Is there a link between very early changes of primary and secondary lymphoid organs in 18F-FDG-PET/MRI and treatment response to checkpoint inhibitor therapy?

Abstract

Response assessment or prediction to checkpoint inhibitor therapy (CIT) is an unsolved problem in current routine diagnostics of patients with melanoma. Here, we evaluated very early changes of primary and secondary lymphoid organs under CIT in multiparametric [18F]-labeled fluorodeoxyglucose-positron emission tomography (18F-FDG-PET)/MRI as possible predictors of treatment response and investigated their correlation with baseline blood immune biomarkers. Between October 2014 and November 2017, 17 patients with unresectable melanoma (8 females; 65±11 years) undergoing CIT were prospectively evaluated using whole-body 18F-FDG-PET/MRI before CIT start (t0), 2 weeks (t1) and 3 months after CIT initiation (t2). At each time point, the volume, the 18F-FDG-uptake and the mean apparent diffusion coefficient (ADC) of the spleen as well as the 18F-FDG uptake of the bone marrow were assessed. Relative lymphocyte count (RLC), relative eosinophil count (REC) and neutrophil-lymphocyte ratio (NLR) were assessed at baseline. Response Evaluation Criteria in Solid Tumours modified for immune-based therapeutics (iRECIST) and decisions from an interdisciplinary tumor board were used for treatment response evaluation at t2 iRECIST was compared with PET response criteria in solid tumors for image-based response evaluation at different time points. Comparative analysis was conducted with Mann-Whitney U test with false discovery rate correction for multiple testing and correlation coefficients were computed. In lymphoid organs, significant differences (p<0.05) between responders (9/17) and non-responders were found for the 18F-FDG-uptake in the spleen at t1 and the increase of the uptake t1-t0 (responders/non-responders: standardized uptake value lean body mass 1.19/0.93; +49%/-1%). The best correlation coefficients to baseline biomarkers were found for the 18F-FDG-uptake in the spleen at t1: NLR, r=-0.46; RLC, r=0.43; REC, r=0.58 (p<0.05), respectively. Compared with the non-responder group, the responder group showed marked increases also in the volume of the spleen (+22%/+10%), the 18F-FDG-uptake of bone marrow (+31%/-9%) at t1 and the ADCmean at t2 (+46%/+15%) compared with t0, however, not reaching significance. Our findings indicate that an effective systemic immune response in patients undergoing CIT can be detected as a significantly increased spleen activity in 18F-FDG-PET as early as 2 weeks after treatment initiation. TRIAL REGISTRATION NUMBER: NCT03132090, DRKS00013925.

Keywords: CTLA-4 antigen; melanoma; programmed cell death 1 receptor.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Overview of cohort selection. A high number of patients quit the study and changes of therapy during the 3 months of observation resulted in a high drop-out rate. In five patients, no metastases with an increased uptake of [18F]-labeled fluorodeoxyglucose (18F-FDG) were found: in two patients, lesions turned out to be inflammatory (lung and liver), in one patient, a spinal meningeal melanocytoma was finally diagnosed and in two patients, suspicious lesions did not show an increased glucose consumption and were therefore not rated as metastases. CIT, checkpoint inhibitor therapy.

Figure 2

Left hand side: DIXON MRI (in and opposed phase) were used to compute a bone mask of the spine (highlighted in the positron emission tomography (PET) maximum intensity projection image), which was copied to the PET images to assess the standardized uptake value lean body mass (SULmean) of the bone marrow. Right hand side: example of a responder (patient no. 10, also shown in online supplementary figure S2) and a non-responder (patient no. 11) to checkpoint inhibitor therapy. Note the changes of [18F]-labeled fluorodeoxyglucose (18F-FDG)-uptake in the bone marrow in the responder especially at t1 while there was no significant change observed in the non-responder.

Figure 3

Morphological (iRECIST) and metabolic (positron emission tomography (PET) response criteria in solid tumors (PERCIST)) response assessment (upper two rows, ‘Response’) as well as multiparametric changes in the spleen (‘Spleen’) and baseline immune biomarkers (bottom line) in a responder (left hand side, patient no. 14) and a non-responder (right hand side, patient no. 11) to checkpoint inhibitor therapy. Left hand side: metastases in the liver and the lung at t0 (black arrows) with an excellent treatment response already visible at t1 in PET: the metastases in the lung disappears in PET and the metabolic activity of the liver metastases decreases significantly, resulting in partial metabolic response (PMR); diameters of metastases did not show significant changes, leading to immune stable disease (iSD) in iRECIST at t1. Avital tumor residue in the liver at t2 (immune partial response (iPR)) without specific tracer uptake (complete metabolic response (CMR)). Note the significant increase of metabolic activity and the volume of the spleen (dotted ring in the PET/MRI), especially at t1 as compared with t0, considerably less pronounced at t2. Right hand side: metastases in the liver, the lung and the soft tissue of the left leg (black arrows). New metastases are visible in both MRI and PET already at t1, resulting in PMD/immune progressive disease (iPD). The volume of the spleen slightly increases under therapy, but the metabolic activity remains stable. The apparent diffusion coefficient (ADC)mean of the spleen did not show clear trends under therapy. The dotted regions of interes (ROIs) in the images aim to highlight the spleen and are not the volume of interest (VOI) used for image evaluation.

Figure 4

Left hand side: results of the evaluation of lymphoid organs demonstrated as relative changes in % to the baseline scan t0 in the responder and non-responder group. Significant differences between the time points were found for SULmean at t1 and for relative differences between t0 and t1. Right hand side: correlation of metabolic activity of the spleen at t1 (SULmean t1) to the baseline immune biomarkers NLR, RLC and REC of all patients. NLR, neutrophile-lymphocyte ratio; REC, relative eosinophil count; RLC, relative lymphocyte count; SULmean, standardized uptake value lean body mass.