Posttransplant lymphoproliferative disorders (PTLD) are a serious but rare consequence of immunosuppression after solid organ transplantation (SOT). For all of the rarer subtypes and the relapsed/refractory setting, case reports and small retrospective case series remain the only source of evidence.1,2
For the most common subtype, CD20-positive B-cell PTLD, which accounts for 80% of cases, a succession of prospective clinical phase II trials has led to a successful, evidence-based standardized treatment protocol. Initial, small trials of rituximab monotherapy had resulted in an overall survival (OS) of 1.2 to 3.5 years.3-5 In 2012, the PTLD-1 trial (n = 70) demonstrated the safety and efficacy of sequential treatment (ST) with 4 cycles of weekly rituximab followed by 4 cycles of CHOP-21 chemotherapy (cyclophosphamide 750 mg/m2 intravenous (IV) day (d) 1, doxorubicin 50 mg/m2 IV d1, vincristine 1.4 mg/m2 (max. 2 mg) IV d1, and prednisone 50 mg/m2 PO d1-5, every 21 days) in CD20-positive PTLD after SOT.6 Median OS was 6.6 years, and response to 4 cycles of rituximab induction was a prognostic factor for OS after completion of sequential therapy.6 Finally, the latest trial of risk-stratified ST (RSST, n = 152) with rituximab consolidation for patients in complete response (CR) after rituximab induction (low-risk group) and R-CHOP-21 (rituximab 375 mg/m2 IV d 1, cyclophosphamide 750 mg/m2 IV d1, doxorubicin 50 mg/m2 IV d1, vincristine 1.4 mg/m2 (max. 2 mg) IV d1, and prednisone 50 mg/m2 PO d1-5, every 21 days) for patients not in CR after 4 weekly cycles of rituximab (high-risk group) demonstrated in 2016 that CR to rituximab induction identifies a group of patients with B-cell PTLD who do not need chemotherapy and that R-CHOP consolidation for all others is safe and effective.7 Despite limiting chemoimmunotherapy to the high-risk group, the overall response rate of 88% and median OS of 6.6 years of RSST closely matched the results of ST. Different risk-stratified approaches have also been reported in pediatric PTLD.8 Patients in a partial response after first-line treatment of CD20-positive PTLD are common. In the RSST trial, 23 (18%) of 126 patients who completed treatment and underwent final staging were in a partial response based on computed tomography (CT) staging.7 Of these 23, 10 (43%) suffered a relapse compared to only 10 (12%) of 86 patients in CR (Trappe, unpublished data). PTLD relapse is a life-threatening diagnosis—second-line chemotherapy in PTLD is effective in only around 50% of patients and associated with significant treatment-related mortality (22% in a small retrospective series from the prerituximab era).9 Early identification of patients at particularly high or low risk of relapse would allow to treat those at risk of relapse early while avoiding potentially toxic treatment in those at low risk of relapse.
Fluorine-18 fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) is a metabolic imaging technique based on the increased uptake and subsequent trapping of a radiolabeled glucose analogue in metabolically hyperactive cells, such as lymphoma cells. It has been recommended as a standard in the staging and response assessment of 18F-FDG-avid lymphoma, specifically Hodgkin and non-Hodgkin lymphoma.10,11 Negative end-of-treatment (EOT) 18F-FDG-PET is significantly associated with better progression-free survival (PFS) in diffuse large B-cell lymphoma (DLBCL) after standard first-line chemotherapy or chemoimmunotherapy.12-14 However, controversy remains and PET funding is limited in Germany based on a negative assessment of patient-relevant benefit by the German Institute for Quality and Efficiency in Health care.15
It has been demonstrated in large patient cohorts that PTLD is an 18F-FDG-avid lymphoma and can be detected by 18F-FDG-PET at diagnosis with an overall sensitivity and specificity of around 90%.16,17 However, the role of EOT PET has to our knowledge only been addressed in small, retrospective analyses.18-20 False-positive results of EOT PET, in the majority inflammatory changes, have been reported in immunocompetent patients with lymphoma.21 Arguably, this risk might be even higher in PTLD, where longstanding immunosuppression increases the rate of infections under antilymphoma therapy. Such false positives have previously been reported in PTLD.18,20 Our goal was therefore to investigate the clinical value of EOT PET in a large cohort of patients with PTLD treated with an up-to-date protocol.
