Molecular profiling and clinical implications of patients with acute myeloid leukemia and extramedullary manifestations

Abstract

Background Extramedullary manifestations (EM) are rare in acute myeloid leukemia (AML) and their impact on clinical outcomes is controversially discussed. Methods We retrospectively analyzed a large multi-center cohort of 1583 newly diagnosed AML patients, of whom 225 (14.21%) had EM. Results AML patients with EM presented with significantly higher counts of white blood cells (p < 0.0001), peripheral blood blasts (p < 0.0001), bone marrow blasts (p = 0.019), and LDH (p < 0.0001). Regarding molecular genetics, EM AML was associated with mutations of NPM1 (OR: 1.66, p < 0.001), FLT3-ITD (OR: 1.72, p < 0.001) and PTPN11 (OR: 2.46, p < 0.001). With regard to clinical outcomes, EM AML patients were less likely to achieve complete remissions (OR: 0.62, p = 0.004), and had a higher early death rate (OR: 2.23, p = 0.003). Multivariable analysis revealed EM as an independent risk factor for reduced overall survival (hazard ratio [HR]: 1.43, p < 0.001), however, for patients who received allogeneic hematopoietic cell transplantation (HCT) survival did not differ. For patients bearing EM AML, multivariable analysis unveiled mutated TP53 and IKZF1 as independent risk factors for reduced event-free (HR: 4.45, p < 0.001, and HR: 2.05, p = 0.044, respectively) and overall survival (HR: 2.48, p = 0.026, and HR: 2.63, p = 0.008, respectively). Conclusion Our analysis represents one of the largest cohorts of EM AML and establishes key molecular markers linked to EM, providing new evidence that EM is associated with adverse risk in AML and may warrant allogeneic HCT in eligible patients with EM.

A case of relapsed acute myeloid leukemia mimicking acute otomastoiditis

“…Limited and challenging access to affected sites (including the most typical ones, such as liver and spleen) likely contributes to the underestimation in former reports, including cases involving the temporal bone. 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 .…”

“…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 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.…”

Sox13 and M2-like leukemia-associated macrophages contribute to endogenous IL-34 caused accelerated progression of acute myeloid leukemia

“…However, enhanced intracerebral invasion has not been observed possibly due to the blood brain barrier. Nevertheless, extramedullary infiltration of leukemia cells has long been observed and considered as a bad marker for leukemia patients [ 2 ]. Patients suffer combined extramedullary and BM relapse has worse prognosis than those with BM relapse alone [ 55 ].…”

“…Although clinical treatment has been greatly improved, most AML patients eventually experience relapse and death. As a highly heterogeneous disease, both intrinsic and microenvironmental abnormalities participate in the transformation, progression and relapse of AML [ 2 – 4 ]. Elucidating the mechanisms causing adverse phenotypes of AML including exuberant proliferation [ 5 ], more leukemia stem cells (LSCs) [ 6 , 7 ], massive extramedullary dissemination [ 2 ], etc.…”

MicroRNA-143 acts as a tumor suppressor through Musashi-2/DLL1/Notch1 and Musashi-2/Snail1/MMPs axes in acute myeloid leukemia

“…Extramedullary AML sometimes involves the central nervous system and other solid organs, which is commonly associated with the former French-American-British (FAB) subtypes of AML-M5 [ 16 ]. Accordingly, increasing evidence supports the involvement of epithelial-mesenchymal transition (EMT) in hematologic diseases, enabling cancer cells to acquire migratory, invasive, and stem-like properties [ 17 – 20 ].…”