Positron emission tomography using F-18 fluorodeoxyglucose pre- and post-autologous stem cell transplant in non-hodgkin s lymphoma

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1 (2008) 41, & 2008 Nature Publishing Group All rights reserved /08 $ REVIEW Positron emission tomography using F-18 fluorodeoxyglucose pre- and post-autologous stem cell transplant in non-hodgkin s lymphoma PB Johnston 1, GA Wiseman 2 and INM Micallef 1 1 Division of Hematology/Blood and Marrow Transplantation, Mayo Clinic, Rochester, MN, USA and 2 Department of Nuclear Medicine, Mayo Clinic, Rochester, MN, USA Positron emission tomography (PET) utilizing fluorodeoxyglucose (FDG) has an ever-increasing role in the management of numerous malignancies. FDG PET in lymphoma is being incorporated into the response assessment in lymphoma as published by the Imaging Subcommittee of International Harmonization Project in Lymphoma. The exact role of FDG PET in non- Hodgkin s lymphoma (NHL) associated with autologous stem cell transplant (ASCT) is unclear. Numerous studies have identified pretransplant PET scans as being highly prognostic with regard to overall and PFS after ASCT. Many included a wide range of histologies, including Hodgkin s lymphoma and NHL. In studies with mixed histologies, PFS at 2 years has been improved by as much as 82% in patients with negative pre-asct PET scans. In studies incorporating only patients with NHL, improvements in failure-free survival have been reported as high as 43% for patients with negative pre-asct PET imaging. Limitations have included inclusion of many histologies, different reported time points, small retrospective studies and variation in the interpretation of a positive PET. Validation is ongoing in larger prospective trials. Future directions include the potential incorporation of post- ASCT therapy, such as radiation therapy or maintenance antibody therapy, for patients with positive pre-asct PET scans. (2008) 41, ; doi: /bmt ; published online 7 April 2008 Keywords: NHL; PET; autologous transplant Introduction The use of fluorodeoxyglucose (FDG) positron emission tomography (PET) in lymphoma has been greatly increasing over the past few years. FDG PET has been demonstrated to improve detection of occult disease after Correspondence: Dr PB Johnston, Division of Hematology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, USA. johnston.patrick@mayo.edu Received 19 February 2008; accepted 19 February 2008; published online 7 April 2008 diagnosis of NHL relative to conventional imaging modalities. 1,2 Moreover, FDG PET has high prognostic value in patients undergoing therapy for aggressive NHL when performed at time points during the treatment of disease. 3 5 Evaluation with FDG PET for NHL after initial therapy has become widespread in an attempt to detect residual disease. In an effort to standardize the utilization of FDG PET after therapy, a consensus statement has been published based on the recommendations of the Imaging Subcommittee of International Harmonization Project in lymphoma. 6 In this consensus statement, specific recommendations were made regarding the use and interpretation of PET scans in lymphoma, noting that PET scanning pretreatment is only recommended for histologies which are routinely PET avid, including diffuse large cell lymphoma and Hodgkin s lymphoma. PET scanning during the course of treatment should only be performed as part of a clinical trial or prospective registry, and PET scanning after completion of therapy should be performed a minimum of 3 weeks after chemotherapy or 8 weeks after radiation or chemoradiation therapy. For residual masses greater than or equal to 2 cm, PET positivity should be defined as activity above the mediastinal blood pool activity; for smaller masses, the activity should be considered positive if the uptake is above that of the surrounding tissue. It was also noted that there is no role in the routine use of PET scans for following patients in remission. No consensus statement was made regarding the use of PET