Leukemia & Lymphoma, May 2015; 56(5): 1229–1232 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2015.1029748
The 5th International Workshop on Positron Emission Tomography in Lymphoma
Report on the 5th International Workshop on Positron Emission Tomography in Lymphoma held in Menton, France, 19–20 September 2014 Michel Meignan1, Andrea Gallamini2, Corinne Haioun1, Sally Barrington3, Emmanuel Itti1, Stefano Luminari4 & Aaron Polliack5 1Nuclear Medicine Department and Lymphoma Unit, Hôpital Henri Mondor, Créteil, France, 2Research, Innovation and Statistic
Department, Antoine Lacassagne Cancer Center, Nice University, Nice, France, 3PET Imaging Centre at St Thomas’ Division of Imaging, King’s College, London, UK, 4Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy and 5Department of Hematology, Hadassah University Hospital Ein-Karem, Jerusalem, Israel
of standardization of PET reporting in lymphoma for clinical practice. The attendees were questioned on a set of topics regarding technical information on the scanning procedure, on specific parameters to be assessed at baseline and the key instruction for interpreting extranodal organ involvement. For the restaging scan, a set of questions regarding visual interpretation procedures and the new Lugano criteria to assess response were raised and answered. Finally, specific recommendations for describing accidental findings unrelated to lymphoma were detailed. A manuscript summarizing this session will soon be circulated, and a draft of proposed guidelines will be sent to the oncology committee of the European Association of Nuclear Medicine (EANM) for definite approval. In this regard, we wish to adhere to the consolidated tradition, which started in Deauville in 2009, to ease the transfer of results of new published studies related to imaging in daily clinical practice. The methodology has been the same during all meetings, starting in Deauville and following later in Menton and Lugano: at the end of the workshop new sets of instructions or rules are proposed which are agreed by an international panel of experts in dedicated sessions during the meeting. Where do we stand now? Recommendations for staging and restaging in lymphoma incorporating PET/computed tomography (CT) in the diagnostic work-up have been proposed, and the interpretation key for interim and final PET suggested is the Deauville 5-point scale (5P-S) using the classical visual assessment [1,2]. Four levels of response have been set using 5P-S: complete metabolic response (CMR), partial metabolic response (PMR), stable disease (SD) and progressive metabolic disease (PMD) [3]. PET/CT is by nature a quantitative imaging technique from which new metrics to measure the tumor bulk can be derived, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG). These quantitative biomarkers can be combined with clinical, biological and molecular information to construct new indices for better patient stratification
Abstract Two hundred and thirty-six nuclear medicine physicians, radiologists and hematologists from 28 countries attended the 5th International Workshop on Postron Emission Tomography (PET) in Lymphoma held in Menton, France in September 2014. Forty-five scientific posters were presented. Following Lugano recommendations, the aim of the 5th workshop was to implement PET/computed tomography (CT) interpretation in a quantitative way (Q-PET) and how to use the new proposed metrics such as metabolic tumor volume (MTV). These parameters, in turn, could be combined with clinical, biological and molecular markers to build new indices for better patient risk stratification and to guide personalized therapy. New imaging techniques such as PET/magnetic resonance imaging (MRI) and genomics related to tumor morphological and structural characteristics and PET for assessment of response to new drugs and targeted therapies was also addressed. Finally, a section dedicated to imaging of pediatric lymphoma was also introduced. Keywords: PET, lymphoma, international PET workshop, consensus
Background Two hundred and thirty-six nuclear medicine physicians, radiologists and hematologists from 28 countries attended the 5th International Workshop on Positron Emission Tomography (PET) in Lymphoma held in Menton, France in September 2014 under the auspices of the European Lymphoma Institute (ELI), the Lymphoma Study Association (LYSA) and the Fondazione Italiana Linfomi (FIL) and European, Italian and French societies of nuclear medicine. For the first time the 5th edition of the meeting included an entire session dedicated to pediatric lymphoma imaging. The day before the opening of the meeting, on 18 September 2014, a closed expert session was held, focusing on the specific issue
Correspondence: Michel Meignan, Nuclear Medicine Department and Lymphoma Unit, Hôpital Henri Mondor, Créteil, France. E-mail: michel.meignan@ hmn.aphp.fr
1229
1230 M. Meignan et al. and personalized therapy. Furthermore, the new available combined imaging techniques such as PET/magnetic resonance imaging (MRI) could open the field to new functional and morphological local tumor characterization. The pros and cons of PET/CT for response assessment to new drugs targeting specific epitopes along activation or cross-talking cell-signaling pathways have also also discussed. Finally, new clinical perspectives and proposals have emerged from the pediatrician experience in PET imaging-based multicenter clinical trials. The 5th workshop has given important preliminary information on these different new challenges. Presentations and abstracts from the meeting are available on the new website http://www.lymphomapet.com.
