01 - 0.8).
Eighteen (75%) patients received treatment with FLT3 inhibitors (2 with midostaurin, 14 with gilteritinib and 2 with both). A non-statistically significant trend towards longer OS was observed for patients receiving a FLT3 inhibitor during any line of therapy (median OS 11.2 vs 9.9 months; HR: 0.6; 95% CI: 0.2 - 2.2), and this trend was even more pronounced for those treated with midostaurin as part of first line therapy (20 vs 10.7 months; p = 0.6). Gilteritinib was administered for a median of 5 cycles (range: 1 - 13) and resulted in a 69% CR rate with successful bridging of 4/16 (25%) patients to alloSCT. Out of 9 patients with CNS localization, 6 (67%) were treated with gilteritinib and 5/6 (83%) achieved a CR. Moreover, patient with CNS MS that were treated with gilteritinib achieved a trend towards longer median OS (11.1 vs 9.3 months; HR: 0.14; 94% CI: 0.01 - 1.4; p = 0.05), compared to those treated with CT.
Discussion
Patients with FLT3 mutated AML and MS generally experience a dismal prognosis. Although this analysis was limited by low numbers, FLT3 inhibitors are effective and may play a role in the treatment of FLT3-mutated MS, as demonstrated by the observed longer survival times and high response rates. Also encouraging, is the good activity of gilteritinib, even in “sanctuary” sites such as the CNS, and its possible role as a bridging therapy to allo-SCT.