# Baseline 18F-FDG Metabolic Tumor Volume Predicts Response to Rituximab Induction in Post-transplant Lymphoproliferative Disorders: A Multi-institutional Retrospective Study

David Morland, Lukshe Kanagaratnam, Fabrice Hubelé, Elise Toussaint, Sylvain Choquet, Aurélie Kas, Pierre-Ambroise Caquot, Corinne Haioun, Emmanuel Itti, Stéphane Leprêtre, et al.

► To cite this version:

David Morland, Lukshe Kanagaratnam, Fabrice Hubelé, Elise Toussaint, Sylvain Choquet, et al. Baseline 18F-FDG Metabolic Tumor Volume Predicts Response to Rituximab Induction in Post-transplant Lymphoproliferative Disorders: A Multi-institutional Retrospective Study. HemaSphere, 2023, 7 (2), pp.e833. 10.1097/HS9.0000000000000833. hal-03977264

HAL Id: hal-03977264

https://hal.science/hal-03977264v1

Submitted on 3 Sep 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
Article

Open Access

# Baseline ¹⁸F-FDG Metabolic Tumor Volume Predicts Response to Rituximab Induction in Post-transplant Lymphoproliferative Disorders: A Multi-institutional Retrospective Study

David Morland<fnref n="1" />,<fnref n="2" />,<fnref n="3" />,<fnref n="4" />, Lukshe Kanagaratnam<fnref n="5" />, Fabrice Hubelé<fnref n="6" />, Elise Toussaint<fnref n="7" />, Sylvain Choquet<fnref n="8" />, Aurélie Kas<fnref n="9" />, Pierre-Ambroise Caquot<fnref n="1" />,<fnref n="9" />, Corinne Haioun<fnref n="10" />, Emmanuel Itti<fnref n="11" />, Stéphane Leprêtre<fnref n="12" />, Pierre Decazes<fnref n="13" />, Fontanet Bijou<fnref n="14" />, Paul Schwartz<fnref n="15" />, Caroline Jacquet<fnref n="16" />, Adrien Chauchet<fnref n="17" />, Julien Matuszak<fnref n="18" />, Nassim Kamar<fnref n="19" />, Pierre Payoux<fnref n="20" />, K-VIROGREF Study Group*, Eric Durot<fnref n="21" />

**Correspondence:** David Morland (david.morland@reims.unicancer.fr).

## ABSTRACT

Post-transplant lymphoproliferative disorder (PTLD) is a rare complication of immunosuppression. Sequential treatment is commonly proposed, combining induction with rituximab (R-induction) followed by either continuation of treatment or addition of chemotherapy depending on response. Response to R-induction, often assessed by CT scan, is a major predictor of overall survival (OS). The aim of the study was to analyze predictive factors of R-induction response, including total metabolic tumor volume (TMTV), and investigate the role of ¹⁸F-FDG PET/CT in response assessment. This retrospective multicenter study is based on patients with PTLD included in the K-VIROGREF cohort. Only patients treated by R-induction with a baseline ¹⁸F-FDG PET/CT were included. Response to R-induction was assessed by ¹⁸F-FDG PET/CT. The optimal threshold of TMTV for rituximab response was determined using receiver operating characteristic curves. Univariate and multivariate analyses were conducted to identify predictive factors of response. A total of 67 patients were included. Survival characteristics were similar to those previously reported: the complete response rate to R-induction was 30%, the 3-year OS estimate was 66%, and the treatment-related mortality was 4%. The optimal threshold for TMTV to predict R-induction response was 135 cm<fnref n="3" />. The response rate to R-induction was 38% in the 21 patients with TMTV ≥ 135 cm<fnref n="3" /> and 72% in the 46 patients with TMTV < 135 cm<fnref n="3" />. TMTV was a significant predictor of response, both at univariate and multivariate analyses (odd ratios = 3.71, *P* = 0.022). Baseline TMTV is predictive of response to R-induction. Early assessment of patient response is feasible with ¹⁸F-FDG PET/CT.

## INTRODUCTION

Post-transplant lymphoproliferative disorder (PTLD) is a rare and serious complication of immunosuppression after organ transplantation and represents the second most frequent

malignancy after skin cancers in immunosuppressed patients.<fnref n="1" />,<fnref n="2" /> These lymphoproliferations constitute a well-defined entity in the World Health Organization (WHO) 2016 classification<fnref n="3" /> with non-destructive, polymorphic, and monomorphic forms corresponding to aggressive lymphomas and Hodgkin's lymphomas.

<footnote n="1">¹Médecine Nucléaire, Institut Godinot, Reims, France</footnote>

<footnote n="2">²Laboratoire de Biophysique, UFR de Médecine, Université de Reims
Champagne-Ardenne, Reims, France</footnote>

<footnote n="3">³CReSTIC, EA 3804, Université de Reims Champagne-Ardenne, Reims, France</footnote>

<footnote n="4">⁴Unité de Medicina Nucleare, TracerGLab, Dipartimento di Radiologia,
Radioterapia ed Ematologia, Fondazione Policlinico Universitario A. Gemelli,
IRCCS, Roma, Italy</footnote>

<footnote n="5">⁵Unité d'Aide Méthodologique, Pôle Recherche et Santé Publique, CHU de
Reims, Reims, France</footnote>

<footnote n="6">⁶Médecine Nucléaire, CHU de Strasbourg, ICANS, Strasbourg, France</footnote>