scans with SCT. FDG PET scanning pre-autologous stem cell transplant (ASCT) for relapsed, chemotherapy-sensitive NHL has become common; however, there appears to be little consensus on use of the scan results. The prognostic value of 18F-FDG PET in the pre- and post-sct setting remains unclear. Background PET scanning has been utilized in a research setting for many years; however, it was limited by the availability of scanners and PET radiopharmaceuticals. More recently, with the development of commercial scanners and PET radiopharmacies, FDG PET scanning has come into clinical use. The most commonly used radionuclide is

2 920 fluorine-18, which is produced in a cyclotron by the bombardment of oxygen-18 with protons. The fluorine-18 has a physical half-life of 110 min. This is bound to 2-deoxy-D-glucose resulting in 2-(fluorine-18)fluoro-2- deoxy-glucose (18F-FDG). FDG is administered i.v. to patients who then undergo positron emission tomographic imaging for detection. Uptake of FDG is increased in many tumor types for increased cellular glycolysis. Intracellular modification of F-18 FDG to F-18 FDG-6-phosphate results in a molecule which is not readily released from the cell. Fluorine-18 decays to oxygen-18 with the release of a positron which is annihilated by an electron resulting in the emission of two MeV photons in opposite directions. The detection of the photons, a ring of detectors in a dedicated PET scanner or PET/CT scanner, is the basis of this modality of imaging. Utilization of FDG PET in NHL PET scanning is a highly sensitive technique for detection of nodal and extranodal tumor in aggressive lymphomas, including diffuse large cell lymphoma, mantle cell lymphoma and Hodgkin s lymphoma. It has also shown benefit in assessing response to therapy and appears to have some prognostic value when performed early in treatment after 1 2 cycles of chemotherapy. Risk-adapted protocols are now being investigated based on early FDG PET scans in standard treatment regimens through groups such as the Eastern Cooperative Oncology Group. There are many excellent reviews of the use of FDG PET scans in the detection and response to therapy in NHL and that subject will therefore not be reviewed here. Utilization of FDG PET pretransplant in NHL Several groups have reported single center data regarding the impact of pre-asct transplant FDG PET scans on outcome (Table 1). The majority of these studies included patients with Hodgkin s lymphoma and non-hodgkin s lymphoma, and within this group many different histologies. Table 1 provides a summary of the presented data in each publication, as well as our Mayo Clinic data presented at the ASBMT/IBMTR annual meeting. 7 In general, the PFS after transplant was better in the pretransplant FDG PET negative group. However, there were mixed results as to the statistical significance in overall survival (OS) based on FDG PET status pretransplant. Some variability in the results may stem from the fact that both NHL and Hodgkin s disease (HD) were included in many of the analyses. Also, within the NHL subsets of each study were included patients with indolent lymphomas. In addition, some studies included patients who were transplanted with chemotherapy refractory disease. Take home points from each study are listed in Table 2. The limitations of these studies are outlined in Table 3. Next, we will attempt to summarize each individual study and its findings. An original retrospective review by Becherer et al. 8 examined the outcome of patients who underwent ASCT or allogeneic SCT for lymphoma. All the 16 reported patients had undergone FDG PET analysis within 8 weeks of undergoing SCT. Of the 16 patients, 10 had NHL and 6 had Hodgkin s lymphoma. All 10 patients with NHL had aggressive histologies, the most common being diffuse large B-cell lymphoma (7 patients). A single patient underwent allogeneic SCT, the remainder autologous. The median follow-up post-sct was 13 months. FDG PET scans pre- ASCT were visually scored and were classified as negative, 5 weakly positive, 3 moderately positive 2 and strongly positive. 