Baseline Metabolic Tumor Volume Research Articles

Healthy tissue metabolism assessed by [18F]FDG PET/CT as a marker of prognosis and adverse events in advanced Hodgkin lymphoma patients

The aim of the study was to assess healthy tissue metabolism (HTM) using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) during chemotherapy in Hodgkin lymphoma (HL) and the association of HTM with baseline metabolic tumour volume (MTV), haematological parameters, adverse events (AEs), early response and progression-free survival (PFS). We retrospectively identified 200 patients with advanced HL from the RATHL trial with [18F]FDG-PET/CT before (PET0) and following 2 cycles of chemotherapy (PET2). [18F]FDG-uptake was measured in bone marrow (BM), spleen, liver and mediastinal blood pool (MBP). Deauville score (DS) 1–3 was used to classify responders and DS 4–5, non-responders. [18F]FDG-uptake decreased significantly in BM and spleen and increased in liver and MBP at PET2 (all p < 0.0001), but was not associated with MTV. Higher BM uptake at PET0 was associated with lower baseline haemoglobin and higher absolute neutrophil counts, platelets, and white blood cells. High BM, spleen, and liver uptake at PET0 was associated with neutropenia after cycles 1–2. BM uptake at PET0 was associated with treatment failure at PET2 and non-responders with higher BM uptake at PET2 had significantly inferior PFS (p = 0.023; hazard ratio = 2.31). Based on these results, we concluded that the change in HTM during chemotherapy was most likely a direct impact of chemotherapy rather than a change in MTV. BM uptake has prognostic value in HL.

Baseline and on Treatment Biodistribution Variability of 18 F-FLT Uptake in Patients With Advanced Melanoma: Brief Communication.

This prospective study evaluates the biodistribution of 18 F-FLT PET in patients with advanced melanoma before and after treatment with BRAF/MEK inhibitors. Eighteen BRAF-positive unresectable stage IIIc or IV melanoma patients referred for 18 F-FLT PET/CT before (BL) and during (D14) BRAF/MEK inhibition were included. 18 F-FLT accumulation in the liver, bone marrow, blood, and muscle was quantified. Baseline interpatient 18 F-FLT uptake had a coefficient-of-variation between 17.5% and 21.5%. During treatment, liver uptake increased (SUV meanBL = 4.86 ± 0.98, SUV meanD14 = 6.31 ± 1.36, P < 0.001) and bone marrow uptake decreased (SUV meanBL = 7.67 ± 1.65, SUV meanD14 = 6.78 ± 1.19, P < 0.025). Both changes were unrelated to baseline metabolic tumor volume or tumor response. To assess 18 F-FLT PET, both liver and bone marrow uptake may be used as normal tissue references at baseline, but 18 F-FLT biodistribution significantly changes in longitudinal response studies when treated with BRAF/MEK inhibitors.

2-[18]F FDG PET/CT dissemination features in adult burkitt lymphoma Are predictive of outcome.

This retrospective study investigated the prognostic role of disease dissemination features (Dmax and Dmaxbsa) measured by 2-[18F]FDG PET/CT in newly diagnosed Burkitt Lymphoma (BL) patients, comparing their performance with other metabolic parameters. We included 78 patients diagnosed with BL between 2010 and 2022 with an available baseline PET, interim PET/CT (iPET) and end of treatment PET/CT (eotPET) and with a minimum of two 2-[18F]FDG avid lesions present at the baseline scan. Dmax was calculated from the three-dimensional coordinates of the baseline metabolic tumor volume (MTV) by using LIFEx software; Dmaxbsa was calculated as Dmax normalized for body surface area according to the Du Bois method. We evaluated their effect on metabolic treatment response evaluated by PET, on progression free survival (PFS) and on overall survival (OS). Dmaxbsa was significantly associated with tumor stage, bulky and extranodal disease, MTV and TLG. At a median follow-up of 49 months, the median PFS and OS were 45 and 48 months. Dmax and Dmaxbsa were significantly higher in not complete metabolic response than complete metabolic response group at iPET and eotPET.As far as PFS, parameters including iPET/CT, eotPET/CT outcomes, MTV and TLG showed to be independent prognostic factors while Dmax and Dmaxbsa were not significantly associated with the outcome. Dissemination features, together with eotPET/CT results, MTV and TLG, demonstrated to be significantly correlated with OS. In conclusion, in this study we demonstrated that dissemination features derived by 2[18F]-FDG PET/CT were significantly correlated with response to treatment and long-term outcome, independently from other PET features.

Prognostic value of baseline and interim [18F]FDG PET metabolic parameters in pediatric Hodgkin's lymphoma.

Hodgkin lymphoma (HL) in pediatric populations has a high survival rate but poses risks for long-term morbidities. Although [18F]fluoro‑2‑deoxy‑2‑d‑glucose positron emission tomography ([18F]FDG PET) scans offer potential for improved risk stratification, the definitive prognostic value of quantitative [18F]FDG PET parameters remains unclear for pediatric HL. A single-center, retrospective study included pediatric patients diagnosed with HL between 2016 and 2023 treated according to EuroNet-PHL-C1 and DAL/GPOH-HD protocols. Patients underwent baseline and interim PET/CT scans after two chemotherapy cycles. Event-free survival (EFS) was the primary endpoint, Deauville score was the secondary endpoint. Quantitative [18F]FDG PET parameters included SUVmax, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) that were evaluated using two segmentation methods (SUV 2.5, 41% SUVmax). Survival outcomes were assessed using Cox regression analysis. A total of 115 patients (50 males, median age 14.2years) were studied, with a median follow-up period of 35months. During this period, 16 cases (13.9%) of relapse or progression were noted. Baseline and interim MTV 2.5, MTV 41%, TLG 2.5, and TLG 41%, along with interim SUVmax, were significantly associated with worse EFS and correlated with post-treatment Deauville scores. In multivariable analysis, interim MTV 2.5 > 0ml (adj. hazard ratio, HR: 3.89, p = 0.009) and interim TLG 41% ≥ 30g (adj. HR: 7.98, p = 0.006) were independent risk factors for EFS. Baseline and interim [18F]FDG PET parameters can serve as significant prognostic indicators for EFS and treatment response in pediatric HL. These quantitative measures could enhance individualized, risk-adapted treatment strategies for children and adolescents with HL.