MATERIALS AND METHODS
Study Design and Patients
This retrospective analysis is based on patients treated at 16 German centers with ST or RSST in the prospective German PTLD registry, including patients treated in the ST (PTLD-1) and RSST trials.6,7 Both the registry and the trials were approved by the appropriate Ethics committees and all patients gave informed consent according to the Declaration of Helsinki. Disease stage at enrolment was determined through a complete patient history, physical examination, laboratory investigations (including full blood count, serum lactate dehydrogenase [LDH] activity, and renal and liver function tests), bone marrow biopsy, cerebrospinal fluid analysis, and CT scans of the head, chest and abdomen.6,7
The German PTLD study group database identified 92 patients who had received PET imaging at any time point: staging, response evaluation, or follow-up. We limited this analysis to those patients who had CD20-positive B-cell PTLD, had received first-line therapy with ST or RSST, and had received EOT PET: this group comprised 37 patients. The total number of patients with CD20-positive B-cell PTLD treated with an up-to-date protocol was 135.
PET imaging was mandated neither by the German PTLD registry nor in the PTLD-1 trials. EOT 18F-FDG-PET was thus performed in addition to CT imaging based on a clinical decision by the treating physician. Contributing factors were local imaging standards and funding, a partial remission on CT staging, or incongruent clinical and radiological findings. EOT PET was performed at the time of final staging (1 month after the last cycle of therapy) or up to 4 weeks later. 18F-FDG-PET scans were performed according to local protocol based on guidelines by the German society for nuclear medicine (Deutsche Gesellschaft für Nuklearmedizin).22 PET reporting was not standardized. The initial analysis was based on written PET reports by local nuclear medicine departments. PET imaging was performed between August 2006 and August 2014. 18F-FDG doses ranged from 200 to 370 MBq (median, 300 MBq). Imaging was performed from 50 to 100 minutes after injection (median, 60 minutes). Four scans were performed as 18F-FDG-PET only, the remainder as combined 18F-FDG-PET/CT scans. Data collected were PET positivity, additional investigations performed based on PET results, complications after such additional investigations, consolidation treatment after PET, and, if performed, PET positivity at diagnosis. The maximal standardized uptake value and the Deauville criteria were not uniformly reported and thus could not be evaluated.23 All EOT PET scans reporting no nonphysiological 18F-FDG uptake were interpreted as negative EOT PET (complete metabolic response). In a second step, we performed a central review by 2 nuclear medicine physicians (consensus read) of all EOT PETs reporting nonphysiological 18F-FDG uptake using the Deauville criteria. According to consensus guidance, scores 1 and 2 were defined as a negative PET (complete metabolic response) and scores 3, 4 and 5 as a positive PET.10 The reviewers had no access to baseline CT or PET imaging.
Patients had either received ST (3 patients) or RSST (34 patients) according to the PTLD-1 trial protocol and its 2007 amendment.6,7 All started with rituximab (375 mg/m2 IV) on days 1, 8, 15, and 22, followed by interim staging by CT (days 40-50). In the ST protocol, all patients received 4 cycles of CHOP every 3 weeks starting 4 weeks after the last dose of rituximab.6 In RSST, patients with a CR at interim staging continued with 4 courses of rituximab monotherapy (375 mg/m2 IV) every 3 weeks, whereas all others received 4 cycles of R-CHOP-21 (rituximab, 375 mg/m2 IV d1; cyclophosphamide, 750 mg/m2 IV d1; doxorubicin, 50 mg/m2 IV d1; vincristine, 1.4 mg/m2 [max, 2 mg] IV d1; and prednisone, 50 mg/m2 PO d1-5, every 21 days). Two patients received rituximab consolidation according to protocol. Two additional patients received rituximab consolidation despite only achieving a PR at interim staging. All other patients received CHOP or R-CHOP consolidation. Supportive treatment with granulocyte-colony stimulating factor after CHOP or R-CHOP chemotherapy was obligatory. Pneumocystis jirovecii chemoprophylaxis was recommended.
