Access the full text.
Sign up today, get DeepDyve free for 14 days.
Loading next page...
/lp/springer-journals/staging-of-lymphoma-under-chimeric-antigen-receptor-t-cell-therapy-2tQHKhqpWL
- Publisher
- Springer Journals
- Copyright
- Copyright © The Author(s) 2023
- eISSN
- 1470-7330
- DOI
- 10.1186/s40644-023-00566-7
- Publisher site
- See Article on Publisher Site
Abstract
Background Chimeric antigen receptor T-cell therapy (CART ) prolongs survival for patients with refractory or relapsed lymphoma. Discrepancies among different response criteria for lymphoma under CART were recently shown. Our objective was to evaluate reasons for discordance among different response criteria and their relation to overall survival. Methods Consecutive patients with baseline and follow-up imaging at 30 (FU1) and 90 days (FU2) after CART were included. Overall response was determined based on Lugano, Cheson, response evaluation criteria in lymphoma (RECIL) and lymphoma response to immunomodulatory therapy criteria (LYRIC). Overall response rate (ORR) and rates of progressive disease (PD) were determined. For each criterion reasons for PD were analyzed in detail. Results 41 patients were included. ORR was 68%, 68%, 63%, and 68% at FU2 by Lugano, Cheson, RECIL, and LYRIC, respectively. PD rates differed among criteria with 32% by Lugano, 27% by Cheson, 17% by RECIL, and 17% by LYRIC. Dominant reasons for PD according to Lugano were target lesion ( TL) progression (84.6%), new appearing lesions (NL; 53.8%), non-TL progression (27.3%), and progressive metabolic disease (PMD; 15.4%). Deviations among the criteria for defining PD were largely explained by PMD of preexisting lesions that are defined as PD only by Lugano and non-TL progression, which is not defined as PD by RECIL and in some cases classified as indeterminate response by LYRIC. Conclusions Following CART, lymphoma response criteria show differences in imaging endpoints, especially in defining PD. The response criteria must be considered when interpreting imaging endpoints and outcomes from clinical trials. Keywords CAR T-cell therapy, F-FDG PET/CT, Lugano criteria, Cheson, RECIL, LYRIC *Correspondence: Wolfgang G. Kunz wolfgang.kunz@med.lmu.de Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Winkelmann et al. Cancer Imaging (2023) 23:44 Page 2 of 11 Background 3. Available CT or PET-CT imaging studies at baseline Chimeric antigen receptor T cell therapy (CART) has (≤ 2 weeks before CART) and at least two follow-up emerged as an effective cell-based immunotherapy using timepoints (FU1 around 30 days and FU2 around 90 patient-derived T cells targeting tumor antigens [1]. As a days, or before if clinical progression was evident). main application, the modified CAR T cells are used for The following exclusion criteria were applied: the treatment of relapsed or refractory (r/r) lymphoma 1. Any non-diagnostic imaging studies. [2] and leukemia [3] with expression of CD19 antigen 2. Patients with non-measurable disease. specific receptor. This has led to high rates of durable 3. Lack of follow-up regarding survival data. responses in large B-cell lymphoma (LBCL) (LBCL) [2; 4; Histologic diagnoses were reviewed by expert patholo- 5], follicular lymphoma (FL) [2; 5], mantle-cell lymphoma gists. Patients received lymphodepletion with fludarabine (MCL) [6]. For initial staging and response assessment in and cyclophosphamide according to the manufacturers’ 18 18 the course of therapy, F-fluorodeoxyglucose ( F-FDG) instructions. positron emission tomography-computed tomography (PET/CT) is most commonly used. F-FDG PET/CT imaging In the currently ongoing phase III trials, treatment PET/CT images were acquired approximately 45 min response is assessed using the Lugano criteria from 2014 after tracer injection (159–275 MBq weight-adapted [7; 8], which were established for lymphomas treated with approximately 2.5–4.5 MBq F-FDG per kg body- with conventional therapy. The Lugano criteria evolved weight) and for the FDG PET/CT contrast-enhanced or from the Cheson criteria from 2007, which were used for unenhanced CTs using a slice thickness of 2 mm 120 kVp, response evaluation in previous studies [9]. In the recent 100–400 mAs, and dose modulations were performed for years, new imaging criteria for lymphoma have been pub- attenuation correction. The following scanners were used: lished. The two most important criteria in this regard are Biograph 64 and Biograph mCT (Siemens Healthineers, the lymphoma response to immunomodulatory therapy Germany) or Discovery 690 (GE Healthcare, USA). Both criteria (LYRIC) [10] from 2016 and the Response Evalu- scanners fulfilled the requirements indicated in the Euro - ation Criteria for Lymphoma (RECIL) [11] from 2017. pean Association of Nuclear Medicine (EANM) imaging These were developed to better reflect the effects in the guidelines and obtained EANM Research Ltd. (EARL1) context of immunotherapies and, in part, to facilitate the accreditation during acquisition. The following recon - measurement method [10; 11]. struction algorithms were used: Biograph 64: TrueX (3 The scientific literature on structured comparisons of iterations, 21 subsets) with Gaussian post-reconstruction these imaging response criteria is scarce for conventional smoothing (2 mm full width at half-maximum). Biograph lymphoma treatments and only two studies indicate con- mCT: TrueX (3 iterations, 21 subsets). Discovery 690: cordance of RECIL and