6 Patients were re-evaluated at 28 days post-sct, including FDG PET analysis. Radiation therapy was administered to patients considered to have bulky disease pretransplant. All five patients who were FDG PET negative prior to SCT remained disease free as of last analysis (median follow up 17 months). Two of three patients with a mildly positive FDG PET pre-sct remained in remission post-sct; however, seven of the eight patients with moderate or strong activity on pre-sct FDG PET relapsed post transplant and the other died of early transplant-related toxicity. Of the patients with moderate or strong activity pre-sct, six had achieved a PR by classical staging, one a CR and one progressive disease (allogeneic transplant recipient). Seven of the eight received post transplant irradiation to areas of bulky disease. Based on FDG PET analysis at 28 days post-sct, 7 of the 8 had no response (NR), and relapsed at a median of 6 months. Although the number of patients was small, this original publication would suggest that pre-sct FDG PET scanning was highly predictive of outcome post transplant. The first published prospective analysis of patients undergoing FDG PET scans pre-sct was reported by Cremerius et al. 9 In total, 23 of the 24 patients had newly diagnosed lymphoma and were scheduled to receive up front chemotherapy followed by ASCT. In this study, patients underwent FDG PET scanning at baseline, after three cycles of induction therapy, before and after ASCT. Patients were classified as having a complete metabolic response (CMR), partial metabolic response (PMR) or no PMR (less than 25% reduction in SUV from baseline at time of analysis). In total, 20 patients had aggressive histologies, whereas 4 had follicular lymphoma grade 1 or 2. In total, 23 of the 24 patients were scheduled for SCT after induction chemotherapy as first-line therapy for their disease. Only 22 patients had results of pre-sct FDG PET scans available for review in the publication; therefore, only data on those patients are reported here. In patients who did not achieve a PMR after induction therapy prior to transplant, 86% had disease progression with median PFS and OS of 9 and 29 months, respectively. In contrast, in the 15patients who achieved a PMR or CMR pre-sct, only 5 progressed. Also, patients who did not achieve a PMR by post transplant FDG PET had a median PFS of 4 months versus 25months for those achieving a PMR or CMR post transplant (P ¼ 0.006). Spaepen et al. 10 reported an experience with 60 patients who underwent FDG PET scanning after salvage chemotherapy but prior to SCT. In total, 41 patients had NHL and 19 had Hodgkin s lymphoma. In total, 54 patients underwent ASCT and 6 underwent allogeneic. In total, 30 patients had negative FDG PET scans pre-sct (20 NHL,

3 Table 1 Overall and progression-free survival utilizing FDG PET scans pre- and post transplant for NHL References Study design N PET positive at ASCT (%) PET negative at ASCT (%) Median follow up (months) OS PET positive (%) OS PET negative (%) PFS PET positive (%) PFS PET negative (%) Becherer et al. 8 Retrospective, non-consecutive 16 6HD 10 NHL Po Po0.01 Cremerius et al. 9 Prospective, consecutive NHL NR Spaepen et al. 10 Retrospective, non-consecutive HD 41 NHL NR Po Po Filmont et al. 11 Prospective, consecutive 20 6HD 14 NHL NR NR 8 88 Svoboda et al. 12 Retrospective NHL 19 HD Filmont et al. 13 Prospective, consecutive NHL 10 HD NR NR Bondly et al. 7 Prospective, consecutive 100 NHL P ¼ P ¼ 0.08 Kassim et al. 14 Retrospective 44 NHL a 33 NR NR NR NR Alousi et al. 15 Retrospective 188 NHL a 47 See text See text See text See text P ¼ P ¼ Schot et al. 16 Prospective, consecutive 78 NHL year reported data NR NR 29% FFS (2 yr) 72% FFS (2 yr) Abbreviations: ASCT ¼ autologous stem cell transplant; FFS ¼ failure-free survival; HD ¼ Hodgkin s disease; NHL ¼ non-hodgkin s lymphoma; NR ¼ not reported; OS ¼ overall survival; PET ¼ positron emission tomography; yr ¼ year. a Indicates PET status unknown in a few patients. 921