CAR-T Phenotype and Efficacy Is Impaired By Lymphoma-Associated CD39 + T Cells

Background: Autologous chimeric antigen receptor (CAR) T-cell therapy is standard of care for patients with relapsed or refractory Large B cell Lymphoma (R/R LBCL). Each patient's CAR T product is unique, and the patient-specific determinants of CAR T-cell quality are poorly understood. CD39 is an ectonucleosidase that participates in the conversion of ATP and ADP and is upregulated in cancer. On T-cells, CD39 is expressed on CD4+ Tregs and on exhausted CD8+ T-cells that are prone to apoptosis. Methods: This is a retrospective single-center cohort study (N=72) of patients who received CD19 CAR T-cell therapy for LBCL (axi-cel n=52; tisa-cel n=20). Leukapheresis material was obtained from n=51 patients and flow cytometry was performed to phenotype CD4+ and CD8+ stem-central memory, memory, and effector T-cell subsets (using CCR7 and CD45RO), and for immune checkpoint expression (PD-1, LAG3, TIGIT, and CD39). 10x multiome (ATAC and RNA) single cell sequencing (scRNA-seq) was performed on n=8 leukapheresis products for deeper characterization. Serum metabolomics was performed on paired samples from n=21 patients. 10X Genomics Chromium scRNAseq was also performed on n=57 CAR T-cell infusion products, including n=36 with paired leukapheresis material previously phenotyped by flow cytometry. In vitro CAR T-cells were manufactured from starting patient T-cells and analyzed for CAR T-cell phenotype and function. Results: In the leukapheresis material of patients that did not achieve long-term remission after CAR T-cell therapy, and in those with high tumor burden, we found higher numbers of CD4+CD39+ and CD8+CD39+ T-cells ( Figs. 1 and 2). 10X multiome sequencing confirmed that CD39+ T-cells exhibit characteristics of exhaustion. Recent platinum-based chemotherapy did not affect CD39+ T-cell levels. In n=21 patients with paired serum analyzed by metabolomics, high CD8+CD39+ T-cells associated with reduced metabolites in the inosine-hypoxanthine pathway, which are downstream of the ectonucleotidase function of CD39 (inosine; P=0.006; hypoxanthine P=0.07). Increased numbers of CD39+ T-cells in the starting leukapheresis material translated into manufactured CAR T-cells having less favorable product characteristics, including higher CD39 expression and fewer memory cells in both paired patient samples and in experiments of in vitro CAR T-cell manufacturing. ScRNA-seq of the infused CAR T-cell product revealed differential gene signatures, both globally and in association with response, between axi-cel and tisa-cel CAR T-cell products, highlighting the profound product-specific differences. Nonetheless, both products were adversely affected by high CD39+ T-cells in the leukapheresis material used for manufacture. Conclusions: CD39+ T-cells, found in patients with high lymphoma tumor burden and an unfavourable immunometabolic environment, associate with poor CAR T-cell quality and adverse patient outcomes in R/R LBCL. Strategies are needed to improve patient T-cell quality prior to leukapheresis and/or improve CAR T-cell manufacturing from patients with high levels of exhausted CD39+ T-cells. Figure 1: Progression-free survival (PFS) stratified by leukapheresis CD8+CD39+ T-cells in the leukapheresis product. Blue - below cohort median percentage of CD8+T-cells that are CD39+ (low); Red - above median percentage of CD8+T-cells that are CD39+ (high). P-value by Log-Rank test. Overall survival (not shown) P-value 0.01. Figure 2: Proportion of CD8+CD39+ T-cells found in patients with low or high baseline metabolic tumor volume (MTV) based on a previously established cutoff (Dean et al. Blood Adv. 2020). MTV was measured on the pre-CAR T-cell PET/CT. P-value by T-test. MDJ, XY, and RMA are co-first authors with equal contribution.

Dynamics of Radiomic Features Following Bridging Therapy Determine CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy Outcome

Introduction: Greater burden of disease is associated with poorer outcomes after CAR T therapies. Bridging therapy (BT) is widely used to debulk or palliate between apheresis and CAR T infusion. We studied whether the degree and dynamics of radiomic cytoreduction during the bridging period are prognostic. Methods: Patients with large B-cell lymphoma (LBCL) treated with CD19 CAR T from 2016-2022 were stratified into 3 BT cohorts: 1) no BT 2) radiotherapy (RT) or 3) systemic therapy (ST) including combined ST+RT. All patients had a pre-apheresis PET. Patients in the RT or ST cohorts also had a repeat PET post-BT but pre-CAR T infusion. Radiomic parameters of interest including max SUV and metabolic tumor volume (MTV) were calculated for all scans. MTV was determined using a semi-automated method and SUV4 threshold. Max SUV and MTV pre- and post-BT were compared using Wilcoxon signed-rank tests. Kaplan Meier was used to calculate progression free survival (PFS) and overall survival (OS) from CAR T infusion; univariable and multivariable analysis were performed by Cox proportional hazards. Patients were stratified by disease burden using an absolute MTV cutpoint established based on pre-BT PET with a maximally selected log-rank statistic for PFS via the maxstat package in R. “High” and “low” MTV were defined as MTV above or below this cutpoint, respectively. To quantify the impact of effective cytoreduction during BT, we created 4 BT MTV risk groups: a) “Low” with low MTV pre and post BT, b) “High” with high MTV pre and post BT, c) “Rising” with baseline low MTV which increased to high post BT and d) “Improved” with baseline high MTV which decreased to low post BT. Results: 158 patients with LBCL (79%), high grade BCL (17%) or primary mediastinal BCL (4%) received CAR T (51% axicabtagene, 28% tisagenlecleucel, 21% lisocabtagene). 42 (27%) received no BT, 93 (59%) had ST, 23 (15%) had RT. With median follow-up of 28.6 months, 12- and 24-month PFS were 43% and 36% and OS were 68% and 54%, respectively. Median pre-BT SUV max was 19 (range: 0-47) which reduced significantly to 13 post-BT (p&amp;lt;0.001). Median baseline MTV was 55cc (0-2,278) which reduced 40% to 33cc post-BT (p=0.001). Of the 116 patients who received BT, 67% had any degree of quantitative cytoreduction post-BT and only 35% achieved at least 50% MTV reduction [Fig A]. In the RT bridged 2yr PFS was 52% (95% CI: 32-83) vs. No BT (37%, 95% CI: 24-56) or ST bridged (33%, 95% CI: 24-45). Our established MTV cutoff was 35.5cc and was significantly associated with PFS both pre-BT and post-BT. The MTV dynamics during BT were further prognostic [Fig B] with best PFS seen in the Low risk group (1yr PFS: 73%) and worst in the High risk (1yr PFS: 21%) and Rising risk groups. In contrast, despite high baseline MTV, the Improved risk group had comparatively better outcomes with 1yr PFS of 52%. In a multivariable model of the 116 patients who had BT, several factors were associated with poorer PFS including higher pre-BT LDH (HR 2.2, p=0.004) and BT MTV risk grouping (p&amp;lt;0.001). Of note, while the High risk group had significantly worse PFS vs. Low risk (HR 4.7, 95% CI: 2.1-10.5) outcomes for the Improved risk group did not differ significantly from Low risk (HR 2.1, 95% CI: 0.8-5.3). Conclusions: In our real-world experience, while most patients required BT, many did not achieve successful disease cytoreduction prior to CAR T cells. While disease extent both pre-apheresis and post-BT are prognostic, the quantitative dynamics of BT cytoreduction may further refine prognostic ability. BT responders have better outcomes while stably high or rising MTV through BT is associated with poor prognosis.