New trends in lymphoma imaging Introducing PET as a biomarker, the first session chaired by Dr. Ceriani and Dr. Federico was dedicated to integrative PET/CT. This is a new concept combining quantitative PET parameters derived from PET scan performed at different time-points before and during treatment with clinical or biological data or other imaging techniques. The aim of this combined approach is to obtain a new prognostic index to tailor the therapeutic strategy to the risk of treatment failure on a single-patient basis. This risk can be defined on the basis of several different parameters (clinical, biological, imaging). Examples of integrative PET were presented by M. Meignan. I. Buvat described another new concept: the so-called radiomics. The assumption is that advanced mathematical models implemented with computer assisted analysis of imaging techniques such as CT, PET and MRI, used as stand-alone or in an integrated modality, can capture additional information not currently used. These new morphological parameters such as tumor texture, shape, gray level or density are matched in an unsupervised analysis with the result of a genomic assay by gene expression profiling (GEP) analysis, in order to find the genes controlling these structural aspects of the tumor. Preliminary studies showed in lung and head and neck cancer that the radiomics signature was related to outcome, and a definite number of genes were found to correlate with specific tumor structural patterns [4]. Drs. Rahmouni and Soricelli shared a presentation on PET/MRI, and after describing the technical issues, they reported their experience in lymphoma. At this time the role of this combined imaging technique is not yet defined, although it seems adequate as a functional and morphological tool for lymphoma management. Prof. Soricelli reported a slightly better sensitivity for PET/MRI using a Siemens machine to detect lymphadenopathy, compared to PET/CT. Dr. Luminari from the FIL correlated, in a subset of 41 patients with high tumor burden follicular lymphoma (FL) from the FOLL05 study, post-induction PET with the minimal residual disease (MRD) measured on a bone marrow (BM) sample (nested polymerase chain reaction [PCR] for 14;18 chromosomal translocation). Although the number of patients was limited, the combination of PET and MRD better predicted outcome. PET and MRD patients had a worse progression-fee survival (PFS) than patients who were PET and MRD (hazard ratio [HR] 3.42). Combining both techniques detected bone marrow involvement with an 81% positive predictive value (PPV).
Metabolic tumor volume The second session was dedicated to new PET metrics including MTV and TLG. Prof. Versari presented a critical analysis of the different techniques proposed for MTV measurement. Prof. Itti showed in 114 patients with diffuse large B-cell lymphoma (DLBCL) from the International Validation Study (IVS) that a baseline MTV 550 cm3 was an independent pre-therapy prognostic factor associated with a poor overall survival (OS) (3-year OS 60% vs. OS 87% in the group with MTV 550 cm3). MTV appeared to be more relevant than the presence of a bulky lesion, and, combined with the early PET response after two chemotherapy cycles, individualized three risk categories (fast responder patients with a low initial volume and an excellent outcome, slow responder patients with a large volume and a poor outcome and an intermediate category). Dr. Mikhaeel confirmed the predictive value of MTV in 147 patients with DLBCL treated with R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, given over 3 weeks) but with a lower MTV threshold value (400 cm3), and obtained the best risk stratification by combining MTV and early PET at two cycles. The interim PET scan was reported with the Deauville score. Casasnovas presented a very similar study in Hodgkin lymphoma: the predictive value of interim PET after two cycles of chemotherapy could further increase when stratified according to different values of tumor bulk, as defined by MTV assessment at baseline. Dr. Trotman reported the prognostic value of MTV in a prospective study in 81 patients with high tumor burden FL, with a cut-off value of 930 cm3.
Imaging techniques to characterize bone marrow and spleen involvement The session was opened by a brilliant lecture from Prof. Lister who put into perspective the history of spleen evaluation and the impact of spleen volume assessment using different imaging techniques on therapy outcome in lymphoma. Casasnovas reported the results of a Groupe d’Etude des Lymphomes de l’Adulte (GELA)/LYSA study in a cohort of 164 patients with high-risk DLBCL with age-adjusted international prognostic index (IPI) 2 or 3; the evidence of spleen involvement by lymphoma in the baseline PET scan, whatever its size, turned out to be a negative factor for PFS and OS. However, spleen involvement was more frequent in patients with splenomegaly (spleen largest diameter 13 cm), B symptoms and high MTV. Dr. Picardi presented the impressive sensitivity for spleen involvement that can be achieved with ultrasonography in experienced hands. Drs. Hutchings and Barrington reported the role of PET for detecting bone marrow infiltration in Hodgkin lymphoma (HL) and DLBCL. They gave a comprehensive description of different patterns of bone marrow fluorodeoxyglucose (FDG) uptake before and after treatment in HL and DLBCL, and an extensive review of the different studies and meta-analysis so far published on this topic [5,6]. In line with the recent recommendations from the International Conference on Malignant Lymphoma (ICML) imaging group they concluded that BM biopsy is no longer indicated for HL. PET may also obviate
5th International Workshop on PET in Lymphoma 1231 the need for biopsy in DLBCL, unless discordant histology is considered important for management.
