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Interim PET Scans in Diffuse Large B-Cell Lymphoma: Is It Ready for Prime Time?
Review
Interim PET Scans in Diffuse Large B-Cell Lymphoma: Is It Ready for Prime Time? Maital Bolshinsky,1 Chadi Nabhan2 Abstract Prognostication of patients with diffuse large B-cell lymphoma (DLBCL) has improved in the past decade with a variety of clinical, morphologic, molecular, and radiographic methods. Comparable to data on the value of interim positron emission tomography (I-PET) in Hodgkin lymphoma, several retrospective and prospective studies are attempting to assess the value of I-PET scanning in DLBCL patients. In this review, we briefly describe and analyze the various prognostic methods in DLBCL with specific focus on the value of I-PET scanning in this disease. This is a timely analysis, as tailoring therapies based on prognosis at diagnosis are becoming of increased investigational interest. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: Interim imaging, Large-cell lymphoma, Lymphoma, PET scanning, Prognosis
Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in the United States, accounting for approximately 30% to 40% of all non-Hodgkin lymphoma.1 Outcomes of DLBCL have significantly improved over the past 2 decades, attributed partly to enhanced supportive care, the introduction of targeted anti-CD20 monoclonal antibodies, and better refinement in choosing the backbone of systemic chemotherapy combinations.2,3 Current standard approach is the combination of rituximab with cyclophosphamide, Adriamycin, vincristine, and prednisone (R-CHOP) provided every 21 days. The number of given cycles and whether radiotherapy is a component of the treatment strategy depends on disease stage, goals of therapy, response, and patient comorbidities.4 In addition to R-CHOP, dose-adjusted etoposide, vincristine, Adriamycin, cyclophosphamide, and prednisone in combination with rituximab (DAEPOCH-R) has gained recognition as the treatment choice for patients with mediastinal large-cell lymphoma and in patients who carry the c-MYC and BCL-2 translocations.5,6 A prospective study comparing R-CHOP to DA-EPOCH-R has completed accrual, but primary efficacy results have not yet been published (NCT00118209).
1
Instituto Oncologico Veneto, Padua, Italy Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 2
Submitted: Jul 10, 2016; Revised: Aug 17, 2016; Accepted: Aug 26, 2016 Address for correspondence: Chadi Nabhan, MD, MBA, FACP, Cardinal Health Specialty Solutions 1500 South Waukegan Road Waukegan, IL 60085 Fax: (773) 702-7075; e-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2016.08.020
Despite these advances, the disease remains incurable in about one third of patients, which underscores the heterogeneity of this disease.7 Identifying these patients at their highest risk of relapse is a major unmet medical need, as alternative therapy or a different strategy could potentially improve outcomes in early progressors. To that end, significant effort has been exercised to prognosticate DLBCL using a variety of methods. In this review, we discuss the various prognostic models for this disease, focusing specifically on recent studies that investigated interim positron emission tomography (PET) scans as a prognostic tool to identify patients with inferior outcomes using standard therapy.
Current Prognostic Tools International Prognostic Index (IPI) On the basis of readily and clinically available information, the IPI has differentiated DLBCL patients into separate risk categories with variations in survival and progression. The IPI allocates 1 point to each of age > 60 years, disease stage (III or IV), elevated serum lactate dehydrogenase, poor performance status, and more than 1 extranodal site. Patients are stratified into low-, loweintermediate, higheintermediate, and high-risk categories. While only 25% of high-risk patients are alive at 5 years, nearly 80% of low-risk patients are alive during the same time period.8 As the original IPI was reported before the use of rituximab in DLBCL, its applicability to patients treated with rituximab has been questioned. Sehn et al9 performed a retrospective analysis of DLBCL patients treated with R-CHOP and defined a new prognostic index, termed the R-IPI, as a better predictor of outcome. However, a subsequent contemporary analysis of more than 1000 patients treated with chemoimmunotherapy suggested that the original IPI remained prognostic in the rituximab era and predicted
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I-PET Scans in DLBCL event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) (Table 1).10 Recently, the National Comprehensive Cancer NetworkeIPI allowed for a further refined risk stratification of patients in the high- and low-risk prognostic category on the basis of the original IPI.11 Although the IPI remains an important practical prognostic tool, it ignores the molecular heterogeneity and pathobiology of the disease. Further, whether treating high-risk IPI patients differently than their lower-risk counterparts offers any additional benefit remains questionable. It should be noted that a recent study proposed that early autologous bone marrow transplantation consolidation might offer a survival advantage in high-risk IPI DLBCL patients.12 However, this study included patients who did not receive rituximab as part of their induction program. The inferior outcome of the control arm in patients who did not receive rituximab might partially explain the witnessed superiority in the transplantation arm.
Histologic and Morphologic Characteristics Several histologic features have identified subsets of DLBCL that portend inferior prognosis. A centroblastic subtype is the most common morphologic variant of DLBCL; it has the appearance of medium-to large-size lymphocytes with scanty cytoplasm. An immunoblastic variant is defined when > 90% of the cells are immunoblasts.13 Importantly, interobserver variability might account for inconsistent results of how histology affects prognosis.14 While earlier studies questioned the significance of centroblasts versus immunoblasts,15 subsequent analyses confirmed that DLBCL with immunoblastic morphology carries inferior EFS and OS.16 In fact, patients with centroblastic features had superior 3-year EFS and OS compared to the immunoblastic variant (58% vs. 41% [P ¼ .002] and 73% vs. 59% [P ¼ .069], respectively). This observed difference could be partially explained by the difference in the cell of origin (COO) between both histologies.17 The anaplastic variant of DLBCL, characterized by CD30-positive cells, carries similar features to other DLBCL patients, but with inferior 5-year survival estimated at 33%.18 Another uncommon histologic variant is the T-cell/histiocyterich large B-cell lymphoma (THRLBCL), representing 1% to 3% of all DLBCL,19 characterized by aggressive clinical course; it often presents with B symptoms, advanced stage, and spleen/liver and bone marrow involvement. Patients with THRLBCL treated with anthracycline-based regimens demonstrate lower response rates, although survival differences are questionable.20 Moreover, high proliferation index and > 80% Ki-67 expression have been
associated with worse outcomes and inferior survival even in the immunochemotherapy era.21 Finally, a plasmablastic variant (PBL) is a very rare subtype of DLBCL that occurs in patients with decreased immune surveillance such as human immunodeficiency virus positivity or advanced age. While patients with PBL might experience an initial response to therapy, relapse rates are high and the overall prognosis poor, with a median survival of 12 to 15 months.22
Cell of Origin Gene expression profiling (GEP) identified 3 principal molecular subtypes of DLBCL reflecting the COO: germinal center B-cellelike (GCB), activated B-cell (ABC or non-GCB), and primary mediastinal B-cell lymphoma.17 The COO classification not only defines subgroups with distinct gene expression profiles and different oncogenic pathways, but it also identifies groups of patients with different outcomes after standard chemoimmunotherapy.17,23 Patients with newly diagnosed ABC subtype have a significantly worse survival compared to GCB when treated with standard CHOP-like regimens with or without rituximab. Initially, the identification of molecular subtypes of DLBCL was labor intensive, requiring fresh frozen biopsy samples with adequate amount of RNA.24 To improve the feasibility of testing the COO, several immunohistochemistry-based algorithms were proposed. Hans et al25 utilized the immunohistochemical (IHC) staining for CD10, bcl-6, and MUM1 to classify DLBCL into GCB and nonGCB subtypes with an outcome similar to that predicted by cDNA microarray analysis. Accordingly, GCB subtype is characterized by CD10 and/or bcl-6 positivity, whereas non-GCB group is identified when both CD10 and bcl-6 are negative. In addition, the presence or absence of the expression of MUM1 defines the nonGCB versus GCB, respectively. The prognostic value of COO based on IHC versus GEP has been discordant. Some have suggested that the concordance between IHC and GEP results is imperfect to varying degrees, and immunostaining algorithms are therefore unable to maintain the prognostic impact of COO subtypes.26 Scott et al27 used the Lymph2Cx assay on formalin-fixed, paraffin-embedded tissue biopsy samples of de novo DLBCL previously classified through the original GEP to show a high rate of concordance between the 2 techniques. The same study group subsequently confirmed the accuracy of the Lymph2Cx assay in assigning GCB and ABC groups and demonstrated its reproducibility.28
Molecular Prognostication Table 1 Prognostic Differences Associated With IPI 3-Year Rate for:
2
-
IPI Score
EFS
PFS
OS
0, 1 2 3 4, 5
81.3 68.5 53.2 49.5
87.0 74.7 58.6 55.8
91.4 80.9 65.1 59.0
Abbreviations: EFS ¼ event-free survival; IPI ¼ international prognostic index; PFS ¼ progression-free survival; OS ¼ overall survival. Data from Ziepert et al.10
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Less than 10% of DLBCL harbor isolated MYC oncogene rearrangements.29 While reports have varied on how best to treat DLBCL patients who carry the MYC protooncogene rearrangement, most agree that this oncogene confers worse prognosis and possibly inferior outcome with standard therapy.30,31 In fact, Savage et al31 reported that 5 years’ PFS in patients with MYC rearrangement was approximately 31% compared to about 66% (P ¼ .006, hazard ratio ¼ 3.28) in the nonrearranged group. Furthermore, the OS in the MYC rearrangement group was significantly inferior, with 5-year rates of 33% versus 72% (P ¼ .016, hazard ratio ¼ 2.98). Moreover, correlating between MYC rearrangement and other clinical prognostic parameters showed that age, IPI, and
Maital Bolshinsky, Chadi Nabhan Table 2 Select Retrospective Studies Evaluating I-PET in Front-Line DLBCL I-PETL/I-PETD for: Study Spaepen52 (2002) Yoo46 (2011) Zinzani41 (2011)a Safar50 (2012) Nols51 (2014) Huntington44 (2015)b
N
Regimen
Timing of I-PET
PFS
OS
P, PFS/OS
70 155 91 112 73 94
Doxorubicin-containing R-CHOP Various, R plus anthracycline containing R plus anthracycline-containing R-CHOP and other anthracycline-containing R-CHOP
3-4 cycles 2-4 cycles 3-4 2 3-4 Variable
2-year 85%/0% 3-year 84%/66% 5-year 75%/18% 84%/47% 2-year 84%/47% NA
3-year 92%/30% NA 5-year 90%/67% 88%/62% 2-year 91%/51% NA
<.0001/<.0001 .07/.24 .0001/.0001 <.0001/<.003 <.0001/<.0001 .001/.046
Abbreviations: CHOP ¼ cyclophosphamide, vincristine, doxorubicin, and prednisone; DLBCL ¼ diffuse large B-cell lymphoma; I-PET ¼ interim positron emission tomography; NA ¼ not applicable; OS ¼ overall survival; PFS ¼ progression-free survival; R ¼ rituximab. a Some patients had primary mediastinal lymphoma. b All patients who were in remission according to I-PET analysis did not experience disease progression at time of report.