The Prognostic Role of [18F]FDG PET/CT in Patients with Advanced Cutaneous Squamous Cell Carcinoma Submitted to Cemiplimab Immunotherapy: A Single-Center Retrospective Study.

Background: Baseline 2-deoxy-2[18F]fluoro-d-glucose ([18F]FDG) positron emission tomography (PET)-derived parameters and 12-week metabolic response were investigated as prognostic factors in advanced cutaneous squamous cell carcinoma (cSCC) submitted to cemiplimab immunotherapy. Materials and Methods: Clinical records of 25 cSCC patients receiving cemiplimab, submitted to [18F]FDG positron emission tomography/computed tomography (PET/CT) at baseline and after ∼12 weeks, were retrospectively reviewed. The Kaplan-Meier (KM) method was applied to analyze differences in event-free survival (EFS), and Cox regression analysis was employed to identify the prognostic factors. Results: At the 12-week PET/CT evaluation, 16 patients (64%) were classified as responders (complete or partial response) and 9 (36%) as nonresponders ("unconfirmed progressive metabolic disease") according to immune PET Response Criteria in Solid Tumors (iPERCIST). By KM analysis, baseline metabolic tumor volume (MTV) and total lesion glycolysis (TLG) significantly correlated with the EFS (p < 0.05). Furthermore, the KM analysis showed that the lack of metabolic response at 12 weeks was associated with meaningfully shorter EFS (7.2 ± 1 months in nonresponders vs. 20.3 ± 2.3 months in responders). In Cox multivariate analysis, metabolic response at 12 weeks remained the only predictor of the EFS (p < 0.05). Conclusions: Baseline tumor load (i.e., MTV and TLG) and metabolic response at 12 weeks may have a prognostic impact in cSCC patients treated with cemiplimab.

Value of Baseline Metabolic Tumor Volume for Survival Prognosis and Optimization of Risk-Adapted Treatment Therapy in Patients with Extranodal Nasal-Type Natural Killer/T-Cell Lymphoma

To assess the association of baseline metabolic tumor volume (MTV) with overall survival (OS) and to explore its potential role in optimization of existing risk-adapted therapy in ENKTCL. A total of 133 ENKTCL patients mainly treated by radiotherapy (RT) alone (33.8%) or RT combined with chemotherapy (combined-modality therapy [CMT]) (60.9%) were prospectively included. The impacts of MTV, SUVmax derived from 18F-FDG PET/CT image and clinical factors on OS were investigated. Survival analyses were conducted using Kaplan-Meier method with log-rank tests. Cox proportional hazards regression analysis was used to identify multivariate predictors of OS. Regression-based mediation analysis estimated the hazard ratio (HR) of death for direct effect (not through distant metastasis or locoregional recurrence) and indirect effect (through distant metastasis or locoregional recurrence) of the pathway MTV→distant metastasis→OS and pathway MTV→locoregional recurrence→OS. Inverse probability of treatment weighting (IPTW) analysis was employed to make covariate adjustments. MTV and SUVmax were correlated with LDH, PTI, Ann Arbor stage, and NRI score. In univariable analysis, SUVmax, MTV, ECOG PS, PTI and Ann Arbor stage were statistically significantly prognostic factors for OS. Multivariate analysis showed that MTV was the only independent factor of short OS (HR 4.98, 95% CI (1.85 - 13.42), p = 0.002). Mediation analysis showed that distant metastasis played a complete mediating role in the increased death caused by higher MTV (HR of indirect effect 3.15, 95% CI (1.34 - 7.41), p = 0.009; HR of direct effect 2.88, 95% CI (0.80 - 10.32), p = 0.767), with proportion of mediation 76.7%, while locoregional recurrence was not a mediating factor (HR of indirect effect 1.16, 95% CI (0.90 - 1.48), p = 0.255; HR of direct effect 4.48, 95% CI (1.30 - 15.44), p = 0.017) . After adjusting the clinical factors by IPTW between RT alone group and CMT group in early intermediate and high risk ENKTCL, CMT had no PFS and OS benefits compared with RT alone in the low-MTV group (MTV < 49.6ml), while in the high-MTV group (MTV ≥ 49.6ml), the use of CMT compared with RT alone prolonged PFS and OS. Baseline metabolic tumor volume is an independent prognostic factor for overall survival and distant metastasis rather than locoregional recurrence mediated increased risk of death in patients with MTV higher than 49.6ml. For early-stage intermediate and risk ENKTCL patients with MTV lower than 49.6ml, omission of chemotherapy may not result in loss of PFS and OS.

18F-AlF-NOTA-FAPI-04 PET/CT can Predict Treatment Response and Survival in Patients with Inoperable Pancreatic Adenocarcinoma