The final response assessment was performed 1 month (plus or minus 7 days) after the last cycle of therapy. Subsequently, patients completed follow-up examinations every 3 months for 2 years, every 6 months for years 3 to 5, and annually thereafter. Interim, final response and follow-up assessment included a complete patient history, physical examination, laboratory investigations (including full blood count, LDH, as well as renal and liver function tests), and CT scans of the chest and abdomen. Further investigations, such as bone marrow biopsy, CT scans of the head, or endoscopy were performed if clinically indicated to determine remission status. Follow-up data was evaluated up to December 2016. Median follow-up was 5.0 years.
Time to progression (TTP) was defined from start of treatment to disease progression (defined as clinical or CT-morphological disease progression). Relapse was also defined as clinical or CT morphological disease progression. OS was defined from start of treatment to death from any cause. PFS was defined from start of treatment to disease progression or death from any cause. Time-to-event outcomes were described using Kaplan-Meier statistics. Exploratory analyses were performed using 2-sided stratified log-rank tests. Multivariable analyses were performed with Cox regression models (log-rank ratio test, backward elimination). The 2-sided significance level was set at 0.05, and statistical tests were performed using IBM SPSS 126.96.36.199.
Baseline patient characteristics are summarized in Table 1. Of the 37 patients, 17 were kidney, 12 liver, 4 lung, 2 heart, and 2 kidney/pancreas transplant recipients. Median age was 53.9 years (range, 20-82 years). Median time from transplantation to PTLD was 7.8 years. Five (13.7 %) cases were early PTLD and occurred in the first year after transplantation. Most cases (26/37, 70.3 %) were of the diffuse large B-cell (DLBCL) type, 16 (44.4 %) of 36 PTLD were Epstein-Barr virus–associated, and 26 (70 %) of 37 PTLD were Ann Arbor stage III or IV. Nineteen (54.3 %) of 35 patients had an elevated LDH at diagnosis, and 12 (35.2 %) of 34 patients an International Prognostic Index (IPI) score of 3 or higher (risk factors are age > 60 years, Ann Arbor stage ≥ III, Eastern Oncology Group performance status ≥ 2, elevated LDH, and more than 1 extranodal disease manifestation).24
Outcome in All 37 Patients
After completion of treatment, 18 (48.6%) of 37 patients had a CR in final CT staging, 18 had a partial response (PR) and 1 patient had stable disease (SD). Median OS was not reached; the 3- and 5-year Kaplan-Meier estimates were 82.9% (95% confidence interval [95% CI], 70%-95%) and 70.6% (95% CI, 54%-87%), respectively. Median TTP was not reached either; the 3- and 5-year Kaplan-Meier estimates were both 83.5% (95% CI, 71%-96%). Median PFS was 6.9 years with 3- and 5-year Kaplan-Meier estimates of 77.7% (95% CI, 64%-91%) and 65.6% (95% CI, 48%-82%), respectively.
Baseline PET imaging at diagnosis had been performed in 15 of 37 patients. All 15 (100%) patients had PET-positive disease. EOT PET was negative in 24 (64.9%) of 37 patients. This included 23 patients with no reported nonphysiological 18F-FDG uptake and 1 patient whose EOT PET was reviewed and assigned a Deauville score of 2. EOT PET was positive in 13 (35.1%) of 37 patients. Deauville scores assigned by central review were 3 in 3 patients, 4 in 6 patients and 5 in 4 patients. Of the 13 patients with a positive EOT PET, 5 (38.5%) of 13 patients had achieved a CR and 8 (61.5%)of 13 patients a PR in CT staging (see Figure 1).