<footnote n="7">⁷Hématologie, CHU de Strasbourg, ICANS, Strasbourg, France</footnote>

<footnote n="8">⁸Hématologie, CHU Pitié-Salpêtrière Charles Foix, Sorbonne Université, AP-HP,
Paris, France</footnote>

<footnote n="9">⁹Médecine Nucléaire, CHU Pitié-Salpêtrière Charles Foix, Sorbonne Université,
AP-HP, Paris, France</footnote>

<footnote n="10">¹⁰Hématologie, CHU Henri Mondor, AP-HP, Créteil, France</footnote>

<footnote n="11">¹¹Médecine Nucléaire, CHU Henri Mondor, AP-HP, Créteil, France</footnote>

<footnote n="12">¹²Inserm U1245 et Département d'Hématologie, Centre Henri Becquerel et
Normandie Univ, UNIROUEN, Rouen, France</footnote>

<footnote n="13">¹³Médecine Nucléaire, Centre Henri Becquerel, Rouen, France</footnote>

<footnote n="14">¹⁴Hématologie, Institut Bergonié, Bordeaux, France</footnote>

<footnote n="15">¹⁵Médecine Nucléaire, Institut Bergonié, Bordeaux, France</footnote>

<footnote n="16">¹⁶Hématologie, CHU de Nancy, France</footnote>

<footnote n="17">¹⁷Hématologie, CHU de Besançon, France</footnote>

<footnote n="18">¹⁸Médecine Nucléaire, CHU de Besançon, France</footnote>

<footnote n="19">¹⁹Néphrologie et transplantation d'organes, CHU Rangueil, Toulouse, France</footnote>

<footnote n="20">²⁰Médecine Nucléaire, CHU de Toulouse, France</footnote>

<footnote n="21">²¹Hématologie clinique, CHU de Reims, France</footnote>

<footnote>*K-VIROGREF Study Group members listed at the end of the manuscript
Supplemental digital content is available for this article.</footnote>

<footnote>Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. HemaSphere (2023) 7:2(e833).</footnote>

<footnote>http://dx.doi.org/10.1097/HS9.0000000000000833.</footnote>

<footnote>Received: October 24, 2022 / Accepted: December 19, 2022</footnote>
The treatment of PTLD is based in the first place on a reduction of immunosuppressive treatment. Formerly, PTLD were treated like their de novo counterparts. However, the use of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy in these fragile patients was associated with a high treatment-related mortality (TRM), estimated at 31%.⁴ The first part of the PTLD-1 trial, consisting of sequential treatment with 4 weekly cycles of rituximab (R-induction) followed by 4 cycles of CHOP chemotherapy every 3 weeks, reported a median overall survival (OS) of 6.6 years and apparent lower treatment-related toxicity.⁵ Response to R-induction therapy was prognostic for OS. These data were confirmed in the second part of the PTLD-1 trial in which a risk-stratified sequential therapy (RSST) was used⁶: patients who achieved a complete response (CR) after R-induction were treated by rituximab alone afterwards instead of (R)-CHOP chemotherapy. The median OS was 6.6 years with a TRM of 8%. In this study, responses after R-induction and at the end of treatment were assessed using CT scans.

Nowadays, 18F-Fluorodeoxyglucose positron emission tomography/ computed tomography (¹⁸F-FDG PET/CT) is recognized as the gold standard for the initial workup of diffuse large-cell B-cell lymphoma (DLBCL).⁷ This examination allows the detection of some lymphomatous lesions not recognized by a CT scan. It also plays an essential role in the assessment of response at the end of treatment with the use of the Deauville visual scale. Several studies have reported the prognostic value of the total metabolic tumor volume (TMTV) calculated on the initial PET/CT on progression-free survival (PFS) and OS in DLBCL.⁸,⁹ There are fewer data on the contribution of ¹⁸F-FDG PET in PTLD. A recent meta-analysis reports the high sensitivity and specificity of PET in the detection of PTLD.¹⁰ PET detects additional lesions compared to conventional imaging in 28% of cases, mainly extranodal lesions.¹¹ Its contribution has also been studied in the evaluation of the response to treatment, to guide monitoring or change of treatment.¹²,¹³ Only 1 recent study on 88 patients explored the value of TMTV or other parameters such as total lesion glycolysis (TTLG) in PTLD and did not find a prognostic value of these parameters on OS.¹⁴ However, the population of this study was heterogeneous in terms of histology and treatment (58/88 patients were treated with R-induction). Baseline high International Prognostic Index (IPI) remained predictive of worse OS as in the RSST PTLD-1 trial. The other strong independent prognostic factor for time to progression and OS in the RSST PTLD-1 trial was response to R-induction. However, the response to R-induction is, by definition, a post-treatment variable, highlighting the need to identify baseline predictive factors of this response.

This prompted us to analyze predictive factors of response to R-induction, including TMTV, and to investigate the role of PET in response assessment after R-induction, in a homogeneous cohort of PTLD patients treated with R-induction.

# MATERIALS AND METHODS

## Patients' selection

This retrospective, non-interventional, multicenter study is based on patients included in the K-VIROGREF cohort (epidemiological, clinical, and immunological study of a cohort of adult patients with viral-induced cancers, after solid organ and hematopoietic stem cell transplantation), across 15 French medical centers. Patients with PTLD were screened from July 2013 to October 2021. The inclusion criteria were as follows: (1) histologically proven polymorphic PTLD or monomorphic DLBCL PTLD; (2) initial treatment by rituximab alone; (3) available baseline ¹⁸F-FDG PET/CT, performed within 30 days before treatment. The exclusion criteria were as follows: (1) age < 18 years; (2) indolent lymphomas; (3) previously treated PTLD; (4) central nervous system involvement;

(5) noncompliance with fasting before PET; (6) incomplete DICOM data.

