Prognostic Value of 2-Deoxy-2-[18F]fluoro-D-glucose Positron Emission Tomography/Computed Tomography after Autologous Hematopoietic Stem Cell Transplantation in Lymphoma Using Deauville Scores

Purpose In the present study, we mainly aimed to evaluate the prognostic value of 2-deoxy-2-[18F]fluoro-D-glucose ([18F]F-FDG) positron emission tomography (PET)/computed tomography (CT) after autologous stem cell transplantation (ASCT) in lymphoma. Procedures. A total of 76 lymphoma patients who benefited from [18F]F-FDG PET-CT (within 3 months and 3–6 months) after ASCT in our institution between April 2010 and December 2019 were enrolled in this retrospective study. These abovementioned patients were divided into two groups based on the Deauville criteria. The Kaplan–Meier method was used in survival analysis, and the log-rank method was adopted in comparison. Prognostic factor analysis was performed by the Cox regression model. Results Positive post-ASCT [18F]F-FDG PET-CT was associated with lower progression-free survival (PFS) and overall survival (OS) (p = 0.001 and p = 0.022, respectively). Univariate analysis showed the post-ASCT PET-CT result was the only independent factor associated with PFS (p = 0.002). Both the number of previous treatments and post-ASCT PET-CT result had a different impact on OS (p = 0.040 and p = 0.028, respectively). Multivariate analysis showed the post-ASCT PET-CT result was the only independent factor associated with OS (p = 0.028). The results showed no significant change from the abovementioned results when DS < 3 was defined as the negative result. For patients who had a PET-CT scan within 3–6 months after ASCT, the negative PET-CT group had a better prognosis including PFS and OS (p = 0.009 and p = 0.025, respectively). However, among the patients receiving PET-CT within 3 months, the result was not statistically significant (p = 0.064 and p = 0.445, respectively). Conclusion Collectively, we found that the post-ASCT [18F]F-FDG PET-CT was a strong indicator for PFS and OS, and a time window of 3–6 months was appropriate for post-ASCT [18F]F-FDG PET-CT. Trial registration number: ChiCTR2100042745.


Introduction
According to the statistics of GLOBOCAN 2018 produced by the International Agency for Research on Cancer, the number of new cases of Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL) is 79,990 and 509,590, respectively [1]. In China, there is an estimate of 52,000 deaths associated with lymphoma and myeloma, and the crude mortality rate was 3.83 per 100,000 in 2017 [2]. Hematopoietic stem cell transplantation (HSCT) plays a very important role in the treatment of lymphoma [3,4]. Salvage chemotherapy followed by high-dose chemotherapy and rescue autologous stem cell transplantation (ASCT) remains the standard therapeutic regimen for relapsed/refractory lymphoma [5,6]. 2-Deoxy-2-[ 18 F]fluoro-D-glucose positron emission tomography/computed tomography ([ 18 F]F-FDG PET-CT) has become an important tool to evaluate the prognosis of lymphoma since PET-CT is incorporated into the National-Cancer-Institute-sponsored international consensus response criteria for lymphoma guidelines in 2007 [7][8][9]. Prognostic assessment can help patients with lymphoma choose more promising treatment options in the early stage after ASCT. Patients with a good prognosis would not need to receive excessive treatment to reduce long-term toxicity. For lymphoma patients receiving ASCT, it has been shown that pretransplant PET-CT status is constantly and strongly associated with outcomes [9][10][11][12][13]. However, the prognostic value of post-ASCT [ 18 F]F-FDG PET-CT still remains controversial.
e Deauville score (DS) has been recommended as the preferred interpretation method for interim response evaluation [8,14]. However, it still remains undetermined whether these Deauville criteria can be used in post-ASCT[ 18 F]F-FDG PET-CT. Besides, given that posttherapy inflammatory changes may contribute to the "falsepositive" PET-CT result, we hypothesized that a proper time window could help improve accuracy.
In the present study, we reported an updated analysis of using the DS to evaluate the prognostic value of early post-ASCT [ 18 F]F-FDG PET-CT in patients with lymphoma.

Study Design.
is study was approved by the medical ethics committee of the First Affiliated Hospital of Soochow University. Institutional databases were reviewed to identify patients with lymphoma who met the following inclusion criteria: all histologic types of NHL were allowed as well as HL, ASCT between January 2010 and December 2019 at the First Affiliated Hospital of Soochow University, and [ 18 F]F-FDG PET/CT within 6 months after ASCT in our institution. e exclusion criteria were set as follows: patients who were lost to follow-up. Finally, 76 patients were included, and the data on these patients were analyzed.
Status at transplantation was determined according to the International Working Group criteria (IWGc) before ASCT [8]. Relapse or disease progression was defined according to the IWGc [7,15].
is study was approved by the institutional review board of the First Affiliated Hospital of Soochow University. Trial registration number: ChiCTR2100042745. Because the trial was a retrospective study, written informed consent for this study was waived by the ethics committee, and no personal information was disclosed. is study was in accordance with the Declaration of Helsinki.