We investigated whether uptake of 18F-AlF-NOTA-FAPI-04 on positron emission tomography/computed tomography (PET/CT) could predict treatment response and survival in patients with pancreatic adenocarcinoma (PAAD). We prospectively evaluated 47 patients with histopathologically confirmed primary PAAD and pretreatment 18F-FAPI PET/CT scans to determine uptake of fibroblast activation protein (FAP) and compare the findings with those from blood tests and immunohistochemically stained tumor specimens. Cox regression and Kaplan-Meier methods were used to assess relationships between disease progression and potential predictors. Receiver operating characteristic (ROC) curve analysis was used to define the optimal cutoff points for distinguishing patients according to good response vs poor response per RECIST v. 1.1. The FAPI PET variables maximum and mean standardized uptake values (SUVmax, SUVmean); metabolic tumor volume (MTV); and total lesion FAP expression (TLF) were positively correlated with cancer-associated fibroblast (CAF) markers (FAP, α-smooth muscle actin, vimentin, S100A4, and platelet-derived growth factor receptor α/β, all P<0.05). MTV and Log2TLF were associated with survival in patients with inoperable PAAD (all P<0.05). Analyses controlling for sex, age, cTNM, and performance status showed that MTV and Log2TLF were associated with overall survival (MTV hazard ratio [HR] = 1.016, P = 0.016 and Log2TLF HR = 4.093, P = 0.003). ROC cutoff analysis indicated that elevated MTV and TLF were associated with poorer survival. Greater changes from before to after chemotherapy in SUVmax, MTV, and TLF were associated with good treatment response (all P<0.05). ΔMTV, ΔTLF and ΔSUVmax had larger areas under the curve than ΔCA19-9 for predicting treatment response. Kaplan-Meier analysis showed that the extent of change in MTV and TLF from before to after treatment predicted progression-free survival, with cutoff values (based on medians) of -4.95 for ΔMTV (HR = 8.09, P = 0.013) and -77.83 for ΔTLF (HR = 4.62, P = 0.012). Higher baseline MTV on 18F-FAPI-04 PET/CT scans was associated with poorer survival in patients with inoperable PAAD. ΔMTV was more sensitive for predicting response than ΔCA19-9. These results are clinically meaningful for identifying patients with PAAD who are at high risk of disease progression.

Prognostic value of baseline metabolic tumor volume (MTV) for forecasting chemotherapy outcome in early-stage unfavorable Hodgkin lymphoma: Data from the phase III HD17 trial.

The prognostic relevance of metabolic tumor volume (MTV) having recently been demonstrated in patients with early-stage favorable and advanced-stage Hodgkin lymphoma. The current study aimed to assess the potential prognostic value of 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in early-stage unfavorable Hodgkin lymphoma patients treated within the German Hodgkin Study Group HD17 trial. 18 F-FDG PET/CT images were available for MTV analysis in 154 cases. We used three different threshold methods (SUV2.5 , SUV4.0 , and SUV41% ) to calculate MTV. Receiver-operating-characteristic analysis was performed to describe the value of these parameters in predicting an adequate therapy response. Therapy response was evaluated as PET negativity after 2 cycles of eBEACOPP followed by 2 cycles of ABVD. All three threshold methods analyzed for MTV showed a positive correlation with the PET response after chemotherapy. Areas under the curve (AUC) were 0.70 (95% CI 0.53-0.87) and 0.65 (0.50-0.80) using the fixed thresholds of SUV4.0 and SUV2.5 , respectively, for MTV- calculation. The calculation of MTV using a relative threshold of SUV41% showed an AUC of 0.63 (0.47-0.79). MTV does have predictive value after chemotherapy in early-stage unfavorable Hodgkin lymphoma, particularly when the fixed threshold of SUV4.0 is used for MTV calculation. ClinicalTrials.gov NCT01356680.

18F] AlF-NOTA-FAPI-04 PET/CT can predict treatment response and survival in patients receiving chemotherapy for inoperable pancreatic ductal adenocarcinoma.

We investigated whether uptake of [18F] AlF-NOTA-FAPI-04 on positron emission tomography/computed tomography (PET/CT) could predict treatment response and survival in patients with pancreatic ductal adenocarcinoma (PDAC). We prospectively evaluated 47 patients with histopathologically confirmed primary PDAC who provided pretreatment [18F] AlF-NOTA-FAPI-04 scans to detect fibroblast activation protein (FAP) on the tumor surface by uptake of [18F] AlF-NOTA-FAPI-04. PDAC specimens were immunohistochemically stained with cancer-associated fibroblast (CAF) markers. We obtained a second PET scan after one cycle of chemotherapy to study changes in FAPI uptake variables from before to during treatment. Correlations between baseline PET variables and CAF-related immunohistochemical markers were assessed with Spearman's rank test. Cox regression and Kaplan-Meier methods were used to assess relationships between disease progression and potential predictors. Receiver operating characteristic (ROC) curve analysis was used to define the optimal cut-off points for distinguishing patients according to good response vs. poor response per RECIST v.1.1. The FAPI PET variables maximum and mean standardized uptake values (SUVmax, SUVmean), metabolic tumor volume (MTV), and total lesion FAP expression (TLF) were positively correlated with CAF markers (FAP, α-smooth muscle actin, vimentin, S100A4, and platelet-derived growth factor receptor α/β, all P < 0.05). MTV was associated with survival in patients with inoperable PDAC (all P < 0.05). Cox multivariate regression showed that MTV was associated with overall survival (MTV hazard ratio [HR] = 1.016, P = 0.016). Greater changes from before to during chemotherapy in SUVmax, MTV, and TLF were associated with good treatment response (all P < 0.05). ΔMTV, ΔTLF, and ΔSUVmax had larger areas under the curve than ΔCA19-9 for predicting treatment response. Kaplan-Meier analysis showed that the extent of change in MTV and TLF from before to after treatment predicted progression-free survival, with cut-off values (based on medians) of - 4.95 for ΔMTV (HR = 8.09, P = 0.013) and - 77.83 for ΔTLF (HR = 4.62, P = 0.012). A higher baseline MTV on [18F] AlF-NOTA-FAPI-04 scans was associated with poorer survival in patients with inoperable PDAC. ΔMTV was more sensitive for predicting response than ΔCA19-9. These results are clinically meaningful for identifying patients with PDAC who are at high risk of disease progression.

Brain FDG-PET findings in chimeric antigen receptor T-cell therapy neurotoxicity for diffuse large B-cell lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy is potentially associated with treatment-related toxicities mainly consisting of cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS). We evaluated brain metabolic correlates of CRS with and without ICANS in diffuse large B-cell lymphoma patients treated with CAR-T. Twenty-one refractory DLCBLs underwent whole-body and brain [18 F]-fluorodeoxyglucose (FDG) PET before and 30days after treatment with CAR-T. Five patients did not develop inflammatory-related side effects, 11 patients developed CRS, while in 5 patients CRS evolved in ICANS. Baseline and post-CAR-T brain FDG-PET were compared with a local controls dataset to identify hypometabolic patterns both at single-patient and group levels (p<.05 after correction for family-wise error [FWE). Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were computed on baseline FDG-PET and compared between patients' subgroups (t-test). ICANS showed an extended and bilateral hypometabolic pattern mainly involving the orbitofrontal cortex, frontal dorsolateral cortex, and anterior cingulate (p<.003 FWE-corrected). CRS without ICANS showed significant hypometabolism in less extended clusters mainly involving bilateral medial and lateral temporal lobes, posterior parietal lobes, anterior cingulate, and cerebellum (p<.002 FWE-corrected). When compared, ICANS showed a more prominent hypometabolism in the orbitofrontal and frontal dorsolateral cortex in both hemispheres than CRS (p<.002 FWE-corrected). Mean baseline MTV and TLG were significantly higher in ICANS than CRS (p<.02). Patients with ICANS are characterized by a frontolateral hypometabolic signature coherently with the hypothesis of ICANS as a predominant frontal syndrome and with the more prominent susceptibility of frontal lobes to cytokine-induced inflammation.