4 922 Table 2 Take home message from published studies Table 3 Limitations of FDG PET scan studies References Becherer et al. 8 Cremerius et al. 9 Spaepen et al. 10 Filmont et al. 11 Svoboda et al. 12 Filmont et al. 13 Bondly et al. 7 Salient features Early study showed improved survival for HD and NHL patients with negative PET pre-asct Interesting study of newly diagnosed patients in an up front transplant regimen; patients with no metabolic response, as measured by pre-asct PET, did poorly post-asct A mixed cohort of NHL and HD with autologous and allogeneic transplant; OS and PFS improved dramatically if pre-sct PET was negative Small study in NHL and HL; with short (o1 year) follow-up, majority of pre-sct PET positive patients relapsed quickly Larger study in NHL and HL noticing if PET positive pre-asct nearly universal early relapse Poor prognosis NHL and HL. EFS double if pre- ASCT PET negative versus PET positive. If day 100 post-asct PET negative then 81% PFS versus 25% if PET positive 100 NHL patients, mixed histologic subtypes; EFS but not OS improved if pre-asct PET negative, after limited follow-up Small patient numbers Retrospective Few publications Heterogeneous patient population Mixed NHL and HL Mixed NHL histologies Timing of PET scan Chemotherapy sensitive versus chemotherapy refractory disease both included Mixed autologous and allogeneic transplant Criteria for PET positivity not established Absolute SUV versus relative SUV above blood background Reliability of PET scan in indolent lymphoma Timing of PET scan relative to autologous stem cell transplant not established Negative PET scan does not exclude active disease Abbreviations: HL ¼ Hodgkin s lymphoma; NHL ¼ non-hodgkin s lymphoma; PET ¼ positron emission tomography; SUV ¼ standard uptake value. Kassim et al. 14 Alousi et al. 15 Schot et al. 16 In this aggressive NHL study, although pre-asct PET status did not affect PFS, post-asct PET status had a high correlation with PFS In this very large retrospective review of patients with large B-cell lymphoma, it showed an independent and additive improvement in PFS with high-dose rituximab and/or PET negative status Demonstrated improvement in the prognostic ability utilizing the secondary age-adjusted IPI and PET status pre-asct Abbreviations: ASCT ¼ autologous stem cell transplant; HD ¼ Hodgkin s disease; HL ¼ Hodgkin s lymphoma; IPI¼ international prognostic index; NHL ¼ non-hodgkin s lymphoma; OS ¼ overall survival; PET ¼ positron emission tomography. 10 HD) and 30 patients had positive FDG PET scans pre- SCT (21 NHL, 9 HD). Of the 30 patients who were FDG PET negative prior to SCT, only 3 relapsed. All the three relapses had undergone ASCT and were not disease-type specific (one each with HD, diffuse large B-cell lymphoma (DLBCL) and anaplastic large cell lymphoma). Two-year actuarial OS and PFS were 100 and 96%, respectively. Of the 30 patients with positive pre-sct FDG PET scans, 26 relapsed and only 4 were progression free. Two-year actuarial OS and PFS in this cohort was 55 and 23%, respectively. Of the patients who underwent allogeneic transplant, the two who were FDG PET negative pretransplant remained disease free, but the four who were FDG PET positive all relapsed. Because of the statistical significance of this analysis, it was suggested that this might serve a prognostic role in the selection of patients who should be considered for SCT. The first prospective consecutive analysis of the use of FDG PET scans in ASCT by Filmont et al. 11 examined two cohorts of patients. The first cohort of 20 patients (14 NHL, 6 HD) underwent FDG PET scans 2 5weeks after initiation of salvage chemotherapy, but prior to ASCT. The second cohort of 23 patients (17 NHL, 6 HD) underwent FDG PET scans after SCT at a median of 2.4 months. Table 1 incorporates the data from cohort 1, but cohort 2 will also be discussed here. In cohort 1, eight patients were FDG PET negative pre-sct, whereas 12 patients were FDG PET positive pre-sct. With a median follow up of 13.3 months, 12 