MYC translocation retained prognostic significance for survival. This implied that young patients with lower IPI score retain a favorable outcome despite the presence of MYC rearrangement; it also underscored the fact that MYC prognostication varies on the basis of other parameters that should be taken into consideration.30 When MYC and either BCL-2 or BCL-6 aberrations are present, a new entity, termed “double-hit lymphoma” (DHL), emerges; when the 3 rearrangements are present, the term “triple-hit lymphoma” is used.32 While the true definition of DHL implies the identification of abnormal chromosomal translocations corresponding to the MYC and either BCL-2 or BCL-6 oncogenes, some patients can have these proteins detected by IHC without abnormal translocations. Whereas some debate the IHC thresholds, most agree that a disease is considered MYC positive if the IHC stains at least 40% of cells for MYC and 50% to 70% for BCL-2.33,34 Of note, patients who express both proteins by IHC appear to have worse prognosis regardless of the COO or the IPI score.35 Treatment of patients with DHL or double-protein expression is debatable. Several retrospective studies suggested that patients with high-risk DHL might benefit from more intensive regimens such as DA-EPOCH-R than the standard R-CHOP in terms of achieving a complete remission and a longer PFS.6,36 The significance of the partner oncogene with MYC is of particular importance. Landsburg et al37 suggested that compared to MYC/BCL-2 coexpression, patients who carried the MYC/BCL-6 coexpression had adverse prognosis with high relapse rates of 50% and lower OS
of 14.5 months. Last, MYC amplification failed to show any prognostic significance.38
PET Scans Functional imaging with 18F-fluoro-2-deoxy-D-glucose positron emission tomography combined with computed tomography (PET/ CT) is currently part of staging, assessment of remission and recurrence, and evaluation of therapeutic efficacy of patients with DLBCL.39 The prognostic utility of interim PET (I-PET) scans in Hodgkin lymphoma patients40 has led to studies exploring whether similar observations are present in DLBCL. The value of I-PET and its prognostic significance in DLBCL have been controversial. Whereas some studies showed a correlation between I-PET and long-term outcomes,41-45 others reported contradictory results46-49 (Tables 2-4).
Retrospective Studies Understanding the results of I-PET studies is challenging as progress in interpreting PET has evolved; older studies did not use contemporary PET scores, which underscore the difficulty of applying older PET data in the current era. Haioun et al59 performed an analysis that showed early positive PET identified poor response regardless of treatment or age-adjusted international prognostic index score. This study, along with other retrospective analyses, led to continued enthusiasm to study the role of I-PET in DLBCL (Table 2). Safar et al50 reported on 112 patients suggesting
Table 3 Select Prospective Studies of I-PET in DLBCL Without Risk-Adaptive Approach I-PETL/I-PETD for: Study 47
Cashen (2011) Micallef53 (2011) Pregno48 (2012) Carr54 (2014) Mamot55 (2015)
N
Regimen
I-PET Timing
PFS
OS
P, PFS/OS
50 69 88 327 156
R-CHOP R-CHOP or ER-CHOP R-CHOP R-CHOP R-CHOP-14
2-3 2 2-4 2-3 2
2-year 85%/63% NA 2-year 85%/72% 2-year 90%/58% 2-year 74%/48%
NA NA NA 2-year 93%/72% 2-year 91%/88%b
.004/.08 .31/.24 .047/NA <.05a .004/.46
Abbreviations: CI ¼ confidence interval; DLBCL ¼ diffuse large B-cell lymphoma; ER-CHOP ¼ R-CHOP plus epratuzumab; HR ¼ hazard ratio; I-PET ¼ interim positron emission tomography; OS ¼ overall survival; PFS ¼ progression-free survival; R-CHOP ¼ rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP-14 ¼ R-CHOP provided every 14 days as dose-dense approach. a Reported as HR. HR for PFS 5.31 (95% CI 3.29-8.56); HR for OS ¼ 3.86 (95% CI 2.12-7.03). b Data are on event-free survival.
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I-PET Scans in DLBCL Table 4 Selected Prospective Studies of I-PET in DLBCL With Risk-Adapted Approach I-PETL/I-PETD for: Study
N
Regimen
I-PET Timing
PFS
OS
P, PFS/OS
Moskowitz49 (2010)
98
R-CHOP
4
NA
NA
.27/NA
Stewart57 (2014)
70
R-CHOP
2
3-year 65.2%/52.7%
NA
>.05 for both
Pardal58 (2014)
71
R-CHOPb
3
3-yeas 81%/57%
3-year 95%/33%
<.05/>.05
Swinnen56 (2015)
74
R-CHOP
3
4-year 71%/33%
4-year 90%/69%
NS for both
Risk-Adapted Approach I-PET: ICE chemotherapya I-PETþ: Biopsy. If negative, then ICE; if positive, ICE followed by ASCT I-PET: Continue R-CHOP I-PETþ: ASCT I-PET: Continue same I-PETþ: ASCT I-PET: Continue R-CHOP I-PETþ: R-ICE
Abbreviations: ASCT ¼ autologous stem-cell transplantation; DLBCL ¼ diffuse large B-cell lymphoma; CHOP ¼ cyclophosphamide, vincristine, doxorubicin, and prednisone; ICE ¼ iphosphamide, carboplatin, and etoposide; I-PET ¼ interim positron emission tomography; NA ¼ not available; NS ¼ not significant; OS ¼ overall survival; PFS ¼ progression-free survival; R ¼ rituximab. a Not statistically significant between patients with I-PET-negative and I-PET-positive but biopsy-negative patients. b Dose-intensified CHOP.
that patients experiencing PET negativity after 2 cycles of an anthracycline-containing regimen have better PFS and OS. When an alternative analysis was performed on 85 patients using a quantitative method based on the maximum change in standardized uptake value (SUV) of more than 66%, the 3-year PFS was 77% for patients with PET-negative findings versus 37.5% for those with positive scan (P ¼ .002).50 If anything, these retrospective findings confirmed the need for prospective studies to better answer the question of I-PET prognostic importance.
