Prognostic Value of Baseline and Interim Positron Emission Tomography Markers in Diffuse Large B-cell Lymphoma Patients: A Real-world Perspective
Authors: Stefan Hatzl, Peter Kalmar, Florian Posch, Jakob M. Riedl, Christine Beham-Schmid, Katharina Prochazka, Hildegard Greinix, Thomas Schwarz, Christian Gstettner, Peter Neumeister, Eduard Schulz
Journal: HemaSphere (2021)

Diffuse large B-cell lymphoma (DLBCL) is treated with 6–8 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) given every 14 or 21 days (R-CHOP14 or R-CHOP21).118F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET-CT) is the international standard for disease staging and is frequently used for response assessment.2 In contrast to Hodgkin lymphoma, optimal PET parameters and imaging time points to prognosticate progression-free survival (PFS) as well as overall survival (OS) of patients with DLBCL have not been established. Here, we present our experience of using PET-CT for prognostication of treatment response. To achieve a tailored therapy, there is a need to reliably identify high-risk disease at diagnosis, early treatment failure at interim, and cure at end of treatment imaging. Prognostic models based solely on clinical features such as the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) are widely used at diagnosis and were validated in several studies comprising thousands of patients.3,4 International guidelines recommend PET-CT for initial staging and end of treatment response assessment, whereas interim PET-CT after 2 (i-PET2) or 4 (i-PET4) cycles of immunochemotherapy reflects chemosensitivity and has been shown to predict the outcome.5–7 Yet, PET-guided treatment escalation has been unsuccessful so far due to lack of more effective therapeutic options.1,5,7 Measurement of baseline total metabolic tumor volume (TMTV) and change of maximum standardized uptake value (ΔSUVmax) at i-PET2 are current approaches under investigation for predicting treatment response.1,5,6,8,9 TMTV and ΔSUVmax were reported to be superior to the widely used Deauville five-point scale (DS).10 Recently, baseline TMTV cutoff >220 cm3 has been proposed as an adverse prognostic factor from a dataset of the prospective phase 3 REMARC study including 301 patients aged 60–80 years who had been treated with 6–8 cycles of R-CHOP14 or R-CHOP21.8 High baseline TMTV, alone or complemented by Eastern Cooperative Oncology Group performance status, showed a strong association with inferior PFS and OS in patients who achieved partial (PR) or complete remission (CR), and outperformed established clinical prognostic models such as the NCCN-IPI. In addition, the prospective PET-CT substudy of the CALGB 50303 trial, which included 158 patients treated with 6 cycles of R-CHOP21 or dose-adjusted EPOCH-R (etoposide plus the same agents of R-CHOP), demonstrated that the change of ΔSUVmax at i-PET2 was significantly associated with OS.9 In this trial, patients were 20–82 years old, and two-third had “very good” or “good” prognosis according to revised IPI (R-IPI). Unexpectedly, ΔSUVmax and DS were not associated with PFS.9,11 Our aim was to study TMTV, ΔSUVmax, DS, and NCCN-IPI in DLBCL patients uniformly treated with the most commonly used regimen R-CHOP21. Hence, we conducted a retrospective analysis of 144 patients with DLBCL who were diagnosed and treated at our institution during January 1, 2015, and December 31, 2019. This study was approved by the ethics committee of the Medical University of Graz. We used stringent inclusion criteria: patients with human immunodeficiency virus infection (n = 2), transformed low-grade lymphoma (n = 23), primary testicular lymphoma (n = 3), primary central nervous system lymphoma (n = 4), or no interim imaging (n = 5) were excluded. All patients underwent PET-CT using 2 similar systems (Discovery MI; GE Healthcare, Chicago, IL; Biograph mCT; Siemens Healthineers, Erlangen, Germany). The patients fasted for at least 6 hours before intravenous administration of 18F-FDG to ensure a serum glucose level below 140 mg/dL. 18F-FDG was administered according to EANM procedure guidelines.12 Analysis of imaging data was performed by 2 nuclear medicine physicians blinded to patient outcome. SUVmax and TMTV were computed using the semiautomatic software Hermes Hybrid 3D Tumorfinder (Hermes Medical Solutions, Stockholm, Sweden). Definitions of ΔSUVmax, TMTV, and visual DS were as previously described.5,9,10 All statistical analyses were performed with Stata (Windows version 15.0; Stata Corp., Houston, TX). Median follow-up was estimated with a reverse Kaplan–Meier estimator. PET-markers were dichotomized into binary variables at the 75th percentile of their distribution. The 75% percentile cutoff was chosen empirically before data analysis to get an unbiased approach for survival estimation since other cutoffs had not been