patients had relapsed, one had FDG PET negative pre-sct and 11 had FDG PET positive. The positive and negative predictive value of pre-sct FDG PET scans were 92 and 88%, respectively. Within the 23 patients in cohort 2, 9 patients had a negative post-sct FDG PET and 14 had a positive FDG PET. In total, 14 patients had disease progression during the follow up, 1 had FDG PET negative post-sct and 13 had FDG PET positive. Thus, the positive and negative predictive value for post-sct FDG PET scans was 93 and 89%, respectively. In a recent retrospective review by Svoboda et al. 12, the charts of 50 patients were analyzed who had undergone FDG PET scanning after at least two cycles of salvage chemotherapy, but prior to ASCT. Of the 50 patients, 31 had NHL, including aggressive and indolent subtypes, and 19 patients had HD. In total, 32 patients were FDG PET negative pre-sct, 18 patients were FDG PET positive. With a median follow up of 19 months post-sct, 16 patients remained progression free, only 1 having been FDG PET positive pre-sct. Thus, the median PFS for the pre-sct FDG PET negative and positive groups was 19 months and 5months, respectively. Of note in this study, patients who had chemotherapy-resistant disease by CT criteria, but were FDG PET negative, had comparable

5 outcomes to patients with chemotherapy-sensitive disease and were FDG PET negative. Filmont et al. 13 recently investigated the use of FDG PET scans pre-sct for poor prognosis lymphoma patients undergoing ASCT. A total of 60 consecutive patients medical records were reviewed, including 50 patients with NHL and 10 with Hodgkin s lymphoma. In total, 22 patients underwent SCT as front-line therapy as part of a clinical trial, 27 patients had recurrent disease after achieving a CR and 11 patients never achieved a CR after their initial chemotherapy. All patients underwent FDG PET scans pre-sct and 100 days post-sct. Pre-SCT FDG PET scans were positive and negative in 75and 25% of patients, respectively. The 1-year event-free survival (EFS) was 80% in patients who had a negative pre-sct FDG PET scan versus 43% in those who had a positive pre-sct FDG PET scan. All patients also underwent a FDG PET scan at 100 days post transplant, 80% of patients had negative FDG PET scans at that point. EFS at 1 year was 81 versus 25% in the post-sct FDG PET negative versus positive patients. Bondly et al. 7 analyzed 100 NHL patients in a prospective manner from May 2003 through December The results of the FDG PET scan did not impact the decision to go to transplant. In total, 89% of patients underwent BEAM (BCNU, etoposide, cytarabine and melphalan) conditioning; the others were in a clinical trial receiving Zevalin plus BEAM. In total, 92% of patient underwent pre transplant FDG PET analysis. In total, 48% were FDG PET positive, 52% were FDG PET negative. The median follow up of the entire group was 8.7 months (11.8 months for those surviving). The median remission duration for the entire group was 7.1 months. The 1 year OS was 61% for the FDG PET positive group, whereas it was 77% for the FDG PET negative group (P ¼ 0.08). The 1-year EFS was improved in the pretransplant FDG PET negative group, 66%, versus the FDG PET positive group, 34% (P ¼ 0.007). When a subset analysis of diffuse large B-cell lymphoma patients was performed, the statistical significance was not present, which may have reflected the limited number of patients and the brevity of follow up. In that group of 50 patients, 45% were FDG PET positive pretransplant, 55% were FDG PET negative. Median follow up for the entire group was 6.5months (10.3 months for survivors). OS in the diffuse large B-cell lymphoma patients was not statistically different between the FDG PET negative group (68%) and the FDG PET positive group (52%), P ¼ The 1-year EFS was 40% for the FDG PET positive group and 52% in the FDG PET negative group (P ¼ 0.11). Thus, the overall study demonstrated that a negative FDG PET scan prior to ASCT does predict a significantly better EFS in NHL and a trend toward improved