Prospective Studies Despite several attempts to answer the question on prognostic value of I-PET in DLBCL, reported studies lack uniformity in how PET scans were interpreted and when I-PET was conducted. In a
prospective study of advanced stage DLBCL patients, I-PET was performed after 2 or 3 cycles of anthracycline-based chemotherapy.47 Interpretation was done according to the International Harmonization Project for Response Criteria in Lymphoma.60 IPET negativity provided patients with improved PFS, but OS was not improved. However, end-of-therapy PET was significantly associated with PFS and OS (P < .001). Similar studies were reported but results were not comparable (Table 3). Importantly, IPET positivity does not always imply persistent disease. This principle was highlighted in a prospective study reported by Moskowitz et al,49 where patients who had negative I-PET after 4 cycles of R-CHOP continued on to receive 3 cycles of ICE chemotherapy (iphosphamide, carboplatin, and etoposide), whereas patients with residual PET-positive disease underwent a repeat biopsy. If the
Figure 1 International Harmonization Project Criteria
Definition of a positive scan: Focal or diffuse FDG uptake above background in a location incompatible with normal physiology Exceptions: 1. Mild FDG uptake at the site of moderate to large residual masses with lower intensity visually compared to the mediastinal blood pool structures 2. FDG uptake in residual hepatic or splenic lesions should be compared to the uptake in surrounding normal liver or spleen
4
-
Adapted from Juweid et al.60
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Maital Bolshinsky, Chadi Nabhan Figure 2 Five-Point Deauville Scale
biopsy results were negative, patients received 3 cycles of ICE. Patients with positive biopsy findings received ICE followed by autologous stem-cell transplantation. The results of the I-PET assessment did not correlate with outcomes, and the PFS of patients with I-PET-positive/biopsy-negative disease was identical to that of patients with a negative I-PET scan (P ¼ .27).49 Whether intensifying therapy to autologous stem-cell transplantation in patients with I-PETepositive disease provides patients with a clinically meaningful benefit remains debatable (Table 4).
Discussion Inconsistencies on the significance of I-PET could reflect the lack of interobserver reproducibility in interpreting PET images or could relate to the heterogeneity of the visual criteria used.61 Indeed, results of a blinded, independent review of the Eastern Cooperative Oncology Group E-3404 study revealed that one-third of the time, the expert panel of nuclear medicine physicians disagreed on the interpretation of the interim scans despite using consensus criteria.56,61 The fact that some studies conducted I-PET after
Figure 3 DSUVmax for I-PET Assessment
Baseline PET (I-PET0): -
SUV max in the most active lesion
2 cycles while others did so after 4 cycles adds complexity to the interpretation. Moreover, not all studies incorporated the same front-line therapy. Moreover, studies that were conducted before the international Harmonization Project might have lacked accurate sensitivity and specificity. Notably, the International Harmonization Project is purely visual, and when strictly applied to evaluate I-PET after 2 or 4 cycles of immunochemotherapy, it was unable to identify patients with different outcomes (Figure 1).47,49,61,62 Subsequently, at a workshop on I-PET in lymphoma held in Deauville, simple and reproducible rules have been proposed for interim 18F-fludeoxyglucose-PET/CT visual interpretation.63 The Deauville criteria use a 5-point scale to determine the positivity or negativity of I-PET and were found to improve the accuracy of the interpretation compared to the International Harmonization Project criteria (Figure 2). Another approach for I-PET response assessment is a semiquantitative method that measures the intensity of 18 F-fludeoxyglucose uptake in the tumor using the SUV (Figure 3). Several studies have suggested that by calculating the reduction of SUV between baseline and interim PET (DSUV) helped to reduce false-positive interpretations and improved the interobserver reproducibility.51,62,65 Collectively, this led to updated guidelines regarding I-PET response assessment, which affirmed the use of quantitative measures using the Deauville criteria to improve on visual analysis in patients with DLBCL, although this requires further validation in clinical trials.39,66 This so-called Lugano classification appeared more consistent and reflective of prognostication than the Harmonization project and is the recommended approach for PET-based ongoing and future clinical trials. However, changes of treatment solely based on I-PET results outside of clinical trials are not recommended unless there is clear evidence of disease progression. Some studies have already attempted altering therapies based on I-PET findings (Table 4). Swinnen et al56 treated PET-positive patients after 3 cycles of R-CHOP with R-ICE, but this study failed to convincingly show that altering therapy improved survival for I-PETepositive patients. In another study referenced above, 98 patients received 4 cycles of R-CHOP followed by I-PET. I-PETepositive patients underwent a biopsy to confirm residual disease.49 Patients with positive biopsy results proceeded to autologous stem-cell transplantation. Although this study failed to show that I-PET predicted outcome because most I-PETepositive patients had negative biopsy results, it highlighted the fact that I-PET positivity had a low positive predictive value for actual disease and underscored the importance of confirming residual disease histologically.
Interim PET: -
If (+): SUV max in the most active lesion
Conclusions
-
If (-): SUV max in the area of PET0 tumor
The interpretation of PET/CT scans for lymphoma has evolved during the past decade, with International Harmonization Project,60 Deauville criteria,63 and most recently the Lugano classification guiding standardized interpretation.39 The overall clinical utility of I-PET during the treatment of patients with DLBCL remains unclear. Most of the studies suggest that midtreatment PET might offer an early prognostication. Nevertheless, I-PET interpretation and its ability to guide changes in management remains uncertain. Although the interpretation of PET-CT for lymphoma has evolved during the past decade, the interpretation of interim PET remains a
Calculation of % of SUV reduction* Optimal cut-off determined by ROC -
66% for ΔSUV max PET0-2
72.9% for ΔSUV max PET0-4
Abbreviations: I-PET ¼ interim positron emission tomography; SUV ¼ standardized uptake value. Data from Lin et al.64
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I-PET Scans in DLBCL concern. Moreover, whether I-PET data provide better prognostication than COO or molecular drivers is uncertain and up for debate. Currently no consensus recommendations exist to help guide treatment based on I-PET response; the National Comprehensive Center Network advocates interim CT scans alone, reserving PET scans until completion of therapy.67 Continued investigation of the role of I-PET in the era of better molecular prognostication is warranted. Ideally this should be performed in the context of a prospective clinical trial that requires central I-PET interpretation and standardized timing of I-PET imaging. We propose that DLBCL patients be randomized to I-PET after 3 cycles of anthracycline-based therapy or to no I-PET. Patients with negative I-PET continue standard therapy, while positive I-PET patients are randomized to continuing the same treatment or to treatment intensification. Unless treatment alteration in I-PETepositive patients shows a better outcome, these interim evaluations remain prognostic at best.
Disclosure The authors have stated that they have no conflict of interest.
References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65: 5-29. 2. Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood 2010; 116: 2040-5. 3. Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large Bcell lymphoma. J Clin Oncol 2006; 24:3121-7. 4. Zelenetz AD, Gordon LI, Wierda WG, et al. Non-Hodgkin’s lymphomas, version 2.2014. J Natl Compr Canc Netw 2014; 12:916-46. 5. Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 2013; 368: 1408-16. 6. Petrich AM, Gandhi M, Jovanovic B, et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis. Blood 2014; 124:2354-61. 7. Zelenetz AD. Guidelines for NHL: updates to the management of diffuse large Bcell lymphoma and new guidelines for primary cutaneous CD30þ T-cell lymphoproliferative disorders and T-cell large granular lymphocytic leukemia. J Natl Compr Canc Netw 2014; 12(5 Suppl):797-800. 8. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 1993; 329: 987-94. 9. Sehn LH, Berry B, Chhanabhai M, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 2007; 109:185761. 10. Ziepert M, Hasenclever D, Kuhnt E, et al. Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20þ B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28:2373-80. 11. Zhou Z, Sehn LH, Rademaker AW, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood 2014; 123:837-42. 12. Stiff PJ, Unger JM, Cook JR, et al. Autologous transplantation as consolidation for aggressive non-Hodgkin’s lymphoma. N Engl J Med 2013; 369:1681-90. 13. Swerdlow SH. Lymphoma classification and the tools of our trade: an introduction to the 2012 USCAP Long Course. Mod Pathol 2013; 26(Suppl 1):S1-14. 14. Harris NL, Jaffe ES, Stein H, et al. Lymphoma classification proposal: clarification. Blood 1995; 85:857-60. 15. Engelhard M, Brittinger G, Huhn D, et al. Subclassification of diffuse large B-cell lymphomas according to the Kiel classification: distinction of centroblastic and immunoblastic lymphomas is a significant prognostic risk factor. Blood 1997; 89: 2291-7. 16. Ott G, Ziepert M, Klapper W, et al. Immunoblastic morphology but not the immunohistochemical GCB/nonGCB classifier predicts outcome in diffuse large B-cell lymphoma in the RICOVER-60 trial of the DSHNHL. Blood 2010; 116: 4916-25.
