**1. Introduction**

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma in adults with a prevalence of almost 40% [1]. Standard treatment regimens are

**Citation:** Reinert, C.P.; Perl, R.M.; Faul, C.; Lengerke, C.; Nikolaou, K.; Dittmann, H.; Bethge, W.A.; Horger, M. Value of CT-Textural Features and Volume-Based PET Parameters in Comparison to Serologic Markers for Response Prediction in Patients with Diffuse Large B-Cell Lymphoma Undergoing CD19-CAR-T Cell Therapy. *J. Clin. Med.* **2022**, *11*, 1522. https://doi.org/10.3390/jcm11061522

Academic Editor: Arnoldo Piccardo

Received: 23 January 2022 Accepted: 8 March 2022 Published: 10 March 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

efficacious, but up to 15% of patients will exhibit primary refractory disease and another 30– 35% will experience relapse after initial response [2,3]. In the refractory/relapsed DLBCL patients, incidence of disease recurrence is high, even after salvage therapy combined with autologous stem cell support, leading to a dismal long-term survival rate [4]. In this setting, novel treatment strategies are explored. A promising, emerging therapy option are CD19 CAR (chimeric antigen receptor)-T cells, which consist of genetically modified autologous T cells by retroviral or lentiviral vectors containing DNA encoding a CAR [1]. It has been shown that CD19 CAR-T cells provide high and durable response rates even in refractory and relapsed DLBCL [5–7].

Imaging is playing a major role for diagnosis and treatment monitoring in patients with DLBCL, and the most frequently recommended technique is the positron emission tomography (PET) using 18F-Fluorodeoxyglucose (FDG) as a tracer targeting glucose metabolism mostly in combination with computed tomography (CT) [8]. Hence, morphologic and glucometabolic changes in tumor herald either lymphoma response or relapse. The latter has been further refined by calculating the entire metabolic tumor volume (MTV) and the total lesion glycolysis (TLG). Both PET and CT image data can be additionally analyzed by using texture analysis with potential for tumor characterization either in the primary setting (baseline) for prognosis evaluation, or during therapy as an adjunct to morphologic and metabolic changes for more accurate response assessment [9,10]. Finally, some laboratory biomarkers like lactate dehydrogenase (LDH) in serum have been used for a long time as prognostic factors in lymphoma patients.

CD19-CAR T cell therapy as immunotherapy leads to a strong immunological response with T cell activation and cytokine release as illustrated by the most commonly observed adverse effect: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Manifestation of CRS goes along with hypersecretion of IL6, IL2-R, ferritin and CRP from activated macrophages following CAR-T cell activation [11].

Hence, the intention of this study was to investigate the value of CT-textural features and volume-based PET parameters in comparison to serologic markers for response prediction in patients with DLBCL undergoing CD19-CAR-T cell therapy.

#### **2. Material and Methods**

This retrospective image and laboratory data analysis was approved by the local ethics committee and the patients waived written consent (project number 277/2020BO2).

#### *2.1. Patient Characteristics*

Twenty-one consecutive patients with DLBCL (mean age 57.7 ± 14.7 year; seven female) undergoing CAR-T cell therapy from 06/2018 to 02/2021 were retrospectively evaluated. All patients had pathologically confirmed DLBCL. According to Ann-Arbor classification, 2/21 patients had a stage I, 3/21 patients had stage II, 5/21 patients had stage III and 11/21 patients were classified stage IV. According to the International Prognostic Index (IPI) scoring system, 3/21 patients were rated score 1, 9/21 patients were rated score 3 and 9/21 patients were rated score 4. Patient characteristics are summarized in Table 1.

#### **Table 1.** Patient characteristics.


At baseline staging, before CAR-T cell therapy, 17/21 patients underwent 18F-FDG-PET/CT and 4/21 patients underwent CT using standardized protocols. All patients were additionally monitored by serologic parameters. At first follow-up after CAR-T cell therapy, 18/21 patients underwent 18F-FDG-PET/CT and 3/21 patients underwent CT.

Therapy response was classified according to the Lugano classification system including CT-based response criteria and the Deauville five-point scale (Deauville 5PS) scoring system [12]. Each FDG-avid (or previously FDG-avid) lesion was rated independently by two readers. Response to CAR-T cell therapy was defined as PR in case of metabolically active disease (Deauville score 4), which is defined as lymphoma manifestations with 18F-FDG-uptake slightly to moderately higher than the liver background 18F-FDG-uptake without metric progression on CT. In case of no measurable 18F-FDG-uptake and 18F-FDGuptake below or equal to uptake in the liver (Deauville score 1–3), CR was assigned.