validated. Primary endpoint for all time-to-event analyses was 5-year PFS defined as the time from diagnosis to disease progression, death, or censoring alive at a maximum follow-up of 5 years, whatever came first. Secondary endpoint was 2-year PFS. Patient characteristics are summarized in Supplemental Digital Table 1, https://links.lww.com/HS/A178. Patients had a median age of 67 (interquartile range [IQR], 53–74) years and a median R-IPI score of 3 points (ie, “poor” prognosis). Treatment consisted of 6–8 cycles of R-CHOP21 at the discretion of the treating physician. During a median follow-up of 2.4 (IQR, 1.4–3.6) years, we observed 19 (18%) primary disease progressions during first-line therapy, 10 (9%) relapses after initial CR or PR, 16 (15%) deaths related to DLBCL, and 4 deaths from other causes. The estimated 2- and 5-year PFS and OS of the whole cohort were 69% (95% confidence interval [CI], 59–77) and 80% (95% CI, 82–88), and 63% (95% CI, 51–73) and 75% (95% CI, 63–84), respectively (Supplemental Digital Table 2, https://links.lww.com/HS/A178), which is comparable with published results.5,7–9 We correlated TMTV and NCCN-IPI at diagnosis with PFS to assess for their prognostic impact (Table 1). Higher baseline TMTV predicted for higher risk of progression and death. Five-year PFS estimates were 41% (95% CI, 19–62) in patients with baseline TMTV above the 75th percentile of its distribution (ie, >177 cm3 in our population), and 69% (95% CI, 55–80) in patients below this cutoff, respectively (log-rank P = 0.006, Supplemental Digital Figure 1A, https://links.lww.com/HS/A178). Consequently, patients with a baseline TMTV >220 cm3 proposed as an optimal cutoff for PFS prognostication by Vercellino et al8 showed also inferior PFS in our cohort (HR 3.54, 95% CI, 1.73–7.22; P = 0.001; Figure 1A). Harrell’s concordance index (with higher c-indices indicating better discrimination) and Aikaike’s information criterion (with lower values indicating better model fit) were comparable between TMTV >220 cm3 and NCCN-IPI. Baseline SUVmax was not associated with PFS outcomes (Table 1, Supplemental Digital Figure 1B and C, https://links.lww.com/HS/A178). Table 1. - Distribution of PET Markers and Their Association With Clinical Outcome Variable N-Missing Measured Value [IQR], or Absolute Count (%) Univariable Harrell’s c for PFS AIC for PFS HR for PFS 95% CI (P) Markers at baseline SUVmax (per doubling) 1 31 [22–43] 1.16 0.80–1.69 (0.442) 0.50 287 TMTV (per doubling) 0 86 [26–188] 1.34 1.11–1.61 (0.002) 0.67 279 TMTV > 220 cm3 0 20 (19%) 3.54 1.73–7.22 (0.001) 0.63 278 NCCN-IPI (points) 0 3 [2–5] 1.34 1.08–1.67 (0.008) 0.60 281 Interim markers SUVmax (per doubling) 6 0 [0–7] 1.71 1.44–2.03 (<0.001) 0.80 219 TMTV (per doubling) 6 0 [0–11] 1.42 1.25–1.60 (0.001) 0.78 231 DS (per point increase) 6 1 [1–4] 2.18 1.66–2.87 (<0.001) 0.80 219 DS 6 / / / 0.76 229 1–2 points / 60 (59%) Ref. Ref. / / 3 points / 7 (7%) 1.22 0.15–9.79 (0.849) / / 4–5 points / 34 (34%) 8.86 3.86–20.36 (<0.001) / / Change between baseline and interim ΔabsSUVmax (per 10 SUV units increase) 7 −25 [−40 to −13] 1.33 1.11–1.58 (0.002) 0.68 248 ΔrelSUVmax (per doubling) 7 −100 [−100 to −57] 4.33 2.80–6.68 (<0.001) 0.79 226 ΔSUVmax < 70% 6 28 (28%) 10.23 4.73–22.17 (<0.001) 0.77 223 ΔabsTMTV (per 100 cm3 increase) 6 −70 [−160 to −25] 0.87 0.79–0.96 (0.004) 0.65 253 ΔrelTMTV (per doubling) 6 −100 [−100 to −88] 1.10 1.03–1.17 (0.004) 0.75 254 Univariable modeling of PFS functions was performed with Cox proportional hazards models. The discriminative potential and model fit of PET-markers toward PFS was quantified with Harrell’s concordance index and Aikaike’s information criterion. N-missing denotes the number of patients without shown variables./ = not applicable; Δ = change; 95%CI = 95% confidence interval; Abs = absolute; AIC = Aikaike’s information criterion; HR = hazard ratio; IQR = interquartile range; P = Wald test P value; PFS = progression-free survival; rel = relative; SUV = standardized uptake value; TMTV = total metabolic tumor volume. Figure 1.: PET markers and clinical outcome. (A) TMTV at baseline using the cutoff 220 cm3. (B) TMTV at interim. (C) SUVmax at interim. (D and E) DS at interim. (F) CMR at interim. PFS was estimated with Kaplan–Meier estimators, and compared between groups using log-rank tests. Cumulative incidences of disease progression for DS categories were calculated with competing risk estimators. The numbers below the x-axis represent a risk table, with the raw numbers indicating the number of patients at risk for a PFS event at the start of each interval and the numbers in round brackets indicating the number of patients who developed a PFS event within an interval, respectively. CMR = complete metabolic response; DS = Deauville 5-point scale; Q3 = third quartile; SUVmax = maximum standardized uptake value; TMTV = total metabolic tumor volume.We sought to establish the best model of PFS prediction using different i-PET markers. Interim PET imaging was uniformly performed after the fourth cycle of R-CHOP (i-PET4) because our center had previously delivered up to eight cycles of R-CHOP. In our dataset, TMTV, SUVmax, and DS comparably predicted PFS with a high discriminatory performance (Harrell’s c-indices between 0.76 and 0.80; Table 1). Five-year PFS were 38% and 17% in patients with interim TMTV or interim SUVmax above the 75th percentile of these variables’ distributions (TMTV: 11 cm3, SUV: 7 units), and 73% and 78% in patients below these thresholds, respectively (both P < 0.0001, Figure 1B and C). The 2-year PFS results are summarized in Supplemental Digital Table 3, https://links.lww.com/HS/A178. The interim DS discriminated particularly well between patients who did or did not experience disease progression or death (Table 1; Figure 1D). In a subanalysis, 5-year cumulative incidences of primary disease progression or relapse were 32% and 76% in patients with DS of 1–3 points (n = 67) and 4–5 points (n = 34), respectively (Gray’s test P < 0.0001, Figure 1E). Complete metabolic response (CMR), defined as lack of measurable metabolic tumor tissue and SUVmax being indistinguishable from surrounding background activity (n = 60 patients), was also a strong PFS predictor with 5-year PFS of 83% and 31% in patients with and without a CMR at i-PET4 (log-rank P < 0.0001, Figure 1F). In a multivariable model of PFS including CMR at i-PET4, double expressor lymphoma biology,13 cell of origin,14 and NCCN-IPI, only CMR prevailed as an independent predictor of PFS (Table 2). Furthermore, we were able to replicate the cutoff ΔSUVmax <70% at i-PET4 as an adverse prognostic parameter (Table 1), which has previously been described in DLBCL patients treated with R-ACVBP or R-CHOP14.5 However, although variables representing absolute or relative changes from baseline to interim were highly prognostic for PFS, they were not superior to interim markers alone in terms of discriminatory performance in our population (Table 1, Supplemental Digital Figure 1D–H, https://links.lww.com/HS/A178). Table 2. - A Multivariable Model of Any Metabolic Activity at Interim PET for Prediction of PFS Variable Adjusted Hazard Ratio 95% CI P CMR 9.88 3.94–24.79 <0.001 DEL biology: 0 points ref. ref. ref. DEL biology: 1 point 5.21 1.18–22.92 0.029 DEL biology: 2 points 3.85 0.82–18.16 0.089 COO: ABC 0.94 0.45–1.98 0.868 NCCN-IPI (per 1 point increase) 1.06 0.81–1.39 0.674 Multivariable modeling of PFS functions was performed with Cox proportional hazards models.95% CI = 95% confidence interval; ABC = activated B-Cell-like; CMR = complete metabolic response; COO = cell of origin (Choi’s immunohistochemical algorithm14); DEL = immunohistochemic double expressor lymphoma status (point-based system according to Green et al13); NCCN-IPI = National Comprehensive Cancer Network International Prognostic Index; P = Wald test P value; ref. = reference category. Our study confirms the prognostic value of NCCN-IPI, baseline TMTV, ΔSUVmax and DS in a “real-world” cohort of newly diagnosed DLBCL. The strength of our study stems from the use of a relatively large contemporary cohort characterized by representative patient age distribution and uniform therapy. Limitations mainly pertain to single-center analysis and retrospective nature. At diagnosis, NCCN-IPI and TMTV cutoff of >220 cm3 significantly predicted for inferior survival allowing to stratify patients for study purposes and to counsel patients on their likely disease course. After 4 cycles of R-CHOP21, visual DS, CMR, and ΔSUVmax <70% significantly predicted relapse or progression with high discrimination in our population. This finding is in line with the report of the GAINED trial by Le Gouill et al15 but contrasts with other studies probably reflecting different time points of i-PET (after 4 vs. 2 cycles) as well as distribution of R-IPI risk groups (“poor” versus “good” prognosis).1,9 At i-PET4, there is likely less residual therapy-induced inflammation compared to i-PET2,7 which might explain the better discrimination by DS in our study. Whereas FDG-avidity at i-PET2 likely reflects a mix of residual cancer cells and inflammation, i-PET4 specifically identifies resistant/refractory lymphoma. In conclusion, our study corroborates findings that PET-CT provides important prognostic information which, after appropriate standardization and availability of more effective agents, might guide therapies in DLBCL. Patients with baseline TMTV >220 cm3 at diagnosis and DS ≥4 or ΔSUVmax <70% at i-PET4 have an exceedingly high risk of relapse and should preferably be assigned to alternative treatments in prospective clinical trials. Disclosures The authors have no conflicts of interest to disclose.