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.

Keywords: Acute myeloid leukemia; Chloroma; Extramedullary; Leukemia cutis; Myeloid sarcoma.

Fig. 1

Distribution of histopathologically confirmed extramedullary manifestations. For 38 out of 225 patients, biomaterial of the affected site was available for histopathological confirmation of extramedullary manifestations (EM). Most frequently, EM was found in the skin, central nervous system (CNS) and pleura. Three patients had two affected EM sites and one patient had three EM sites

Fig. 2

Parameters associated with extramedullary manifestations in AML. Logistic regression was used to obtain univariable odds ratios for presence or absence of extramedullary manifestations (EM) in AML patients (A). We found the presence of EM to be significantly associated with cytomorphologic phenotypes according to the French-American-British (FAB) classification. FAB-M5a and -M5b were associated with increased odds while -M2 and -M6 were associated with decreased odds. As for molecular genetics, mutations of NPM1, FLT3-ITD and PTPN11 were associated with EM while IDH2 and CEBPA were less likely to be associated with EM. Previous reports have suggested an association of inv [16], t(8;21) and trisomy 8 with EM, however in our analysis we did not find a statistically significant association. Molecular and cytogenetic interconnections of patients with (B) or without (C) EM AML are displayed

Fig. 3

Impact of extramedullary manifestations on survival in acute myeloid leukemia. For the comparison between both clinically and histologically determined EM AML and non EM-AML, both event-free (A) and relapse-free survival (B) did not differ significantly while overall survival (C) was significantly reduced. When we focused only on histologically confirmed EM AML (n = 38) excluding cases for whom only clinical diagnosis of EM AML was available, we found that both event-free survival (D) as well as overall survival (F) were significantly reduced compared to AML patients without EM while relapse-free survival did not differ (E). Significance was determined at α = 0.05; * p < 0.05, ** p < 0.01, ***p < 0.001; EM AML_h+c = histologically and clinically diagnosed cases of EM AML (panel A–C); EML AML_h = only histologically confirmed cases of EM AML (panel D–F)

Fig. 4

Risk factors in acute myeloid leukemia with extramedullary manifestations. Among AML patients bearing extramedullary manifestations (EM) mutations of TP53 and IKZF1 were rare (7/225 [3.1%] and 9/225 [4.0%], respectively). However, EM AML patients with TP53 mutations showed significantly decreased event-free (A) and overall survival (B). Likewise, EM AML patients with IKZF1 mutations also showed significantly decreased event-free (C) and overall survival (D)