6
-
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17. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002; 346:1937-47. 18. Campo E, Swerdlow SH, Harris NL, et al. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 2011; 117:5019-32. 19. Bouabdallah R, Mounier N, Guettier C, et al. T-cell/histiocyte-rich large B-cell lymphomas and classical diffuse large B-cell lymphomas have similar outcome after chemotherapy: a matched-control analysis. J Clin Oncol 2003; 21:1271-7. 20. Aki H, Tuzuner N, Ongoren S, et al. T-cell-rich B-cell lymphoma: a clinicopathologic study of 21 cases and comparison with 43 cases of diffuse large B-cell lymphoma. Leuk Res 2004; 28:229-36. 21. Gaudio F, Giordano A, Perrone T, et al. High Ki67 index and bulky disease remain significant adverse prognostic factors in patients with diffuse large B cell lymphoma before and after the introduction of rituximab. Acta Haematol 2011; 126:44-51. 22. Castillo JJ, Bibas M, Miranda RN. The biology and treatment of plasmablastic lymphoma. Blood 2015; 125:2323-30. 23. Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med 2010; 362:1417-29. 24. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403:503-11. 25. Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004; 103:275-82. 26. Thieblemont C, Briere J, Mounier N, et al. The germinal center/activated B-cell subclassification has a prognostic impact for response to salvage therapy in relapsed/refractory diffuse large B-cell lymphoma: a bio-CORAL study. J Clin Oncol 2011; 29:4079-87. 27. Scott DW, Wright GW, Williams PM, et al. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffinembedded tissue. Blood 2014; 123:1214-7. 28. Scott DW, Mottok A, Ennishi D, et al. Prognostic significance of diffuse large Bcell lymphoma cell of origin determined by digital gene expression in formalinfixed paraffin-embedded tissue biopsies. J Clin Oncol 2015; 33:2848-56. 29. Kramer MH, Hermans J, Wijburg E, et al. Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma. Blood 1998; 92:3152-62. 30. Barrans S, Crouch S, Smith A, et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol 2010; 28:3360-5. 31. Savage KJ, Johnson NA, Ben-Neriah S, et al. MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood 2009; 114:3533-7. 32. Petrich AM, Nabhan C, Smith SM. MYC-associated and double-hit lymphomas: a review of pathobiology, prognosis, and therapeutic approaches. Cancer 2014; 120: 3884-95. 33. Green TM, Young KH, Visco C, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 2012; 30:3460-7. 34. Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 2012; 30:3452-9. 35. Hu S, Xu-Monette ZY, Tzankov A, et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. Blood 2013; 121:4021-31. 36. Oki Y, Noorani M, Lin P, et al. Double hit lymphoma: the MD Anderson Cancer Center clinical experience. Br J Haematol 2014; 166:891-901. 37. Landsburg DJ, Petrich AM, Abramson JS, et al. Impact of oncogene rearrangement patterns on outcomes in patients with double-hit non-Hodgkin lymphoma. Cancer 2015; 122:559-64. 38. Landsburg DJ, Falkiewicz MK, Petrich AM, et al. Sole rearrangement but not amplification of MYC is associated with a poor prognosis in patients with diffuse large B cell lymphoma and B cell lymphoma unclassifiable. Br J Haematol 2016. http://dx.doi.org/10.1111/bjh.14282 [Epub ahead of print]. 39. Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol 2014; 32:304858. 40. Evens AM, Kostakoglu L. The role of FDG-PET in defining prognosis of Hodgkin lymphoma for early-stage disease. Blood 2014; 124:3356-64. 41. Zinzani PL, Gandolfi L, Broccoli A, et al. Midtreatment 18F-fluorodeoxyglucose positron-emission tomography in aggressive non-Hodgkin lymphoma. Cancer 2011; 117:1010-8. 42. Yang DH, Ahn JS, Byun BH, et al. Interim PET/CT-based prognostic model for the treatment of diffuse large B cell lymphoma in the post-rituximab era. Ann Hematol 2013; 92:471-9. 43. Yang DH, Min JJ, Song HC, et al. Prognostic significance of interim (1)(8)F-FDG PET/CT after three or four cycles of R-CHOP chemotherapy in the treatment of diffuse large B-cell lymphoma. Eur J Cancer 2011; 47:1312-8. 44. Huntington SF, Nasta SD, Schuster SJ, et al. Utility of interim and end-oftreatment [(18)F]-fluorodeoxyglucose positron emission tomography-computed tomography in frontline therapy of patients with diffuse large B-cell lymphoma. Leuk Lymphoma 2015; 56:2579-84.
Maital Bolshinsky, Chadi Nabhan 45. Itti E, Lin C, Dupuis J, et al. Prognostic value of interim 18F-FDG PET in patients with diffuse large B-Cell lymphoma: SUV-based assessment at 4 cycles of chemotherapy. J Nucl Med 2009; 50:527-33. 46. Yoo C, Lee DH, Kim JE, et al. Limited role of interim PET/CT in patients with diffuse large B-cell lymphoma treated with R-CHOP. Ann Hematol 2011; 90:797802. 47. Cashen AF, Dehdashti F, Luo J, et al. 18F-FDG PET/CT for early response assessment in diffuse large B-cell lymphoma: poor predictive value of international harmonization project interpretation. J Nucl Med 2011; 52:386-92. 48. Pregno P, Chiappella A, Bello M, et al. Interim 18-FDG-PET/CT failed to predict the outcome in diffuse large B-cell lymphoma patients treated at the diagnosis with rituximab-CHOP. Blood 2012; 119:2066-73. 49. Moskowitz CH, Schoder H, Teruya-Feldstein J, et al. Risk-adapted dose-dense immunochemotherapy determined by interim FDG-PET in Advanced-stage diffuse large B-Cell lymphoma. J Clin Oncol 2010; 28:1896-903. 50. Safar V, Dupuis J, Itti E, et al. Interim [18F]fluorodeoxyglucose positron emission tomography scan in diffuse large B-cell lymphoma treated with anthracycline-based chemotherapy plus rituximab. J Clin Oncol 2012; 30:184-90. 51. Nols N, Mounier N, Bouazza S, et al. Quantitative and qualitative analysis of metabolic response at interim positron emission tomography scan combined with International Prognostic Index is highly predictive of outcome in diffuse large Bcell lymphoma. Leuk Lymphoma 2014; 55:773-80. 52. Spaepen K, Stroobants S, Dupont P, et al. Early restaging positron emission tomography with (18)F-fluorodeoxyglucose predicts outcome in patients with aggressive non-Hodgkin’s lymphoma. Ann Oncol 2002; 13:1356-63. 53. Micallef IN, Maurer MJ, Wiseman GA, et al. Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma. Blood 2011; 118: 4053-61. 54. Carr R, Fanti S, Paez D, et al. Prospective international cohort study demonstrates inability of interim PET to predict treatment failure in diffuse large B-cell lymphoma. J Nucl Med 2014; 55:1936-44. 55. Mamot C, Klingbiel D, Hitz F, et al. Final results of a prospective evaluation of the predictive value of interim positron emission tomography in patients with diffuse large B-cell lymphoma treated with R-CHOP-14 (SAKK 38/07). J Clin Oncol 2015; 33:2523-9. 56. Swinnen LJ, Li H, Quon A, et al. Response-adapted therapy for aggressive nonHodgkin’s lymphomas based on early [18F] FDG-PET scanning: ECOG-
57.
58. 59. 60.
61.
62. 63. 64. 65.
66. 67.
ACRIN Cancer Research Group study (E3404). Br J Haematol 2015; 170: 56-65. Stewart DA, Kloiber R, Owen C, et al. Results of a prospective phase II trial evaluating interim positron emission tomography-guided high dose therapy for poor prognosis diffuse large B-cell lymphoma. Leuk Lymphoma 2014; 55: 2064-70. Pardal E, Coronado M, Martin A, et al. Intensification treatment based on early FDG-PET in patients with high-risk diffuse large B-cell lymphoma: a phase II GELTAMO trial. Br J Haematol 2014; 167:327-36. Haioun C, Itti E, Rahmouni A, 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; 106:1376-81. Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 2007; 25:571-8. Horning SJ, Juweid ME, Schoder H, et al. Interim positron emission tomography scans in diffuse large B-cell lymphoma: an independent expert nuclear medicine evaluation of the Eastern Cooperative Oncology Group E3404 study. Blood 2010; 115:775-7. Casasnovas RO, Meignan M, Berriolo-Riedinger A, et al. SUVmax reduction improves early prognosis value of interim positron emission tomography scans in diffuse large B-cell lymphoma. Blood 2011; 118:37-43. Meignan M, Gallamini A, Meignan M, et al. Report on the First International Workshop on Interim-PET-Scan in Lymphoma. Leuk Lymphoma 2009; 50:125760. Lin C, Itti E, Haioun C, et al. Early 18F-FDG PET for prediction of prognosis in patients with diffuse large B-cell lymphoma: SUV-based assessment versus visual analysis. J Nucl Med 2007; 48:1626-32. Meignan M, Gallamini A, Itti E, et al. Report on the Third International Workshop on Interim Positron Emission Tomography in Lymphoma held in Menton, France, 26-27 September 2011 and Menton 2011 consensus. Leuk Lymphoma 2012; 53:1876-81. 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; 32:3059-68. Zelenetz AD, Gordon LI, Wierda WG, et al. Diffuse large B-cell lymphoma version 1.2016. J Natl Compr Canc Netw 2016; 14:196-231.