The diagnosis of PTLD was made in accordance with the WHO classification³ of malignant lymphoma and confirmed by expert hematopathologists from the Lymphopath network, according to the standard French procedures.¹⁵

This study was conducted in accordance with the Declaration of Helsinki and was declared on the Health Data Hub (N°F20210407155710) in conformity with the reference methodology MR004 of the “Commission Nationale de l’Informatique et des Libertés,” allowing the computerized management of medical data. The participants were informed of the possibility of using the information concerning them and had a right of opposition.

## Data collection

For each patient, the following information were collected: sex, age at diagnosis of PTLD, transplanted organ, the time between transplantation and diagnosis of PTLD, histology, Epstein-Barr virus status of the tumor, Ann Arbor stage, lactate dehydrogenase (LDH) levels, extranodal involvement, Eastern Cooperative Oncology Group-Performance Status (ECOG PS), B symptoms, IPI, and National Comprehensive Cancer Network (NCCN) IPI scores. Treatment response, whether after R-induction or after the end of treatment, was based on ¹⁸F-FDG PET/CT using Cheson criteria¹⁶ (CR, partial response [PR], stable disease [SD], progressive disease [PD]). No centralized review was performed.

PFS was calculated from diagnosis until disease progression, relapse, or death from any cause or last follow-up. OS was defined from diagnosis to death or last follow-up. Disease-specific survival (DSS) was defined as the time from diagnosis until death from PTLD or TRM.

Regarding ¹⁸F-FDG PET/CT: DICOM data, administered activity, weight, height, and capillary blood glucose were collected.

## Baseline PET measurements

PET/CT were displayed on a dedicated interpretation console (AW server; General Electrics, Milwaukee, WI). TMTV and TTLG were measured. TMTV was obtained by summing the metabolic volumes of all nodal and extranodal lesions according to the method detailed by Meignan et al¹⁷ (41% SUVmax threshold, inclusion of only focal bone marrow involvement, spleen considered involved in case of focal increased uptake or diffuse increased uptake of at least 1.5 times the liver uptake). TTLG was obtained by multiplying each metabolic volume composing the TMTV by their respective SUVmean (mean standard uptake value). These measurements were performed by an experienced nuclear medicine physician (DM) who was blinded to the clinical data of the patients.

## Statistical analysis

For descriptive analysis, qualitative variables were described by their absolute and relative frequency (%). Quantitative variables were described by mean, standard deviation, median, interquartile range (IQR), and extreme values.

The main endpoint was the response to R-induction defined by patients in CR or PR after 4 weekly doses of rituximab. The optimal threshold of TMTV regarding rituximab response (CR and PR vs SD and PD) was determined using receiver operating characteristic (ROC) curves and was chosen to maximize specificity (maximal specificity with a sensitivity of at least 50%). The area under the curve (AUC) and corresponding 95% confidence intervals (95% CI) are reported.