Positron emission tomography scan in old and new therapeutic approaches It is important to know how FDG-PET metabolism is modified by new drugs, especially in the case of targeted therapy, and whether a decrease of signal is translated into response and a favorable outcome The session started with a presentation by A. Moskowitz on the role of PET during treatment rescue for relapsed and refractory Hodgkin lymphoma. The group used a PET-guided strategy to modulate the treatment intensity before autologous stem cell transplant (ASCT). Patients were first treated with two doses of brentuximab– vedotin (BV) and a PET scan was performed afterward; PETnegative patients went straight to ASCT, while PET-positive were treated with two augmented ifosfamide, carboplatin, etoposide (ICE) cycles: patients with a negative scan proceeded to ASCT, patients with a positive scan were taken off study (Memorial Sloan Kettering Cancer Center, MSKCC 11– 142). In 45 evaluable patients a 76% complete response (CR) rate was achieved with PET adapted sequential therapy with BV and augmented ICE. One-quarter of patients (27%) were spared augmented ICE thanks to PET. Forty-four transplants were completed. The median time to relapse after ASCT was 19 months (range 6–29 months). Dr. Federico reported an overview of trials using the BV regimen combined with doxorubicin, bleomycin, vinblastine and darcarbazine (ABVD) in first-line therapy of classical HL (cHL) and on a pilot study exploring the role of pretreatment with two doses of BV in a very small cohort (12 patients) of early-intermediate stage HL. Two out of 12 (83%) patients achieved a CMR. PET scan was very informative in assessing the response of BV-treated patients with HL. Younes and Meignan addressed the topic of targeted therapies and FDG-PET. The main issue is that interpreting FDG uptake changes under targeted therapies is complicated by interactions between various oncogenic pathways and sometimes by activation of negative feedback loops. These mechanisms could interact with FDG transport into cells with different kinetics. In addition, tumor cells utilize glucose uptake and metabolism and/or glutamine to generate energy. Targeted agents that could alter glucose or glutamine uptake may also alter the results of FDG-PET imaging, irrespective of the clinical response. Animal data in experimental lymphoma are useless, as they were obtained from studies conducted in other cancers. The scarcity of data so far available, and the small number of studies conducted in humans treated with these new drugs (such as the small studies in patients treated with anaplastic lymphoma kinase [ALK] inhibitors), do not allow any definite conclusion on the role of FDG-PET in response assessment [7].
End of therapy imaging modalities One of the main (and innovative) proposals of the Lugano classification has been to adopt the 5P-S criteria, which were originally proposed for interim PET, to report the end
of treatment PET scan (see “Background” section). Despite confirmatory studies in DLBCL and FL, the arbitrary cut-off between scores 3 and 4 as threshold value for a positive scan has been questioned [8]. S. Barrington presented the different studies supporting this recommendation, and reminded us that at the end of treatment residual or new metabolic disease does not necessarily represent a harbinger of active residual disease, and requires, when feasible, a biopsy confirmation before start of a rescue treatment. Alternatively, a second scan could be appropriate at a short time interval if the clinical suspicion of persisting lymphoma is low. The role of other imaging approaches was also discussed. Dr. Younes reported preliminary results of an International Harmonization Project of International Working Group (IWG) lymphoma response criteria along with RECIST (response evaluation criteria in solid tumors) to evaluate the effect of targeted therapies and comparatively assess the role of unidimensional rather than bidimensional measurement of the target lesion. The study conducted in 2842 patients supported the equivalence of uni- and bidimensional evaluation in terms of waterfall plot analysis, time to progression and PFS. In the same perspective, Dr. Luciani presented an innovative study on the role of the new generation of PET/MRI machines in lymphoma staging and restaging. In particular, he presented a study aimed to answer the question of whether whole body diffusion weighted MRI (WB-DWMRI) performed as a stand-alone sequence could provide adequate target measurements in patients with lymphoma and supersede the contrast-enhanced CT scan (CECT). In a preliminary study in 16 patients (seven HL, eight DLBCL, one FL) he reported an excellent correlation between twodimensional measurements performed in WB-DW-MRI and CECT at staging and for response evaluation at interim and end of treatment.
Poster session (viewing and plenary) The 45 posters were divided into technical and clinical categories. The poster book is on the website. The session was moderated by Dr. Duhrsen, Dr. Kostakoglu and Dr. Vander Borght. Twenty-five posters were clinically oriented. Among the different issues addressed were: (1) at baseline, the avidity for FDG of mucosa associated lymphoid tissue (MALT) lymphoma and nodular lymphocyte predominant HL (NLPHL), BM involvement in HL and other lymphoma subtypes, the prognostic impact of MTV in HL and peripheral T-cell lymphoma (PTCL); (2) at interim, the prognostic impact of interim PET reported with Deauville scale in HL and mediastinal lymphoma, in DLBCL (with negative results), in Burkitt lymphoma and in acquired immune deficiency syndrome (AIDS)-related lymphoma. The value of the following additional prognostic factors combined with interim PET were reported: BCL2 expression in DLBCL, tumor shrinkage upon CT in HL and the lymphocyte/monocyte ratio in HL; (3) at post-treatment, the value in primary central nervous system lymphoma (PCNSL), in FL and in FL coupled to MRD. One poster reported an imaging follow-up trial in HL. Among the different issues addressed by the technically oriented
1232 M. Meignan et al. posters were: the importance of a central review panel, the application of the Deauville 5-PS to the end of therapy PET in FL, the variability of liver uptake between baseline and interim PET, interim PET as a biomarker of response in nonHodgkin lymphoma (NHL), the hematologist’s perspective on PET reporting and CECT, fluorodeoxythymidine (FLT)and FDG-PET for early therapy evaluation, 89Zr-rituximab and 89Zr-ofatumumab in DLBCL, the evaluation of interim PET using quantitative PET parameters, dual-time PET in suspected malignant lymphoma, and a proposal of clinical trial qualification of PET scanners and cross-calibration for standardized uptake value (SUV) analysis. Fourteen posters were selected for oral presentation and are published in the current issue of Leukemia and Lymphoma.