OS. However, a substantial number of patients with a positive FDG PET scan pretransplant can achieve a good outcome. In subset analysis of DLBCL patients, a positive FDG PET scan pretransplant did not predict a significantly worse EFS or OS. A retrospective study, presented at the American Society of Hematology 2004 Annual meeting by Kassim et al. 14 examined the impact of pre- and post-asct PET scans in patients with aggressive B-cell NHL in first or subsequent relapse. The majority of the 44 patients had diffuse large B-cell lymphoma (30 patients); however, other histologic subtypes were examined including follicular lymphoma, mantle cell lymphoma and T cell-rich B-cell lymphoma. In total, 68% underwent pretransplant PET scans. The mean observation time of remission cases was 691 days and the pretransplant PET scan did not correlate with PFS. The post transplant PET scans at day 30 and day 100 demonstrated an improved PFS (P ¼ and P ¼ 0.007, respectively) for those patients with negative PET scans at these time points. A recent presentation at the American Society of Hematology 2006 Annual meeting by Alousi et al. 15 examined the impact of PET/gallium scans and high-dose rituximab (HDR) therapy during conditioning on patients with large B-cell lymphoma undergoing ASCT. This retrospective review of a large cohort of patients (188) identified four risk groups based on PFS at 54 months. Patients not receiving HDR who were PET/GAL negative had 40% PFS versus 17% in the PET/GAL positive group. Whereas, in those patients receiving HDR during conditioning, the PFS at 54 months was 81 versus 23% in the PET/GAL negative versus positive groups, respectively (P ¼ 0.007). This study would suggest that the addition of rituximab in conditioning provided a benefit to PET/GAL negative patients in PFS. A fascinating study presented by Schot et al. 16 examined the impact of PET scanning pre-sct in combination with the secondary age-adjusted international prognostic index (IPI) (saa-ipi, for patients with NHL) and the recurring Hodgkin s score (for patients with Hodgkin s lymphoma); only the NHL patient data will be presented herein. In total, 78 of the 91 patients with NHL were evaluable with PET scans. In total, 53 of the 78 evaluable patients had DLBCL; other histologies included were mantle cell lymphoma (7 patients), follicular lymphoma grade III (7 patients), peripheral T-cell lymphoma (3 patients), anaplastic large cell lymphoma (2 patients) and other (6 patients). CR was defined as complete disappearance of all previous lesions with abnormal uptake on PET scans, PR was defined as only residual FDG uptake above background at sites of previous uptake and NR was defined as no response or progression at sites with prior FDG uptake. Patients were planned to undergo two cycles of DHAP- VIM, then BEAM conditioning followed by ASCT. Because some patients were nonresponders or progressed after DHAP-VIM, the analysis was based on intent to treat. A few patients did not go on to transplant. In this study, both the saa-ipi and PET scans pretransplant were independent prognostic factors for failure-free survival (FFS) at 2 years. Examining the FFS relative to PET status pretransplant, patients with a PET CR had a 72% FFS versus 38 and 10% for patients with a PET PR and PET NR, respectively (Po0.001). When analyzing only those patients who underwent SCT, 8 of 11 nonresponders relapsed versus 15of 29 PET PR patients, as compared to 3 of 17 PET CR patients. Thus, although it would be ideal to be PET negative prior to SCT, patients who achieve a PET PR also have a high FFS at 2 years, but this likely identifies a group of patients who might benefit from planned post-sct additional therapy. 923