Lugano criteria in previously VUE Point Fx algorithm with 2 iterations and 36 subsets. untreated LBCL and FL [12; 13]. Recently, differences All systems resulted in a PET image with a voxel size of in OS stratification and median PFS among different 2 × 2 × 2 mm3. Images were normalized to decay cor- response assessment criteria in lymphoma under CART rected injected activity per kg body weight (SUV g/ml). were shown [14]. As there are no further reports on sur- vival outcomes and the prognostic value for lymphoma Imaging response assessment patients treated with CART, we investigated the rea- To evaluate overall response, the Lugano criteria were sons for discordance among different imaging response applied and up to 6 target lesions (TL) were manually criteria. segmented by consensus of two radiologists with at least 5 years of experience in radiology and nuclear medicine. Methods The sum of the product of the diameters (SPD) was mea - Study design and population sured to determine tumor burden (TB) for Lugano crite- The study population was based on a prospective registry ria, Cheson criteria, and LYRIC. In addition, spleen size of all consecutive patients who were treated at the Com- was measured and splenomegaly defined by a vertical prehensive Cancer Center Munich-Ludwig-Maximilian length > 13.0 cm according to Lugano criteria. Additional LMU University Munich (CCCM ) with standard-of-care response criteria were applied to compare the over- CD19-specific CART products in between 01/2019 and all response status. For Cheson criteria and LYRIC the 02/2022 (data cutoff). The following inclusion criteria same TL (≤ 6) as for Lugano criteria were evaluated. To were applied: assess response according to RECIL, the sum of longest 1. Patients with r/r lymphoma (LBCL, FL and MCL). diameters (SLD) of ≤ 3 TL was measured to define tumor 2. Any measurable disease on imaging according to burden. Depth of response (DoR) according to Lugano Lugano criteria [7]. criteria, Cheson criteria, and LYRIC was calculated as the percentage decrease or increase in SPD from BL to FU2. Winkelmann et al. Cancer Imaging (2023) 23:44 Page 3 of 11 DoR per RECIL was computed as the percentage change and a SLD of 14.0 cm. Tumor burden, PFS and its corre- in SLD from BL to FU2. lation to OS are shown in Table 2. Target lesions (TL), non-target lesions (NTL), and new appearing lesions (NL) in the course of therapy were Depth of response (DoR) evaluated quantitatively and qualitatively. The reason for DoR at FU1 and FU2 was calculated for all response cri- progressive disease (PD) was analyzed for each response teria and is shown in Table 2. At FU1, median SPD was criterion and classified in the following categories: target 1,265 mm and SLD 7.5 cm. At FU2, TB decreased to a lesion progression (TL PD), non-target lesion progres- median SPD of 1,101 mm and SLD of 6.8 cm. According sion (NTL PD), appearance of new lesion(s) (NL PD), and to RECIL, median depth of response (DoR) was − 4.3 cm progressive metabolic disease (PMD). The patient group (-41.7%) at FU1 and − 6.1 cm (-48.4%) at FU2. For all with TL PD was divided in the 3 subgroups: progression other response criteria median DoR was − 2,284 mm of a single TL (uni), progression of up to 50% of the TL (-60.5%) at FU1 and − 2,338 mm (-78.1%) at FU2. DoR by (oligo) or progression of ≥ 50% of the TL (multi). Lugano criteria, Cheson criteria, and LYRIC as percent We aligned our efficacy reporting standards with the increase or decrease in SPD for all 41 patients is illus- Trial Reporting in Immuno-Oncology (TRIO) consensus trated in Fig. 2. The color coding of the waterfall plot was statement by the American Society of Clinical Oncology chosen according to the categories of the Lugano crite- (ASCO) and the Society of Immunotherapy of Cancer ria. Although most patients showed a good DoR, some of (SITC) [15]. All imaging analyses were performed with them only had a PR after 3 month or even a PD according dedicated trial reporting software mintLesion 3.8 (mint to Lugano criteria, despite showing a significant decrease Medical GmbH; Heidelberg, Germany). Organ distri- in TB. bution for TL, NTL and NL was documented and sub- grouped as nodal lesions and extranodal lesions. Overall response according to Lugano, Cheson, RECIL, and LYRIC Statistical analysis The overall response rate (ORR) was comparable among All statistical analyses were performed using GraphPad the different criteria with 59%, 59%, 56%, and 59% at FU1 Prism 9. For survival analysis, OS was visualized using and 68%, 68%, 63%, and 68% at 90 day FU (FU2) accord- Kaplan-Meier survival curves with categorization for the ing to Lugano, Cheson, RECIL, and LYRIC, respec- patients to the response categories complete response tively. Applying the Lugano criteria in FU2, 23 patients (CR), partial response (PR), stable disease (SD), and pro- (56.1%) showed a CR and 5 patients (12.2%) showed a PR, gressive disease (PD) for all response criteria. The addi - whereas 13 patients (31.7%) had a PD. Discordance in the tional category of minor response (MR) was added for classification of overall response and rate of progressive RECIL and indeterminate response (IR) for LYRIC. The patients was observed when other response criteria were overall response rate (ORR) was calculated as the rate applied (Fig. 3). Interestingly, Cheson criteria and RECIL of patients with CR and PR. Log-rank (Mantel-Cox) test classified 4 patients as a