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Interim PET Scans in Diffuse Large B-Cell Lymphoma: Is It Ready for Prime Time? Maital Bolshinsky,1 Chadi Nabhan2 Abstract Prognostication of patients with diffuse large B-cell lymphoma (DLBCL) has improved in the past decade with a variety of clinical, morphologic, molecular, and radiographic methods. Comparable to data on the value of interim positron emission tomography (I-PET) in Hodgkin lymphoma, several retrospective and prospective studies are attempting to assess the value of I-PET scanning in DLBCL patients. In this review, we briefly describe and analyze the various prognostic methods in DLBCL with specific focus on the value of I-PET scanning in this disease. This is a timely analysis, as tailoring therapies based on prognosis at diagnosis are becoming of increased investigational interest. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: Interim imaging, Large-cell lymphoma, Lymphoma, PET scanning, Prognosis
Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in the United States, accounting for approximately 30% to 40% of all non-Hodgkin lymphoma.1 Outcomes of DLBCL have significantly improved over the past 2 decades, attributed partly to enhanced supportive care, the introduction of targeted anti-CD20 monoclonal antibodies, and better refinement in choosing the backbone of systemic chemotherapy combinations.2,3 Current standard approach is the combination of rituximab with cyclophosphamide, Adriamycin, vincristine, and prednisone (R-CHOP) provided every 21 days. The number of given cycles and whether radiotherapy is a component of the treatment strategy depends on disease stage, goals of therapy, response, and patient comorbidities.4 In addition to R-CHOP, dose-adjusted etoposide, vincristine, Adriamycin, cyclophosphamide, and prednisone in combination with rituximab (DAEPOCH-R) has gained recognition as the treatment choice for patients with mediastinal large-cell lymphoma and in patients who carry the c-MYC and BCL-2 translocations.5,6 A prospective study comparing R-CHOP to DA-EPOCH-R has completed accrual, but primary efficacy results have not yet been published (NCT00118209).
1
Instituto Oncologico Veneto, Padua, Italy Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 2
Submitted: Jul 10, 2016; Revised: Aug 17, 2016; Accepted: Aug 26, 2016 Address for correspondence: Chadi Nabhan, MD, MBA, FACP, Cardinal Health Specialty Solutions 1500 South Waukegan Road Waukegan, IL 60085 Fax: (773) 702-7075; e-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2016.08.020
Despite these advances, the disease remains incurable in about one third of patients, which underscores the heterogeneity of this disease.7 Identifying these patients at their highest risk of relapse is a major unmet medical need, as alternative therapy or a different strategy could potentially improve outcomes in early progressors. To that end, significant effort has been exercised to prognosticate DLBCL using a variety of methods. In this review, we discuss the various prognostic models for this disease, focusing specifically on recent studies that investigated interim positron emission tomography (PET) scans as a prognostic tool to identify patients with inferior outcomes using standard therapy.
Current Prognostic Tools International Prognostic Index (IPI) On the basis of readily and clinically available information, the IPI has differentiated DLBCL patients into separate risk categories with variations in survival and progression. The IPI allocates 1 point to each of age > 60 years, disease stage (III or IV), elevated serum lactate dehydrogenase, poor performance status, and more than 1 extranodal site. Patients are stratified into low-, loweintermediate, higheintermediate, and high-risk categories. While only 25% of high-risk patients are alive at 5 years, nearly 80% of low-risk patients are alive during the same time period.8 As the original IPI was reported before the use of rituximab in DLBCL, its applicability to patients treated with rituximab has been questioned. Sehn et al9 performed a retrospective analysis of DLBCL patients treated with R-CHOP and defined a new prognostic index, termed the R-IPI, as a better predictor of outcome. However, a subsequent contemporary analysis of more than 1000 patients treated with chemoimmunotherapy suggested that the original IPI remained prognostic in the rituximab era and predicted
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I-PET Scans in DLBCL event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) (Table 1).10 Recently, the National Comprehensive Cancer NetworkeIPI allowed for a further refined risk stratification of patients in the high- and low-risk prognostic category on the basis of the original IPI.11 Although the IPI remains an important practical prognostic tool, it ignores the molecular heterogeneity and pathobiology of the disease. Further, whether treating high-risk IPI patients differently than their lower-risk counterparts offers any additional benefit remains questionable. It should be noted that a recent study proposed that early autologous bone marrow transplantation consolidation might offer a survival advantage in high-risk IPI DLBCL patients.12 However, this study included patients who did not receive rituximab as part of their induction program. The inferior outcome of the control arm in patients who did not receive rituximab might partially explain the witnessed superiority in the transplantation arm.
Histologic and Morphologic Characteristics Several histologic features have identified subsets of DLBCL that portend inferior prognosis. A centroblastic subtype is the most common morphologic variant of DLBCL; it has the appearance of medium-to large-size lymphocytes with scanty cytoplasm. An immunoblastic variant is defined when > 90% of the cells are immunoblasts.13 Importantly, interobserver variability might account for inconsistent results of how histology affects prognosis.14 While earlier studies questioned the significance of centroblasts versus immunoblasts,15 subsequent analyses confirmed that DLBCL with immunoblastic morphology carries inferior EFS and OS.16 In fact, patients with centroblastic features had superior 3-year EFS and OS compared to the immunoblastic variant (58% vs. 41% [P ¼ .002] and 73% vs. 59% [P ¼ .069], respectively). This observed difference could be partially explained by the difference in the cell of origin (COO) between both histologies.17 The anaplastic variant of DLBCL, characterized by CD30-positive cells, carries similar features to other DLBCL patients, but with inferior 5-year survival estimated at 33%.18 Another uncommon histologic variant is the T-cell/histiocyterich large B-cell lymphoma (THRLBCL), representing 1% to 3% of all DLBCL,19 characterized by aggressive clinical course; it often presents with B symptoms, advanced stage, and spleen/liver and bone marrow involvement. Patients with THRLBCL treated with anthracycline-based regimens demonstrate lower response rates, although survival differences are questionable.20 Moreover, high proliferation index and > 80% Ki-67 expression have been
associated with worse outcomes and inferior survival even in the immunochemotherapy era.21 Finally, a plasmablastic variant (PBL) is a very rare subtype of DLBCL that occurs in patients with decreased immune surveillance such as human immunodeficiency virus positivity or advanced age. While patients with PBL might experience an initial response to therapy, relapse rates are high and the overall prognosis poor, with a median survival of 12 to 15 months.22
Cell of Origin Gene expression profiling (GEP) identified 3 principal molecular subtypes of DLBCL reflecting the COO: germinal center B-cellelike (GCB), activated B-cell (ABC or non-GCB), and primary mediastinal B-cell lymphoma.17 The COO classification not only defines subgroups with distinct gene expression profiles and different oncogenic pathways, but it also identifies groups of patients with different outcomes after standard chemoimmunotherapy.17,23 Patients with newly diagnosed ABC subtype have a significantly worse survival compared to GCB when treated with standard CHOP-like regimens with or without rituximab. Initially, the identification of molecular subtypes of DLBCL was labor intensive, requiring fresh frozen biopsy samples with adequate amount of RNA.24 To improve the feasibility of testing the COO, several immunohistochemistry-based algorithms were proposed. Hans et al25 utilized the immunohistochemical (IHC) staining for CD10, bcl-6, and MUM1 to classify DLBCL into GCB and nonGCB subtypes with an outcome similar to that predicted by cDNA microarray analysis. Accordingly, GCB subtype is characterized by CD10 and/or bcl-6 positivity, whereas non-GCB group is identified when both CD10 and bcl-6 are negative. In addition, the presence or absence of the expression of MUM1 defines the nonGCB versus GCB, respectively. The prognostic value of COO based on IHC versus GEP has been discordant. Some have suggested that the concordance between IHC and GEP results is imperfect to varying degrees, and immunostaining algorithms are therefore unable to maintain the prognostic impact of COO subtypes.26 Scott et al27 used the Lymph2Cx assay on formalin-fixed, paraffin-embedded tissue biopsy samples of de novo DLBCL previously classified through the original GEP to show a high rate of concordance between the 2 techniques. The same study group subsequently confirmed the accuracy of the Lymph2Cx assay in assigning GCB and ABC groups and demonstrated its reproducibility.28
Molecular Prognostication Table 1 Prognostic Differences Associated With IPI 3-Year Rate for:
2
-
IPI Score
EFS
PFS
OS
0, 1 2 3 4, 5
81.3 68.5 53.2 49.5
87.0 74.7 58.6 55.8
91.4 80.9 65.1 59.0
Abbreviations: EFS ¼ event-free survival; IPI ¼ international prognostic index; PFS ¼ progression-free survival; OS ¼ overall survival. Data from Ziepert et al.10
Clinical Lymphoma, Myeloma & Leukemia Month 2016
Less than 10% of DLBCL harbor isolated MYC oncogene rearrangements.29 While reports have varied on how best to treat DLBCL patients who carry the MYC protooncogene rearrangement, most agree that this oncogene confers worse prognosis and possibly inferior outcome with standard therapy.30,31 In fact, Savage et al31 reported that 5 years’ PFS in patients with MYC rearrangement was approximately 31% compared to about 66% (P ¼ .006, hazard ratio ¼ 3.28) in the nonrearranged group. Furthermore, the OS in the MYC rearrangement group was significantly inferior, with 5-year rates of 33% versus 72% (P ¼ .016, hazard ratio ¼ 2.98). Moreover, correlating between MYC rearrangement and other clinical prognostic parameters showed that age, IPI, and
Maital Bolshinsky, Chadi Nabhan Table 2 Select Retrospective Studies Evaluating I-PET in Front-Line DLBCL I-PETL/I-PETD for: Study Spaepen52 (2002) Yoo46 (2011) Zinzani41 (2011)a Safar50 (2012) Nols51 (2014) Huntington44 (2015)b
N
Regimen
Timing of I-PET
PFS
OS
P, PFS/OS
70 155 91 112 73 94
Doxorubicin-containing R-CHOP Various, R plus anthracycline containing R plus anthracycline-containing R-CHOP and other anthracycline-containing R-CHOP
3-4 cycles 2-4 cycles 3-4 2 3-4 Variable
2-year 85%/0% 3-year 84%/66% 5-year 75%/18% 84%/47% 2-year 84%/47% NA
3-year 92%/30% NA 5-year 90%/67% 88%/62% 2-year 91%/51% NA
<.0001/<.0001 .07/.24 .0001/.0001 <.0001/<.003 <.0001/<.0001 .001/.046
Abbreviations: CHOP ¼ cyclophosphamide, vincristine, doxorubicin, and prednisone; DLBCL ¼ diffuse large B-cell lymphoma; I-PET ¼ interim positron emission tomography; NA ¼ not applicable; OS ¼ overall survival; PFS ¼ progression-free survival; R ¼ rituximab. a Some patients had primary mediastinal lymphoma. b All patients who were in remission according to I-PET analysis did not experience disease progression at time of report.