Additional Treatment After EOT PET Imaging
Eight of 37 patients received additional consolidation treatment after EOT PET (Figure 1). This was immunochemotherapy with 2 additional cycles of R-CHOP in 3 cases and 2 to 4 cycles of R-CE (rituximab 375 mg/m2 IV d1, carboplatin AUC4 d1, etoposide 120 mg/m2 d1-3, every 21 days) in 2 cases. Two patients received consolidating radiotherapy and 1 patient received rituximab maintenance therapy. Five of 8 had achieved a PET-positive PR and received immunochemotherapy in 4 cases and rituximab consolidation in 1 case. One of 8 patients had achieved a PET-positive CR and received radiotherapy. Two of 8 patients had achieved a PET-negative PR and received radiotherapy and immunochemotherapy respectively. In this group of 8 patients, there were 3 clinical or CT morphological relapses. One relapse occurred 5.2 years after PET-negative PR and consolidation radiotherapy and 2 after PET-positive PR and additional, consolidating R-CHOP immunochemotherapy (both relapses within the first year of starting treatment).
EOT PET Results and Prognosis
Seven of the 37 patients went on to suffer a clinical or CT-morphological PTLD relapse during the follow-up period. Of these 7, 5 had a positive EOT 18F-FDG-PET result. Their EOT PET Deauville scores were 5 in 3 cases and 3 and 4 in 1 case each. Thirty patients suffered no PTLD relapse; 22 of them had a negative EOT PET and 8 a positive EOT PET. The EOT PET Deauville scores of the latter were 4 in 5 cases, 3 in 2 cases and 5 in 1 case. The specificity of EOT PET for PTLD relapse was therefore 71%; sensitivity, 73%; positive predictive value (PPV), 38%; and negative predictive value (NPV), 92%. Of note, of the 4 patients who received EOT-PET imaging as PET only (not PET/CT), only 1 patient had a positive PET, and this patient was the only 1 of the 4 to suffer a relapse. There was no significant difference in OS between the PET-positive and PET-negative groups (P = 0.115). Median OS was not reached in the PET negative group and was 6.9 years in the PET positive group (Figure 2A). However, TTP and PFS were significantly better in the PET-negative group (P = 0.019 and P = 0.013, respectively, Figures 2B and C). Median TTP was reached in neither group and both 3- and 5-year TTP estimates were 95.8% (95% CI, 88%-100%) in the PET-negative and 59.2% (95% CI, 32%-87%) in the PET-positive group (Figure 2B). Median PFS was not reached in the PET-negative group and was 3.3 years in the PET-positive group (Figure 2C).
PET Results in Patients With a CR
Limiting the analysis of EOT PET results to patients in a CR by CT staging (n = 18), there was no significant difference in OS (P = 0.408), TTP (P = 0.430), and PFS (0.979). Of particular note, both 3- and 5-year Kaplan Meier TTP estimates were similar in the PET-negative group (92.3%; 95% CI, 78%-100%) and the PET-positive group (80.0%; 95% CI, 45%-100%).
PET Results in Patients With a Partial Response
In the 18 patients in a PR by CT staging, we noted highly significant differences in OS (P = 0.001), TTP (P = 0.007), and PFS (P < 0.001) by EOT PET results (see Figure 3). For patients with a PR in CT final staging and a negative PET scan (n = 10), the 3- and 5-year Kaplan-Meier estimates of OS, TTP, and PFS were all 100%. On the other hand, those 8 patients with a PR in CT final staging and a positive PET scan had a median OS of 16.4 months (95% CI, 0-34.1 months), median TTP of 12.4 months (95% CI, 10.0-14.6 months), and median PFS of 11.4 months (95% CI, 3.6-18.3 months). Eleven patients were in a partial remission and received no additional consolidation treatment after EOT PET. In the subgroup, 2 of 3 patients with a positive EOT PET suffered a relapse. Of the 8 patients with a negative EOT PET, none suffered a relapse. In this subgroup of 11 patients, sensitivity, specificity, PPV, and NPV were thus 89%, 100%, 67%, and 100%, respectively.