SD, whereas there were none was performed to examine the significance of the results. according to Lugano criteria. In addition, RECIL classi- P values below 0.05 were considered to indicate statistical fied 2 patients as minor response (MR) and LYRIC classi - significance. fied 6 patients as indeterminate response (IR). Results PFS and reasons for progression according to different Patient characteristics criteria Forty-one out of 74 patients met the inclusion criteria Median PFS was 153 days, PFS 169 days, Lugano Cheson (median age: 64 years, 41% female). A flow chart is pro - PFS 198 days, and PFS 200 days. The reason for RECIL LYRIC vided in Fig. 1. International prognostic index (IPI) was progressive disease was analyzed for each response crite- determined for all patients. IPI score 1 was present in 7 rion, as shown in Table 3. The categories TL PD, NTL PD, patients (17.1%), score 2 in 13 patients (31.7%), score 3 NL PD, and PMD were applied as described above. Dom- in 13 (31.7%), score 4 in 4 patients (9.8%), and score 5 in inant reasons for PD according to Lugano criteria were 4 patients (9.8%). 6 patients (14.6%) had stage I disease, target lesion (TL) progression as size increase of one or 6 patients (14.6%) stage II, 7 patients (17.1%) stage III, more TL (84.6%), appearance of new lesions (NL; 53.8%), and 22 patients (53.7%) stage IV according to Ann Arbor non-TL progression (27.3%), and progressive metabolic staging system. 31 out of 41 patients (75.6%) received a disease (PMD, 15.4%). In most patients with progressive bridging therapy between apheresis and CAR T-cell infu- disease, there was a multifactorial cause for progres- sion. Patient characteristics are shown in Table 1. Median sion. According to Lugano criteria, 7/13 patients (53.8%), TB at baseline was measured with a SPD of 4,835 mm by Cheson criteria 6/11 patients (54.5%), by RECIL 4/7 patients (57.1%), and by LYRIC 6/7 patients (85.7%) had Winkelmann et al. Cancer Imaging (2023) 23:44 Page 4 of 11 Fig. 1 Flow Chart. A total of 74 lymphoma patients were treated with CAR T-cell therapy at our site in between 01/2019 and 02/2022. 17 patients who died before reaching FU2 and 11 patients without complete FU2 examination were excluded. 5 patients had no measurable lesion according to the Lugano criteria were also excluded. Finally, 41 patients met the inclusion criteria progression with multiple causes. An example of two response criteria (Supplementary Fig. 1; p < 0.001), with patients with discordant response criteria is illustrated in those who responded having longer OS. For the new IR Fig. 4. Deviations among the criteria for defining PD were category introduced by LYRIC, we observed a non-signif- largely explained by PMD of preexisting lesions that are icant difference compared to the non-responding group defined as PD only by Lugano and non-TL progression, (Supplementary Fig. 1D; p = 0.224). which is not defined as PD by RECIL and in some cases In a next step, we analyzed whether there was a dif- classified as IR by LYRIC. ference in the OS for the main reasons for discordance between the respective criteria. As mentioned above Survival analysis and reasons for progression by different and shown in Table 2, the main reasons for discordance response Criteria were focality of TL PD, organ location of NL PD, meta- There was a significant difference in survival between bolic progression (Lugano-based PMD vs. non-PMD), patients who responded to therapy in FU2 with a CR or and whether the progression was unifactorial or mul- PR compared to patients who did not respond to therapy tifactorial. There was a non-significant difference in OS with MR, SD or PD. Classification of patients into these for patients with multifactorial causes for PD compared two groups allowed significant stratification of OS for all to patients with an unifactorial cause (Fig. 5A; p = 0.185). Winkelmann et al. Cancer Imaging (2023) 23:44 Page 5 of 11 Table 1 Patient Characteristics endpoints based on different reasons for definition of PD. Age (median) 64 While the ORR was almost unaffected, classification of Gender Female: 17 (41%) patients as SD and PD differed significantly. In addition, Male: 24 (59%) some patients with the new proposed response categories Lymphoma entity LBCL: 35 (85%) MR by RECIL and IR by LYRIC were identified. Dichoto - MCL: 5 (12%) mization into responding and non-responding patients tFL: 1 (2%) based on 3-month FU stratified OS by all criteria. Inter - Ann Arbor Stage I: 6 (15%) II: 6 (15%) estingly, grouping patients based on the Lugano TL PD III: 7 (17%) into groups with uni TL, oligo TL and multi TL progres- IV: 22 (54%) sion showed a significant trend for OS stratification. IPI 1: 7 (17%) Lymphoma response criteria have historically been 2: 13 (32%) developed and established in the first-line treatment set - 3: 13 (32%) ting, and notably in an era of cytotoxic chemotherapies. 