Univariate analyses were conducted using the Chi-square or Fisher exact test when appropriate for binary and ordinal variables, and the Wilcoxon test for continuous variables. The odds
<table><caption>**Table 1**</caption><caption>Patients Characteristics</caption><thead><tr><th></th><th>Total<br>(n = 67)</th><th>Responders<br>to Rituximab<br>Induction<br>(n = 41)</th><th>Non-responders<br>to Rituximab<br>Induction<br>(n = 26)</th></tr></thead><tbody><tr><td><strong>Clinical data</strong></td><td></td><td></td><td></td></tr><tr><td>Median age (range)</td><td>59 (20–80)</td><td>59 (20–80)</td><td>59 (28–73)</td></tr><tr><td>Sex</td><td></td><td></td><td></td></tr><tr><td>Female</td><td>21 (31%)</td><td>14 (34%)</td><td>7 (27%)</td></tr><tr><td>Male</td><td>46 (69%)</td><td>27 (66%)</td><td>19 (73%)</td></tr><tr><td>PS ECOG ≥2</td><td>21 (31%)</td><td>10 (24%)</td><td>11 (42%)</td></tr><tr><td>B symptoms</td><td>33 (49%)</td><td>16 (39%)</td><td>17 (65%)</td></tr><tr><td><strong>Lymphoma characteristics</strong></td><td></td><td></td><td></td></tr><tr><td>Histology</td><td></td><td></td><td></td></tr><tr><td>Monomorphic<br>(DLBCL)</td><td>56 (84%)</td><td>33 (81%)</td><td>23 (88%)</td></tr><tr><td>Polymorphic</td><td>11 (16%)</td><td>8 (19%)</td><td>3 (12%)</td></tr><tr><td>EBER (n = 66)</td><td></td><td></td><td></td></tr><tr><td>Positive</td><td>20 (30%)</td><td>11 (27%)</td><td>9 (35%)</td></tr><tr><td>Negative</td><td>46 (70%)</td><td>29 (73%)</td><td>17 (65%)</td></tr><tr><td>Ann Arbor stage</td><td></td><td></td><td></td></tr><tr><td>I (including<br>9-stage IE)</td><td>11 (16%)</td><td>6 (15%)</td><td>5 (19%)</td></tr><tr><td>II</td><td>6 (9%)</td><td>4 (10%)</td><td>2 (8%)</td></tr><tr><td>III</td><td>10 (15%)</td><td>6 (15%)</td><td>4 (15%)</td></tr><tr><td>IV</td><td>40 (60%)</td><td>25 (60%)</td><td>15 (58%)</td></tr><tr><td>Nodal involvement</td><td>41 (61%)</td><td>26 (63%)</td><td>15 (58%)</td></tr><tr><td>Extranodal<br>involvement</td><td>54 (81%)</td><td>34 (83%)</td><td>20 (77%)</td></tr><tr><td>Extranodal organs<br>involved ≥2</td><td>18 (27%)</td><td>8 (20%)</td><td>10 (38%)</td></tr><tr><td><strong>Biological results</strong></td><td></td><td></td><td></td></tr><tr><td>Elevated LDH</td><td>32 (48%)</td><td>20 (49%)</td><td>12 (46%)</td></tr><tr><td>B2m (n = 37)</td><td></td><td></td><td></td></tr><tr><td>Median (range)</td><td>4.51 (2–17.12)</td><td>4.46 (2–14)</td><td>4.98 (2.5–17.12)</td></tr><tr><td>Albumin (n = 62)</td><td></td><td></td><td></td></tr><tr><td>Median (range)</td><td>35.1 (21–47)</td><td>35.7 (25.1–47)</td><td>33.6 (21–41.8)</td></tr><tr><td><strong>Prognostic scores</strong></td><td></td><td></td><td></td></tr><tr><td>IPI</td><td></td><td></td><td></td></tr><tr><td>0</td><td>9 (13%)</td><td>4 (10%)</td><td>5 (19%)</td></tr><tr><td>1–2</td><td>30 (45%)</td><td>22 (54%)</td><td>8 (31%)</td></tr><tr><td>3–5</td><td>28 (42%)</td><td>15 (36%)</td><td>13 (50%)</td></tr><tr><td>NCCN-IPI</td><td></td><td></td><td></td></tr><tr><td>0–1</td><td>5 (7%)</td><td>2 (5%)</td><td>3 (12%)</td></tr><tr><td>2–3</td><td>29 (43%)</td><td>21 (51%)</td><td>8 (31%)</td></tr><tr><td>4–5</td><td>22 (33%)</td><td>12 (29%)</td><td>10 (38%)</td></tr><tr><td>>5</td><td>11 (16%)</td><td>6 (15%)</td><td>5 (19%)</td></tr><tr><td><strong>Transplantation related data</strong></td><td></td><td></td><td></td></tr><tr><td>Time from transplantation to PTLD (y)</td><td></td><td></td><td></td></tr><tr><td>Median (range)</td><td>8.3 (0.3–34)</td><td>9.9 (0.5–34)</td><td>8.1 (0.3–20.2)</td></tr><tr><td>Age at transplantation (y)</td><td></td><td></td><td></td></tr><tr><td>Median (range)</td><td>46 (2–73)</td><td>39 (2–73)</td><td>51 (22–70)</td></tr><tr><td><strong>Transplant type</strong></td><td></td><td></td><td></td></tr><tr><td>Kidney</td><td>34 (51%)</td><td>23 (56%)</td><td>11 (42%)</td></tr><tr><td>Liver</td><td>17 (25%)</td><td>12 (29%)</td><td>5 (19%)</td></tr><tr><td>Heart</td><td>3 (4%)</td><td>1 (2%)</td><td>2 (8%)</td></tr><tr><td>Lung</td><td>2 (3%)</td><td>1 (2%)</td><td>1 (4%)</td></tr><tr><td>Hematopoietic SCT</td><td>5 (7%)</td><td>2 (5%)</td><td>3 (12%)</td></tr><tr><td>Multiple</td><td>6 (9%)</td><td>2 (5%)</td><td>4 (15%)</td></tr><tr><td>Graft involvement</td><td>6 (9%)</td><td>3 (7%)</td><td>3 (12%)</td></tr><tr><td>Reduction of<br>immunosuppression</td><td>60 (90%)</td><td>37 (90%)</td><td>23 (88%)</td></tr></tbody></table>

(Continued)

<table><caption>**Table 1 (Continued)**</caption><thead><tr><th></th><th>Total<br>(n = 67)</th><th>Responders<br>to Rituximab<br>Induction<br>(n = 41)</th><th>Non-responders<br>to Rituximab<br>Induction<br>(n = 26)</th></tr></thead><tbody><tr><td><strong>Baseline PET measurements</strong></td><td></td><td></td><td></td></tr><tr><td>TMTV (cm³)</td><td></td><td></td><td></td></tr><tr><td>Mean (standard<br>deviation)</td><td>217.5 (476)</td><td>209.6 (579.8)</td><td>229.8 (245.1)</td></tr><tr><td>Median<br>[1st quartile;<br>3rd quartile]</td><td>70 [26;222]</td><td>51 [23;112]</td><td>126.5 [56;431]</td></tr><tr><td>Minimum—<br>Maximum</td><td>1–3603</td><td>1–3603</td><td>3.1–809</td></tr><tr><td>TTLG (cm³)</td><td></td><td></td><td></td></tr><tr><td>Mean (standard<br>deviation)</td><td>2432.2 (4126.3)</td><td>2340.9 (4753.6)</td><td>2576.1 (2959.6)</td></tr><tr><td>Median<br>[1st quartile;<br>3rd quartile]</td><td>721 [222–2512]</td><td>496.5 [178–2110]</td><td>1968.5 [539–3678]</td></tr><tr><td>Minimum—<br>Maximum</td><td>9–23718</td><td>9–23718</td><td>17–12426</td></tr></tbody></table>

DLBCL = diffuse large-cell B-cell lymphoma; NCCN = National Comprehensive Cancer Network.

ratios (OR) were calculated for variables with a *P*-value of less than 0.1. A multivariable analysis using logistic regression was conducted using a manual backward selection procedure. All variables with a *P*-value less than 0.1 were retained in the final model. OR are presented along with their 95% CI. A *P*-value of <0.05 was considered significant.