6 924 Post transplant FDG PET scanning in non-hodgkin s lymphoma Limited studies have included post transplant FDG PET scans as correlated to outcome. In the original study by Becherer et al. 8 post-sct FDG PET scans were performed and reported, but were not independently analyzed with regard to outcome. In the analysis by Cremerius et al., 9 16 of 23 patients achieved a CMR, 7 patients did not. Median PFS was 38 versus 14 months, respectively (not statistically significant). However, when patient were reported as PMR or CMR versus those not achieving a PMR the median PFS was 25 versus 4 months (P ¼ 0.006). As previously noted, in the original study published by Filmont et al., 11 the second cohort of 23 patients (17 NHL, 6 HD) underwent FDG PET scans after SCT at a median of 2.4 months. Within the 23 patients in cohort 2, 9 patients had a negative post-sct FDG PET and 14 had a positive FDG PET. In total, 14 patients had disease progression during the follow up, 1 had FDG PET negative post-sct and 13 had FDG PET positive. Thus, the positive and negative predictive value for post-sct FDG PET scans was 93 and 89%, respectively. In the second publication by Filmont et al., 13 all 60 patients also underwent a FDG PET scan at 100 days post transplant, 80% of patients had negative FDG PET scans at that point. EFS at 1 year was 81 versus 25% in the post-sct FDG PET negative versus positive patients. In the study from Vanderbilt by Kassim et al., 14 89% of patients with aggressive histology lymphomas undergoing SCT had either day 30 or day 100 post-sct PET scans. In this limited retrospective study of 44 patients, there was a statistically significant improvement in PFS in those patients who had negative PET scans on day 30 or day 100. Thus, patients with post transplant positive PET scans would likely be candidates for early intervention with additional therapy. Conclusions In summary, pre-asct negative FDG PET scans correlate with an improvement in PFS and suggested an improvement in OS. It should be noted however that most of the studies have included many pathologic subtypes, including both NHL and HD. Also, only a limited number of reports have investigated post-sct FDG PET scans and the impact on PFS. It appears that patients with positive FDG PET scans post-sct have shorter PFS relative to those with negative FDG PET scans. Patients with less tumor bulk prior to ASCT with a normal or near normal FDG PET scan would be expected to have a better outcome than patients with positive scans and larger amounts of tumor. Further analysis of patients with individual disease histologies, such as DLBCL, within prospective trials should be performed to ascertain the impact of FDG PET scanning pre- and post-asct. Since the original PARMA trial did not incorporate FDG PET scanning into the decision analysis, at this point it does not seem that FDG PET positivity alone should be an exclusion for patient eligibility for SCT. Future directions Clinical trials utilizing risk-adapted therapy based on FDG PET scan results pre- and post-asct may be the way of the future. Timing of interventions can be divided into mobilization, conditioning and post transplant. In vivo purging of PBSCs with rituximab has been investigated in phase II studies and may purify the mobilized product to diminish the content of lymphomatous cells. In addition, increasing the lymphocyte content of the autograft has also been shown to be of prognostic value. Augmentedconditioning regimens such as the addition of Bexxar or Zevalin BEAM may also improve outcome. A randomized trial is ongoing through the Blood and Marrow Transplant Clinical Trials Network. Maintenance rituximab post- ASCT is also being investigated in a randomized trial in Europe in patients with DLBCL and mantle cell lymphoma. Post transplant radiation therapy to sites of residual PET positivity is our current clinical practice at Mayo Clinic. Early post transplant maintenance therapy could also incorporate newer oral agents such as lenalidomide or everolimus, which has shown promising phase II efficacy in heavily pretreated patients. PET results pre- and post- ASCT clearly identify a high-risk population; whether these interventions will change their outcome remains to be studied. The prognostic value of FDG PET scanning preand post-asct will hopefully serve to cure more patients with poor-risk disease