MYC translocation retained prognostic significance for survival. This implied that young patients with lower IPI score retain a favorable outcome despite the presence of MYC rearrangement; it also underscored the fact that MYC prognostication varies on the basis of other parameters that should be taken into consideration.30 When MYC and either BCL-2 or BCL-6 aberrations are present, a new entity, termed “double-hit lymphoma” (DHL), emerges; when the 3 rearrangements are present, the term “triple-hit lymphoma” is used.32 While the true definition of DHL implies the identification of abnormal chromosomal translocations corresponding to the MYC and either BCL-2 or BCL-6 oncogenes, some patients can have these proteins detected by IHC without abnormal translocations. Whereas some debate the IHC thresholds, most agree that a disease is considered MYC positive if the IHC stains at least 40% of cells for MYC and 50% to 70% for BCL-2.33,34 Of note, patients who express both proteins by IHC appear to have worse prognosis regardless of the COO or the IPI score.35 Treatment of patients with DHL or double-protein expression is debatable. Several retrospective studies suggested that patients with high-risk DHL might benefit from more intensive regimens such as DA-EPOCH-R than the standard R-CHOP in terms of achieving a complete remission and a longer PFS.6,36 The significance of the partner oncogene with MYC is of particular importance. Landsburg et al37 suggested that compared to MYC/BCL-2 coexpression, patients who carried the MYC/BCL-6 coexpression had adverse prognosis with high relapse rates of 50% and lower OS
of 14.5 months. Last, MYC amplification failed to show any prognostic significance.38
PET Scans Functional imaging with 18F-fluoro-2-deoxy-D-glucose positron emission tomography combined with computed tomography (PET/ CT) is currently part of staging, assessment of remission and recurrence, and evaluation of therapeutic efficacy of patients with DLBCL.39 The prognostic utility of interim PET (I-PET) scans in Hodgkin lymphoma patients40 has led to studies exploring whether similar observations are present in DLBCL. The value of I-PET and its prognostic significance in DLBCL have been controversial. Whereas some studies showed a correlation between I-PET and long-term outcomes,41-45 others reported contradictory results46-49 (Tables 2-4).
Retrospective Studies Understanding the results of I-PET studies is challenging as progress in interpreting PET has evolved; older studies did not use contemporary PET scores, which underscore the difficulty of applying older PET data in the current era. Haioun et al59 performed an analysis that showed early positive PET identified poor response regardless of treatment or age-adjusted international prognostic index score. This study, along with other retrospective analyses, led to continued enthusiasm to study the role of I-PET in DLBCL (Table 2). Safar et al50 reported on 112 patients suggesting
Table 3 Select Prospective Studies of I-PET in DLBCL Without Risk-Adaptive Approach I-PETL/I-PETD for: Study 47
Cashen (2011) Micallef53 (2011) Pregno48 (2012) Carr54 (2014) Mamot55 (2015)
N
Regimen
I-PET Timing
PFS
OS
P, PFS/OS
50 69 88 327 156
R-CHOP R-CHOP or ER-CHOP R-CHOP R-CHOP R-CHOP-14
2-3 2 2-4 2-3 2
2-year 85%/63% NA 2-year 85%/72% 2-year 90%/58% 2-year 74%/48%
NA NA NA 2-year 93%/72% 2-year 91%/88%b
.004/.08 .31/.24 .047/NA <.05a .004/.46
Abbreviations: CI ¼ confidence interval; DLBCL ¼ diffuse large B-cell lymphoma; ER-CHOP ¼ R-CHOP plus epratuzumab; HR ¼ hazard ratio; I-PET ¼ interim positron emission tomography; OS ¼ overall survival; PFS ¼ progression-free survival; R-CHOP ¼ rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP-14 ¼ R-CHOP provided every 14 days as dose-dense approach. a Reported as HR. HR for PFS 5.31 (95% CI 3.29-8.56); HR for OS ¼ 3.86 (95% CI 2.12-7.03). b Data are on event-free survival.
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I-PET Scans in DLBCL Table 4 Selected Prospective Studies of I-PET in DLBCL With Risk-Adapted Approach I-PETL/I-PETD for: Study
N
Regimen
I-PET Timing
PFS
OS
P, PFS/OS
Moskowitz49 (2010)
98
R-CHOP
4
NA
NA
.27/NA
Stewart57 (2014)
70
R-CHOP
2
3-year 65.2%/52.7%
NA
>.05 for both
Pardal58 (2014)
71
R-CHOPb
3
3-yeas 81%/57%
3-year 95%/33%
<.05/>.05
Swinnen56 (2015)
74
R-CHOP
3
4-year 71%/33%
4-year 90%/69%
NS for both
Risk-Adapted Approach I-PET: ICE chemotherapya I-PETþ: Biopsy. If negative, then ICE; if positive, ICE followed by ASCT I-PET: Continue R-CHOP I-PETþ: ASCT I-PET: Continue same I-PETþ: ASCT I-PET: Continue R-CHOP I-PETþ: R-ICE
Abbreviations: ASCT ¼ autologous stem-cell transplantation; DLBCL ¼ diffuse large B-cell lymphoma; CHOP ¼ cyclophosphamide, vincristine, doxorubicin, and prednisone; ICE ¼ iphosphamide, carboplatin, and etoposide; I-PET ¼ interim positron emission tomography; NA ¼ not available; NS ¼ not significant; OS ¼ overall survival; PFS ¼ progression-free survival; R ¼ rituximab. a Not statistically significant between patients with I-PET-negative and I-PET-positive but biopsy-negative patients. b Dose-intensified CHOP.
that patients experiencing PET negativity after 2 cycles of an anthracycline-containing regimen have better PFS and OS. When an alternative analysis was performed on 85 patients using a quantitative method based on the maximum change in standardized uptake value (SUV) of more than 66%, the 3-year PFS was 77% for patients with PET-negative findings versus 37.5% for those with positive scan (P ¼ .002).50 If anything, these retrospective findings confirmed the need for prospective studies to better answer the question of I-PET prognostic importance.