As a prerequisite to validate our main endpoint, we checked if IPI and R-induction response were predictive of OS, as stated in previous studies, using Cox proportional hazards models. IPI was divided into two groups (0–2 versus 3–5) based on the RSST PTLD-1 study.⁶ Results were presented as hazard ratios (HRs) and 95% CI. Survival data were estimated based on Kaplan-Meier curves.

## RESULTS

### Population

Among the 97 PTLD patients screened with available baseline ¹⁸F-FDG PET/CT, 30 were not treated by R-induction and were excluded. The baseline characteristics of the remaining 67 patients are presented in Table 1. The median age at PTLD diagnosis was 59 years (range: 20–80 y), with a majority of male patients (69%). Half of the patients had undergone kidney transplantation (51%), followed by liver (25%). The median time from transplantation to PTLD was 8.3 years, with 10% of early PTLD (ie, PTLD occurred less than 1 y after transplantation). All cases were B-cell lymphomas with predominantly monomorphic DLBCL PTLD (86%). EBV-associated PTLD represented 20 (30%) of the cases. Fifty of 67 patients (75%) had stage III or IV disease and 32 of 67 (48%) had elevated LDH. Extranodal involvement assessed by PET/CT was seen in 81% of patients, especially gastro-intestinal, liver and bone localizations (48%, 21%, and 12%, respectively). No surgical resection was performed. Forty-two percent of patients had an IPI score ≥3 and 49% had an NCCN-IPI score ≥4. Median TMTV and TTLG were 70 cm³ (IQR 26–222) and 721 cm³ (IQR 222–2512), respectively.

### Treatment and outcome

Immunosuppressive treatment was reduced for 90% of patients. The overall response rate (ORR) after R-induction was 61% (41/67 patients), including a 30% CR rate (20/67 patients)
(Figure 1). All patients in CR after R-induction received rituximab monotherapy consolidation. Of the 47 patients who were not in CR after R-induction, 44 received R-CHOP21, 2 received further rituximab monotherapy (1 in PR and 1 in SD) and 1 died of infectious complication after R-induction. No TOR inhibitors were used. The ORR at the end of treatment (R-induction and rituximab consolidation for patients in CR, and R-induction and R-CHOP for 4 cycles every 21 d for patients not in CR) was 82% (55/67 patients) and the CR rate was 78% (52 patients).

Median PFS was 4.2 years (95% CI, 1.2-not reached), with a 3-year estimate of 53% (42-67). Median OS and DSS were not reached. The 3-year estimates were 66% (95% CI, 55-79) and 76% (95% CI, 66-87) for OS and DSS, respectively (Suppl. Figure 2). After a median follow-up of 3.6 years (95% CI, 3.1-5.1), 22 patients (33%) died. Only 3 of 67 patients (4%) experienced TRM. One patient developed rejection. Thirteen deaths were related to lymphoma: 11 patients died from refractory/relapsing PTLD and 2 from infection (with PTLD on salvage therapy). Six deaths were unrelated to PTLD and due to infection (n = 4), hepatic failure (n = 1), and cardiac cause (n = 1).

Response to R-induction and IPI ≥ 3 were significant predictors of OS: HR = 0.26 (0.11-0.62) (P = 0.001) and HR = 2.77 (1.17-6.56) (P = 0.02), respectively (Suppl. Figure 3).

## Prognostic factors

Univariate analysis was conducted for R-induction response prediction (Table 2): B symptoms and TMTV were significant (P = 0.036 and P = 0.031, respectively). The presence of B symptoms resulted in an OR of 2.95 (1.06-8.21). The optimal threshold for TMTV derived from ROC curve analysis was 135 cm³. Sensitivity, specificity, positive, and negative predictive values were 0.50, 0.80, 0.62, and 0.72, respectively. The AUC was 0.66 (95% CI, 0.52-0.80).

TMTV ≥ 135 cm³ was highly significant at univariate analysis (P = 0.009). The response rate to R-induction was 38% in the 21 patients with TMTV ≥ 135 cm³ compared to 72% in the 46 patients with TMTV < 135 cm³. In a multivariate model including B symptoms and TMTV ≥ 135 cm³ (Table 2), only TMTV ≥

135 cm³ remained significant regarding response to R-induction (P = 0.022, OR = 3.71, 95% CI, 1.21-11.36).

## DISCUSSION

The introduction of R-induction instead of upfront chemotherapy has profoundly changed the management of PTLD, with the promise of reduced side effects without altering treatment efficacy. Treatment after R-induction is guided by the early response: continuation of rituximab alone in case of CR, the addition of chemotherapy in other cases.