EOT PET-Negative Patients With Relapse
Two patients with negative EOT PET suffered a PTLD relapse during the follow-up period. These included a lung transplant recipient who relapsed 10 months after the start of first-line treatment (he had achieved a PET-negative CR) and a kidney transplant recipient who relapsed 5.2 years after the start of first-line treatment which had resulted in a PET-negative PR.
EOT PET-Positive Patients Without Relapse
Eight (22%) of the 37 patients had positive EOT PET but did not suffer a clinical or CT morphological relapse. These included 5 proven false positives: in 3 patients in CR according to CT staging, additional invasive investigations were performed after positive EOT PET. These were colonoscopy in 1 case and biopsies of suspected bone involvement in the other 2 (mandible and os ileum, respectively). These led to the diagnosis and treatment of a potentially life-threatening condition (osteomyelitis, EOT PET Deauville score 5) in 1 case. In another, colitis was diagnosed but resolved without treatment (EOT PET Deauville score 3) and in the final case, the biopsied bone was normal (EOT PET Deauville score 4) but the patient received radiotherapy nonetheless. In this group of 3 patients, follow-up ranged from 6.9 to 10.0 years. There was 1 death and no relapse of PTLD. Two further patients (1 in CR, 1 in PR according to CT staging) had residual metabolic activity on EOT PET, but did not receive further treatment. In 1 patient (EOT PET Deauville score 3), metabolic activity normalized over the course of 3 further PET investigations during the subsequent 9 months, and the patient is alive and without relapse 6 years later. The second patient (EOT PET Deauville score 4) died of sepsis 2 months after treatment; autopsy did not reveal evidence of PTLD. Three cases were not so clear-cut: these patients were in PR according to CT with positive EOT PET (all EOT PET Deauville score 4) and received additional treatment without biopsy. This treatment was second-line immunochemotherapy (R-CE) over 2 to 4 cycles in 2 cases and rituximab maintenance over 2 years in 1 case. There were no reports of a manifest PTLD relapse in these 3 patients. Of note, 1 patient with a negative EOT PET (Deauville 2) suffered a complication caused by an additional investigation after EOT PET: severe bleeding after endoscopic resection of rectal high-grade intraepithelial neoplasia.
We compared outcomes by result of CT staging after treatment (18 patients in CR, 18 patients in PR, excluding the 1 patient in SD). OS, TTP, and PFS were superior in the CR group, but there were no significant differences: median OS was not reached in the CR group and was 5.6 years in the PR group (P = 0.150). Median TTP was reached in neither group (P = 0.165). TTP estimates at both 3 and 5 years were 88.9% (95% CI, 74%-100%) in the CR group and 76.7% (95% CI, 57%-97%) in the PR group. Median PFS was not reached in the CR group and was 5.2 years in the PR group (P = 0.231). IPI (≥3 vs ≤ 2) has been previously described as a prognostic factor in PTLD in the ST and RSST trials.7,25 In the 34 of 37 patients with available IPI data in this cohort of 37 patients, IPI (≥3 vs ≤ 2) was a significant prognostic factor for OS (P = 0.014) and PFS (P = 0.035) but not TTP (P = 0.992). We included IPI at diagnosis, EOT PET positivity as well as the previously described prognostic factors thoracic organ transplant and response to rituximab at interim staging in multivariable log-rank, backward elimination Cox regression analyses (Table 2).25 For OS, only IPI score of 3 or higher remained in the model as an independent, significant risk factor (P = 0.025). For TTP, only PET positivity remained in the model, albeit with a significance level of P = 0.079.
