[18 F]-Fludarabine Positron Emission Tomography in Chronic Lymphocytic Leukemia Patients: Results of a Phase I Study
Authors: Hovhannisyan Narinée , Chantepie Sylvain P , Ibazizene Meziane , Manrique Alain , Reman Oumedaly , Barre Louisa , Leporrier Michel 
Published: October 2019

Abstract
Introduction. [18 F]-Fludarabine is a promising novel positron emission tomography (PET) radiotracer for lymphoid malignancies. The rationale supporting its development is the high selectivity of fludarabine uptake within lymphoid cells irrespective of their cycle activity, and the fluorine atom within the drug, which replaced by a [18 F] confers the positron-emitter property. Pre-clinical studies with [18 F]-fludarabine (Dhilly M et al, Mol Imaging Biol 2014,16:118-26; Hovhannisyan N et al, EJNMMI Res 2015,5:23) showed a marked tumor uptake in lymphoma-bearing mice. The aim of this study was to describe anatomical sites with abnormal [18 F]-fludarabine uptake in patients with B-cell chronic lymphocytic leukemia (B-CLL), in whom [18 F]-FDG PET imaging appears to be less informative than in other lymphoid malignancies. This study was designed as a clinical proof of concept.
Methods. [18 F]-Fludarabine was produced according to a method already described (Guillouet S et al, Mol Imaging Biol 2014,16:28-35). [18 F]-Fludarabine PET/CT (Discovery RX VCT 64, GE Healthcare) was performed in 5 patients (51-70 years old) with a diagnosis of B-CLL (according to current recommendations), without suspicion of Richter's syndrome. Successive partial body scans (skull vertex to mid-thigh) were acquired for 250 min after intravenous injection of [18 F]-fludarabine with an activity of 4MBq/kg. PET images were analyzed by drawing volumes of interest (VOI) over the uptake sites on a late scan and projected onto all co-registered scans of the same subject. The intensity of tracer uptake was evaluated with the maximum standardized uptake value (SUVmax). The images of [18 F]-fludarabine PET/CT were visually compared with conventional modalities (high-resolution CT) and [18 F]-FDG PET in one patient.
Results. No adverse event was recorded during and after the procedure. In the 5 patients studied, the uptake of [18 F]-fludarabine coincides with sites expected to be involved following conventional clinical and CT scan staging (i.e. lymph nodes, spleen, tonsils). Additionally, [18 F]-fludarabine PET/CT displayed a significant uptake in hematopoietic bone marrow, and unexpected uptake in the medulla of some bones (femur, humerus, sphenoid, calvarium), and in Peyer's patches. SUVmax were significantly greater in involved sites in comparison with normal tissues or organs (Figure 1). Within the involved sites, [18 F]-fludarabine demonstrated a wide range of uptake which would indicate heterogeneity and differing micro-environments. For instance, the most active sites of the case illustrated in Figure 1 (scan period 30-50 min) are lymph nodes (SUVmax 7.4), spleen (SUVmax 6.3) and bone marrow (SUVmax 3.8) with aortic uptake (SUVmax 1.5) as background level.
Conclusion. These preliminary results showed a clear specificity of this novel radiotracer for lymphoid tissues. [18 F]-Fludarabine PET/CT appears to be a promising tool for the diagnosis and follow-up of B-CLL. These scans indicate variable activity within proliferation sites, information otherwise not accessible by current non-invasive procedures. Further studies for a more accurate comparison with [18 F]-FDG PET, evaluation of response during and after treatment and correlation with B-CLL prognostic criteria are underway.
Figure 2. Figure 2.

Disclosures
No relevant conflicts of interest to declare.