In this article, we present a large real-life cohort of patients treated homogeneously according to the RSST PTLD-1 protocol. The outcome of patients is similar to the few data available in the literature with CR rates of 30% after R-induction, 78% after treatment, and 66% of 3-year OS. Indeed, since the RSST PTLD-1 trial⁶ included 148 patients, survival data related to this strategy in PTLD remain scarce and heterogeneous. In this study, a CR rate of 25% and 70% after R-induction and at the end of treatment respectively were reported, with a 3-year OS of 70%. Boyle et al¹⁸ conducted a study on a subgroup of 24 patients treated by R-induction, with R-induction CR of 45% and 3-year OS of 70%. A study performed by Montes de Jesus et al included 58 patients treated with R-induction¹⁴ but did not report survival data restricted to this group. Two other studies included patients treated by R-induction, but with a slightly different treatment strategy. González-Barca et al.¹⁹ presented two cohorts of 38 and 22 patients with R-induction CR of 61% and 38%, respectively. Patients with PR were not treated upfront by R-CHOP but with additional rituximab and then R-CHOP if needed. End of treatment CR were 76.3% (29/38) and 81.8% (18/22), respectively. Jain et al²⁰ used a similar protocol on 109 patients (25% of PR patients treated by chemotherapy) and reported an R-induction CR rate of 43%.

As in the RSST PTLD-1 study,⁶ TRM remains low in our population (4% versus 8% in the RSST PTLD-1 study).

IPI ≥ 3 and response to R-induction are confirmed as prognostic factors of OS with an HR of 2.77 (pejorative factor, P =

<figure><img src="image_2.png" /><figcaption>**Figure 1.** Diagram of patients treated with rituximab induction (4 weekly doses). CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; PTLD = post-transplant lymphoproliferative disorder; R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; SD = stable disease.</figcaption></figure>
<table><caption>**Table 2**</caption><caption>Univariate and Multivariate Analysis—Prediction of Rituximab Response</caption><thead><tr><th rowspan="2"></th><th colspan="2">Univariate Analysis</th><th colspan="2">Multivariate Analysis</th></tr><tr><th>P</th><th>Odd Ratio</th><th>P</th><th>Odd Ratio</th></tr></thead><tbody><tr><td><strong>Clinical data</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Age</td><td>0.954</td><td></td><td></td><td></td></tr><tr><td>Sex</td><td>0.535</td><td></td><td></td><td></td></tr><tr><td>PS ECOG ≥2</td><td>0.123</td><td></td><td></td><td></td></tr><tr><td>B symptoms</td><td>0.036*</td><td>2.95<br>(1.06–8.21)</td><td>0.08</td><td>2.60<br>(0.89–7.56)</td></tr><tr><td><strong>Lymphoma characteristics</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Histology</td><td>0.508</td><td></td><td></td><td></td></tr><tr><td>EBER</td><td>0.539</td><td></td><td></td><td></td></tr><tr><td>Stage</td><td>0.976</td><td></td><td></td><td></td></tr><tr><td>Extranodal organs<br>involved ≥2</td><td>0.088</td><td>2.58<br>(0.85–7.78)</td><td></td><td></td></tr><tr><td><strong>Biological results</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>LDH > N</td><td>0.834</td><td></td><td></td><td></td></tr><tr><td>B2m</td><td>0.693</td><td></td><td></td><td></td></tr><tr><td>Albumin</td><td>0.142</td><td></td><td></td><td></td></tr><tr><td><strong>Prognostic scores</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>IPI ≥3</td><td>0.278</td><td></td><td></td><td></td></tr><tr><td>NCCN-IPI ≥4</td><td>0.271</td><td></td><td></td><td></td></tr><tr><td><strong>Transplantation related data</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Time between<br>transplantation and<br>PTLD</td><td>0.298</td><td></td><td></td><td></td></tr><tr><td>Age at<br>transplantation</td><td>0.287</td><td></td><td></td><td></td></tr><tr><td>Multiple<br>transplantation</td><td>0.197</td><td></td><td></td><td></td></tr><tr><td>Graft involvement</td><td>0.670</td><td></td><td></td><td></td></tr><tr><td>Reduction of<br>immunosuppression</td><td>1.000</td><td></td><td></td><td></td></tr><tr><td><strong>PET measurements</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>TMTV</td><td>0.031*</td><td>1.00<br>(1.00–1.00)</td><td></td><td></td></tr><tr><td>TMTV > 135 ml</td><td>0.009*</td><td>4.13<br>(1.39–12.27)</td><td>0.022*</td><td>3.71<br>(1.21–11.36)</td></tr><tr><td>TTLG</td><td>0.070</td><td>1.00<br>(1.00–1.00)</td><td></td><td></td></tr></tbody></table>

Odds ratios are calculated for variables with *P* < 0.10.

* *P* < 0.05.

TTLG = total lesion glycolysis.

0.02) and 0.26 (protective factor, *P* = 0.001) in our study, as previously described in prospective and retrospective studies.⁶,¹⁴,²⁰ Patients who were failing R-induction in the study by Jain et al²⁰ had a particular poor outcome (2-year OS between 32% and 45%). The prediction of the response to R-induction, which by definition is not an accessible factor at baseline, is in this context a major shortfall.

TMTV, using an optimal threshold of 135 mL, is a predictive factor of the response to R-induction in our study, with an OR of 3.7 (1.2-11.4). TMTV has only been studied so far for the prediction of OS in PTLD, with negative results.¹⁴ These findings are not incompatible insofar as the response to R-induction (and thus the TMTV that predicts it) influences the subsequent therapeutic management.

Median TMTV in our cohort is low compared with that reported in Montes et al's study (70 versus 272). Several hypotheses can be advanced to explain this difference. The method of calculating the MTV is different: we used Meignan's method¹⁷ based on ROI thresholds of 41%, whereas Montes' study¹⁴ used a threshold derived from hepatic uptake. A second hypothesis

could be that of an earlier detection due to a more regular monitoring of these patients and the use of more sensitive imaging techniques such as ¹⁸F-FDG PET/CT. Finally, the inclusion in the Montes study of patients treated with upfront chemotherapy may have introduced a high MTV population, but there are insufficient data to confirm this hypothesis. The rest of the characteristics are comparable, with notably a similar proportion of stage IV (60% in our study, 64.8%), IPI (42% with IPI ≥ 3 in our study vs 47.7%), and extranodal involvement (81% in our study vs 70.5%).

The multiplicity of segmentation methods and the lack of consensus may be limiting factors to the use of TMTV and call for special attention. However, the method used in this study remains simple in its implementation.¹⁷

A normal level of LDH was previously reported as predictive of R-response,²¹ however only on univariate analysis. Those results were not confirmed with our cohort (*P* = 0.83).

IPI ≥ 3 was not found to be predictive of the R-response despite being predictive of the OS. This factor was not investigated in the only previous study focusing on R-response.²¹ In the RSST PTLD-1 study,⁶ IPI and R-response were independent predictors of OS, which may support the fact that IPI does not predict response to rituximab.

Regardless of prediction, the imaging technique for R-induction response assessment is heterogeneous and alternates between CT and ¹⁸F-FDG PET/CT, ranging from 100% of CT evaluation (RSST PTLD-1 study⁶ and study of González-Barca et al¹⁹), to less than 20%.¹⁸ Our cohort is systematically evaluated by ¹⁸F-FDG PET-CT. The comparability of survival data and outcome shows that this second strategy is also valid.

The retrospective nature of this study and the lack of validation cohort is an inherent limitation to this study. However, we must underline the rarity of PTLD and stress the very homogeneous characteristics of our patient cohort. Compared to the study by Jain et al,²⁰ where 75% of patients in PR after R-induction were not treated with R-CHOP, patients in our cohort were more closely treated according to the RSST PTLD-1 trial (94% of patients not in CR were managed with further R-CHOP). Including only patients staged with PET/CT could have introduced a selection bias: some patients with high-tumor burden and/or compressive symptoms may have been referred to CT evaluation due to the need for urgent treatment. Nevertheless, the baseline characteristics of our patients are comparable to those of other retrospective and prospective studies and this uniform baseline staging allowed us to describe the response to R-induction in a homogeneous way and, thus, analyzed predictive factors of response.

The RSST PTLD-1 trial included only patients with solid organ transplant. However, we chose not to exclude hematopoietic SCT from our study considering they are treated in the same way and that the number of patients was low (5/67). Finally, a central review of images was not performed. The interobserver reproducibility of the Deauville Score assessment is however good (up to 0.86²²) so that the uncertainties related to the assessment are probably low.

PTLD patients in CR after R-induction are a group of patients with an excellent long-term outcome. On the contrary, patients not responding to R-induction represent an unmet medical need. The good performance of TMTV in predicting response to R-induction may help refine the clinician's assessment, although additional prospective data will be needed to consider a change in therapeutic management.

Our findings may also allow us to discuss the treatment to be offered to patients with PR. The management of these patients is heterogeneous among studies: R-CHOP according to the RSST approach⁶ or treatment with 4 additional rituximab in the article by González-Barca et al.¹⁹ A better risk stratification of these patients by TMTV could allow the second option to be favored, or even to treat these patients like those in CR. Zimmermann²³ suggests this
approach for patients with an IPI of less than 3. However, further studies, particularly prospective ones, are needed.

In conclusion, early assessment of patient response and treatment stratification is feasible with ¹⁸F-FDG PET/CT and leads to response, toxicity, and survival rates similar to those described in the literature. This study is the first to link baseline ¹⁸F-FDG TMTV and response to R-induction in PTLD and opens the door to a better assessment of these patients.

## AUTHOR CONTRIBUTIONS

Conceptualization, D.M., E.D.; methodology, D.M., L.K., E.D.; software, D.M., L.K.; validation, D.M., E.D., L.K.; formal analysis, L.K.; investigation, all authors; data curation, all authors; writing—original draft preparation, D.M.; writing—review and editing; all authors. All authors have read and agreed to the published version of the manuscript.

## K-VIROGREF STUDY GROUP

Loïc Renaud (Hématologie, Hôpital Saint-Louis, APHP, Paris, France); Laetitia Vercellino (Médecine Nucléaire, Hôpital Saint Louis, APHP, Paris, France); Jérôme Paillassa (Hématologie, CHU d'Angers, Angers, France); Pacôme Fosse (Médecine Nucléaire, CHU d'Angers, Angers, France); Morgane Cheminant (Hématologie, Hôpital Necker, APHP, Paris, France); Jean Michel Correas (Radiologie Adulte, Hôpital Necker, Paris, France); Roch Houot (Hématologie, CHU Rennes, Rennes, France); Xavier Palard (Médecine Nucléaire, Centre Eugène Marquis, Rennes, France); Marie Le Cann (Hématologie, Hôpital Bicêtre, APHP, Le Kremlin-Bicêtre, France); Maria-Angéla Castilla-Lièvre (Médecine Nucléaire, Hôpital Antoine Béclère, APHP, Clamart, France); Yann Guillermin (Hématologie, Centre Léon Bérard, Lyon, France); Haifa Bahri (Médecine Nucléaire, Centre Léon Bérard, Lyon, France).