THE LOW‐RISK EARLY‐STAGE HODGKIN LYMPHOMA PATIENTS WITH INADEQUATE RESPONSE TO CHEMOTHERAPY. THE PRELIMINARY EXPERIENCE FROM THE RAFTING TRIAL

Introduction: Early-stage Hodgkin Lymphoma (eHL) treated with a combined modality approach (CMT): chemotherapy (CT) and radiotherapy (RT) is a highly curable disease. However, for 70% of eHL patients (pts.) CT alone might be sufficient for cure. The RAFTING trial is a phase 2, multicenter, international prospective study investigating risk-adapted treatment strategy in eHL pts. We hypothesized that CT alone will be sufficient for to cure low-risk pts. Here we would like to present the clinical characteristics of low-risk pts. for whom CT was not sufficient to achieve a complete response (CR). Methods: Treatment intensity in RAFTING is tailored to two risk categories: low or high risk. Low-risk pts. are defined by low baseline metabolic tumor volume (MTV) and negative interim PET after 2 ABVD cycles. High-risk pts. were defined by high baseline MTV and/or positive iPET2. Within the low-risk group the pts. without any risk factors according to modified EORTC (mEORTC) criteria (largest nodal mass (LNM) 5–10 cm, Age > 50 yo, ESR > 50 mm/h, ≥4 nodal areas (NA)) (group 1a) are treated with 2 ABVD cycles only whereas pts. with at least 1 risk factor (group 1b)—with 4 ABVD cycles. High-risk pts. (group 3) receive “triple” therapy (4 ABVD cycles, RT and nivolumab for 12 months; RT-NIV). In case of “limited relapse” (i.e., within initially involved lymph nodes and/or up to 3 new nodal areas) pts. receive delayed RT-NIV. Results: In a per-protocol analysis, out of 77 stratified pts. in March 2023, seven pts. (9%) with low-risk disease, had inadequate response to ABVD alone (defined as achievement less than CR or early relapse (<6 months after the end of the CT): 2 pts. from group 1a and 5 pts. from group 1b. Specifically, one pt. from Group 1a had an extended and symptomatic (B symptoms) relapse, and underwent salvage therapy with ASCT and two pts. from group 1b were withdrawn due to PI decision. While 4 pts. (1 in Group 1a and 3 in Group 1b) with less than CR (2 pts.) or early relapse (2 pts.) received RT + NIV. The most frequent risk factor among 1b pts. was LNM, which was observed in 4 pts., age >50 yo—in 2 patients, and ≥4 NA—in 1 pt. More than 1 risk factor had 2 pts. In 4 cases the confirmatory biopsy was done and was positive for HL in 3 out of 4 cases. Conclusion: The frequency of inadequate response after CT alone observed in the RAFTING trial was similar to that reported by the literature. The most frequent adverse prognostic factor presented in these small pts. subset was a LNM. Keywords: combination therapies, Hodgkin lymphoma, radiation therapy No conflicts of interests pertinent to the abstract.

A novel prognostic index for diffuse large B-cell lymphoma combined baseline metabolic tumour volume with clinical and pathological risk factors.

This study aimed to develop a novel prognostic index integrating baseline metabolic tumour volume (MTV) along with clinical and pathological parameters for diffuse large B-cell lymphoma (DLBCL). This prospective trial enrolled 289 patients with newly diagnosed DLBCL. The predictive value of novel prognostic index was compared with Ann Arbor staging and National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI). We used the concordance index (C-index) and a calibration curve to determine its predictive capacity. Multivariate analysis revealed high MTV (>191 cm 3 ), Ann Arbor stage (III-IV) and MYC/BCL2 double expression lymphoma (DEL) to be independently associated with inferior progression-free survival (PFS) and overall survival (OS). Ann Arbor stage and DEL could be stratified by MTV. Our index, combining MTV with Ann Arbor stage and DEL status, identified four prognostic groups: group 1 (no risk factors,), group 2 (one risk factor), group 3 (two risk factors), and group 4 (three risk factors). The 2-year PFS rates were 85.5, 73.9, 53.6, and 13.9%; 2-year OS rates were 94.6, 87.0, 67.5, and 24.2%, respectively. The C-index values of the novel index were 0.697 and 0.753 for PFS and OS prediction, which was superior to Ann Arbor stage and NCCN-IPI. The novel index including tumour burden and clinicopathological features may help predict outcome of DLBCL (clinicaltrials.gov identifier: NCT02928861).

Abstract P6-01-42: BASELINE 18FDG-PET METABOLIC TUMOUR VOLUME (MTV) AS A POTENTIAL PREDICTIVE FACTOR OF RESPONSE TO METRONOMIC CHEMOTHERAPY (mCHT) IN HR+/HER2- METASTATIC BREAST CANCER (MBC) PATIENTS (pts). PRELIMINARY RESULTS OF THE METRO-PET STUDY