Prospective Studies Despite several attempts to answer the question on prognostic value of I-PET in DLBCL, reported studies lack uniformity in how PET scans were interpreted and when I-PET was conducted. In a
prospective study of advanced stage DLBCL patients, I-PET was performed after 2 or 3 cycles of anthracycline-based chemotherapy.47 Interpretation was done according to the International Harmonization Project for Response Criteria in Lymphoma.60 IPET negativity provided patients with improved PFS, but OS was not improved. However, end-of-therapy PET was significantly associated with PFS and OS (P < .001). Similar studies were reported but results were not comparable (Table 3). Importantly, IPET positivity does not always imply persistent disease. This principle was highlighted in a prospective study reported by Moskowitz et al,49 where patients who had negative I-PET after 4 cycles of R-CHOP continued on to receive 3 cycles of ICE chemotherapy (iphosphamide, carboplatin, and etoposide), whereas patients with residual PET-positive disease underwent a repeat biopsy. If the
Figure 1 International Harmonization Project Criteria
Definition of a positive scan: Focal or diffuse FDG uptake above background in a location incompatible with normal physiology Exceptions: 1. Mild FDG uptake at the site of moderate to large residual masses with lower intensity visually compared to the mediastinal blood pool structures 2. FDG uptake in residual hepatic or splenic lesions should be compared to the uptake in surrounding normal liver or spleen
4
-
Adapted from Juweid et al.60
Clinical Lymphoma, Myeloma & Leukemia Month 2016
Maital Bolshinsky, Chadi Nabhan Figure 2 Five-Point Deauville Scale
biopsy results were negative, patients received 3 cycles of ICE. Patients with positive biopsy findings received ICE followed by autologous stem-cell transplantation. The results of the I-PET assessment did not correlate with outcomes, and the PFS of patients with I-PET-positive/biopsy-negative disease was identical to that of patients with a negative I-PET scan (P ¼ .27).49 Whether intensifying therapy to autologous stem-cell transplantation in patients with I-PETepositive disease provides patients with a clinically meaningful benefit remains debatable (Table 4).
Discussion Inconsistencies on the significance of I-PET could reflect the lack of interobserver reproducibility in interpreting PET images or could relate to the heterogeneity of the visual criteria used.61 Indeed, results of a blinded, independent review of the Eastern Cooperative Oncology Group E-3404 study revealed that one-third of the time, the expert panel of nuclear medicine physicians disagreed on the interpretation of the interim scans despite using consensus criteria.56,61 The fact that some studies conducted I-PET after
Figure 3 DSUVmax for I-PET Assessment
Baseline PET (I-PET0): -
SUV max in the most active lesion
2 cycles while others did so after 4 cycles adds complexity to the interpretation. Moreover, not all studies incorporated the same front-line therapy. Moreover, studies that were conducted before the international Harmonization Project might have lacked accurate sensitivity and specificity. Notably, the International Harmonization Project is purely visual, and when strictly applied to evaluate I-PET after 2 or 4 cycles of immunochemotherapy, it was unable to identify patients with different outcomes (Figure 1).47,49,61,62 Subsequently, at a workshop on I-PET in lymphoma held in Deauville, simple and reproducible rules have been proposed for interim 18F-fludeoxyglucose-PET/CT visual interpretation.63 The Deauville criteria use a 5-point scale to determine the positivity or negativity of I-PET and were found to improve the accuracy of the interpretation compared to the International Harmonization Project criteria (Figure 2). Another approach for I-PET response assessment is a semiquantitative method that measures the intensity of 18 F-fludeoxyglucose uptake in the tumor using the SUV (Figure 3). Several studies have suggested that by calculating the reduction of SUV between baseline and interim PET (DSUV) helped to reduce false-positive interpretations and improved the interobserver reproducibility.51,62,65 Collectively, this led to updated guidelines regarding I-PET response assessment, which affirmed the use of quantitative measures using the Deauville criteria to improve on visual analysis in patients with DLBCL, although this requires further validation in clinical trials.39,66 This so-called Lugano classification appeared more consistent and reflective of prognostication than the Harmonization project and is the recommended approach for PET-based ongoing and future clinical trials. However, changes of treatment solely based on I-PET results outside of clinical trials are not recommended unless there is clear evidence of disease progression. Some studies have already attempted altering therapies based on I-PET findings (Table 4). Swinnen et al56 treated PET-positive patients after 3 cycles of R-CHOP with R-ICE, but this study failed to convincingly show that altering therapy improved survival for I-PETepositive patients. In another study referenced above, 98 patients received 4 cycles of R-CHOP followed by I-PET. I-PETepositive patients underwent a biopsy to confirm residual disease.49 Patients with positive biopsy results proceeded to autologous stem-cell transplantation. Although this study failed to show that I-PET predicted outcome because most I-PETepositive patients had negative biopsy results, it highlighted the fact that I-PET positivity had a low positive predictive value for actual disease and underscored the importance of confirming residual disease histologically.
Interim PET: -
If (+): SUV max in the most active lesion
Conclusions
-
If (-): SUV max in the area of PET0 tumor
The interpretation of PET/CT scans for lymphoma has evolved during the past decade, with International Harmonization Project,60 Deauville criteria,63 and most recently the Lugano classification guiding standardized interpretation.39 The overall clinical utility of I-PET during the treatment of patients with DLBCL remains unclear. Most of the studies suggest that midtreatment PET might offer an early prognostication. Nevertheless, I-PET interpretation and its ability to guide changes in management remains uncertain. Although the interpretation of PET-CT for lymphoma has evolved during the past decade, the interpretation of interim PET remains a
Calculation of % of SUV reduction* Optimal cut-off determined by ROC -
66% for ΔSUV max PET0-2
72.9% for ΔSUV max PET0-4
Abbreviations: I-PET ¼ interim positron emission tomography; SUV ¼ standardized uptake value. Data from Lin et al.64
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I-PET Scans in DLBCL concern. Moreover, whether I-PET data provide better prognostication than COO or molecular drivers is uncertain and up for debate. Currently no consensus recommendations exist to help guide treatment based on I-PET response; the National Comprehensive Center Network advocates interim CT scans alone, reserving PET scans until completion of therapy.67 Continued investigation of the role of I-PET in the era of better molecular prognostication is warranted. Ideally this should be performed in the context of a prospective clinical trial that requires central I-PET interpretation and standardized timing of I-PET imaging. We propose that DLBCL patients be randomized to I-PET after 3 cycles of anthracycline-based therapy or to no I-PET. Patients with negative I-PET continue standard therapy, while positive I-PET patients are randomized to continuing the same treatment or to treatment intensification. Unless treatment alteration in I-PETepositive patients shows a better outcome, these interim evaluations remain prognostic at best.
Disclosure The authors have stated that they have no conflict of interest.
References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65: 5-29. 2. Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood 2010; 116: 2040-5. 3. Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large Bcell lymphoma. J Clin Oncol 2006; 24:3121-7. 4. Zelenetz AD, Gordon LI, Wierda WG, et al. Non-Hodgkin’s lymphomas, version 2.2014. J Natl Compr Canc Netw 2014; 12:916-46. 5. Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 2013; 368: 1408-16. 6. Petrich AM, Gandhi M, Jovanovic B, et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis. Blood 2014; 124:2354-61. 7. Zelenetz AD. Guidelines for NHL: updates to the management of diffuse large Bcell lymphoma and new guidelines for primary cutaneous CD30þ T-cell lymphoproliferative disorders and T-cell large granular lymphocytic leukemia. J Natl Compr Canc Netw 2014; 12(5 Suppl):797-800. 8. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 1993; 329: 987-94. 9. Sehn LH, Berry B, Chhanabhai M, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 2007; 109:185761. 10. Ziepert M, Hasenclever D, Kuhnt E, et al. Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20þ B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28:2373-80. 11. Zhou Z, Sehn LH, Rademaker AW, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood 2014; 123:837-42. 12. Stiff PJ, Unger JM, Cook JR, et al. Autologous transplantation as consolidation for aggressive non-Hodgkin’s lymphoma. N Engl J Med 2013; 369:1681-90. 13. Swerdlow SH. Lymphoma classification and the tools of our trade: an introduction to the 2012 USCAP Long Course. Mod Pathol 2013; 26(Suppl 1):S1-14. 14. Harris NL, Jaffe ES, Stein H, et al. Lymphoma classification proposal: clarification. Blood 1995; 85:857-60. 15. Engelhard M, Brittinger G, Huhn D, et al. Subclassification of diffuse large B-cell lymphomas according to the Kiel classification: distinction of centroblastic and immunoblastic lymphomas is a significant prognostic risk factor. Blood 1997; 89: 2291-7. 16. Ott G, Ziepert M, Klapper W, et al. Immunoblastic morphology but not the immunohistochemical GCB/nonGCB classifier predicts outcome in diffuse large B-cell lymphoma in the RICOVER-60 trial of the DSHNHL. Blood 2010; 116: 4916-25.
