Page 95 - Haematologica - Vol. 105 n. 6 - June 2020

Extramedullary AML - PETAML trial
since they rely on findings from physical examination only or on coincidental findings in standard imaging pro- cedures. Others have performed retrospective analyses from autopsy series, which might over-estimate the prevalence of EM AML, since these series accumulate data on AML patients succumbing to their disease. So far, EM AML prevalence has been seen to range from 2.5% to 9.1%.2,3 Previous studies and AML treatment recommendations identified EM AML as an adverse prognostic factor in patients with AML.4 In contrast, a recent retrospective analysis based on clinical data from a large number of AML patients included in clinical trials revealed a high proportion of patients with EM AML (23.7%), but could not identify EM AML as an independ- ent prognostic factor.5 Nevertheless, this analysis and others also included patients with, for example, hepatomegaly and/or splenomegaly, gingival hyperplasia based on clinical examination, suggesting these repre- sent EM AML or leukemic meningitis. These findings per se do not fulfill the criteria for EM AML.5,6 However, without a precise assessment of EM AML, valid risk fac- tor analyses cannot be performed. 18Fluorodesoxy-glu- cose positron emission tomography/computed tomogra- phy (18FDG-PET/CT) is able to detect highly metabolic tissue and has proven efficacy in imaging studies for var- ious types of malignant diseases. We and others have demonstrated the utility of 18FDG-PET/CT imaging in AML patients with histologically proven EM AML.7-13 We were able to demonstrate a sensitivity of 90% using 18FDG-PET/CT imaging and found additional EM sites in 60% of the patients.8 Another study in ten unselected AML patients using 18Fluorodeoxythymidine-PET discov- ered EM AML in 4 of 10.14 Prospective studies to assess the prevalence of EM disease in AML in unselected patients have, so far, not been performed. The aim of this prospective, observational study was to use 18FDG- PET/CT to determine the prevalence of EM AML in patients prior to initiation of AML therapy.
Methods
This open, prospective observational study was approved by the institutional review board (EK309102009) and registered at clinicaltrials.gov identifier: 01278069. Informed consent was col- lected prior to the first PET scan. Patients with AML aged 18-80 years underwent baseline total body 18FDG-PET/CT scans before initiation of therapy. Patients were included only if a delay of ≤5 days of initiation of treatment was clinically justifi- able in order to perform the study.15 Hydroxyurea for disease control was admissible before the 18FDG-PET/CT. The primary objective of this study was to determine the prevalence of EM AML at diagnosis. The sample size was calculated such that the width of the 95% confidence interval (CI) would stay within 20%. Assuming a prevalence of 40% EM AML, 93 patients would need to be studied. The prevalence of 40% was based on the only data available at the time from a case series of ten unelected patients undergoing PET/CT scanning, demonstrating existence of EM AML in 4 of those 10 patients.14 This trial was not powered to compare survival differences in EM AML as compared to AML patients without EM. Since there is no evi- dence to indicate that the treatment of AML patients with EM manifestation of AML needs to be intensified or modified, the presence of EM AML was not part of the decision-making process for treatment of these patients.
In total, 106 patients were screened for the study between February 2011 and July 2013 in the Department of Haematology of the University Hospital Dresden. Of those, 13 patients were considered to be screening failures and were not considered for further analyses, such that the planned sample size of 93 patients was reached. Reasons for screening failure were: age >80 years or 18FDG-PET/CT not feasible due to the clinical con- dition of the patient (n = 7) or other (n=6). Interestingly, two of these 13 patients had EM AML (histologically confirmed diagno- sis in one patient and clinical diagnosis in the other). Patients with PET-positive EM AML at baseline underwent a second 18FDG-PET/CT scan after therapy initiation either at the date of complete remission or until day 60 in case of not achieving CR. A complete diagram of screened and included patients is shown in Figure 1. Hybrid 18FDG-PET/CT scans were performed as recently published using a Siemens Sensation 16 as part of a bio- graph (Siemens, Knoxville, TN, USA) with intravenous applica- tion of 18FDG and 120 mL contrast media Ultravist 370 (Bayer Schering Pharma, Leverkusen, Germany).8 PET 3-dimensional emission scans were conducted with a median activity of 367 MBq (range, 223-433 Mbq), as recently published.8 For assess- ment of 18FDG-PET/CT imaging, no specific threshold or meta- bolic activity (e.g. maximum standardized uptake value, SUVmax) was applied. Instead, subtle correlation of any 18FDG- positive lesion with the fused CT images was performed to detect a corresponding tissue proliferation before suspecting an EM manifestation of AML. In cases in which no morphological correlate was apparent, 18FDG-positive lesions were declared to be unspecific. The estimated prevalence of EM AML was ascer- tained by calculating the specificity of baseline 18FDG-PET/CT positivity in relation to those EM AML lesions confirmed posi- tive for EM AML upon histology. Thereafter, the total number of baseline 18FDG-PET/CT positive EM AML patients was multi- plied by this specificity to derive an estimate for the prevalence in the total sample of 93. A CI with at least 95% coverage was derived by calculating the exact Clopper-Pearson-Confidence Intervals. Complete remission (CR) was defined according to the standard consensus criteria.16 The Mann-Whitney U-test was used to compare continuous variables between patient groups, while the χ2-test was applied to categorical variables. All statis- tical analyses were performed using SPSS version 25 (SPSS Inc., Chicago, IL, USA); two-sided tests were applied. P<0.05 was considered statistically significant.
Results
Patient population and safety
A total of 93 patients with AML (n=9 with relapsed AML) underwent total body 18FDG-PET/CT scans at diagnosis after giving informed consent. Median age of all patients was 61 years (range, 27-79 years). Clinical characteristics of the patient population are shown in Table 1. The majority were diagnosed with de novo AML (n=53, 57%) while 22 patients (23%) had secondary AML after preceding myelodysplastic syndrome (MDS) / myeloproliferative neoplasm (MPN), and n=18 (19%) patients had therapy-related AML (tAML) / therapy- related MPN (tMN). Median follow up of alive patients is 46 months (range, 5-60 months). There were no adverse reactions due to the application of intravenous 18FDG and intravenous contrast media. No deterioration in renal function, as determined by measurement of creatinine serum levels and estimation of GFR (eGFR) by Cockroft- Gault, was observed after 18FDG-PET/CT imaging.
haematologica | 2020; 105(6)
1553