Positron emission tomography in pediatric lymphoma This very attractive session demonstrated the interest of our colleagues in guiding the therapeutic strategy for PET/CT in children. The specificities of PET and clinical issues were presented by Dr. Brugieres and Dr. Montravers. Dr. Kluge, on behalf of the German group. presented a simplified method to interpret interim PET results by quantitative analysis of the residual FDG-avid lesion compared with the liver SUVmean.
Positron emission tomography and biological markers Dr. Copie-Bergman and Dr. Agostinelli reported their results on the combination of interim PET with molecular data in DLBCL and HL. Dr. Copie-Bergman noted that in a cohort of patients with DLBCL uniformly treated with R-CHOP, BCL2 protein expression and BCL2 gene alteration combined with early PET/CT response after two cycles in terms of ΔSUVmax was significantly predictive of PFS and OS and improved risk stratification [9]. In a large group of 310 patients with advanced-stage HL treated with ABVD, Dr. Agostinelli reported that the presence of different markers in the accessory cells (CD68KP-1 and PD1) and in Reed–Sternberg (RS) cells (STAT-1) was predictive of outcome, and was helpful to stratify the interim PET response after two cycles of ABVD. Interim PET-negative patients could be differentiated into two risk categories: interim PET-negative patients with a low molecular risk profile, with 94.7% 5-year PFS, and interim PET-negative patients with a high molecular risk profile, with 63.6% 5-year PFS [10].
Positron emission tomography adapted trials: the ongoing studies Ongoing trials including PET were presented by Dr. Luminari, Dr. Caballero, Dr. Hellwig and Dr. Casanovas on behalf of
the different European cooperative groups from Italy (FIL), Spain (Grupo Español de Linfoma y Trasplante Autólogo de Médula Ósea, GELTAMO), Germany (Deutsche Studiengruppe für Hochmaligne Non-Hodgkin-Lymphome, DSHNHL) and France (LYSA). The descriptions of these trials are available on the workshop website. The meeting ended with a presentation on PET reporting: recommendations from the expert sessions. These recommendations will circulate among the expert committee and the attendants of the workshop and then should be validated by the oncology group of the EANM. They will be available on the website after this validation procedure. Several preliminary reports presented during the 5th International Workshop of PET in Lymphoma will be updated at the next meeting, scheduled to be in Menton on 20–21 September 2016. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] 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;32:3048–3058. [2] Meignan M, Gallamini A, Haioun C, et al. Report on the Second International Workshop on interim positron emission tomography in lymphoma held in Menton, France, 8–9 April 2010. Leuk Lymphoma 2010;51:2171–2180. [3] 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;32:3059–3068. [4] Aerts HJ, Velazquez ER, Leijenaar RT, et al. Decoding tumour phenotype by noninvasive imaging using a quantitative radiomics approach. Nat Commun 2014;5:4006. [5] El-Galaly TC, d’Amore F, Mylam KJ, et al. Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/computed tomography-staged treatmentnaive patients with Hodgkin lymphoma. J Clin Oncol 2012;30: 4508–4514. [6] Khan AB, Barrington SF, Mikhaeel NG, et al. PET-CT staging of DLBCL accurately identifies and provides new insight into the clinical significance of bone marrow involvement. Blood 2013;122:61–67. [7] Gambacorti Passerini C, Farina F, Stasia A, et al. Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients. J Natl Cancer Inst 2014;106:djt378. [8] Trotman J, Luminari S, Boussetta S, et al. Prognostic value of PET-CT after first-line therapy in patients with follicular lymphoma: a pooled analysis of central scan review in three multicentre studies. Lancet Haematol 2014;1:e17–e27. [9] Copie-Bergman C, Itti E, Moroch J, et al. BCL2 protein expression combined with early 18F FDG PET response allows improved stratification of large B-cell lymphoma patients. Hematol Oncol 2013;31(Suppl.):96–150. [10] Gallamini A, Agostinelli C, Tripolo C, et al. Analysis of myeloid suppressor marker arginase identifies CD68/arginase myeloid/ monocytic subsets and exerts stronger prognostic influence than macrophage quantification in classical Hodgkin lymphoma. Haematologica 2013;98(Suppl. 2): Abstract T051.