6
-
Clinical Lymphoma, Myeloma & Leukemia Month 2016
17. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002; 346:1937-47. 18. Campo E, Swerdlow SH, Harris NL, et al. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 2011; 117:5019-32. 19. Bouabdallah R, Mounier N, Guettier C, et al. T-cell/histiocyte-rich large B-cell lymphomas and classical diffuse large B-cell lymphomas have similar outcome after chemotherapy: a matched-control analysis. J Clin Oncol 2003; 21:1271-7. 20. Aki H, Tuzuner N, Ongoren S, et al. T-cell-rich B-cell lymphoma: a clinicopathologic study of 21 cases and comparison with 43 cases of diffuse large B-cell lymphoma. Leuk Res 2004; 28:229-36. 21. Gaudio F, Giordano A, Perrone T, et al. High Ki67 index and bulky disease remain significant adverse prognostic factors in patients with diffuse large B cell lymphoma before and after the introduction of rituximab. Acta Haematol 2011; 126:44-51. 22. Castillo JJ, Bibas M, Miranda RN. The biology and treatment of plasmablastic lymphoma. Blood 2015; 125:2323-30. 23. Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med 2010; 362:1417-29. 24. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403:503-11. 25. Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004; 103:275-82. 26. Thieblemont C, Briere J, Mounier N, et al. The germinal center/activated B-cell subclassification has a prognostic impact for response to salvage therapy in relapsed/refractory diffuse large B-cell lymphoma: a bio-CORAL study. J Clin Oncol 2011; 29:4079-87. 27. Scott DW, Wright GW, Williams PM, et al. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffinembedded tissue. Blood 2014; 123:1214-7. 28. Scott DW, Mottok A, Ennishi D, et al. Prognostic significance of diffuse large Bcell lymphoma cell of origin determined by digital gene expression in formalinfixed paraffin-embedded tissue biopsies. J Clin Oncol 2015; 33:2848-56. 29. Kramer MH, Hermans J, Wijburg E, et al. Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma. Blood 1998; 92:3152-62. 30. Barrans S, Crouch S, Smith A, et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol 2010; 28:3360-5. 31. Savage KJ, Johnson NA, Ben-Neriah S, et al. MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood 2009; 114:3533-7. 32. Petrich AM, Nabhan C, Smith SM. MYC-associated and double-hit lymphomas: a review of pathobiology, prognosis, and therapeutic approaches. Cancer 2014; 120: 3884-95. 33. Green TM, Young KH, Visco C, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 2012; 30:3460-7. 34. Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 2012; 30:3452-9. 35. Hu S, Xu-Monette ZY, Tzankov A, et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. Blood 2013; 121:4021-31. 36. Oki Y, Noorani M, Lin P, et al. Double hit lymphoma: the MD Anderson Cancer Center clinical experience. Br J Haematol 2014; 166:891-901. 37. Landsburg DJ, Petrich AM, Abramson JS, et al. Impact of oncogene rearrangement patterns on outcomes in patients with double-hit non-Hodgkin lymphoma. Cancer 2015; 122:559-64. 38. Landsburg DJ, Falkiewicz MK, Petrich AM, et al. Sole rearrangement but not amplification of MYC is associated with a poor prognosis in patients with diffuse large B cell lymphoma and B cell lymphoma unclassifiable. Br J Haematol 2016. http://dx.doi.org/10.1111/bjh.14282 [Epub ahead of print]. 39. Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol 2014; 32:304858. 40. Evens AM, Kostakoglu L. The role of FDG-PET in defining prognosis of Hodgkin lymphoma for early-stage disease. Blood 2014; 124:3356-64. 41. Zinzani PL, Gandolfi L, Broccoli A, et al. Midtreatment 18F-fluorodeoxyglucose positron-emission tomography in aggressive non-Hodgkin lymphoma. Cancer 2011; 117:1010-8. 42. Yang DH, Ahn JS, Byun BH, et al. Interim PET/CT-based prognostic model for the treatment of diffuse large B cell lymphoma in the post-rituximab era. Ann Hematol 2013; 92:471-9. 43. Yang DH, Min JJ, Song HC, et al. Prognostic significance of interim (1)(8)F-FDG PET/CT after three or four cycles of R-CHOP chemotherapy in the treatment of diffuse large B-cell lymphoma. Eur J Cancer 2011; 47:1312-8. 44. Huntington SF, Nasta SD, Schuster SJ, et al. Utility of interim and end-oftreatment [(18)F]-fluorodeoxyglucose positron emission tomography-computed tomography in frontline therapy of patients with diffuse large B-cell lymphoma. Leuk Lymphoma 2015; 56:2579-84.
Maital Bolshinsky, Chadi Nabhan 45. Itti E, Lin C, Dupuis J, et al. Prognostic value of interim 18F-FDG PET in patients with diffuse large B-Cell lymphoma: SUV-based assessment at 4 cycles of chemotherapy. J Nucl Med 2009; 50:527-33. 46. Yoo C, Lee DH, Kim JE, et al. Limited role of interim PET/CT in patients with diffuse large B-cell lymphoma treated with R-CHOP. Ann Hematol 2011; 90:797802. 47. Cashen AF, Dehdashti F, Luo J, et al. 18F-FDG PET/CT for early response assessment in diffuse large B-cell lymphoma: poor predictive value of international harmonization project interpretation. J Nucl Med 2011; 52:386-92. 48. Pregno P, Chiappella A, Bello M, et al. Interim 18-FDG-PET/CT failed to predict the outcome in diffuse large B-cell lymphoma patients treated at the diagnosis with rituximab-CHOP. Blood 2012; 119:2066-73. 49. Moskowitz CH, Schoder H, Teruya-Feldstein J, et al. Risk-adapted dose-dense immunochemotherapy determined by interim FDG-PET in Advanced-stage diffuse large B-Cell lymphoma. J Clin Oncol 2010; 28:1896-903. 50. Safar V, Dupuis J, Itti E, et al. Interim [18F]fluorodeoxyglucose positron emission tomography scan in diffuse large B-cell lymphoma treated with anthracycline-based chemotherapy plus rituximab. J Clin Oncol 2012; 30:184-90. 51. Nols N, Mounier N, Bouazza S, et al. Quantitative and qualitative analysis of metabolic response at interim positron emission tomography scan combined with International Prognostic Index is highly predictive of outcome in diffuse large Bcell lymphoma. Leuk Lymphoma 2014; 55:773-80. 52. Spaepen K, Stroobants S, Dupont P, et al. Early restaging positron emission tomography with (18)F-fluorodeoxyglucose predicts outcome in patients with aggressive non-Hodgkin’s lymphoma. Ann Oncol 2002; 13:1356-63. 53. Micallef IN, Maurer MJ, Wiseman GA, et al. Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma. Blood 2011; 118: 4053-61. 54. Carr R, Fanti S, Paez D, et al. Prospective international cohort study demonstrates inability of interim PET to predict treatment failure in diffuse large B-cell lymphoma. J Nucl Med 2014; 55:1936-44. 55. Mamot C, Klingbiel D, Hitz F, et al. Final results of a prospective evaluation of the predictive value of interim positron emission tomography in patients with diffuse large B-cell lymphoma treated with R-CHOP-14 (SAKK 38/07). J Clin Oncol 2015; 33:2523-9. 56. Swinnen LJ, Li H, Quon A, et al. Response-adapted therapy for aggressive nonHodgkin’s lymphomas based on early [18F] FDG-PET scanning: ECOG-
57.
58. 59. 60.
61.
62. 63. 64. 65.
66. 67.
ACRIN Cancer Research Group study (E3404). Br J Haematol 2015; 170: 56-65. Stewart DA, Kloiber R, Owen C, et al. Results of a prospective phase II trial evaluating interim positron emission tomography-guided high dose therapy for poor prognosis diffuse large B-cell lymphoma. Leuk Lymphoma 2014; 55: 2064-70. Pardal E, Coronado M, Martin A, et al. Intensification treatment based on early FDG-PET in patients with high-risk diffuse large B-cell lymphoma: a phase II GELTAMO trial. Br J Haematol 2014; 167:327-36. Haioun C, Itti E, Rahmouni A, 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; 106:1376-81. Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 2007; 25:571-8. Horning SJ, Juweid ME, Schoder H, et al. Interim positron emission tomography scans in diffuse large B-cell lymphoma: an independent expert nuclear medicine evaluation of the Eastern Cooperative Oncology Group E3404 study. Blood 2010; 115:775-7. Casasnovas RO, Meignan M, Berriolo-Riedinger A, et al. SUVmax reduction improves early prognosis value of interim positron emission tomography scans in diffuse large B-cell lymphoma. Blood 2011; 118:37-43. Meignan M, Gallamini A, Meignan M, et al. Report on the First International Workshop on Interim-PET-Scan in Lymphoma. Leuk Lymphoma 2009; 50:125760. Lin C, Itti E, Haioun C, et al. Early 18F-FDG PET for prediction of prognosis in patients with diffuse large B-cell lymphoma: SUV-based assessment versus visual analysis. J Nucl Med 2007; 48:1626-32. Meignan M, Gallamini A, Itti E, et al. Report on the Third International Workshop on Interim Positron Emission Tomography in Lymphoma held in Menton, France, 26-27 September 2011 and Menton 2011 consensus. Leuk Lymphoma 2012; 53:1876-81. 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; 32:3059-68. Zelenetz AD, Gordon LI, Wierda WG, et al. Diffuse large B-cell lymphoma version 1.2016. J Natl Compr Canc Netw 2016; 14:196-231.
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