4: 4 (10%) 5: 4 (10%) The Cheson and Lugano criteria have evolved from the CAR T Product Tisagenlecleucel: 20 (58,8%) unidimensional Response Evaluation Criteria in Solid Axicabtagene ciloleucel: 13 (14,7%) Tumors (RECIST1.1) criteria [16] and measure the bidi- Brexucabtagene autoleucel: 5 (23,5%) mensional extension for this typically nodal-dominant Lisocabtagene maraleucel: 3 (2,9%) tumor phenotype [7; 9]. On CT imaging, patients with Bridging Chemotherapy: 21 (51%) pretreated lymphoma often have residual masses that Radiation: 5 (12%) can easily be mistaken as vital tumor [17]. Therefore, Immunotherapy: 2 (5%) Combined therapy: 3 (7%) the imaging response criteria for lymphoma incorporate No bridging: 10 (24%) metabolic activity of lymphoma manifestations as visual- LDH (median) Apheresis: 343 U/L ized by F-FDG PET/CT in order to identify a complete Prior Lymphodepletion: 277 U/L response [7; 9–11]. CAR, chimeric antigen receptor; LBCL, large B cell lymphoma; IPI, International In the development of the response evaluation crite- Prognostic Index; LDH, lactate dehydrogenase; MCL, mantle cell lymphoma; tFL, transformed follicular lymphoma ria in lymphoma (RECIL), the panelists set out to facili- tate the response assessment of lymphoma by reducing Similar results could be observed for the location of the number of target lesions that need to be measured the NL with the groups: nodal, extranodal, and mixed to achieve similar validity as the Lugano criteria [11]. A (Fig. 5C; p = 0.700), as well as metabolic progression reduction to 3 target lesions to represent tumor burden according to Lugano criteria (Figs. 0 and 5D.192). A sig- enabled robust response classification compared to the nificant trend between the uni, oligo, and multi groups other criteria that rely on 6 manifestations. In addition, for location of TL PD (Fig. 5B; p = 0.036) was detected, RECIL require a combination of depth of response and with patients with progression of only one TL having a reduction of metabolic activity to classify a response. longer OS. In the first-line treatment setting, the association of imaging endpoint surrogates of survival as PFS is known Discussion to be strong regarding OS [18; 19]. However, in the course In this population of patients treated with CD19 CART, of the disease with r/r lymphomas, changes in the pheno- both the established and explorative lymphoma response type and metabolism of the manifestations occur. Typi- criteria showed considerable discordance in imaging cally, distant lymph nodes are more commonly affected Table 2 PFS, OS Association, Absolute and Relative DoR at 30d and 90d According to Criteria Criteria Baseline TB FU1 FU2 Median PFS-OS DoR DoR TB TB PFS Association FU1 (30d) FU2 (90d) 2 2 Lugano 4,835 mm 1,265 mm 1,101 153 d r = 0.499 -60.5 -78.1% 2 2 mm p = 0.03 -2,284 mm -2,338 mm 2 2 2 Cheson 4,835 mm 1,265 mm 1,101 mm 169 d r = 0.476 -60.5 -78.1% 2 2 p = 0.03 -2,284 mm -2,338 mm RECIL 14.0 7.5 6.8 198 d r = 0.535 -41.7 -48.4% cm cm cm p = 0.01 -4.3 cm -6.1 cm 2 2 2 LYRIC 4,835 mm 1,265 mm 1,101 mm 200 d r = 0.758 -60.5% -78,1% 2 2 p < 0.001 -2,284 mm -2,338 mm Patient characteristics showing tumor burden (TB) at baseline (BL), follow-up 1 (FU1), and FU2. Median progression-free survival (PFS) is shown in days (d). The association of PFS and OS is presented as Pearson’s r. Both absolute and percentage depth of response (DoR) are reported according to each response criterion Winkelmann et al. Cancer Imaging (2023) 23:44 Page 6 of 11 Fig. 2 Target Lesion Change and Overall Response According to Lugano Criteria. Shown is a color-coded waterfall plot for depth of response (DoR) as percentage change of Lugano tumor burden ( TB) of all 41 patients at FU2 (90d) compared to baseline. Positive values indicate an increase and negative values a decrease in TB. Bars are labeled red for progressive disease (PD), yellow for partial response (PR) and green for complete response (CR) at FU2 according to Lugano criteria Fig. 3 Overall Response According to Lugano, Cheson, RECIL, and LYRIC. The upper row (A) depicts the distribution of patients with overall response (ORR; green) and non-responders (gray) for different response criteria: Lugano, Cheson, response evaluation criteria for lymphoma (RECIL) and lymphoma response to immunomodulatory therapy criteria (LYRIC). In the lower part (B), the bar plot visualizes the number of patients allocated to the different re - sponse categories according to each criterion. Patients with complete response (CR) are labeled green, patients with partial response (PR) yellow, patients with stable disease (SD) gray, and patients with progressive disease (PD) red. For RECIL, patients with minor response (MR) are labeled orange. For LYRIC, patients with indeterminant response (IR) are labeled blue Winkelmann et al. Cancer Imaging (2023) 23:44 Page 7 of 11 Table 3 Reasons for Classification of Progressive Disease According to Criteria Criteria TL PD Focality of NTL PD NL PD New Organ PMD Progressive Lesions Lesion Uni Oligo Multi Total Nodal Extra-nodal Both Lugano 10 4 1 5 3 7 2 1 4 Bone (3) 2 Muscle (3) Cheson 10 4 1 5 3 7 2 1 4 0 Peritoneal (2) RECIL 7 1 1 5 0 7 2 1 4 0 Fat tissue LYRIC 6 0 1 5 1 6 1 1 4 0 Kidney Liver Lung Pancreas Pleura Comparison of different imaging response criteria and the reasons for progressive disease. Shown are patient numbers with uni, oligo or multi target lesion (TL) progression, non-target lesion (NTL) progression, appearance of new lesions (NL) and progressive metabolic disease (PMD). Overlap of progression by multiple causes occurred in 53.8% of progressive patients by Lugano criteria, in 54.5% of patients by Cheson criteria, in 57.1% by RECIL, and 85.7% by LYRIC. and extranodal lesions are more frequent. In addition, 3 subcategories: IR1, increase in SPD increase ≥ 50% preexisting remnants may be mistaken for active lym- within the first 12 weeks of therapy, without clinical phoma if previous imaging studies are not reviewed. deterioration; IR2, appearance