FDG-PET Imaging.
e images were acquired on a GE Discovery STE16 PET/CT. All patients had blood glucose levels<11 mmol/L before injection. e dose of [ 18 F]F-FDG was determined based on body weight, which was 4.07-5.18 MBq/kg (0.11-0.14 mCi/kg). Image acquisition for the whole-body PET scan started approximately 60 min after injection. Patients were imaged from the skull base to mid-thigh (approximately 2 min per bed position, with an average of 7-10 bed positions per scan). CT scans were obtained based on the correlative diagnostic CT images (3.5 mm/slice, 140 kV, 120 mA).
All serial scans were evaluated by two independent reviewers, who were blinded to clinical and radiologic data. e above mentioned patients were divided into two groups using the Deauville 5-point scale as indicated by Lugano's recommendations in lymphoma [8,16]. DS 4 or 5 that could not be attributed to a physiologic or inflammatory cause was defined as the positive result, while DS < 4 was defined as the negative result. Considering using a fixed score for PET-positivity (i.e., DS 4) can leave outside less metabolically avid forms, and results by using DS < 3 a limit for negativity were also reported. In case of a discrepancy between the two observers, an independent panel of PET readers made the final decision.

Statistical Analysis.
Overall survival (OS) was defined as the time from day 0 of ASCT to death or last follow-up for survivors. Progression-free survival (PFS) was defined as the time from day 0 of ASCT to the date of progression/relapse, death, or last follow-up without evidence of relapse or disease progression. e Kaplan-Meier method was used in survival analysis, and the log-rank method was adopted in comparison. Prognostic factor analysis was performed by the Cox regression model.
Statistical analyses were performed using the IBM SPSS Statistics (version 26.0). All tests were two sided, and p < 0.05 was considered statistically significant.

Patient Characteristics.
Between April 2010 and December 2019, 76 patients were enrolled in our present study according to the abovementioned inclusion criteria, including 51 males and 25 females. e median age of the cohort was 34 years (range 12-70).

Timing of Post-ASCT [ 18 F]F-FDG PET-CTand Outcomes.
For patients who had a PET-CT scan within 3-6 months after ASCT, the negative PET-CT group had a better prognosis, including PFS and OS (p � 0.009 and p � 0.025, respectively) ( Figure 2

Discussion
Disease recurrence/progression is one of the main causes of HSCT failure and death in patients, especially those receiving ASCT. In the present retrospective study, we aimed to use DS to evaluate the prognostic value of post-ASCT [ 18 F]F-FDG PET-CT in patients with lymphoma. Here, positive post-ASCT [ 18 F]F-FDG PET-CT was associated with lower PFS and OS. In univariate and multivariate analyses, the post-ASCT [ 18 F]F-FDG PET-CT result was an independent factor associated with both PFS and OS. We also found that, for patients who had a PET-CT scan within 3-6 months after ASCT, the negative PET-CT group had a better prognosis, including PFS and OS. However, an Contrast Media & Molecular Imaging 3 opposite conclusion was drawn among patients who had a PET-CT scan within 3 months after ASCT. is early evaluation could be crucially important because it is performed before the occurrence of relapse in most patients [17][18][19].
Several studies have investigated the prognostic value of pre-ASCT [ 18 F]F-FDG PET-CT [20][21][22][23][24][25][26][27][28]. It has been confirmed that pre-ASCT [ 18 F]F-FDG PET-CT can help identify lymphoma patients for treatment failure with ASCT. In this cohort, only 32/76 patients underwent pretransplant PET. Also, the result showed positive pre-ASCT [18F]F-FDG PET-CT was associated with lower PFS but not OS. is inconsistency may be attributed to the deficient number of cases. A few of studies have assessed the prognostic value of post-ASCT [ 18 F]F-FDG PET-CT for lymphoma [29][30][31][32][33][34]. Most of these studies have confirmed the prognostic value of post-ASCT [ 18 F]F-FDG PET-CT [29][30][31]. However, in Palmer's multivariate analysis, the post-ASCT [ 18 F]F-FDG PET-CT scan cannot predict the outcome for patients undergoing ASCT [32]. In our retrospective study, we found that lymphoma patients with negative post-ASCT [ 18 F]F-FDG PET-CT results had a better prognosis compared with the positive group, indicating that the post-ASCT [ 18 F]F-FDG PET-CT result was an independent factor associated with both PFS and OS. Furthermore, in our univariate analysis, the number of previous treatments was an independent factor associated with OS but not PFS. However, in the multivariate analysis, the number of previous treatments was associated with neither PFS nor OS. Nevertheless, several previous studies have shown that patients receiving ASCT as a first-line consolidation treatment can have better outcomes compared with patients with relapsed/refractory lymphoma [35][36][37]. is discrepancy may be related to different PET criteria and different time windows for post-ASCT [ 18 F]F-FDG PET-CT.
To minimize the frequency of posttherapy inflammatory changes, which potentially make the PET-CT result "false-positive," PET should not be performed before at least 3 weeks after chemotherapy and preferably 8 to 12 weeks after the completion of radiotherapy [38]. However, the appropriate time window for post-ASCT [ 18 F]F-FDG PET-CT remains largely undetermined. Several new agents have been reported to modulate tumor metabolism, glucose uptake, and inflammation in the tumor microenvironment, therefore potentially increasing the false-positive or false-negative [ 18 F]F-FDG-PET results [39]. Although Ulaner et al. have reported that patients receiving ASCT rarely demonstrate FDG-avid lesions suggestive of disease without malignant pathology [40], in their research, the posttransplantation PET-CT for each patient is performed between 1 and 16 months after transplantation (median 6 months). In other previous studies, the time window for posttransplantation PET-CT is inconsistent, some even within 1 month [26,41,42]. In our current study, we tended to narrow down the time window to make the result more accurate. We separately studied the effects of PET-CT on PFS and OS within 3 months and within 3-6 months after ASCT. We found that PET-CT within 3-6 months, but not within 3 months, after ASCT was valuable in

Conclusions
Taken together, we found that the positive post-ASCT [ 18  Data Availability e underlying data supporting the results of our study can be found at http://www.chictr.org.cn/index.aspx.