This retrospective multicenter analysis is the largest study of EOT PET in adult PTLD to date. All patients had CD20-positive PTLD, the most common form of the disease. Treatment, staging, and follow-up were standardized, and median follow-up was 5 years. All EOT PET scans reporting nonphysiological 18F-FDG uptake were centrally reviewed and reported according to the Deauville criteria. Limitations of this study include its retrospective format, potential selection bias and lack of baseline PET imaging in 22/37 patients as well as lack of a standardized PET protocol. Furthermore, any outcome analyses after EOT PET are potentially confounded by the use of nonstandardized consolidating treatment in 8 of 37 patients—6 after positive and 2 after negative EOT PET.
Our key findings are a NPV of 92% of EOT PET for PTLD relapse and the significantly better TTP and PFS of patients with a negative EOT PET. In the clinically particularly relevant subgroup of patients in a partial response, the results were even more encouraging. A negative EOT PET was a highly significant prognostic factor for OS, TTP, and PFS.
We have been careful not to overestimate the sensitivity, specificity, and the PPV of EOT for PTLD relapse by classifying cases of positive EOT PET as false positives if there was no histological confirmation or clinical or CT morphological relapse—even if these patients received effective consolidating therapy. Our results thus represent a conservative estimate of the sensitivity and specificity of EOT PET in PTLD. However, our long follow-up allows a reliable estimation of the NPV of EOT PET for PTLD relapse.
We observed false-positive EOT PET results in 8 of 37 patients. This rate could potentially be reduced by the use of baseline PET imaging, thus allowing a more reliable differentiation of PTLD from other (pre)malignant processes and infection.16 Although 5 patients had confirmed false-positive results, a further 3 cases received additional treatment and never developed a manifest PTLD relapse and are difficult to categorize. The rate of false-positive results of 22% should thus be interpreted as an upper-level estimate. On the other hand, in 2 cases, the information gathered in EOT PET and subsequent diagnosis of unrelated, life-threatening illness led to clinically relevant patient benefit. Regarding patient safety, only 1 patient suffered a serious adverse event after invasive diagnostic procedures after 18F-FDG-PET (severe bleeding after endoscopic resection of rectal high-grade intraepithelial neoplasia).
EOT PET was performed in selected patients where additional information was required for clinical treatment decisions—this selection bias likely reduces the observed sensitivity, specificity, and PPV of EOT-PET by underrepresenting the majority of patients (70%) who achieve a CR according to CT and excluding patients with progressive disease.7 On the other hand, this is a clinically relevant selection because these are the patients most in need of imaging information in addition to CT staging. EOT-PET was significantly associated with TTP despite this selection basis. Furthermore, we observed a highly significant association of EOT PET with disease control and survival in patients with a PR according to CT staging. In this group (20% of patients who complete up-to-date therapy) with a relevant risk of relapse, EOT PET is a clinically valuable tool to separate patients that can be safely managed with follow-up, and those who need further investigations and additional therapy if refractory/relapsed PTLD is confirmed.
Previous studies of EOT PET in lymphoma have been criticized for not demonstrating additional value compared to clinical baseline risk scores.26 Multivariable analysis is challenging in small patient cohorts such as this one. Nonetheless, we have performed multivariable analyses, and although the IPI (≥3 vs. ≤ 2) was the only significant independent risk factor for OS in our multivariable analysis, only EOT PET positivity remained in the model in multivariable analysis of TTP, albeit not as a significant risk factor.
In summary, EOT PET in PTLD is significantly associated with PTLD disease control. A negative result offers a high level of confidence that the patient will not suffer a relapse and can enter standard follow-up—this is of particular relevance in PTLD, as second-line treatment is associated with significant treatment-related mortality. A positive EOT PET has a low PPV (38%) for PTLD relapse, and additional investigations should, if feasible, precede additional therapy.
Our results should ideally be confirmed in a prospective clinical trial. The use of baseline PET imaging and standardized PET protocols could potentially improve the results reported here. Furthermore, the poor outcome of EOT PET-positive patients highlights the need for a more effective second-line treatment in PTLD.
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