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The 5th International Workshop on Positron Emission Tomography in Lymphoma
Report on the 5th International Workshop on Positron Emission Tomography in Lymphoma held in Menton, France, 19–20 September 2014 Michel Meignan1, Andrea Gallamini2, Corinne Haioun1, Sally Barrington3, Emmanuel Itti1, Stefano Luminari4 & Aaron Polliack5 1Nuclear Medicine Department and Lymphoma Unit, Hôpital Henri Mondor, Créteil, France, 2Research, Innovation and Statistic
Department, Antoine Lacassagne Cancer Center, Nice University, Nice, France, 3PET Imaging Centre at St Thomas’ Division of Imaging, King’s College, London, UK, 4Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy and 5Department of Hematology, Hadassah University Hospital Ein-Karem, Jerusalem, Israel
of standardization of PET reporting in lymphoma for clinical practice. The attendees were questioned on a set of topics regarding technical information on the scanning procedure, on specific parameters to be assessed at baseline and the key instruction for interpreting extranodal organ involvement. For the restaging scan, a set of questions regarding visual interpretation procedures and the new Lugano criteria to assess response were raised and answered. Finally, specific recommendations for describing accidental findings unrelated to lymphoma were detailed. A manuscript summarizing this session will soon be circulated, and a draft of proposed guidelines will be sent to the oncology committee of the European Association of Nuclear Medicine (EANM) for definite approval. In this regard, we wish to adhere to the consolidated tradition, which started in Deauville in 2009, to ease the transfer of results of new published studies related to imaging in daily clinical practice. The methodology has been the same during all meetings, starting in Deauville and following later in Menton and Lugano: at the end of the workshop new sets of instructions or rules are proposed which are agreed by an international panel of experts in dedicated sessions during the meeting. Where do we stand now? Recommendations for staging and restaging in lymphoma incorporating PET/computed tomography (CT) in the diagnostic work-up have been proposed, and the interpretation key for interim and final PET suggested is the Deauville 5-point scale (5P-S) using the classical visual assessment [1,2]. Four levels of response have been set using 5P-S: complete metabolic response (CMR), partial metabolic response (PMR), stable disease (SD) and progressive metabolic disease (PMD) [3]. PET/CT is by nature a quantitative imaging technique from which new metrics to measure the tumor bulk can be derived, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG). These quantitative biomarkers can be combined with clinical, biological and molecular information to construct new indices for better patient stratification
Abstract Two hundred and thirty-six nuclear medicine physicians, radiologists and hematologists from 28 countries attended the 5th International Workshop on Postron Emission Tomography (PET) in Lymphoma held in Menton, France in September 2014. Forty-five scientific posters were presented. Following Lugano recommendations, the aim of the 5th workshop was to implement PET/computed tomography (CT) interpretation in a quantitative way (Q-PET) and how to use the new proposed metrics such as metabolic tumor volume (MTV). These parameters, in turn, could be combined with clinical, biological and molecular markers to build new indices for better patient risk stratification and to guide personalized therapy. New imaging techniques such as PET/magnetic resonance imaging (MRI) and genomics related to tumor morphological and structural characteristics and PET for assessment of response to new drugs and targeted therapies was also addressed. Finally, a section dedicated to imaging of pediatric lymphoma was also introduced. Keywords: PET, lymphoma, international PET workshop, consensus
Background Two hundred and thirty-six nuclear medicine physicians, radiologists and hematologists from 28 countries attended the 5th International Workshop on Positron Emission Tomography (PET) in Lymphoma held in Menton, France in September 2014 under the auspices of the European Lymphoma Institute (ELI), the Lymphoma Study Association (LYSA) and the Fondazione Italiana Linfomi (FIL) and European, Italian and French societies of nuclear medicine. For the first time the 5th edition of the meeting included an entire session dedicated to pediatric lymphoma imaging. The day before the opening of the meeting, on 18 September 2014, a closed expert session was held, focusing on the specific issue
Correspondence: Michel Meignan, Nuclear Medicine Department and Lymphoma Unit, Hôpital Henri Mondor, Créteil, France. E-mail: michel.meignan@ hmn.aphp.fr
1229
1230 M. Meignan et al. and personalized therapy. Furthermore, the new available combined imaging techniques such as PET/magnetic resonance imaging (MRI) could open the field to new functional and morphological local tumor characterization. The pros and cons of PET/CT for response assessment to new drugs targeting specific epitopes along activation or cross-talking cell-signaling pathways have also also discussed. Finally, new clinical perspectives and proposals have emerged from the pediatrician experience in PET imaging-based multicenter clinical trials. The 5th workshop has given important preliminary information on these different new challenges. Presentations and abstracts from the meeting are available on the new website http://www.lymphomapet.com.