## DISCLOSURES

The authors have no conflicts of interest to disclose.

## SOURCES OF FUNDING

No funding to disclose.

## REFERENCES

1. Dierickx D, Habermann TM. Post-transplantation lymphoproliferative disorders in adults. Longo DL, ed. *N Engl J Med*. 2018;378:549–562.

2. Turshudzhyan A. Post-renal transplant malignancies: opportunities for prevention and early screening. *Cancer Treat Res Commun*. 2021;26:100283.

3. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. *Blood*. 2016;127:2375–2390.

4. Choquet S, Trappe R, Leblond V, et al. CHOP-21 for the treatment of post-transplant lymphoproliferative disorders following solid organ transplantation. *Haematologica*. 2007;92:273–274.

5. Trappe R, Oertel S, Leblond V, et al. Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial. *Lancet Oncol*. 2012;13:196–206.

6. Trappe RU, Dierickx D, Zimmermann H, et al. Response to Rituximab induction is a predictive marker in B-cell post-transplant lymphoproliferative disorder and allows successful stratification into rituximab or R-CHOP consolidation in an international, prospective, multicenter phase II trial. *J Clin Oncol*. 2017;35:536–543.

7. Tilly H, Gomes da Silva M, Vitolo U, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. *Ann Oncol*. 2015;26:v116–v125.

8. Vercellino L, Cottereau AS, Casasnovas O, et al. High total metabolic tumor volume at baseline predicts survival independent of response to therapy. *Blood*. 2020;135:1396–1405.

9. Cottereau AS, Lanic H, Mareschal S, et al. Molecular profile and FDG-PET/CT total metabolic tumor volume improve risk classification at diagnosis for patients with diffuse large B-cell lymphoma. *Clin Cancer Res*. 2016;22:3801–3809.

10. Kim DH, Kim SJ. Diagnostic performances of F-18 FDG PET or PET/CT for detection of post-transplant lymphoproliferative disorder: a systematic review and meta-analysis. *Nucl Med Commun*. 2020;41:533–539.

11. Montes de Jesus FM, Kwee TC, Nijland M, et al. Performance of advanced imaging modalities at diagnosis and treatment response evaluation of patients with post-transplant lymphoproliferative disorder: a systematic review and meta-analysis. *Crit Rev Oncol Hematol*. 2018;132:27–38.

12. Zimmermann H, Denecke T, Dreyling MH, et al. End-of-treatment position emission tomography after uniform first-line therapy of B-cell post-transplant lymphoproliferative disorder identifies patients at low risk of relapse in the prospective German PTLD registry. *Transplantation*. 2018;102:868–875.

13. Van Keerberghen CA, Goffin K, Vergote V, et al. Role of interim and end of treatment positron emission tomography for response assessment and prediction of relapse in posttransplant lymphoproliferative disorder. *Acta Oncol*. 2019;58:1041–1047.

14. Montes de Jesus F, Dierickx D, Vergote V, et al. Prognostic superiority of International Prognostic Index over [18F]FDG PET/CT volumetric parameters in post-transplant lymphoproliferative disorder. *EJNMMI Res*. 2021;11:29.

15. Laurent C, Baron M, Amara N, et al. Impact of expert pathologic review of lymphoma diagnosis: study of patients from the French Lymphopath Network. *J Clin Oncol*. 2017;35:2008–2017.

16. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. *J Clin Oncol*. 2014;32:3059–3067.

17. Meignan M, Sasanelli M, Casasnovas RO, et al. Metabolic tumour volumes measured at staging in lymphoma: methodological evaluation on phantom experiments and patients. *Eur J Nucl Med Mol Imaging*. 2014;41:1113–1122.

18. Boyle S, Tobin JWD, Perram J, et al. Management and outcomes of diffuse large B-cell lymphoma post-transplant lymphoproliferative disorder in the era of PET and rituximab: a multicenter study from the Australasian lymphoma alliance. *HemaSphere*. 2021;5:e648e648.

19. González-Barca E, Capote FJ, Gómez-Codina J, et al. Long-term follow-up of a prospective phase 2 clinical trial of extended treatment with rituximab in patients with B cell post-transplant lymphoproliferative disease and validation in real world patients. *Ann Hematol*. 2021;100:1023–1029.

20. Jain MD, Lam R, Liu Z, et al. Failure of rituximab is associated with a poor outcome in diffuse large B cell lymphoma-type post-transplant lymphoproliferative disorder. *Br J Haematol*. 2020;189:97–105.

21. Choquet S, Leblond V, Herbrecht R, et al. Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study. *Blood*. 2006;107:3053–3057.

22. Toledano MN, Vera P, Tilly H, et al. Comparison of therapeutic evaluation criteria in FDG-PET/CT in patients with diffuse large-cell B-cell lymphoma: prognostic impact of tumor/liver ratio. *Treglia G*, ed. *PLoS One*. 2019;14:e0211649.

23. Zimmermann H, Koenecke C, Dreyling MH, et al. Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell Post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multicentre phase II PTLD-2 trial. *Leukemia*. 2022;36:2468–2478.