Quantitative Change in Metabolic Tumor Volume May Assist in Distinguishing between Pseudoprogressors and Responders in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma Treated with PD-1 Blockade
Authors: Wills Beatriz , Michaud Laure , Schöder Heiko , Ganesan Nivetha , Moskowitz Craig H. , Straus David J. , Falchi Lorenzo , Matasar Matthew J. , Zelenetz Andrew D. , Joffe Erel , von Keudell Gottfried , Batlevi Connie Lee , Hamilton Audrey , Caron Philip C , Noy Ariela , Salles Gilles , Moskowitz Alison J. 
Published: November 2021

Abstract
Background:
In untreated Hodgkin lymphoma (HL), metabolic tumor volume (MTV) significantly declined following pembrolizumab monotherapy, regardless of baseline MTV, and may serve as a better measure of treatment response to PD-1 blockade than the Lugano Classification (Allen, et al. Blood 2021). Furthermore, standard PET evaluation can fail to differentiate between malignancy, pseudoprogression and physiological background in patients (pts) receiving PD-1 blockade. The predictive power and prognostic significance of MTV in patients with relapsed or refractory (RR) HL receiving PD-1 blockade is unknown. We sought to examine the role of MTV in HL pts treated with PD-1 blockade.
Methods:
We identified 30 pts who received pembrolizumab or nivolumab-based therapy off-study for RR HL between July 2015 and May 2021. In the PET/CT analysis, all lesions were visually identified, and all measurable lesions were selected for the analysis. Responses were assessed by Lugano Classification. Indeterminant response (IR) was defined as evidence of progression on PET without clinical deterioration as per the Lyric Criteria. MTV was obtained by summing the metabolic volumes of all measurable lesions, using the 41% SUVmax threshold to measure each lesion MTV using Beth Israel plugin. MTV was evaluated at baseline (MTV0) and at first reassessment (MTV1) after initiation of PD-1 blockade. Δ (delta) MTV was calculated as % change in MTV from MTV0 to MTV1. Receiver operating characteristic (ROC) curve was performed for ΔMTV and best overall response rate (BOR) to determine the optimal cut-off value. Overall survival (OS) was measured from PD-1 blockade initiation to death or last follow-up. We examined the association between MTV and clinical factors, PET-1 response, and overall survival using Cox proportional hazards model and Fisher exact test, respectively.
Results:
25 patients had complete clinical data and PET/CT analysis (Table 1). The median age at first relapse was 39 years (range: 18-81); 64% were male. 6 pts previously received PD-1 blockade on clinical trials and discontinued treatment due to study completion or toxicity. The median time between PET0 and PET1 was 3.4 months (range 2.0-7.3). Median MTV0 and MTV1 values were 39.8 ml and 17.1 ml, respectively. With a median follow up from initiation of PD-1 blockade among survivors of 38.7 months, 5 pts (19%) died. The median OS of the entire cohort was not reached (95%CI: 76.4-NR) (Figure 1). The best response to PD-1 blockade included 15 (60%) with complete metabolic response (CMR), 5 (20%) with partial metabolic response (PMR), and 5 (20%) with progression of disease (POD). Median ΔMTV was -70% (range -100 to +909%).
MTV0 was not predictive of OS, PET1 response, or BOR. However, ΔMTV predicted for PET1 response (p=0.004) and BOR (p=0.004). 18 (72%) pts had a reduction in ΔMTV (range: -100, -22), while 7 (28%) pts had an increase in ΔMTV (range: 33-909). The optimal ΔMTV threshold for prediction of BOR was 120% (Figure 1). ΔMTV &lt;120% was associated with improved OS with a median OS not reached (95% CI: NA-NA) compared to 61.7 Mo (95% CI: 9.4-NR) (Log-rank p=0.05) (Figure 2).
Among pts with IR on PET-1, ΔMTV &lt;120% appeared to distinguish eventual responders from those with POD. Of 4 pts with IR who eventually achieved response at later time points, 3 had ΔMTV below the 120% threshold. Conversely, of 4 pts with IR with eventual POD at their subsequent evaluation, all 4 had ΔMTV above the 120% threshold.
Conclusions:
Quantitative change in MTV from baseline to first reassessment may aid in predicting treatment response and long-term outcomes in patients with RR HL receiving PD-1 blockade, particularly those initially characterized as achieving indeterminate response. Further prospective clinical trials are needed to validate the role of ΔMTV in predicting response and long-term outcomes for RR HL pts receiving PD-1 blockade.
Figure 1 Figure 1.

Disclosures
Moskowitz: Merck & Co., Inc.: Research Funding. Matasar: Seattle Genetics: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Juno Therapeutics: Consultancy; Merck: Consultancy; Pharmacyclics: Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Teva: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Takeda: Consultancy, Honoraria. Zelenetz: Amgen: Honoraria; MorphoSys: Honoraria; Novartis: Honoraria; MEI Pharma: Honoraria, Research Funding; Beigene: Honoraria, Other, Research Funding; Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria; SecuraBio: Honoraria; Genentech/Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Verastem: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; MethylGene: Research Funding; AstraZeneca: Honoraria; Janssen: Honoraria; NCCN: Other; LFR: Other; Gilead: Honoraria. Joffe: AstraZeneca. Epizyme: Consultancy. von Keudell: Merck: Research Funding; Janssen: Research Funding; BMS: Research Funding; Incyte: Consultancy, Honoraria; AbbVie: Research Funding; Merck: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria. Batlevi: Medscape: Honoraria; Memorial Sloan Kettering Cancer Center: Current Employment; Moderna: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; ADC Therapeutics: Consultancy; Regeneron: Current holder of individual stocks in a privately-held company; TG Therapeutics: Consultancy; Kite Pharma: Consultancy; Seattle Genetics: Consultancy; TouchIME: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Bayer: Research Funding; Viatris: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; Juno/Celgene: Consultancy; Life Sciences: Consultancy; Dava Oncology: Honoraria; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Caron: Astra-Zeneca: Current holder of individual stocks in a privately-held company; bristol myers: Current holder of individual stocks in a privately-held company; GlaxoSmithKlein: Current holder of individual stocks in a privately-held company; Johnson and Johnson: Current holder of individual stocks in a privately-held company; Novartis: Current holder of individual stocks in a privately-held company; pfizer: Current holder of individual stocks in a privately-held company; Teva: Current holder of individual stocks in a privately-held company. Noy: Rafael Parhma: Research Funding; Morphosys: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Targeted Oncology: Consultancy; Epizyme: Consultancy; Janssen: Consultancy, Honoraria. Salles: Velosbio: Consultancy; Morphosys: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Novartis: Consultancy; Epizyme: Consultancy, Honoraria; Allogene: Consultancy; Rapt: Consultancy; Genentech/Roche: Consultancy; Takeda: Consultancy; Miltneiy: Consultancy; Loxo: Consultancy; Kite/Gilead: Consultancy; Genmab: Consultancy; Incyte: Consultancy; Ipsen: Consultancy; Janssen: Consultancy; Debiopharm: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria. Moskowitz: ADC Therapeutics: Research Funding; Takeda: Consultancy; Incyte: Research Funding; Merck: Consultancy, Research Funding; Beigene: Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Miragen: Research Funding; Janpix Ltd.: Consultancy; Imbrium Therapeutics L.P./Purdue: Consultancy.