Abstract Background: MBC is an incurable disease and chemotherapy (CHT) represents one option of treatment upfront, in TNBC pts, or at failure of an endocrine therapy + targeted agents in HR+ ones. mCHT was extensively studied in different types of ABC pts and is largely used in clinical practice. 18FDG-PET is often used as a tool for disease staging at baseline and for disease restaging during treatment. Different quantitative and semi-quantitative 18FDG-PET parameters have been investigated as predictive and prognostic biomarkers in NSCLC and other tumours. Aim of the present study is to evaluate the role of baseline SUVmax , global SUVmean, SUVpeak, Metabolic Tumour Volume (MTV) and Total Lesion Glycolysis (TLG) as predictive factors of response to mCHT. Patients and Methods: We identified 36 MBC pts treated with mCHT between 2014 and 2021, with at least two separate 18FDG-PET evaluations. Patients and biological tumour characteristics, previous treatments, site of relapse as well as quantitative pre-treatment 18FDG-PET parameters have been collected. Tumour response was assessed using PERCIST Criteria. Median and mean ± SD 18FDG-PET parameters have been reported according to the type of response. Complete and Partial responses have been grouped together with Stable Disease. Results: Median age was 69 (33-82). Luminal pts were 25 (67.6%), TNBC pts were 16.2%); most were heavily pre-treated for their metastatic disease (≥ 3 lines: 14, 37.8%) and presented ≥ 3 metastatic sites (14, 37.8%). All pts received mCHT, 26 (70.3%) as combination therapy (VRL+CAPE or VRL+CAPE+CTX), or single agent (VRL, 11). Bone was the commonest metastatic site (62.2%). ORR was 43.2%; 7 pts had SD (18.9%), the remaining developed PD (37.8%). Similar values have been observed between the 2 groups in terms of SUVmax , global SUVmean and SUVpeak,. Mean MTV was higher in responder (n=22) vs non responder (n=14) pts, as TLG. Details are reported in Table 1. Conclusions: High mean baseline MTV and TLG seem to be related to response to mCHT in MBC pts. Our observation is in contrast to what is described for other cancer types, especially NSCLC, and for standard neoadjuvant treatment of BC. Considering the peculiar mechanisms of action of mCHT, our preliminary findings warrant further exploration in a larger series of BC pts. Table 1 Baseline 18FDG-PET uptake values in responder and non responder patients Citation Format: Marco Meazza Prina, Irene Gotuzzo, Marina Elena Cazzaniga, Elisabetta De Bernardi, Pietro Cafaro, Serena Capici, Viola Cogliati, Francesca Fulvia Pepe, Federica Cicchiello, Francesca Riva, Nicoletta Cordani, Maria Grazia Cerrito, Elia Anna Turolla, Claudio Landoni, Federica Elisei, Cinzia Crivellaro, Leonardo Virdone, Lavinia Monaco, Alessandro Guidi, Luca Guerra. BASELINE 18FDG-PET METABOLIC TUMOUR VOLUME (MTV) AS A POTENTIAL PREDICTIVE FACTOR OF RESPONSE TO METRONOMIC CHEMOTHERAPY (mCHT) IN HR+/HER2- METASTATIC BREAST CANCER (MBC) PATIENTS (pts). PRELIMINARY RESULTS OF THE METRO-PET STUDY [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-42.

Prognostic Value of 18F-FDG PET/CT in Diffuse Large B-Cell Lymphoma Treated with a Risk-Adapted Immunochemotherapy Regimen.

Early identification of patients with diffuse large B-cell lymphoma (DLBCL) who are likely to experience disease recurrence or refractory disease after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) would be useful for improving risk-adapted treatment strategies. We aimed to assess the prognostic value of 18F-FDG PET/CT parameters at baseline, interim, and end of treatment (EOT). Methods: We analyzed the prognostic impact of 18F-FDG PET/CT in 166 patients with DLBCL treated with a risk-adapted immunochemotherapy regimen. Scans were obtained at baseline, after 4 cycles of R-CHOP or 3 cycles of RR-CHOP (double dose of R) and 1 cycle of CHOP alone (interim) and 6 wk after completing therapy (EOT). Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier and the impact of clinical/PET factors assessed with Cox models. We also assessed the predictive ability of the recently proposed International Metabolic Prognostic Index (IMPI). Results: The median follow-up was 7.9 y. International Prognostic Index (IPI), baseline metabolic tumor volume (MTV), and change in maximum SUV (ΔSUVmax) at interim scans were statistically significant predictors for OS. Baseline MTV, interim ΔSUVmax, and EOT Deauville score were statistically significant predictors of PFS. Combining interim PET parameters demonstrated that patients with Deauville 4-5 and positive ΔSUVmax ≤ 70% at restaging (∼10% of the cohort) had extremely poor prognosis. The IMPI had limited discrimination and slightly overestimated the event rate in our cohort. Conclusion: Baseline MTV and interim ΔSUVmax predicted both PFS and OS with this sequential immunochemotherapy program. Combining interim Deauville score with interim ΔSUVmax may identify an extremely high-risk DLBCL population.

Brentuximab Vedotin Combined with Chemotherapy in Newly Diagnosed, Early-Stage, Unfavorable-Risk Hodgkin Lymphoma: Extended Follow-up with Evaluation of Baseline Metabolic Tumor Volume and PET2

INTRODUCTION: While the majority of patients with early-stage (ES), bulky Hodgkin lymphoma (HL) can be cured with modern approaches, approximately 15% of patients with bulky HL relapse. Improving upfront approaches while minimizing long-term adverse effects remains integral. We previously reported the results of a multicenter pilot study of 4 cycles of brentuximab vedotin (BV) and doxorubicin, vinblastine, and dacarbazine (AVD) followed by 1 of 4 approaches if positron emission tomography (PET)-4 negative. The treatment program was highly active and well-tolerated. We now present extended results and prognostic evaluation of baseline metabolic tumor volume (MTV) and PET2 results. METHODS: Full methodology has been published (Kumar et al., J. Clin Oncol. 2021). Briefly, patients with untreated HL were enrolled into 1 of 4 sequential cohorts. In cohort 1 (C1), eligible patients had any of the following unfavorable (UF) risk factors: bulky mediastinal mass, ESR ≥ 50 mm/h or ≥ 30 mm/h if B symptoms, extranodal involvement, > 2 lymph node sites, or infradiphragmatic disease. The same criteria applied to C2, except for bulk being defined by the Memorial Sloan Kettering (MSK) definition (maximal transverse or coronal diameter of the largest mass > 7 cm). In C3 and C4, all patients were required to have MSK criteria bulk. All cohorts received BV-AVD x 4. Patients with a PET-negative response after 4 cycles received 30-Gy involved site radiation therapy (ISRT) in C1, 20-Gy ISRT in C2, 30-Gy consolidative-volume RT (CVRT) in C3, and no RT in C4. For 84 patients at MSK, baseline MTV was measured using the 41% maximum standard uptake value (SUV) threshold method. Interim PET after 2 cycles was interpreted using the 5-point scale with scores ≤ 3 considered negative. Survival data was updated through July 1, 2022. Progression-free (PFS) and overall survival (OS) probabilities were estimated by the Kaplan-Meier method and compared for various features using the log-rank test, with a p-value of ≤ 0.05 statistically significant. RESULTS: Of 117 patients enrolled, 116 completed chemotherapy. With a median followup of 4.6 years (6.7, 5.3, 4.5, and 3.3 years for C1-4), there were 8 progression events and 2 deaths. Since original publication, 1 further progression occurred amongst a patient in C4. The median PFS and OS have not been reached in either group. The overall 4-year PFS and OS were 93% and 98%, respectively. The 4-year PFS for C1-4 was 93%, 96%, 90%, and 93%, respectively (p=0.78). Next, outcomes were compared by MTV and PET2. Among 84 patients assessed for baseline MTV, median MTV was 150 (range 13-827) cm3. Using the median MTV to stratify patients, overall 4-year PFS in the MTV-high (n=43) versus MTV-low (n=41) group was 91% versus 100%, respectively (p=0.047). Fourteen patients (12%) had positive PET2. Four-year PFS in the PET2 positive versus negative group was 79% versus 95%, respectively (p=0.02). By MTV and PET2, 4-year PFS for the MTV-low/PET2-negative (n=36), MTV-low/PET2-positive (n=5), MTV-high/PET2-negative (n=38), and MTV-high/PET2-positive (n=5) groups was 100%, 100%, 95%, and 60%, respectively (p=0.001) (Figure 1). Within these 4 groups, there were 4 progression events, 2 within the MTV-high/PET2-negative group and 2 within the MTV-high/PET2-positive group. The 2 patients in the MTV-high/PET2-negative group had Deauville score (DS) 2 on PET2 and then developed DS4 on PET4; 1 received salvage R-ICE (concomitant CD20 expression) followed by autologous transplant (autoSCT), and 1 received salvage pembrolizumab-GVD followed by autoSCT. The 2 patients within the MTV-high/PET2-positive group had DS4 on PET2 and PET4. One patient received salvage augmented ICE followed by radiation and autoSCT. The other patient had a negative biopsy of PET4 disease and completed CVRT, but relapsed 2 months later and received salvage augmented ICE and autoSCT. All 4 of these patients remain without disease after a median follow-up post autoSCT of 65 (28-86) months. CONCLUSIONS: We report extended followup of short-course BV-AVD followed by various doses/fields of RT, including no RT, in ES, bulky HL. The BV-AVD program remains highly active and well-tolerated, including in the absence of consolidative RT for certain patients. Baseline MTV and PET2 identifies an unfavorable cohort at higher risk of treatment failure. Trials in ES, bulky HL should evaluate stratified treatment paradigms using baseline MTV and PET2. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immune Signature of Pembrolizumab Plus Gemcitabine, Vinorelbine, and Liposomal Doxorubicin As Second-Line Therapy for Relapsed or Refractory Classical Hodgkin Lymphoma

Introduction: In our phase II study (Moskowitz AJ et al, JCO 2021), pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (P-GVD) was found to be highly effective as salvage for patients (pts) with relapsed or refractory (R/R) classic Hodgkin lymphoma (cHL) proceeding to high dose therapy and autologous hematopoietic cell transplantation (AHCT). We present analyses assessing immunologic changes associated with P-GVD treatment as well as updated clinical outcome. Methods: Transplant eligible pts with R/R cHL following failure of 1-line of therapy were eligible. Treatment consisted of 2 to 4 cycles of P-GVD followed by AHCT. Peripheral blood samples were collected at baseline, after 2 cycles of P-GVD, before AHCT, 3 and 9 months after AHCT. Peripheral blood was analyzed for serum thymus and activation-regulated chemokine (TARC) and immune cell subsets. TARC was measured by enzyme-linked immunosorbent assay. Immune cell subsets, including T-cells and myeloid-derived suppressor cells (MDSC), were measured by multi-parametric flow cytometry (FC). Metabolic tumor volume (MTV) was evaluated at baseline. Changes in MDSC and TARC levels were assessed using Wilcoxon rank sum and Friedman tests, respectively. Correlations between MTV and either TARC or MDSC were assessed using Pearson's R. Results: Of 38 evaluable pts, the complete response (CR) rate after 2 or 4 cycles of P-GVD was 95%. Two pts declined AHCT and 36 proceeded to AHCT. After a median follow-up of 30 months (range: 2-43), only 1 pt experienced disease progression 23 months after AHCT. The estimated 30-month progression-free survival (PFS) is 96%. The median baseline MTV value was 37 cm3 (range 4- 845). 36/38 and 27/38 pts had sufficient correlative samples to perform analysis for TARC and MDSC analysis, respectively. The median baseline TARC level was 526 pg/mL (range: 12-4017). TARC levels decreased significantly after 2 cycles of P-GVD (p < 0.001) and increased post-AHCT. Circulating MDSCs were 0.05% of total mononuclear cells (range: 0.003-0.59%) and significantly increased after 2 cycles of P-GVD (p<0.001). Higher baseline TARC and circulating MDSC levels correlated with higher baseline MTV (r=0.45, 95% CI: 0.11-0.70, p<0.01 and r=0.46, 95%CI 0.03-0.76, p=0.03, respectively). High-dimensional analysis of FC data revealed several distinct immune clusters (Figure 1), of which non-proliferating PD-1+ CD4+ T-cells decreased most significantly following treatment (Figure 2). Additional markers (ICOS, CTLA-4, LAG-3, FOXP3) of immune exhaustion showed only a mild decrease over the treatment course. Conclusions: After a median of 30-months follow-up, second-line P-GVD continues to be associated with durable remissions after AHCT. These analyses provide insights into key immune changes associated with chemoimmunotherapy in HL. Baseline TARC correlated with baseline MTV and was significantly lower after P-GVD, illustrating its role as a marker of tumor bulk. The subsequent rise in serum TARC post AHCT suggests immune reconstitution of TARC-secreting cells. Higher circulating levels of MDSCs correlated with baseline MTV, which may reflect an association between immune suppression and tumor bulk. MDSC levels unexpectedly increased after P-GVD, indicating that a rise in MDSCs after treatment may not necessarily predict for poor outcomes. Ongoing single-cell RNA sequencing analysis of peripheral blood mononuclear cells (PBMC) may provide further understanding into immune dynamics associated with P-GVD treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Circulating Tumor DNA in Untreated Classical Hodgkin Lymphoma Patients Treated with Pembrolizumab and Chemotherapy: Dynamic Response Assessment and Correlation with Baseline Metabolic Tumor Volume

Introduction We have previously presented early results of untreated CHL patients treated with concurrent pembrolizumab + AVD (Lynch et al. ASH 2021) which was highly effective but had increased rates of false positive PET/CT results leading to additional scans and/or biopsies. Circulating tumor DNA (ctDNA) may represent a more sensitive and specific method of response assessment. Herein we report updated clinical results with correlation of dynamic ctDNA monitoring as well as data on total metabolic tumor volume (TMTV). Methods This was a single arm pilot study combining pembrolizumab with AVD in untreated CHL of any stage. Pembrolizumab 200 mg IV was administered every 21 days concurrently with AVD chemotherapy. AVD was administered at the standard dosing and schedule. Plasma samples were analyzed for ctDNA at baseline, post cycle 1 (if available), post cycle 2, and end of treatment. ctDNA levels were quantified as haploid genome equivalents/mL plasma using CAPP-Seq and PhasED-Seq (Kurtz et al. Nat Biotech 2021). Baseline, post cycle 2, and end of treatment PET/CT were analyzed for TMTV using a threshold based semiautomated technique that included any tumor with standardized uptake value (SUV) above the liver background SUVmax using MIM Encore (version 7.1.3 Cleveland, OH). Results Among the 30 patients enrolled, 29 are evaluable for response and/or exploratory analysis (one patient withdrew from study treatment prior to any response assessment). With median follow-up of 21 months, 2-year PFS and OS were 97% and 100%, respectively. While 5 patients had residual FDG uptake at EOT, only 1 (20%) has developed recurrent Hodgkin lymphoma. ctDNA data was available for 18 patients. Pretreatment ctDNA levels were significantly correlated with TMTV (RS=0.68, p=0.003). 17/18 patients had detectable ctDNA at baseline and were therefore evaluable for MRD assessment. Among 8 PET2+ patients, only 1 patient had detectable ctDNA, and ctDNA became undetectable by the end of treatment. Importantly, of these 8 patients, none have relapsed. Only 1/9 (11%) patients who were PET2- had detectable ctDNA after 2 cycles, and the cancer ultimately recurred. At EOT for those who received > 2 cycles, 2/14 had detectable ctDNA (one CHL relapse, one with secondary DLBCL 11 months later). ctDNA analyses for the remaining patients are in process and will be presented at the meeting. Conclusion Concurrent pembrolizumab + AVD represents highly effective frontline therapy for CHL, but results in spurious PET findings in a significant proportion of patients despite most patients having undetectable ctDNA and no relapse. ctDNA may represent a more sensitive and specific response assessment tool to be studied in larger datasets. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High Metabolic Tumor Volume Is Associated with Higher Toxicity and Decreased Efficacy of BCMA CAR-T Cell Therapy in Multiple Myeloma

Background Recently, two chimeric antigen receptor T-cell (CAR-T) constructs have been FDA approved for relapsed/refractory multiple myeloma (RRMM) after exposure to at least 4 prior lines of therapy. High tumor burden has been associated with inferior outcomes, reduced CAR-T expansion and higher rates of toxicity. Patients relapsing after multiple lines of therapy more frequently have oligosecretory and extra-medullary disease that may not be well captured by serum-based markers of disease or bone marrow infiltration, respectively. Functional imaging with FDG-PET is well established as a useful tool in patients with myeloma but its prognostic impact in highly refractory patients or those proceeding with CAR-T has not been described. Metabolic tumor volume (MTV) capturing all metabolically active disease can be useful as a more global assessment of disease burden. We sought to evaluate tumor burden as measured by MTV in a cohort of patients presenting for anti-BCMA CAR-T with RRMM. Methods We identified all patients presenting to our center treated with anti-BCMA CAR-T with available restaging imaging performed within 60 days prior to lymphodepleting chemotherapy (LD-chemo). Baseline skull to midthigh with or without leg/whole-body 18F-FDG PET/CT scans were evaluated for MTV using a custom tool implemented on MIM PACS version 7.1 (MIM Software, Cleveland, OH) as previously reported (Dean et al, Blood Adv 2020). Briefly, images were semi-automatically analyzed to identify abnormal regions with reference to average metabolic activity of normal liver defined by PET SUV. Metabolically active volume at the lesion level were converged based on PERCIST criteria (41% of SUVmax). Summation of the metabolically active volumes across the human body is reported as the Metabolically Tumor Volume (MTV), measured in ml. Patient image scans were reviewed centrally by a radiologist blinded to outcomes, who removed any false positive uptake unrelated to metabolically active disease. Patients with the following FISH cytogenetics were considered high risk (HR): t(4;14), t(14;16) and deletion 17p/monosomy 17 whereas the remainder were standard risk (SR). The high and low tumor volume groups were selected based on the median MTV value in cohort. Baseline laboratory tests (e.g. beta2 microglobulin (b2M), C-reactive protein (CRP)) and repeat bone marrow biopsy were obtained prior to LD-chemo. Soluble BCMA (sBCMA) was measured by ELISA on patients with available serum samples (R&D Systems, MN, USA #DY193). All analyses were conducted in Stata (16.1, StataCorp LLC, College Station, TX). Results The study cohort consisted of 66 patients. Median age was 65 years (range 36 - 81), 55% were male, 55% had ECOG 0-1 prior to LD-chemo and 65% received bridging therapy. 25 (38%) were categorized as HR based on FISH cytogenetics. Patients had received a median of 6 prior lines of therapy and median interval between PET and date of CART infusion was 14.5 days (range 2-54). Median MTV was 26.3ml (0.26-1073.87ml) and only 3/66 (5%) had no measurable PET-avid lesions captured by this algorithm. Patients with high MTV (>26) were more likely to have elevated baseline CRP >0.5mg/dL (p=0.007) and receive bridging therapy (60% vs 40%, p=0.02). MTV correlated with sBCMA levels on day -6 (r=0.82, p=0.003), and with baseline b2M (r=0.47, p=0.005), but MTV did not correlate well with percentage plasma cells in pre-CAR-T bone marrow biopsy (r=0.12, p=0.3). The risk of ³G2 CRS was significantly higher (44% vs 12%, p=0.02) and any grade ICANS was numerically higher (27% vs 12%, p=0.1) in those with high vs low MTV, respectively. Finally, fewer patients with high MTV achieved CR by D30 (19% vs 31%, p=0.2) and with limited follow up 12/14 (86%) of deaths had occurred in patients with high baseline MTV (p=0.003). Conclusion These preliminary data confirm the added value of MTV calculated from baseline imaging as part of standard of care in patients with heavily pre-treated relapsed myeloma presenting for anti-BCMA CAR-T therapy. MTV correlated highly with sBCMA measured at day-6 and may be more representative for risk assessment than basing burden on bone marrow plasma cell percentage, which has not demonstrated a consistent relationship in predicting adverse events to date. High MTV appears to be associated with an increased risk of CAR-T specific adverse events and inferior outcomes and warrants further investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal