Ludovic Ferrer

90Y-labelled anti-CD22 epratuzumab tetraxetan in adults with refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia: a phase 1 dose-escalation study

BACKGROUNDnPrognosis of patients with relapsed or refractory acute lymphoblastic leukaemia is poor and new treatments are needed. We aimed to assess the feasibility, tolerability, dosimetry, and efficacy of yttrium-90-labelled anti-CD22 epratuzumab tetraxetan ((90)Y-DOTA-epratuzumab) radioimmunotherapy in refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia in a standard 3u2008+u20083 phase 1 study.nnnMETHODSnAdults (≥18 years) with relapsed or refractory B-cell acute lymphoblastic leukaemia (with CD22 expression on at least 70% of blast cells) were enrolled at six centres in France. Patients received one cycle of (90)Y-DOTA-epratuzumab on days 1 and 8 (give or take 2 days) successively at one of four dose levels: 2·5 mCi/m(2) (92·5 MBq/m(2); level 1), 5·0 mCi/m(2) (185 MBq/m(2); level 2), 7·5 mCi/m(2) (277·5 MBq/m(2); level 3), and 10·0 mCi/m(2) (370 MBq/m(2); level 4). The primary objective was to identify the maximum tolerated dose of (90)Y-DOTA-epratuzumab. We assessed safety during infusions and regularly after radioimmunotherapy over a 6-month period. Analyses included only patients who received radioimmunotherapy. The trial is closed to inclusion and is registered at ClinicalTrials.gov, NCT01354457.nnnFINDINGSnBetween Aug 25, 2011, and June 11, 2014, 17 patients (median age 62 years; range 27-77) were treated (five at level 1, three at level 2, three at level 3, and six at level 4). Radioimmunotherapy infusion was overall well tolerated. One dose-limiting toxic effect (aplasia lasting 8 weeks) occurred at level 4, but the maximum tolerated dose was not reached. The most common grade 3-4 adverse events were pancytopenia (one patient at level 2, one at level 3, and six at level 4) and infections (three at level 1, one at level 2, and five at level 4).nnnINTERPRETATIONn(90)Y-DOTA-epratuzumab radioimmunotherapy is well tolerated. We recommend the dose of 2u2008×u200810·0 mCi/m(2) 1 week apart per cycle for phase 2 studies.nnnFUNDINGnImmunomedics and Direction de la Recherche Clinique of Nantes.

TestDose: a SPECT image generator for clinical dosimetry studies

Patient-specific dosimetry in nuclear medicine relies on activity quantification in volumes of interest from scintigraphic imaging. Clinical dosimetry protocols have to be benchmarked against results computed from test phantoms. The design of an adequate model is a crucial step for the validation of image-based activ ity quantification. We propose a computing platform to automatically generate simulated SPECT images from a dynamic phantom for arbitrary scintigraphic image protocols. As regards the image generation, we first use the open-source NCAT phantom code to generate an anatomical model and 3D activity maps for different source compartments. This information is used as input for an image simulator and each source is modelled separately. Then, a compartmental model is designed, which describes interactions between dif ferent functional compartments. As a result, we can derive time-activity curves for each compartment with sampling time determined from real image acquisition protocols. Finally, to get an image at a given time after radionuclide injection, the resulting projections are aggregated by scaling the compartment contribution using the specific pharmacokinetics and corrupted by Poisson noise. Our platform consists of many software packages, either in-house developments or open-source codes. In particular, an important part of our work has been to integrate the GATE simulator in our platform, in order to generate automatically the command files needed to run a simulation. Furthermore, some developments were added in the GATE code, to optimize the generation of projections with multiple energy windows in a minimum computation time.

Generation of whole-body scintigraphic images with new GATE output capacities

This paper describes the framework for the creation of whole-body planar acquisitions from Monte Carlo modelling with GATE. The ground truth is a complex model representing a `virtual patient based on the NCAT-WB anthropomorphic model. Radiopharmaceutical kinetic was generated from compartmental modelling, to assign a time-activity curve (TAC) to each functional compartment. In order to match the kinetic models functional compartments, the geometrical NCAT-WB model was used to define the corresponding functional volumes, where each geometric voxel results from a linear combination of the functional contributions for that voxel. Image generation was performed by Monte Carlo modelling with GATE. However, Monte Carlo modelling necessitates huge computation times. It is therefore important to save as much time as possible - for example by decreasing the total number of simulations required to generate a dataset. The originality of our approach is twofold: Each functional volume is simulated only once and the resulting output is weighted using the respective TAC, allowing for several image time-points to be generated from the same simulation. The second innovation deals with the way to corrupt images with Poisson noise. The classical way is to simulate enough photons to obtain almost-noiseless projections and then apply a noise filter on the GATE projections. In case of complete simulation of an anthropomorphic model, the simulation time becomes far too long. We propose a method to generate an image with sufficient statistics while preserving the Poisson noise modeled by GATE. We developed a new GATE output which stores in a list the projection pixel indices of the detected photons. It is then possible to build projections with the number of detected events needed for a specific compartment over an acquisition time period. The proposed output is compatible with the generation of SPECT images based on the compartmental approach.