and not overtreat those with a better prognosis. References 1 Moog F, Bangerter M, Diederichs CG, Guhlmann A, Kotzerke J, Merkle E et al. Lymphoma: role of whole-body 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) PET in nodal staging. Radiology 1997; 203: Moog F, Bangerter M, Diederichs CG, Guhlmann A, Merkle E, Frickhofen N et al. Extranodal malignant lymphoma: detection with FDG PET versus CT. Radiology 1998; 206: Haioun C, Itti E, Rahmouni A, Brice P, Rain JD, Belhadj K et al. [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in aggressive lymphoma: an early prognostic tool for predicting patient outcome. Blood 2005; 106: Kostakoglu L, Coleman M, Leonard JP, Kuji I, Zoe H, Goldsmith SJ. PET predicts prognosis after 1 cycle of chemotherapy in aggressive lymphoma and Hodgkin s disease. J Nucl Med 2002; 43: Spaepen K, Stroobants S, Dupont P, Vandenberghe P, Thomas J, de Groot T et al. Early restaging positron emission tomography with (18)F-fluorodeoxyglucose predicts outcome in patients with aggressive non-hodgkin s lymphoma. Ann Oncol 2002; 13: Juweid ME, Stroobants S, Hoekstra OS, Mottaghy FM, Dietlein M, Guermazi A et al. Use of positron emission tomography for response assessment of lymphoma: consensus

7 of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 2007; 25: Bondly C, Johnston PB, Lowe V, Ansell SM, Inwards DJ, Porrata LF et al. Positive positron emission tomography (PET) pre-autologous stem cell transplant (ASCT) in non- Hodgkin lymphoma (NHL) does not preclude successful outcome. Biol Blood Marrow Transplant 2006; 12: Becherer A, Mitterbauer M, Jaeger U, Kalhs P, Greinix HT, Karanikas G et al. Positron emission tomography with [18F]2- fluoro-d-2-deoxyglucose (FDG-PET) predicts relapse of malignant lymphoma after high-dose therapy with stem cell transplantation. Leukemia 2002; 16: Cremerius U, Fabry U, Wildberger JE, Zimny M, Reinartz P, Nowak B et al. Pre-transplant positron emission tomography (PET) using fluorine-18-fluoro-deoxyglucose (FDG) predicts outcome in patients treated with high-dose chemotherapy and autologous stem cell transplantation for non-hodgkin s lymphoma. Bone Marrow Transplant 2002; 30: Spaepen K, Stroobants S, Dupont P, Vandenberghe P, Maertens J, Bormans G et al. Prognostic value of pretransplantation positron emission tomography using fluorine 18-fluorodeoxyglucose in patients with aggressive lymphoma treated with high-dose chemotherapy and stem cell transplantation. Blood 2003; 102: Filmont JE, Czernin J, Yap C, Silverman DH, Quon A, Phelps ME et al. Value of F-18 fluorodeoxyglucose positron emission tomography for predicting the clinical outcome of patients with aggressive lymphoma prior to and after autologous stemcell transplantation. Chest 2003; 124: Svoboda J, Andreadis C, Elstrom R, Chong EA, Downs LH, Berkowitz A et al. Prognostic value of FDG-PET scan imaging in lymphoma patients undergoing autologous stem cell transplantation. Bone Marrow Transplant 2006; 38: Filmont JE, Gisselbrecht C, Cuenca X, Deville L, Ertault M, Brice P et al. The impact of pre- and post-transplantation positron emission tomography using 18-fluorodeoxyglucose on poor-prognosis lymphoma patients undergoing autologous stem cell transplantation. Cancer 2007; 110: Kassim A, Mineishi S, Greer J, Koyama T, Chinratanalab W, Brandt S et al. Post-transplant positron emission tomography using fluorine 18-fluor-deoxyglucose ([18F]FDG-PET) correlates with outcome in patients with aggressive non-hodgkin s lymphoma undergoing high dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT). Blood 2004; 104: 259a. 15Alousi A, Saliba R, Okoroji G, Hosing C, Samuels B, Champlin R et al. The influence of PET-gallium (PET/Gal) status and high-dose rituximab in patients with aggressive, large, b-cell lymphoma (LBCL) receiving autologous stem cell transplants. Blood 2006; 108: 3058a. 16 Schot BW, Zijlstra JM, Sluiter WJ, van Imhoff GW, Pruim J, Vaalburg W et al. Early FDG-PET assessment in combination with clinical risk scores determines prognosis in recurring lymphoma. Blood 2007; 109: