Page 97 - Haematologica - Vol. 105 n. 6 - June 2020

Extramedullary AML - PETAML trial
(19%) who were diagnosed with EM AML as per 18FDG- PET/CT were treated with hydroxyurea prior to 18FDG- PET/CT imaging.
Follow-up 18FDG-PET/CT
Patients with EM diagnosed by 18FDG-PET/CT under- went a second 18FDG-PET/CT scan at confirmation of CR or, at the latest, until day 60 after initiation of therapy in case no CR was achieved. A total of 14 of 21 patients with EM AML as per baseline 18FDG-PET/CT at diagnosis underwent a second 18FDG-PET/CT. The remaining patients did not undergo a second 18FDG-PET/CT because of severe disease and intensive care treatment (n=3), men- tal distress (n=1), palliative care in a hospice (n=1), and withdrawal of study consent for the second 18FDG- PET/CT (n=2). When we analyzed only the follow up
18FDG-PET/CT of those patients who were 18FDG-PET/CT positive and had a positive confirmatory biopsy (n=10 patients), 60% of these patients (n=6) were still positive for EM AML as diagnosed per the second 18FDG-PET/CT. Exemplary 18FDG-PET/CT imaging of a responding and a non-responding patient (who both underwent intensive induction chemotherapy) is available in Figures 2C and 3C-E. Interestingly, of the six patients who still had EM AML (as per 18FDG-PET/CT imaging) at the time of their second 18FDG-PET/CT, four patients with EM AML and AML bone marrow infiltration at diagnosis were in CR as determined by bone marrow cytomorphology at the time of second 18FDG-PET/CT. Of those four patients who still had EM AML in their second 18FDG-PET/CT, but who were in CR as per bone marrow cytomorphology, three patients subsequently relapsed. The other two (of the six patients with persistent metabolic disease) had isolated EM AML as per 18FDG-PET/CT: one patient had unchanged EM AML manifestations in the second 18FDG- PET/CT, while the other had a progression of EM AML manifestations in the second 18FDG-PET/CT. The metabol- ic and numerical dynamics of EM AML manifestations in patients with histologically confirmed EM AML from baseline to follow up 18FDG-PET/CT are shown in Online Supplementary Figure 1A and B.
Discussion
Our study is the first to prospectively evaluate 18FDG- PET/CT imaging for the diagnosis of EM AML in patients with AML. Furthermore, this is the first prospective study combining 18FDG-PET/CT imaging, clinical findings, and histological examination after biopsy to systematically estimate EM AML. According to our results, 18FDG- PET/CT is a useful and safe tool to detect EM AML with a high sensitivity and specificity of 77% and 97%, respec- tively. While the prevalence of EM AML as per baseline 18FDG-PET/CT was 23%, we found an estimated preva- lence of EM AML of 19% using 18FDG-PET/CT when including the sensitivity of 18FDG-PET/CT after histologi- cal examination of biopsied lesions. When also adding the three patients with histologically confirmed EM AML, who were initially 18FDG-PET/CT negative, the combined prevalence of the whole study cohort is 22%. An analysis of only patients with newly diagnosed AML led to a com- bined prevalence of EM AML of 17% in our study. This is 3- to 11-fold higher than previously reported2,3 but lower than in other reported studies.5,17,18 Some reports over-esti- mated the prevalence of EM AML since data were derived from autopsy studies, which have a natural selection in favor of relapsed and/or refractory patients, or because a positive selection in favor of myelomonocytic AML sub- types occurred, as these are known to have a higher like- lihood of presenting with EM AML.17,18 Other studies under-estimate the prevalence of EM AML because they rely on the clinical findings of EM AML, which only rep- resents the tip of the iceberg.3,5 Some reports also include EM AML sites in their calculation, such as gingival hyper- plasia, splenomegaly or leukemic meningitis, which does not per se fulfill the World Health Organization (WHO) criteria for EM AML and therefore might over-estimate the prevalence of EM AML.5,6,17,19 A recent retrospective analysis by Ganzel et al. reported a clinical prevalence of 24% and argued that with a PET-based screening the rate
Table 1. Patients’ characteristics at diagnosis. Median age at diagnosis (range)
Gender, n. (%) Female
Male
Median percentage of bone marrow blasts (range) Median WBC count at diagnosis × 109/L (range) Median platelet count at diagnosis × 109/L (range) Median hemoglobin level at diagnosis in g/dL (range)
FAB subtypes, n. (%) M0
PETAML n=93
61 (27-79)
42 (44)
51 (55) 47.5 (3 - 96.5) 6.3 (0.4 - 222.4) 55 (3 - 278) 9 (4 - 14.8)
7(8) 17 (18) 36 (39) 9 (10) 12 (13) 4 (4) 3 (3) 5 (5)
22 (24) 64 (69) 6 (7)
13 (15) 74 (85)
72 (82)
16 (18)
75 (99) 1 (1)
53 (57) 22 (23) 18 (19) 9
M1 M2 M4 M5 M6 M7 other
Cytogenetic risk groups, n. (%)1 adverse
intermediate
favorable
FLT3-ITD status, n. (%)2 FLT3-ITD FLT3-wildtype
NPM1 status, n. (%)3 wildtype NPM1 mutated NPM1
CEBPA status, n. (%)4
no biallelic mutated CEBPA biallelic mutated CEBPA
AML status, n. (%) de novo AML secondary AML tAML/tMN relapsed AML
a,b
1Assignment to cytogenetic risk-group was not possible for n=1 patient.2FLT3-ITD mutational sta- tus could not be obtained for n=6 patients. 3NPM1 mutational status could not be obtained for n=5 patients. 4CEBPA mutational status could not be obtained for n=17 patients. AML: acute myeloid leukemia; WBC: white blood cell; FAB: French-American-British classification; FLT3: Fms-Like-Tyrosine Kinase 3; ITD: internal tandem duplication; NPM1: nucleophosmin 1; CEBPA: CCAAT/enhancer-binding protein alpha; tAML/tMN: therapy-related AML/therapy-related myeloidneoplasia;secondaryAML:AMLafterprecedingmyelodysplasticsyndrome ormyelo- proliferative neoplasm.
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