of new lesions, or growth Notably, response criteria have not been adjusted for of one or more existing lesions ≥ 50% at any time dur- such changes in disease progression, neither in solid nor ing treatment in the absence of overall progression; IR3, hematologic malignancies, and data on the association of increase in FDG uptake of one or more lesions without PFS and OS in lymphoma is scarce [7; 16]. a concomitant increase in lesion size or number [10]. In the context of CAR T-cell therapy data on charac- LYRIC suggests follow-up in all IR cases after 12 weeks terization of response by classification system is very and encourages a biopsy for IR1 and IR2. In contrast to limited. A single-arm, prospective study of 7 patients LYRIC, the other response criteria do not provide recom- with LBCL and FL, treated with CD19 CART evaluated mendations for lesion follow-up [7; 9; 11]. early response according to Lugano criteria on 1-month Another feasible method for distinguishing pseudopro- F-FDG PET/CT [20]. Interestingly all patients in this gression from true progression would be immuno-PET, study with less than CR subsequently relapsed [20]. A which uses mAbs or antibody fragments radiolabeled multicenter study with 171 patients analyzed the Deau- with a positron emitter radionuclide that can be detected ville score of NHL patients under CART in 1 month FU on PET/CT imaging [27]. For lymphoma patients, there F-FDG PET/CT with similar results. Patients with are a variety of potential targets, such as T-cell mark- Deauville Score 1 + 2 at 1 month FU had an improved ers (CD3, CD4, and CD8), B-cell markers (CD19 or long-term outcome compared to patients with Deauville CD20), and immune checkpoints (PD-1, PD-L1, or Score 3–5, who were at risk for an early relapse. More- CTLA-4) [28]. The first clinical trial with 5 patients over, all patients with Deauville Score 5 relapsed by included demonstrated the suitability of immuno-PET month 3 [21]. Another group suggested a SUVmax ≥ 10 with Zr-rituximab (anti-CD20 MAC) in patients with at 1 month as a predictor of progression [22]. Recently, relapsed B-cell NHL [29]. In a later study, iPET with it was shown that pretreatment tumor burden metrics of Zr-labeled anti-CD20 mAbs was suggested as a poten- lymphoma under CART vary significantly based on the tial biomarker for predicting the response of r/r DLBCL assessment method, impacting their association with [30]. Immuno-PET has also been used to visualize the survival outcomes [23]. migration, activation, and expansion of CD19-specific The analysis of specific response patterns of lymphoma CAR-T cells in an in vivo mouse model of B-cell lym- and the impact of pseudoprogression in the context of phoma [31]. However, there is very few clinical data, CART, has not yet been studied in detail [24]. Pseudopro- especially in the context of CART and limited availability gression is defined by a transient increase in tumor size of immune-PET in clinical routine. due to an infiltration of the tumor by immune cells and is In our study, there was no difference in terms of OS mainly described in solid tumors under immunotherapy, in patients with NL PD, even when sub-analyzed by the particularly in melanoma, affecting 5–12% of cases [ 25]. location of newly appearing lesions. In addition, patients Few studies described cases of pseudoprogression after with LYRIC-based IR had a nonsignificant difference CART analogous to solid tumors [26]. in survival compared with patients with PD. There - To prevent patients with pseudoprogression from fore, patients with solely newly appearing lesions and being misclassified as progressive disease LYRIC intro - patients with LYRIC-based IR should be further investi- duced the category of indeterminate response (IR) with gated regarding clinical benefit and may represent a new Winkelmann et al. Cancer Imaging (2023) 23:44 Page 8 of 11 Fig. 4 Patient Examples with Discrepancy Between Lugano, RECIL and LYRIC. PET/CT images of patient example 1 are illustrated in the upper panel with baseline scan on the left (A) and follow-up staging after 90 days (FU2) on the right (B). The patient had progressive metabolic disease of a mediastinal nodal lymphoma manifestation (red circle) without increase in size. All other TL and NTL showed significant DoR, and no NL appeared. This results in progressive disease according to Lugano criteria, but partial response by Cheson criteria and RECIL, and indeterminate response according to LYRIC. The second patient example is shown in the lower panel (C + D) with a progressive metabolic disease of the spleen without further increase in size. This was defined as PD by Lugano criteria and IR by LYRIC. The decrease in size of all other TLs indicated response according to RECIL (PR) and stable disease ac - cording to Cheson criteria response category. NL biopsy for histological workup growth of a single TL are also classified as IR, in contrast should be considered in these cases. Alternatively, liquid to the Lugano or Cheson criteria, in which a single signif- biopsy using ctDNA may represent a minimally invasive icantly growing TL is classified as PD. In these patients, test to resolve diagnostic uncertainties in this clinical sce- the lymphoma may indeed progress, but perhaps with nario [32; 33]. low kinetics, resulting in longer OS. This would be con - In addition, LYRIC-based PFS showed the strongest sistent with our findings that patients with