New trends in lymphoma imaging Introducing PET as a biomarker, the first session chaired by Dr. Ceriani and Dr. Federico was dedicated to integrative PET/CT. This is a new concept combining quantitative PET parameters derived from PET scan performed at different time-points before and during treatment with clinical or biological data or other imaging techniques. The aim of this combined approach is to obtain a new prognostic index to tailor the therapeutic strategy to the risk of treatment failure on a single-patient basis. This risk can be defined on the basis of several different parameters (clinical, biological, imaging). Examples of integrative PET were presented by M. Meignan. I. Buvat described another new concept: the so-called radiomics. The assumption is that advanced mathematical models implemented with computer assisted analysis of imaging techniques such as CT, PET and MRI, used as stand-alone or in an integrated modality, can capture additional information not currently used. These new morphological parameters such as tumor texture, shape, gray level or density are matched in an unsupervised analysis with the result of a genomic assay by gene expression profiling (GEP) analysis, in order to find the genes controlling these structural aspects of the tumor. Preliminary studies showed in lung and head and neck cancer that the radiomics signature was related to outcome, and a definite number of genes were found to correlate with specific tumor structural patterns [4]. Drs. Rahmouni and Soricelli shared a presentation on PET/MRI, and after describing the technical issues, they reported their experience in lymphoma. At this time the role of this combined imaging technique is not yet defined, although it seems adequate as a functional and morphological tool for lymphoma management. Prof. Soricelli reported a slightly better sensitivity for PET/MRI using a Siemens machine to detect lymphadenopathy, compared to PET/CT. Dr. Luminari from the FIL correlated, in a subset of 41 patients with high tumor burden follicular lymphoma (FL) from the FOLL05 study, post-induction PET with the minimal residual disease (MRD) measured on a bone marrow (BM) sample (nested polymerase chain reaction [PCR] for 14;18 chromosomal translocation). Although the number of patients was limited, the combination of PET and MRD better predicted outcome. PET and MRD patients had a worse progression-fee survival (PFS) than patients who were PET and MRD (hazard ratio [HR] 3.42). Combining both techniques detected bone marrow involvement with an 81% positive predictive value (PPV).
Metabolic tumor volume The second session was dedicated to new PET metrics including MTV and TLG. Prof. Versari presented a critical analysis of the different techniques proposed for MTV measurement. Prof. Itti showed in 114 patients with diffuse large B-cell lymphoma (DLBCL) from the International Validation Study (IVS) that a baseline MTV 550 cm3 was an independent pre-therapy prognostic factor associated with a poor overall survival (OS) (3-year OS 60% vs. OS 87% in the group with MTV 550 cm3). MTV appeared to be more relevant than the presence of a bulky lesion, and, combined with the early PET response after two chemotherapy cycles, individualized three risk categories (fast responder patients with a low initial volume and an excellent outcome, slow responder patients with a large volume and a poor outcome and an intermediate category). Dr. Mikhaeel confirmed the predictive value of MTV in 147 patients with DLBCL treated with R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, given over 3 weeks) but with a lower MTV threshold value (400 cm3), and obtained the best risk stratification by combining MTV and early PET at two cycles. The interim PET scan was reported with the Deauville score. Casasnovas presented a very similar study in Hodgkin lymphoma: the predictive value of interim PET after two cycles of chemotherapy could further increase when stratified according to different values of tumor bulk, as defined by MTV assessment at baseline. Dr. Trotman reported the prognostic value of MTV in a prospective study in 81 patients with high tumor burden FL, with a cut-off value of 930 cm3.
Imaging techniques to characterize bone marrow and spleen involvement The session was opened by a brilliant lecture from Prof. Lister who put into perspective the history of spleen evaluation and the impact of spleen volume assessment using different imaging techniques on therapy outcome in lymphoma. Casasnovas reported the results of a Groupe d’Etude des Lymphomes de l’Adulte (GELA)/LYSA study in a cohort of 164 patients with high-risk DLBCL with age-adjusted international prognostic index (IPI) 2 or 3; the evidence of spleen involvement by lymphoma in the baseline PET scan, whatever its size, turned out to be a negative factor for PFS and OS. However, spleen involvement was more frequent in patients with splenomegaly (spleen largest diameter 13 cm), B symptoms and high MTV. Dr. Picardi presented the impressive sensitivity for spleen involvement that can be achieved with ultrasonography in experienced hands. Drs. Hutchings and Barrington reported the role of PET for detecting bone marrow infiltration in Hodgkin lymphoma (HL) and DLBCL. They gave a comprehensive description of different patterns of bone marrow fluorodeoxyglucose (FDG) uptake before and after treatment in HL and DLBCL, and an extensive review of the different studies and meta-analysis so far published on this topic [5,6]. In line with the recent recommendations from the International Conference on Malignant Lymphoma (ICML) imaging group they concluded that BM biopsy is no longer indicated for HL. PET may also obviate
5th International Workshop on PET in Lymphoma 1231 the need for biopsy in DLBCL, unless discordant histology is considered important for management.
Positron emission tomography scan in old and new therapeutic approaches It is important to know how FDG-PET metabolism is modified by new drugs, especially in the case of targeted therapy, and whether a decrease of signal is translated into response and a favorable outcome The session started with a presentation by A. Moskowitz on the role of PET during treatment rescue for relapsed and refractory Hodgkin lymphoma. The group used a PET-guided strategy to modulate the treatment intensity before autologous stem cell transplant (ASCT). Patients were first treated with two doses of brentuximab– vedotin (BV) and a PET scan was performed afterward; PETnegative patients went straight to ASCT, while PET-positive were treated with two augmented ifosfamide, carboplatin, etoposide (ICE) cycles: patients with a negative scan proceeded to ASCT, patients with a positive scan were taken off study (Memorial Sloan Kettering Cancer Center, MSKCC 11– 142). In 45 evaluable patients a 76% complete response (CR) rate was achieved with PET adapted sequential therapy with BV and augmented ICE. One-quarter of patients (27%) were spared augmented ICE thanks to PET. Forty-four transplants were completed. The median time to relapse after ASCT was 19 months (range 6–29 months). Dr. Federico reported an overview of trials using the BV regimen combined with doxorubicin, bleomycin, vinblastine and darcarbazine (ABVD) in first-line therapy of classical HL (cHL) and on a pilot study exploring the role of pretreatment with two doses of BV in a very small cohort (12 patients) of early-intermediate stage HL. Two out of 12 (83%) patients achieved a CMR. PET scan was very informative in assessing the response of BV-treated patients with HL. Younes and Meignan addressed the topic of targeted therapies and FDG-PET. The main issue is that interpreting FDG uptake changes under targeted therapies is complicated by interactions between various oncogenic pathways and sometimes by activation of negative feedback loops. These mechanisms could interact with FDG transport into cells with different kinetics. In addition, tumor cells utilize glucose uptake and metabolism and/or glutamine to generate energy. Targeted agents that could alter glucose or glutamine uptake may also alter the results of FDG-PET imaging, irrespective of the clinical response. Animal data in experimental lymphoma are useless, as they were obtained from studies conducted in other cancers. The scarcity of data so far available, and the small number of studies conducted in humans treated with these new drugs (such as the small studies in patients treated with anaplastic lymphoma kinase [ALK] inhibitors), do not allow any definite conclusion on the role of FDG-PET in response assessment [7].
End of therapy imaging modalities One of the main (and innovative) proposals of the Lugano classification has been to adopt the 5P-S criteria, which were originally proposed for interim PET, to report the end
of treatment PET scan (see “Background” section). Despite confirmatory studies in DLBCL and FL, the arbitrary cut-off between scores 3 and 4 as threshold value for a positive scan has been questioned [8]. S. Barrington presented the different studies supporting this recommendation, and reminded us that at the end of treatment residual or new metabolic disease does not necessarily represent a harbinger of active residual disease, and requires, when feasible, a biopsy confirmation before start of a rescue treatment. Alternatively, a second scan could be appropriate at a short time interval if the clinical suspicion of persisting lymphoma is low. The role of other imaging approaches was also discussed. Dr. Younes reported preliminary results of an International Harmonization Project of International Working Group (IWG) lymphoma response criteria along with RECIST (response evaluation criteria in solid tumors) to evaluate the effect of targeted therapies and comparatively assess the role of unidimensional rather than bidimensional measurement of the target lesion. The study conducted in 2842 patients supported the equivalence of uni- and bidimensional evaluation in terms of waterfall plot analysis, time to progression and PFS. In the same perspective, Dr. Luciani presented an innovative study on the role of the new generation of PET/MRI machines in lymphoma staging and restaging. In particular, he presented a study aimed to answer the question of whether whole body diffusion weighted MRI (WB-DWMRI) performed as a stand-alone sequence could provide adequate target measurements in patients with lymphoma and supersede the contrast-enhanced CT scan (CECT). In a preliminary study in 16 patients (seven HL, eight DLBCL, one FL) he reported an excellent correlation between twodimensional measurements performed in WB-DW-MRI and CECT at staging and for response evaluation at interim and end of treatment.
Poster session (viewing and plenary) The 45 posters were divided into technical and clinical categories. The poster book is on the website. The session was moderated by Dr. Duhrsen, Dr. Kostakoglu and Dr. Vander Borght. Twenty-five posters were clinically oriented. Among the different issues addressed were: (1) at baseline, the avidity for FDG of mucosa associated lymphoid tissue (MALT) lymphoma and nodular lymphocyte predominant HL (NLPHL), BM involvement in HL and other lymphoma subtypes, the prognostic impact of MTV in HL and peripheral T-cell lymphoma (PTCL); (2) at interim, the prognostic impact of interim PET reported with Deauville scale in HL and mediastinal lymphoma, in DLBCL (with negative results), in Burkitt lymphoma and in acquired immune deficiency syndrome (AIDS)-related lymphoma. The value of the following additional prognostic factors combined with interim PET were reported: BCL2 expression in DLBCL, tumor shrinkage upon CT in HL and the lymphocyte/monocyte ratio in HL; (3) at post-treatment, the value in primary central nervous system lymphoma (PCNSL), in FL and in FL coupled to MRD. One poster reported an imaging follow-up trial in HL. Among the different issues addressed by the technically oriented
1232 M. Meignan et al. posters were: the importance of a central review panel, the application of the Deauville 5-PS to the end of therapy PET in FL, the variability of liver uptake between baseline and interim PET, interim PET as a biomarker of response in nonHodgkin lymphoma (NHL), the hematologist’s perspective on PET reporting and CECT, fluorodeoxythymidine (FLT)and FDG-PET for early therapy evaluation, 89Zr-rituximab and 89Zr-ofatumumab in DLBCL, the evaluation of interim PET using quantitative PET parameters, dual-time PET in suspected malignant lymphoma, and a proposal of clinical trial qualification of PET scanners and cross-calibration for standardized uptake value (SUV) analysis. Fourteen posters were selected for oral presentation and are published in the current issue of Leukemia and Lymphoma.