single-site TL association with OS. One explanation could be that PD have a longer OS than patients with oligo- or multi- LYRIC effectively classifies patients with pseudoprogres - site TL PD. To address this issue, further characteriza- sion into one of the IR categories. Another explanation tion of tumor kinetics would be interesting. Recently, it is that patients with a small increase in tumor burden or has been shown that the increase in tumor growth rate Winkelmann et al. Cancer Imaging (2023) 23:44 Page 9 of 11 Fig. 5 Overall Survival Stratification by Reason for Progression. Illustrated are the Kaplan-Meier survival curves for overall survival (OS) for the different reasons for progressive disease (PD) according to Lugano criteria. Patients with multifactorial causes for classification as PD had a non-significant differ - ence in OS compared to patients with an unifactorial cause for PD (p = 0.185) as shown in A. Similar results were observed for metabolic progression (D) with a small yet non-significant difference between patients with progressive metabolic disease (PMD) and patients with no PMD (p = 0.192). Between the groups with uni, oligo, and multi target lesion ( TL) PD (B), there was a significant stratification of OS (p = 0.036) with patients with unifocal TL progres- sion having a longer OS. Grouping patients according to the location of new lesions (NL), either nodal only, extranodal or mixed showed no significant difference in OS ( C; p = 0.700) post-baseline compared to pre-baseline in lymphomas absolute number and size of new lesions. Such criteria treated with CART has a significant impact on OS [ 34]. refinements have been successfully applied in other can - Future response assessment in lymphoma with novel cer entities in the advanced, later-line disease stage, for imaging endpoints and response criteria will likely be example in metastatic prostate cancer [38; 39]. based on assessment of whole tumor burden (e.g. meta- Recently, differences in imaging endpoints among bolic tumor volume) and not only based on selected response criteria in lymphoma were reported [14]. To lesions. In the first-line setting of LBCL, the recently pub - our knowledge, there is no further literature comparing lished International Metabolic Prognostic Index (IMPI), the response assessment in the context of r/r lymphoma that consists of metabolic tumor volume, age, and stage, under CART. Our study has limitations which need to has outperformed the conventional IPI in estimating be considered when interpreting the results. First, this is outcome [35]. These imaging findings may be integrated a single-center study with a limited number of subjects. with prognostic risk-stratification tools such as the CAR- Second, there were a few patients that were missed to HEMATOTOX [36; 37]. Further areas of study may also follow-up or had no measurable disease. Not all patients focus on patterns of response, e.g. volume changes or the had a PET-based assessment at day 30. Winkelmann et al. Cancer Imaging (2023) 23:44 Page 10 of 11 Funding Conclusions The work was supported by funding from the research program “Förderung für Forschung und Lehre (FöFoLe) project number 1147” of the Medical Faculty We investigated overall response by Lugano criteria, of Ludwig Maximilian University (LMU) Munich and the Bavarian Cancer Cheson criteria, RECIL, and LYRIC. While the ORR Research Center (BZKF) to M.W. The work was further supported by the Else- was comparable between the different criteria, consider - Kröner-Fresenius Stiftung (to V.B.) and the German Cancer Consortium DKTK (to V.B.). able discordances in imaging endpoints based on differ - Open Access funding enabled and organized by Projekt DEAL. ent reasons for definition of PD. Response assessment by LYRIC exhibited superior association between PFS Data Availability The datasets generated during and/or analysed during the current study are and OS. In addition, we could detect a significant trend available from the corresponding author on reasonable request. for OS stratification by grouping the patients into the 3 groups: uni, oligo, and multi TL PD. The response assess - Declarations ment method must therefore be considered when inter- preting the impact of imaging endpoints on outcomes in Ethics approval, consent to participate and publication All medical records and imaging studies were reviewed with the approval clinical trials. Considering the heterogeneity, our results of the LMU Munich Institutional Review Board (LMU Ethics Committee, argue for standardization and harmonization across project number 19–817). Informed consent was obtained from all individual centers. participants included in the study. List of abbreviations Competing interests CART Chimeric antigen receptor T-cell therapy V.B.: BMS/Celgene: Research Funding; Kite/Gilead: Consultancy, Honoraria, CR Complete response Research Funding; Janssen: Research Funding, Honoraria; Novartis: Research DoR Depth of response Funding, Honoraria,; Roche: Research Funding; Takeda: Research Funding. K.R.: FDG Fluorodeoxyglucose Kite/Gilead: Research Funding; Kite/Gilead: Travel Support; Novartis: Honoraria. FL Follicular lymphoma V.L.B.: Amgen: Honoraria; Celgene/BMS: Research Funding; Kite/Gilead: FU Follow-up Research Funding, Honoraria; Novartis: Honoraria; Pfizer: Honoraria. C.S.: IPI International prognostic index Kite/Gilead: Travel Support. M.v.B.: Astellas: Consultancy, Research Funding IR Indeterminate response and Honoraria; BMS: Consultancy, Research Funding and Honoraria; Kite/ LBCL Large B-cell lymphoma Gilead: Consultancy, Research Funding and Honoraria; Miltenyi: Consultancy, LYRIC Lymphoma response to immunomodulatory therapy criteria Research Funding and Honoraria; Mologen: Consultancy, Research Funding MCL Mantle-cell lymphoma and Honoraria; MSD Sharp & Dohme: Consultancy, Research Funding and MR Minor response Honoraria; Novartis: Consultancy, Research Funding and Honoraria; Roche: NL New appearing lesions Consultancy, Research Funding and Honoraria. M.S.: Amgen: Research NTL Non-target lesion Funding, Speakers Bureau; Astra Zeneca: Speakers Bureau; Aven Cell: ORR Overall response rate Consultancy, BMS/Celgene: Research Funding, Speakers Bureau; CDR-Life: OS Overall survival Consultancy, Gilead: Research Funding, Speakers Bureau; GSK: Speakers PET/CT Positron emission tomography-computed tomography Bureau; Ichnos Sciences: Consultancy; Incyte Biosciences: Consultancy; PD Progressive disease Janssen: Research Funding, Consultancy, Speakers Bureau; Miltenyi Biotec: PFS Progression-free survival Research Funding, Consultancy; Morphosys: Research Funding; Molecular PMD Progressive metabolic disease Partners: Consultancy; Novartis: Research Funding, Consultancy, Speakers PR Partial response Bureau; Pfizer: Consultancy, Speakers Bureau; Roche: Research Funding, r/r Relapsed or refractory Speakers Bureau; Seattle Genetics: Research Funding; Takeda: Research RECIL Response evaluation criteria in lymphoma Funding, Consultancy, Speakers Bureau. W.G.K.: Bristol Myers Squibb: Advisor. SD Stable disease The remaining authors declare no competing financial interests. None of the SLD Sum of longest diameters mentioned conflicts of interest were related to financing of the content of this SPD Sum of the product of the diameters manuscript. TB Tumor burden TL Target lesion Author details Department of Radiology, University Hospital, LMU Munich, Marchioninistr. 15, 81377 Munich, Germany Laboratory for Translational Cancer Immunology, Gene Center of the Supplementary Information LMU Munich, Munich, Germany The online version contains supplementary material available at https://doi. German Cancer Consortium (DKTK) and Bavarian Center for Cancer org/10.1186/s40644-023-00566-7. Research (BZKF), partner site Munich, Munich, Germany Department of Medicine III, University Hospital, LMU Munich, Munich, Additional File 1 Supplementary Figure 1. Overall Survival of Different Germany Criteria According to Response Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany Comprehensive Cancer Center München-LMU (CCCM LMU ), LMU Acknowledgements Munich, Munich, Germany Not applicable. Authors’ contributions Received: 10 January 2023 / Accepted: 6 May 2023 M.W. and W.G.K. conceived and design the study; V.B., K.R., V.L.B., M.I., M.U., and C.S. collected the data; M.W., V.B., K.R., V.L.B., and W.G.K. analyzed and interpreted the data; and M.W. and W.G.K. drafted the manuscript; and V.B., K.R., M.I., F.J.D., P.B., J.R., M.v.B.-B., and M.S. revised the manuscript. All authors read and approved the final manuscript. Winkelmann et al. Cancer Imaging (2023) 23:44 Page 11 of 11 References 24. Vercellino L, de Jong D, di Blasi R, et al. Current and future role of medical 1. June CH, Sadelain M. Chimeric Antigen receptor therapy. N Engl J Med. imaging in guiding the management of patients with relapsed and refrac- 2018;379:64–73. tory non-hodgkin lymphoma treated with CAR T-Cell therapy. Front Oncol. 2. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel CAR 2021;11:664688. T-Cell Therapy in Refractory large B-Cell lymphoma. N Engl J Med. 25. Chiou VL, Burotto M. Pseudoprogression and Immune-Related response in 2017;377:2531–44. solid tumors. J Clin Oncol. 2015;33:3541–3. 3. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sus- 26. Wang J, Hu Y, Yang S, et al. Role of Fluorodeoxyglucose Positron Emission tained remissions in leukemia. N Engl J Med. 2014;371:1507–17. Tomography/Computed Tomography in Predicting the adverse Eec ff ts of 4. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or chimeric Antigen receptor T cell therapy in patients with Non-Hodgkin refractory diffuse large B-Cell lymphoma. N Engl J Med. 2019;380:45–56. Lymphoma. Biol Blood Marrow Transplant. 2019;25:1092–8. 5. Schuster SJ, Svoboda J, Chong EA, et al. Chimeric Antigen receptor T cells in 27. Knowles SM, Wu AM. Advances in immuno-positron emission tomography: Refractory B-Cell Lymphomas. N Engl J Med. 2017;377:2545–54. antibodies for molecular imaging in oncology. J Clin Oncol. 2012;30:3884–92. 6. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-Cell therapy in relapsed or 28. Decazes P, Bohn P. Immunotherapy by Immune checkpoint inhibitors and Refractory Mantle-Cell Lymphoma. N Engl J Med. 2020;382:1331–42. Nuclear Medicine Imaging: current and future applications. Cancers (Basel; 7. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial 2020. p. 12. evaluation, staging, and response assessment of Hodgkin and non-hodgkin 29. Muylle K, Flamen P, Vugts DJ, et al. Tumour targeting and radiation dose lymphoma: the Lugano classification. J Clin Oncol. 2014;32:3059–68. of radioimmunotherapy with (90)Y-rituximab in CD20 + B-cell lymphoma 8. Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging as predicted by (89)Zr-rituximab immuno-PET: impact of preloading with and response assessment of lymphoma: consensus of the International unlabelled rituximab. Eur J Nucl Med Mol Imaging. 2015;42:1304–14. Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol. 30. Jauw YW, Zijlstra JM, de Jong D, et al. Performance of 89Zr-Labeled-Ritux- 2014;32:3048–58. imab-PET as an imaging biomarker to assess CD20 targeting: a pilot study in 9. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malig - patients with Relapsed/Refractory diffuse large B cell lymphoma. PLoS ONE. nant lymphoma. J Clin Oncol. 2007;25:579–86. 2017;12:e0169828. 10. Cheson BD, Ansell S, Schwartz L, et al. Refinement of the Lugano classification 31. Simonetta F, Alam IS, Lohmeyer JK, et al. Molecular imaging of chimeric Anti- lymphoma response criteria in the era of immunomodulatory therapy. Blood. gen receptor T cells by ICOS-ImmunoPET. Clin Cancer Res. 2021;27:1058–68. 2016;128:2489–96. 32. Frank MJ, Hossain NM, Bukhari A, et al. Monitoring of circulating Tumor DNA 11. Younes A, Hilden P, Coiffier B, et al. International Working Group consen - improves early relapse detection after Axicabtagene Ciloleucel infusion in sus response evaluation criteria in lymphoma (RECIL 2017). Ann Oncol. large B-Cell lymphoma: results of a prospective multi-institutional trial. J Clin 2017;28:1436–47. Oncol. 2021;39:3034–43. 12. Berzaczy D, Haug A, Staber PB et al. (2019) RECIL versus Lugano for Treatment 33. Meriranta L, Alkodsi A, Pasanen A, et al. Molecular features encoded in the Response Assessment in FDG-Avid Non-Hodgkin Lymphomas: A Head-to- ctDNA reveal heterogeneity and predict outcome in high-risk aggressive Head Comparison in 54 Patients. Cancers (Basel) 12. B-cell lymphoma. Blood. 2022;139:1863–77. 13. Kostakoglu L, Martelli M, Sehn LH, et al. Complete response Status according 34. Winkelmann M, Blumenberg V, Rejeski K, et al. Prognostic value of pre- to RECIL 2017 Criteria shows high concordance with Lugano 2014 Criteria infusion tumor growth rate for patients with lymphoma receiving chimeric and is highly prognostic for outcome in previously untreated patients with antigen receptor T-cell therapy. Cytotherapy. 2023. https://doi.org/10.1016/j. CD20-Positive diffuse large B-Cell lymphoma (DLBCL). Blood. 2019;134:489–9. jcyt.2023.03.007. 14. Winkelmann M, Rejeski K, Blumenberg V, et al. Chimeric Antigen receptor 35. Mikhaeel NG, Heymans MW, Eertink JJ, et al. Proposed new dynamic T-cell therapy: imaging response criteria and relation to progression-free and prognostic index for diffuse large B-Cell lymphoma: International overall survival. Hemasphere. 2022;6:e781. Metabolic Prognostic Index. J Clin Oncol. 2022. https://doi.org/10.1200/ 15. Tsimberidou AM, Levit LA, Schilsky RL, et al. Trial reporting in Immuno-Oncol- JCO.21.02063:JCO2102063. ogy ( TRIO): an american society of clinical oncology-society for immuno- 36. Rejeski K, Perez A, Iacoboni G et al. (2022) The CAR-HEMATOTOX risk-stratifies therapy of cancer statement. J Clin Oncol. 2018;6:108. patients for severe infections and disease progression after CD19 CAR-T in 16. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation R/R LBCL. J Immunother Cancer 10. criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 37. Rejeski K, Perez A, Sesques P, et al. CAR-HEMATOTOX: a model for CAR T-cell- 2009;45:228–47. related hematologic toxicity in relapsed/refractory large B-cell lymphoma. 17. Mikhaeel NG, Timothy AR, Hain SF, O’Doherty MJ. 18-FDG-PET for the assess- Blood. 2021;138:2499–513. ment of residual masses on CT following treatment of lymphomas. Ann 38. Gafita A, Rauscher I, Fendler WP, et al. Measuring response in metastatic Oncol. 2000;11(Suppl 1):147–50. castration-resistant prostate cancer using PSMA PET/CT: comparison of 18. Batlevi CL, Younes A. Surrogate end points in lymphoma. Ann Oncol. RECIST 1.1, aPCWG3, aPERCIST, PPP, and RECIP 1.0 criteria. Eur J Nucl Med Mol 2018;29:1622–3. Imaging. 2022. https://doi.org/10.1007/s00259-022-05882-x. 19. Zhu J, Yang Y, Tao J, et al. Association of progression-free or event-free survival 39. Gafita A, Rauscher I, Weber M, et al. Novel framework for treatment response with overall survival in diffuse large B-cell lymphoma after immunochemo - evaluation using PSMA-PET/CT in patients with metastatic castration-resis- therapy: a systematic review. Leukemia. 2020;34:2576–91. tant prostate cancer (RECIP 1.0): an international multicenter study. J Nucl 20. Shah NN, Nagle SJ, Torigian DA, et al. Early positron emission tomography/ Med. 2022. https://doi.org/10.2967/jnumed.121.263072. computed tomography as a predictor of response after CTL019 chimeric antigen receptor -T-cell therapy in B-cell non-hodgkin lymphomas. Cyto- therapy. 2018;20:1415–8. Publisher’s Note 21. Kuhnl A, Roddie C, Kirkwood AA, et al. Early FDG-PET response predicts CAR-T Springer Nature remains neutral with regard to jurisdictional claims in failure in large B-cell lymphoma. Blood Adv. 2022;6:321–6. published maps and institutional affiliations. 22. Breen WG, Hathcock MA, Young JR, et al. Metabolic characteristics and prog- nostic differentiation of aggressive lymphoma using one-month post-CAR-T FDG PET/CT. J Hematol Oncol. 2022;15:36. 23. Winkelmann M, Bücklein VL, Blumenberg V, et al. Lymphoma tumor burden before chimeric antigen receptor T-Cell treatment: RECIL vs. lugano vs. meta- bolic tumor assessment. Front Oncol. 2022;12:974029.
Journal
Cancer Imaging – Springer Journals
Published: May 15, 2023
Keywords: CAR T-cell therapy; 18F-FDG PET/CT; Lugano criteria; Cheson; RECIL; LYRIC