Positron emission tomography in pediatric lymphoma This very attractive session demonstrated the interest of our colleagues in guiding the therapeutic strategy for PET/CT in children. The specificities of PET and clinical issues were presented by Dr. Brugieres and Dr. Montravers. Dr. Kluge, on behalf of the German group. presented a simplified method to interpret interim PET results by quantitative analysis of the residual FDG-avid lesion compared with the liver SUVmean.
Positron emission tomography and biological markers Dr. Copie-Bergman and Dr. Agostinelli reported their results on the combination of interim PET with molecular data in DLBCL and HL. Dr. Copie-Bergman noted that in a cohort of patients with DLBCL uniformly treated with R-CHOP, BCL2 protein expression and BCL2 gene alteration combined with early PET/CT response after two cycles in terms of ΔSUVmax was significantly predictive of PFS and OS and improved risk stratification [9]. In a large group of 310 patients with advanced-stage HL treated with ABVD, Dr. Agostinelli reported that the presence of different markers in the accessory cells (CD68KP-1 and PD1) and in Reed–Sternberg (RS) cells (STAT-1) was predictive of outcome, and was helpful to stratify the interim PET response after two cycles of ABVD. Interim PET-negative patients could be differentiated into two risk categories: interim PET-negative patients with a low molecular risk profile, with 94.7% 5-year PFS, and interim PET-negative patients with a high molecular risk profile, with 63.6% 5-year PFS [10].
Positron emission tomography adapted trials: the ongoing studies Ongoing trials including PET were presented by Dr. Luminari, Dr. Caballero, Dr. Hellwig and Dr. Casanovas on behalf of
the different European cooperative groups from Italy (FIL), Spain (Grupo Español de Linfoma y Trasplante Autólogo de Médula Ósea, GELTAMO), Germany (Deutsche Studiengruppe für Hochmaligne Non-Hodgkin-Lymphome, DSHNHL) and France (LYSA). The descriptions of these trials are available on the workshop website. The meeting ended with a presentation on PET reporting: recommendations from the expert sessions. These recommendations will circulate among the expert committee and the attendants of the workshop and then should be validated by the oncology group of the EANM. They will be available on the website after this validation procedure. Several preliminary reports presented during the 5th International Workshop of PET in Lymphoma will be updated at the next meeting, scheduled to be in Menton on 20–21 September 2016. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] 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;32:3048–3058. [2] Meignan M, Gallamini A, Haioun C, et al. Report on the Second International Workshop on interim positron emission tomography in lymphoma held in Menton, France, 8–9 April 2010. Leuk Lymphoma 2010;51:2171–2180. [3] 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;32:3059–3068. [4] Aerts HJ, Velazquez ER, Leijenaar RT, et al. Decoding tumour phenotype by noninvasive imaging using a quantitative radiomics approach. Nat Commun 2014;5:4006. [5] El-Galaly TC, d’Amore F, Mylam KJ, et al. Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/computed tomography-staged treatmentnaive patients with Hodgkin lymphoma. J Clin Oncol 2012;30: 4508–4514. [6] Khan AB, Barrington SF, Mikhaeel NG, et al. PET-CT staging of DLBCL accurately identifies and provides new insight into the clinical significance of bone marrow involvement. Blood 2013;122:61–67. [7] Gambacorti Passerini C, Farina F, Stasia A, et al. Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients. J Natl Cancer Inst 2014;106:djt378. [8] Trotman J, Luminari S, Boussetta S, et al. Prognostic value of PET-CT after first-line therapy in patients with follicular lymphoma: a pooled analysis of central scan review in three multicentre studies. Lancet Haematol 2014;1:e17–e27. [9] Copie-Bergman C, Itti E, Moroch J, et al. BCL2 protein expression combined with early 18F FDG PET response allows improved stratification of large B-cell lymphoma patients. Hematol Oncol 2013;31(Suppl.):96–150. [10] Gallamini A, Agostinelli C, Tripolo C, et al. Analysis of myeloid suppressor marker arginase identifies CD68/arginase myeloid/ monocytic subsets and exerts stronger prognostic influence than macrophage quantification in classical Hodgkin lymphoma. Haematologica 2013;98(Suppl. 2): Abstract T051.
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